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1.
J Exp Biol ; 226(5)2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36808489

RESUMO

Climate warming could challenge the ability of endotherms to thermoregulate and maintain normal body temperature (Tb), but the effects of warming summer temperatures on activity and thermoregulatory physiology in many small mammals remain poorly understood. We examined this issue in deer mice (Peromyscus maniculatus), an active nocturnal species. Mice were exposed in the lab to simulated seasonal warming, in which an environmentally realistic diel cycle of ambient temperature (Ta) was gradually warmed from spring conditions to summer conditions (controls were maintained in spring conditions). Activity (voluntary wheel running) and Tb (implanted bio-loggers) were measured throughout, and indices of thermoregulatory physiology (thermoneutral zone, thermogenic capacity) were assessed after exposure. In control mice, activity was almost entirely restricted to the night-time, and Tb fluctuated ∼1.7°C between daytime lows and night-time highs. Activity, body mass and food consumption were reduced and water consumption was increased in later stages of summer warming. This was accompanied by strong Tb dysregulation that culminated in a complete reversal of the diel pattern of Tb variation, with Tb reaching extreme highs (∼40°C) during daytime heat but extreme lows (∼34°C) at cooler night-time temperatures. Summer warming was also associated with reduced ability to generate body heat, as reflected by decreased thermogenic capacity and decreased mass and uncoupling protein (UCP1) content of brown adipose tissue. Our findings suggest that thermoregulatory trade-offs associated with daytime heat exposure can affect Tb and activity at cooler night-time temperatures, impacting the ability of nocturnal mammals to perform behaviours important for fitness in the wild.


Assuntos
Atividade Motora , Peromyscus , Animais , Temperatura , Estações do Ano , Peromyscus/fisiologia , Regulação da Temperatura Corporal/fisiologia
2.
Immunol Cell Biol ; 99(4): 403-418, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33217047

RESUMO

Glioblastoma is a highly aggressive brain malignancy commonly refractory to classical and novel chemo-, radio- and immunotherapies, with median survival times of ~15 months following diagnosis. Poor immunological responses exemplified by the downregulation of T-cell activity, and upregulation of immunosuppressive cells within the tumor microenvironment have limited the effectiveness of immunotherapy in glioblastoma to date. Here we show that glioblastoma cells express a large repertoire of inhibitory checkpoint ligands known to control effector T cell responses. Furthermore, flow cytometry analysis reveals that glioblastoma cells with an enhanced stem cell-like phenotype express several investigated ligands at significant levels on their cell surface. This reveals that glioblastoma stem-like cells express suppressive ligands with the potential of suppressing major T cell checkpoint receptors. With this information, it is now essential that we understand the relevance of this extensive repertoire of immune checkpoint ligands and their functional consequence on immune evasion in glioblastoma. This is necessary to develop effective immunotherapeutics and to be able to match treatment to patient, especially in the light of CheckMate 143.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Imunoterapia , Ligantes , Microambiente Tumoral
3.
Am J Physiol Regul Integr Comp Physiol ; 317(3): R407-R417, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31242021

RESUMO

High-altitude natives have evolved to overcome environmental hypoxia and provide a compelling system to understand physiological function during reductions in oxygen availability. The sympathoadrenal system plays a key role in responses to acute hypoxia, but prolonged activation of this system in chronic hypoxia may be maladaptive. Here, we examined how chronic hypoxia exposure alters adrenal catecholamine secretion and how adrenal function is altered further in high-altitude natives. Populations of deer mice (Peromyscus maniculatus) native to low and high altitudes were each born and raised in captivity at sea level, and adults from each population were exposed to normoxia or hypobaric hypoxia for 5 mo. Using carbon fiber amperometry on adrenal slices, catecholamine secretion evoked by low doses of nicotine (10 µM) or acute hypoxia (Po2 ∼15-20 mmHg) was reduced in lowlanders exposed to hypobaric hypoxia, which was attributable mainly to a decrease in quantal charge rather than event frequency. However, secretion evoked by high doses of nicotine (50 µM) was unaffected. Hypobaric hypoxia also reduced plasma epinephrine and protein expression of 3,4-dihydroxyphenylalanine (DOPA) decarboxylase in the adrenal medulla of lowlanders. In contrast, highlanders were unresponsive to hypobaric hypoxia, exhibiting typically low adrenal catecholamine secretion, plasma epinephrine, and DOPA decarboxylase. Highlanders also had consistently lower catecholamine secretion evoked by high nicotine, smaller adrenal medullae with fewer chromaffin cells, and a larger adrenal cortex compared with lowlanders across both acclimation environments. Our results suggest that plastic responses to chronic hypoxia along with evolved changes in adrenal function attenuate catecholamine release in deer mice at high altitude.


