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1.
Brain Nerve ; 71(9): 936-942, 2019 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-31506395

RESUMO

The aim of drug repositioning is to identify and develop new uses for existing drugs. Many drugs for neurological disorders have been established by drug repositioning. Conventional drug repositioning approaches are based on chance findings or close clinical observations. Nowadays, computational drug repositioning can complement these approaches. Drug repositioning has many advantages. For example, unexpected adverse events occur less frequently in clinical trials using repositioned drugs than in trials with new drugs because safety information for repositioned drugs has often already accumulated before the start of a clinical trial. Another advantage is that drug repositioning can shorten the time needed for drug development and thereby reduce costs related to drug innovation. If results of pharmacological and toxic tests are available, pre-clinical studies may also be omitted. Drug repositioning is especially promising in the development of treatments for neurodegenerative disorders because the development of new drugs for chronic disorders often takes more than 20 years and has a high financial burden. Strategic patenting is important to cooperate with pharmaceutical companies and to accomplish drug repositioning.


Assuntos
Reposicionamento de Medicamentos , Doenças Neurodegenerativas/tratamento farmacológico , Humanos
2.
Brain Nerve ; 71(9): 961-970, 2019 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-31506398

RESUMO

To date, all clinical trials of disease-modifying drugs for Alzheimer's disease (AD) have been unsuccessful, making investments into AD drug development very risky despite the high unmet need. Drug repositioning or repurposing approaches are relatively less expensive and more promising compared to novel drug development in AD. About 40% of clinical trials for AD currently in progress across the world use the drug repositioning method. They are expected to be a trigger for AD drug discovery that breaks the current deadlock situation. By using drugs approved for other indications, these clinical trials target dysregulated pathways of AD with different or a combination of modes of action, including anti-amyloid, anti-tau, anti-inflammatory, metabolic, neuroprotective, and neurotransmission-based approaches. In these clinical trials, cardiovascular drugs such as insulin, cilostazol, probucol, telmisartan, and dabigatran are tested for their effect on different mechanisms of AD pathology. This is in line with the recent emphasis that AD should be studied as a complex multifactorial disorder, not dominated by one dominant biological factor such as beta-amyloid, and without disregarding any relevant pathologic factor, such as vascular dysregulation. It is strongly expected that drug repositioning approaches will create a paradigm shift in treatment approaches for AD patients.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Reposicionamento de Medicamentos , Cilostazol , Dabigatrana , Humanos , Insulina , Probucol , Telmisartan
3.
Artigo em Inglês | MEDLINE | ID: mdl-31531868

RESUMO

BACKGROUND: A challenging decision exists as whether to abandon or remove noninfectious superfluous leads during lead revisions or cardiac implantable electronic device (CIED) upgrades. There is insufficient data in the Asian population to guide decision making. METHODS: This study investigated the safety and efficacy of transvenous lead extractions (TLEs) in a high-volume Japanese center. Among a total of 341 patients who underwent lead revisions or CIED upgrades between 2008 and 2018, 53 patients (16%) who underwent TLEs to remove the superfluous leads were analyzed. RESULTS: Indications for TLE were vascular issues (60%), recalled leads (21%), growth of the body size (6%), abandoned leads in young patients (6%), switch to a subcutaneous implanted cardiac defibrillator (4%), need for an MRI conditional CIED (2%), and risks of vascular injury (2%). The population included 29 patients (55%) with nonfunctional leads and 24 (45%) with functional abandoned leads. A total of 74 target leads (mean 1.4 leads/person, median lead age 6.7 years) were extracted with a complete removal achieved in 98%. All coexisting leads, intended for continued use, were not damaged. All new leads (mean 1.4 leads/person) that had been simultaneously implanted during the TLE procedures were successfully implanted. There was one minor complication (2%) involving a pericardial effusion but it did not affect the hemodynamics. CONCLUSIONS: In this Japanese single center experience, the removal of noninfectious superfluous leads with TLEs seemed to be a safe and effective therapeutic option.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31447456

