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1.
Br J Haematol ; 202(3): 498-503, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37303189

RESUMO

Limited data exist on COVID-19 vaccination efficacy in patients with acute myeloid leukemia and myelodysplasia with excess blasts (AML/MDS-EB2). We report results from a prospective study, PACE (Patients with AML and COVID-19 Epidemiology). 93 patients provided samples post-vaccine 2 or 3 (PV2, PV3). Antibodies against SARS-COV-2 spike antigen were detectable in all samples. Neutralization of the omicron variant was poorer than ancestral variants but improved PV3. In contrast, adequate T-cell reactivity to SARS-COV-2 spike protein was seen in only 16/47 (34%) patients PV2 and 23/52 (44%) PV3. Using regression models, disease response (not in CR/Cri), and increasing age predicted poor T cell response.


Assuntos
COVID-19 , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Vacinas contra COVID-19 , Estudos Prospectivos , Linfócitos T , COVID-19/prevenção & controle , SARS-CoV-2 , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Vacinação , Anticorpos Antivirais
2.
Parasitology ; 150(14): 1307-1315, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37395052

RESUMO

Host­parasite associations provide a benchmark for investigating evolutionary arms races and antagonistic coevolution. However, potential ecological mechanisms underlying such associations are difficult to unravel. In particular, local adaptations of hosts and/or parasites may hamper reliable inferences of host­parasite relationships and the specialist­generalist definitions of parasite lineages, making it problematic to understand such relationships on a global scale. Phylogenetic methods were used to investigate co-phylogenetic patterns between vector-borne parasites of the genus Haemoproteus and their passeriform hosts, to infer the ecological interactions of parasites and hosts that may have driven the evolution of both groups in a local geographic domain. As several Haemoproteus lineages were only detected once, and given the occurrence of a single extreme generalist, the effect of removing individual lineages on the co-phylogeny pattern was tested. When all lineages were included, and when all singly detected lineages were removed, there was no convincing evidence for host­parasite co-phylogeny. However, when only the generalist lineage was removed, strong support for co-phylogeny was indicated, and ecological interactions could be successfully inferred. This study exemplifies the importance of identifying locally abundant lineages when sampling host­parasite systems, to provide reliable insights into the precise mechanisms underlying host­parasite interactions.


Assuntos
Doenças das Aves , Haemosporida , Parasitos , Passeriformes , Animais , Filogenia , Haemosporida/genética , Interações Hospedeiro-Parasita , Doenças das Aves/parasitologia
3.
J Evol Biol ; 32(7): 675-682, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30916425

RESUMO

In both plants and animals, male gametogenesis is particularly sensitive to heat stress, to the extent that a single hot or cold day can compromise crop productivity or population persistence. In animals, heat stress during development can impact a male's ability to secure copulations and/or his post-copulatory fertility. Despite such observations, relatively few studies have examined the consequences of developmental temperature on the reproductive behaviour and physiology of individuals. Here, we report for the first time the effects of developmental temperature on the phenotypic expression of both apyrene and eupyrene sperm and the copulatory behaviour of the Indian meal moth, Plodia interpunctella. We show that the length of both apyrene and eupyrene sperm decreases with increasing developmental temperature and that males are less likely to engage in copulation when reared at the highest and lowest temperatures. Where copulation occurred, the duration of copula decreased as male developmental temperature increased. We argue that identification of the mechanisms and consequences of reproductive failure in animals facing heat stress will help understand how wild and domesticated populations will respond to global climate change. We also contend that such studies will help elucidate long-standing evolutionary questions around the maintenance of genetic variation in traits highly relevant to fitness and the role of phenotypic plasticity in driving the evolution of novel traits.


Assuntos
Adaptação Fisiológica/fisiologia , Mariposas/crescimento & desenvolvimento , Espermatozoides/citologia , Temperatura , Animais , Feminino , Masculino , Reprodução
4.
Lancet ; 388(10059): 2501-2509, 2016 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-27793431