Assuntos
Medula Suprarrenal/metabolismo , Altitude , Catecolaminas/metabolismo , Regulação da Expressão Gênica/fisiologia , Peromyscus/metabolismo , Distribuição Animal , Animais , Catecolaminas/genética , Hipóxia , Nicotina/farmacologia , Oxigênio , Consumo de Oxigênio/fisiologia
4.
J Exp Biol ; 222(Pt 7)2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30846536

RESUMO

We examined the control of breathing and respiratory gas exchange in six species of high-altitude duck that independently colonized the high Andes. We compared ducks from high-altitude populations in Peru (Lake Titicaca at ∼3800 m above sea level; Chancay River at ∼3000-4100 m) with closely related populations or species from low altitude. Hypoxic ventilatory responses were measured shortly after capture at the native altitude. In general, ducks responded to acute hypoxia with robust increases in total ventilation and pulmonary O2 extraction. O2 consumption rates were maintained or increased slightly in acute hypoxia, despite ∼1-2°C reductions in body temperature in most species. Two high-altitude taxa - yellow-billed pintail and torrent duck - exhibited higher total ventilation than their low-altitude counterparts, and yellow-billed pintail exhibited greater increases in pulmonary O2 extraction in severe hypoxia. In contrast, three other high-altitude taxa - Andean ruddy duck, Andean cinnamon teal and speckled teal - had similar or slightly reduced total ventilation and pulmonary O2 extraction compared with low-altitude relatives. Arterial O2 saturation (SaO2 ) was elevated in yellow-billed pintails at moderate levels of hypoxia, but there were no differences in SaO2  in other high-altitude taxa compared with their close relatives. This finding suggests that improvements in SaO2  in hypoxia can require increases in both breathing and haemoglobin-O2 affinity, because the yellow-billed pintail was the only high-altitude duck with concurrent increases in both traits compared with its low-altitude relative. Overall, our results suggest that distinct physiological strategies for coping with hypoxia can exist across different high-altitude lineages, even among those inhabiting very similar high-altitude habitats.


Assuntos
Aclimatação , Altitude , Temperatura Corporal/fisiologia , Patos/fisiologia , Animais , Feminino , Hipóxia , Masculino , Oregon , Consumo de Oxigênio/fisiologia , Peru , Respiração
5.
Br J Clin Pharmacol ; 85(6): 1247-1259, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30731514

RESUMO

AIMS: This investigation aimed to quantitatively characterize the relationship between the gonadotropin-releasing hormone agonist leuprorelin, testosterone (T) and prostate specific antigen (PSA) concentrations over time, to aid identification of a target T concentration that optimises the balance of the benefits of T suppression whilst reducing the risk of side effects related to futile over-suppression. METHODS: Data from a single dose study to investigate the effect of leuprorelin in a 6-month depot formulation on T and PSA in prostate cancer patients were analysed using a population pharmacokinetic-pharmacodynamic modelling approach. The developed model was qualified using external data from 3 studies, in which the effect of different formulations of leuprorelin on T and PSA was evaluated in prostate cancer patients. RESULTS: The effect of leuprorelin on the relationship between T and PSA was adequately characterized by the Romero model with minor modifications, combined with a turnover model to describe the delay in response between T and PSA. The data were significantly better described when assuming a minimum PSA level that is independent on the treatment-related reduction in T, as compared to a model with a proportional reduction in PSA and T. CONCLUSIONS: The model-based analysis suggests that on a population level, reducing T concentrations below 35 ng/dL does not result in a further decrease in PSA levels (>95% of the minimal PSA level is reached). More data are required to support this relationship in the lower T and PSA range.


