RESUMO
Diabetic Kidney Disease (DKD) is a significant complication of diabetes and primary cause of end-stage renal disease globally. The exact mechanisms underlying DKD remain poorly understood, but multiple factors, including the renin-angiotensin-aldosterone system (RAAS), play a key role in its progression. Aldosterone, a mineralocorticoid steroid hormone, is one of the key components of RAAS and a potential mediator of renal damage and inflammation in DKD. miRNAs, small noncoding RNA molecules, have attracted interest due to their regulatory roles in numerous biological processes. These processes include aldosterone signaling and mineralocorticoid receptor (MR) expression. Numerous miRNAs have been recognized as crucial regulators of aldosterone signaling and MR expression. These miRNAs affect different aspects of the RAAS pathway and subsequent molecular processes, which impact sodium balance, ion transport, and fibrosis regulation. This review investigates the regulatory roles of particular miRNAs in modulating aldosterone signaling and MR activation, focusing on their impact on kidney injury, inflammation, and fibrosis. Understanding the complex interaction between miRNAs and the RAAS could lead to a new strategy to target aldosterone signaling and MR activation using miRNAs. This highlights the potential of miRNA-based interventions for DKD, with the aim of enhancing kidney outcomes in individuals with diabetes.
Assuntos
Nefropatias Diabéticas , MicroRNAs , Humanos , Aldosterona , Nefropatias Diabéticas/genética , Fibrose , Inflamação , MicroRNAs/genética , Mineralocorticoides , Receptores de Mineralocorticoides/genéticaRESUMO
Yes-associated protein 1 (YAP1) and its paralogue PDZ-binding motif (TAZ) play pivotal roles in cell proliferation, migration, and invasion, and abnormal activation of these TEAD transcriptional coactivators is found in diverse cancers in humans and mice. Targeting YAP1/TAZ signaling is thus a promising therapeutic avenue but, to date, few selective YAP1/TAZ inhibitors have been effective against cancer cells either in vitro or in vivo. We screened chemical libraries for potent YAP1/TAZ inhibitors using a highly sensitive luciferase reporter system to monitor YAP1/TAZ-TEAD transcriptional activity in cells. Among 29 049 low-molecular-weight compounds screened, we obtained nine hits, and the four of these that were the most effective shared a core structure with the natural product alantolactone (ALT). We also tested 16 other structural derivatives of ALT and found that natural ALT was the most efficient at increasing ROS-induced LATS kinase activities and thus YAP1/TAZ phosphorylation. Phosphorylated YAP1/TAZ proteins were subject to nuclear exclusion and proteosomic degradation such that the growth of ALT-treated tumor cells was inhibited both in vitro and in vivo. Our data show for the first time that ALT can be used to target the ROS-YAP pathway driving tumor cell growth and so could be a potent anticancer drug.
Assuntos
Aciltransferases/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Antineoplásicos Fitogênicos/farmacologia , Produtos Biológicos/farmacologia , Lactonas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos de Eudesmano/farmacologia , Aciltransferases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Auranofina/farmacologia , Movimento Celular , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Autorrenovação Celular , Proteínas de Ligação a DNA/metabolismo , Descoberta de Drogas , Feminino , Inula/química , Luciferases , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Proteínas Nucleares/metabolismo , Fosforilação/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas , Fatores de Transcrição de Domínio TEA , Neoplasias da Língua/induzido quimicamente , Neoplasias da Língua/prevenção & controle , Fatores de Transcrição/metabolismo , Ativação Transcricional , Proteínas de Sinalização YAPRESUMO
PURPOSE: The clinical application of gemcitabine (GEM) is limited by its pharmacokinetic properties. The aim of this study was to characterize the stability in circulating plasma, tumor targeting, and payload release of liposome-encapsulated GEM, FF-10832. METHODS: Antitumor activity was assessed in xenograft mouse models of human pancreatic cancer. The pharmacokinetics of GEM and its active metabolite dFdCTP were also evaluated. RESULTS: In mice with Capan-1 tumors, the dose-normalized areas under the curve (AUCs) after FF-10832 administration in plasma and tumor were 672 and 1047 times higher, respectively, than after using unencapsulated GEM. The tumor-to-bone marrow AUC ratio of dFdCTP was approximately eight times higher after FF-10832 administration than after GEM administration. These results indicated that liposomal encapsulation produced long-term stability in circulating plasma and tumor-selective targeting of GEM. In mice with Capan-1, SUIT-2, and BxPC-3 tumors, FF-10832 had better antitumor activity and tolerability than GEM. Internalization of FF-10832 in tumor-associated macrophages (TAMs) was revealed by flow cytometry and confocal laser scanning microscopy, and GEM was efficiently released from isolated macrophages of mice treated with FF-10832. These results suggest that TAMs are one of the potential reservoirs of GEM in tumors. CONCLUSION: This study found that FF-10832 had favorable pharmacokinetic properties. The liposomal formulation was more effective and tolerable than unencapsulated GEM in mouse xenograft tumor models. Hence, FF-10832 is a promising candidate for the treatment of pancreatic cancer.
