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2.
BMJ Case Rep ; 14(1)2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431469

RESUMO

Bilateral sight threatening macular and optic nerve inflammation may occur with dengue fever, necessitating the use of systemic steroids. We report a case of bilateral dengue maculopathy in an elderly woman managed with targeted intravitreal steroid therapy. A 63-year-old woman presented with acute-onset painless diminution of vision in both eyes following a dengue fever episode. She had bilateral foveal inflammatory lesions, macular oedema, small vessel occlusions at the macula and scattered retinal haemorrhages and cotton-wool spots. Following systemic evaluation, intravitreal triamcinolone acetonide injection was performed in both eyes at an interval of 3 days. The foveal lesion and macular oedema resolved quickly in both eyes with a normal foveal architecture at the end of 6-week follow-up. The visual acuity improved considerably in both eyes. Inflammatory retinopathy in dengue fever may be managed with a targeted intravitreal steroid injection approach.


Assuntos
Dengue/complicações , Glucocorticoides/administração & dosagem , Edema Macular/tratamento farmacológico , Edema Macular/virologia , Triancinolona Acetonida/administração & dosagem , Dengue/diagnóstico , Dengue/terapia , Feminino , Humanos , Injeções Intravítreas , Edema Macular/diagnóstico , Pessoa de Meia-Idade
3.
Diabetes Res Clin Pract ; 172: 108627, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33333205

RESUMO

AIM: To compare zinc (Zn) and copper (Cu) levels in US adults with normoglycemia, prediabetes and diabetes, and study the association of serum Zn and Cu levels with pancreatic ß cell insulin secretion, pancreatic dysfunction and insulin resistance in US adults with normoglycemia and prediabetes. METHOD: Homeostatic Model Assessment (HOMA2) calculator was used to compute estimates of steady state ß cell insulin secretion (HOMA2-B), peripheral insulin sensitivity (HOMA2-S), insulin resistance (HOMA-IR), and disposition index (HOMA-DI) in 804 adult individuals from the National Health and Nutrition Examination Survey (NHANES 2011-2012). RESULTS: There was no significant difference between serum Zn and Cu levels among subjects with normoglycemia, prediabetes, and diabetes. After adjusting for multiple possible confounders, higher serum Zn concentrations were associated with lower ß cell insulin secretion (HOMA2-B; p = 0.01) and lower insulin resistance (HOMA-IR; p = 0.04) in the prediabetic subjects. In normoglycemic group, higher serum Zn levels were associated with improved pancreatic function (HOMA-DI; P = 0.02). On the other hand, higher serum Cu levels were associated with increased ß cell insulin secretion (HOMA2-B, P = 0.03) only in the subjects with prediabetes. CONCLUSION: These findings support the need for further studies to investigate the role of trace elements in diabetes pathogenesis.

4.
Heart Fail Rev ; 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33169339

RESUMO

Atrial fibrillation (AF) is a common arrhythmia in patients with mitral regurgitation (MR) undergoing transcatheter mitral valve repair (TMVR). In this systematic review, we aimed to investigate the outcomes of TMVR using MitraClip in AF patients. We performed a systematic search using PubMed, SCOPUS, EMBASE, and Google Scholar, from inception to May 10, 2020, for studies that reported outcomes following MitraClip, in patients with AF versus without AF. Seven studies with a total of 7678 patients met the inclusion criteria. The risk of 1-year all-cause mortality following TMVR was higher in AF patients (RR 1.40, 95% CI 1.27-1.54, p ≤ 0.001). Similarly, the risk of heart failure hospitalization was higher in patients with AF (RR 1.17, 95% CI 1.06-1.30, p = 0.002) and the risk of bleeding was elevated in AF patients (RR 1.29, 95% CI 1.15-1.45, p ≤ 0.001). The risk of procedural failure, in-hospital mortality, cardiovascular mortality, and stroke was not significantly different between the two groups. The higher risk of all-cause mortality, HF hospitalization, and risk of bleeding in AF patients undergoing MitraClip warrants attention.