Assuntos
Antineoplásicos Hormonais/farmacocinética , Calicreínas/sangue , Leuprolida/farmacocinética , Modelos Biológicos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/tratamento farmacológico , Testosterona/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Monitoramento de Medicamentos , Humanos , Leuprolida/administração & dosagem , Leuprolida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Adulto Jovem
6.
Physiol Biochem Zool ; 91(3): 859-867, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29513620

RESUMO

Hypoxia at high altitudes constrains O2 supply to support metabolism, thermoregulation in the cold, and exercise. High-altitude natives that somehow overcome this challenge-who live, reproduce, and sometimes perform impressive feats of exercise at high altitudes-are a powerful group in which to study the evolution of physiological systems underlying hypoxia resistance. Here, we sought to determine whether a common pulse oximetry system for rodents (MouseOx Plus) can be used reliably in studies of high-altitude birds by examining the hypoxia responses of the Andean goose. We compared concurrent measurements of heart rate obtained using pulse oximetry versus electrocardiography. We also compared our measurements of peripheral arterial O2 saturation (SaO2) in uncannulated birds with published data collected from blood samples in birds that were surgically implanted arterial cannulae. Responses to acute hypoxia were measured during stepwise reductions in inspired partial pressure of O2. Andean geese exhibited very modest breathing and heart rate responses to hypoxia but were nevertheless able to maintain normal O2 consumption rates during severe hypoxia exposure down to 5 kPa O2. There were some minor quantitative differences between uncannulated and cannulated birds, which suggest that surgery, cannulation, and/or other sources of variability between studies had modest effects on the hypoxic ventilatory response, heart rate, blood hemoglobin, and hematocrit. Nevertheless, measurements of heart rate and SaO2 by pulse oximetry had small standard errors and were generally concordant and well correlated with measurements using other techniques. We conclude that the MouseOx Plus pulse oximetry system can be a valuable tool for studying the cardiorespiratory physiology of waterfowl without the deleterious effects of surgery/cannulation.


Assuntos
Adaptação Fisiológica/fisiologia , Altitude , Anseriformes/sangue , Oximetria/veterinária , Consumo de Oxigênio/fisiologia , Animais , Anseriformes/fisiologia , Oximetria/métodos , Reprodutibilidade dos Testes
7.
J Comp Physiol B ; 187(1): 117-133, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27461227

RESUMO

Air breathing in fish is commonly believed to have arisen as an adaptation to aquatic hypoxia. The effectiveness of air breathing for tissue O2 supply depends on the ability to avoid O2 loss as oxygenated blood from the air-breathing organ passes through the gills. Here, we evaluated whether the armoured catfish (Hypostomus aff. pyreneusi)-a facultative air breather-can avoid branchial O2 loss while air breathing in aquatic hypoxia, and we measured various other respiratory and metabolic traits important for O2 supply and utilization. Fish were instrumented with opercular catheters to measure the O2 tension (PO2) of expired water, and air breathing and aquatic respiration were measured during progressive stepwise hypoxia in the water. Armoured catfish exhibited relatively low rates of O2 consumption and gill ventilation, and gill ventilation increased in hypoxia due primarily to increases in ventilatory stroke volume. Armoured catfish began air breathing at a water PO2 of 2.5 kPa, and both air-breathing frequency and hypoxia tolerance (as reflected by PO2 at loss of equilibrium, LOE) was greater in individuals with a larger body mass. Branchial O2 loss, as reflected by higher PO2 in expired than in inspired water, was observed in a minority (4/11) of individuals as water PO2 approached that at LOE. Armoured catfish also exhibited a gill morphology characterized by short filaments bearing short fused lamellae, large interlamellar cell masses, low surface area, and a thick epithelium that increased water-to-blood diffusion distance. Armoured catfish had a relatively low blood-O2 binding affinity when sampled in normoxia (P50 of 3.1 kPa at pH 7.4), but were able to rapidly increase binding affinity during progressive hypoxia exposure (to a P50 of 1.8 kPa). Armoured catfish also had low activities of several metabolic enzymes in white muscle, liver, and brain. Therefore, low rates of metabolism and gill ventilation, and a reduction in branchial gas-exchange capacity, may help minimize branchial O2 loss in armoured catfish while air breathing in aquatic hypoxia.


