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OBJECTIVE AND CONTEXT: Maturity onset diabetes of the young due to variants in HNF1A (HNF1A-MODY) is the most common form of monogenic diabetes. Individuals with HNF1A-MODY usually have a lean phenotype which contrasts with type 2 diabetes (T2DM). Data from hepatocytes derived from Hnf1a knock-out mice demonstrated dysregulation of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), which regulates glucocorticoid availability and action in target tissues, together with 11ß-HSD2 and steroid A-ring reductases, 5α- and 5ß-reductase. We proposed that altered glucocorticoid metabolism might underpin some of the phenotypic differences between patients with HNF1A-MODY and those with T2DM. DESIGN: A retrospective matched cohort study. PATIENTS AND MEASUREMENTS: 24-hours urine steroid metabolome profiling was carried out by gas chromatography-mass spectrometry in 35 subjects with HNF1A-MODY, 35 individuals with T2DM and 35 healthy controls matched for age, sex and BMI. The steroid metabolites were expressed as µg/L in all groups and measured in mid-morning urine in diabetic subjects and 24-hour urine collection in healthy controls. Hence, only ratios were compared not the individual steroids. Established ratios of glucocorticoid metabolites were used to estimate 11ß-HSD1/2 and 5α- and 5ß-reductase activities. RESULTS: While 11ß-HSD1 activity was similar in all groups, 11ß-HSD2 activity was significantly lower in subjects with HNF1A-MODY and T2DM than in healthy controls. The ratio of 5ß- to 5α-metabolites of cortisol was higher in subjects with HNF1A-MODY than in T2DM and healthy controls, probably due to increased activity of the 5ß-reductase (AKR1D1) in HNF1A-MODY. CONCLUSIONS: This is the first report of steroid metabolites in HNF1A-MODY. We have identified distinct differences in steroid metabolism pathways in subjects with HNF1A-MODY that have the potential to alter steroid hormone availability. Further studies are required to explore whether these changes link to phenotype.
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Diabetes Mellitus Tipo 2 , Animais , Estudos de Coortes , Fator 1-alfa Nuclear de Hepatócito/genética , Humanos , Hidrocortisona , Camundongos , Estudos RetrospectivosRESUMO
A synthesis of the 2-azatricyclo[4.3.2.04,9]undecane ring system-a hitherto unreported bridged azatricyclic ring system-beginning from tricarbonyl(tropone)iron and allylamine was accomplished in three steps: (1) aza-Michael addition of allylamine to tricarbonyl(tropone)iron; (2) Boc-protection of the resulting secondary amine; and (3) oxidative demetallation leading to a spontaneous intramolecular Diels-Alder reaction. The effect of a variety of parameters on the intramolecular Diels-Alder reaction was investigated, including diene and dienophile substitution patterns and dienophile tether length.
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INTRODUCTION: The presentation of primary hyperparathyroidism (PHPT) has shifted from a disease characterized by renal and skeletal complications to a mild or asymptomatic condition. Modern imaging allows localization of a surgical target in the majority of cases. SOURCES OF DATA: Data were collected from literature searches of online databases including PUBMED, MEDLINE and Cochrane. A narrative review was performed. AREAS OF AGREEMENT: Parathyroidectomy is the only therapy with curative potential with good outcomes and low risk of complications in experienced hands. Current guidelines advocate that surgery is offered in all symptomatic cases and in those who meet criteria depending on age, serum calcium concentration, skeletal and renal parameters. A structured monitoring approach should be offered to those who do not undergo surgery. AREAS OF CONTROVERSY: Thresholds for intervention to improve skeletal and renal outcomes are debatable. In addition, controversy persists over the benefit of surgery for non-skeletal/renal outcomes. GROWING POINTS: The role of medical management of PHPT using agents such as bisphosphonates, denosumab and cinacalcet are discussed. AREAS TIMELY FOR DEVELOPING RESEARCH: In summary, further data on the natural history and effects of treatment of mild and asymptomatic PHPT are required to determine thresholds for surgery. In particular, further investigations of non-skeletal and non-renal parameters, such as neurocognitive quality of life and cardiovascular disease are required. Data on normocalcaemic PHPT are lacking. Large-scale randomized controlled trials would be welcome in these areas, however in view of the cost implications a more pragmatic approach may be to develop collaborative multi-centre registries.
