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1.
Circ Genom Precis Med ; 16(2): e003887, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36960729

RESUMO

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extremely elevated plasma low-density lipoprotein cholesterol and accelerated atherosclerosis. Accurate identification of patients with HoFH is essential as they may be eligible for specialized treatments. We hypothesized that a subset of patients with clinically diagnosed heterozygous FH (HeFH) may in fact have HoFH, and this could be identified by genetic diagnosis. METHODS: We recruited patients with a clinical diagnosis of HeFH based on a Dutch Lipid Clinic Network score ≥6 and no secondary cause of hypercholesterolemia. We performed targeted next-generation sequencing of the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and low-density lipoprotein receptor adapter protein 1 (LDLRAP1) genes, followed by long-read sequencing of the LDLR gene in patients with >1 pathogenic LDLR variant. We examined lipid levels and cardiovascular events. RESULTS: Among 705 patients with clinically diagnosed HeFH, we identified a single pathogenic variant in 300 (42.6%) and >1 pathogenic variant in the LDLR gene in 11 patients (1.6%). We established a genetic diagnosis of HoFH in 6 (0.9%) patients (3 true homozygotes and 3 compound heterozygotes). The mean baseline low-density lipoprotein cholesterol and prevalence of premature cardiovascular disease of patients with genetically identified HoFH was significantly higher than patients with HeFH. CONCLUSIONS: In a cohort of patients with clinically diagnosed HeFH, genetic testing including long-read sequencing revealed that 0.9% had HoFH. These patients tended to have a more severe clinical phenotype. Genetic testing of patients with clinical FH may identify patients with HoFH that had eluded clinical diagnosis.


Assuntos
Hipercolesterolemia Familiar Homozigota , Hiperlipoproteinemia Tipo II , Humanos , Pró-Proteína Convertase 9/genética , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , LDL-Colesterol
2.
Can J Diabetes ; 46(8): 843-850, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36068154

RESUMO

BACKGROUND: Euglycemic diabetic ketoacidosis (DKA) is a potentially life-threatening adverse condition associated with use of sodium-glucose cotransporter-2 inhibitors (SGLT2i). This risk is further pronounced in the perioperative period. There is no consensus for when SGLT2i should be held preoperatively, and recommendations from various organizations have evolved from 1 day to 3 to 4 days in the latest American Diabetes Association guidelines. Further study of patients with perioperative euglycemic DKA is required to help clarify the optimal timing of preoperative discontinuation of SGLT2i agents. METHODS: In this retrospective, single-centre case series we examined 4 patients who developed postoperative euglycemic DKA after coronary artery bypass grafting, 3 of whom underwent semiurgent surgery. We characterized their clinical course, predisposing factors and treatment characteristics. RESULTS: The SGLT2i were held for 1 to 5 days preoperatively, with times since last dose before surgery being 54, 79, 80 and 151 hours. Surgery was semiurgent for 3 patients, and elective for 1 patient. Three patients were diagnosed with euglycemic DKA within 24 hours after surgery. The fourth patient developed euglycemic DKA on postoperative day 3 in the context of significant hypovolemia and exhibited potential signs of protracted SGLT2i action at 7 days since the last dose. CONCLUSIONS: The duration of SGLT2i action and risk for DKA is variable and complex. Providers should hold SGLT2i at least 3 days before elective major surgery, with potentially longer times in high-risk patients. Careful vigilance should be used for perioperative DKA development in all patients recently exposed to SGLT2i.


Assuntos
Diabetes Mellitus Tipo 2 , Cetoacidose Diabética , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Cetoacidose Diabética/induzido quimicamente , Cetoacidose Diabética/complicações , Diabetes Mellitus Tipo 2/complicações , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Estudos Retrospectivos , Ponte de Artéria Coronária/efeitos adversos , Glucose , Sódio/uso terapêutico
3.
Pathogens ; 10(9)2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34578224

RESUMO

Medroxyprogesterone acetate (MPA) is one of the most widely used contraceptives in the world. Epidemiologic studies have uncovered a possible link between the use of MPA and an increased risk of HIV-1 transmission. However, the understanding of the mechanism is still limited. Our previous publication demonstrated that the lysosomal activity in human vaginal epithelial cells attenuated the trafficking of viral particles during HIV-1 transcytosis. In this study, we show that treating human primary cervical epithelial cells with MPA led to a reduction in lysosomal activity. This reduction caused an increase in the intracellular HIV-1 accumulation and, consequently, an increase in viral release. Our study uncovers a novel mechanism by which MPA enhances HIV-1 release in primary cervical epithelial cells, thus providing vital information for HIV intervention and prevention.