RESUMO

BACKGROUND: It is not known whether early intervention can improve long-term autism symptom outcomes. We aimed to follow-up the Preschool Autism Communication Trial (PACT), to investigate whether the PACT intervention had a long-term effect on autism symptoms and continued effects on parent and child social interaction. METHODS: PACT was a randomised controlled trial of a parent-mediated social communication intervention for children aged 2-4 years with core autism. Follow-up ascertainment was done at three specialised clinical services centres in the UK (London, Manchester, and Newcastle) at a median of 5·75 years (IQR 5·42-5·92) from the original trial endpoint. The main blinded outcomes were the comparative severity score (CSS) from the Autism Diagnostic Observation Schedule (ADOS), the Dyadic Communication Assessment Measure (DCMA) of the proportion of child initiatiations when interacting with the parent, and an expressive-receptive language composite. All analyses followed the intention-to-treat principle. PACT is registered with the ISRCTN registry, number ISRCTN58133827. FINDINGS: 121 (80%) of the 152 trial participants (59 [77%] of 77 assigned to PACT intervention vs 62 [83%] of 75 assigned to treatment as usual) were traced and consented to be assessed between July, 2013, and September, 2014. Mean age at follow-up was 10·5 years (SD 0·8). Group difference in favour of the PACT intervention based on ADOS CSS of log-odds effect size (ES) was 0·64 (95% CI 0·07 to 1·20) at treatment endpoint and ES 0·70 (95% CI -0·05 to 1·47) at follow-up, giving an overall reduction in symptom severity over the course of the whole trial and follow-up period (ES 0·55, 95% CI 0·14 to 0·91, p=0·004). Group difference in DCMA child initiations at follow-up showed a Cohen's d ES of 0·29 (95% CI -0.02 to 0.57) and was significant over the course of the study (ES 0·33, 95% CI 0·11 to 0·57, p=0·004). There were no group differences in the language composite at follow-up (ES 0·15, 95% CI -0·23 to 0·53). INTERPRETATION: The results are the first to show long-term symptom reduction after a randomised controlled trial of early intervention in autism spectrum disorder. They support the clinical value of the PACT intervention and have implications for developmental theory. FUNDING: Medical Research Council.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico/terapia , Criança , Comunicação , Seguimentos , Humanos , Pais
5.
Cell Biochem Funct ; 35(5): 269-277, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28749080

RESUMO

Glucocorticoids are important for skeletal muscle energy metabolism, regulating glucose utilization, insulin sensitivity, and muscle mass. Nicotinamide adenine dinucleotide phosphate-dependent 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1)-mediated glucocorticoid activation in the sarcoplasmic reticulum (SR) is integral to mediating the detrimental effects of glucocorticoid excess in muscle. 11ß-Hydroxysteroid dehydrogenase type 1 activity requires glucose-6-phosphate transporter (G6PT)-mediated G6P transport into the SR for its metabolism by hexose-6-phosphate dehydrogenase (H6PDH) for NADPH generation. Here, we examine the G6PT/H6PDH/11ß-HSD1 triad in differentiating myotubes and explore the consequences of muscle-specific knockout of 11ß-HSD1 and H6PDH. 11ß-Hydroxysteroid dehydrogenase type 1 expression and activity increase with myotube differentiation and in response to glucocorticoids. Hexose-6-phosphate dehydrogenase shows some elevation in expression with differentiation and in response to glucocorticoid, while G6PT appears largely unresponsive to these particular conditions. When examining 11ß-HSD1 muscle-knockout mice, we were unable to detect significant decrements in activity, despite using a well-validated muscle-specific Cre transgene and confirming high-level recombination of the floxed HSD11B1 allele. We propose that the level of recombination at the HSD11B1 locus may be insufficient to negate basal 11ß-HSD1 activity for a protein with a long half-life. Hexose-6-phosphate dehydrogenase was undetectable in H6PDH muscle-knockout mice, which display the myopathic phenotype seen in global KO mice, validating the importance of SR NADPH generation. We envisage these data and models finding utility when investigating the muscle-specific functions of the 11ß-HSD1/G6PT/H6PDH triad.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , Antiporters/genética , Desidrogenases de Carboidrato/genética , Proteínas de Transporte de Monossacarídeos/genética , Músculo Esquelético/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Animais , Antiporters/metabolismo , Desidrogenases de Carboidrato/metabolismo , Metabolismo Energético/genética , Glucocorticoides/genética , Glucocorticoides/metabolismo , Glucose/metabolismo , Resistência à Insulina/genética , Camundongos , Camundongos Knockout , Proteínas de Transporte de Monossacarídeos/metabolismo , Retículo Sarcoplasmático/genética , Retículo Sarcoplasmático/metabolismo
6.
Nat Commun ; 14(1): 7725, 2023 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-38001082

