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1.
Tissue Barriers ; : 2300580, 2024 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-38179897

RESUMEN

Lipids and their mediators have important regulatory functions in many cellular processes, including the innate antiviral response. The aim of this study was to compare the lipid membrane composition of in vitro differentiated primary bronchial epithelial cells (PBECs) with ex vivo bronchial brushings and to establish whether any changes in the lipid membrane composition affect antiviral defense of cells from donors without and with severe asthma. Using mass spectrometry, we showed that the lipid membrane of in vitro differentiated PBECs was deprived of polyunsaturated fatty acids (PUFAs) compared to ex vivo bronchial brushings. Supplementation of the culture medium with arachidonic acid (AA) increased the PUFA-content to more closely match the ex vivo membrane profile. Rhinovirus (RV16) infection of AA-supplemented cultures from healthy donors resulted in significantly reduced viral replication while release of inflammatory mediators and prostaglandin E2 (PGE2) was significantly increased. Indomethacin, an inhibitor of prostaglandin-endoperoxide synthases, suppressed RV16-induced PGE2 release and significantly reduced CXCL-8/IL-8 release from AA-supplemented cultures indicating a link between PGE2 and CXCL8/IL-8 release. In contrast, in AA-supplemented cultures from severe asthmatic donors, viral replication was enhanced whereas PTGS2 expression and PGE2 release were unchanged and CXCL8/IL-8 was significantly reduced in response to RV16 infection. While the PTGS2/COX-2 pathway is initially pro-inflammatory, its downstream products can promote symptom resolution. Thus, reduced PGE2 release during an RV-induced severe asthma exacerbation may lead to prolonged symptoms and slower recovery. Our data highlight the importance of reflecting the in vivo lipid profile in in vitro cell cultures for mechanistic studies.

2.
Water Res ; 222: 118858, 2022 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-35872519

RESUMEN

The framework, model and methods of Nürnberg were applied and evaluated in Lough Neagh and 19 other lakes in order to establish inflow phosphorus concentrations that support target lake values. Supporting concentrations, in the absence of an internal load, were derived and the effect of uncertainty in the model retention coefficient was relatively small, ±11-20 % in Lough Neagh and an average (n = 17) of ±9.7 % in the other lakes. There was further support for the model and methods from an independent estimate of the net internal load in Lough Neagh (13 % difference) and from another model in the other lakes (Supporting concentrations, which should be lower, were by an average of 11 mg P m-3). In the framework, steady state with the phosphorus load is assumed, but, based on a generic lake model, is not likely if the hydraulic residence time>0.5-0.8 yr and should lead to a decrease in phosphorus retention, which was found during three periods in Lough Neagh. Based on a compilation of internal load recovery times from 23 lakes in the literature, it could take between 8 and 20 years for lakes with an internal load to approach their targets.


Asunto(s)
Lagos , Fósforo , Monitoreo del Ambiente , Eutrofización , Nitrógeno , Fósforo/análisis
3.
Water Res ; 200: 117283, 2021 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-34102385

RESUMEN

It is important for lake management and policy to estimate the timescale of recovery from long-term P release from sediment after a reduction in the external load. To provide a scientific basis for this, a condensed model was elaborated, applied and evaluated in four lakes. The model is based on first order kinetics, with an overall rate constant composed of the rate of diagenesis of labile P (kd,2) and rate of burial of P (kb) below an active sediment layer. Using the variation of P fractions in dated sediment cores, kd,2 varied from 0.0155 to 0.383 yr-1, kb from 0.0184 to 0.073 yr-1 and the overall rate constant from 0.0230 to 0.446 yr-1. The active layer depths, 8 to 29 cm, and kd,2 values are within the ranges found by others. The time for a 75% reduction (t75) of labile P in the active layer is 60 years in Lough Melvin, 3 in Ramor, 33 in Sheelin and 41 in Neagh, although P release is only important in Ramor and Neagh. Combining the kd,2 values with other estimates (mean 0.0981 yr-1, median 0.0426; n=14) produces a t75 value of less than 14 and 33 years. A review of other models indicates a timescale of one to two decades and from lake monitoring also of one to two decades. It is desirable to estimate the timescale directly in all lakes if sediment P release is important, but, generally, it should take between one and three decades.


