RESUMEN
OBJECTIVES: As a well-documented social determinant of health, food insecurity may be associated with COVID-19 infection in households with older adults. We examined whether older adults were vulnerable to COVID-19 infection during the early pandemic if they were food insecure versus food secure. STUDY DESIGN: A cross-sectional study using a nationally representative population-based survey of US older adults. METHODS: We used a random subsample of Health and Retirement Study (HRS) drawn in June 2020 (N = 3212). We compared the odds of reporting COVID-19 infection in a household, COVID-19 infection and mortality among acquaintances, and respondent's perceived fair or poor health across household food insecurity status resulted from financial or non-financial barriers. Baseline health and socioeconomic circumstances were adjusted in the models. RESULTS: Results showed a higher COVID-19 infection rate among food-insecure households than among their food-secure counterparts during the pandemic. Food insecurity due to non-financial obstacles was associated with greater likelihood of COVID-19 infection both within respondents' households (adjusted odds ratio [aOR] = 1.73, 95% confidence interval [CI]: 1.03-2.90) and among their acquaintances (aOR = 1.32, 95% CI: 1.05-1.65). Food insecurity caused by both non-financial and financial constraints was associated with twice the likelihood of knowing someone who died from COVID-19 than their food-secure counterparts (aOR = 2.14, 95% CI: 1.27-3.61). CONCLUSIONS: Food insecurity driven by non-financial constraints played an important role in the ongoing pandemic among US older adults. Policies addressing COVID-19 need to recognize the vulnerability of food-insecure older adults beyond lack of monetary resources.
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COVID-19 , Inseguridad Alimentaria , Anciano , Estudios Transversales , Abastecimiento de Alimentos , Humanos , SARS-CoV-2RESUMEN
BACKGROUND: The efficacy of ixekizumab, an anti-interleukin-17A (anti-IL-17A) monoclonal IgG4 antibody, was demonstrated in moderate-to-severe psoriasis patients when administered via prefilled syringe (PFS). OBJECTIVE: To evaluate the effect of two drug delivery devices on the pharmacokinetics (PK) of ixekizumab as well as efficacy and safety with both devices. METHODS: In the first 12 weeks of an open-label, phase 3 study, moderate-to-severe psoriasis patients were randomized to ixekizumab delivery via PFS or autoinjector device. Randomization was stratified by weight (<80 kg, 80-100 kg, >100 kg), injection assistance (yes/no) and injection site (arm, thigh or abdomen). Following a 160-mg initial dose at week 0, patients received subcutaneous 80-mg ixekizumab as a single injection every 2 weeks for 12 weeks. Blood samples were collected following the initial 160-mg dose on days 2, 4, 7, 10 and 14 for PK analysis. Primary PK parameters were maximum concentration (Cmax ) and area under the curve (AUC0-tlast ) where tlast is the time of last sample (14 days ± 24 h). Efficacy was assessed by percent improvement on the Psoriasis Area and Severity Index (PASI) at week 12. Adverse event reporting, vital signs and clinical laboratory data were used to evaluate safety. RESULTS: Of 204 randomized patients, 192 were included in the PK analysis (PFS: 94; autoinjector: 98). The PFS and autoinjector showed similar geometric mean Cmax (90% CI) [15.0 µg/mL (13.9-16.1) vs. 14.8 µg/mL (13.8-15.9)] and geometric mean AUC0-tlast (90% CI) [157 µg × day/mL (147-168) vs. 154 µg × day/mL (144-165)]. When comparing Cmax and AUC0-tlast of the autoinjector to PFS, the geometric LS mean ratios were 0.97. At week 12, mean percent PASI improvement (via modified baseline observation carried forward) was similar with the PFS (89.3%) and autoinjector (86.9%). Both devices had safety results that were consistent with the known safety profile of ixekizumab. CONCLUSION: The PK, efficacy and safety of ixekizumab administered subcutaneously by PFS and autoinjector were similar. Clinicaltrials.gov number: NCT01777191 https://clinicaltrials.gov/ct2/show/NCT01777191.