RESUMO

Current therapies for myeloproliferative neoplasms (MPNs) improve symptoms but have limited effect on tumor size. In preclinical studies, tamoxifen restored normal apoptosis in mutated hematopoietic stem/progenitor cells (HSPCs). TAMARIN Phase-II, multicenter, single-arm clinical trial assessed tamoxifen's safety and activity in patients with stable MPNs, no prior thrombotic events and mutated JAK2V617F, CALRins5 or CALRdel52 peripheral blood allele burden ≥20% (EudraCT 2015-005497-38). 38 patients were recruited over 112w and 32 completed 24w-treatment. The study's A'herns success criteria were met as the primary outcome ( ≥ 50% reduction in mutant allele burden at 24w) was observed in 3/38 patients. Secondary outcomes included ≥25% reduction at 24w (5/38), ≥50% reduction at 12w (0/38), thrombotic events (2/38), toxicities, hematological response, proportion of patients in each IWG-MRT response category and ELN response criteria. As exploratory outcomes, baseline analysis of HSPC transcriptome segregates responders and non-responders, suggesting a predictive signature. In responder HSPCs, longitudinal analysis shows high baseline expression of JAK-STAT signaling and oxidative phosphorylation genes, which are downregulated by tamoxifen. We further demonstrate in preclinical studies that in JAK2V617F+ cells, 4-hydroxytamoxifen inhibits mitochondrial complex-I, activates integrated stress response and decreases pathogenic JAK2-signaling. These results warrant further investigation of tamoxifen in MPN, with careful consideration of thrombotic risk.


Assuntos
Transtornos Mieloproliferativos , Neoplasias , Humanos , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Transdução de Sinais , Neoplasias/metabolismo , Tamoxifeno/uso terapêutico , Tamoxifeno/metabolismo , Mutação , Calreticulina/genética , Calreticulina/metabolismo
7.
Nutrients ; 14(19)2022 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-36235630

RESUMO

Declining health, gut dysbiosis, and cognitive impairments are hallmarks of advanced age. While caloric restriction is known to robustly extend the healthspan and alter gut microbiome composition, it is difficult maintain. Time-restricted feeding or changes in dietary macronutrient composition could be feasible alternatives for enhancing late life cognitive and physical health that are easier to comply with for extended periods of time. To investigate this possibility, 8-month-old rats were placed on time-restricted feeding with a ketogenic or micronutrient- and calorically matched control diet for 13 months. A third group of rats was permitted to eat standard chow ad libitum during this time. At 22 months, all rats were tested on a biconditional association task and fecal samples were collected for microbiome composition analysis. Regardless of dietary composition, time-restricted-fed rats had better cognitive performance than ad libitum-fed rats. This observation could not be accounted for by differences in motivation, procedural or sensorimotor impairments. Additionally, there were significant differences in gut microbiome diversity and composition between all diet conditions. Allobaculum abundance was associated with cognitive task performance, indicating a link between gut health and cognitive outcomes in aged subjects. Overall, time restricted feeding had the largest influence on cognitive performance in aged rats.


Assuntos
Jejum , Microbioma Gastrointestinal , Animais , Cognição , Micronutrientes , Nutrientes , Ratos
8.
Lancet Haematol ; 9(2): e121-e132, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34906334