Asunto(s)
Lagos , Contaminantes Químicos del Agua , Monitoreo del Ambiente , Sedimentos Geológicos , Cinética , Fósforo/análisis , Contaminantes Químicos del Agua/análisis
4.
Mindfulness (N Y) ; 12(2): 392-404, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33737986

RESUMEN

OBJECTIVES: Behavioral evidence suggests that parenting-focused mindfulness interventions can improve parenting practices and enhance family wellbeing, potentially operating through altered emotional processing in parents. However, the mechanisms through which parent mindfulness interventions achieve their positive benefits have not yet been empirically tested, knowledge which is key to refine and maximize intervention effects. Thus, as part of a randomized controlled trial, the present study examined the affective mechanisms of an 8-week parenting-focused mindfulness intervention, the Parenting Mindfully (PM) intervention, versus a minimal-intervention parent education control. METHODS: Twenty highly stressed mothers of adolescents completed pre- and post-intervention behavioral and fMRI sessions, in which mothers completed a parent-adolescent conflict interaction, fMRI emotion task, and fMRI resting state scan. Mothers reported on their mindful parenting, and maternal emotional reactivity to the parent-adolescent conflict task was assessed via observed emotion expression, self-reported negative emotion, and salivary cortisol reactivity. RESULTS: Results indicated that the PM intervention increased brain responsivity in left posterior insula in response to negative affective stimuli, and altered resting state functional connectivity in regions involved in self-reference, behavioral regulation, and social-emotional processing. Changes in mothers' brain function and connectivity were associated with increased mindful parenting and decreased emotional reactivity to the parent-adolescent conflict task. CONCLUSIONS: Findings suggest that mindfulness-based changes in maternal emotional awareness at the neurobiological level are associated with decreased emotional reactivity in parenting interactions, illuminating potential neurobiological targets for future parent-focused intervention.

5.
Eur Urol Oncol ; 3(3): 283-290, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-31103721

RESUMEN

BACKGROUND: Focal irreversible electroporation (IRE) can be used to treat men with localised prostate cancer (PCa) with reduced impact on quality of life (QoL). OBJECTIVE: To assess oncological and functional outcomes. DESIGN, SETTING, AND PARTICIPANTS: To report on a prospective database of patients undergoing primary IRE between February 2013 and August 2018. A minimum of 12-mo follow-up was available for 123 patients. Median follow-up was 36 mo (interquartile range [IQR] 24-52 mo). A total of 112 (91%) patients had National Comprehensive Cancer Network intermediate risk and 11 (9%) had low risk. A total of 12 (9.8%) had International Society of Urological Pathology (ISUP) grade 1, 88 (71.5%) had ISUP 2, and 23 (18.7%) had ISUP 3. INTERVENTION: Focal IRE ablation of PCa lesions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Follow-up involved serial prostate-specific antigen (PSA), multiparametric magnetic resonance imaging (mpMRI), and transperineal template mapping biopsy (TTMB) at 12 mo. Failure-free survival (FFS) was defined as progression to whole-gland or systemic treatment or metastasis/death. Functional outcomes were assessed. RESULTS AND LIMITATIONS: Median age was 68yr (IQR 62-73yr). Median preoperative PSA was 5.7ng/ml (IQR 3.8-8.0ng/ml). On post-treatment TTMB, in-field recurrence was present in 2.7-9.8% of patients. FFS at 3yr was 96.75%, metastasis-free survival 99%, and overall survival 100%. A total of 18 patients required salvage treatment (12 had repeat IRE; six had whole-gland treatment). The negative predictive value of mpMRI was 94% and sensitivity 40% for detecting in-field residual disease 6 mo after treatment. Among patients who returned questionnaires, 80/81 (98.8%) remained pad free and 40/53 (76%) had no change in erectile function. CONCLUSIONS: Focal IRE in select patients with localised clinically significant PCa has satisfactory short-term oncological outcomes with a minimal impact on patient QoL. PATIENT SUMMARY: In this study, 123 patients underwent focal therapy using irreversible electroporation. Follow-up biopsy was clear of residual disease in 90.2-97.3% of patients. Of patients, 96.75% avoided whole gland treatment at 3yr.


