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1.
Nature ; 590(7845): 256-261, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33568821

RESUMO

Accurate three-dimensional (3D) imaging is essential for machines to map and interact with the physical world1,2. Although numerous 3D imaging technologies exist, each addressing niche applications with varying degrees of success, none has achieved the breadth of applicability and impact that digital image sensors have in the two-dimensional imaging world3-10. A large-scale two-dimensional array of coherent detector pixels operating as a light detection and ranging system could serve as a universal 3D imaging platform. Such a system would offer high depth accuracy and immunity to interference from sunlight, as well as the ability to measure the velocity of moving objects directly11. Owing to difficulties in providing electrical and photonic connections to every pixel, previous systems have been restricted to fewer than 20 pixels12-15. Here we demonstrate the operation of a large-scale coherent detector array, consisting of 512 pixels, in a 3D imaging system. Leveraging recent advances in the monolithic integration of photonic and electronic circuits, a dense array of optical heterodyne detectors is combined with an integrated electronic readout architecture, enabling straightforward scaling to arbitrarily large arrays. Two-axis solid-state beam steering eliminates any trade-off between field of view and range. Operating at the quantum noise limit16,17, our system achieves an accuracy of 3.1 millimetres at a distance of 75 metres when using only 4 milliwatts of light, an order of magnitude more accurate than existing solid-state systems at such ranges. Future reductions of pixel size using state-of-the-art components could yield resolutions in excess of 20 megapixels for arrays the size of a consumer camera sensor. This result paves the way for the development and proliferation of low-cost, compact and high-performance 3D imaging cameras that could be used in applications from robotics and autonomous navigation to augmented reality and healthcare.

2.
Subst Use Misuse ; 59(5): 643-650, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38115623

RESUMO

Background: As of May 2023, 23 states and Washington, DC have legalized the sale of cannabis for adults aged 21+, and 38 states, three territories, and D.C. have legalized medical cannabis. Exposure to cannabis retailers could increase adolescent cannabis use. Few studies have examined the impact of residential proximity to cannabis retailers on adolescent cannabis use, and previous findings are inconsistent. Methods: This study examined associations between proximity to cannabis retailers and past 30-day cannabis use. Data were from Project Cal Teens, a statewide survey of California adolescents regarding cannabis-related opinions/behaviors (N = 1406, mean age = 15.5 years, 48% female, 38% Hispanic/Latinx, 33% White, 15% Asian/Pacific Islander, 10% Black/African American, 5% Other/Multiracial). Participants were recruited via schools/social media in 2018-2020. Results: For every additional 5 driving miles to the nearest cannabis retailer, the risk of past 30-day cannabis use was reduced by 3.6% [IRR: 0.964; 95% CI: 0.935-0.994]. For every additional 5 miles from a licensed retailer, the risk of past 30-day cannabis use was reduced by 4.3% [IRR: 0.957; 95% CI: 0.926-0.989]. Interaction analyses revealed that among Hispanic/Latinx students, every 5 miles from a licensed retailer was associated with an 11.9% reduction in the risk of past 30-day cannabis use [IRR: 0.881; 95% CI: 0.820-0.945]. Conclusions: As the number of cannabis retailers in the U.S. increases with the continued legalization of adult cannabis use, research examining the effects of these policies on underage use is crucial. Interventions could include enforcement of zoning laws in/near residential areas to reduce accessibility of adolescents to cannabis retailers.


Assuntos
Cannabis , Fumar Maconha , Adolescente , Feminino , Humanos , Masculino , California/epidemiologia , Maconha Medicinal , Comércio , Fumar Maconha/epidemiologia , Características da Vizinhança
3.
Mol Ther ; 30(12): 3552-3569, 2022 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-35821634

RESUMO

Hepatic adeno-associated viral (AAV) gene transfer has the potential to cure the X-linked bleeding disorder hemophilia A. However, declining therapeutic coagulation factor VIII (FVIII) expression has plagued clinical trials. To assess the mechanistic underpinnings of this loss of FVIII expression, we developed a hemophilia A mouse model that shares key features observed in clinical trials. Following liver-directed AAV8 gene transfer in the presence of rapamycin, initial FVIII protein expression declines over time in the absence of antibody formation. Surprisingly, loss of FVIII protein production occurs despite persistence of transgene and mRNA, suggesting a translational shutdown rather than a loss of transduced hepatocytes. Some of the animals develop ER stress, which may be linked to hepatic inflammatory cytokine expression. FVIII protein expression is preserved by interleukin-15/interleukin-15 receptor blockade, which suppresses CD8+ T and natural killer cell responses. Interestingly, mice with initial FVIII levels >100% of normal had diminishing expression while still under immune suppression. Taken together, our findings of interanimal variability of the response, and the ability of the immune system to shut down transgene expression without utilizing cytolytic or antibody-mediated mechanisms, illustrate the challenges associated with FVIII gene transfer. Our protocols based upon cytokine blockade should help to maintain efficient FVIII expression.