5.
Am J Med ; 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33181103

RESUMO

AIM: Marijuana is the most commonly used psychoactive drug, while its effects on cardiovascular health are not well known and remain a subject of interest. METHODS: We used the pooled 2016 - 2018 data from the Behavioral Risk Factor Surveillance System (BRFSS) to perform a cross-sectional analysis evaluating the association of marijuana and cardiovascular disease, among US adults who never smoked cigarettes. RESULTS: Among US adults aged 18-74 years, when compared to non-users, frequent marijuana use was associated with 88% higher odds of myocardial infarction or coronary artery disease [adjusted odds ratio (aOR) 1.88, 95% confidence interval (CI) 1.15-3.08], and 81% higher odds of stroke (aOR 1.81, 95% CI 1.14-2.89). Among the premature cardiovascular disease group, frequent marijuana users had 2.3 times higher odds of myocardial infarction or coronary artery disease (aOR 2.27, 95% CI 1.20-4.30), and 1.9 times higher odds of stroke (aOR 1.92, 95% CI 1.07-3.43). In terms of the modality of marijuana use, frequent marijuana smoking had 2.1 times higher odds of myocardial infarction or coronary artery disease (aOR 2.07, 95% CI 1.21-3.56), and 1.8 times higher odds of stroke (aOR 1.84, 95% CI 1.09-3.10). A similar association was observed in the premature cardiovascular disease group who smoked marijuana [aOR (for myocardial infarction or coronary artery disease) 2.64, 95% CI 1.37-5.09; aOR (for stroke) 2.00, 95% CI 1.05-3.79)]. No association was observed between marijuana use in any form other than smoking and cardiovascular disease, across all age groups. CONCLUSION: Frequent marijuana smoking is associated with significantly higher odds of stroke and myocardial infarction or coronary artery disease, with a possible role in premature cardiovascular disease.

6.
PLoS One ; 15(10): e0241006, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33119640

RESUMO

Gene therapy is now an effective approach to treat many forms of retinal degeneration. Delivery agents that are cell-specific, allow for multiple dosing regimens, and have low immunogenicity are needed to expand the utility of gene therapy for the retina. We generated eight novel lipid nanoparticles (LNPs) ranging in size from 50 nm to 150 nm by changing the PEG content from 5% to 0.5%, respectively. Subretinal injections of LNP-mRNA encoding luciferase revealed that 0.5% PEG content within nanoparticles elicits the highest expression. Similar injections of LNP delivered cre mRNA into Ai9 mice revealed cell-specific protein expression in the retinal pigment epithelium (RPE), confirmed by fundus photography and immunohistochemistry of whole globe cross-sections. To investigate mechanisms of LNP delivery to the eye, we injected mCherry mRNA using the subretinal approach in apoE-/- and Mertk-/- mice. RPE transfection was observed in both mouse models suggesting that LNP intracellular delivery is not solely dependent on apolipoprotein adsorption or phagocytosis. To investigate LNP penetration, particles were delivered to the vitreous chamber via an intravitreal injection. The 0.5% PEG particles mediated the highest luciferase activity and expression was observed in the Müller glia, the optic nerve head and the trabecular meshwork, but failed to reach the RPE. Overall, particles containing less PEG (~150 nm in size) mediated the highest expression in the eye. Thus far, these particles successfully transfect RPE, Müller cells, the optic nerve head and the trabecular meshwork based on route of administration which can expand the utility of LNP-mediated gene therapies for the eye.

