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1.
Arterioscler Thromb Vasc Biol ; 43(5): 609-617, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36861478

RESUMEN

The recent identification of the cell-surface protein DSC1 (desmocollin 1) as a negative regulator of HDL (high-density lipoprotein) biogenesis has attracted us to revisit the old HDL biogenesis hypothesis: HDL biogenesis reduces atherosclerosis. The location and function of DSC1 suggest that DSC1 is a druggable target for the promotion of HDL biogenesis, and the discovery of docetaxel as a potent inhibitor of the DSC1 sequestration of apolipoprotein A-I has provided us with new opportunities to test this hypothesis. The FDA-approved chemotherapy drug docetaxel promotes HDL biogenesis at low-nanomolar concentrations that are far lower than used in chemotherapy. Docetaxel has also been shown to inhibit atherogenic proliferation of vascular smooth muscle cells. In accordance with these atheroprotective effects of docetaxel, animal studies have shown that docetaxel reduces dyslipidemia-induced atherosclerosis. In the absence of HDL-directed therapies for atherosclerosis, DSC1 constitutes an important new target for the promotion of HDL biogenesis, and the DSC1-targeting compound docetaxel serves as a model compound to prove the hypothesis. In this brief review, we discuss opportunities, challenges, and future directions for using docetaxel in the prevention and treatment of atherosclerosis.


Asunto(s)
Aterosclerosis , Lipoproteínas HDL , Animales , Lipoproteínas HDL/metabolismo , Docetaxel/uso terapéutico , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/prevención & control , Aterosclerosis/metabolismo , HDL-Colesterol
2.
AIDS Behav ; 28(1): 174-185, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37751108

RESUMEN

In this observational study, we assessed the extent to which a community-created pilot intervention, providing trauma-informed care for persons with HIV (PWH), affected HIV care retention and viral suppression among PWH attending an HIV Services Organization in the Southern US. PWH with trauma exposure and/or trauma symptoms (N = 166) were offered a screening and referral to treatment (SBIRT) session. Per self-selection, 30 opted-out, 29 received SBIRT-Only, 25 received SBIRT-only but reported receiving other behavioral health care elsewhere, and 82 participated in the Safety and Stabilization (S&S) Intervention. Estimates from multivariable logistic regression analyses indicated S&S Intervention participants had increased retention in HIV care (adjusted odds ratio [aOR] 5.46, 95% CI 1.70-17.50) and viral suppression (aOR 17.74, 95% CI 1.83-172), compared to opt-out participants. Some evidence suggested that PTSD symptoms decreased for intervention participants. A randomized controlled trial is needed to confirm findings.


Asunto(s)
Infecciones por VIH , Retención en el Cuidado , Trastornos por Estrés Postraumático , Humanos , Estados Unidos/epidemiología , Trastornos por Estrés Postraumático/epidemiología , Trastornos por Estrés Postraumático/terapia , Infecciones por VIH/epidemiología , Derivación y Consulta
3.
Mol Ecol ; 32(24): 6924-6938, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37873915

RESUMEN

Environmental circumstances shaping soil microbial communities have been studied extensively. However, due to disparate study designs, it has been difficult to resolve whether a globally consistent set of predictors exists, or context-dependency prevails. Here, we used a network of 18 grassland sites (11 of those containing regional plant productivity gradients) to examine (i) if similar abiotic or biotic factors predict both large-scale (across sites) and regional-scale (within sites) patterns in bacterial and fungal community composition, and (ii) if microbial community composition differs consistently at two levels of regional plant productivity (low vs. high). Our results revealed that bacteria were associated with particular soil properties (such as base saturation) and both bacteria and fungi were associated with plant community composition across sites and within the majority of sites. Moreover, a discernible microbial community signal emerged, clearly distinguishing high and low-productivity soils across different grasslands independent of their location in the world. Hence, regional productivity differences may be typified by characteristic soil microbial communities across the grassland biome. These results could encourage future research aiming to predict the general effects of global changes on soil microbial community composition in grasslands and to discriminate fertile from infertile systems using generally applicable microbial indicators.