RESUMO

PURPOSE: Immunosuppressant and steroid are inevitable for graft survival after renal transplantation, and their usage is known to be a risk factor for mortality and morbidity after cardiac surgery. We evaluated the long-term clinical outcomes in patients who underwent cardiac surgery after renal transplantation. METHODS: We retrospectively reviewed 23 patients who underwent cardiac surgery after renal transplantation with maintained grafts at the time of the cardiac surgery in our institution between June 2000 and June 2018 (19 males, 4 females; mean age, 55 (38-81) years). RESULTS: The interval from renal transplantation to cardiac surgery was 80.0 ± 84.6 (0.25-298) months. The mean follow-up period after cardiac surgery was 78.3 (range: 1-216) months. Cumulative survival rates at 1, 5, 7, and 10 years were 95.7%, 95.7%, 87.7%, and 68.2%, respectively. Renal graft survival rates at 1 and 5 years were 86.1% and 79.9%, respectively. CONCLUSIONS: This retrospective review suggests that cardiac surgery in kidney transplant patients can result in good survival rates. Thanks to dedicated postoperative and long-term management, approximately 80% of the renal grafts still maintained their function 5 years after cardiac surgery.

5.
Rinsho Shinkeigaku ; 59(8): 530-535, 2019 Aug 29.
Artigo em Japonês | MEDLINE | ID: mdl-31341129

RESUMO

A 41-year-old woman experienced back pain upon waking up. Immediately afterward, she experienced a continual orthostatic headache. Thereafter, right ear fullness and dizziness also occurred. One month later, she became aware of repeated numbness that started in the right hand and spread to the right half of the body and lower limbs and continued for repeated periods of approximately 20-30 min. Neurological examination revealed no abnormal findings except for orthostatic headache. Electroencephalography showed no epileptic discharge. Head MRI revealed left convexal subarachnoid hemorrhage (cSAH) restricted to the prefrontal sulcus, left frontal cerebral venous thrombosis, diffuse dural thickening with gadolinium enhancement, and subdural hematoma in the posterior cranial fossa. Spinal MRI revealed epidural fluid accumulation around the thoracic spine. CT myelography revealed cerebrospinal fluid leakages at the cervical, thoracic, and lumbar vertebrae levels. The patient was diagnosed with spontaneous intracranial hypotension (SIH), which was treated effectively with a blood patch. In this case, cSAH may have resulted from rupturing of the vessel wall as a result of cortical venous thrombosis induced by SIH. The repeated transient neurologic symptoms suggesting migraine aura may have originated from cSAH, which in turn led to cortical spreading depression. The diagnosis and management of SIH can be often difficult; therefore, repeated migraine-aura-like symptoms are a critical sign of complication with cSAH and cortical venous thrombosis.

6.
Brain Res ; 1720: 146294, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31201815

RESUMO

Oligodendrocytes (OLGs) support neuronal system and have crucial roles for brain homeostasis. As the renewal and regeneration of OLGs derived from oligodendrocyte precursor cells (OPCs) are inhibited by various pathological conditions, the restoration of impaired oligodendrogenesis is a therapeutic strategy for OLG-related diseases such as subcortical ischemic vascular dementia (SIVD). Fingolimod (FTY720), a drug for multiple sclerosis, is reported to elicit a cytoprotective effect on OPCs in vitro. However, the effects of fingolimod against ischemia-induced suppression of OPC differentiation remain unknown. Hence, the purpose of this study was to investigate the effectiveness of fingolimod against ischemia-induced suppression of oligodendrogenesis. For the in vitro experiments, primary rat cultured OPCs were incubated with a non-lethal concentration of CoCl2 to induce chemical hypoxic conditions and were treated with or without fingolimod-phosphate. We found that low concentration fingolimod-phosphate directly rescued ischemia-induced suppression of OPC differentiation via the phosphoinositide 3-kinase-Akt pathway. For the in vivo experiments, we used a mouse model of SIVD generated by bilateral common carotid artery stenosis. On day 28 after surgery, fingolimod ameliorated ischemia-induced demyelination and promoted oligodendrogenesis under prolonged cerebral hypoperfusion. The present study demonstrates that fingolimod can promote oligodendrogenesis under ischemic conditions and may be a therapeutic candidate for SIVD.

