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1.
EMBO J ; 42(18): e113256, 2023 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-37439264

RESUMO

Replication of the mitochondrial genome and expression of the genes it encodes both depend on a sufficient supply of nucleotides to mitochondria. Accordingly, dysregulated nucleotide metabolism not only destabilises the mitochondrial genome, but also affects its transcription. Here, we report that a mitochondrial nucleoside diphosphate kinase, NME6, supplies mitochondria with pyrimidine ribonucleotides that are necessary for the transcription of mitochondrial genes. Loss of NME6 function leads to the depletion of mitochondrial transcripts, as well as destabilisation of the electron transport chain and impaired oxidative phosphorylation. These deficiencies are rescued by an exogenous supply of pyrimidine ribonucleosides. Moreover, NME6 is required for the maintenance of mitochondrial DNA when the access to cytosolic pyrimidine deoxyribonucleotides is limited. Our results therefore reveal an important role for ribonucleotide salvage in mitochondrial gene expression.


Assuntos
Genes Mitocondriais , Pirimidinas , Pirimidinas/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Nucleotídeos , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Ribonucleotídeos/genética
2.
EMBO J ; 38(10)2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30979779

RESUMO

TP53INP2 positively regulates autophagy by binding to Atg8 proteins. Here, we uncover a novel role of TP53INP2 in death-receptor signaling. TP53INP2 sensitizes cells to apoptosis induced by death receptor ligands. In keeping with this, TP53INP2 deficiency in cultured cells or mouse livers protects against death receptor-induced apoptosis. TP53INP2 binds caspase-8 and the ubiquitin ligase TRAF6, thereby promoting the ubiquitination and activation of caspase-8 by TRAF6. We have defined a TRAF6-interacting motif (TIM) and a ubiquitin-interacting motif in TP53INP2, enabling it to function as a scaffold bridging already ubiquitinated caspase-8 to TRAF6 for further polyubiquitination of caspase-8. Mutations of key TIM residues in TP53INP2 abrogate its interaction with TRAF6 and caspase-8, and subsequently reduce levels of death receptor-induced apoptosis. A screen of cancer cell lines showed that those with higher protein levels of TP53INP2 are more prone to TRAIL-induced apoptosis, making TP53INP2 a potential predictive marker of cancer cell responsiveness to TRAIL treatment. These findings uncover a novel mechanism for the regulation of caspase-8 ubiquitination and reveal TP53INP2 as an important regulator of the death receptor pathway.


Assuntos
Autofagia/genética , Proteínas Nucleares/fisiologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Autofagia/efeitos dos fármacos , Caspase 8/metabolismo , Células Cultivadas , Células HEK293 , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Células MCF-7 , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Nucleares/genética , Receptores de Morte Celular/genética , Receptores de Morte Celular/metabolismo , Transdução de Sinais/genética , Fator 6 Associado a Receptor de TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/uso terapêutico , Ubiquitina/metabolismo , Ubiquitinação/efeitos dos fármacos , Ubiquitinação/genética
3.
Clin J Sport Med ; 33(5): 475-482, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-36853900

RESUMO

OBJECTIVE: To describe injury mechanisms and magnetic resonance imaging (MRI) findings in acute rectus femoris (RF) injuries of soccer players using a systematic video analysis. DESIGN: Descriptive case series study of consecutive RF injuries from November 2017 to July 2022. SETTING: Two specialized sports medicine hospitals. PARTICIPANTS: Professional male soccer players aged between 18 and 40 years, referred for injury assessment within 7 days after a RF injury, with an available video footage of the injury and a positive finding on an MRI. INDEPENDENT VARIABLES: Rectus femoris injury mechanisms (specific scoring based on standardized models) in relation to RF muscle injury MRI findings. MAIN OUTCOME MEASURES: Rectus femoris injury mechanism (playing situation, player/opponent behavior, movement, and biomechanics), location of injury in MRI. RESULTS: Twenty videos of RF injuries in 19 professional male soccer players were analyzed. Three different injury mechanisms were seen: kicking (80%), sprinting (10%), and change of direction (10%). Isolated single-tendon injuries were found in 60% of the injuries. Of the kicking injuries, 62.5% included complete tendon ruptures, whereas both running injuries and none of the change of direction injuries were complete ruptures. The direct tendon was involved in 33% of the isolated injuries, and the common tendon was affected in all combined injuries. CONCLUSIONS: Rectus femoris injuries typically occur during kicking among football players. Most of the RF injuries involve a complete rupture of at least one tendon. Kicking injuries can also affect the supporting leg, and sprinting can cause a complete tendon rupture, whereas change of direction seems not to lead to complete ruptures.