Assuntos
Antimetabólitos Antineoplásicos/sangue , Desoxicitidina/análogos & derivados , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Neoplasias Pancreáticas/sangue , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/síntese química , Linhagem Celular Tumoral , Desoxicitidina/administração & dosagem , Desoxicitidina/sangue , Desoxicitidina/síntese química , Estabilidade de Medicamentos , Feminino , Humanos , Lipossomos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Nus , Neoplasias Pancreáticas/tratamento farmacológico , Resultado do Tratamento , GencitabinaRESUMO
An activating mutation of Fms-like tyrosine kinase 3 (FLT3) is the most frequent genetic alteration associated with poor prognosis in acute myeloid leukemia (AML). Although many FLT3 inhibitors have been clinically developed, no first-generation inhibitors have demonstrated clinical efficacy by monotherapy, due to poor pharmacokinetics or unfavorable safety profiles possibly associated with low selectivity against FLT3 kinase. Recently, a selective FLT3 inhibitor, quizartinib, demonstrated favorable outcomes in clinical studies. However, several resistant mutations emerged during the disease progression. To overcome these problems, we developed a novel FLT3 inhibitor, FF-10101, designed to possess selective and irreversible FLT3 inhibition. The co-crystal structure of FLT3 protein bound to FF-10101 revealed the formation of a covalent bond between FF-10101 and the cysteine residue at 695 of FLT3. The unique binding brought high selectivity and inhibitory activity against FLT3 kinase. FF-10101 showed potent growth inhibitory effects on human AML cell lines harboring FLT3 internal tandem duplication (FLT3-ITD), MOLM-13, MOLM-14, and MV4-11, and all tested types of mutant FLT3-expressing 32D cells including quizartinib-resistant mutations at D835, Y842, and F691 residues in the FLT3 kinase domain. In mouse subcutaneous implantation models, orally administered FF-10101 showed significant growth inhibitory effect on FLT3-ITD-D835Y- and FLT3-ITD-F691L-expressing 32D cells. Furthermore, FF-10101 potently inhibited growth of primary AML cells harboring either FLT3-ITD or FLT3-D835 mutation in vitro and in vivo. These results indicate that FF-10101 is a promising agent for the treatment of patients with AML with FLT3 mutations, including the activation loop mutations clinically identified as quizartinib-resistant mutations.