Assuntos
Fator VIII , Interleucina-15 , Camundongos , Animais , Fator VIII/genética , Interleucina-15/genética , Sirolimo/farmacologia
4.
Prev Sci ; 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38038891

RESUMO

School-based surveys of adolescents can be logistically difficult and exclude students who do not attend school. Social media recruitment could be a promising strategy to recruit representative samples of adolescents. However, few studies have compared adolescent survey data collected via different methodologies. Our team was conducting a school-based survey when the COVID-19 pandemic closed all schools, necessitating a shift to online adolescent recruitment. To achieve our goal of obtaining a sample of high school students throughout California, we placed ads on social media. We compared the adolescents recruited in schools with those recruited on social media on demographic characteristics, mental health, and substance use. The sample of students recruited in schools (N = 737) and adolescents recruited via social media (N = 953) did not differ significantly on gender or substance use. However, compared with school-based recruitment, social media recruitment yielded a higher proportion of boys, whites, and Asians and a lower proportion of girls, Hispanic/Latinx adolescents, and those who spoke other languages at home. The social media sample had significantly higher levels of depression and anxiety symptoms and perceived stress than the school-based sample. Results indicate that social media can be useful for recruiting adolescents for survey research, especially if strategies such as Spanish-language social media ads are used to recruit and consent Hispanic/Latinx adolescents and those with non-English-speaking parents. This method could potentially replace school-based surveys in cases where schools are unwilling to participate in research, or it could be used to supplement school-based samples. Advantages and disadvantages of both methods are discussed.

5.
J Sleep Res ; 31(5): e13595, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35366024

RESUMO

Although adverse childhood experiences (traumatic events such as maltreatment and household dysfunction) are associated with increased risk for sleep difficulties among adults, the association between adverse childhood experiences and poor sleep health among young adult college populations is understudied. This study examined the adverse childhood experience-sleep health (self-reported sleep difficulty and diagnosis of insomnia or "other" sleep disorder) association among college students. Data are from the 2018/2019 American College Health Association-National College Health Assessment II (ACHA-NCHA-II) survey administered at public universities in California (n = 3606) and Texas (n = 407). Logistic regression models investigated the relative effect of adverse childhood experiences (maltreatment only, household dysfunction only, and maltreatment + household dysfunction) on three sleep health indicators. Approximately 40% of the sample reported adverse childhood experiences: 11% maltreatment only, 14% household dysfunction only, and 17% both. Compared with students with no adverse childhood experience history, students who reported only household dysfunction or only maltreatment had higher odds of experiencing sleep difficulty in the past year [adjusted odds ratios: 1.52-2.40; 95% confidence intervals: 1.26-2.97]. Additionally, students who reported maltreatment only had 2.47 times the odds of receiving an insomnia diagnosis [95% confidence interval: 1.52, 4.01]. However, students who reported both had higher odds of all three sleep health indicators: past-year sleep difficulty, insomnia diagnosis, and "other" sleep disorder diagnosis [adjusted odds ratios: 2.53-3.10; 95% confidence intervals: 1.51-4.66]. Sleep is an important facet of health among the college student population, and plays a crucial role in overall well-being, psychosocial processes, attention and academic success. Results point toward a need for sleep health programmes and interventions on college campuses focused on healthy sleep behaviours in order to mitigate further negative health effects.