Assuntos
Traumatismos em Atletas , Futebol , Traumatismos dos Tendões , Humanos , Masculino , Recém-Nascido , Futebol/lesões , Músculo Quadríceps/diagnóstico por imagem , Músculo Quadríceps/lesões , Traumatismos em Atletas/diagnóstico por imagem , Traumatismos em Atletas/etiologia , Ruptura/complicações , Imageamento por Ressonância Magnética
4.
Clin J Sport Med ; 33(3): 217-224, 2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-36730099

RESUMO

OBJECTIVE: To describe the injury mechanisms and magnetic resonance imaging (MRI) findings in acute hamstring injuries of male soccer players using a systematic video analysis. DESIGN: Descriptive case series study of consecutive acute hamstring injuries from September 2017 to January 2022. SETTING: Two specialized sports medicine hospitals. PARTICIPANTS: Professional male soccer players aged between 18 and 40 years, referred for injury assessment within 7 days after an acute hamstring injury, with an available video footage of the injury and positive finding on MRI. INDEPENDENT VARIABLES: Hamstring injury mechanisms (specific scoring based on standardized models) in relation to hamstring muscle injury MRI findings. MAIN OUTCOME MEASURES: Hamstring injury mechanism (playing situation, player/opponent behavior, movement, and biomechanical body positions) and MRI injury location. RESULTS: Fourteen videos of acute hamstring injuries in 13 professional male soccer players were analyzed. Three different injury mechanisms were seen: mixed-type (both sprint-related and stretch-related, 43%), stretch-type (36%), and sprint-type (21%). Most common actions during injury moments were change of direction (29%), kicking (29%), and running (21%). Most injuries occurred at high or very high horizontal speed (71%) and affected isolated proximal biceps femoris (BF) (36%). Most frequent body positions at defined injury moments were neutral trunk (43%), hip flexion 45-90 degrees (57%), and knee flexion <45 degrees (93%). Magnetic resonance imaging findings showed that 79% were isolated single-tendon injuries. CONCLUSIONS: According to a video analysis, most hamstring injuries in soccer occur during high-speed movements. Physicians should suspect proximal and isolated single-tendon-most often BF-hamstring injury, if represented injury mechanisms are seen during game play. In addition to sprinting and stretching, also mixed-type injury mechanisms occur.


Assuntos
Traumatismos em Atletas , Músculos Isquiossurais , Traumatismos da Perna , Futebol , Lesões dos Tecidos Moles , Traumatismos dos Tendões , Humanos , Masculino , Recém-Nascido , Futebol/lesões , Músculos Isquiossurais/lesões , Traumatismos em Atletas/diagnóstico por imagem , Imageamento por Ressonância Magnética
5.
Aten Primaria ; 55(11): 102694, 2023 Jul 21.
Artigo em Espanhol | MEDLINE | ID: mdl-37481824

RESUMO

The Research Network on Preventive Activities and Health Promotion (redIAPP), a reference network and promoter of primary care research was created in 2003 thanks to the program Thematic Networks for Cooperative Research in Health (RETICS) of the Instituto de Salud Carlos III (ISCIII). Its creation has meant a radical change in the situation of research in primary care. Throughout its 19 years (2003-2021), different research groups and autonomous communities have participated, and different lines of research have been developed with numerous projects and publications. Despite the difficulties suffered, it has created a collaborative research experience between different autonomous communities with great vitality and with important results for primary care. The redIAPP, therefore, has been a great reference for research in primary care and for the deepening of its area of knowledge. Several lines of improvement are suggested for the future of primary care research.