Assuntos
Peixes-Gato/metabolismo , Peixes-Gato/fisiologia , Brânquias/fisiologia , Hipóxia/metabolismo , Hipóxia/fisiopatologia , Ar , Animais , Encéfalo/metabolismo , Peixes-Gato/anatomia & histologia , Citrato (si)-Sintase/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Proteínas de Peixes/metabolismo , Brânquias/anatomia & histologia , Brânquias/ultraestrutura , L-Lactato Desidrogenase/metabolismo , Fígado/metabolismo , Microscopia Eletrônica de Varredura , Músculo Esquelético/metabolismo , Mioglobina/metabolismo , Consumo de Oxigênio , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Piruvato Quinase/metabolismo , Respiração
8.
Sci Rep ; 6: 19371, 2016 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-26778406

RESUMO

Microglia, the resident macrophages of the central nervous system play vital roles in brain homeostasis through clearance of pathogenic material. Microglia are also implicated in neurological disorders through uncontrolled activation and inflammatory responses. To date, the vast majority of microglial studies have been performed using rodent models. Human microglia differ from rodent counterparts in several aspects including their response to pharmacological substances and their inflammatory secretions. Such differences highlight the need for studies on primary adult human brain microglia and methods to isolate them are therefore required. Our procedure generates microglial cultures of >95% purity from both biopsy and autopsy human brain tissue using a very simple media-based culture procedure that takes advantage of the adherent properties of these cells. Microglia obtained in this manner can be utilised for research within a week. Isolated microglia demonstrate phagocytic ability and respond to inflammatory stimuli and their purity makes them suitable for numerous other forms of in vitro studies, including secretome and transcriptome analysis. Furthermore, this protocol allows for the simultaneous isolation of neural precursor cells during the microglial isolation procedure. As human brain tissue is such a precious and valuable resource the simultaneous isolation of multiple cell types is highly beneficial.


Assuntos
Separação Celular , Microglia/citologia , Microglia/fisiologia , Biomarcadores , Separação Celular/métodos , Células Cultivadas , Quimiocinas/biossíntese , Citocinas/biossíntese , Regulação da Expressão Gênica , Humanos , Imuno-Histoquímica , Interleucina-1beta/metabolismo , NF-kappa B/metabolismo , Fagocitose , Fenótipo , Transporte Proteico
10.
Nurs Stand ; 29(35): 3, 2015 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-25921983

RESUMO

Should you be paid extra for working weekends? What about nights, or public holidays? Unsocial hours go with the job for most nurses, but the issue of whether and how staff should be rewarded is currently being scrutinised by the NHS Pay Review Body. In the past week there has also been a heated political discussion, as the parties vie for nurses' votes.


Assuntos
Serviço Hospitalar de Enfermagem/economia , Recursos Humanos de Enfermagem Hospitalar/economia , Salários e Benefícios , Humanos , Programas Nacionais de Saúde , Medicina Estatal , Reino Unido , Carga de Trabalho/economia
11.
Life (Basel) ; 4(3): 491-510, 2014 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-25370382

RESUMO

Projecting a vision for space radiobiological research necessitates understanding the nature of the space radiation environment and how radiation risks influence mission planning, timelines and operational decisions. Exposure to space radiation increases the risks of astronauts developing cancer, experiencing central nervous system (CNS) decrements, exhibiting degenerative tissue effects or developing acute radiation syndrome. One or more of these deleterious health effects could develop during future multi-year space exploration missions beyond low Earth orbit (LEO). Shielding is an effective countermeasure against solar particle events (SPEs), but is ineffective in protecting crew members from the biological impacts of fast moving, highly-charged galactic cosmic radiation (GCR) nuclei. Astronauts traveling on a protracted voyage to Mars may be exposed to SPE radiation events, overlaid on a more predictable flux of GCR. Therefore, ground-based research studies employing model organisms seeking to accurately mimic the biological effects of the space radiation environment must concatenate exposures to both proton and heavy ion sources. New techniques in genomics, proteomics, metabolomics and other "omics" areas should also be intelligently employed and correlated with phenotypic observations. This approach will more precisely elucidate the effects of space radiation on human physiology and aid in developing personalized radiological countermeasures for astronauts.