Assuntos
Maus-Tratos Infantis , Distúrbios do Início e da Manutenção do Sono , Transtornos do Sono-Vigília , Criança , Maus-Tratos Infantis/psicologia , Humanos , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Transtornos do Sono-Vigília/epidemiologia , Estudantes/psicologia , Universidades , Adulto Jovem
6.
Atmos Environ (1994) ; 274: 1-13, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-37941818

RESUMO

Collection methods critical load values and total nitrogen budgets for high-elevation and fog-impacted sites requires reliable cloud and fog water deposition estimates. The cost and labor intensity of cloud/fog water sample collection have made it difficult to conduct long-term studies that would provide the data needed to develop accurate estimates. Current understanding of fog formation, transport, and the role of fog and cloud deposition in hydrogeological and biogeochemical cycles is incomplete due, in part, to lack of a concerted interdisciplinary approach to the problem. Historically, these obstacles have limited interest in and collection of cloud and fog water samples. In addition to measurements of cloud/fog chemical composition, documenting fog/cloud deposition fluxes of pollutant and nutrient species requires knowledge of cloud/fog physical properties, frequency and duration of fog/cloud interception with landscapes, properties of vegetation on those landscapes, and properties of the wind that drive droplet/vegetation interactions. Because drop deposition efficiency is dependent on drop size, it is also important to consider variations in fog/cloud drop composition with drop size as species enriched in larger/ smaller drops will experience enhanced/reduced deposition rates. This paper presents summary results from a small U.S. cloud water monitoring network that operated from the mid-nineties through 2011, as well as a brief qualitative review of other cloud and fog water studies conducted in the United States (including Puerto Rico), Europe, South America/Pacific, and Asia. Current collection methods are also reviewed. Recent scientific efforts by the National Atmospheric Deposition Program's (NADP) Total Deposition Science Committee and NADP's Critical Loads of Atmospheric Deposition Science Committee have identified occult (cloud/fog) deposition as a "need" in developing critical loads for ecosystems that experience.

7.
Subst Use Misuse ; 57(3): 373-379, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34903134

RESUMO

PURPOSE: Cannabis use among adolescents may have detrimental effects and use among this age group is increasing. It is important to understand how expansion of laws permitting cannabis sales may impact adolescent use. Much of the current research has explored how state-level policy decisions may impact adolescents' use behaviors; however, there is a gap in the understanding of how differences in local jurisdictional policies may also influence underage cannabis use.Procedures: The present study cross-sectionally assesses local variation in cannabis policies to explore the potential effects of local policy on underage use behaviors. Data were collected from (N = 1,573) adolescents representing 120 different localities across California, collected as a part of Project Cal Teens. Linear regression models were used to assess associations between local jurisdiction's allowance of retail sale of cannabis for adult-use and past 30-day use of non-medical (adult use) cannabis and perceived access to cannabis products. FINDINGS: Local policy allowing cannabis retail was associated with adolescents' significantly higher past 30-day use of cannabis (ß = 0.25 95% CI = 0.08, 0.42) and perceived access (ß = 0.60 95% CI = 0.27, 0.94). CONCLUSIONS: Results highlight the impact of local cannabis policies on adolescent cannabis use and perception. Considering the effects of cannabis use on adolescent development, this is an important public health concern because 14 states have already legalized recreational retail sales and growing numbers of local jurisdictions are allowing the retail sale of recreational cannabis.


Assuntos
Cannabis , Adolescente , Adulto , California , Comércio , Humanos , Marketing , Políticas , Saúde Pública
8.
Int J Mol Sci ; 23(3)2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-35163289

RESUMO

Sugar beet crown and root rot caused by Rhizoctonia solani is a major yield constraint. Root rot is highly increased when R. solani and Leuconostoc mesenteroides co-infect roots. We hypothesized that the absence of plant cell-wall-degrading enzymes in L. mesenteroides and their supply by R. solani during close contact, causes increased damage. In planta root inoculation with or without cell-wall-degrading enzymes showed greater rot when L. mesenteroides was combined with cellulase (22 mm rot), polygalacturonase (47 mm), and pectin lyase (57 mm) versus these enzymes (0-26 mm), R. solani (20 mm), and L. mesenteroides (13 mm) individually. Carbohydrate analysis revealed increased simpler carbohydrates (namely glucose + galactose, and fructose) in the infected roots versus mock control, possibly due to the degradation of complex cell wall carbohydrates. Expression of R. solani cellulase, polygalacturonase, and pectin lyase genes during root infection corroborated well with the enzyme data. Global mRNAseq analysis identified candidate genes and highly co-expressed gene modules in all three organisms that might be critical in host plant defense and pathogenesis. Targeting R. solani cell-wall-degrading enzymes in the future could be an effective strategy to mitigate root damage during its interaction with L. mesenteroides.


