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1.
Drugs Today (Barc) ; 56(10): 623-641, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33185628

RESUMO

Lambert-Eaton myasthenic syndrome (LEMS) is a presynaptic autoimmune disabling neuromuscular disease caused by antibodies against presynaptic voltage-gated calcium channels. It reduces the quantal release of acetylcholine (Ach), causing muscle weakness, reduced or absent reflex and dysautonomia. About half of LEMS patients have associated small cell lung cancer. For symptomatic treatment, amifampridine (3,4-diaminopyridine [3,4-DAP]) is ideal because it increases the release of Ach at the presynaptic membrane. Since the first use of 3,4-DAP in LEMS patients in the 1980s, 136 LEMS patients were treated with amifampridines in the open-label studies and 208 patients in the eight randomized studies. These studies showed that amifampridine is the most effective drug for symptomatic treatment in LEMS. Now, 3,4-DAPP (3,4-DAP phosphate) is approved for adult LEMS patients and 3,4-DAP for pediatric patients. The recommended dose is 80 mg a day, divided 3 or 4 times a day. Side effects are usually mild, and the most frequently reported are paresthesia.

2.
Br J Dermatol ; 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33131051

RESUMO

Dear Editor, segmental vitiligo (SV) is a distinct subtype of vitiligo, characterized by unilateral distribution, early age of onset, and stabilization after rapid progression.1-3 . A classification according to distributions could provide valuable clues to the etiology of SV. Although several studies have proposed classification of SV, we attempted to integrate the classification across the entire body using a large number of patients.

3.
Eur J Paediatr Dent ; 21(3): 238-242, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32893659

RESUMO

BACKGROUND: Molar Incisor Malformation (MIM) or Molar Root Incisor malformation (MRIM) is a recently discovered root malformation with constricted pulp and abnormally located furcation presented in permanent first molars and sometimes incisors. CASE REPORT: Two cases that feature MIM are presented with the description of the characteristic tooth form, clinical/radiographic examination, medical history, the supposed aetiology, treatment procedure and results at the 2-year follow-up. Conservative endodontic treatment was performed in both cases, furcation perforation and canal perforation were filled with MTA (Mineral Trioxide Aggregate), and a good prognosis was observed after 2 years of follow-up. Furthermore, recommended treatment options are discussed to provide a more appropriate treatment for the patients. CONCLUSION: Patients with MIM need to be treated at the right time to avoid severe infection and other problems. Early diagnosis with appropriate treatment is more likely to lead to a more favourable prognosis.


Assuntos
Incisivo , Materiais Restauradores do Canal Radicular , Compostos de Alumínio , Compostos de Cálcio , Polpa Dentária , Cavidade Pulpar , Combinação de Medicamentos , Humanos , Dente Molar , Óxidos , Silicatos , Raiz Dentária
4.
Hernia ; 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32862259

RESUMO

INTRODUCTION: As patients with recurrent inguinal hernia (RIH) are at a higher risk of perioperative complications, international guidelines have been developed to mitigate these risks by recommending the reverse approach for repair. We aim to study the characteristics of RIH, compliance to guidelines-based repair (GR) and determine factors influencing compliance to guidelines. METHODS: A retrospective study of patients with RIH was carried out at two tertiary institutions in Singapore, over 10 years from January 2010 to 2020. RESULTS: There were 16 patients with bilateral recurrences and 214 patients with unilateral recurrences. The characteristics of patients with non-guidelines-based repair (NGR) versus GR were similar, p > 0.05. GR was performed for 128 (52.1%) hernias as compared to NGR for 118 (47.9%) hernias. The open approach was more common in NGR than GR, 115/118 (89.8%) versus 58/128 (45.3%), p < 0.001. Forty (n = 40, 16.3%) RIH presented emergently, of which 37 underwent NGR while 3 underwent GR, p < 0.0001. More consultants were present during GR 103/128 (80.5%) as compared to NGR 78/118 (66.1%), p = 0.018. Emergency presentation of hernia recurrence, OR 7.74 (CI 6.11-9.20), p = 0.005, and open repair during the index repair were significantly associated with NGR, OR 6.63 (CI 4.42-8.84), p = 0.01. Median length of stay was shorter in the GR 1 day (IQR 1-2 days) versus 2 days (IQR 2-5 days) in the NGR group, p = 0.02. CONCLUSION: The compliance rate of GR for RIH is 52%. NGR for RIH had acceptable short-term outcomes. For elective presentation of RIH, GR should be encouraged given a shorter length of hospital stay.