Asunto(s)
Técnicas de Ablación/métodos , Electrocirugia/métodos , Próstata/patología , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Calidad de Vida , Anciano , Biopsia , Estudios de Cohortes , Electroporación , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento
6.
Curr Biol ; 26(18): 2516-2521, 2016 09 26.
Artículo en Inglés | MEDLINE | ID: mdl-27618264

RESUMEN

Humans possess the unique ability for cumulative culture [1, 2]. It has been argued that hunter-gatherer's complex social structure [3-9] has facilitated the evolution of cumulative culture by allowing information exchange among large pools of individuals [10-13]. However, empirical evidence for the interaction between social structure and cultural transmission is scant [14]. Here we examine the reported co-occurrence of plant uses between individuals in dyads (which we define as their "shared knowledge" of plant uses) in BaYaka Pygmies from Congo. We studied reported uses of 33 plants of 219 individuals from four camps. We show that (1) plant uses by BaYaka fall into three main domains: medicinal, foraging, and social norms/beliefs; (2) most medicinal plants have known bioactive properties, and some are positively associated with children's BMI, suggesting that their use is adaptive; (3) knowledge of medicinal plants is mainly shared between spouses and biological and affinal kin; and (4) knowledge of plant uses associated with foraging and social norms is shared more widely among campmates, regardless of relatedness, and is important for camp-wide activities that require cooperation. Our results show the interdependence between social structure and knowledge sharing. We propose that long-term pair bonds, affinal kin recognition, exogamy, and multi-locality create ties between unrelated families, facilitating the transmission of medicinal knowledge and its fitness implications. Additionally, multi-family camps with low inter-relatedness between camp members provide a framework for the exchange of functional information related to cooperative activities beyond the family unit, such as foraging and regulation of social life.


Asunto(s)
Conducta Cooperativa , Evolución Cultural , Relaciones Interpersonales , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , República Democrática del Congo , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Adulto Joven
7.
Bioorg Med Chem Lett ; 26(4): 1245-8, 2016 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-26804232

RESUMEN

Diamide compounds were identified as potent DGAT1 inhibitors in vitro, but their poor molecular properties resulted in low oral bioavailability, both systemically and to DGAT1 in the enterocytes of the small intestine, resulting in a lack of efficacy in vivo. Replacing an N-alkyl group on the diamide with an N-aryl group was found to be an effective strategy to confer oral bioavailability and oral efficacy in this lipophilic diamide class of inhibitors.


Asunto(s)
Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Diamida/química , Inhibidores Enzimáticos/química , Animales , Línea Celular Tumoral , Diacilglicerol O-Acetiltransferasa/metabolismo , Diamida/síntesis química , Diamida/farmacocinética , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Semivida , Humanos , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad
8.
Can Vet J ; 56(9): 947-52, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26345136

RESUMEN

This study reports electrolyte and acid/base disturbances observed in clinical cases receiving autologous transfusion of blood processed by a cell salvage device. The records of 12 client-owned dogs that received an autologous transfusion via a cell salvage device with pre- and post-autologous transfusion blood work available were reviewed. Blood work from the 12 case dogs was compared to blood work from 12 control dogs with similar diseases. Control dogs received similar surgical treatment and were administered a similar volume per kg of packed red blood cells as case dogs, but did not undergo autologous transfusion. Case dogs that received autologous transfusion via a cell salvage device were significantly more likely to experience a decrease in ionized calcium and magnesium levels post-transfusion than were control dogs. Calcium and magnesium levels should be closely monitored during and after autologous transfusion. Calcium and/or magnesium supplementation may be required.