8.
Cardiol Rev ; 28(6): 295-302, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33017364

RESUMO

The 2019 novel coronavirus, declared a pandemic, has infected 2.6 million people as of April 27, 2020, and has resulted in the death of 181,938 people. D-dimer is an important prognostic tool, is often elevated in patients with severe coronavirus disease-19 (COVID-19) infection and in those who suffered death. In this systematic review, we aimed to investigate the prognostic role of D-dimer in COVID-19-infected patients. We searched PubMed, Medline, Embase, Ovid, and Cochrane for studies reporting admission D-dimer levels in COVID-19 patients and its effect on mortality. Eighteen studies (16 retrospective and 2 prospective) with a total of 3682 patients met the inclusion criteria. The pooled weighted mean difference (WMD) demonstrated significantly elevated D-dimer levels in patients who died versus those who survived (WMD, 6.13 mg/L; 95% confidence interval [CI] 4.16-8.11; P < 0.001). Similarly, the pooled mean D-dimer levels were significantly elevated in patients with severe COVID-19 infection (WMD, 0.54 mg/L; 95% CI 0.28-0.80; P < 0.001). The risk of mortality was fourfold higher in patients with positive D-dimer versus negative D-dimer (risk ratio, 4.11; 95% CI, 2.48-6.84; P < 0.001) and the risk of developing severe disease was twofold higher in patients with positive D-dimer levels versus negative D-dimer (risk ratio, 2.04; 95% CI, 1.34-3.11; P < 0.001). Our meta-analysis demonstrates that patients with COVID-19 infection presenting with elevated D-dimer levels have an increased risk of severe disease and mortality.


Assuntos
Infecções por Coronavirus , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Pandemias , Pneumonia Viral , Betacoronavirus , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/mortalidade , Humanos , Mortalidade , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico , Pneumonia Viral/mortalidade , Valor Preditivo dos Testes , Prognóstico , Medição de Risco/métodos
10.
Cardiol Rev ; 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32665526

RESUMO

The 2019 novel coronavirus, declared a pandemic, has infected 2.6 million people as of April 27, 2020, and has resulted in the death of 181,938 people. D-dimer is an important prognostic tool, is often elevated in patients with severe coronavirus disease-19 (COVID-19) infection and in those who suffered death. In this systematic review, we aimed to investigate the prognostic role of D-dimer in COVID-19-infected patients. We searched PubMed, Medline, Embase, Ovid, and Cochrane for studies reporting admission D-dimer levels in COVID-19 patients and its effect on mortality. Eighteen studies (16 retrospective and two prospective) with a total of 3,682 patients met the inclusion criteria. The pooled weighted mean difference (WMD) demonstrated significantly elevated D-dimer levels in patients who died versus those who survived (WMD 6.13 mg/L, 95% confidence interval [CI] 4.16 - 8.11, p <0.001). Similarly, the pooled mean D-dimer levels were significantly elevated in patients with severe COVID-19 infection (WMD 0.54 mg/L, 95% CI 0.28 - 0.80, p< 0.001). The risk of mortality was four-fold higher in patients with positive D-dimer vs. negative D-dimer (risk ratio 4.11, 95% CI 2.48 - 6.84, p< 0.001) and the risk of developing severe disease was two-fold higher in patients with positive D-dimer levels vs. negative D-dimer (risk ratio 2.04, 95% CI 1.34 - 3.11, p < 0.001). Our meta-analysis demonstrates that patients with COVID-19 infection presenting with elevated D-dimer levels have an increased risk of severe disease and mortality.

11.
Nano Lett ; 20(6): 4543-4549, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32375002

RESUMO

Lipid nanoparticle (LNP) packaged mRNA vaccines have been deployed against infectious diseases such as COVID-19, yet their structural features remain unclear. Cholesterol, a major constituent within LNPs, contributes to their morphology that influences gene delivery. Herein, we examine the structure of LNPs containing cholesterol derivatives using electron microscopy, differential scanning calorimetry, and membrane fluidity assays. LNPs formulated with C24 alkyl derivatives of cholesterol show a polymorphic shape and various degrees of multilamellarity and lipid partitioning, likely due to phase separation. The addition of methyl and ethyl groups to the C24 alkyl tail of the cholesterol backbone induces multilamellarity (>50% increase compared to cholesterol), while the addition of a double bond induces lipid partitioning (>90% increase compared to cholesterol). LNPs with multilamellar and faceted structures, as well as a lamellar lipid phase, showed higher gene transfection. Unraveling the structure of mRNA-LNPs can enable their rational design toward enhanced gene delivery.