4.
Am J Physiol Endocrinol Metab ; 318(2): E87-E101, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31846372

RESUMO

Live-cell imaging of mitochondrial function and dynamics can provide vital insights into both physiology and pathophysiology, including of metabolic diseases like type 2 diabetes. However, without super-resolution microscopy and commercial analysis software, it is challenging to accurately extract features from dense multilayered mitochondrial networks, such as those in insulin-secreting pancreatic ß-cells. Motivated by this, we developed a comprehensive pipeline and associated ImageJ plugin that enables 2D/3D quantification of mitochondrial network morphology and dynamics in mouse ß-cells and by extension other similarly challenging cell types. The approach is based on standard confocal microscopy and shareware, making it widely accessible. The pipeline was validated using mitochondrial photolabeling and unsupervised cluster analysis and is capable of morphological and functional analyses on a per-organelle basis, including in 4D (xyzt). Overall, this tool offers a powerful framework for multiplexed analysis of mitochondrial state/function and provides a valuable resource to accelerate mitochondrial research in health and disease.


Assuntos
Células Secretoras de Insulina/fisiologia , Células Secretoras de Insulina/ultraestrutura , Microscopia Confocal/métodos , Mitocôndrias/fisiologia , Mitocôndrias/ultraestrutura , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Processamento de Imagem Assistida por Computador , Imageamento Tridimensional/métodos , Secreção de Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reprodutibilidade dos Testes , Software , Imagem com Lapso de Tempo , Fluxo de Trabalho
5.
Microbes Infect ; 14(6): 500-8, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22227318

RESUMO

Bacterial vaginosis (BV), a common condition seen in premenopausal women, is associated with preterm labor, pelvic inflammatory disease, and delivery of low birth weight infants. Gardnerella vaginalis is the predominant bacterial species associated with BV, although its exact role in the pathology of BV is unknown. Using immunofluorescence, confocal and transmission electron microscopy, we found that VK2 vaginal epithelial cells take up G. vaginalis after exposure to the bacteria. Confocal microscopy also indicated the presence of internalized G. vaginalis within vaginal epithelial cells obtained from a subject with BV. Using VK2 cells and (35)S labeled bacteria in an invasion assay, we found that a 1 h uptake of G. vaginalis was 21.8-fold higher than heat-killed G. vaginalis, 84-fold compared to Lactobacillus acidophilus and 6.6-fold compared to Lactobacillus crispatus. Internalization was inhibited by pre-exposure of cells to cytochalasin-D. In addition, the cytoskeletal protein vimentin was upregulated in VK2 cells exposed to G. vaginalis, but there was no change in actin cytoskeletal polymerization/rearrangements or vimentin subcellular relocalization post exposure. Cytoskeletal protein modifications could represent a potential mechanism for G. vaginalis mediated internalization by vaginal epithelial cells. Finally, understanding vaginal bacteria/host interactions will allow us to better understand the underlying mechanisms of BV pathogenesis.


Assuntos
Células Epiteliais/microbiologia , Gardnerella vaginalis/patogenicidade , Interações Hospedeiro-Patógeno , Vagina/microbiologia , Vaginose Bacteriana/microbiologia , Hidrocarboneto de Aril Hidroxilases/farmacologia , Células Epiteliais/ultraestrutura , Feminino , Gardnerella vaginalis/efeitos dos fármacos , Humanos , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Esteroide Hidroxilases/farmacologia , Vaginose Bacteriana/fisiopatologia , Virulência
6.
BJU Int ; 96(9): 1397-402, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16287465

RESUMO

OBJECTIVE: To investigate the potential protective effect of a grape suspension in a rabbit model of in vivo bilateral ischaemia/reperfusion (I/R), which is a causal factor in obstructive bladder dysfunction. MATERIALS AND METHODS: Six groups of four New Zealand White rabbits were treated by twice-daily gavage with aqueous grape suspension (groups 1-3) or sugar-water vehicle (groups 4-6) for 3 weeks. Groups 1 and 4 then received bilateral ischaemia for 2 h, and groups 2 and 5 received bilateral ischaemia for 2 h and reperfusion (recovery) for 1 week. Groups 3 and 6 were controls (sham-operated). The effects on cystometry, in vitro contractile responses, and morphology were evaluated. RESULTS: Ischaemia resulted in significant reductions in the contractile responses to all forms of stimulation in vehicle-fed rabbits, whereas there were no reductions in grape-fed rabbits. Contractile responses were significantly reduced in both I/R groups, but significantly more in vehicle-fed than in grape-fed rabbits. Immunohistochemical studies showed less hypoxia in the bladders of grape-fed rabbits than in vehicle-fed rabbits for both ischaemia-only and I/R groups. CONCLUSIONS: Feeding rabbits with grape suspension provided significant protection against the hypoxic effects of bilateral ischaemia and I/R.


Assuntos
Fitoterapia/métodos , Extratos Vegetais/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Doenças da Bexiga Urinária/tratamento farmacológico , Bexiga Urinária/irrigação sanguínea , Vitis , Animais , Antioxidantes/uso terapêutico , Masculino , Contração Muscular/efeitos dos fármacos , Coelhos
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