7.
J Stroke Cerebrovasc Dis ; 28(7): e95-e97, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31053373

RESUMO

Mobile plaque in the innominate artery is extremely rare and difficult to diagnose, especially in its acute stage. Its diagnosis is often delayed in many cases, resulting in delayed treatment and poor prognosis. Herein, we report the case of a 69-year-old patient with multiple cerebral infarction only in the right internal carotid artery and vertebrobasilar territories. No embolic sources were found until arterial ultrasonography detected a large balloon-like mobile plaque in the IA. Mobile plaque consisted of high-and low-echoic components and showed balloon-like plaque. Despite sufficient antiplatelet therapy, recurrence of cerebral embolism could not be prevented. IA replacement was eventually performed by cardiac surgeons. Pathological examinations showed that organized mobile plaque could have existed previously and acute thrombi, generated after the atheromatous plaque rupture caused by the mechanical burden of organized mobile plaque, could expand along with the organized mobile plaque and caused balloon-like plaque and related with repeated embolism. The IA should be explored immediately in cases of repetitive right-sided cerebral embolisms to prevent further recurrence.


Assuntos
Tronco Braquiocefálico/diagnóstico por imagem , Tronco Braquiocefálico/patologia , Infarto Cerebral/etiologia , Embolia Intracraniana/etiologia , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/patologia , Placa Aterosclerótica , Ultrassonografia de Intervenção , Idoso , Biópsia , Implante de Prótese Vascular , Tronco Braquiocefálico/cirurgia , Infarto Cerebral/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Humanos , Embolia Intracraniana/diagnóstico por imagem , Masculino , Doença Arterial Periférica/complicações , Doença Arterial Periférica/terapia , Inibidores da Agregação de Plaquetas/uso terapêutico , Valor Preditivo dos Testes , Recidiva , Resultado do Tratamento
8.
Proc Natl Acad Sci U S A ; 116(20): 10031-10038, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31036637

RESUMO

Cerebral amyloid angiopathy (CAA) results from amyloid-ß deposition in the cerebrovasculature. It is frequently accompanied by Alzheimer's disease and causes dementia. We recently demonstrated that in a mouse model of CAA, taxifolin improved cerebral blood flow, promoted amyloid-ß removal from the brain, and prevented cognitive dysfunction when administered orally. Here we showed that taxifolin inhibited the intracerebral production of amyloid-ß through suppressing the ApoE-ERK1/2-amyloid-ß precursor protein axis, despite the low permeability of the blood-brain barrier to taxifolin. Higher expression levels of triggering receptor expressed on myeloid cell 2 (TREM2) were associated with the exacerbation of inflammation in the brain. Taxifolin suppressed inflammation, alleviating the accumulation of TREM2-expressing cells in the brain. It also mitigated glutamate levels and oxidative tissue damage and reduced brain levels of active caspases, indicative of apoptotic cell death. Thus, the oral administration of taxifolin had intracerebral pleiotropic neuroprotective effects on CAA through suppressing amyloid-ß production and beneficially modulating proinflammatory microglial phenotypes.