5.
BJOG ; 2020 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-32783284

RESUMO

OBJECTIVE: To examine the concordance rate of non-chromosomal congenital malformations in twin pairs based on zygosity. DESIGN: Retrospective cohort study. SETTING: A tertiary hospital in Korea. POPULATION: Twin pairs born at Seoul National University Hospital between 2001 and 2019. METHODS: Congenital malformations were diagnosed by postnatal workups of neonates or autopsy in cases of stillborn infants. Zygosity was confirmed by sex, chorionicity and DNA analysis. MAIN OUTCOME MEASURES: Concordance rate of congenital malformations in twin pairs based on zygosity. RESULTS: In total, 3386 twin pairs were included. The risk of a congenital malformation in the index twin increased significantly if the co-twin had the congenital malformation, and the concordance rate was higher in monozygotic (MZ) than in dizygotic (DZ) twins (37.04 versus 16.77, P < 0.001). An increased risk of a congenital malformation in the presence of the same congenital malformation in the co-twin was observed only for malformations of the nervous system, eye/ear/face/neck, circulatory system, cleft lip/palate, genital organs, urinary system and musculoskeletal system. Significantly higher concordance rates in MZ than in DZ twin pairs were observed only for the nervous system (40.00 versus 0.00, P < 0.001), circulatory system (32.97 versus 19.74, P = 0.021), cleft lip/palate (44.44 versus 0.00, P = 0.017) and urinary system (22.22 versus 0.00, P = 0.004), whereas significant differences were not found for the genital organs or musculoskeletal system. CONCLUSIONS: Monozygotic twins had higher concordance rates than DZ twins only in specific organ systems. It may be speculated that nervous system, circulatory system, cleft lip/palate and urinary system are primarily genetically affected. TWEETABLE ABSTRACT: Monozygotic twins had higher concordance rates than dizygotic twins only in specific organ systems.

6.
Circ Res ; 127(9): 1122-1137, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-32762495

RESUMO

RATIONALE: Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease caused by mutations in ENG, ALK1, or SMAD4. Since proteins from all 3 HHT genes are components of signal transduction of TGF-ß (transforming growth factor ß) family members, it has been hypothesized that HHT is a disease caused by defects in the ENG-ALK1-SMAD4 linear signaling. However, in vivo evidence supporting this hypothesis is scarce. OBJECTIVE: We tested this hypothesis and investigated the therapeutic effects and potential risks of induced-ALK1 or -ENG overexpression (OE) for HHT. METHODS AND RESULTS: We generated a novel mouse allele (ROSA26Alk1) in which HA (human influenza hemagglutinin)-tagged ALK1 and bicistronic eGFP expression are induced by Cre activity. We examined whether ALK1-OE using the ROSA26Alk1 allele could suppress the development of arteriovenous malformations (AVMs) in wounded adult skin and developing retinas of Alk1- and Eng-inducible knockout (iKO) mice. We also used a similar approach to investigate whether ENG-OE could rescue AVMs. Biochemical and immunofluorescence analyses confirmed the Cre-dependent OE of the ALK1-HA transgene. We could not detect any pathological signs in ALK1-OE mice up to 3 months after induction. ALK1-OE prevented the development of retinal AVMs and wound-induced skin AVMs in Eng-iKO as well as Alk1-iKO mice. ALK1-OE normalized expression of SMAD and NOTCH target genes in ENG-deficient endothelial cells (ECs) and restored the effect of BMP9 (bone morphogenetic protein 9) on suppression of phosphor-AKT levels in these endothelial cells. On the other hand, ENG-OE could not inhibit the AVM development in Alk1-iKO models. CONCLUSIONS: These data support the notion that ENG and ALK1 form a linear signaling pathway for the formation of a proper arteriovenous network during angiogenesis. We suggest that ALK1 OE or activation can be an effective therapeutic strategy for HHT. Further research is required to study whether this therapy could be translated into treatment for humans.