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Hiperparatireoidismo Primário/terapia , Densidade Óssea , Hormônios e Agentes Reguladores de Cálcio/uso terapêutico , Doenças Cardiovasculares/etiologia , Cinacalcete/uso terapêutico , Tomada de Decisão Clínica/métodos , Humanos , Hiperparatireoidismo Primário/complicações , Hiperparatireoidismo Primário/fisiopatologia , Neoplasias/etiologia , Nefrolitíase/etiologia , Paratireoidectomia , Qualidade de VidaRESUMO
To understand trends in individual responses to medication, one can take a purely data-driven machine learning approach, or alternatively apply pharmacokinetics combined with mixed-effects statistical modelling. To take advantage of the predictive power of machine learning and the explanatory power of pharmacokinetics, we propose a latent variable mixture model for learning clusters of pharmacokinetic models demonstrated on a clinical data set investigating 11ß-hydroxysteroid dehydrogenase enzymes (11ß-HSD) activity in healthy adults. The proposed strategy automatically constructs different population models that are not based on prior knowledge or experimental design, but result naturally as mixture component models of the global latent variable mixture model. We study the parameter of the underlying multi-compartment ordinary differential equation model via identifiability analysis on the observable measurements, which reveals the model is structurally locally identifiable. Further approximation with a perturbation technique enables efficient training of the proposed probabilistic latent variable mixture clustering technique using Estimation Maximization. The training on the clinical data results in 4 clusters reflecting the prednisone conversion rate over a period of 4 h based on venous blood samples taken at 20-min intervals. The learned clusters differ in prednisone absorption as well as prednisone/prednisolone conversion. In the discussion section we include a detailed investigation of the relationship of the pharmacokinetic parameters of the trained cluster models for possible or plausible physiological explanation and correlations analysis using additional phenotypic participant measurements.
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Glucocorticoides/farmacocinética , Modelos Biológicos , Prednisolona/farmacocinética , Prednisona/farmacocinética , 11-beta-Hidroxiesteroide Desidrogenases/metabolismo , Adulto , Idoso , Feminino , Glucocorticoides/administração & dosagem , Humanos , Aprendizado de Máquina , Pessoa de Meia-Idade , Prednisolona/administração & dosagem , Prednisona/administração & dosagemRESUMO
Introduction: Vitamin D deficiency is common worldwide with adverse effects on skeletal health. In recent years, there has been great interest in non-classical actions of vitamin D. Basic research has uncovered actions in a range of non-skeletal tissues, and observational studies have identified inverse relationships with risk of a number of disease states including sarcopenia, obesity, the metabolic syndrome, cardiovascular disease, cancer and autoimmune diseases. Sources of data: PubMed, Medline and Cochrane Systematic Reviews. Areas of agreement: Current evidence supports the use of vitamin D supplementation in deficiency to improve skeletal outcomes such as falls/fracture risk and bone mineral density. Areas of controversy: There is debate reflected in guidelines on optimal thresholds for circulating levels of vitamin D. Further studies are required to refine dosing regimens and treatment target levels of vitamin D. Growing points: A number of studies have investigated the extra-skeletal effects of vitamin D deficiency but causality in humans has yet to be confirmed. Areas timely for developing research: Large-scale randomized controlled trials incorporating data on vitamin D status at baseline and follow up, adverse events, and comparison of dosing regimens are required. It is imperative that studies are carried out with a diverse range of participants (age, gender and ethnicity), and settings to allow for a more individualized approach. In addition, we would advocate incorporating cutting-edge research tools into human studies to advance our understanding of the mechanisms of vitamin D action in extra-skeletal disease. This may involve multi-metabolite analysis of vitamin D metabolites, or unbiased approaches to assess regulation of gene/protein expression in tissues of interest.