RESUMO

BACKGROUND: Outcomes for patients with blast-phase chronic myeloid leukaemia are poor. Long-term survival depends on reaching a second chronic phase, followed by allogeneic haematopoietic stem-cell transplantation (HSCT). We investigated whether the novel combination of the tyrosine-kinase inhibitor ponatinib with fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) could improve response and optimise allogeneic HSCT outcomes in patients with blast-phase chronic myeloid leukaemia. The aim was to identify a dose of ponatinib, which combined with FLAG-IDA, showed clinically meaningful activity and tolerability. METHODS: MATCHPOINT was a seamless, phase 1/2, multicentre trial done in eight UK Trials Acceleration Programme-funded centres. Eligible participants were adults (aged ≥16 years) with Philadelphia chromosome-positive or BCR-ABL1-positive blast-phase chronic myeloid leukaemia, suitable for intensive chemotherapy. Participants received up to two cycles of ponatinib with FLAG-IDA. Experimental doses of oral ponatinib (given from day 1 to day 28 of FLAG-IDA) were between 15 mg alternate days and 45 mg once daily and the starting dose was 30 mg once daily. Intravenous fludarabine (30 mg/m2 for 5 days), cytarabine (2 g/m2 for 5 days), and idarubicin (8 mg/m2 for 3 days), and subcutaneous granulocyte colony-stimulating factor (if used), were delivered according to local protocols. We used an innovative EffTox design to investigate the activity and tolerability of ponatinib-FLAG-IDA; the primary endpoints were the optimal ponatinib dose meeting prespecified thresholds of activity (inducement of second chronic phase defined as either haematological or minor cytogenetic response) and tolerability (dose-limiting toxicties). Analyses were planned on an intention-to-treat basis. MATCHPOINT was registered as an International Standard Randomised Controlled Trial, ISRCTN98986889, and has completed recruitment; the final results are presented. FINDINGS: Between March 19, 2015, and April 26, 2018, 17 patients (12 men, five women) were recruited, 16 of whom were evaluable for the coprimary outcomes. Median follow-up was 41 months (IQR 36-48). The EffTox model simultaneously considered clinical responses and dose-limiting toxicities, and determined the optimal ponatinib dose as 30 mg daily, combined with FLAG-IDA. 11 (69%) of 16 patients were in the second chronic phase after one cycle of treatment. Four (25%) patients had a dose-limiting toxicity (comprising cardiomyopathy and grade 4 increased alanine aminotransferase, cerebral venous sinus thrombosis, grade 3 increased amylase, and grade 4 increased alanine aminotransferase), fulfilling the criteria for clinically relevant activity and toxicity. 12 (71%) of 17 patients proceeded to allogeneic HSCT. The most common grade 3-4 non-haematological adverse events were lung infection (n=4 [24%]), fever (n=3 [18%]), and hypocalcaemia (n=3 [18%]). There were 12 serious adverse events in 11 (65%) patients. Three (18%) patients died due to treatment-related events (due to cardiomyopathy, pulmonary haemorrhage, and bone marrow aplasia). INTERPRETATION: Ponatinib-FLAG-IDA can induce second chronic phase in patients with blast-phase chronic myeloid leukaemia, representing an active salvage therapy to bridge to allogeneic HSCT. The number of treatment-related deaths is not in excess of what would be expected in this very high-risk group of patients receiving intensive chemotherapy. The efficient EffTox method is a model for investigating novel therapies in ultra-orphan cancers. FUNDING: Blood Cancer UK and Incyte.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Mielogênica Crônica BCR-ABL Positiva , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Citarabina/efeitos adversos , Feminino , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Idarubicina/efeitos adversos , Imidazóis/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Piridazinas/efeitos adversos , Vidarabina/efeitos adversos , Vidarabina/análogos & derivados
9.
J Endocrinol ; 251(1): 111-123, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34370682

RESUMO

Supplementation with precursors of NAD has been shown to prevent and reverse insulin resistance, mitochondrial dysfunction, and liver damage in mouse models of diet-induced obesity. We asked whether the beneficial effects of supplementation with the NAD precursor nicotinamide riboside (NR) are dependent on mouse strain. We compared the effects of NR supplementation on whole-body energy metabolism and mitochondrial function in mildly obese C57BL/6N and C57BL/6J mice, two commonly used strains to investigate metabolism. Male C57BL/6N and C57BL/6J mice were fed a high-fat diet (HFD) or standard chow with or without NR supplementation for 8 weeks. Body and organ weights, glucose tolerance, and metabolic parameters as well as mitochondrial O2 flux in liver and muscle fibers were assessed. We found that NR supplementation had no influence on body or organ weight, glucose metabolism or hepatic lipid accumulation, energy expenditure, or metabolic flexibility but increased mitochondrial respiration in soleus muscle in both mouse strains. Strain-dependent differences were detected for body and fat depot weight, fasting blood glucose, hepatic lipid accumulation, and energy expenditure. We conclude that, in mild obesity, NR supplementation does not alter metabolic phenotype in two commonly used laboratory mouse strains.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Niacinamida/análogos & derivados , Obesidade/tratamento farmacológico , Compostos de Piridínio/uso terapêutico , Animais , Respiração Celular/efeitos dos fármacos , Dieta Hiperlipídica , Modelos Animais de Doenças , Avaliação de Medicamentos , Intolerância à Glucose/prevenção & controle , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Niacinamida/uso terapêutico , Obesidade/metabolismo
10.
J Asthma ; 47(5): 568-73, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20560830