7.
J Dairy Sci ; 103(9): 7752-7760, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32622594

RESUMO

Osteoporosis is a systemic skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and fracture susceptibility. In an aged society with increased life expectancy, the incidence rate of osteoporosis is also rapidly increasing. Inadequate nutrition may negatively influence bone metabolism. Recently, many studies have investigated the functionality of milk-derived exosomes, which play important roles in cell-to-cell communication. However, there are few reports of how milk-derived exosomes influence osteoblast proliferation and differentiation. Here, we determined whether bovine colostrum-derived exosomes promote anti-osteoporosis in vitro and in vivo. Tartrate-resistant acid phosphatase-stained cells were significantly inhibited in Raw264.7 cells treated with exosomes, indicating reduced osteoclast differentiation. We induced osteoporosis in mice using glucocorticoid pellets after orally administering exosomes for 2 mo. Interestingly, the bone mineral density of exosome-fed mouse groups was significantly improved compared with the glucocorticoid-induced osteoporosis group without exosome treatment. In addition, Lactobacillus were decreased in the gut microbiota community of osteoporosis-induced mice, but the gut microbiota community composition was effectively restored by exosome intake. Taken together, we propose that exosomes isolated from bovine colostrum could be a potential candidate for osteoporosis prevention, bone remodeling improvement, and inhibition of bone resorption. To our knowledge, this is the first time that a protective effect of milk exosomes against osteoporosis has been demonstrated in vivo. Our results strongly suggest that bovine colostrum exosomes might be used as a prophylaxis to prevent the onset of osteoporosis. Indeed, our results offer promising alternative strategies in the nutritional management of age-related bone complications.

8.
Phys Rev Lett ; 124(22): 226403, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32567905

RESUMO

Light can be strongly confined in subwavelength spatial regions through the interaction with plasmons, the collective electronic modes appearing in metals and semiconductors. This confinement, which is particularly important in the terahertz spectral region, amplifies light-matter interaction and provides a powerful mechanism for efficiently generating nonlinear optical phenomena. These effects are particularly relevant in graphene and topological insulators, where massless Dirac fermions show a naturally nonlinear optical behavior in the terahertz range. The strong interaction scenario has been considered so far from the point of view of light. In this Letter, we investigate instead the effect of strong interaction on the plasmon itself. In particular, we will show that Dirac plasmons in Bi_{2}Se_{3} topological insulator are strongly renormalized when excited by high-intensity terahertz radiation by displaying a huge red-shift down to 60% of its characteristic frequency. This opens the road towards tunable terahertz nonlinear optical devices based on topological insulators.

9.
J Dent Res ; 99(11): 1287-1295, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32531176

RESUMO

The cause of chronic inflammatory periodontitis, which leads to the destruction of periodontal ligament and alveolar bone, is multifactorial. An increasing number of studies have shown the clinical significance of NLRP3-mediated low-grade inflammation in degenerative disorders, but its causal linkage to age-related periodontitis has not yet been elucidated. In this study, we investigated the involvement of the NLRP3 inflammasome and the therapeutic potential of NLRP3 inhibition in age-related alveolar bone loss by using in vivo and in vitro models. The poor quality of alveolar bones in aged mice was correlated with caspase-1 activation by macrophages and elevated levels of IL-1ß, which are mainly regulated by the NLRP3 inflammasome, in periodontal ligament and serum, respectively. Aged mice lacking Nlrp3 showed better bone mass than age-matched wild-type mice via a way that affects bone resorption rather than bone formation. In line with this finding, treatment with MCC950, a potent inhibitor of the NLRP3 inflammasome, significantly suppressed alveolar bone loss with reduced caspase-1 activation in aged mice but not in young mice. In addition, our in vitro studies showed that the addition of IL-1ß encourages RANKL-induced osteoclastogenesis from bone marrow-derived macrophages and that treatment with MCC950 significantly suppresses osteoclastic differentiation directly, irrelevant to the inhibition of IL-1ß production. Our results suggest that the NLRP3 inflammasome is a critical mediator in age-related alveolar bone loss and that targeting the NLRP3 inflammasome could be a novel option for controlling periodontal degenerative changes with age.