Asunto(s)
Pradera , Microbiota , Microbiología del Suelo , Microbiota/genética , Hongos/genética , Bacterias/genética , Plantas/microbiología , Suelo
4.
Am J Obstet Gynecol ; 229(1): 55.e1-55.e10, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-36539025

RESUMEN

BACKGROUND: Prediction of preeclampsia risk is key to informing effective maternal care. Current screening for preeclampsia at 11 to 13 weeks of gestation using maternal demographic characteristics and medical history with measurements of mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor can identify approximately 75% of women who develop preterm preeclampsia with delivery at <37 weeks of gestation. Further improvements to preeclampsia screening tests will likely require integrating additional biomarkers. Recent research suggests the existence of distinct maternal risk profiles. Therefore, biomarker evaluation should account for the possibility that a biomarker only predicts preeclampsia in a specific maternal phenotype. OBJECTIVE: This study aimed to verify metabolite biomarkers as preterm preeclampsia predictors early in pregnancy in all women and across body mass index groups. STUDY DESIGN: Observational case-control study drawn from a large prospective study on the early prediction of pregnancy complications in women attending their routine first hospital visit at King's College Hospital, London, United Kingdom, in 2010 to 2015. Pregnant women underwent a complete first-trimester assessment, including the collection of blood samples for biobanking. In 11- to 13-week plasma samples of 2501 singleton pregnancies, the levels of preselected metabolites implicated in the prediction of pregnancy complications were analyzed using a targeted liquid chromatography-mass spectrometry method, yielding high-quality quantification data on 50 metabolites. The ratios of amino acid levels involved in arginine biosynthesis and nitric oxide synthase pathways were added to the list of biomarkers. Placental growth factor and pregnancy-associated plasma protein A were also available for all study subjects, serving as comparator risk predictors. Data on 1635 control and 106 pregnancies complicated by preterm preeclampsia were considered for this analysis, normalized using multiples of medians. Prediction analyses were performed across the following patient strata: all subjects and the body mass index classes of <25, 25 to <30, and ≥30 kg/m2. Adjusted median levels were compared between cases and controls and between each body mass index class group. Odds ratios and 95% confidence intervals were calculated at the mean ±1 standard deviation to gauge clinical prediction merits. RESULTS: The levels of 13 metabolites were associated with preterm preeclampsia in the entire study population (P<.05) with particularly significant (P<.01) associations found for 6 of them, namely, 2-hydroxy-(2/3)-methylbutyric acid, 25-hydroxyvitamin D3, 2-hydroxybutyric acid, alanine, dodecanoylcarnitine, and 1-(1Z-octadecenyl)-2-oleoyl-sn-glycero-3-phosphocholine. Fold changes in 7 amino acid ratios, all involving glutamine or ornithine, were also significantly different between cases and controls (P<.01). The predictive performance of some metabolites and ratios differed according to body mass index classification; for example, ornithine (P<.001) and several ornithine-related ratios (P<.0001 to P<.01) were only strongly associated with preterm preeclampsia in the body mass index of <25 kg/m2 group, whereas dodecanoylcarnitine and 3 glutamine ratios were particularly predictive in the body mass index of ≥30 kg/m2 group (P<.01). CONCLUSION: Single metabolites and ratios of amino acids related to arginine bioavailability and nitric oxide synthase pathways were associated with preterm preeclampsia risk at 11 to 13 weeks of gestation. Differential prediction was observed according to body mass index classes, supporting the existence of distinct maternal risk profiles. Future studies in preeclampsia prediction should account for the possibility of different maternal risk profiles to improve etiologic and prognostic understanding and, ultimately, clinical utility of screening tests.


Asunto(s)
Preeclampsia , Complicaciones del Embarazo , Embarazo , Femenino , Humanos , Primer Trimestre del Embarazo , Preeclampsia/epidemiología , Factor de Crecimiento Placentario , Estudios Prospectivos , Índice de Masa Corporal , Estudios de Casos y Controles , Glutamina , Bancos de Muestras Biológicas , Medición de Riesgo , Biomarcadores , Ornitina , Arteria Uterina/diagnóstico por imagen
5.
Anal Chem ; 87(20): 10172-7, 2015 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-26383896