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Anticuerpos Monoclonales Humanizados/farmacocinética , Psoriasis/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Humanos , Inyecciones Subcutáneas , Índice de Severidad de la EnfermedadRESUMEN
AIMS: Basal insulin peglispro (BIL), a novel PEGylated basal insulin with a large hydrodynamic size, has a delayed absorption and reduced clearance that prolongs the duration of action. The current study compared the effects of BIL and insulin glargine (GL) on endogenous glucose production (EGP), glucose disposal rate (GDR) and lipolysis in patients with type 1 diabetes. MATERIALS AND METHODS: This was a randomized, open-label, four-period, crossover study. Patients received intravenous infusions of BIL and GL, each at two dose levels selected for partial and maximal suppression of EGP, during an 8 to 10 h euglycemic clamp procedure with d-[3-3 H] glucose. RESULTS: Following correction for equivalent human insulin concentrations (EHIC), low-dose GL infusion resulted in similar EGP at the end of the clamp compared to low-dose BIL infusion (GL/BIL ratio of 1.03) but a higher GDR (GL/BIL ratio of 2.42), indicating similar hepatic activity but attenuated peripheral activity of BIL. Consistent with this, the EHIC-corrected GDR/EGP at the end of the clamp was 1.72-fold greater for GL than BIL following low-dose administration. At the lower dose of BIL and GL (concentrations in the therapeutic range), BIL produced less suppression of lipolysis compared with GL as indicated by free fatty acid and glycerol levels at the end of the clamp. CONCLUSIONS: Compared with GL, BIL restored the hepato-peripheral insulin action gradient seen in normal physiology via its peripherally restricted action on target tissues related to carbohydrate and lipid metabolism.
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Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemiantes/farmacología , Insulina Glargina/farmacología , Insulina Lispro/análogos & derivados , Lipólisis/efectos de los fármacos , Hígado/efectos de los fármacos , Polietilenglicoles/farmacología , Adulto , Glucemia/metabolismo , Estudios Cruzados , Diabetes Mellitus Tipo 1/metabolismo , Ácidos Grasos no Esterificados/metabolismo , Técnica de Clampeo de la Glucosa , Glicerol/metabolismo , Humanos , Hipoglucemiantes/uso terapéutico , Infusiones Intravenosas , Insulina Glargina/uso terapéutico , Insulina Lispro/farmacología , Insulina Lispro/uso terapéutico , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Polietilenglicoles/uso terapéutico , Tritio , Adulto JovenRESUMEN
AIMS: To assess the pharmacokinetics (PK) and glucodynamics (GD) of LY2605541 in patients with type 2 diabetes mellitus. METHODS: This parallel-group, open-label, dose-escalation study examined the PK and GD of basal insulin LY2605541 after single and multiple-dose administration. Fixed doses of LY2605541 (0.33-1.00 U/kg) were given once-daily (QD) for 14 days to insulin-treated patients with type 2 diabetes. A 24-h euglycaemic glucose clamp was conducted on days 1 and 14. RESULTS: PK steady state was achieved within 7-10 days and the peak-to-trough fluctuation was <2, translating to a nearly 'peakless' glucose infusion rate at steady state and with a duration of action of at least 24 h. Across dose levels t1/2 ranged from 44.7 to 75.5 h (~2-3 days). As steady state was achieved, there were dose-dependent reductions in the prandial insulin dose and in fasting blood glucose, which decreased to 60-100 mg/dl across dose levels. Within-patient variability was <14 and <26% for the area under the concentration versus time curve (AUC) of the 8-point blood glucose profile and fasting blood glucose, respectively. The nocturnal glucose control between 03:00 and 09:00 hours was relatively unchanged. Mild hypoglycaemia was the most common adverse event. CONCLUSIONS: In this Phase I study of fixed LY2605541 doses without titration, LY2605541 was well-tolerated and demonstrated a flat PK and GD profile accompanied by glucose normalization, prandial insulin dose reduction and no severe hypoglycaemia.