13.
J Clin Pharmacol ; 54(4): 453-61, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24214217

RESUMO

The pharmacokinetics of sipoglitazar, a peroxisome proliferator activated receptor agonist, are subject to high inter-individual variability resulting from a polymorphism of the UGT2B15 genotype. The aim of the current analysis was to apply a PK-PD model-based approach to evaluate the influence of UGT2B15 driven pharmacokinetic differences on the clinical response. Efficacy and safety of sipoglitazar compared to placebo were assessed in Type 2 Diabetes Mellitus patients in two Phase II randomized, double-blind studies (sipoglitazar once daily: 8, 16, 32, or 64 mg; sipoglitazar twice daily: 16 or 32 mg; rosiglitazone 8 mg once daily and placebo for 13 weeks; n = 780). Changes in fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) levels over time were described as a function of individual drug exposure using a simultaneous, cascading indirect response model structure. The effects on FPG and HbA1c could successfully be described for placebo, rosiglitazone, and sipoglitazar treated groups in all three UGT2B15 genotypes. Differences in drug effects between genotypes were fully explained by differences in drug exposure. The current PK-PD analysis confirms that UGT2B15 genotype is a major determinant for differences in FPG and HbA1c response to sipoglitazar treatment between Type 2 Diabetes mellitus patients, due to related differences in drug exposure.


Assuntos
Diabetes Mellitus Tipo 2/genética , Glucuronosiltransferase/genética , Hipoglicemiantes/farmacocinética , Modelos Biológicos , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Propionatos/farmacocinética , Tiazóis/farmacocinética , Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Método Duplo-Cego , Genótipo , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/farmacologia , Polimorfismo Genético , Propionatos/farmacologia , Rosiglitazona , Tiazóis/farmacologia , Tiazolidinedionas/farmacocinética , Tiazolidinedionas/farmacologia
14.
J Clin Pharmacol ; 53(3): 256-63, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23444281

RESUMO

Sipoglitazar is a peroxisome proliferator-activated receptor α, δ, and γ agonist. During phase I, a wide distribution of clearance between individuals was observed. Hypothesized to result from a polymorphism in the uridine 5'-diphospate-glucuronosyltransferase (UGT)2B15 enzyme, pharmacogenetic samples were collected from each individual for genotyping UGT2B15 in a subsequent phase I trial in healthy subjects (n = 524) and in 2 phase II trials in type 2 diabetes subjects (n = 627), total genotype frequency was as follows: *1/*1 (22%), *1/*2 (51%), and *2/*2 (27%). The impact of genotype on exposure was assessed using a pharmacokinetic modeling approach; the influence of genotype on efficacy was evaluated using 12-week HbA1c change from baseline. Model analysis demonstrated UGT2B15 genotype accounted significantly for the variability in sipoglitazar clearance; however, a small fraction of subjects had a clearance that could not be explained entirely by genotype. HbA1c drop increased with daily drug dose. When stratified by both dose and genotype, HbA1c drop was larger in the UGT2B15*2/*2 compared with UGT2B15*1/*1 and UGT2B15*1/*2 genotypes (P < .05). In summary, UGT2B15 genotype is a strong predictor for sipoglitazar clearance; a greater clinical response observed in the UGT2B15*2/*2 genotype appears to confirm this. However, overlap in individual rates of clearance across genotypes remains after accounting for genotype.