Assuntos
Beta vulgaris/microbiologia , Leuconostoc mesenteroides/metabolismo , Rhizoctonia/enzimologia , Beta vulgaris/crescimento & desenvolvimento , Beta vulgaris/metabolismo , Parede Celular/metabolismo , Expressão Gênica/genética , Regulação da Expressão Gênica de Plantas/genética , Leuconostoc mesenteroides/patogenicidade , Defesa das Plantas contra Herbivoria/imunologia , Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Imunidade Vegetal/genética , Raízes de Plantas/metabolismo , Raízes de Plantas/microbiologia , Rhizoctonia/patogenicidade
9.
J Ethn Subst Abuse ; 21(2): 439-456, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-32539637

RESUMO

Acculturation is associated with substance use behaviors in Hispanic adolescents. However, there is limited research determining whether the individual's friends' acculturation patterns also influence substance use. Tenth-grade students (N = 970) participated in Project RED, a study of substance use and social networks among Hispanic youth in Southern California. Acculturation and substance use data from both the respondent and their nominated friends were regressed on lifetime cigarette use, marijuana use, and alcohol use controlling for sibling substance use, sex, depressive symptoms, and network measures. Respondent's Hispanic orientation was significantly associated with lower odds of both cigarette and marijuana use, whereas respondent's friends' US orientation was associated with higher odds of cigarette use. When controlling for network-level acculturation, individual-level U.S. orientation was not associated with substance use. Participants who nominated more friends had lower odds of cigarette use. Among this sample of Hispanic adolescents, affiliating with U.S.-oriented friends was associated with a higher risk for smoking. Substance use prevention efforts should consider encouraging Hispanic youth to maintain their cultural heritage and foster friendship groups that support abstinence and promote Hispanic and bicultural identity.


Assuntos
Fumar Maconha , Transtornos Relacionados ao Uso de Substâncias , Aculturação , Adolescente , Hispânico ou Latino , Humanos , Rede Social
10.
Am J Physiol Regul Integr Comp Physiol ; 321(2): R100-R111, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34132115

RESUMO

Hyperbaric oxygen (HBO2) is breathing >1 atmosphere absolute (ATA; 101.3 kPa) O2 and is used in HBO2 therapy and undersea medicine. What limits the use of HBO2 is the risk of developing central nervous system (CNS) oxygen toxicity (CNS-OT). A promising therapy for delaying CNS-OT is ketone metabolic therapy either through diet or exogenous ketone ester (KE) supplement. Previous studies indicate that KE induces ketosis and delays the onset of CNS-OT; however, the effects of exogeneous KE on cognition and performance are understudied. Accordingly, we tested the hypothesis that oral gavage with 7.5 g/kg induces ketosis and increases the latency time to seizure (LSz) without impairing cognition and performance. A single oral dose of 7.5 g/kg KE increases systemic ß-hydroxybutyrate (BHB) levels within 0.5 h and remains elevated for 4 h. Male rats were separated into three groups: control (no gavage), water-gavage, or KE-gavage, and were subjected to behavioral testing while breathing 1 ATA (101.3 kPa) of air. Testing included the following: DigiGait (DG), light/dark (LD), open field (OF), and novel object recognition (NOR). There were no adverse effects of KE on gait or motor performance (DG), cognition (NOR), and anxiety (LD, OF). In fact, KE had an anxiolytic effect (OF, LD). The LSz during exposure to 5 ATA (506.6 kPa) O2 (≤90 min) increased 307% in KE-treated rats compared with control rats. In addition, KE prevented seizures in some animals. We conclude that 7.5 g/kg is an optimal dose of KE in the male Sprague-Dawley rat model of CNS-OT.


Assuntos
Anticonvulsivantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Ésteres/farmacologia , Cetonas/farmacologia , Atividade Motora/efeitos dos fármacos , Convulsões/prevenção & controle , Animais , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/toxicidade , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Ésteres/farmacocinética , Ésteres/toxicidade , Oxigenoterapia Hiperbárica/efeitos adversos , Cetonas/farmacocinética , Cetonas/toxicidade , Masculino , Ratos Sprague-Dawley , Tempo de Reação , Convulsões/etiologia , Convulsões/fisiopatologia , Convulsões/psicologia
11.
Proc Natl Acad Sci U S A ; 115(35): E8143-E8152, 2018 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-30104387

RESUMO

Mutations in ß-cardiac myosin, the predominant motor protein for human heart contraction, can alter power output and cause cardiomyopathy. However, measurements of the intrinsic force, velocity, and ATPase activity of myosin have not provided a consistent mechanism to link mutations to muscle pathology. An alternative model posits that mutations in myosin affect the stability of a sequestered, super relaxed state (SRX) of the protein with very slow ATP hydrolysis and thereby change the number of myosin heads accessible to actin. Here we show that purified human ß-cardiac myosin exists partly in an SRX and may in part correspond to a folded-back conformation of myosin heads observed in muscle fibers around the thick filament backbone. Mutations that cause hypertrophic cardiomyopathy destabilize this state, while the small molecule mavacamten promotes it. These findings provide a biochemical and structural link between the genetics and physiology of cardiomyopathy with implications for therapeutic strategies.