RESUMEN

Countercurrent chromatography (CCC) is a separation technique based on the liquid-liquid partitioning of compounds between the two phases of a biphasic solvent system. Limitations in the separation efficiency and peak capacity of one-dimensional (1D) CCC often result in insufficiently resolved peaks. Therefore, partially resolved peak fractions have to be rechromatographed in order to improve the yield and purity. Additional solvent evaporation steps can be circumvented by the application of two-dimensional CCC (2D CCC). Existing 2D CCC configurations are based on the linking of two CCC instruments which are not readily available in every laboratory. In this study, we introduce a technical improvement which allows performing multiple heart-cuts and 2D CCC separations with one instrument which has up to four independent coils, one pump, and one detector. For this purpose, we modified a commercially available CCC system by the addition of three six-port selection valves and a T-piece. The applicability of the 2D CCC system was shown under overloading conditions with eight alkyl hydroxybenzoates with nonideal conditions. We used two solvent systems which were hydrodynamically compatible and which showed different selectively characteristics with regard to the compounds. Four unresolved compounds in the first dimension were baseline resolved by means of the heart-cut technique, in which between 4 and 9 mL of the flow from coil 1 was transferred to coil 2. Three successive heart-cuts were performed that led to baseline resolution of unresolved compounds in the first dimension. The obtained recovery rates were 94-100%, and the purities of the compounds as determined by GC/MS were 90-100%.


Asunto(s)
Distribución en Contracorriente/instrumentación , Distribución en Contracorriente/métodos , Hidroxibenzoatos/aislamiento & purificación , Cromatografía de Gases y Espectrometría de Masas/instrumentación , Hidrodinámica , Hidroxibenzoatos/química , Solventes/química
6.
AIDS Care ; 27(7): 921-5, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25734697

RESUMEN

Engaging newly diagnosed HIV+ individuals in treatment is a significant global challenge. As South Africa expands HIV counseling and testing (HCT) services, the growing numbers of people diagnosed with HIV will need innovative links to care approaches in order for treatment to be most effective. While definitions vary, we have defined "linkage to care" as connecting an HIV+ individual to medical care, so that CD4 cell test results are obtained and antiretroviral therapy (ART) eligibility assessed. The study is of HIV+ participants (n = 1096), from either Limpopo or Gauteng provinces from a "Links to Care" program. A two-pronged expanded HCT service was used, which included a community outreach approach to address HIV testing and a call center to encourage and track each patient's linkage to care post-HIV diagnosis. The majority of individuals (51%) were linked to care with a mean time to linkage of 31 days (with most individuals linked in less than 14 days). More females (54%) were linked to care than males (47%) and had higher CD4 cell counts than males; females had a mean CD4 cell count of 440, while males took longer to link to care and had a lower mean CD4 cell count of 331. Females of 23 years or younger had the lowest linkage rate of all females. Findings suggest that expanding HCT services to include innovative links to care approaches can improve linkage to care and subsequently impact HIV prevention.


Asunto(s)
Recuento de Linfocito CD4/métodos , Consejo Dirigido , Infecciones por VIH/terapia , Centros de Información , Tamizaje Masivo/métodos , Unidades Móviles de Salud , Adulto , Femenino , Infecciones por VIH/epidemiología , Infecciones por VIH/psicología , Necesidades y Demandas de Servicios de Salud , Humanos , Masculino , Aceptación de la Atención de Salud/psicología , Aceptación de la Atención de Salud/estadística & datos numéricos , Sudáfrica/epidemiología
7.
Biochem Biophys Res Commun ; 445(3): 656-60, 2014 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-24569075

RESUMEN

The synthetic ~5 kDa ABP (amyloid-ß binding peptide) consists of a region of the 228 kDa human pericentrioloar material-1 (PCM-1) protein that selectively and avidly binds in vitro Aß1-42 oligomers, believed to be key co-drivers of Alzheimer's disease (AD), but not monomers (Chakravarthy et al., (2013) [3]). ABP also prevents Aß1-42 from triggering the apoptotic death of cultured human SHSY5Y neuroblasts, likely by sequestering Aß oligomers, suggesting that it might be a potential AD therapeutic. Here we support this possibility by showing that ABP also recognizes and binds Aß1-42 aggregates in sections of cortices and hippocampi from brains of AD transgenic mice and human AD patients. More importantly, ABP targets Aß1-42 aggregates when microinjected into the hippocampi of the brains of live AD transgenic mice.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Autoantígenos/química , Autoantígenos/farmacología , Encéfalo/metabolismo , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/farmacología , Fragmentos de Péptidos/antagonistas & inhibidores , Péptidos/química , Péptidos/farmacología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Secuencia de Aminoácidos , Péptidos beta-Amiloides/metabolismo , Animales , Autoantígenos/administración & dosificación , Encéfalo/efectos de los fármacos , Encéfalo/patología , Proteínas de Ciclo Celular/administración & dosificación , Línea Celular , Humanos , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Datos de Secuencia Molecular , Fragmentos de Péptidos/metabolismo , Péptidos/administración & dosificación , Unión Proteica
8.
J Clin Lipidol ; 18(2): e189-e196, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38281851