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Países Desenvolvidos , Deficiência de Vitamina D/terapia , Vitamina D/administração & dosagem , Vitaminas/administração & dosagem , Suplementos Nutricionais , Humanos , Vitamina D/efeitos adversos , Vitamina D/fisiologia , Deficiência de Vitamina D/complicações , Vitaminas/efeitos adversosRESUMO
The adverse metabolic effects of prescribed and endogenous glucocorticoid (GC) excess, Cushing syndrome, create a significant health burden. We found that tissue regeneration of GCs by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), rather than circulating delivery, is critical to developing the phenotype of GC excess; 11ß-HSD1 KO mice with circulating GC excess are protected from the glucose intolerance, hyperinsulinemia, hepatic steatosis, adiposity, hypertension, myopathy, and dermal atrophy of Cushing syndrome. Whereas liver-specific 11ß-HSD1 KO mice developed a full Cushingoid phenotype, adipose-specific 11ß-HSD1 KO mice were protected from hepatic steatosis and circulating fatty acid excess. These data challenge our current view of GC action, demonstrating 11ß-HSD1, particularly in adipose tissue, is key to the development of the adverse metabolic profile associated with circulating GC excess, offering 11ß-HSD1 inhibition as a previously unidentified approach to treat Cushing syndrome.
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11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Tecido Adiposo/metabolismo , Síndrome de Cushing/sangue , Síndrome de Cushing/genética , Glucocorticoides/sangue , Hidrocortisona/sangue , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , Animais , Anti-Inflamatórios/química , Pressão Sanguínea , Modelos Animais de Doenças , Ácidos Graxos não Esterificados/sangue , Regulação da Expressão Gênica , Intolerância à Glucose , Teste de Tolerância a Glucose , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Regeneração/efeitos dos fármacos , Triglicerídeos/sangueRESUMO
The aged phenotype shares several metabolic similarities with that of circulatory glucocorticoid excess (Cushing's syndrome), including type 2 diabetes, obesity, hypertension, and myopathy. We hypothesise that local tissue generation of glucocorticoids by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), which converts 11-dehydrocorticosterone to active corticosterone in rodents (corticosterone to cortisol in man), plays a role in driving age-related chronic disease. In this study, we have examined the impact of ageing on glucocorticoid metabolism, insulin tolerance, adiposity, muscle strength, and blood pressure in both wildtype (WT) and transgenic male mice with a global deletion of 11ß-HSD1 (11ß-HSD1-/-) following 4 months high-fat feeding. We found that high fat-fed 11ß-HSD1-/- mice were protected from age-related glucose intolerance and hyperinsulinemia when compared to age/diet-matched WTs. By contrast, aged 11ß-HSD1-/- mice were not protected from the onset of sarcopenia observed in the aged WTs. Young 11ß-HSD1-/- mice were partially protected from diet-induced obesity; however, this partial protection was lost with age. Despite greater overall obesity, the aged 11ß-HSD1-/- animals stored fat in more metabolically safer adipose depots as compared to the aged WTs. Serum analysis revealed both WT and 11ß-HSD1-/- mice had an age-related increase in morning corticosterone. Surprisingly, 11ß-HSD1 oxo-reductase activity in the liver and skeletal muscle was unchanged with age in WT mice and decreased in gonadal adipose tissue. These data suggest that deletion of 11ß-HSD1 in high fat-fed, but not chow-fed, male mice protects from age-related insulin resistance and supports a metabolically favourable fat distribution.