RESUMO

BACKGROUND: Eosinophil numbers and eosinophil cationic protein (ECP) levels have been proposed as markers of disease activity; however, the usefulness of eosinophil-derived neurotoxin (EDN)--another eosinophil granular protein--as a marker in pediatric asthma has not been established. OBJECTIVE: The authors compared the concentrations of blood eosinophil counts (TECs), serum ECP, and serum EDN to asthma symptom severity in young children. METHODS: Forty-three young children with asthma (Asthma group: mean age, 2.9 years; range, 1.4-5.0 years) were evaluated during both the acute and stable phases of disease. Asthma severity was measured using a symptom-scoring technique, and serum eosinophil indices (EDN and ECP levels and TECs) were determined. Nineteen age-matched controls (Control group: mean age, 2.7 years; range, 1.0-5.0 years) were used for comparison. RESULTS: Levels of serum EDN, serum ECP, and TECs were significantly higher in children with acute asthma compared with Controls (p < .0001). However, in stable asthma only EDN and ECP levels differed significantly when compared to Controls (p < .0001 and p < .001, respectively). When comparing acute and stable phases, EDN and TECs differed significantly (p < .0001), whereas ECP did not. Symptom scores correlated significantly with EDN (r = 0.850, p < 0.0001), ECP (r = 0.374, p < 0.01) and TECs (r = 0.457, p < 0.01) in acute asthma patients. When symptom scores were divided into three subgroups based on severity, only EDN levels showed significant differences amongst the three groups. CONCLUSION: These findings suggest that serum EDN is a useful marker for identifying disease activity in children with asthma. EDN levels may better reflect disease severity than ECP levels or total eosinophil counts.


Assuntos
Asma/sangue , Asma/diagnóstico , Proteína Catiônica de Eosinófilo/sangue , Neurotoxina Derivada de Eosinófilo/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Pré-Escolar , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Proteína Catiônica de Eosinófilo/metabolismo , Neurotoxina Derivada de Eosinófilo/metabolismo , Feminino , Humanos , Lactente , Masculino , Valor Preditivo dos Testes , Probabilidade , Prognóstico , Valores de Referência , Medição de Risco , Índice de Gravidade de Doença , Estatísticas não Paramétricas
11.
Skelet Muscle ; 10(1): 5, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32075690

RESUMO

BACKGROUND: Hexose-6-Phosphate Dehydrogenase (H6PD) is a generator of NADPH in the Endoplasmic/Sarcoplasmic Reticulum (ER/SR). Interaction of H6PD with 11ß-hydroxysteroid dehydrogenase type 1 provides NADPH to support oxo-reduction of inactive to active glucocorticoids, but the wider understanding of H6PD in ER/SR NAD(P)(H) homeostasis is incomplete. Lack of H6PD results in a deteriorating skeletal myopathy, altered glucose homeostasis, ER stress and activation of the unfolded protein response. Here we further assess muscle responses to H6PD deficiency to delineate pathways that may underpin myopathy and link SR redox status to muscle wide metabolic adaptation. METHODS: We analysed skeletal muscle from H6PD knockout (H6PDKO), H6PD and NRK2 double knockout (DKO) and wild-type (WT) mice. H6PDKO mice were supplemented with the NAD+ precursor nicotinamide riboside. Skeletal muscle samples were subjected to biochemical analysis including NAD(H) measurement, LC-MS based metabolomics, Western blotting, and high resolution mitochondrial respirometry. Genetic and supplement models were assessed for degree of myopathy compared to H6PDKO. RESULTS: H6PDKO skeletal muscle showed adaptations in the routes regulating nicotinamide and NAD+ biosynthesis, with significant activation of the Nicotinamide Riboside Kinase 2 (NRK2) pathway. Associated with changes in NAD+ biosynthesis, H6PDKO muscle had impaired mitochondrial respiratory capacity with altered mitochondrial acylcarnitine and acetyl-CoA metabolism. Boosting NAD+ levels through the NRK2 pathway using the precursor nicotinamide riboside elevated NAD+/NADH but had no effect to mitigate ER stress and dysfunctional mitochondrial respiratory capacity or acetyl-CoA metabolism. Similarly, H6PDKO/NRK2 double KO mice did not display an exaggerated timing or severity of myopathy or overt change in mitochondrial metabolism despite depression of NAD+ availability. CONCLUSIONS: These findings suggest a complex metabolic response to changes in muscle SR NADP(H) redox status that result in impaired mitochondrial energy metabolism and activation of cellular NAD+ salvage pathways. It is possible that SR can sense and signal perturbation in NAD(P)(H) that cannot be rectified in the absence of H6PD. Whether NRK2 pathway activation is a direct response to changes in SR NAD(P)(H) availability or adaptation to deficits in metabolic energy availability remains to be resolved.