9.
Int J Mol Sci ; 20(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052203

RESUMO

Amyloid-ß (Aß) has been closely implicated in the pathogenesis of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD), the major causes of dementia. Thus, Aß could be a target for the treatment of these diseases, for which, currently, there are no established effective treatments. Taxifolin is a bioactive catechol-type flavonoid present in various plants, such as herbs, and it exhibits pleiotropic effects including anti-oxidant and anti-glycation activities. Recently, we have demonstrated that taxifolin inhibits Aß fibril formation in vitro and have further shown that it improves cerebral blood flow, facilitating Aß clearance in the brain and suppressing cognitive decline in a mouse model of CAA. These findings suggest the novel therapeutic potentials of taxifolin for CAA. Furthermore, recent extensive studies have reported several novel aspects of taxifolin supporting its potential as a therapeutic drug for AD and metabolic diseases with a high risk for dementia as well as for CAA. In this review, we have summarized the recent advances in taxifolin research based on in vitro, in vivo, and in silico approaches. Furthermore, we have discussed future research directions on the potential of taxifolin for use in novel therapeutic strategies for CAA, AD, and metabolic diseases with an increased risk for dementia.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Angiopatia Amiloide Cerebral/tratamento farmacológico , Quercetina/análogos & derivados , Animais , Humanos , Fármacos Neuroprotetores/uso terapêutico , Quercetina/uso terapêutico
10.
Int J Mol Sci ; 20(10)2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31126115

RESUMO

Vascular risk factors, such as type 2 diabetes mellitus (T2DM), are associated with the increased risk of Alzheimer's disease. One of the common T2DM medications, dipeptidyl peptidase (DPP)-4 inhibitors, have a minimum risk for hypoglycemia and have recently been suggested to ameliorate ß-amyloid pathology. However, conflicting results have been reported regarding the effects of DPP-4 inhibition on cognitive function and tau pathology. Thus, we investigated whether inhibiting DPP-4 affects tau pathology and cognition in a mouse model of tauopathy with hyperglycemia. Male mice overexpressing the P301S mutant human microtubule-associated protein tau gene (PS19) were fed either a low or high-fat diet. PS19 mice were then administered either linagliptin, a DPP-4 inhibitor, or vehicle, from 6 weeks to 8 months of age. Linagliptin-treated mice exhibited higher levels of glucagon-like peptide-1 and decreased fasting blood glucose, compared with the vehicle-treated mice at 8 months. Linagliptin treatment significantly restored spatial reference memory and increased cerebral blood flow without affecting phosphorylation levels of tau or endothelial nitric oxide synthase (eNOS) in the brain. Linagliptin may ameliorate HFD-induced cognitive worsening in tauopathy, at least partially, by increasing cerebral perfusion via the eNOS-independent pathway.

11.
Intern Med ; 58(10): 1495-1499, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30713304

RESUMO

A 64-year-old woman with no previous mental illness took a single 500 mg tablet of levofloxacin for cystitis. Two hours later, she developed psychosis with involuntary movement and severe hyperventilation with respiratory alkalosis. Cranial magnetic resonance imaging findings were unremarkable, and an electroencephalogram revealed no epileptiform discharge. Her symptoms improved on the third day after levofloxacin was discontinued. Levofloxacin-associated encephalopathy with psychotic features is a rare adverse event. Disturbance of gamma-aminobutyric acid-ergic (GABAergic) interneurons by levofloxacin may lead to hyperventilation via dysfunction of the brainstem respiratory network. Physicians should be aware of hyperventilation as an additional serious symptom of levofloxacin-associated encephalopathy in acute settings.


Assuntos
Anti-Infecciosos Urinários/efeitos adversos , Anti-Infecciosos Urinários/uso terapêutico , Encefalopatias/induzido quimicamente , Cistite/tratamento farmacológico , Hiperventilação/induzido quimicamente , Levofloxacino/efeitos adversos , Levofloxacino/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Resultado do Tratamento
12.
Circulation ; 139(2): 295-298, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30615506
13.
J Alzheimers Dis ; 67(2): 621-629, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30584149