RESUMEN

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare, autosomal semi-dominant lipid metabolism disorder characterized by extremely high low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease. The objective of this study was to investigate sex-differences in the treatment and outcomes of patients with HoFH. METHODS: We examined clinical characteristics, lipid-lowering therapy (LLT), and cardiovascular events using descriptive statistics of patients in the Canadian HoFH registry. Major adverse cardiovascular events (MACE) were defined as the composite of cardiovascular death, non-fatal myocardial infarction, and stroke. Sex differences between continuous and categorical variables were analyzed using Mann-Whitney U test and Fisher's Exact test, respectively. RESULTS: This study included 48 patients (27 (56%) female). The median age at diagnosis in females was 14.0 (interquartile range (IQR) 9.0-30.0) and in males was 8.0 (IQR 2.0-23.0) (p = 0.07). Baseline clinical characteristics were comparable between both sexes. The median baseline LDL-C was 12.7 mmol/L (10.0-18.3) in females and 15.3 (10.5-20.0) in males (p = 0.51). Follow up LDL-C levels were 7.6 mmol/L (IQR 4.8-11.0) in females and 6.3 (IQR 4.6-7.5) in males (p = 0.1). Most patients were taking 3 or more LLTs, with comparable proportions in both sexes (p = 0.26). Apheresis was similar in both sexes, 14 (51.8%) vs. 10 (47.6%) (p = 0.2). Over a mean of 10 years of follow-up, MACE occurred in 3 females (11.1%) and 4 males (19.1%) (p = 0.2). CONCLUSION: Lipid levels and treatment were similar between sexes. MACE occurred in similar proportions between sexes, indicating that HoFH offsets the inherently lower cardiovascular risk in pre-menopausal females. Further investigation into sex-differences in HoFH in larger sample sizes is warranted.


Asunto(s)
Caracteres Sexuales , Humanos , Masculino , Femenino , Adulto , Adolescente , Resultado del Tratamiento , Adulto Joven , Niño , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/terapia , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/diagnóstico , LDL-Colesterol/sangre , Homocigoto , Factores Sexuales
9.
J Neurochem ; 126(3): 415-24, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23432034

RESUMEN

We have recently reported that a ~19-kDa polypeptide, rPK-4, is a protein kinase Cs inhibitor that is 89% homologous to the 1171-1323 amino acid region of the 228-kDa human pericentriolar material-1 (PCM-1) protein (Chakravarthy et al. 2012). We have now discovered that rPK-4 binds oligomeric amyloid-ß peptide (Aß)1-42 with high affinity. Most importantly, a PCM-1-selective antibody co-precipitated Aß and amyloid ß precursor protein (AßPP) from cerebral cortices and hippocampi from AD (Alzheimer's disease) transgenic mice that produce human AßPP and Aß1-42 , suggesting that PCM-1 may interact with amyloid precursor protein/Aß in vivo. We have identified rPK-4's Aß-binding domain using a set of overlapping synthetic peptides. We have found with ELISA, dot-blot, and polyacrylamide gel electrophoresis techniques that a ~ 5 kDa synthetic peptide, amyloid binding peptide (ABP)-p4-5 binds Aß1-42 at nM levels. Most importantly, ABP-p4-5, like rPK-4, appears to preferentially bind Aß1-42 oligomers, believed to be the toxic AD-drivers. As expected from these observations, ABP-p4-5 prevented Aß1-42 from killing human SH-SY5Y neuroblastoma cells via apoptosis. These findings indicate that ABP-p4-5 is a possible candidate therapeutic for AD.