6.
J Clin Pediatr Dent ; 47(4): 116-120, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37408355

RESUMO

This study aimed to estimate the cumulative incidence and the progression of erosive tooth wear (ETW) according to tooth type over a follow-up period of 18 months in adolescents living in Mexico City. We examined 10,776 teeth from 424 participants and used the Basic Erosive Wear Examination index (BEWE) to assess ETW. Our results showed that the overall cumulative incidence rate of ETW was 5.9% (587 from 9933 teeth), and the progression of ETW was 10% (85 from 843 teeth). Notably, the cumulative incidence of initial texture loss (BEWE = 1) was 29.1% for maxillary central incisors, and 30.4% of mandibular first molars progressed to loss of hard tissues (BEWE ≥2).


Assuntos
Erosão Dentária , Desgaste dos Dentes , Adolescente , Humanos , Criança , Erosão Dentária/epidemiologia , Incidência , México/epidemiologia , Prevalência , Desgaste dos Dentes/epidemiologia
7.
Eur J Neurosci ; 55(2): 377-387, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34963191

RESUMO

Animals can cope with isolated stressful situations without enduring long-term consequences. However, when exposure to stressors becomes recurrent, behavioural symptoms of anxiety and depression can emerge. Yet, the neuronal mechanisms governing responsivity to isolated stressor remain elusive. Here, we investigate synaptic adaptations following mild stress in the lateral habenula (LHb), a structure engaged in aversion encoding and dysfunctional in depression. We describe that neuronal depolarization in the LHb drives long-term depression of inhibitory, but not excitatory, synaptic transmission (GABA LTD). This plasticity requires nitric oxide and presynaptic GABAB receptors, leading to a decrease in probability of GABA release. Mild stressors such as brief social isolation, or exposure to novel environment in the company of littermates, do not alter GABA LTD. In contrast, GABA LTD is absent after mice experience a novel environment in social isolation. Altogether, our results suggest that LHb GABAergic plasticity is sensitive to stress accumulation, which could represent a threshold mechanism for long-term alterations of LHb function.


Assuntos
Habenula , Animais , Habenula/fisiologia , Camundongos , Plasticidade Neuronal/fisiologia , Receptores de GABA-B/metabolismo , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico
8.
Retina ; 42(3): 465-475, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-34914345

RESUMO

PURPOSE: To describe clinical and ophthalmologic features and outcomes of patients with coronavirus disease-19 with retinal vascular occlusions. METHODS: Retrospective multicenter case series and PubMed review of cases reported from March 2020 to September 2021. Outcome measures are as follows: type of occlusion, treatments, best-corrected visual acuity, and central macular thickness on optical coherence tomography. RESULTS: Thirty-nine patients were identified. Fifteen patients with a median age of 39 (30-67) years were included in the multicenter study. Vascular occlusions included central retinal vein occlusion (12 eyes), branch retinal vein occlusion (4 eyes), and central retinal artery occlusion (2 eyes). Three cases were bilateral. Baseline best-corrected visual acuity was 20/45 (no light perception-20/20). Baseline central macular thickness was 348.64 (±83) µm. Nine eyes received anti-vascular endothelial growth factor agents, dexamethasone intravitreal implant, or both. Final best-corrected visual acuity was 20/25 (no light perception-20/20), and central macular thickness was 273.7 ± 68 µm (follow-up of 19.6 ± 6 weeks). Among the 24 cases from the literature review, retinal vein occlusion was the predominant lesion. Clinical characteristics and outcomes were similar to those found in our series. CONCLUSION: Coronavirus disease-19-associated retinal vascular occlusions tend to occur in individuals younger than 60 years. Retinal vein occlusion is the most frequent occlusive event, and outcomes are favorable in most cases.