10.
J Laryngol Otol ; 134(6): 526-532, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32524919

RESUMO

OBJECTIVE: Patulous Eustachian tube appears to be caused by a concave defect in the anterolateral wall of the tubal valve of the Eustachian tube. This study aimed to compare the clinical features of patulous Eustachian tube patients with or without a defect in the anterolateral wall of the tubal valve. METHODS: Sixty-six patients with a patulous Eustachian tube completed a questionnaire, which was evaluated alongside endoscopic findings of the tympanic membrane, nasal cavity and Eustachian tube orifice. RESULTS: Females were more frequently diagnosed with a patulous Eustachian tube, but the valve defect was more common in males (p = 0.007). The ratio of patulous Eustachian tube patients with or without defects in the anterolateral wall of the tubal valve was 1.6:1. Weight loss in the previous six months and being refractory to conservative management were significantly associated with the defect (p = 0.035 and 0.037, respectively). Symptom severity was significantly higher in patients with the defect. CONCLUSION: Patulous Eustachian tube patients without a defect in the anterolateral wall of the tubal valve can be non-surgically treated more often than those with the defect. Identification of the defect could assist in making treatment decisions for patulous Eustachian tube patients.


Assuntos
Tratamento Conservador/métodos , Otopatias/etiologia , Tuba Auditiva/patologia , Otite Média/complicações , Adulto , Tratamento Conservador/estatística & dados numéricos , Otopatias/diagnóstico , Endoscopia/métodos , Tuba Auditiva/diagnóstico por imagem , Tuba Auditiva/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Cavidade Nasal/diagnóstico por imagem , Cavidade Nasal/patologia , Otite Média/diagnóstico por imagem , Otite Média/patologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Inquéritos e Questionários/normas , Membrana Timpânica/diagnóstico por imagem , Perda de Peso
11.
BMJ Mil Health ; 2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32409616

RESUMO

BACKGROUND: Obesity is a serious health problem with an incidence that is increasing rapidly. Enlisted men are a distinctive group characterised by 24-hour community-living and are likely to experience changes in body weight as a result of regular diet and exercise during enlistment. METHODS: This study reviewed data from the Second Military Health Survey. Changes in body mass index (BMI) before and during military service were analysed using paired t-test. We calculated OR and 95% CI for factors affecting weight improvement during military service through logistic regression. RESULTS: The mean BMI in the underweight group increased by 5.87 kg/m2 during service, while that in the normal weight group increased by 1.18 kg/m2. In contrast, the mean BMI in the overweight group decreased by 5.47 kg/m2 during service. The OR for an improved BMI in the subjective good health group compared with the subjective poor health group was statistically significant (OR=1.71, 95% CI 1.02 to 2.87). The OR for an improved BMI was significantly higher in the group with three or more times per week of strength training than in the group with one to two times per week of strength training, and was higher among the marines compared with the Army soldiers (OR=1.48, 95% CI 1.03 to 2.12 and OR=2.15, 95% CI 1.07 to 4.32, respectively). CONCLUSIONS: Strength training showed a statistically significant increase in BMI during military service. Furthermore, the BMI of men who were underweight before their service increased, while it decreased among those who were overweight.