Asunto(s)
Péptidos beta-Amiloides/metabolismo , Autoantígenos/química , Autoantígenos/metabolismo , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Péptidos/química , Péptidos/metabolismo , Secuencia de Aminoácidos , Animales , Western Blotting , Línea Celular Tumoral , Ensayo de Inmunoadsorción Enzimática , Humanos , Immunoblotting , Inmunoprecipitación , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Datos de Secuencia Molecular , Estructura Terciaria de Proteína
10.
Am J Phys Anthropol ; 151(1): 22-37, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23440681

RESUMEN

This study investigates two key variables-residential context and subsistence-among sacrificial victims dating to the Late Horizon (A.D. 1450-1532) in the Huaca de los Sacrificios at the Chotuna-Chornancap Archaeological Complex in north coastal Peru. We investigate whether aspects of sacrifice in this distant coastal province mirrored that found in Inca heartland contexts such as the capacocha, or remained more typical of coastal sacrificial traditions. Stable carbon, nitrogen, and oxygen isotope values were characterized in bone carbonate, bone collagen, and hair keratin to estimate geographic residence during the decade before death and diet in the decade, versus months, before death. Bone δ18 Ocarbonate values have a mean (±SD) of 26.8 ± 1.1%, bone δ13 Ccarbonate values -6.7 ± 1.7%, and bone δ(13) Ccollagen values 11.8 ± 1.3%; bone δ15 Ncollagen values have a mean of 11.5 ± 1.3%. Combined hair δ13 Ckeratin values have a mean of -12.8 ± 1.6%, and hair δ15 Nkeratin values 10.8 ± 1.3%. In contrast to contemporaneous coastal and highland contexts, we are unable to identify immigrants among the sacrificed individuals or changes in diet that indicate provisioning with a standardized diet leading up to death. Instead, results suggest that victims were local to the area, but consumed moderately variable diets consistent with local subsistence patterns. These findings suggest a distinct pattern of human sacrifice in the Late Horizon and underscore the regional and temporal variation in sacrificial practices in the central Andes.


Asunto(s)
Huesos/química , Conducta Ceremonial , Colágeno/química , Cabello/química , Queratinas/química , Adolescente , Adulto , Antropología Física , Arqueología , Entierro/historia , Isótopos de Carbono/análisis , Niño , Preescolar , Dieta , Femenino , Historia Antigua , Humanos , Indígenas Sudamericanos , Masculino , Isótopos de Nitrógeno/análisis , Perú , Análisis de Regresión , Adulto Joven
11.
Biosci Rep ; 43(7)2023 07 26.
Artículo en Inglés | MEDLINE | ID: mdl-37278746

RESUMEN

Ergothioneine, an antioxidant nutraceutical mainly at present derived from the dietary intake of mushrooms, has been suggested as a preventive for pre-eclampsia (PE). We analysed early pregnancy samples from a cohort of 432 first time mothers as part of the Screening for Endpoints in Pregnancy (SCOPE, European branch) project to determine the concentration of ergothioneine in their plasma. There was a weak association between the ergothioneine levels and maternal age but none for BMI. Of these 432 women, 97 went on to develop pre-term (23) or term (74) PE. If a threshold was set at the 90th percentile of the reference range in the control population (≥462 ng/ml), only one of these 97 women (1%) developed PE, versus 96/397 (24.2%) whose ergothioneine level was below this threshold. One possible interpretation of these findings, consistent with previous experiments in a reduced uterine perfusion model in rats, is that ergothioneine may indeed prove protective against PE in humans. An intervention study of some kind now seems warranted.


Asunto(s)
Ergotioneína , Preeclampsia , Embarazo , Femenino , Ratas , Humanos , Animales , Preeclampsia/prevención & control , Antioxidantes , Suplementos Dietéticos , Útero , Biomarcadores
12.
Res Sq ; 2023 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-37645914

RESUMEN

Background: Trauma-Informed Care (TIC) is an evidence-based approach for improving health outcomes by providing systematic, trauma- sensitive and -responsive care. Because TIC adoption varies by setting and population, Implementation Science (IS) is particularly well-suited to guide roll-out efforts. Process Mapping (PM) is an IS model for creating shared visual depictions of systems as they are to identify rate-limiting steps of intervention adoption, but guidance on how to apply PM to guide TIC adoption is lacking. Authors of this study aimed to develop a novel method for conducting TIC-focused PM. Methods: A real-life TIC implementation study is presented to show how TIC-focused PM was conducted in the case example of a pediatric HIV clinic in a Southern urban area with a high burden of psychological trauma among youth with HIV. A five-phase PM model was applied to evince clinic standards of care, including Preparation, planning and process identification; Data and information gathering; Map generation; Analysis; and Taking it forward. Practices and conditions from four TIC domains were assessed, including Trauma responsive services; Practices of inclusivity, safety, and wellness; Training and sustaining trauma responsiveness; and Cultural responsiveness. Results: The TIC-focused PM method indicated the case clinic provided limited and non-systematic patient trauma screening, assessment, and interventions; limited efforts to promote professional quality of life and elicit and integrate patient experiences and preferences for care; no ongoing efforts to train and prepare workforce for trauma- sensitive or -responsive care; and no clinic-specific efforts to promote diversity, equity, and inclusion for patients and personnel. Conclusion: Principles and constructs of resilience-focused TIC were synthesized with a five-phase PM model to generate a baseline depiction of TIC in a pediatric HIV clinic. Results will inform the implementation of TIC in the clinic. Future champions may follow the TIC-focused PM model to guide context-tailored TIC adoption.