Changements électrolytiques et acido-basiques chez les chiens subissant une transfusion sanguine autologue à l'aide d'un dispositif de récupération des cellules. Cette étude signale les perturbations électrolytiques et acido-basiques observées dans des cas cliniques recevant une transfusion de sang autologue traitée à l'aide d'un dispositif de récupération des cellules. On a évalué les dossiers de 12 chiens, appartenant à des propriétaires, qui avaient reçu une transfusion autologue à l'aide d'un dispositif de récupération des cellules et avaient subi des analyses sanguines avant et après la transfusion autologue. Les analyses sanguines des 12 chiens ont été comparées aux analyses de 12 chiens témoins atteints de maladies semblables. Les chiens témoins ont reçu des traitements chirurgicaux semblables et un volume semblable par kg de concentré de globules rouges que les chiens du cas, mais n'ont pas subi la transfusion autologue. Il était significativement plus probable que les chiens du cas qui avaient reçu une transfusion autologue à l'aide d'un dispositif de récupération des cellules subissent une baisse du niveau de calcium ionisé et de magnésium après la transfusion que les chiens témoins. Le niveau de calcium et de magnésium devrait être étroitement surveillé durant et après la transfusion autologue. Des suppléments de calcium et/ou de magnésium pourront être requis.(Traduit par Isabelle Vallières).


Asunto(s)
Desequilibrio Ácido-Base/veterinaria , Transfusión de Sangre Autóloga/veterinaria , Enfermedades de los Perros/etiología , Recuperación de Sangre Operatoria/veterinaria , Desequilibrio Hidroelectrolítico/veterinaria , Desequilibrio Ácido-Base/etiología , Animales , Pérdida de Sangre Quirúrgica/veterinaria , Transfusión de Sangre Autóloga/efectos adversos , Transfusión de Sangre Autóloga/instrumentación , Estudios de Casos y Controles , Enfermedades de los Perros/terapia , Perros , Transfusión de Eritrocitos/métodos , Transfusión de Eritrocitos/veterinaria , Femenino , Masculino , Estudios Retrospectivos , Desequilibrio Hidroelectrolítico/etiología
9.
Clin Lymphoma Myeloma Leuk ; 15 Suppl: S73-9, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26297284

RESUMEN

BACKGROUND: Acute myeloid leukemia (AML) characterized by Feline McDonough Sarcoma-like tyrosine kinase-3 (FLT-3) internal tandem duplication (ITD) mutations have poor outcomes. Treatment options are limited, because these mutations confer resistance to conventional chemotherapy. FLT-3 inhibitors such as sorafenib have been studied as a single agent and in combination with conventional chemotherapy or azacytidine with fair responses. PATIENTS AND METHODS: Here we describe our preclinical and clinical experience with the combination of the DNA hypomethylating agent, decitabine and sorafenib for the treatment of FLT-3 ITD-mutant AML. RESULTS: In vitro treatment of the human FLT-3 ITD-mutant AML cell line, MV4-11, with both drugs significantly improved growth inhibition over single-agent therapy and resulted in synergistic antitumor effects (combination index < 1). A case series of 6 patients treated with off protocol combination of decitabine and sorafenib demonstrated overall responses in 5 patients (83%) with a median survival of 155 days. Four of the 5 patients (80%) with relapsed/refractory AML achieved complete responses with incomplete count recovery. The combination was also well tolerated. CONCLUSION: Further investigation is warranted to confirm these responses.


Asunto(s)
Azacitidina/análogos & derivados , Leucemia Mieloide Aguda/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismo , Azacitidina/administración & dosificación , Azacitidina/uso terapéutico , Línea Celular Tumoral , Decitabina , Femenino , Humanos , Leucemia Mieloide Aguda/mortalidad , Persona de Mediana Edad , Mutación , Niacinamida/administración & dosificación , Niacinamida/uso terapéutico , Compuestos de Fenilurea/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Sorafenib , Análisis de Supervivencia
10.
Neuroimage ; 113: 268-78, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25818689