Assuntos
COVID-19/diagnóstico , Infecções Oculares Virais/diagnóstico , Oclusão da Veia Retiniana/diagnóstico , SARS-CoV-2/isolamento & purificação , Adulto , Idoso , Inibidores da Angiogênese/uso terapêutico , COVID-19/virologia , Teste de Ácido Nucleico para COVID-19 , Dexametasona/uso terapêutico , Implantes de Medicamento , Infecções Oculares Virais/tratamento farmacológico , Infecções Oculares Virais/virologia , Feminino , Angiofluoresceinografia , Glucocorticoides/uso terapêutico , Humanos , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Oclusão da Veia Retiniana/tratamento farmacológico , Oclusão da Veia Retiniana/virologia , Estudos Retrospectivos , SARS-CoV-2/genética , Tomografia de Coerência Óptica , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Acuidade Visual/fisiologia , Tratamento Farmacológico da COVID-19
9.
Salud Publica Mex ; 64(4, jul-ago): 367-376, 2022 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-36130380

RESUMO

OBJECTIVE: To determine the prevalence and factors related to depressive symptoms in older Mexican adults in urban and rural areas. MATERIALS AND METHODS: Cross-sectional study. We examined older adults from a sample taken from the Mexican Health and Aging Study (MHAS-2018). 14 230 older Mexicans were screened for self-reported depressive symptoms. RESULTS: The prevalence of depressive symptoms was 29.8% (33.4% rural vs. 28.9% urban). In the rural and urban population, the probability of a high prevalence of depressive symptoms was higher in older adults with multimorbidity ≥3, severe pain, and fair/poor SRH. Only in the urban population the prevalence of depressive symptoms increased with lower schooling. CONCLUSION: Identification of the factors related to depressive symptoms may help healthcare professionals provide better treatment for specific groups in the population.


Assuntos
Depressão , População Rural , Idoso , Envelhecimento , Estudos Transversais , Depressão/epidemiologia , Humanos , Prevalência
10.
J Clin Pediatr Dent ; 46(5): 31-37, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36624911

RESUMO

BACKGROUND: Erosive tooth wear (ETW) and dental caries have common etiological factors, such as unhealthy eating habits, and reduced salivary flow rate. AIM: To analyze the association between caries experience (CE) and ETW in adolescents 13-14 years. STUDY DESIGNS: Ninety-seven cases with distinctive ETW were identified and then sex-matched with a group of 97 controls and a group of 97 cases with initial ETW. The variables included were CE, presence of debris/dental calculus, salivary parameters, food and beverage consumption, chewable vitamin C tablet consumption, gastroesophageal reflux, frequent vomiting, and tooth brushing. Multinomial logistic regression models were adjusted. RESULTS: An association was found between cases with a distinctive ETW defect and CE (OR = 1.09 (95% CI: 1.01-1.17); p = 0.020), sweet carbonated drinks consumption (OR = 1.16 (95% CI: 1.03-1.31); p = 0.012), and frequent vomiting (OR = 3.19 (95% CI: 1.02-10.01); p = 0.047). CONCLUSIONS: The preventive management of both ETW and dental caries should aim to reduce exposure to foods and beverages with high acid and sugar content. Given the association between ETW and acid attack by gastric juice, this would be an indicator of the need for referral to a specialist for treatment.


Assuntos
Cárie Dentária , Erosão Dentária , Desgaste dos Dentes , Humanos , Adolescente , Erosão Dentária/epidemiologia , Erosão Dentária/etiologia , Cárie Dentária/etiologia , Cárie Dentária/complicações , Estudos de Casos e Controles , Suscetibilidade à Cárie Dentária , Prevalência , Desgaste dos Dentes/complicações , Vômito/complicações
11.
BMC Public Health ; 21(1): 2208, 2021 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-34863136