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11-beta-Hidroxiesteroide Desidrogenase Tipo 1 , Diabetes Mellitus Tipo 2 , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Animais , Corticosterona/metabolismo , Glucocorticoides/metabolismo , Hidrocortisona , Insulina , Masculino , Camundongos , Camundongos Transgênicos , Obesidade/genéticaRESUMO
This European expert consensus statement provides recommendations for the diagnosis and management of primary hyperparathyroidism (PHPT), chronic hypoparathyroidism in adults (HypoPT), and parathyroid disorders in relation to pregnancy and lactation. Specified areas of interest and unmet needs identified by experts at the second ESE Educational Program of Parathyroid Disorders (PARAT) in 2019, were discussed during two virtual workshops in 2021, and subsequently developed by working groups with interest in the specified areas. PHPT is a common endocrine disease. However, its differential diagnosing to familial hypocalciuric hypercalcemia (FHH), the definition and clinical course of normocalcemic PHPT, and the optimal management of its recurrence after surgery represent areas of uncertainty requiring clarifications. HypoPT is an orphan disease characterized by low calcium concentrations due to insufficient PTH secretion, most often secondary to neck surgery. Prevention and prediction of surgical injury to the parathyroid glands are essential to limit the disease-related burden. Long-term treatment modalities including the place for PTH replacement therapy and the optimal biochemical monitoring and imaging surveillance for complications to treatment in chronic HypoPT, need to be refined. The physiological changes in calcium metabolism occurring during pregnancy and lactation modify the clinical presentation and management of parathyroid disorders in these periods of life. Modern interdisciplinary approaches to PHPT and HypoPT in pregnant and lactating women and their newborns children are proposed. The recommendations on clinical management presented here will serve as background for further educational material aimed for a broader clinical audience, and were developed with focus on endocrinologists in training.
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Hipercalcemia , Hiperparatireoidismo Primário , Hipoparatireoidismo , Doenças das Paratireoides , Adulto , Cálcio , Feminino , Humanos , Hipercalcemia/complicações , Hiperparatireoidismo Primário/complicações , Hiperparatireoidismo Primário/diagnóstico , Hiperparatireoidismo Primário/terapia , Hipoparatireoidismo/diagnóstico , Recém-Nascido , Lactação , Hormônio Paratireóideo , GravidezRESUMO
Sarcopenia describes low muscle mass and strength associated with ageing, whilst reduced physical performance indicates the severity of the condition. It can happen independently of other medical conditions and can be a key feature of the frailty phenotype. Frailty is a syndrome of increased vulnerability to incomplete resolution of homeostasis, following a stressor event. Researchers have described the implications of hypothalamic pituitary dysregulation in the pathogenesis of both entities. This review summarizes the recent evidence in this area as well as other endocrine factors such as insulin resistance and vitamin D status and outlines current research priorities. We conducted searches to PubMed and Embase databases for articles, reviews and studies reporting new data on the interaction between hormones of the endocrine system and frailty and/ or sarcopenia in the last 5 years. Interventional studies, cohort studies, case-control studies and animal studies were included. Clinical trials register was also searched to identify ongoing relevant studies. Studies have given us insights into the complex relationships between factors such as anabolic hormones, glucocorticoids and vitamin D on muscle strength and performance and their involvement in ageing phenotypes. However, robust randomized controlled trials are needed to consolidate existing evidence in humans and inform clinical practice. Current evidence supports hormone replacement in patients with confirmed deficiencies, to optimize health and prevent complications. Hormone replacement has limited use for age-related conditions. Current interest is focused on muscle/bone/fat interactions and health outcomes in "sarcopenic obesity." A life-course approach to improving 'health-span' is advocated. Lifestyle factors such as nutrition and physical activity have important interactions with body composition, physical function and metabolic outcomes. Large-scale clinical trials will determine the efficacy and long-term safety of hormone supplementation in the management of sarcopenia and frailty.