Assuntos
Glucuronosiltransferase/genética , Hipoglicemiantes/farmacologia , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Propionatos/farmacologia , Tiazóis/farmacologia , Adolescente , Adulto , Idoso , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Genótipo , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/farmacocinética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Polimorfismo Genético , Propionatos/farmacocinética , Tiazóis/farmacocinética , Adulto Jovem
15.
Eur J Clin Pharmacol ; 69(3): 423-30, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22960998

RESUMO

PURPOSE: Sipoglitazar was a novel, azolealkanoic acid derivative that possesses selective activity for the peroxisome proliferator-activated receptors (PPAR) PPARγ, PPARα, and PPARδ. The compound undergoes phase II biotransformation by conjugation catalyzed by UDP-glucuronosyltransferase (UGT). The aim of this analysis was to explore the influence of genetic polymorphism in UGT on the pharmacokinetics of sipoglitazar. METHODS: Three preliminary phase I clinical pharmacology studies were conducted in tandem in healthy human subjects. Genotyping was undertaken in a total of 82 subjects in the phase I program for the purpose of genotyping UGT polymorphisms. Plasma samples were collected for up to 48 h post-dose to characterize the pharmacokinetic profile following a single oral dose of the drug. RESULTS: Plasma concentrations of sipoglitazar and the distribution of dose-normalized individual values for area under the plasma concentration-time curve from time 0 to infinity (AUC(0-∞)) before any stratification were considerably skewed with a multi-modal distribution. The proportion of variability in AUC(0-∞) explained by UGT2B15 was 66.7 % (P < 0.0001); the addition of other genetic or demographic factors was not statistically significant. Subjects homozygous for the UGT2B15 D85Y variant (UGT2B15*2/*2) were exposed to greater plasma concentrations of sipoglitazar than subjects homozygous for the wild-type allele UGT2B15*1/*1 (3.26-fold higher) or heterozygous allele UGT2B15*1/*2 (2.16-fold higher). CONCLUSIONS: These results indicate that sipoglitazar clearance is substantially modified by UGT2B15 enzyme variants, with higher exposure observed in the UGT2B15*2/*2 genotype group.


Assuntos
Glucuronosiltransferase/genética , Hipoglicemiantes/farmacocinética , Polimorfismo Genético , Propionatos/farmacocinética , Tiazóis/farmacocinética , Administração Oral , Adulto , Análise de Variância , Área Sob a Curva , Biotransformação , Estudos Cross-Over , Método Duplo-Cego , Feminino , Glucuronosiltransferase/metabolismo , Meia-Vida , Heterozigoto , Homozigoto , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/sangue , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Farmacogenética , Fenótipo , Propionatos/administração & dosagem , Propionatos/sangue , Tiazóis/administração & dosagem , Tiazóis/sangue , Reino Unido , Adulto Jovem
16.
Br J Clin Pharmacol ; 75(2): 381-91, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22803642

RESUMO

AIMS: Two randomized, double-blind, placebo-controlled studies were performed to characterize the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the investigational metastin analogue, TAK-683, in healthy men. METHODS: We first investigated a single subcutaneous (s.c.) dose of TAK-683 (0.01-2.0 mg) in 60 subjects (TAK-683, n = 42; placebo, n = 18). We then assessed a single s.c. bolus of 0.03-1.0 mg TAK-683 on day 1, followed by a 0.01-2.0 mg day(-1) continuous infusion on days 2-13, to simulate a depot formulation, in 30 subjects (TAK-683, n = 25; placebo, n = 5) for 14 days. RESULTS: TAK-683 was well tolerated up to a dose of 2.0 mg day(-1) by continuous s.c. infusion for 14 days. Adverse events were similar between TAK-683 and placebo subjects at all dose levels. TAK-683 plasma concentrations generally increased in proportion to dose with single and continuous dosing, with steady-state concentrations achieved by day 2 of continuous dosing. TAK-683 at 2.0 mg day(-1) suppressed testosterone below castration level (<50 ng dl(-1)) in four of five subjects by day 7 of continuous dosing. Luteinizing hormone and follicle stimulating hormone concentrations were suppressed with TAK-683 continuous dosing compared with placebo by up to 70 and 43%, respectively, but this was not consistently dose-dependent. CONCLUSIONS: In healthy men, s.c. administration of TAK-683 was well tolerated at all dose levels. The PK profile of TAK-683 was favourable, and TAK-683 suppressed testosterone profoundly during continuous dosing. Further investigation of metastin analogues is warranted for the treatment of castration-resistant prostate cancer.