13.
JACC Adv ; 2(3): 100309, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-38939573

RESUMEN

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease characterized by very high levels of low-density lipoprotein cholesterol (LDL-C). Untreated patients present with extensive xanthomas and premature atherosclerosis. Lipid-lowering therapy is highly efficacious and has dramatically increased life expectancy of patients with HoFH. Objectives: The aim of the study was to obtain a comprehensive registry of HoFH in Canada, known to have several founder effect regions, and describe the clinical characteristics and cardiovascular outcomes of this population over time. Methods: Clinical and genetic data on patients with HoFH were collected via a standardized questionnaire sent to academic sites participating in the Familial Hypercholesterolemia Canada network. Results: A total of 48 patients with HoFH were enrolled. The median age at diagnosis was 12 years (interquartile range [IQR]: 5-24) and untreated LDL-C levels were 15.0 mmol/L (IQR: 10.5-18.6 mmol/L; 580 mg/dL IQR: 404-717 mg/dL). At last follow-up visit, median age was 40 years (IQR: 26-54 years). Treated LDL-C levels were 6.75 mmol/L (IQR: 4.73-9.51 mmol/L; 261 mg/dL IQR: 183-368 mg/dL) with 95.5% of patients on statins, 88.6% on ezetimibe, 34.1% on proprotein convertase subtilisin/kexin type 9 inhibitors, 27.3% on lomitapide, 13.6% on evinacumab, and 56.8% were treated with low-density lipoprotein apheresis or plasmapheresis. Deaths were reported in 7 (14.5%) and major adverse cardiovascular events were observed in 14.6% of patients with the average onset at 30 years (IQR: 20-36 years). Aortic stenosis was reported in one-half the patients (47.9%) and 10 (20.8%) underwent aortic valve replacement. Conclusions: This HoFH patient registry in Canada will provide important new health-related knowledge about the phenotypic manifestations and determinants of cardiovascular risk in this population, allowing for closer examination of quality of life and burden to the health care system.

14.
Biochem Biophys Res Commun ; 424(1): 147-51, 2012 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-22732405

RESUMEN

We had previously identified a protein kinase C (PKC) inhibitor in murine neuroblastoma cells (Chakravarthy et al. [1]). Similar PKC inhibitory activity was also found in adult rat brain. Using polyclonal antibodies raised against the partially purified PKC inhibitor from rat brain as bait, we isolated a putative brain PKC inhibitor using a T-7 phage display system expressing human brain cDNA library. After enriching the phage population expressing the putative PKC inhibitor with four rounds of biopanning using ELISA and in vitro PKC binding assays, we identified a phage clone that expressed a product with significant PKC inhibitory activity. We have cloned and expressed this cDNA in a bacterial system and purified the recombinant protein. This polypeptide (174 amino acids) is highly homologous to a region of the 228-kDa PCM-1, the human pericentriolar material 1 protein. We have mapped this polypeptide's PKC-inhibitory domain and shown its PKC inhibitory activity in vitro. However, it will need to be determined whether the full-length PCM-1 protein possesses PKC inhibitory activity in vivo, and if so, how this might contribute to PCM-1's recently demonstrated roles in ciliogenesis and neurogenesis.