Assuntos
Músculo Esquelético/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Retículo Sarcoplasmático/metabolismo , Acetilcoenzima A/metabolismo , Animais , Desidrogenases de Carboidrato/genética , Desidrogenases de Carboidrato/metabolismo , Carnitina/análogos & derivados , Carnitina/metabolismo , Feminino , Masculino , Metaboloma , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/metabolismo , Niacinamida/análogos & derivados , Niacinamida/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Compostos de Piridínio/metabolismo
12.
Cell Rep ; 28(7): 1717-1728.e6, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31412242

RESUMO

Nicotinamide adenine dinucleotide (NAD+) is modulated by conditions of metabolic stress and has been reported to decline with aging in preclinical models, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD+ metabolome and if it can alter muscle mitochondrial bioenergetics. We supplemented 12 aged men with 1 g NR per day for 21 days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD+ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways, without altering mitochondrial bioenergetics. NR also depressed levels of circulating inflammatory cytokines. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR.


Assuntos
Envelhecimento/metabolismo , Anti-Inflamatórios/sangue , Citocinas/sangue , Metaboloma/efeitos dos fármacos , Músculo Esquelético/metabolismo , Niacinamida/análogos & derivados , Transcriptoma/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/efeitos dos fármacos , Estudos Transversais , Citocinas/efeitos dos fármacos , Método Duplo-Cego , Humanos , Masculino , Músculo Esquelético/efeitos dos fármacos , NAD/metabolismo , Niacinamida/farmacologia , Compostos de Piridínio
13.
J Mol Endocrinol ; 61(3): R107-R121, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30307159

RESUMO

The concept of replenishing or elevating NAD+ availability to combat metabolic disease and ageing is an area of intense research. This has led to a need to define the endogenous regulatory pathways and mechanisms cells and tissues utilise to maximise NAD+ availability such that strategies to intervene in the clinical setting are able to be fully realised. This review discusses the importance of different salvage pathways involved in metabolising the vitamin B3 class of NAD+ precursor molecules, with a particular focus on the recently identified nicotinamide riboside kinase pathway at both a tissue-specific and systemic level.


Assuntos
NAD/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Animais , Humanos , Transdução de Sinais
14.
Prehosp Disaster Med ; 33(4): 441-447, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29962356

RESUMO

IntroductionImproving medical record keeping is a key part of the World Health Organization's (WHO's; Geneva, Switzerland) drive to standardize and evaluate emergency medical team (EMT) response to sudden onset disasters (SODs).ProblemIn response to the WHO initiative, the UK EMT is redeveloping its medical record template in line with the WHO minimum dataset (MDS) for daily reporting. When changing a medical record, it is important to understand how well it functions before it is implemented. METHODS: The redeveloped medical record was piloted at a UK EMT deployment course using simulated patients in order to examine ease of use by practitioners, and rates of data capture for key MDS variables. RESULTS: Some parts of the form were consistently poorly filled in, and the way in which the form was completed suggested that the flow of the form did not align with the recorder's natural thought processes when under pressure. CONCLUSION: Piloting of a single-sheet triplicate medical record during an EMT deployment simulation led to significant modifications to improve data capture and function.Jafar AJN, Fletcher RJ, Lecky F, Redmond AD. A pilot of a UK emergency medical team (EMT) medical record during a deployment training course. Prehosp Disaster Med. 2018;33(4):441-447.


Assuntos
Desastres , Prontuários Médicos/normas , Serviços Médicos de Emergência/normas , Humanos , Cooperação Internacional , Projetos Piloto , Reino Unido
15.
Wellcome Open Res ; 3: 147, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30607371