RESUMEN

A remarkable aspect of conscious perception is that moments carryover from one to the next, also known as temporal continuity. This ability is thus crucial for detecting regularities, such as in speech and music, and may rely on an accurate perception of time. Investigations of human time perception have detailed two electroencephalographic (EEG) components associated with timing, the contingent negative variation (CNV) and late positive component of timing (LPCt); however, the precise roles of these components in timing remain elusive. Recently, we demonstrated that the perception of duration is influenced by durations presented on prior trials, which we explained by the creation of an implicit memory standard that adapts to local changes in sequence presentation. Here, we turn to the neural basis of this effect. Human participants performed a temporal bisection task in which they were required to classify the duration of auditory stimuli into short and long duration categories; crucially, the presentation order was first-order counterbalanced, allowing us to measure the effect of each presented duration on the next. EEG recordings revealed that the CNV and LPCt signals both covaried with the duration presented on the current trial, with CNV predicting reaction time and LPCt predicting choice. Additionally, both signals covaried with the duration presented in the prior trial but in different ways, with the CNV amplitude reflecting the change in the memory standard and the LPCt reflecting decision uncertainty. Furthermore, we observed a repetition enhancement effect of duration only for the CNV, suggesting that this signal additionally indexes the similarity of successive durations. These findings demonstrate dissociable roles for the CNV and LPCt, and demonstrate that both signals are continuously updated on a trial-by-trial basis that reflects shifts in temporal decisions.


Asunto(s)
Variación Contingente Negativa/fisiología , Memoria/fisiología , Práctica Psicológica , Percepción del Tiempo/fisiología , Estimulación Acústica , Adolescente , Adulto , Percepción Auditiva/fisiología , Electroencefalografía , Potenciales Evocados/fisiología , Femenino , Humanos , Masculino , Modelos Neurológicos , Desempeño Psicomotor/fisiología , Adulto Joven
11.
Environ Technol ; 36(9-12): 1398-404, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25420588

RESUMEN

Phosphorus was recovered from dairy manure via a microwave-enhanced advanced oxidation process (MW/H2O2-AOP) followed by struvite crystallization in a pilot-scale continuous flow operation. Soluble phosphorus in dairy manure increased by over 50% after the MW/H2O2-AOP, and the settleability of suspended solids was greatly improved. More than 50% of clear supernatant was obtained after microwave treatment, and the maximum volume of supernatant was obtained at a hydrogen peroxide dosage of 0.3% and pH 3.5. By adding oxalic acid into the supernatant, about 90% of calcium was removed, while more than 90% of magnesium was retained. As a result, the resulting solution was well suited for struvite crystallization. Nearly 95% of phosphorus in the treated supernatant was removed and recovered as struvite.


Asunto(s)
Estiércol , Fósforo/aislamiento & purificación , Calcio/aislamiento & purificación , Industria Lechera , Peróxido de Hidrógeno/química , Compuestos de Magnesio/química , Microondas , Oxidación-Reducción , Fosfatos/química , Proyectos Piloto , Estruvita
12.
Leuk Res Rep ; 3(2): 62-6, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25180154

RESUMEN

Dual differentiation therapy with arsenic trioxide and tretinoin (all-trans-retinoic acid; ATRA) for the management of low and intermediate risk acute promyelocytic leukemia has recently been recommended by the National Comprehensive Cancer Network. Some less common toxicities of the combination may have yet to be fully realized. Of ten patients we have treated thus far, five (50%) have developed pseudotumor cerebri. In one patient, temporary discontinuation of ATRA and initiation of acetazolamide controlled symptoms. In four patients, topiramate was substituted for acetazolamide to relieve symptoms and allow ATRA dose re-escalation. We conclude that providers should monitor for pseudotumor cerebri and consider topiramate if acetazolamide fails.