RESUMO

BACKGROUND: Time and resource limitations prevent cognitive assessment in acute-to-subacute settings, even in comprehensive stroke centers. OBJECTIVE: To assess cognitive function in acute stroke patients undergoing routine clinical, laboratory, and radiological investigations, with a view to improving post-stroke care and treatment. METHODS: Sixty-nine patients (72.6±11.1 years; 65% male) were prospectively enrolled within 14 days of acute ischemic stroke. Patients with altered consciousness, aphasia, or dysarthria were excluded. Clinical features including modified Rankin and NIH stroke scales, and vascular risk factors were assessed, as well as neuroimaging parameters by semi-quantitative evaluation of medial temporal lobe atrophy (MTLA) using MRA source images, FLAIR images for white matter changes (Fazekas scores), and T2∗ images for cerebral microbleeds. Neuropsychological screening was conducted using the Montreal Cognitive Assessment (MoCA) test. Univariate and multivariate analyses were used to evaluate the influence of variables on MoCA total and subscale scores. RESULTS: Lower MoCA scores of 22 or less were associated with MTLA [OR (95% CI), 5.3 (1.0-27.5); p = 0.045], education years [OR (95% CI), 0.71 (0.55-0.91); p = 0.007], and modified Rankin scale at discharge [OR (95% CI), 2.4 (1.3-4.5); p = 0.007]. The delayed recall MoCA score was correlated with MTLA (r = - 0.452, p < 0.001), periventricular (r = - 0.273, p = 0.024), and deep (r = - 0.242, p = 0.046), white matter changes. CONCLUSIONS: MTLA, together with lower educational history, are quick indicators of amnestic cognitive impairment after stroke. The association between cognitive impairment and physical disability at discharge may signify the importance of earlier cognitive assessment.

14.
Kyobu Geka ; 71(11): 953-956, 2018 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-30310009

RESUMO

A 61-year-old man presented by ambulance with dyspnea. He was diagnosed with myocardial infarction complicated with ventricular septal perforation (VSP), and intraaortic balloon pumping support and intensive care were started. Because of instability of hemodynamic status, modified David-Komeda operation with double patch was performed in the subacute phase of VSP. Although he developed acute respiratory distress syndrome( ARDS) on the 21st day after operation, he was successfully treated with corticosteroid pulse therapy and artificial ventilation. He was transferred to a rehabilitation hospital on the 141st postoperative day.

15.
Clin Neurol Neurosurg ; 174: 68-74, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30216810

RESUMO

OBJECTIVE: Valid and reliable measures are needed to assess post-stroke cognitive impairment. The Montreal Cognitive Assessment (MoCA) has been considered a superior screening test to the Mini-Mental State Examination (MMSE) for patients with post-stroke cognitive impairment, particularly in executive function, which may be related to reduction in regional cerebral blood flow (rCBF). In this study, we determined whether MoCA and MMSE scores correlate with rCBF assessed with SPECT in the subacute phase after ischemic stroke. PATIENTS AND METHODS: We retrospectively enrolled 28 patients who were admitted to the Red Cross Otsu Hospital with acute cerebral infarction, which was confirmed by magnetic resonance imaging (MRI), if they underwent cognitive assessment (MoCA/MMSE) and 123I-IMP SPECT imaging within 3 weeks post-stroke during a study period of 5 months. Correlation analyses between rCBF and MoCA or MMSE scores were performed by statistical parametric mapping (SPM) and volume-of-interest (VOI) analyses. RESULTS: Total MoCA score correlated with the rCBF in the prefrontal cortex, cingulate cortex, caudate nucleus and thalamus by SPM analysis (uncorrected p < 0.001; cluster-level corrected p < 0.05). Among the subtest scores of MoCA, visuoexecutive function, attention, language and delayed recall scores were positively correlated with rCBF in the prefrontal cortex by VOI analysis (p < 0.05). However, total MMSE score did not correlate significantly with any of the rCBF measures. CONCLUSIONS: Post-stroke cognitive performance assessed with MoCA positively correlated with rCBF in brain regions mainly comprising the prefrontal-subcortical circuits. The findings of this hypothesis-generating study support the notion that MoCA is useful for assessing post-stroke cognitive status.