RESUMO

BACKGROUND: This study aimed to evaluate the effectiveness of a) a Multiple Health Behaviour Change (MHBC) intervention on reducing smoking, increasing physical activity and adherence to a Mediterranean dietary pattern in people aged 45-75 years compared to usual care; and b) an implementation strategy. METHODS: A cluster randomised effectiveness-implementation hybrid trial-type 2 with two parallel groups was conducted in 25 Spanish Primary Health Care (PHC) centres (3062 participants): 12 centres (1481 participants) were randomised to the intervention and 13 (1581 participants) to the control group (usual care). The intervention was based on the Transtheoretical Model and focused on all target behaviours using individual, group and community approaches. PHC professionals made it during routine care. The implementation strategy was based on the Consolidated Framework for Implementation Research (CFIR). Data were analysed using generalised linear mixed models, accounting for clustering. A mixed-methods data analysis was used to evaluate implementation outcomes (adoption, acceptability, appropriateness, feasibility and fidelity) and determinants of implementation success. RESULTS: 14.5% of participants in the intervention group and 8.9% in the usual care group showed a positive change in two or all the target behaviours. Intervention was more effective in promoting dietary behaviour change (31.9% vs 21.4%). The overall adoption rate by professionals was 48.7%. Early and final appropriateness were perceived by professionals as moderate. Early acceptability was high, whereas final acceptability was only moderate. Initial and final acceptability as perceived by the participants was high, and appropriateness moderate. Consent and recruitment rates were 82.0% and 65.5%, respectively, intervention uptake was 89.5% and completion rate 74.7%. The global value of the percentage of approaches with fidelity ≥50% was 16.7%. Eight CFIR constructs distinguished between high and low implementation, five corresponding to the Inner Setting domain. CONCLUSIONS: Compared to usual care, the EIRA intervention was more effective in promoting MHBC and dietary behaviour change. Implementation outcomes were satisfactory except for the fidelity to the planned intervention, which was low. The organisational and structural contexts of the centres proved to be significant determinants of implementation effectiveness. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03136211 . Registered 2 May 2017, "retrospectively registered".


Assuntos
Dieta Saudável , Abandono do Hábito de Fumar , Adulto , Idoso , Exercício Físico , Comportamentos Relacionados com a Saúde , Promoção da Saúde/métodos , Humanos , Pessoa de Meia-Idade , Atenção Primária à Saúde
12.
Br J Neurosurg ; : 1-7, 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34615413

RESUMO

BACKGROUND: The H3K27M-mutant spinal cord gliomas are very aggressive with a dismal prognosis, very few cases have been reported in the thoracic spinal cord and conus medullaris, and it is extremely rare with morphological features of pilocytic astrocytoma. CASE PRESENTATION: A 20-year-old man presented with thoracolumbar pain, progressive paraparesis, and urinary incontinence. Magnetic resonance imaging revealed an intramedullary solid-cystic lesion from D9 to conus medullaris. Subtotal resection was performed, restricted by the indistinct margins and the decline of the motor evoked potential during the surgery. Pathologic findings revealed a pilocytic astrocytoma with anaplastic features. However, a further assessment determined a diffuse midline glioma H3K27M-mutant, and adjuvant chemoradiotherapy was administered. After seven months of progression-free survival, the paraparesis worsened; at twelve months of follow-up, the patient developed paraplegia, and at 24 months the patient remains alive without any neurologic functions distal to the tumor and he is still under adjuvant treatment. CONCLUSIONS: The H3K27M-mutant spinal cord glioma is a very infrequent tumor with a wide variety of histological presentations even as indolent as pilocytic astrocytoma, which should be considered in spinal cord tumors, especially if there are clinical, histological, or radiological data that suggest aggressiveness. On the other hand, the fast progression led to the loss of complete neurological function distal to the tumor, in spinal tumors could explain a not so poor prognosis as it is in functionally and vital structures.