13.
Cancer ; 120(4): 521-9, 2014 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-24166051

RESUMEN

BACKGROUND: Several studies have suggested that low 25(OH) vitamin D3 levels may be prognostic in some malignancies, but no studies have evaluated their impact on treatment outcome in patients with acute myeloid leukemia (AML). METHODS: Vitamin D levels were evaluated in 97 consecutive, newly diagnosed, intensively treated patients with AML. MicroRNA expression profiles and single nucleotide polymorphisms (SNPs) in the 25(OH) vitamin D3 pathway genes were evaluated and correlated with 25(OH) vitamin D3 levels and treatment outcome. RESULTS: Thirty-four patients (35%) had normal 25(OH) vitamin D3 levels (32-100 ng/mL), 34 patients (35%) had insufficient levels (20-31.9 ng/mL), and 29 patients (30%) had deficient levels (<20 ng/mL). Insufficient/deficient 25(OH) vitamin D3 levels were associated with worse relapse-free survival (RFS) compared with normal vitamin D3 levels. In multivariate analyses, deficient 25(OH) vitamin D3 , smoking, European Leukemia Network genetic group, and white blood cell count retained their statistical significance for RFS. Several microRNAs and SNPs were associated with 25(OH) vitamin D3 levels, although none remained significant after multiple test corrections; one 25(OH) vitamin D3 receptor SNP, rs10783219, was associated with a lower complete remission rate (P = .0442) and with shorter RFS (P = .0058) and overall survival (P = .0011). CONCLUSIONS: It remains to be determined what role microRNA and SNP profiles play in contributing to low 25(OH) vitamin D3 level and/or outcome and whether supplementation will improve outcomes for patients with AML.


Asunto(s)
Calcifediol/sangre , Colecalciferol/sangre , Regulación Neoplásica de la Expresión Génica , Leucemia Mieloide Aguda/sangre , MicroARNs/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/patología , Polimorfismo de Nucleótido Simple/genética , Pronóstico , Receptores de Calcitriol/genética , Transcriptoma , Resultado del Tratamiento
14.
Am J Physiol Renal Physiol ; 303(11): F1555-62, 2012 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-22993075

RESUMEN

Nephrolithiasis is a major public health problem with a complex and varied etiology. Most stones are composed of calcium oxalate (CaOx), with dietary excess a risk factor. Because of complexity of mammalian system, the details of stone formation remain to be understood. Here we have developed a nephrolithiasis model using the genetic model Drosophila melanogaster, which has a simple, transparent kidney tubule. Drosophilia reliably develops CaOx stones upon dietary oxalate supplementation, and the nucleation and growth of microliths can be viewed in real time. The Slc26 anion transporter dPrestin (Slc26a5/6) is strongly expressed in Drosophilia kidney, and biophysical analysis shows that it is a potent oxalate transporter. When dPrestin is knocked down by RNAi in fly kidney, formation of microliths is reduced, identifying dPrestin as a key player in oxalate excretion. CaOx stone formation is an ancient conserved process across >400 My of divergent evolution (fly and human), and from this study we can conclude that the fly is a good genetic model of nephrolithiasis.


Asunto(s)
Drosophila/genética , Modelos Animales , Modelos Genéticos , Nefrolitiasis/genética , Animales , Animales Modificados Genéticamente , Proteínas de Transporte de Anión/genética , Proteínas de Transporte de Anión/metabolismo , Oxalato de Calcio/metabolismo , Técnicas de Silenciamiento del Gen , Túbulos Renales/metabolismo , Nefrolitiasis/metabolismo
15.
Nucleic Acid Ther ; 22(4): 255-64, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22913596

RESUMEN

We report the toxicological and pharmacokinetic properties of the synthetic, small interfering RNA I5NP following intravenous administration in rodents and nonhuman primates. I5NP is designed to act via the RNA interference (RNAi) pathway to temporarily inhibit expression of the pro-apoptotic protein p53 and is being developed to protect cells from acute ischemia/reperfusion injuries such as acute kidney injury that can occur during major cardiac surgery and delayed graft function that can occur following renal transplantation. Following intravenous administration, I5NP was very rapidly cleared from plasma was distributed predominantly to the kidney, with very low levels in liver and other tissues. Doses of 800 mg/kg I5NP in rodents, and 1,000 mg/kg I5NP in nonhuman primates, were required to elicit adverse effects, which in the monkey were isolated to direct effects on the blood that included a sub-clinical activation of complement and slightly increased clotting times. In the rat, no additional adverse effects were observed with a rat analogue of I5NP, indicating that the effects likely represent class effects of synthetic RNA duplexes rather than toxicity related to the intended pharmacologic activity of I5NP. Taken together, these data support clinical testing of intravenous administration of I5NP for the preservation of renal function following acute ischemia/reperfusion injury.