Assuntos
Amidas/uso terapêutico , Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/genética , Amidas/farmacocinética , Amidas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Tirosina Quinase 3 Semelhante a fms/químicaRESUMO
Chemotherapy has been the treatment of choice for unresectable peritoneal dissemination; however, it is difficult to eradicate such tumors because of poor drug delivery. To solve this issue, we developed FF-10832 as liposome-encapsulated gemcitabine to maintain a high concentration of gemcitabine in peritoneal tumors from the circulation and ascites. A syngeneic mouse model of peritoneal dissemination using murine Colon26 cell line was selected to compare the drug efficacy and pharmacokinetics of FF-10832 with those of gemcitabine. Despite the single intravenous administration, FF-10832 treatment enabled long-term survival of the lethal model mice as compared with those treated with gemcitabine. Pharmacokinetic analysis clarified that FF-10832 could achieve a more effective gemcitabine delivery to peritoneal tumors owing to better stability in the circulation and ascites. The novel liposome-encapsulated gemcitabine FF-10832 may be a curative therapeutic tool for cancer patients with unresectable peritoneal dissemination via the effective delivery of gemcitabine to target tumors.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Ascite/metabolismo , Desoxicitidina/análogos & derivados , Neoplasias Peritoneais/tratamento farmacológico , Peritônio/patologia , Animais , Antimetabólitos Antineoplásicos/farmacocinética , Ascite/etiologia , Linhagem Celular Tumoral/transplante , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacocinética , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Feminino , Humanos , Injeções Intravenosas , Estimativa de Kaplan-Meier , Lipossomos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Peritoneais/complicações , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/patologia , Distribuição Tecidual , Resultado do Tratamento , GencitabinaRESUMO
We describe a case involving subarachnoid and intraperitoneal hemorrhage due to segmental arterial mediolysis(SAM). A 77-year-old female patient with sudden subarachnoid hemorrhage was immediately transferred to our institution. The hemorrhage was classified as grade 2 according to the World Federation of Neurosurgical Societies system. The patient was a non-smoker and did not drink alcohol regularly. A right internal carotid aneurysm was detected using CT angiography and was clipped during frontotemporal craniotomy. Bleeding was observed from the anterior wall of the internal carotid artery, and the tear was clipped. The patient had an uneventful postoperative course until sudden cardiopulmonary arrest eight days after craniotomy. She died of massive intraperitoneal hemorrhage. Autopsy revealed that the hemorrhage was due to dissection of the celiac artery. Tunica media denaturation was observed not only in the celiac artery, but also in the splenic and internal carotid arteries, which exhibited ruptured aneurysms, and the patient was diagnosed with segmental arterial mediolysis(SAM). SAM is an arterial degenerative disease affecting the medial layer of the arterial and dissecting walls. Multiple lesions are sometimes found. Radiographic imaging findings of SAM are similar to those of dissecting aneurysms, which are characterized by a single continuous dissection of the medial layer. As observed in this case, abdominal bleeding caused by SAM can occur after intracranial bleeding. When surgeons encounter unusual intracranial dissecting aneurysms, SAM should be considered as a differential diagnosis.
Assuntos
Aneurisma Roto , Dissecção Aórtica , Hemorragia Gastrointestinal , Aneurisma Intracraniano , Hemorragia Subaracnóidea , Abdome , Idoso , Dissecção Aórtica/complicações , Aneurisma Roto/complicações , Artérias , Feminino , Hemorragia Gastrointestinal/complicações , Humanos , Aneurisma Intracraniano/complicações , Hemorragia Subaracnóidea/complicaçõesRESUMO
UNLABELLED: CASE: A 30-year-old woman presented with posterior cervical pain and left-sided omalgia. The patient had a history of non-Hodgkin's lymphoma for which she had received prophylactic whole-brain irradiation(including at the upper cervical level)17 years previously. A magnetic resonance imaging(MRI)scan obtained 1 month previously showed an intradural extramedullary mass lesion at the left C1/2 level. We initially considered the tumor to be a benign schwannoma, but the patient subsequently developed left hemiparesis and was consequently admitted 2 days after her first visit. A second MRI scan showed that the tumor had progressed markedly. Hence, the patient underwent emergency surgical excision of the tumor. However, the tumor could only be partially removed because it had strongly adhered to the ventral aspect of the spinal cord. The tumor was pathologically diagnosed as a malignant peripheral nerve sheath tumor(MPNST). The residual tumor was subjected to local irradiation and surgery, but the treatment was unsuccessful, and the patient died on the 91st day of her illness. Conclusion:We report a case of radiation-induced high cervical MPNST arising from a benign schwannoma. All 9 previously reported cases of radiation-induced spinal MPNST were reviewed. Intraspinal MPNST of the high cervical region are extremely rare and are associated with a very poor prognosis. The 5-year survival rate of such tumors is markedly worse than that of other types of MPNST, and no standard treatment has been established for this condition.