Assuntos
Colesterol/análogos & derivados , Infecções por Coronavirus/prevenção & controle , Portadores de Fármacos/química , Nanopartículas/química , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , RNA Mensageiro/administração & dosagem , Vacinas Virais/administração & dosagem , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/genética , Técnicas de Transferência de Genes , Células HeLa , Humanos , Lipídeos/química , Nanopartículas/ultraestrutura , Transição de Fase , Fitosteróis/química , RNA Mensageiro/genética , Transfecção , Vacinas Virais/genética
12.
Chronic Obstr Pulm Dis ; 7(2): 107-117, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32324982

RESUMO

Introduction: Low-income chronic obstructive pulmonary disease (COPD) individuals are known to have higher rates of COPD-related hospitalizations and readmissions. Levels of psychological stress are also higher in low-income populations and may be associated with acute care use. We sought to: (1) determine the association between stress and acute care use in COPD, (2) evaluate the social determinants of health (SDH) in low and high stress individuals, and (3) determine the association between low income and high stress with acute care use. Materials and Methods: Using results from a survey-based study of individuals with COPD at the University of Alabama (UAB), we used multivariable regression modeling to evaluate the association of high stress with acute care use (COPD-related emergency department [ED] visits or hospitalizations). We then compared SDH between low and high stress groups and evaluated the association of low income + high stress with acute care use in a secondary model. Results: We included 126 individuals in our study. The high stress group was more likely to be < 65 years old and female. No differences in race, smoking, years of smoking, body mass index, dyspnea, or lung function (forced expiratory volume in 1 second [FEV1]%) by stress group were observed. The high stress group had a 2.5-fold increased adjusted odds of acute care use (adjusted odds ratio [AOR]95% confidence interval [CI], 2.51, 1.06-5.98) compared to the low stress group, while the low-income + high stress group had a 4-fold increased adjusted odds of acute care use (AOR, 95% CI, 4.38, 1.25-15-45) compared to high-income + low-stress group. Conclusions: Acute care use and stress are associated in COPD. These associations are more pronounced in the low-income + high stress population who disproportionately contribute to health care utilization and frequently lack the resources needed to cope with stress.

13.
J Family Med Prim Care ; 9(1): 337-339, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32110615

RESUMO

Background: Globally, ocular morbidities are one of the most underdiagnosed, underreported, and undertreated public health concern. Among estimated 39 billion blind in world, India shares major proportions, with majority of them living in rural population. In India, religious festivals like Kumbh Mela that involve mass gatherings are mainly attended by middle and elderly population who are usually susceptible to various ocular diseases. Therefore, we analyzed the data of our eye camp to document pattern and magnitude of ocular morbidities among pilgrims attending a mega religious festive event. Methods: In a cross-sectional, descriptive study, we included all those patients who participated in a mega eye camp "Netrakumbh" from January to March 2019 at Kumbh Mela, Prayagraj, India and were attended by voluntary ophthalmologist from All India Institute of Medical Sciences, Rishikesh. Presenting chief complaints and detailed history were collected from all participants. All patients underwent comprehensive eye examination including visual acuity, slit lamp biomicroscopic examination, tonometry, etc., Data were compiled and analyzed utilizing SPSS 22.0. Results: A total of 47142 eyes of 23571 persons of all age groups (range 5 years to 70 years) with approximate equal gender distribution attending the mega eye camp were examined. The most common ocular morbidity noticed after ocular examination was refractive error with underlying cause majorly as presbyopia, followed by cataract, after cataract, convergence insufficiency, lids, and adnexal disease, etc. Conclusions: This study highlights the changing pattern of common ocular morbidities presently among middle and elderly populations in developing countries like India.