Asunto(s)
Autoantígenos/química , Proteínas de Ciclo Celular/química , Péptidos/química , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Secuencia de Aminoácidos , Animales , Autoantígenos/genética , Autoantígenos/farmacología , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/farmacología , Biblioteca de Genes , Humanos , Ratones , Datos de Secuencia Molecular , Biblioteca de Péptidos , Péptidos/genética , Péptidos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética
15.
Biochem Biophys Res Commun ; 427(1): 218-22, 2012 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-22995307

RESUMEN

The hippocampal dentate gyrus is one of the two sites of continuous neurogenesis in adult rodents and humans. Virtually all dentate granule cells have a single immobile cilium with a microtubule spine or axoneme covered with a specialized cell membrane loaded with receptors such as the somatostatin receptor 3 (SSTR3), and the p75 neurotrophin receptor (p75(NTR)). The signals from these receptors have been reported to stimulate neuroprogenitor proliferation and the post-mitotic maturation of newborn granule cells into functioning granule cells. We have found that in 6-24-months-old triple transgenic Alzheimer's disease model mice (3xTg-AD) producing both Aß(1-42) and the mutant human tau protein tau(P301L,) the dentate granule cells still had immunostainable SSTR3- and p75(NTR)-bearing cilia but they were only half the length of the immunostained cilia in the corresponding wild-type mice. However, the immunostainable length of the granule cell cilia was not reduced either in 2xTg-AD mice accumulating large amounts of Aß(1-42) or in mice accumulating only a mutant human tau protein. Thus it appears that a combination of Aß(1-42) and tau protein accumulation affects the levels of functionally important receptors in 3xTg-AD mice. These observations raise the important possibility that structural and functional changes in granule cell cilia might have a role in AD.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/biosíntesis , Giro Dentado/metabolismo , Fragmentos de Péptidos/biosíntesis , Proteínas tau/biosíntesis , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Animales , Biomarcadores/metabolismo , Cilios/metabolismo , Giro Dentado/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fragmentos de Péptidos/genética , Receptores de Factor de Crecimiento Nervioso/metabolismo , Receptores de Somatostatina/metabolismo , Coloración y Etiquetado , Proteínas tau/genética
16.
Compr Psychiatry ; 53(5): 409-21, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21831368

RESUMEN

OBJECTIVES: Current clinical and epidemiological research provides support for a continuum of bipolar psychopathology: a bipolar spectrum that ranges from subclinical manifestations to full-blown bipolar disorders. Examining subthreshold bipolar symptoms may identify individuals at risk for clinical disorders, promote early interventions and monitoring, and increase the likelihood of appropriate treatment. The present studies examined the construct validity of bipolar spectrum psychopathology using the Hypomanic Personality Scale. METHODS: Study 1 used interview and questionnaire measures of bipolar spectrum psychopathology in a sample of 145 nonclinically ascertained young adults. Study 2 assessed the expression of the bipolar spectrum in daily life using experience sampling methodology in the same sample. RESULTS: In study 1, Hypomanic Personality Scale scores were positively associated with clinical bipolar disorders, bipolar spectrum disorders, the presence of hypomania or hyperthymia, depressive symptoms, poor psychosocial functioning, cyclothymia, irritability, and symptoms of borderline personality disorder. In study 2, bipolar spectrum psychopathology was associated with negative affect, thought disturbance, risky behavior, and measures of grandiosity. These findings remained independent of clinical bipolar disorders. CONCLUSIONS: In the present studies, bipolar-like disruptions in cognition, affect, and behavior were not limited to clinical diagnoses or mood episodes, providing further validation of the bipolar spectrum construct. The bipolar spectrum model appears to provide a conceptually richer basis for understanding and ultimately treating bipolar psychopathology than current diagnostic formulations.


Asunto(s)
Actividades Cotidianas , Trastorno Bipolar/diagnóstico , Tamizaje Masivo , Inventario de Personalidad , Trastorno Bipolar/prevención & control , Trastorno Bipolar/psicología , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Diagnóstico Precoz , Femenino , Humanos , Entrevista Psicológica , Masculino , Análisis Multivariante , Análisis de Regresión , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , Estados Unidos , Adulto Joven
17.
Pers Individ Dif ; 53(3): 185-190, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27013770

RESUMEN

An experience sampling study assessed the relation between psychological functioning in daily life and emotional expressivity as measured by the emotional expressivity scale (EES). Four hundred and twenty-nine participants carried personal digital assistants that signaled them 8 times daily to complete questionnaires assessing affect, activities, and social contact. As predicted, participants high in emotional expressivity were more likely to have elevated state positive affect, but not negative affect. These participants were also less likely to be alone and more likely to demonstrate better social functioning when with others. Cross-level interactions indicated that emotional expressivity moderated the association of social context and functioning in the moment. The findings support the validity of the EES as a measure of emotional expressivity and demonstrate the utility of experience sampling for describing personality traits in daily life.