13.
Trop Anim Health Prod ; 53(3): 345, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34091738

RESUMO

We evaluated if alternative treatments achieve at least similar results as traditional long treatments with intravaginal sponges (IVS) in three experiments considering (1) the use of 6-day treatments associated or not with the administration of PGF2alpha at IVS insertion; (2) a reduction of 50% MAP content in short-term or traditional treatments, with or without change of the IVS 6 days after its insertion; and (3) the substitution of IVS for long-time acting injected progesterone associated with the administration of a PGF2alpha. More ewes came into estrus with long than short IVS treatments, independently of the MAP IVS content. Fewer ewes came into estrus if the IVS containing 30 mg was replaced 6 days after its insertion. The length of the treatment did not affect the conception rate, but the pregnancy rate was greater in 12 than 6 days treatments. The administration of long-acting progesterone did not prevent the lower conception rate associated with the use of PGF2alpha and was less effective to synchronize estrus, but the conception rate did not differ from that of 12d IVS treatments. Overall, MAP content could be decreased without affecting the estrous rate; thereafter, the MAP IVS content should be decreased in the commercial devices. Although pregnancy rate was lower using long-acting injected progesterone than with IVS, as the conception rate did not differ, it is interesting to study deeper the use of this treatment, especially if preparations of progesterone with a longer half-life are developed. However considering all the results, the traditional long IVS treatment still provided the best result.


Assuntos
Medroxiprogesterona , Progesterona , Administração Intravaginal , Animais , Dinoprosta , Estro , Sincronização do Estro , Feminino , Inseminação Artificial/veterinária , Gravidez , Ovinos
14.
BMC Med Educ ; 20(1): 41, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32041592

RESUMO

BACKGROUND: In recent years, Spanish medical schools (MSs) have incorporated training in communication skills (CS), but how this training is being carried out has not yet been evaluated. OBJECTIVE: To identify the barriers to the introduction and development of CS teaching in Spanish MSs. METHODS: In a previous study, 34 MSs (83% of all MSs in Spain) were invited to participate in a study that explored the factual aspects of teaching CS in these schools. The person responsible for teaching CS at each school was contacted again for this study and asked to respond to a single open-ended question. Two researchers independently conducted a thematic analysis of the responses. RESULTS: We received responses from 30 MSs (85.7% of those contacted and 73% of all MSs in Spain). Five main thematic areas were identified, each with different sub-areas: negative attitudes of teachers and academic leaders; organisation, structure and presence of CS training in the curriculum; negative attitudes of students; a lack of trained teachers; and problems linked to teaching methods and necessary educational logistics. CONCLUSIONS: The identified barriers and problems indicate that there are areas for improvement in teaching CS in most Spanish MSs. There seems to be a vicious circle based on the dynamic relationship and interdependence of all these problems that should be faced with different strategies and that requires a significant cultural shift as well as decisive institutional support at the local and national levels. The incorporation of CS training into MS curricula represents a major challenge that must be addressed for students to learn CS more effectively and avoid negative attitudes towards learning CS.


Assuntos
Comunicação , Currículo , Educação de Graduação em Medicina , Atitude do Pessoal de Saúde , Docentes/psicologia , Humanos , Pesquisa Qualitativa , Espanha , Estudantes de Medicina/psicologia , Inquéritos e Questionários
15.
Eur J Neurosci ; 50(3): 2124-2133, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30118546

RESUMO

Lateral habenula (LHb) hyperactivity plays a pivotal role in the emergence of negative emotional states, including those occurring during withdrawal from addictive drugs. We have previously implicated cocaine-driven adaptations at synapses from the entopeduncular nucleus (EPN) to the LHb in this process. Specifically, ionotropic GABAA receptor (R)-mediated neurotransmission at EPN-to-LHb synapses is reduced during cocaine withdrawal, due to impaired vesicle filling. Recent studies have shown that metabotropic GABAB R signaling also controls LHb activity, although its role at EPN-to-LHb synapses during drug withdrawal is unknown. Here, we predicted that cocaine treatment would reduce GABAB R-mediated neurotransmission at EPN-to-LHb synapses. We chronically treated mice with saline or cocaine, prepared brain slices after two days of withdrawal and performed voltage-clamp recordings from LHb neurons whilst optogenetically stimulating EPN terminals. Compared with controls, mice in cocaine withdrawal exhibited reduced GABAA R-mediated input to LHb neurons, and a reduced occurrence of GABAB R-signaling at EPN-to-LHb synapses. We then assessed the underlying mechanism of this decrease. Application of GABAB R agonist baclofen evoked similar postsynaptic responses in EPN-innervated LHb neurons in saline- and cocaine-treated mice. Release probability at EPN-to-LHb GABAergic synapses was also comparable between groups. However, incubating brain slices in glutamine to facilitate GABA vesicle filling, normalized GABAB R-currents at EPN-to-LHb synapses in cocaine-treated mice. Overall, we show that during cocaine withdrawal, together with reduced GABAA R transmission, also GABAB R-mediated inhibitory signaling is diminished at EPN-to-LHb synapses, likely via the same presynaptic deficit. In concert, these alterations are predicted to contribute to the emergence of drug withdrawal symptoms, facilitating drug relapse.