Assuntos
Neoplasias Induzidas por Radiação/diagnóstico por imagem , Neoplasias de Bainha Neural/diagnóstico por imagem , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Adulto , Quimiorradioterapia , Evolução Fatal , Feminino , Humanos , Linfoma não Hodgkin/terapia , Imageamento por Ressonância Magnética , Neoplasias Induzidas por Radiação/patologia , Neoplasias Induzidas por Radiação/cirurgia , Neoplasias de Bainha Neural/patologia , Neoplasias de Bainha Neural/cirurgia , Radioterapia/efeitos adversos , Neoplasias da Coluna Vertebral/patologia , Neoplasias da Coluna Vertebral/cirurgiaRESUMO
The cytokine transforming growth factor (TGF)-ß1 plays a central role in diabetic nephropathy (DN) with data implicating the miRNA (miR) miR-21 as a key modulator of its prosclerotic actions. In the present study, we demonstrate data indicating that miR-21 up-regulation positively correlates with the severity of fibrosis and rate of decline in renal function in human DN. Furthermore, concomitant analyses of various models of fibrotic renal disease and experimental DN, confirm tubular miR-21 up-regulation. The fibrotic changes associated with increased miR-21 levels are proposed to include the regulation of TGF-ß1-mediated mothers against decapentaplegic homolog 3 (SMAD3)- and phosphoinositide 3-kinase (PI3K)-dependent signalling pathways via co-ordinated repression of mothers against decapentaplegic homolog 7 (SMAD7) and phosphatase and tensin homologue (PTEN) respectively. This represents a previously uncharacterized interaction axis between miR-21 and PTEN-SMAD7. Targeting of these proteins by miR-21 resulted in de-repression of the respective pathways as reflected by increases in SMAD3 and V-Akt murine thymoma viral oncogene homolog 1 (AKT) phosphorylation. Many of the changes typically induced by TGF-ß1, including phosphorylation of signalling mediators, were further enhanced by miR-21. Collectively, these data present a unified model for a key role for miR-21 in the regulation of renal tubular extracellular matrix (ECM) synthesis and accumulation and provide important insights into the molecular pathways implicated in the progression of DN.
Assuntos
Nefropatias Diabéticas/metabolismo , Túbulos Renais Proximais/metabolismo , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Proteína Smad7/metabolismo , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Estudos de Casos e Controles , Linhagem Celular , Colágeno/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Fibrose , Taxa de Filtração Glomerular , Humanos , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/patologia , Túbulos Renais Proximais/fisiopatologia , Camundongos Knockout , MicroRNAs/genética , Fosforilação , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Ratos Sprague-Dawley , Índice de Gravidade de Doença , Transdução de Sinais , Proteína Smad7/genética , Transfecção , Fator de Crescimento Transformador beta1/farmacologia , Regulação para CimaRESUMO
In recent years, several studies have reported dysregulation of microRNA expression in disease with a growing interest focussed on targeting microRNAs as a novel therapy for human disease. This is especially true in diabetic nephropathy where the expression of several microRNAs is dysregulated, contributing to the increased expression and accumulation of extracellular matrix proteins and increased pro-fibrotic signalling, ultimately resulting in renal fibrosis. The development of various techniques and microRNA reagents has enabled work to progress very rapidly in this area. In the present article, the authors describe the methods they have used that have enabled them to contribute to our current understanding of the role of microRNAs in diabetic nephropathy.
Assuntos
Nefropatias Diabéticas/genética , Rim/metabolismo , MicroRNAs/genética , Regiões 3' não Traduzidas , Animais , Sequência de Bases , Linhagem Celular , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/fisiopatologia , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Rim/fisiopatologia , MicroRNAs/metabolismo , Dados de Sequência Molecular , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/metabolismo , Interferência de RNA , Transdução de Sinais , TransfecçãoRESUMO
Among 238 patients with bilateral trigeminal neuralgia(TN)who visited our hospital between April 2007 and June 2014, 5(2%)were surgically treated by microvascular decompression(MVD). The initial symptom was on the right side in four and on both sides in one patient. Intervals between the initial and second onset on the other side(left)were two months, and four, six, and eight years. None of the patients showed involvement of the first branch of the trigeminal nerve. The patients with bilateral TN were younger than the 154 patients with unilateral TN who were treated surgically by MVD in this period(45 vs. 65 years), and the bilateral TN patients predominantly were women(4/5 vs. 99/154). In the surgical field, the trigeminal nerve and root entry zone were compressed more by veins in the bi lateral TN patients than in the unilateral TN(4/5 vs. 60/154, respectively)patients. We could not identify any differences in MRI CISS before versus after the onset of left trigeminal neuralgia, suggesting that compression is not the sole cause of the symptom.