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Glucemia/efectos de los fármacos , Péptido C/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hemoglobina Glucada/efectos de los fármacos , Hipoglucemiantes/farmacocinética , Insulina Lispro/farmacocinética , Polietilenglicoles/farmacocinética , Adolescente , Adulto , Anciano , Área Bajo la Curva , Glucemia/metabolismo , Péptido C/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Esquema de Medicación , Femenino , Técnica de Clampeo de la Glucosa , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemiantes/administración & dosificación , Insulina Lispro/administración & dosificación , Masculino , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: In prostate cancer patients treated with androgen deprivation therapy (ADT) and radiation therapy (RT), a pre-RT PSA level î¶0.5 ng ml(-1), determined after neoadjuvant ADT and before RT, predicts for worse survival measures. The present study sought to identify patient, tumor and treatment characteristics associated with the pre-RT PSA in prostate cancer patients. METHODS: We reviewed the charts of all patients diagnosed with intermediate- and high-risk prostate cancer and treated with a combination of neoadjuvant (median, 2.2 and 2.5 months, respectively), concurrent, and adjuvant ADT and RT between 1990 and 2011. RESULTS: A total of 170 intermediate- and 283 high-risk patients met inclusion criteria. On multivariate analysis, both intermediate- and high-risk patients with higher pre-treatment PSA (iPSA) were significantly less likely to achieve a pre-RT PSA <0.5 ng ml(-1) (iPSA 10.1-20 ng ml(-1): P=0.005 for intermediate risk; iPSA 10.1-20 ng ml(-1): P=0.005, iPSA >20 ng ml(-1): P<0.001 for high risk). High-risk patients undergoing total androgen blockade were more likely to achieve a pre-RT PSA <0.5 ng ml(-1) (P=0.031). We observed an interaction between race and type of neoadjuvant ADT (P=0.074); whereas African-American men on total androgen blockade reached pre-RT PSA <0.5 ng ml(-1) as frequently as other men on total androgen blockade (P=0.999), African-American men on luteinizing hormone-releasing hormone (LH-RH) agonist monotherapy/orchiectomy were significantly less likely to reach pre-RT PSA <0.5 ng ml(-1) compared with other men on LH-RH monotherapy/orchiectomy (P=0.001). CONCLUSIONS: Our findings suggest that total androgen blockade in the neoadjuvant period may be beneficial compared with LH-RH monotherapy for achieving a pre-RT PSA <0.5 ng ml(-1) in African-American men with high-risk prostate cancer. In addition, men with higher iPSA are more likely to have a pre-RT PSA greater than 0.5 ng ml(-1) in response to neoadjuvant ADT and are therefore candidates for clinical trials testing newer, more aggressive hormone-ablative therapies.
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Antagonistas de Andrógenos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Clasificación del Tumor , Estadificación de Neoplasias , Antígeno Prostático Específico/genética , Antígeno Prostático Específico/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/radioterapia , Factores de Riesgo , Resultado del TratamientoRESUMEN
AMP-activated protein kinase (AMPK), a heterotrimeric serine/threonine kinase, is activated by conditions leading to an increase of the intracellular AMP:ATP ratio. However, how AMPK is regulated under the oxidative stress is completely unknown. In the present study, we examined effects of the oxidative agent H(2)O(2) on AMPK. AMPK was transiently and concentration-dependently activated by H(2)O(2) in NIH-3T3 cells. This activation was tightly associated with an increased AMP:ATP ratio, an electrophoretic mobility shift of AMPK alpha1 catalytic subunit, and an increased phosphorylation level of AMPK alpha1 threonine 172, which is a major in vitro phosphorylation site by the upstream AMPK kinase. All of these events were significantly blocked by the pretreatment of 0.5% dimethyl sulfoxide, a potent hydroxyl radical scavenger, indicating that AMPK cascades are highly sensitive to the oxidative stress. Interestingly, a specific tyrosine kinase inhibitor, genistein, further stimulated the H(2)O(2)-induced AMPK activity by 70% without altering the AMP:ATP. Taken together, our results suggest that AMP:ATP ratio is the major parameter to which AMPK responds under the oxidative stress, but AMPK may be regulated in part by a tyrosine kinase-dependent pathway, which is independent of the cellular adenosine nucleotides level.