Assuntos
Cocaína/farmacologia , Receptores de GABA-B/metabolismo , Síndrome de Abstinência a Substâncias/fisiopatologia , Animais , Comportamento Animal/fisiologia , Núcleo Entopeduncular/efeitos dos fármacos , Habenula/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Receptores de GABA-B/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
16.
J Org Chem ; 84(21): 13764-13779, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31559826

RESUMO

We have developed and rationalized a biomimetic transformation mimicking halimane synthases based on a Lewis acid-catalyzed cascade of cyclizations and rearrangements of epoxypolyprenes. Two rings, three stereogenic centers, and a new double bond were generated in a single chemical operation. Based on this cascade transformation, we achieved a unified strategy toward the stereoselective total syntheses of halimene-type terpenoids and analogues as a proof-of-concept study. This method has been applied to the rapid synthesis of diterpene isotuberculosinol, a virulence factor of Mycobacterium tuberculosis as a representative example.


Assuntos
Diterpenos/metabolismo , Compostos de Epóxi/química , Ligases/metabolismo , Catálise , Ciclização , Compostos de Epóxi/síntese química
17.
J Nat Prod ; 82(1): 9-15, 2019 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-30601659

RESUMO

The first total synthesis of a natural diterpene valparane, (-)-valpara-2,15-diene (1), has been achieved from all -trans-geranylgeraniol (9), a natural renewable compound. The key steps involve a Ti(III)-mediated radical cyclization of the chiral monoepoxypolyene (14 R,15 R)-14,15-epoxy,16- tert-butyldimethylsilyloxygeranyllinalyl acetate (8) to give the 6,6,7-tricyclic intermediate 7 with stereocontrolled formation of six stereocenters; a stereo- and regio-directed contraction of the A ring in 7 to produce a cyclopentane ring; and the ready generation of the target isopropenyl group. This research provides access to structurally related natural products such as the sesquiterpene (+)-isodaucene (3), the synthesis of which is also reported herein.


Assuntos
Diterpenos/síntese química , Sesquiterpenos/síntese química , Ciclização , Diterpenos/química , Estereoisomerismo
18.
J Craniofac Surg ; 30(5): 1539-1543, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31299762

RESUMO

OBJECTIVE: Evaluate the electromyographic changes in the Masseter (MM) and Temporalis (TM) muscles during voluntary clenching of the teeth both before and after orthognathic surgery in patients aged 18 years and older and diagnosed with mandibular prognathism. METHODS: Eleven patients with prognathism were included in the study, in all of whom the initial phase of orthodontic treatment had been completed. The orthognathic procedure to reduce prognathism comprised intraoral oblique sliding (or subsigmoid) osteotomy, after which intermaxillary fixation with ligaments in the maxilla and mandible was undertaken in all patients for 6 weeks post-surgery. Electromyographic activity was recorded during the baseline maximum voluntary contraction of the teeth, with the same measurement taken 3 and then 6 months after orthognathic surgery. RESULTS: Significant differences were found in the mean amplitude (17.0 vs 14.7, P = 0.020) and peak-to-peak amplitude (left [761.6 vs 457.0, P = 0.003] and right [676.9 vs 357.4, P = 0.007]) for the MM between the baseline score and 6 months after surgery. Likewise, significant differences were found in the mean amplitude (18.2 vs 25.6, P = 0.009) and peak-to-peak amplitude (left [856.4 vs 1594.2, P = 0.004] and right [804.4 vs 1813.4, P = 0.004]) for the TM between the baseline score and that taken 6 months post-surgery. Only 18.2% (2/11) presented orthodontic appliances problem in the 3 months post-surgery. CONCLUSION: Electromyographic activity was restored 6 months after the orthognathic surgery. From a clinical perspective, the results obtained confirm that orthognathic surgery has not only an esthetic but also a functional objective in terms of achieving equilibrium and occlusal harmony.