Assuntos
Antineoplásicos , Kisspeptinas , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Injeções Subcutâneas , Kisspeptinas/efeitos adversos , Kisspeptinas/química , Kisspeptinas/farmacocinética , Kisspeptinas/farmacologia , Masculino , Pessoa de Meia-Idade , Testosterona/sangue
17.
Healthc Pap ; 12(3): 30-4, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23107903

RESUMO

The year 1962 was pre-medicare. The public was concerned about access and individual affordability of care. Funding involved public or private responsibility and the role of government. Physicians, the most influential providers, were concerned that government funding would result in the loss of their independence and their becoming state employees. The retrospective analysis "Looking Back 50 Years in Hospital Administration" by Graham and Sibbald is arresting as it underlines just how much progress we have made in what could be termed "hardware" in support of healthcare policy and hospital administration. From this perspective, the progress has been eye opening, given the advent of universal healthcare, the advancement in our physical facilities, the development of high-quality diagnostic equipment, the explosion of new research centres and new and complex clinical procedures. The development of this hardware has given our providers better weapons and contributed to a remarkable improvement in life expectancy. But progress in health administration and policy management involves more than hardware. If the hardware constitutes the tools, then the "software" of the healthcare system involves the human resources and the culture change that must be positioned to make maximum use of the hardware. In 2062, looking back at the 2012 experience, the legacy test may be whether we dealt with health human resources and culture change at a rate that matched our progress in hardware.


Assuntos
Biotecnologia/métodos , Administração Hospitalar , Cultura Organizacional , Canadá , Educação Médica/organização & administração , Humanos , Liderança , Recursos Humanos de Enfermagem Hospitalar/organização & administração , Equipe de Assistência ao Paciente/organização & administração , Assistência Centrada no Paciente/organização & administração
18.
Am J Physiol Regul Integr Comp Physiol ; 297(4): R1066-74, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19657102

RESUMO

Bar-headed geese fly at altitudes of up to 9,000 m on their biannual migration over the Himalayas. To determine whether the flight muscle of this species has evolved to facilitate exercise at high altitude, we compared the respiratory properties of permeabilized muscle fibers from bar-headed geese and several low-altitude waterfowl species. Respiratory capacities were assessed for maximal ADP stimulation (with single or multiple inputs to the electron transport system) and cytochrome oxidase excess capacity (with an exogenous electron donor) and were generally 20-40% higher in bar-headed geese when creatine was present. When respiration rates were extrapolated to the entire pectoral muscle mass, bar-headed geese had a higher mass-specific aerobic capacity. This may represent a surplus capacity that counteracts the depressive effects of hypoxia on mitochondrial respiration. However, there were no differences in activity for mitochondrial or glycolytic enzymes measured in homogenized muscle. The [ADP] leading to half-maximal stimulation (K(m)) was approximately twofold higher in bar-headed geese (10 vs. 4-6 microM), and, while creatine reduced K(m) by 30% in this species, it had no effect on K(m) in low-altitude birds. Mitochondrial creatine kinase may therefore contribute to the regulation of oxidative phosphorylation in flight muscle of bar-headed geese, which could promote efficient coupling of ATP supply and demand. However, this was not based on differences in creatine kinase activity in isolated mitochondria or homogenized muscle. The unique differences in bar-headed geese existed without prior exercise or hypoxia exposure and were not a result of phylogenetic history, and may, therefore, be important evolutionary specializations for high-altitude flight.


Assuntos
Altitude , Migração Animal , Patos/fisiologia , Metabolismo Energético , Voo Animal , Gansos/fisiologia , Contração Muscular , Músculos Peitorais/metabolismo , Aclimatação , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Evolução Biológica , Respiração Celular , Creatina/metabolismo , Creatina Quinase Mitocondrial/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Glicólise , Cinética , Mitocôndrias Musculares/metabolismo , Fosforilação Oxidativa , Músculos Peitorais/enzimologia , Ácido Succínico/metabolismo
19.
J Exp Biol ; 211(Pt 15): 2450-9, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18626079