Assuntos
Benzilaminas/química , Uracila/análogos & derivados , Miosinas Ventriculares/química , Animais , Benzilaminas/farmacologia , Cardiomegalia/enzimologia , Cardiomegalia/genética , Humanos , Músculo Esquelético/enzimologia , Mutação , Suínos , Porco Miniatura , Uracila/química , Uracila/farmacologia , Miosinas Ventriculares/genética , Miosinas Ventriculares/metabolismo
12.
Subst Use Misuse ; 56(1): 140-144, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33222604

RESUMO

INTRODUCTION: Adverse childhood experiences (ACE) predict health-compromising behaviors such as substance use. However, few studies have examined the association between ACE and prescription drug misuse among young adults-a growing public health concern. College students are especially vulnerable to prescription drug misuse due to social and academic stressors. This study investigated associations between ACE and prescription drug misuse (e.g., antidepressants, opiates, sedatives and stimulants) among a diverse college population, as well as gender and racial/ethnic variations in these associations. Methods: Data are from the 2018 American College Health Association's National College Health Assessment II (N = 3899) at a large, diverse university in California. Logistic regression models assessed the association between ACE and prescription drug misuse adjusting for gender and race/ethnicity and explored gender and racial/ethnic differences in the ACE/prescription drug misuse association. Results: ACE was associated with misuse of all prescription drugs. Due to significant effect modification by ethnicity in the relationship between ACE and stimulant misuse (p < 0.05), models were stratified by race/ethnicity. Every additional ACE was associated with an increase in adjusted odds of stimulant use among students identifying as Asian/Pacific Islander (API) and Hispanic, but not Whites. Conclusions: This study contributes to the mounting evidence regarding the importance of ACE screening and the use of campus-based prevention programs. This study also suggests programs should be tailored to address cultural variation.


Assuntos
Estimulantes do Sistema Nervoso Central , Uso Indevido de Medicamentos sob Prescrição , Transtornos Relacionados ao Uso de Substâncias , Estimulantes do Sistema Nervoso Central/uso terapêutico , Humanos , Estudantes , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Estados Unidos , Universidades , Adulto Jovem
13.
Am J Forensic Med Pathol ; 42(1): 96-98, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32852292

RESUMO

ABSTRACT: Infections due to bacteria of the genus Paenibacillus are exceedingly rare and therefore predominately described on a case-by-case basis. Here, we present a case of a 25-day-old premature neonate who died from presumed Paenibacillus sepsis and meningitis. Most prior reported cases of Paenibacillus bacteremia were among patients who had prosthetic medical devices, were immunocompromised, or were injection drug users. However, to our knowledge, this is the first reported case of infant death from presumed Paenibacillus thiaminolyticus. This case suggests the potential for severe human infection by an environmental bacterium previously considered to be of little consequence.


Assuntos
Infecções por Bactérias Gram-Positivas/diagnóstico , Recém-Nascido Prematuro , Meningites Bacterianas/microbiologia , Paenibacillus/isolamento & purificação , Sepse/microbiologia , Infarto Encefálico/patologia , Feminino , Parada Cardíaca/etiologia , Humanos , Hipóxia-Isquemia Encefálica/etiologia , Recém-Nascido
14.
Int Orthop ; 45(5): 1179-1188, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33649891