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Fragilidade , Sarcopenia , Envelhecimento , Sistema Endócrino , Humanos , Força MuscularRESUMO
PURPOSE OF REVIEW: We review the recent literature on the interplay between mild vitamin D deficiency and skeletal muscle strength and performance. RECENT FINDINGS: Preclinical studies indicate that vitamin D is important in muscle proliferation, differentiation and mitochondrial function, whereas some epidemiological studies demonstrate associations with muscle strength and low physical performance. Recent studies have implicated vitamin D deficiency in the development of frailty and sarcopenia in the older population. Some small studies have assessed its impact on muscle function in special circumstances such as elite sport and critical illness. Advances in liquid chromatography/mass spectrometry technologies have allowed the inter-relationships between the vitamin D metabolome and muscle phenotype to be characterized. There is evidence of distinct effects on human skeletal muscle gene expression between vitamin D metabolites. SUMMARY: Large-scale clinical trials with well defined cohorts and outcomes are needed to provide clinically meaningful insights into this area. Care should be taken to stratify participants by vitamin D status at baseline and over follow-up in addition to observing a range of measures of muscle function.
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Força Muscular/fisiologia , Músculo Esquelético/fisiologia , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/fisiopatologia , Animais , Humanos , Músculo Esquelético/metabolismo , Sarcopenia/tratamento farmacológico , Sarcopenia/epidemiologia , Sarcopenia/etiologia , Sarcopenia/fisiopatologia , Vitamina D/metabolismo , Vitamina D/uso terapêutico , Deficiência de Vitamina D/epidemiologia , Deficiência de Vitamina D/terapiaRESUMO
OBJECTIVE: To explore variability in acute changes in muscle mass and function in older patients undergoing elective colorectal surgery, as well as feasibility of measures, in order to refine study processes to inform the protocol for a larger study. RESULTS: Results are presented for seven participants recruited to this pilot study. It is possible to perform serial measurements of bilateral anterior thigh thickness (BATT) and handgrip strength prior to, within 24 h of surgery, and 1 week postoperatively. Gait speed can be reliably measured preoperatively and at 1 week postoperatively. In this pilot study, BATT and gait speed declined at 1 week postoperatively (median BATT 4.17 cm, 3.47 cm, p = 0.028; median gait speed 0.89 m/s, 0.83 m/s, p = 0.043). Baseline hsCRP correlated with change in BATT (τb = 0.73, p = 0.04) and baseline DHEA-S correlated with change in gait speed (τb = 0.87, p = 0.02). This pilot study has assisted to refine the protocol for our larger study, which will further characterise these changes.
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Cirurgia Colorretal/efeitos adversos , Complicações Pós-Operatórias , Sarcopenia , Velocidade de Caminhada/fisiologia , Doença Aguda , Idoso , Biomarcadores , Estudos de Viabilidade , Feminino , Seguimentos , Avaliação Geriátrica , Humanos , Masculino , Projetos Piloto , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/fisiopatologia , Sarcopenia/sangue , Sarcopenia/diagnóstico por imagem , Sarcopenia/etiologia , Sarcopenia/fisiopatologiaRESUMO
aza-Michael adducts of tricarbonyl(tropone)iron are synthesized by two different methods. Primary aliphatic amines and cyclic secondary amines participate in a direct aza-Michael reaction with tricarbonyl(tropone)iron under solvent-free conditions. Less nucleophilic aniline derivatives and more hindered secondary amines add efficiently to the cationic tropone complex formed by protonation of tricarbonyl(tropone)iron. While the protocol utilizing the cationic complex is less efficient overall for accessing the aza-Michael adducts than the direct, solvent-free addition to the neutral complex, it allows the use of a broader range of amine nucleophiles. Following protection of the amine of the aza-Michael adduct as a tert-butyl carbamate, the diene is decomplexed from the iron tricarbonyl fragment upon treatment with cerium(IV) ammonium nitrate to provide derivatives of 6-aminocyclohepta-2,4-dien-1-one. These products can serve as precursors to diverse compounds containing a seven-membered carbocyclic ring. Because the demetallation requires protection of the amine as a carbamate, the aza-Michael adducts of secondary amines cannot be decomplexed using the protocol described here.