14.
Nat Commun ; 11(1): 983, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080183

RESUMO

Endosomal sequestration of lipid-based nanoparticles (LNPs) remains a formidable barrier to delivery. Herein, structure-activity analysis of cholesterol analogues reveals that incorporation of C-24 alkyl phytosterols into LNPs (eLNPs) enhances gene transfection and the length of alkyl tail, flexibility of sterol ring and polarity due to -OH group is required to maintain high transfection. Cryo-TEM displays a polyhedral shape for eLNPs compared to spherical LNPs, while x-ray scattering shows little disparity in internal structure. eLNPs exhibit higher cellular uptake and retention, potentially leading to a steady release from the endosomes over time. 3D single-particle tracking shows enhanced intracellular diffusivity of eLNPs relative to LNPs, suggesting eLNP traffic to productive pathways for escape. Our findings show the importance of cholesterol in subcellular transport of LNPs carrying mRNA and emphasize the need for greater insights into surface composition and structural properties of nanoparticles, and their subcellular interactions which enable designs to improve endosomal escape.


Assuntos
Colesterol/análogos & derivados , Lipídeos/química , Nanopartículas/química , RNA Mensageiro/administração & dosagem , Animais , Transporte Biológico Ativo , Linhagem Celular , Colesterol/química , Microscopia Crioeletrônica , Endossomos/metabolismo , Células HEK293 , Células HeLa , Humanos , Camundongos , Nanopartículas/ultraestrutura , Células RAW 264.7 , RNA Mensageiro/genética , Sitosteroides/química , Transfecção , Difração de Raios X
15.
Curr Opin Cardiol ; 34(6): 721-727, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31464773

RESUMO

PURPOSE OF REVIEW: Residual risk for atherosclerotic cardiovascular disease (ASCVD) persists even among patients with optimal low-density lipoprotein cholesterol (LDL-C) levels. Randomized trials attempting to modulate other lipids beyond LDL-C have failed to demonstrate significant reductions in ischemic events. RECENT FINDINGS: Mounting evidence suggests that triglyceride elevation is an independent risk factor for ASCVD. Though trials of triglyceride-lowering therapy in the statin era have failed to provide protection from ASCVD events, subgroup analyses have revealed that those with the highest triglycerides at time of enrollment appeared to receive the greatest clinical benefit. REDUCE-IT was a trial that enrolled patients with high triglycerides despite having goal LDL-C levels on statin therapy. Treatment with icosapent ethyl, a highly purified omega-3 fatty acid (OM3FA), eicosapentaenoic acid ethyl ester, provided a 25% relative risk reduction for the primary composite cardiovascular endpoint (hazard ratio 0.75, 95% CI 0.68--0.83; P = 0.00000001), as well as a 30% relative risk reduction in total ischemic events (P = 0.00000000036). SUMMARY: Icosapent ethyl was rigorously shown to decrease residual risk for cardiovascular events, though the benefits seen were likely because of mechanisms beyond mere triglyceride lowering. Clinical application of icosapent ethyl in this cohort of patients with residual risk is urgently needed.


Assuntos
Aterosclerose/prevenção & controle , Doenças Cardiovasculares/prevenção & controle , Ácido Eicosapentaenoico/análogos & derivados , Hipertrigliceridemia/tratamento farmacológico , Reguladores do Metabolismo de Lipídeos/uso terapêutico , Aterosclerose/sangue , Aterosclerose/etiologia , Aterosclerose/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Ácido Eicosapentaenoico/uso terapêutico , Humanos , Hipertrigliceridemia/complicações , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Comportamento de Redução do Risco , Triglicerídeos/efeitos adversos , Triglicerídeos/sangue , Triglicerídeos/metabolismo
16.
Adv Drug Deliv Rev ; 144: 90-111, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31419450