16.
Circ J ; 82(9): 2305-2310, 2018 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-30012930

RESUMO

BACKGROUND: Recurrent ventricular tachyarrhythmias (VTA) are "A factor" modifiers in the Interagency Registry for Mechanically Assisted Circulatory Support profile. The effect of recurrent VTA on clinical outcome, however, is controversial. We evaluated the impact of recurrent VTA on outcome in Japanese heart transplant candidates with a left ventricular assist device (LVAD). Methods and Results: Sixty-six adult patients with advanced heart failure who were listed for heart transplantation between January 2005 and October 2017 were enrolled in the study. Recurrent VTA (modifier A status) was defined as a sustained ventricular tachycardia or fibrillation that required implantable cardioverter defibrillator shocks or an external defibrillator more than twice weekly. The primary outcome was death from any cause. The secondary outcomes were the first occurrence of VTA and recurrent VTA after LVAD implantation. Sixteen patients (24%) met the criteria for modifier A status, and 15 patients had an LVAD implanted. During a median follow-up of 1,124 days, 21 of 60 patients with an LVAD died. There was a significantly higher mortality rate in LVAD patients with modifier A status than in those who did not meet the modifier A criteria. On multivariate analysis, patients with modifier A status had an increased risk of mortality (HR, 3.43; 95% CI: 1.30-8.61, P=0.001). CONCLUSIONS: Recurrent VTA might be a marker for worse outcome in Japanese heart transplant candidates with an LVAD.

17.
J Cardiol ; 72(3): 200-207, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29898865

RESUMO

BACKGROUND: Coronary artery vasospasm (CS) can be identified as either a diffuse type or focal type; however, the difference in endothelial characteristics between these spasm types remains unclear. The features of coronary intima associated with diffuse spasm and focal spasm using coronary angioscopy (CAS) were evaluated and the optical coherence tomography (OCT) findings were compared. METHODS: CAS and/or OCT observational analysis was performed in 55 patients (mean age: 61.4 years, 31 men) who had acetylcholine-provoked CS (diffuse CS, 31 patients; focal CS, 24 patients). The yellowness of the intima, presence of thrombus in CAS, and intimal characteristics based on the OCT results were evaluated. RESULTS: CAS showed more atherosclerotic yellow plaques at the focal spasm segment than at the diffuse spasm segment (p=0.032). Moreover, there were more thrombi at the focal spasm segment (p=0.039). In addition, OCT results revealed that the intima area, maximum intima thickness, and lipid content in the focal CS group were larger than the diffuse CS group (4.22±1.67mm2 vs. 3.45±2.36mm2; 0.71±0.29mm vs. 0.53±0.30mm; 55.9% vs. 32.0%, p<0.001, respectively). CONCLUSIONS: These results indicate that the presence of atherosclerotic plaques at the spasm site is likely to be related to the occurrence of a focal vasospasm. This may support the difference of features between focal CS and diffuse CS and contribute to precise treatment for each spasm type.