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Química Farmacêutica/métodos , Ferro/química , Tropolona/análogos & derivados , Aminas/síntese química , Catálise , Hidrogenação , Nitratos/síntese química , Solventes/síntese química , Tropolona/síntese químicaRESUMO
BACKGROUND: The GH secretagogue receptor type 1a gene (GHSR) encodes the cognate receptor of ghrelin, a gut hormone that regulates food intake and pituitary GH secretion. Previous studies in U.S. families and a German population suggested GHSR to be a candidate quantitative locus for association with human obesity and growth. AIM: The aim of the study was to test common genetic variation in GHSR for association with body size in children and adults. METHODS: Sequencing was performed to systematically identify novel single nucleotide polymorphisms (SNPs) in GHSR. A set of three haplotype-tagging SNPs that captured all the genetic variation in GHSR was identified. These three haplotype-tagging SNPs were then genotyped in three large population-based U.K. cohort studies (two adult and one childhood cohort) comprising 5807 adults and 843 children. RESULTS: No significant genotype or haplotype associations were found with adult or childhood height, weight, or body mass index. CONCLUSION: Common variation in GHSR is not associated with body size in U.K. adults or children.
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Tamanho Corporal/genética , Polimorfismo de Nucleotídeo Único , Receptores de Grelina/genética , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Frequência do Gene , Genótipo , Humanos , Lactente , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Reino UnidoRESUMO
The present study was designed to study the influence of different concentrations of oviduct fluid (OF) and follicular fluid (FF) on ram sperm capacitation and acrosome reaction in vitro. Forty semen samples were collected from three Barki rams throughout the period of study (10â¯weeks). Fresh semen was evaluated, layered under S-TALP (sperm Tyrode's albumin lactate pyruvate) medium and subjected to swim up techniques. Split fractions of semen were incubated in media enriched with different levels of OF (10, 20, 40, 50 and 75⯵L/mL) or FF (10, 20, 40, 50, 100, 150 and 200⯵L/mL). Best concentrations were compared and used to evaluate the ram sperm functions including progressive motility, hyperactivity and acrosome reaction. The present findings showed a significant increase in individual motility percentage (IM %) when ram spermatozoa were treated with 10 and 50⯵L of oviduct fluids as compared to the other treatments after 1â¯h of incubation. Addition of 50⯵L/mL of OF or FF had beneficial effect on sperm hyperactivity after 2 and 1â¯h incubation respectively. Furthermore, addition of 50⯵L/mL oviduct fluid to ram sperm maintained significantly (Pâ¯<â¯.05) higher total acrosome reaction (AR %) after 3â¯h of incubations than those observed in other groups. In conclusion, treatment of ram spermatozoa with 50⯵L/mL of OF or 40⯵L/mL of FF for 3-4â¯h incubation respectively was considered the best level of oviduct or follicular fluid to be used for IVF.