RESUMO

The complexity of nanoscale interactions between biomaterials and cells has limited the realization of the ultimate vision of nanotechnology in diagnostics and therapeutics. As such, significant effort has been devoted to advancing our understanding of the biophysical interactions of the myriad nanoparticles. Endocytosis of nanomedicine has drawn tremendous interest in the last decade. Here, we highlight the ever-present barriers to efficient intracellular delivery of nanoparticles as well as the current advances and strategies deployed to breach these barriers. We also introduce new barriers that have been largely overlooked such as the glycocalyx and macromolecular crowding. Additionally, we draw attention to the potential complications arising from the disruption of the newly discovered functions of the lysosomes. Novel strategies of exploiting the inherent intracellular defects in disease states to enhance delivery and the use of exosomes for bioanalytics and drug delivery are explored. Furthermore, we discuss the advances in imaging techniques like electron microscopy, super resolution fluorescence microscopy, and single particle tracking which have been instrumental in our growing understanding of intracellular pathways and nanoparticle trafficking. Finally, we advocate for the push towards more intravital analysis of nanoparticle transport phenomena using the multitude of techniques available to us. Unraveling the underlying mechanisms governing the cellular barriers to delivery and biological interactions of nanoparticles will guide the innovations capable of breaching these barriers.


Assuntos
Endocitose , Nanopartículas/administração & dosagem , Animais , Humanos , Nanomedicina
17.
Theranostics ; 9(11): 3191-3212, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31244949

RESUMO

Cells utilize natural supramolecular assemblies to maintain homeostasis and biological functions. Naturally inspired modular assembly of biomaterials are now being exploited for understanding or manipulating cell biology for treatment, diagnosis, and detection of diseases. Supramolecular biomaterials, in particular peptides and oligonucleotides, can be precisely tuned to have diverse structural, mechanical, physicochemical and biological properties. These merits of oligonucleotides and peptides as building blocks have given rise to the evolution of numerous nucleic acid- and peptide-based self-assembling nanomaterials for various medical applications, including drug delivery, tissue engineering, regenerative medicine, and immunotherapy. In this review, we provide an extensive overview of the intracellular delivery approaches using supramolecular self-assembly of DNA, RNA, and peptides. Furthermore, we discuss the current challenges related to subcellular delivery and provide future perspectives of the application of supramolecular biomaterials for intracellular delivery in theranostics.


Assuntos
Endocitose , Substâncias Macromoleculares/metabolismo , Nanopartículas/metabolismo , Oligonucleotídeos/metabolismo , Peptídeos/metabolismo
18.
J Control Release ; 303: 91-100, 2019 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-30986436

RESUMO

Retinal gene therapy has had unprecedented success in generating treatments that can halt vision loss. However, immunogenic response and long-term toxicity with the use of viral vectors remain a concern. Non-viral vectors are relatively non-immunogenic, scalable platforms that have had limited success with DNA delivery to the eye. Messenger RNA (mRNA) therapeutics has expanded the ability to achieve high gene expression while eliminating unintended genomic integration or the need to cross the restrictive nuclear barrier. Lipid-based nanoparticles (LNPs) remain at the forefront of potent delivery vectors for nucleic acids. Herein, we tested eleven different LNP variants for their ability to deliver mRNA to the back of the eye. LNPs that contained ionizable lipids with low pKa and unsaturated hydrocarbon chains showed the highest amount of reporter gene transfection in the retina. The kinetics of gene expression showed a rapid onset (within 4 h) that persisted for 96 h. The gene delivery was cell-type specific with majority of the expression in the retinal pigmented epithelium (RPE) and limited expression in the Müller glia. LNP-delivered mRNA can be used to treat monogenic retinal degenerative disorders of the RPE. The transient nature of mRNA-based therapeutics makes it desirable for applications that are directed towards retinal reprogramming or genome editing. Overall, non-viral delivery of RNA therapeutics to diverse cell types within the retina can provide transformative new approaches to prevent blindness.


Assuntos
Olho/metabolismo , Técnicas de Transferência de Genes , Nanopartículas/administração & dosagem , RNA Mensageiro/administração & dosagem , Animais , Feminino , Lipídeos/administração & dosagem , Masculino , Camundongos Endogâmicos BALB C
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