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Peróxido de Hidrógeno/farmacología , Complejos Multienzimáticos/metabolismo , Estrés Oxidativo/fisiología , Proteínas Serina-Treonina Quinasas/metabolismo , Células 3T3 , Proteínas Quinasas Activadas por AMP , Adenosina Monofosfato/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Catálisis , Activación Enzimática/efectos de los fármacos , Ratones , Fosforilación/efectos de los fármacos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Treonina/metabolismoRESUMEN
AMP-activated protein kinase (AMPK) is tightly regulated by the cellular AMP:ATP ratio and plays a central role in the regulation of energy homeostasis. Previously, AMPK was reported to phosphorylate serine 621 of Raf-1 in vitro. In the present study, we investigated a possible role of AMPK in extracellular signal-regulated kinase (Erk) cascades, using 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR), a cell-permeable activator of AMPK and antisense RNA experiments. Activation of AMPK by AICAR in NIH-3T3 cells resulted in drastic inhibitions of Ras, Raf-1, and Erk activation induced by insulin-like growth factor 1 (IGF-1). Expression of an antisense RNA for the AMPK catalytic subunit decreased the AMPK activity and significantly diminished the AICAR effect on IGF-1-induced Ras activation and the subsequent Erk activation, indicating that its effect is indeed mediated by AMPK. Phosphorylation of Raf-1 serine 621, however, was not involved in AMPK-mediated inhibition of Erk cascades. In contrast to IGF-1, AICAR did not block epidermal growth factor (EGF)-dependent Raf-1 and Erk activation, but our results demonstrated that multiple Raf-1 upstream pathways induced by EGF were differentially affected by AICAR: inhibition of Ras activation and simultaneous induction of Ras-independent Raf activation. The activities of IGF-1 and EGF receptor were not affected by AICAR. Taken together, our results suggest that AMPK differentially regulate Erk cascades by inhibiting Ras activation or stimulating the Ras-independent pathway in response to the varying energy status of the cell.
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Aminoimidazol Carboxamida/análogos & derivados , Factor de Crecimiento Epidérmico/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Complejos Multienzimáticos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Células 3T3 , Proteínas Quinasas Activadas por AMP , Aminoimidazol Carboxamida/farmacología , Animales , Células COS , Catálisis , Línea Celular , Colforsina/farmacología , ADN/efectos de los fármacos , ADN Complementario/metabolismo , Activación Enzimática , Inhibidores Enzimáticos/farmacología , Flavonoides/farmacología , Ratones , Fosforilación , Unión Proteica , Proteínas Proto-Oncogénicas c-raf/metabolismo , ARN/metabolismo , ARN sin Sentido/metabolismo , Ribonucleótidos/farmacología , Serina/química , Transducción de Señal , Factores de Tiempo , TransfecciónRESUMEN
The activation of both phosphatidylinositol 3-kinase (PI3-kinase) and p38 mitogen-activated protein kinase (p38 MAPK) is required for muscle differentiation. However, it is not known whether the signals from these two kinases interact during this process. In this work, we have investigated this using H9c2 cardiac myoblasts. The p38 MAPK-specific inhibitor SB203580 blocked muscle differentiation and suppressed the expression of myogenin and myosin heavy chain in a concentration-dependent manner. Consistent with this, expression of a wild-type p38 MAPK (Ha-p38) or a constitutively active MAPK kinase 6 (MKK6(glu)) promoted the rate of differentiation into multinucleated myotubes. LY294002, a PI3-kinase inhibitor, suppressed in a dose-dependent manner not only muscle differentiation but also activation of p38 MAPK. In addition, expression of a constitutively active form of PI3-kinase (p110*) enhanced myotube formation and p38 MAPK activation, while expression of a dominant negative form of PI3-kinase (Deltap85) attenuated these responses. Furthermore, SB203580 suppressed differentiation of H9c2 cells expressing p110*. Interestingly, LY294002 also suppressed differentiation of H9c2 cells expressing Ha-p38 or MKK6(glu). However, SB203580 did not affect PI3-kinase activity, suggesting that PI3-kinase myogenic signaling to p38 MAPK is unidirectional. Taken together, we concluded that PI3-kinase activates p38 MAPK, which in turn stimulates muscle differentiation, but that p38 MAPK does not substitute for PI3-kinase in this process.