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A 48-year-old man was diagnosed with a large macroprolactinoma in 1982 treated with surgery, adjuvant radiotherapy and bromocriptine. Normal prolactin was achieved in 2005 but in 2009 it started rising. Pituitary MRIs in 2009, 2012, 2014 and 2015 were reported as showing empty pituitary fossa. Prolactin continued to increase (despite increasing bromocriptine dose). Trialling cabergoline had no effect (prolactin 191,380 mU/L). In January 2016, he presented with right facial weakness and CT head was reported as showing no acute intracranial abnormality. In late 2016, he was referred to ENT with hoarse voice; left hypoglossal and recurrent laryngeal nerve palsies were found. At this point, prolactin was 534,176 mU/L. Just before further endocrine review, he had a fall and CT head showed a basal skull mass invading the left petrous temporal bone. Pituitary MRI revealed a large enhancing mass within the sella infiltrating the clivus, extending into the left petrous apex and occipital condyle with involvement of the left Meckel's cave, internal acoustic meatus, jugular foramen and hypoglossal canal. At that time, left abducens nerve palsy was also present. CT thorax/abdomen/pelvis excluded malignancy. Review of previous images suggested that this lesion had started becoming evident below the fossa in pituitary MRI of 2015. Temozolomide was initiated. After eight cycles, there is significant tumour reduction with prolactin 1565 mU/L and cranial nerve deficits have remained stable. Prolactinomas can manifest aggressive behaviour even decades after initial treatment highlighting the unpredictable clinical course they can demonstrate and the need for careful imaging review. LEARNING POINTS: Aggressive behaviour of prolactinomas can manifest even decades after first treatment highlighting the unpredictable clinical course these tumours can demonstrate.Escape from control of hyperprolactinaemia in the absence of sellar adenomatous tissue requires careful and systematic search for the anatomical localisation of the lesion responsible for the prolactin excess.Temozolomide is a valuable agent in the therapeutic armamentarium for aggressive/invasive prolactinomas, particularly if they are not amenable to other treatment modalities.
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A 26-year-old man presented following blunt abdominal trauma to a regional major trauma centre for emergency embolisation of a retroperitoneal bleed from a presumed renal laceration. Imaging had also revealed a large right suprarenal mass. Embolisation resulted in a hypertensive crisis raising the suspicion of a metabolically active adrenal tumour. The course was further complicated by the development of ischaemic bowel requiring emergency laparotomy. Intraoperatively he became haemodynamically unstable from an actively haemorrhaging lesion. Emergency laparotomy and adrenalectomy was performed as a life-saving procedure. Histology confirmed a phaeochromocytoma. The patient made a gradual recovery and was discharged home with no sequelae. Definitive management of phaeochromocytoma is surgical resection which requires prolonged preoperative optimisation with alpha receptor blockers to adequately control blood pressure and prevent hypertensive crises. Parenteral alpha receptor blockers, such as phentolamine, are optimal treatment for intraoperative hypertensive emergencies, yet they are currently not available in the UK.
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Traumatismos Abdominais , Neoplasias das Glândulas Suprarrenais , Feocromocitoma , Ferimentos não Penetrantes , Traumatismos Abdominais/complicações , Traumatismos Abdominais/diagnóstico por imagem , Traumatismos Abdominais/patologia , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Adulto , Emergências , Humanos , Laparotomia , Masculino , Feocromocitoma/complicações , Feocromocitoma/diagnóstico por imagem , Feocromocitoma/patologia , Feocromocitoma/cirurgia , Tomografia Computadorizada por Raios X , Ferimentos não Penetrantes/complicações , Ferimentos não Penetrantes/diagnóstico por imagem , Ferimentos não Penetrantes/patologiaRESUMO
The construction of molecular machines has captured the imagination of scientists for decades. Despite significant progress in the synthesis and studies of the properties of small-molecule components (smaller than 2-5 kilo Dalton), challenges regarding the incorporation of molecular components into real devices are still eminent. Nano-sized molecular machines operate the complex biological machinery of life, and the idea of mimicking the amazing functions using artificial nano-structures is intriguing. Both in small-molecule molecular machine components and in many naturally occurring molecular machines, mechanically interlocked molecules and structures are key functional components. In this work, we describe our initial efforts to interface mechanically-interlocked molecules and gold-nanoparticles (AuNPs); the molecular wire connecting the AuNPs is covered in an insulating rotaxane-layer, thus mimicking the macroscopic design of a copper wire. Taking advantage of recent progress in the preparation of supramolecular complexes of the cucurbit[7]uril (CB[7]) macrocycle, we have prepared a bis-thiol functionalised pseudo-rotaxane that enables us to prepare a AuNP-stoppered [2]rotaxane in water. The pseudo-rotaxane is held together extremely tightly (Ka > 1013 M-1), Ka being the association constant. We have studied the solution and gas phase guest-host chemistry using NMR spectroscopy, mass spectroscopy, and electrochemistry. The bis-thiol functionalised pseudo-rotaxane holds further a ferrocene unit in the centre of the rotaxane; this ferrocene unit enables us to address the system in detail with and without CB[7] and AuNPs using electrochemical methods.