RESUMO

PURPOSE: The aim of this study is to evaluate the outcomes of autologous microfragmented adipose tissue (MFAT) injection in elderly patients with knee osteoarthritis (OA). We hypothesized that MFAT knee infiltration for the treatment of knee OA would yield good clinical results out to two years follow-up. METHODS: Multi-centric, international, open-label study conducted by orthopedic surgery, and/or regenerative medicine facilities utilizing patient registries. Subjects recruited for eligibility. The primary outcome measure was Knee Injury and Osteoarthritis Outcome Score (KOOS). Outcomes and patient factors were compared to baseline, at six, 12, and 24 months. Statistical models were used to assess KOOS subscores and probability of exceeding the Minimally Clinically Important Difference (MCID) or Patient Acceptable Symptom State (PASS), and to assess the effect of the treatment variables on KOOS - Pain. RESULTS: Seventy-five patients, 120 primary treatments, mean age 69.6 years, (95%CI 68.3-70.9), BMI 28.4 (95%CI 27.3-29.6), with KL grade 2 to 4 knee OA treated with a single MFAT injection. KL grades 2 (15.1%), 3 (56.3%), and 4 (28.6%), with 20.8% of knees having previously undergone surgery. Patients with KL grade 2 disease had the best results in KOOS - Pain (P = 0.001), at six, 12, and 24 months. Including advanced KL grade 3 and 4 osteoarthritis patients, significant functional and quality of life success was seen in 106/120 treatments (88.3%, 66 patients) at all follow-up time points. Fourteen treatments (11.7%, 9 patients) failed prior to the study endpoint. CONCLUSION: This study shows that a single-dose MFAT injection leads to clinical, functional, and quality of life improvement at two years in elderly patients, in KL grades 2 to 4 of knee osteoarthritis. These findings provide evidence that this treatment modality could be a safe and effective option to other commonly available treatments in carefully selected patients.


Assuntos
Osteoartrite do Joelho , Tecido Adiposo , Idoso , Humanos , Articulação do Joelho/cirurgia , Osteoartrite do Joelho/cirurgia , Qualidade de Vida , Resultado do Tratamento
15.
Int J Mol Sci ; 22(23)2021 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-34884867

RESUMO

Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive disorder caused by mutations in the DMD gene and the subsequent lack of dystrophin protein. Recently, phosphorodiamidate morpholino oligomer (PMO)-antisense oligonucleotides (ASOs) targeting exon 51 or 53 to reestablish the DMD reading frame have received regulatory approval as commercially available drugs. However, their applicability and efficacy remain limited to particular patients. Large animal models and exon skipping evaluation are essential to facilitate ASO development together with a deeper understanding of dystrophinopathies. Using recombinant adeno-associated virus-mediated gene targeting and somatic cell nuclear transfer, we generated a Yucatan miniature pig model of DMD with an exon 52 deletion mutation equivalent to one of the most common mutations seen in patients. Exon 52-deleted mRNA expression and dystrophin deficiency were confirmed in the skeletal and cardiac muscles of DMD pigs. Accordingly, dystrophin-associated proteins failed to be recruited to the sarcolemma. The DMD pigs manifested early disease onset with severe bodywide skeletal muscle degeneration and with poor growth accompanied by a physical abnormality, but with no obvious cardiac phenotype. We also demonstrated that in primary DMD pig skeletal muscle cells, the genetically engineered exon-52 deleted pig DMD gene enables the evaluation of exon 51 or 53 skipping with PMO and its advanced technology, peptide-conjugated PMO. The results show that the DMD pigs developed here can be an appropriate large animal model for evaluating in vivo exon skipping efficacy.


Assuntos
Distrofina/genética , Éxons , Músculo Esquelético/patologia , Distrofia Muscular de Duchenne/genética , Animais , Animais Geneticamente Modificados , Dependovirus/genética , Modelos Animais de Doenças , Proteínas Associadas à Distrofina/genética , Proteínas Associadas à Distrofina/metabolismo , Feminino , Deleção de Genes , Masculino , Fibras Musculares Esqueléticas/patologia , Técnicas de Transferência Nuclear , Oligonucleotídeos Antissenso/genética , Sarcolema/metabolismo , Suínos , Porco Miniatura
16.
Int J Mol Sci ; 22(2)2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33467646

RESUMO

Achilles tendon ruptures are very common tendon ruptures and their incidence is increasing in modern society, resulting in work incapacity and months off sport, which generate a need for accelerated and successful therapeutic repair strategy. Platelet-rich plasma (PRP) is emerging as adjuvant human blood-derived constructs to assist Achilles tendon rupture treatment. However, myriad PRP preparation methods in conjunction with poor standardization in the modalities of their applications impinge on the consistent effectiveness of clinical and structural outcomes regarding their therapeutic efficacy. The purpose of this review is to provide some light on the application of PRP for Achilles tendon ruptures. PRP has many characteristics that make it an attractive treatment. Elements such as the inclusion of leukocytes and erythrocytes within PRP, the absence of activation and activation ex vivo or in vivo, the modality of application, and the adjustment of PRP pH can influence the biology of the applied product and result in misleading therapeutic conclusions. The weakest points in demonstrating their consistent effectiveness are primarily the result of myriad PRP preparation methods and the poor standardization of modalities for their application. Selecting the right biological scaffold and applying it correctly to restitutio ad integrum of ruptured Achilles tendons remains a daunting and complex task.