12.
Angiogenesis ; 23(3): 339-355, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32112176

RESUMO

BACKGROUND: TMEM100 is identified as a downstream gene of bone morphogenetic protein 9 (BMP9) signaling via activin receptor-like kinase 1 (ALK1), which is known to participate in lymphangiogenesis as well as angiogenesis. TMEM100 has been shown to be important for blood vessel formation and maintenance, but its role in the development of lymphatic vasculature remains unknown. The objective is to investigate the role of TMEM100 in development of the lymphatic system. METHODS AND RESULTS: Global Tmem100 gene deletion was induced by tamoxifen on 10.5 days post-coitus. Tmem100-inducible knockout (iKO) embryos in embryonic days (E)14.5-16.5 exhibited edema and blood-filled enlarged lymphatics with misconnections between veins and lymphatic vessels. For a reciprocal approach, we have generated a novel mouse line in which TMEM100 overexpression (OE) can be induced in endothelial cells by intercrossing with Tie2-Cre driver. TMEM100-OE embryos at E12.5-14.5 exhibited edema with small size and number of lymphatic vessels, the exact opposite phenotypes of Tmem100-iKOs. In Tmem100-iKO embryos, the number of progenitors of lymphatic endothelial cells (LECs) in the cardinal vein was increased, while it was decreased in TMEM100-OE embryos. The activity of NOTCH signaling, which limits the number of progenitors of LECs in the cardinal vein, was decreased in Tmem100-iKO embryos, whereas it was increased in TMEM100-OE embryos. CONCLUSION: TMEM100 plays an important role in the specification of LECs in the cardinal veins, at least in part, by regulating the NOTCH signaling.

13.
BMJ Mil Health ; 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32139412

RESUMO

INTRODUCTION: The easiest way to prevent noise-induced hearing loss (NIHL) is to wear earplugs. The Republic of Korea (ROK) Ministry of National Defense (MND) is supplying earplugs to prevent NIHL, but many patients still suffer from this. We speculated that earplugs would have a high NIHL rate, depending on the rate of use of earplugs, regardless of the rate of supply. Therefore, we conducted this study to investigate the relationship between the use of earplugs and hearing loss by ROK military personnel. METHODS: The study used data from the Military Health Survey conducted in 2014-2015, which included 13 470 questionnaires completed by ROK military personnel. Hearing loss and earplug use were self-reported. Logistic regression analysis was used to assess associations between earplug use and hearing loss. RESULTS: The study sample included 13 470 ROK military personnel (response rate of 71.2%) (Army, 8330 (61.8%); Navy/Marines, 2236 (16.6%); and Air Force, 2904 (21.6%)). Overall, 18.8% of Korean military personnel reported that they always wore earplugs, and 2.8% reported hearing loss. In logistic regression analysis, there were significant differences in the rates of hearing loss associated with wearing earplugs sometimes (OR=1.48, 95% CI 1.07 to 2.05) and never wearing earplugs (OR=1.53, 95% CI 1.12 to 2.10). In subgroup analysis, in Air Force, non-combat branch, forward area and long-term military service personnel increased hearing loss was associated with not wearing earplugs. CONCLUSION: Our study confirmed that within the ROK military, there is an association between hearing loss and lack of earplug use. In the ROK MND, Army, Navy/Marines and Air Force headquarters must provide guidelines for the use of earplugs during field training to protect military personnel's hearings and, if necessary, need to be regulated or institutionalised.

14.
Eur J Cancer ; 127: 150-157, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32014812

RESUMO

BACKGROUND: The RAINBOW trial showed that second-line ramucirumab with paclitaxel prolongs overall survival (OS) and progression-free survival (PFS) compared with placebo plus paclitaxel for treatment of advanced gastric/gastroesophageal junction cancer. Plasma samples were collected from patients during the trial and tested to identify predictive and prognostic biomarkers. PATIENTS AND METHODS: Circulating factors in plasma samples from mutually exclusive subsets of RAINBOW patients were assayed using: Intertek assays (24 markers, 380 samples, 57% of patients) and Lilly-developed assay (LDA) platform (5 markers, 257 samples, 39% of patients). Time-trend plots were generated for each marker from the Intertek assays. Baseline patient data were dichotomized into low- and high-marker subgroups. Markers were analyzed for predictive effects using interaction models and for prognostic effects using main-effects models. RESULTS: The Intertek and LDA populations were representative of the full trial population. Plasma levels of VEGF-D and PlGF increased from baseline levels during treatment, then declined after treatment discontinued. Angiopoietin-2 exhibited a decrease during treatment, then increased after treatment discontinuation. No clear time trend was evident with the other markers. Analyses of baseline biomarker expression and its relationship with efficacy variables found no biomarker was predictive for efficacy outcomes, including VEGF-D. However, CRP, HGF, ICAM-3, IL-8, SAA, and VCAM-1 were identified as potential prognostic markers with low baseline levels corresponding to longer OS and PFS. CONCLUSIONS: Pharmacodynamic and prognostic relationships were found from the exploratory biomarker analyses in RAINBOW; however, no predictive markers for ramucirumab in gastric cancer were identified in this trial.