Assuntos
Neuralgia do Trigêmeo/patologia , Neuralgia do Trigêmeo/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Descompressão Cirúrgica , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Microcirurgia/métodos , Cirurgia de Descompressão Microvascular , Pessoa de Meia-Idade , Resultado do Tratamento , Neuralgia do Trigêmeo/diagnóstico , Neuralgia do Trigêmeo/etiologiaRESUMO
Renal fibrosis results from excessive accumulation of extracellular matrix mainly driven by transforming growth factor-ß1 (TGF-ß1). Certain microRNAs have been implicated in this disease, and here we examine the role of let-7b. Rat proximal tubular epithelial cells (NRK52E) were treated with TGF-ß1 for 3 days to assess the expression of markers of fibrosis and let-7b. These factors were also assessed in two mouse models representing early and more advanced diabetic nephropathy and in the non-diabetic adenine-induced renal fibrosis model. TGF-ß1 downregulated the expression of let-7b and induced fibrogenesis in NRK52E cells. Ectopic expression of let-7b repressed TGF-ß1 receptor 1 (TGFBR1) expression directly by targeting the two let-7b binding sites in the 3'-untranslated region of that gene, reduced expression of extracellular matrix proteins, decreased SMAD3 activity, and attenuated the profibrotic effects of TGF-ß1. Knockdown of let-7b elevated TGFBR1 expression and mimicked some of the profibrotic effects of TGF-ß1. Consistent with these observations, let-7b expression was also reduced in models of both diabetic and non-diabetic renal fibrosis with the upregulation of TGFBR1. Thus, let-7b microRNA represents a potential new target for the treatment of renal fibrosis in diabetic and non-diabetic nephropathy.
Assuntos
Nefropatias Diabéticas/metabolismo , Rim/metabolismo , MicroRNAs/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Insuficiência Renal Crônica/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Regiões 3' não Traduzidas , Adenina , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Sítios de Ligação , Linhagem Celular , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Fibrose , Regulação da Expressão Gênica , Humanos , Rim/patologia , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Células Mesangiais/metabolismo , Células Mesangiais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Proteínas Serina-Treonina Quinases/genética , Interferência de RNA , Ratos , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/genética , Proteínas Recombinantes/metabolismo , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Transdução de Sinais , Proteína Smad3/metabolismo , Fatores de Tempo , Transfecção , Fator de Crescimento Transformador beta1/genéticaRESUMO
PURPOSE OF REVIEW: Several factors are now known to contribute to the development and progression of nephropathy, particularly in diabetes. In recent times, there has been surge of interest in the role of small noncoding RNA, with several reports focusing on the effects of microRNAs on their target genes that are of relevance to nephropathy. This review focuses on recent progress in this field. RECENT FINDINGS: The list of microRNAs that have been identified to play a role in nephropathy continues to grow. Of particular interest is the fact that most microRNAs that are implicated in nephropathy are regulated by the profibrotic factor, transforming growth factor-ß. Additionally, some recent studies have used the presence of microRNAs in biofluids as a source of potential biomarkers for many diseases, particularly in diabetic nephropathy. SUMMARY: MicroRNAs hold much promise given their novelty, promiscuity and involvement in many biological and pathological processes. There are promising early signs of their potential as biomarkers as well as therapeutic targets.