RESUMO

Background: Skeletal muscle is central to whole body metabolic homeostasis, with age and disease impairing its ability to function appropriately to maintain health. Inadequate NAD + availability is proposed to contribute to pathophysiology by impairing metabolic energy pathway use. Despite the importance of NAD + as a vital redox cofactor in energy production pathways being well-established, the wider impact of disrupted NAD + homeostasis on these pathways is unknown. Methods: We utilised skeletal muscle myotube models to induce NAD + depletion, repletion and excess and conducted metabolic tracing to provide comprehensive and detailed analysis of the consequences of altered NAD + metabolism on central carbon metabolic pathways. We used stable isotope tracers, [1,2-13C] D-glucose and [U- 13C] glutamine, and conducted combined 2D-1H,13C-heteronuclear single quantum coherence (HSQC) NMR spectroscopy and GC-MS analysis. Results: NAD + excess driven by nicotinamide riboside (NR) supplementation within skeletal muscle cells resulted in enhanced nicotinamide clearance, but had no effect on energy homeostasis or central carbon metabolism. Nicotinamide phosphoribosyltransferase (NAMPT) inhibition induced NAD + depletion and resulted in equilibration of metabolites upstream of glyceraldehyde phosphate dehydrogenase (GAPDH). Aspartate production through glycolysis and TCA cycle activity was increased in response to low NAD +, which was rapidly reversed with repletion of the NAD + pool using NR. NAD + depletion reversibly inhibits cytosolic GAPDH activity, but retains mitochondrial oxidative metabolism, suggesting differential effects of this treatment on sub-cellular pyridine pools. When supplemented, NR efficiently reversed these metabolic consequences. However, the functional relevance of increased aspartate levels after NAD + depletion remains unclear, and requires further investigation. Conclusions: These data highlight the need to consider carbon metabolism and clearance pathways when investigating NAD + precursor usage in models of skeletal muscle physiology.

16.
Chem Sci ; 8(11): 7483-7491, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29163901

RESUMO

Zeolites, microporous aluminosilicates, are amongst the most widely used catalysts in the petrochemical industry. Zeolite catalytic functionality is influenced by the location of tetrahedral alumina and associated counter-cations in the aluminosilicate framework, yet little is definitively known about the factors that govern the framework aluminium arrangement. It is generally accepted that all zeolites obey Löwenstein's rule of "aluminium avoidance", and that -Al-O-Al- bond formation is forbidden. Here, we describe an unprecedented screening of aluminium distribution in catalytically active zeolite SSZ-13 (CHA) in both its protonated and sodium-containing forms, H-SSZ-13 and Na-SSZ-13, using density functional theory (DFT). We predict violations of Löwenstein's rule in high and low silica H-SSZ-13 and other protonated frameworks considered in this investigation: H-LTA, H-RHO, H-ABW and H-MOR. The synthetic realisation of these zeolites could spur the development of new catalytic routes and materials, and the optimisation of existing zeolite catalysts.

17.
Endocrinology ; 158(6): 1964-1976, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28368470

RESUMO

Glucocorticoids (GCs) are potent regulators of energy metabolism. Chronic GC exposure suppresses brown adipose tissue (BAT) thermogenic capacity in mice, with evidence for a similar effect in humans. Intracellular GC levels are regulated by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activity, which can amplify circulating GC concentrations. Therefore, 11ß-HSD1 could modulate the impact of GCs on BAT function. This study investigated how 11ß-HSD1 regulates the molecular architecture of BAT in the context of GC excess and aging. Circulating GC excess was induced in 11ß-HSD1 knockout (KO) and wild-type mice by supplementing drinking water with 100 µg/mL corticosterone, and the effects on molecular markers of BAT function and mitochondrial activity were assessed. Brown adipocyte primary cultures were used to examine cell autonomous consequences of 11ß-HSD1 deficiency. Molecular markers of BAT function were also examined in aged 11ß-HSD1 KO mice to model lifetime GC exposure. BAT 11ß-HSD1 expression and activity were elevated in response to GC excess and with aging. 11ß-HSD1 KO BAT resisted the suppression of uncoupling protein 1 (UCP1) and mitochondrial respiratory chain subunit proteins normally imposed by GC excess. Furthermore, brown adipocytes from 11ß-HSD1 KO mice had elevated basal mitochondrial function and were able to resist GC-mediated repression of activity. BAT from aged 11ß-HSD1 KO mice showed elevated UCP1 protein and mitochondrial content, and a favorable profile of BAT function. These data reveal a novel mechanism in which increased 11ß-HSD1 expression, in the context of GC excess and aging, impairs the molecular and metabolic function of BAT.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/fisiologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Glucocorticoides/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , Animais , Células Cultivadas , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteína Desacopladora 1/metabolismo
18.
Dev Psychol ; 53(7): 1265-1275, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28471220