18.
Violence Against Women ; 28(6-7): 1505-1522, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-34157908

RESUMEN

Intimate partner violence (IPV) and HIV are correlated and endemic in South Africa. However, safety strategy use to prevent IPV among HIV-positive women is understudied. This study assesses correlates of specific safety strategy use among 166 Black South African women recently experiencing IPV and testing positive for HIV. Associations were observed between consultation with formal (i.e., counselors, clergy, IPV specialists) and informal networks (i.e., friends/family) and participant language (isiZulu, isiXhosa, Sesotho, and English), past year IPV, and engaging in HIV care. Future HIV-IPV programs should consider how characteristics of different IPV safety strategies may influence strategy uptake and ultimately HIV care.


Asunto(s)
Infecciones por VIH , Violencia de Pareja , Femenino , Infecciones por VIH/prevención & control , Humanos , Prevalencia , Factores de Riesgo , Parejas Sexuales , Sudáfrica/epidemiología
19.
J Nerv Ment Dis ; 199(6): 403-9, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21629020

RESUMEN

Both clinical and subclinical depression are associated with social impairment; however, few studies have examined the impact of social contact in the daily lives of people with depressive symptoms. The current study used the experience-sampling methodology to examine associations between depressive symptoms, social contact, and daily life impairment in 197 young adults. Depressive symptoms were associated with increased isolation, negative affect, anhedonia, and physical symptoms, decreased positive affect, and social and cognitive impairment in daily life. For people with more depressive symptoms, being with social partners who were perceived as close was associated with greater decreases in negative affect, as well as increases in positive affect. Ironically, participants with depressive symptoms reported spending less time with people whom they perceived as close, minimizing the protective effects of socializing. These results suggest that people experiencing depressive symptoms may be especially sensitive to the nature of social interactions.


Asunto(s)
Depresión/diagnóstico , Depresión/psicología , Acontecimientos que Cambian la Vida , Autoevaluación (Psicología) , Apoyo Social , Adolescente , Depresión/epidemiología , Femenino , Humanos , Masculino , Muestreo , Medio Social , Encuestas y Cuestionarios , Adulto Joven
20.
PLoS One ; 16(5): e0251421, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33975332

RESUMEN

Variability of ephemeral resources provided by woody plants is related to fluctuating environmental conditions, specifically the predominant climate variables temperature and rainfall. Photoperiod has less impact but also plays a role in the onset of resource pulses. In the seasonally affected bushveld of southern Africa, declining resources could have dire consequences to various animals that depend on these resources. Understanding the impact that rainfall, temperature and photoperiod has on woody plant resources allows managers of natural areas to plan for times when resources are scarce. Using a series of General Linear Models, this baseline study investigates the effects that these variables have on flower production, numbers of new fruit/pods and numbers of new leaves for 113 tagged trees from 26 woody plant species. Leads, lags and coincidental relationships observed between environmental predictor and phenological response variables were explored using time-series cross-correlations and concomitant correlograms. Model results indicated that temperature was the predominant indicator for flowering, with initial flowering starting when temperatures increase in September. A significant lead was observed between flowering and rainfall, suggesting that flower numbers increase approximately one month before rainfall increases. Temperature had the biggest effect on the number of species with new fruits and pods. Significant lags were observed between new fruits and pods and all environmental variables investigated, indicating that these resources depend on rainfall, temperature and photoperiod to reach their full potential. Photoperiod, temperature and the interaction between these variables had a noticeable effect on the number of species with new leaves. Peaks in species with new leaves coincide with peaks in rainfall, temperature and photoperiod. No leading or lagging indicators were observed between new leaves and the environmental variables investigated. In areas containing wildlife populations, recommendations are to undertake regular monitoring of climatic variables investigated, and the ephemeral resources on woody plant species.


Asunto(s)
Pradera , Periodicidad , Fotoperiodo , Plantas , Lluvia , Temperatura , África Austral , Biodiversidad , Modelos Lineales , Fenómenos Fisiológicos de las Plantas , Plantas/efectos de la radiación , Estaciones del Año , Sudáfrica
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