Asunto(s)
ARN Mensajero/genética , ARN Interferente Pequeño/toxicidad , Proteína p53 Supresora de Tumor/genética , Administración Intravenosa , Animales , Área Bajo la Curva , Evaluación Preclínica de Medicamentos , Femenino , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Macaca fascicularis , Masculino , Tasa de Depuración Metabólica , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/farmacocinética , Ratas , Ratas Sprague-Dawley , Insuficiencia Renal/metabolismo , Distribución Tisular
16.
Arch Biochem Biophys ; 523(1): 77-86, 2012 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-22426203

RESUMEN

The kidney is essential for the maintenance of normal calcium and phosphorus homeostasis. Calcium and inorganic phosphorus are filtered at the glomerulus, and are reabsorbed from tubular segments by transporters and channels which are regulated by 1α,25-dihydroxyvitamin (1α,25(OH)(2)D) and parathyroid hormone (PTH). The kidney is the major site of the synthesis of 1α,25(OH)(2)D under physiologic conditions, and is one of the sites of 24,25-dihydroxyvitamin D (24,25(OH)(2)D) synthesis. The activity of the 25(OH)D-1α-hydroxylase, the mixed function oxidase responsible for the synthesis of 1α,25(OH)(2)D, is regulated by PTH, 1α,25(OH)(2)D, fibroblast growth factor 23 (FGF23), inorganic phosphorus and other growth factors. Additionally, the vitamin D receptor which binds to, and mediates the activity of 1α,25(OH)(2)D, is widely distributed in the kidney. Thus, the kidney, by regulating multiple transport and synthetic processes is indispensible in the maintenance of mineral homeostasis in physiological states.


Asunto(s)
Riñón/metabolismo , Vitamina D/metabolismo , Absorción , Animales , Calcio/metabolismo , Factor-23 de Crecimiento de Fibroblastos , Humanos , Riñón/enzimología , Fósforo/metabolismo
17.
Int J Drug Policy ; 21(6): 445-51, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20810266

RESUMEN

BACKGROUND: Between 2002 and 2005 fresh or unprepared psilocin-based 'magic' mushrooms were legal to possess and traffic in the UK, and commercial sales demonstrated a significant market for this hallucinogenic drug. During and after this time there has been relatively little analysis concerning how magic mushroom users accounted for their drug use, nor on the wider political and cultural discourses that might have shaped this sense making. METHOD: In this paper we present a critical analysis of contemporary discourses around magic mushroom use in the UK through a multi-level discourse analysis of focus group data from 20 magic mushroom users (13 male and 7 female, mean age 25 years), taken at a time when magic mushrooms were being legally sold in the UK. RESULTS: Locating participants' use of magic mushrooms within the context of a culture of intoxication, neo-liberalism and the legacy of 1960s psychedelic philosophy, we identify six interpretative repertoires in their talk, which were subsumed within two overarching discourses. The first discourse drew on neo-liberal rhetoric, constructing participants as rational risk managing subjects engaged in a form of calculated hedonism that was legitimated as an act of personal freedom and consumer choice. The second discourse, identified as 'post-psychedelic', both celebrated and problematised a collective, connected 'hippy' form of spirituality. CONCLUSION: The paper analyses the relationships between identity, consumption and citizenship by arguing that people's ability to imagine collectivist, spiritual or interconnected social worlds has been contained within neo-liberalism rhetoric.


Asunto(s)
Alucinógenos/administración & dosificación , Psilocibina/análogos & derivados , Espiritualidad , Trastornos Relacionados con Sustancias/psicología , Adolescente , Adulto , Femenino , Grupos Focales , Humanos , Masculino , Filosofía , Política , Psilocybe/química , Psilocibina/administración & dosificación , Reino Unido , Adulto Joven
18.
Bioorg Med Chem Lett ; 19(12): 3238-42, 2009 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-19423344

RESUMEN

Novel 1-(2-aminopyrazin-3-yl)methyl-2-thioureas are described as inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2). These compounds demonstrate potent in vitro activity against the enzyme with IC(50) values as low as 15 nM, and suppress expression of TNFalpha in THP-1 cells and in vivo in an acute inflammation model in mice. The synthesis, structure-activity relationship (SAR), and biological evaluation of these compounds are discussed.


Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Tiourea/química , Animales , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Humanos , Inflamación/tratamiento farmacológico , Concentración 50 Inhibidora , Ratones , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Relación Estructura-Actividad , Tiourea/farmacología , Tiourea/uso terapéutico , Factor de Necrosis Tumoral alfa/efectos de los fármacos
19.
Acupunct Med ; 27(1): 9-12, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19369187

RESUMEN

BACKGROUND: Acupuncture has potential value in producing analgesia in the postoperative period, but previous trials have inconsistent results. We aimed to study the effect of electroacupuncture on pain and nausea and the requirement for postoperative analgesia via patient-controlled analgesia. METHOD: 107 patients who were undergoing abdominal hysterectomy or laparascopic cholecystectomy were randomised to receive either electroacupuncture (n = 56) or no additional treatment (n = 46) during the operative period. We measured the use of patient-controlled analgesia and time in recovery as well as pain, postoperative nausea and vomiting, and sedation. 102 patients were included in the analysis. The majority of patients were female: the laparoscopic cholecystectomy group included 10 males. Adhesive dressings were placed over all acupuncture points in both groups, to ensure blinding of patients and assessors during the recovery period. RESULTS: The electroacupuncture group had a longer duration of operation but the difference was not statistically significant. There were no significant differences between the groups for the requirement for patient-controlled analgesia or total time in recovery. Pain scores were marginally lower in the acupuncture group, but not significantly, and there were no differences between the groups in nausea or sedation scores. CONCLUSION: Electroacupuncture at 10 Hz given under general anaesthetic has no effect on postoperative nausea or analgesic requirement. Future studies should investigate acupuncture given before or after surgery.


Asunto(s)
Analgesia Controlada por el Paciente , Sedación Consciente , Electroacupuntura , Cuidados Intraoperatorios , Dolor Postoperatorio/prevención & control , Náusea y Vómito Posoperatorios/prevención & control , Colecistectomía Laparoscópica , Método Doble Ciego , Electroacupuntura/métodos , Femenino , Humanos , Histerectomía , Masculino
20.
Neuropsychologia ; 45(1): 93-106, 2007 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-16766000

RESUMEN

During social interactions our brains continuously integrate incoming auditory and visual input from the movements and vocalizations of others. Yet, the dynamics of the neural events elicited to these multisensory stimuli remain largely uncharacterized. Here we recorded audiovisual scalp event-related potentials (ERPs) to dynamic human faces with associated human vocalizations. Audiovisual controls were a dynamic monkey face with a species-appropriate vocalization, and a house with opening front door with a creaking door sound. Subjects decided if audiovisual stimulus trials were congruent (e.g. human face-human sound) or incongruent (e.g. house image-monkey sound). An early auditory ERP component, N140, was largest to human and monkey vocalizations. This effect was strongest in the presence of the dynamic human face, suggesting that species-specific visual information can modulate auditory ERP characteristics. A motion-induced visual N170 did not change amplitude or latency across visual motion category in the presence of sound. A species-specific incongruity response consisting of a late positive ERP at around 400 ms, P400, was selectively larger only when human faces were mismatched with a non-human sound. We also recorded visual ERPs at trial onset, and found that the category-specific N170 did not alter its behavior as a function of stimulus category-somewhat unexpected as two face types were contrasted with a house image. In conclusion, we present evidence for species-specificity in vocalization selectivity in early ERPs, and in a multisensory incongruity response whose amplitude is modulated only when the human face motion is paired with an incongruous auditory stimulus.


Asunto(s)
Encéfalo/fisiología , Cara , Percepción de Movimiento/fisiología , Percepción del Habla/fisiología , Vocalización Animal/fisiología , Estimulación Acústica , Adulto , Animales , Área Bajo la Curva , Electroencefalografía , Potenciales Evocados/fisiología , Femenino , Haplorrinos , Humanos , Masculino , Persona de Mediana Edad , Estimulación Luminosa , Percepción Social , Lóbulo Temporal/fisiología
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