Assuntos
Adenocarcinoma/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias Esofágicas/sangue , Junção Esofagogástrica/patologia , Neoplasias Gástricas/sangue , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Método Duplo-Cego , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/efeitos dos fármacos , Seguimentos , Humanos , Paclitaxel/administração & dosagem , Prognóstico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Fator D de Crescimento do Endotélio Vascular/sangue
15.
Eur J Neurol ; 27(7): 1296-1303, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31999861

RESUMO

BACKGROUND AND PURPOSE: The patterns of head-shaking nystagmus (HSN) aid in differentiation between central and peripheral vestibular disorders, and perverted HSN (pHSN) has been considered a central sign. The aim was to determine the characteristics of HSN in a large number of patients with either peripheral or central vestibular disorders in a dizziness clinic of a university hospital. METHODS: The medical records of 7544 dizzy patients were reviewed during a year and 822 patients with a clinical diagnosis of vestibular disorders were recruited. The findings of spontaneous nystagmus (SN) and HSN in these patients were compared with those of healthy controls (n = 48). RESULTS: A total of 217 of the 822 patients (26.4%) were classified as having a central vestibular disorder, whilst 397 (48.3%) had a peripheral vestibular disorder. In the peripheral vestibular disorder group, SN was observed in 14.1% and HSN in 40.8%, amongst whom 24.1% were the pHSN form. In the central group, SN was observed in 17.5% and HSN in 24.0% of whom 57.7% was pHSN. HSN was more frequently observed in the peripheral vestibular disorder group than in the central group (40.8% vs. 24.0%, P < 0.01). However, the proportion of pHSN was significantly increased in the central group compared to the peripheral vestibular patient group (57.7% vs. 24.1%, P < 0.01). CONCLUSIONS: Since pHSN is not specific for central vestibular disorders, other clinical features should be considered in pursuing a central lesion in patients with pHSN.

17.
J Clin Invest ; 130(2): 942-957, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31689244

RESUMO

Hereditary hemorrhagic telangiectasia (HHT), a genetic bleeding disorder leading to systemic arteriovenous malformations (AVMs), is caused by loss-of-function mutations in the ALK1/ENG/Smad1/5/8 pathway. Evidence suggests that HHT pathogenesis strongly relies on overactivated PI3K/Akt/mTOR and VEGFR2 pathways in endothelial cells (ECs). In the BMP9/10-immunoblocked (BMP9/10ib) neonatal mouse model of HHT, we report here that the mTOR inhibitor, sirolimus, and the receptor tyrosine kinase inhibitor, nintedanib, could synergistically fully block, but also reversed, retinal AVMs to avert retinal bleeding and anemia. Sirolimus plus nintedanib prevented vascular pathology in the oral mucosa, lungs, and liver of the BMP9/10ib mice, as well as significantly reduced gastrointestinal bleeding and anemia in inducible ALK1-deficient adult mice. Mechanistically, in vivo in BMP9/10ib mouse ECs, sirolimus and nintedanib blocked the overactivation of mTOR and VEGFR2, respectively. Furthermore, we found that sirolimus activated ALK2-mediated Smad1/5/8 signaling in primary ECs - including in HHT patient blood outgrowth ECs - and partially rescued Smad1/5/8 activity in vivo in BMP9/10ib mouse ECs. These data demonstrate that the combined correction of endothelial Smad1/5/8, mTOR, and VEGFR2 pathways opposes HHT pathogenesis. Repurposing of sirolimus plus nintedanib might provide therapeutic benefit in patients with HHT.