Assuntos
Má Oclusão Classe III de Angle/cirurgia , Mandíbula/cirurgia , Músculo Masseter/diagnóstico por imagem , Cirurgia Ortognática , Procedimentos Cirúrgicos Ortognáticos , Músculo Temporal/diagnóstico por imagem , Eletromiografia , Estética Dentária , Feminino , Humanos , Masculino , Maxila/cirurgia , Prognatismo/cirurgia
19.
J Clin Pediatr Dent ; 43(5): 324-330, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31560591

RESUMO

Objective: To evaluate the impact of Molar Incisor Hypomineralization (MIH) in the OHRQoL in a group of 8 to 10 year-old Mexican schoolchildren. Study design: A cross-sectional study of 411 8 to 10 year-old schoolchildren selected from public schools in Naucalpan, in the State of Mexico. The presence and severity of MIH was evaluated using the European Academy of Pediatric Dentistry (EAPD) criteria. The OHRQoL was evaluated using the Child Perceptions Questionnaire (CPQ). Poisson regression models were performed for the analysis. Results: The prevalence of MIH in the permanent dentition was 40.4%. High scores were found in the four domains of the CPQ for children with MIH compared to children without MIH (p<0.001). In the Poisson model, a greater negative impact in the four CPQ domains was found for schoolchildren with MIH: oral symptoms [RR=1.75 (CI95% 1.63-1.78)]; functional limitations [RR=2.17 (CI95% 2.01-2.35)]; emotional wellbeing [RR=1.94 (CI95% 1.80-2.08)]; and, social well-being [RR=2.62 (CI95% 2.49-2.77)]. A greater impact on the four CPQ domains were found for children with moderate/severe MIH compared to children without MIH (p<0.001). Conclusion: Children with moderate/severe MIH experienced a greater negative impact on their OHRQoL compared to children without MIH.


Assuntos
Hipoplasia do Esmalte Dentário , Qualidade de Vida , Criança , Estudos Transversais , Humanos , Incisivo , México , Dente Molar , Saúde Bucal , Prevalência
20.
Sensors (Basel) ; 18(12)2018 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-30544879

RESUMO

Schools are amongst the most densely occupied indoor areas and at the same time children and young adults are the most vulnerable group with respect to adverse health effects as a result of poor environmental conditions. Health, performance and well-being of pupils crucially depend on indoor environmental quality (IEQ) of which air quality and thermal comfort are central pillars. This makes the monitoring and control of environmental parameters in classes important. At the same time most school buildings do neither feature automated, intelligent heating, ventilation, and air conditioning (HVAC) systems nor suitable IEQ monitoring systems. In this contribution, we therefore investigate the capabilities of a novel wireless gas sensor network to determine carbon dioxide concentrations, along with temperature and humidity. The use of a photoacoustic detector enables the construction of long-term stable, miniaturized, LED-based non-dispersive infrared absorption spectrometers without the use of a reference channel. The data of the sensor nodes is transmitted via a Z-Wave protocol to a central gateway, which in turn sends the data to a web-based platform for online analysis. The results show that it is difficult to maintain adequate IEQ levels in class rooms even when ventilating frequently and that individual monitoring and control of rooms is necessary to combine energy savings and good IEQ.


Assuntos
Poluição do Ar em Ambientes Fechados , Monitoramento Ambiental/instrumentação , Gases/isolamento & purificação , Tecnologia sem Fio/instrumentação , Criança , Gases/toxicidade , Humanos , Instituições Acadêmicas , Ventilação
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