RESUMO

Paying attention is a critical first step toward learning. For children in primary school classrooms there can be many things to attend to other than the focus of a lesson, such as visual displays on classroom walls. The aim of this study was to use eye-tracking techniques to explore the impact of visual displays on attention and learning for children. Critically, we explored these issues for children developing typically and for children with autism spectrum disorder (ASD). Both groups of children watched videos of a teacher delivering classroom activities-2 of "story-time" and 2 mini lessons. Half of the videos each child saw contained high levels of classroom visual displays in the background (high visual display [HVD]) and half had none (no visual display [NVD]). Children completed worksheets after the mini lessons to measure learning. During viewing of all videos children's eye movements were recorded. The presence of visual displays had a significant impact on attention for all children, but to a greater extent for children with ASD. Visual displays also had an impact on learning from the mini lessons, whereby children had poorer learning scores in the HVD compared with the NVD lesson. Individual differences in age, verbal, nonverbal, and attention abilities were important predictors of learning, but time spent attending the visual displays in HVD was the most important predictor. This novel and timely investigation has implications for the use of classroom visual displays for all children, but particularly for children with ASD. (PsycINFO Database Record


Assuntos
Atenção/fisiologia , Transtorno do Espectro Autista/fisiopatologia , Aprendizagem/fisiologia , Instituições Acadêmicas , Percepção Visual/fisiologia , Criança , Medições dos Movimentos Oculares , Feminino , Humanos , Masculino
19.
Mol Metab ; 6(8): 819-832, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28752046

RESUMO

OBJECTIVE: Augmenting nicotinamide adenine dinucleotide (NAD+) availability may protect skeletal muscle from age-related metabolic decline. Dietary supplementation of NAD+ precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) appear efficacious in elevating muscle NAD+. Here we sought to identify the pathways skeletal muscle cells utilize to synthesize NAD+ from NMN and NR and provide insight into mechanisms of muscle metabolic homeostasis. METHODS: We exploited expression profiling of muscle NAD+ biosynthetic pathways, single and double nicotinamide riboside kinase 1/2 (NRK1/2) loss-of-function mice, and pharmacological inhibition of muscle NAD+ recycling to evaluate NMN and NR utilization. RESULTS: Skeletal muscle cells primarily rely on nicotinamide phosphoribosyltransferase (NAMPT), NRK1, and NRK2 for salvage biosynthesis of NAD+. NAMPT inhibition depletes muscle NAD+ availability and can be rescued by NR and NMN as the preferred precursors for elevating muscle cell NAD+ in a pathway that depends on NRK1 and NRK2. Nrk2 knockout mice develop normally and show subtle alterations to their NAD+ metabolome and expression of related genes. NRK1, NRK2, and double KO myotubes revealed redundancy in the NRK dependent metabolism of NR to NAD+. Significantly, these models revealed that NMN supplementation is also dependent upon NRK activity to enhance NAD+ availability. CONCLUSIONS: These results identify skeletal muscle cells as requiring NAMPT to maintain NAD+ availability and reveal that NRK1 and 2 display overlapping function in salvage of exogenous NR and NMN to augment intracellular NAD+ availability.


Assuntos
Fibras Musculares Esqueléticas/metabolismo , Niacinamida/análogos & derivados , Mononucleotídeo de Nicotinamida/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Animais , Linhagem Celular , Células Cultivadas , Citocinas/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Niacinamida/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Compostos de Piridínio
20.
Artigo em Inglês | MEDLINE | ID: mdl-27933155

RESUMO

The risk of falls is higher in patients with people with Parkinsonism (PwP) compared to those without Parkinsonism, and leads to adverse outcomes including fragility fractures. Osteoporosis is under-recognised, and the prevalence of fragility fractures in not well studied. The primary aim of this project is for 100% of new patient referrals to, and 80% of follow up patients within the movement disorder (MD) service with osteoporosis to be treated in accordance with evidence based osteoporosis guidance. Routinely captured information regarding demographics and fragility fractures was retrospectively extracted from the clinical workstation, clinic letters, and clinical coding between July and November 2015. The prevalence of fragility fracture was 22.6% (68/300), and only 40% (27/68) were on appropriate treatment for osteoporosis. A quality improvement (QI) methodology based on the model of improvement, Plan-Do-Study-Act (PDSA) cycles were used, and a monthly multidisciplinary team (MDT) meeting was introduced. This QI initiative has shown that MDT input can reduce referrals to physiotherapists; and also 100% of new patients, and 91% of follow up patients received evidence based osteoporosis treatment.

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