Assuntos
Nefropatias Diabéticas/genética , Rim/metabolismo , MicroRNAs/metabolismo , Animais , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/terapia , Marcadores Genéticos , Terapia Genética/métodos , Humanos , MicroRNAs/uso terapêutico , Valor Preditivo dos Testes , Prognóstico , Sistema Renina-AngiotensinaRESUMO
Epidermoid rarely appears in the cavernous sinus. We encountered a 41-year-old man with left abducens nerve palsy. A round-shaped, low-density lesion on CT was located lateral to the left cavernous sinus with a compressed and thinned lateral wall of the sphenoid sinus. We could not identify cranial nerves in the cavernous sinus, which was found to be packed with a non-enhanced, high-intensity tumor on both T1 and T2 MRI. Part of the tumor capsule and its pearly contents were removed with an intradural subtemporal approach, and an inner membranous layer with cranial nerves and a tumor capsule were seen at the bottom of the tumor cavity. Postoperatively, complete cure was achieved. Reviewing similar cases, we found 18 cavernous sinus epidermoids:extracavernous type in 5;interdural in 10;and intracavernous in 3. The interdural type could be further divided into two subtypes:superficial cavernous sinus and inner membranous types. The present case belongs to the former. Frontotemporal and subtemporal procedures via both intra- and extradural approaches are relatively safe for lesions except for the intracavernous type, because cranial nerves are not located in the lateral wall of the tumor. MRI provides more useful information on cranial nerves and aid in choosing a better treatment strategy.
Assuntos
Seio Cavernoso/cirurgia , Nervos Cranianos/cirurgia , Cisto Epidérmico/cirurgia , Seio Esfenoidal/cirurgia , Adulto , Seio Cavernoso/patologia , Nervos Cranianos/patologia , Cisto Epidérmico/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Seio Esfenoidal/patologia , Resultado do TratamentoRESUMO
A 59-year-old man presented with right trigeminal neuralgia of the second branch, which had been treated with carbamazepine. The pain could not be controlled adequately because of side effects. CT and MRI revealed a 2-cm lesion in the right cerebellopontine angle. Retrosigmoid lateral suboccipital craniectomy was performed, and a soft yellowish mass was found to be associated with the 5th, 7th, and 8th cranial nerves, anterior inferior cerebellar artery, and small vessels. The lipoma was partially resected from around the root entry zone(REZ)of the 5th nerve and small vessels were coagulated around the REZ. After surgery, there was no trigeminal neuralgia, but facial numbness and cerebellar signs were noted. Postoperative MRI showed decompression of the trigeminal nerve and venous infarction in the middle cerebellar peduncle. Reviewing similar cases, we found 19 lipoma patients presenting with trigeminal neuralgia. Symptoms of involvement of other cranial nerves were also present in 11 patients, and 14 were younger than 30 years old. Of 17 surgical cases, total resection was not attempted apart from one case. Although pain relief was achieved in all surgical cases, complications developed in 11. Surgery should be performed only in patients with disabling and uncontrolled symptoms.
Assuntos
Ângulo Cerebelopontino/cirurgia , Lipoma/cirurgia , Neuralgia do Trigêmeo/cirurgia , Neoplasias Cerebelares/patologia , Descompressão Cirúrgica/métodos , Humanos , Lipoma/complicações , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Neuralgia do Trigêmeo/diagnóstico , Neuralgia do Trigêmeo/etiologiaRESUMO
Status epilepticus (SE) can be a sign of brain tumor progression or recurrence, but there are few reports of nonconvulsive status epilepticus (NCSE) being a sign of tumor progression or recurrence. Moreover, much remains to be elucidated about its clinical course, and outcome. This is the first report of NCSE associated with the progression of a metastatic brain tumor treated by surgical excision of the tumor. The patient was 74-year-old woman. She had a history of craniotomy for tumor resection and gamma knife treatment for multiple metastatic brain tumors originating from breast cancer. She suddenly developed dysarthria and right hemiparesis, followed by convulsive seizures in the right side of her body. Magnetic resonance imaging showed tumor recurrence in the left parietal lobe and worsening edematous changes around the tumor. Antiseizure medication was initiated, however her seizures did not improve; therefore, tumor resection was performed. Postoperatively, her consciousness, seizures, and electroencephalogram findings improved. NCSE caused by brain tumors may be refractory to treatment with antiseizure medications, and early surgical treatment may be useful for seizure control.