Assuntos
Células Endoteliais , Indóis/farmacologia , Sirolimo/farmacologia , Proteína Smad1 , Proteína Smad5 , Proteína Smad8 , Serina-Treonina Quinases TOR , Telangiectasia Hemorrágica Hereditária , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Receptores de Activinas Tipo II/genética , Receptores de Activinas Tipo II/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fator 2 de Diferenciação de Crescimento/genética , Fator 2 de Diferenciação de Crescimento/metabolismo , Camundongos , Camundongos Knockout , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteína Smad1/genética , Proteína Smad1/metabolismo , Proteína Smad5/genética , Proteína Smad5/metabolismo , Proteína Smad8/genética , Proteína Smad8/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Telangiectasia Hemorrágica Hereditária/tratamento farmacológico , Telangiectasia Hemorrágica Hereditária/genética , Telangiectasia Hemorrágica Hereditária/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
18.
J Dent Res ; 99(1): 107-114, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31718465

RESUMO

Hyperosmolar sweet foods onto exposed tooth dentin evoke sudden and intense dental pain, called dentin hypersensitivity. However, it remains unclear how hyperosmolar stimuli excite dental primary afferent (DPA) neurons and thereby lead to dentin hypersensitivity. This study elucidated whether TRPM8, which is well known as a cold temperature- or menthol-activated receptor, additionally mediates nociception in response to hyperosmolar stimuli in adult mouse DPA neurons, which are identified by a fluorescent retrograde tracer: DiI. Single-cell reverse transcription polymerase chain reaction revealed that TRPM8 was expressed in subsets of DPA neurons and that TRPM8 was highly colocalized with TRPV1 and Piezo2. Immunohistochemical analysis also confirmed TRPM8 expression in DPA neurons. By using Fura-2-based calcium imaging, application of hyperosmolar sucrose solutions elicited calcium transients in subsets of the trigeminal ganglion neurons, which was significantly abolished by a selective TRPM8 antagonist: N-(3-Aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)benzamide (AMTB) hydrochloride. When we further examined changes of c-fos expression (a neuronal activation marker) in the spinal trigeminal nucleus after hyperosmolar stimulation onto exposed tooth dentin, c-fos mRNA and protein expression were increased and were also significantly reduced by AMTB, especially in the spinal trigeminal interpolaris-caudalis transition zone (Vi/Vc). Taken together, our results provide strong evidence that TRPM8 expressed in DPA neurons might mediate dental pain as a hyperosmosensor in adult mice.


Assuntos
Nociceptividade , Canais de Cátion TRPM , Animais , Canais Iônicos , Camundongos , Neurônios , Neurônios Aferentes , Proteínas Proto-Oncogênicas c-fos , Canais de Cátion TRPM/fisiologia , Gânglio Trigeminal
20.
Int J Mol Sci ; 20(21)2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31731545

RESUMO

Arteriovenous malformations (AVMs) are abnormal connections of vessels that shunt blood directly from arteries into veins. Rupture of brain AVMs (bAVMs) can cause life-threatening intracranial bleeding. Even though the majority of bAVM cases are sporadic without a family history, some cases are familial. Most of the familial cases of bAVMs are associated with a genetic disorder called hereditary hemorrhagic telangiectasia (HHT). The mechanism of bAVM formation is not fully understood. The most important advances in bAVM basic science research is the identification of somatic mutations of genes in RAS-MAPK pathways. However, the mechanisms by which mutations of these genes lead to AVM formation are largely unknown. In this review, we summarized the latest advance in bAVM studies and discussed some pathways that play important roles in bAVM pathogenesis. We also discussed the therapeutic implications of these pathways.


Assuntos
Malformações Arteriovenosas Intracranianas , Hemorragias Intracranianas , Sistema de Sinalização das MAP Quinases/genética , Mutação , Telangiectasia Hemorrágica Hereditária , Feminino , Humanos , Malformações Arteriovenosas Intracranianas/genética , Malformações Arteriovenosas Intracranianas/metabolismo , Malformações Arteriovenosas Intracranianas/patologia , Malformações Arteriovenosas Intracranianas/terapia , Hemorragias Intracranianas/genética , Hemorragias Intracranianas/metabolismo , Hemorragias Intracranianas/patologia , Hemorragias Intracranianas/terapia , Masculino , Telangiectasia Hemorrágica Hereditária/genética , Telangiectasia Hemorrágica Hereditária/metabolismo , Telangiectasia Hemorrágica Hereditária/patologia , Telangiectasia Hemorrágica Hereditária/terapia
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