Assuntos
Tendão do Calcâneo/lesões , Tendão do Calcâneo/cirurgia , Colágeno/química , Queratinócitos/citologia , Plasma Rico em Plaquetas/metabolismo , Ruptura/cirurgia , Traumatismos dos Tendões/cirurgia , Ciclo Celular , Movimento Celular , Proliferação de Células , Receptores ErbB/metabolismo , Humanos , Integrina beta1/metabolismo , Queratinócitos/metabolismo , Ligantes , NF-kappa B/metabolismo , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais , Cicatrização
17.
J Transl Med ; 18(1): 203, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32423449

RESUMO

In late 2019, a novel coronavirus (SARS-CoV-2) emerged in Wuhan, capital city of Hubei province in China. Cases of SARS-CoV-2 infection quickly grew by several thousand per day. Less than 100 days later, the World Health Organization declared that the rapidly spreading viral outbreak had become a global pandemic. Coronavirus disease 2019 (COVID-19) is typically associated with fever and respiratory symptoms. It often progresses to severe respiratory distress and multi-organ failure which carry a high mortality rate. Older patients or those with medical comorbidities are at greater risk for severe disease. Inflammation, pulmonary edema and an over-reactive immune response can lead to hypoxia, respiratory distress and lung damage. Mesenchymal stromal/stem cells (MSCs) possess potent and broad-ranging immunomodulatory activities. Multiple in vivo studies in animal models and ex vivo human lung models have demonstrated the MSC's impressive capacity to inhibit lung damage, reduce inflammation, dampen immune responses and aid with alveolar fluid clearance. Additionally, MSCs produce molecules that are antimicrobial and reduce pain. Upon administration by the intravenous route, the cells travel directly to the lungs where the majority are sequestered, a great benefit for the treatment of pulmonary disease. The in vivo safety of local and intravenous administration of MSCs has been demonstrated in multiple human clinical trials, including studies of acute respiratory distress syndrome (ARDS). Recently, the application of MSCs in the context of ongoing COVID-19 disease and other viral respiratory illnesses has demonstrated reduced patient mortality and, in some cases, improved long-term pulmonary function. Adipose-derived stem cells (ASC), an abundant type of MSC, are proposed as a therapeutic option for the treatment of COVID-19 in order to reduce morbidity and mortality. Additionally, when proven to be safe and effective, ASC treatments may reduce the demand on critical hospital resources. The ongoing COVID-19 outbreak has resulted in significant healthcare and socioeconomic burdens across the globe. There is a desperate need for safe and effective treatments. Cellular based therapies hold great promise for the treatment of COVID-19. This literature summary reviews the scientific rationale and need for clinical studies of adipose-derived stem cells and other types of mesenchymal stem cells in the treatment of patients who suffer with COVID-19.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Pneumonia Viral/terapia , Animais , COVID-19 , Ensaios Clínicos como Assunto , Humanos , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Pandemias , SARS-CoV-2
18.
J Surg Res ; 252: 37-46, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32222592

RESUMO

BACKGROUND: Abdominal aortic aneurysm (AAA) is a permanent and irreversible dilation of the lower region of the aorta. It is typically an asymptomatic condition that if left untreated can expand to the point of rupture. In simple mechanical terms, rupture of an artery occurs when the local wall stress exceeds the local wall strength. It is therefore understandable that numerous studies have attempted to estimate the AAA wall stress and investigate the relationship between the AAA wall stress and AAA symptoms. MATERIALS AND METHODS: We conducted computational biomechanics analysis for 19 patients with AAA (a proportion of these patients were classified as symptomatic) to investigate whether the AAA wall stress fields (both the patterns and magnitude) correlate with the clinical definition of symptomatic and asymptomatic AAAs. For computation of AAA wall stress, we used a very efficient method recently presented by the Intelligent Systems for Medicine Laboratory. The Intelligent Systems for Medicine Laboratory's method uses geometry from computed tomography images and mean arterial pressure as the applied load. The method is embedded in the software platform BioPARR-Biomechanics based Prediction of Aneurysm Rupture Risk, freely available from http://bioparr.mech.uwa.edu.au/. The uniqueness of our stress computation approach is three-fold: i) the results are insensitive to unknown patient-specific mechanical properties of arterial wall tissue; ii) the residual stress is accounted for, according to Y.C. Fung's Uniform Stress Hypothesis; and iii) the analysis is automated and quick, making our approach compatible with clinical workflows. RESULTS: Symptomatic patients could not be identified from the plots (pattern) of AAA wall stress and stress magnitude. Although the largest stress was predicted for a patient who suffered from AAA symptoms, the three patients with the smallest stress were also symptomatic. CONCLUSIONS: The results demonstrate, contrary to the common view, that neither the wall stress magnitude nor the stress distribution appears to be associated with the presence of clinical symptoms.