RESUMO
OBJECTIVE: This retrospective study evaluated whether earlier timing of appropriate treatment of high-grade aneurysmal subarachnoid hemorrhage (aSAH), defined as management of ruptured intracranial aneurysm (RIA) combined with required additional surgical measures for control of increased intracranial pressure (ICP), is associated with more favorable outcomes. METHODS: The study cohort comprised 253 patients with high-grade aSAH. Modified Rankin Scale score of 0-3 at 3-month follow-up after the ictus was considered as favorable outcome. RESULTS: Appropriate treatment of aSAH was completed in 205 patients (81 %), and included clipping or coiling of RIA without (64 cases) and with (141 cases) additional surgical measures for control of increased ICP (evacuation of intracranial hematoma, decompressive craniotomy, and/or cerebrospinal fluid drainage). Favorable outcome was noted significantly more often if appropriate treatment was completed within 13 h after aSAH than between 13 and 72 h (37 % vs. 17 %; adjusted P = 0.0475), which was confirmed by evaluation in the multivariate model along with other prognostic factors. Subgroup analysis revealed that completion of the appropriate treatment within 13 h was associated with more favorable outcome in those patients, who underwent management of RIA in combination with additional surgical measures for control of increased ICP (P = 0.0023), and in those, who felt into poor outcome predicting group (P = 0.0046). CONCLUSIONS: Appropriate treatment of high-grade aSAH with management of RIA in combination with required additional surgical measures for control of increased ICP, may be associated with more favorable outcomes if completed within 13 h after the ictus.
Assuntos
Aneurisma Roto , Aneurisma Intracraniano , Hipertensão Intracraniana , Acidente Vascular Cerebral , Hemorragia Subaracnóidea , Humanos , Hemorragia Subaracnóidea/cirurgia , Hemorragia Subaracnóidea/complicações , Estudos Retrospectivos , Resultado do Tratamento , Aneurisma Intracraniano/cirurgia , Aneurisma Intracraniano/complicações , Hipertensão Intracraniana/complicações , Aneurisma Roto/cirurgia , Aneurisma Roto/complicações , Acidente Vascular Cerebral/complicaçõesRESUMO
Diabetic nephropathy is the leading cause of endstage renal disease, with both the incidence and prevalence continuing to increase worldwide. Current treatments include optimization of glycemic and blood pressure control by targeting the renin-angiotensin-aldosterone system (RAAS) with angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers. More innovative strategies are needed to prevent and treat this disease. New agents and approaches have recently been described that have the potential to delay the progression of diabetic kidney disease and minimize the growing burden of endstage renal disease. Possible targets include the formation of advanced glycation end products (AGEs) and the AGE receptor, increased oxidative stress and inflammation, protein kinase C, endothelin receptors, growth factors and cytokines, the vitamin D receptor, Rho-associated kinases, and the renal sympathetic system. This article reviews these recent developments as potential therapeutic interventions that may prevent this disease, with targets generally beyond the RAAS.
Assuntos
Anti-Hipertensivos/uso terapêutico , Nefropatias Diabéticas/prevenção & controle , Falência Renal Crônica/prevenção & controle , Rim/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Doença Crônica , Nefropatias Diabéticas/etiologia , Humanos , Estresse Oxidativo/efeitos dos fármacosRESUMO
Presented retrospective analysis evaluated whether preoperative plasma D-dimer level may predict the success of cerebral reperfusion and outcome after emergency mechanical thrombectomy (MT) for intracranial large vessel occlusion (ILVO). Study cohort comprised 121 patients (mean age, 76 ± 12 years) from two participating centers. ILVO mostly affected the M1 segment (48 cases) and internal carotid artery (ICA; 37 cases). Mean preoperative National Institutes of Health Stroke Scale (NIHSS) score was 18 ± 8. Mean preoperative plasma D-dimer level was 4.4 ± 6.6 µg/ml. In 88 patients (73%) MT resulted in successful cerebral reperfusion. Multivariate analysis revealed independent associations of non-successful cerebral reperfusion with preoperative plasma D-dimer level > 6.7 µg/ml (P = 0.0021), location of ILVO other than ICA (P = 0.0056), and prolonged antiplatelet or anticoagulant therapy before stroke onset (P = 0.0172). Plasma D-dimer level ≤ 6.7 µg/ml predicted successful cerebral reperfusion with 0.91 sensitivity and 0.36 specificity. In 39 patients (32%) treatment resulted in favorable outcome. Multivariate analysis revealed independent associations of the unfavorable outcome with non-successful cerebral reperfusion after MT (P = 0.0005), preoperative plasma D-dimer level > 1.9 µg/ml (P = 0.0131), higher preoperative NIHSS score (P = 0.0171), and chronic arterial hypertension before stroke onset (P = 0.0254). Plasma D-dimer level ≤ 1.9 µg/ml predicted favorable outcome with 0.64 sensitivity and 0.62 specificity. In conclusion, preoperative plasma D-dimer level may be predictive for success of cerebral reperfusion and outcome after emergency MT for ILVO, which may be potentially helpful for prediction of prognosis in selected treatment candidates.