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Diferenciación Celular/fisiología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Músculos/citología , Fosfatidilinositol 3-Quinasas/fisiología , Animales , Células Cultivadas , Activación Enzimática , Inhibidores Enzimáticos/farmacología , Imidazoles/farmacología , Proteínas Quinasas Activadas por Mitógenos/fisiología , Músculos/enzimología , Piridinas/farmacología , Ratas , Transducción de Señal , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
Mannan-binding lectin (MBL)-associated plasma protein (MAp19) is an alternatively spliced form of MBL-associated serine protease-2, a component of a complement activation cascade. We observed that MAp19 is excreted in human urine. Interestingly, the amount of MAp19 was higher in urine of renal cell carcinoma patients than healthy people. Pretreatment of urine dialysate with 50 mM EDTA increased the recovery of MAp19, suggesting that MAp19 is a calcium-binding protein. The recombinant MAp19 showed a strong inhibition of calcium oxalate crystal growth in vitro in a concentration-dependent manner. Thus, we conclude that MAp19 plays a role in the inhibition of calcium oxalate renal stone formation.
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Proteínas Sanguíneas/orina , Oxalato de Calcio/química , Lectinas , Mananos , Serina Endopeptidasas/orina , Empalme Alternativo , Secuencia de Aminoácidos , Proteínas Sanguíneas/química , Proteínas Sanguíneas/aislamiento & purificación , Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al Calcio/orina , Cristalización , Humanos , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa , Datos de Secuencia Molecular , Proteínas Recombinantes/química , Análisis de Secuencia , Serina Endopeptidasas/químicaRESUMEN
Phosphatidylinositol (PI) 3-kinase plays an important role in transducing the signals of various growth factor receptors. However, the regulatory mechanism of PI3-kinase activity by these growth factor receptors is not completely understood. Therefore, we attempted to clarify the regulatory mechanism of PI3-kinase using insulin and 3T3 L1 fibroblasts. Our results showed that insulin stimulated PI3-kinase activity seven-fold and concomitantly phosphorylated a p85 subunit at the tyrosine residue. However, this tyrosine phosphorylation was not significant in the activation of PI3-kinase as the PI3-kinase pulled down by the overexpressed GST-p85 fusion protein showed as high an activity as the immunoprecipitated one. The p110 subunit was phosphorylated at both serine and tyrosine residues without insulin treatment. Since the phosphorylation state was not changed by insulin. The results suggested that phosphorylation of the p110 subunit does not control PI3-kinase activity. Finally, it was shown that the insulin receptor substrate-1 (IRS-1) binding to PI3-kinase was not sufficient for full activation because the amount of IRS-1 pulled down by the GST-p85 fusion protein reached almost maximum, after incubation with insulin-treated cell lysates for 20 min, whereas PI3-kinase activity reached its maximum only after incubation for 5 h. All results suggest that the phosphorylation of p85 subunit at tyrosine residues and phosphorylation of p110 subunit at tyrosine or serine residues are not functionally significant in the regulation of PI3-kinase activity. They also suggest that P13-kinase is needed to bind to other protein(s) as well as the insulin receptor substrate-1 for full activation.