Assuntos
Aorta Abdominal/fisiopatologia , Aneurisma da Aorta Abdominal/diagnóstico , Ruptura Aórtica/prevenção & controle , Modelos Cardiovasculares , Estresse Mecânico , Idoso , Idoso de 80 Anos ou mais , Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/complicações , Aneurisma da Aorta Abdominal/fisiopatologia , Ruptura Aórtica/etiologia , Ruptura Aórtica/fisiopatologia , Doenças Assintomáticas , Simulação por Computador , Feminino , Análise de Elementos Finitos , Humanos , Masculino , Pessoa de Meia-Idade , Modelagem Computacional Específica para o Paciente , Estudos Retrospectivos , Medição de Risco/métodos , Software , Tomografia Computadorizada por Raios X
19.
Int J Behav Med ; 27(6): 660-667, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32643038

RESUMO

BACKGROUND: The original Adverse Childhood Experiences (ACE) study demonstrated strong, graded relationships between child maltreatment and household dysfunction and adult health status. The present study re-examined these relationships in a sample of young adult, college students to better characterize the developmental timing of health problems related to ACE exposure and differences by biological sex. METHOD: A cross-sectional general health questionnaire that included items on ACE was administered to young adults (ages 18-29) at universities in California (n = 3880), Minnesota (n = 7708), and Texas (n = 451) between 2017 and 2018. Seven ACE were assessed: psychological, physical, or sexual abuse; violence between parents; or living with household members who were substance misusers, mentally ill, or ever imprisoned. Binary health indicators were regressed on number of ACE as 0 (referent), 1, 2, 3, and 4 or more using logistic regression controlling for age, biological sex, race/ethnicity, and site. RESULTS: Approximately 51.7% of the sample reported at least one ACE with a significantly higher rate among Texas participants (p < 0.001). We observed graded relationships between levels of ACE exposure and physical, mental, and behavioral health indicators including cigarette use, e-cigarette use, drinking and driving, obesity, lifetime depression, suicide ideation and attempt, non-suicidal self-injury, and lack of restful sleep. ACE-exposed females reported worse mental health status than ACE-exposed males while males reported more substance use than females. Most outcomes did not vary significantly by sex. CONCLUSION: The strong, graded relationships observed between ACE exposure and health status among young adults reinforce the need for trauma-informed intervention programs on college campuses.


Assuntos
Maus-Tratos Infantis , Sistemas Eletrônicos de Liberação de Nicotina , Transtornos Relacionados ao Uso de Substâncias , Adolescente , Adulto , Criança , Estudos Transversais , Feminino , Humanos , Masculino , Fatores de Risco , Estudantes , Adulto Jovem
20.
Am J Forensic Med Pathol ; 41(3): 160-162, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32796204

RESUMO

Contagious disease reporting is an important mechanism for public health officials to be informed of emerging and ongoing risks to the community's health. There are several mechanisms for reporting, including automated reporting from computer sources, required reporting from physicians and other health care professionals, and reporting of sales of certain over-the-counter medications such as cold remedies.Reporting by medical examiners is a significant source of information because contagious disease may first come to the medical examiner by causing sudden unexpected death. This study describes how the Los Angeles County Department of Medical Examiner-Coroner improved contagious disease reporting from coroner's cases. Methods used include computerized transmission to public health of initial coroner's case reports, e-mailed requests to the coroner to obtain cultures, having all results of coroner's cultures come through a single person who reports contagious disease as necessary, and including infectious disease screening in retrospective case review.


Assuntos
Médicos Legistas , Notificação de Doenças , Influenza Humana/mortalidade , Controle de Doenças Transmissíveis , Humanos , Los Angeles/epidemiologia , Vigilância em Saúde Pública
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