Assuntos
Procedimentos Endovasculares , Acidente Vascular Cerebral , Idoso , Idoso de 80 Anos ou mais , Procedimentos Endovasculares/métodos , Produtos de Degradação da Fibrina e do Fibrinogênio , Humanos , Pessoa de Meia-Idade , Reperfusão/métodos , Estudos Retrospectivos , Acidente Vascular Cerebral/cirurgia , Trombectomia/métodos , Resultado do TratamentoRESUMO
Background: Meningiomas associated with acute subdural hematoma (ASDH) are rare. The rapid growth of meningiomas has been shown to be one of the mechanisms underlying bleeding. We report the first case of ASDH during an imaging follow-up for the rapid growth of a falx meningioma. Case Description: A 77-year-old woman was diagnosed with an incidental tumor along the right falx cerebri 3 years before bleeding. The follow-up magnetic resonance imaging (MRI) after 3 years showed that the tumor volume had rapidly increased from 4.31 cm3 to 22.27 cm3. The blood vessels around the tumor were stretched. The patient was scheduled to undergo tumor removal surgery. However, the patient experienced a sudden onset of disturbance of consciousness and was transferred to our hospital. On arrival, her Glasgow Coma Scale (GCS) score was 6 (E1V1M4) and right hemiplegia was observed. The patient had no history of traumatic events. Computed tomography (CT) showed left hemispheric and interhemispheric ASDH. Digital subtraction angiography revealed neither tumor staining nor abnormal vessels. Gross total tumor removal and hematoma evacuation were performed. There were no obvious active intraoperative bleeding points. The pathologic diagnosis was meningioma, the World Health Organization Grade I. Postoperative course revealed a GCS score of 10 (E4V1M5) and she was transferred to a rehabilitation hospital. Conclusion: The disruption of tumor vessels due to the rapid growth of meningiomas may be a cause of bleeding. Incidental falx meningiomas with stretched tumor vessels due to rapid growth could indicate the need for early surgery.
RESUMO
ANG-(1-7) is associated with vasodilation and nitric oxide synthase stimulation. However, the role of ANG-(1-7) in type 2 diabetes mellitus is unknown. In this study, we examined the hypothesis that ANG-(1-7) attenuates ANG II-induced reactive oxygen species stress (ROS)-mediated injury in type 2 diabetic nephropathy of KK-A(y)/Ta mice. KK-A(y)/Ta mice were divided into four groups: 1) a control group; 2) ANG II infusion group; 3) ANG II+ANG-(1-7) coinfusion group; and 4) ANG II+ANG-(1-7)+d-Ala(7)-ANG-(1-7) (A779) coinfusion group. In addition, primary mesangial cells were cultured and then stimulated with 25 mM glucose with or without ANG II, ANG-(1-7), and A779. The ANG II+ANG-(1-7) coinfusion group showed a lower urinary albumin/creatinine ratio increase than the ANG II group. ANG-(1-7) attenuated ANG II-mediated NAD(P)H oxidase activation and ROS production in diabetic glomeruli and mesangial cells. ANG II-induced NF-κB and MAPK signaling activation was also attenuated by ANG-(1-7) in the mesangial cells. These findings were related to improved mesangial expansion and to fibronectin and transforming growth factor-ß1 production in response to ANG II and suggest that ANG-(1-7) may attenuate ANG II-stimulated ROS-mediated injury in type 2 diabetic nephropathy. The ACE2-ANG-(1-7)-Mas receptor axis should be investigated as a novel target for treatment of type 2 diabetic nephropathy.