18.
Sci Rep ; 8(1): 3607, 2018 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-29483617

RESUMO

RNF213 is a susceptibility gene for moyamoya disease, yet its exact functions remain unclear. To evaluate the role of RNF213 in adaptation of cerebral blood flow (CBF) under cerebral hypoperfusion, we performed bilateral common carotid artery stenosis surgery using external microcoils on Rnf213 knockout (KO) and vascular endothelial cell-specific Rnf213 mutant (human p.R4810K orthologue) transgenic (EC-Tg) mice. Temporal CBF changes were measured by arterial spin-labelling magnetic resonance imaging. In the cortical area, no significant difference in CBF was found before surgery between the genotypes. Three of eight (37.5%) KO mice died after surgery but all wild-type and EC-Tg mice survived hypoperfusion. KO mice had a significantly more severe reduction in CBF on day 7 than wild-type mice (KO, 29.7% of baseline level; wild-type, 49.3%; p = 0.038), while CBF restoration on day 28 was significantly impaired in both KO (50.0%) and EC-Tg (56.1%) mice compared with wild-type mice (69.5%; p = 0.031 and 0.037, respectively). Changes in the subcortical area also showed the same tendency as the cortical area. Additionally, histological analysis demonstrated that angiogenesis was impaired in both EC-Tg and KO mice. These results are indicative of the essential role of RNF213 in the maintenance of CBF.

19.
Biomaterials ; 154: 12-23, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29117575

RESUMO

Transplantation of mesenchymal stromal cells (MSCs) is an emerging therapy for the treatment of heart failure. However, the delivery method of MSC is currently suboptimal. The use of self-assembling peptide hydrogels, including PuraMatrix® (PM; 3-D Matrix, Ltd), has been reported for clinical hemostasis and in research models. This study demonstrates the feasibility and efficacy of an advanced approach for MSC-therapy, that is coating of the epicardium with the instantly-produced PM hydrogel incorporating MSCs (epicardial PM-MSC therapy). We optimized the conditions/procedure to produce "instant" 2PM-MSC complexes. After spreading on the epicardium by easy pipetting, the PM-MSC complex promptly and stably adhere to the beating heart. Of note, this treatment achieved more extensive improvement of cardiac function, with greater initial retention and survival of donor MSCs, compared to intramyocardial MSC injection in rat heart failure models. This enhanced efficacy was underpinned by amplified myocardial upregulation of a group of tissue repair-related genes, which led to enhanced repair of the damaged myocardium, i.e. augmented microvascular formation and reduced interstitial fibrosis. These data suggest a potential for epicardial PM-MSC therapy to be a widely-adopted treatment of heart failure. This approach may also be useful for treating diseases in other organs than the heart.


Assuntos
Materiais Revestidos Biocompatíveis/farmacologia , Insuficiência Cardíaca/terapia , Hidrogel de Polietilenoglicol-Dimetacrilato/farmacologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Peptídeos/farmacologia , Pericárdio/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Insuficiência Cardíaca/fisiopatologia , Testes de Função Cardíaca , Concentração de Íons de Hidrogênio , Masculino , Células-Tronco Mesenquimais/metabolismo , Infarto do Miocárdio/terapia , Ratos Endogâmicos Lew , Ratos Sprague-Dawley
20.
Gan To Kagaku Ryoho ; 45(13): 2102-2104, 2018 Dec.
Artigo em Japonês | MEDLINE | ID: mdl-30692298

RESUMO

A 73-year-old male presented with melena and severe anemia. An esophagogastroduodenoscopy(EGD)and colonoscopy( CS)revealed no source of hemorrhage. Multiple small intestinal tumors were observed on abdominal ultrasound(US). CT also showed mesenteric lymph node metastases and multiple lung and liver metastases. Since active bleeding was suspected, we performed an emergency surgery. The small intestine including 2 tumors and 2 mesenteric lymph node metastases were resected. On histopathological examination, choriocarcinoma was diagnosed. The blood hCG level was remarkably elevated. The primary lesion could not be detected. Chemotherapy containing cisplatin(CDDP)and irinotecan(CPT-11)was initiated; although the blood hCG level was temporally lowered, the patient died of liver failure 8 months after the surgery.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Coriocarcinoma , Neoplasias Intestinais , Neoplasias Hepáticas , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Coriocarcinoma/tratamento farmacológico , Coriocarcinoma/secundário , Cisplatino/administração & dosagem , Humanos , Neoplasias Intestinais/tratamento farmacológico , Neoplasias Intestinais/secundário , Irinotecano/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Masculino
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