RESUMO

We have explored the molecular and physiological responses of the euryhaline killifish Fundulus heteroclitus to transfer from brackish water (10% seawater) to 100% seawater for 12 h, 3 days or 7 days. Plasma [Na+] and [Cl-] were unchanged after transfer, and plasma cortisol underwent a transient increase. Na+/K+-ATPase activity increased 1.5-fold in the gills and opercular epithelium at 7 days (significant in gills only), responses that were preceded by three- to fourfold increases in Na+/K+-ATPase alpha(1a) mRNA expression. Expression of Na+/K+/2Cl- cotransporter 1, cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel, Na+/H+-exchanger 3 (significant in opercular epithelium only) and carbonic anhydrase II mRNA also increased two- to fourfold after transfer. Drinking rate increased over twofold after 12 h and remained elevated for at least 7 days. Surprisingly, net rates of water and ion absorption measured in vitro across isolated intestines decreased approximately 50%, possibly due to reduced salt demands from the diet in seawater, but water absorption capacity still exceeded the drinking rate. Changes in bulk water absorption were well correlated with net ion absorption, and indicated that slightly hyperosmotic solutions (>or=298 mmol l(-1)) were transported. There were no reductions in unidirectional influx of Na+ from luminal to serosal fluid or intestinal Na+/K+-ATPase activity after transfer. Overall, our results indicate that gill and opercular epithelia function similarly at a molecular level in seawater, in contrast to their divergent function in freshwater, and reveal unexpected changes in intestinal function. As such they provide further insight into the mechanisms of euryhalinity in killifish.


Assuntos
Fundulidae/fisiologia , Água do Mar , Equilíbrio Hidroeletrolítico/fisiologia , Animais , Cloretos/sangue , Comportamento de Ingestão de Líquido , Epitélio/enzimologia , Fundulidae/sangue , Regulação Enzimológica da Expressão Gênica , Brânquias/enzimologia , Hidrocortisona/sangue , Absorção Intestinal , Intestinos/enzimologia , Transporte de Íons , Sódio/sangue , ATPase Trocadora de Sódio-Potássio/metabolismo , Água/metabolismo
20.
J Exp Biol ; 209(Pt 20): 4040-50, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17023598

RESUMO

We have explored intestinal function in the euryhaline killifish Fundulus heteroclitus after transfer from brackish water (10% seawater) to fresh water. Plasma Na+ and Cl- concentrations fell at 12 h post-transfer, but recovered by 7 days. Drinking rate decreased substantially at 12 h (32% of control value) and remained suppressed after 3 and 7 days in fresh water (34 and 43%). By contrast, there was a transient increase in the capacity for water absorption measured across isolated intestines in vitro (3.3- and 2.6-fold at 12 h and 3 days), which returned to baseline after 7 days. These changes in water absorption could be entirely accounted for by changes in net ion flux: there was an extremely strong correlation (R2=0.960) between water absorption and the sum of net Na+ and net Cl- fluxes (3.42+/-0.10 microl water micromol(-1) ion). However, enhanced ion transport across the intestine in fresh water would probably not increase water uptake in vivo, because the drinking rate was far less than the capacity for water absorption across the intestine. The increased intestinal ion absorption after freshwater transfer may instead serve to facilitate ion absorption from food when it is present in the gut. Modulation of net ion flux occurred without changes in mRNA levels of many ion transporters (Na+/K+-ATPase alpha(1a), carbonic anhydrase 2, CFTR Cl- channel, Na+/K+/2Cl- cotransporter 2, and the signalling protein 14-3-3a), and before a measured increase in Na+/K+-ATPase activity at 3 days, suggesting that there is some other mechanism responsible for increasing ion transport. Interestingly, net Cl- flux always exceeded net Na+ flux, possibly to help maintain Cl- balance and/or facilitate bicarbonate excretion. Our results suggest that intestinal NaCl absorption from food is important during the period of greatest ionic disturbance after transfer to fresh water, and provide further insight into the mechanisms of euryhalinity in killifish.


Assuntos
Fundulidae/fisiologia , Animais , Transporte Biológico Ativo , Ingestão de Líquidos/fisiologia , Água Doce , Fundulidae/genética , Expressão Gênica , Homeostase , Hidrocortisona/sangue , Intestinos/fisiologia , Transporte de Íons , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Cloreto de Sódio/metabolismo , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo , Água/metabolismo , Equilíbrio Hidroeletrolítico
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