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Age-associated decline in muscle function represents a significant public health burden. Vitamin D-deficiency is also prevalent in aging subjects, and has been linked to loss of muscle mass and strength (sarcopenia), but the precise role of specific vitamin D metabolites in determining muscle phenotype and function is still unclear. To address this we quantified serum concentrations of multiple vitamin D metabolites, and assessed the impact of these metabolites on body composition/muscle function parameters, and muscle biopsy gene expression in a retrospective study of a cohort of healthy volunteers. Active serum 1,25-dihydroxyvitamin D3 (1α,25(OH)2D3), but not inactive 25-hydroxyvitamin D3 (25OHD3), correlated positively with measures of lower limb strength including power (rho = 0.42, p = 0.02), velocity (Vmax, rho = 0.40, p = 0.02) and jump height (rho = 0.36, p = 0.04). Lean mass correlated positively with 1α,25(OH)2D3 (rho = 0.47, p = 0.02), in women. Serum 25OHD3 and inactive 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) had an inverse relationship with body fat (rho = -0.30, p = 0.02 and rho = -0.33, p = 0.01, respectively). Serum 25OHD3 and 24,25(OH)2D3 were also correlated with urinary steroid metabolites, suggesting a link with glucocorticoid metabolism. PCR array analysis of 92 muscle genes identified vitamin D receptor (VDR) mRNA in all muscle biopsies, with this expression being negatively correlated with serum 25OHD3, and Vmax, and positively correlated with fat mass. Of the other 91 muscle genes analysed by PCR array, 24 were positively correlated with 25OHD3, but only 4 were correlated with active 1α,25(OH)2D3. These data show that although 25OHD3 has potent actions on muscle gene expression, the circulating concentrations of this metabolite are more closely linked to body fat mass, suggesting that 25OHD3 can influence muscle function via indirect effects on adipose tissue. By contrast, serum 1α,25(OH)2D3 has limited effects on muscle gene expression, but is associated with increased muscle strength and lean mass in women. These pleiotropic effects of the vitamin D 'metabolome' on muscle function indicate that future supplementation studies should not be restricted to conventional analysis of the major circulating form of vitamin D, 25OHD3.
Assuntos
Calcifediol/sangue , Calcitriol/sangue , Regulação da Expressão Gênica/fisiologia , Proteínas Musculares/biossíntese , Força Muscular/fisiologia , Músculo Esquelético/metabolismo , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Adrenal aldosterone excess is the most common cause of secondary hypertension and is associated with increased cardiovascular morbidity. However, adverse metabolic risk in primary aldosteronism extends beyond hypertension, with increased rates of insulin resistance, type 2 diabetes, and osteoporosis, which cannot be easily explained by aldosterone excess. METHODS: We performed mass spectrometry-based analysis of a 24-hour urine steroid metabolome in 174 newly diagnosed patients with primary aldosteronism (103 unilateral adenomas, 71 bilateral adrenal hyperplasias) in comparison to 162 healthy controls, 56 patients with endocrine inactive adrenal adenoma, 104 patients with mild subclinical, and 47 with clinically overt adrenal cortisol excess. We also analyzed the expression of cortisol-producing CYP11B1 and aldosterone-producing CYP11B2 enzymes in adenoma tissue from 57 patients with aldosterone-producing adenoma, employing immunohistochemistry with digital image analysis. RESULTS: Primary aldosteronism patients had significantly increased cortisol and total glucocorticoid metabolite excretion (all P < 0.001), only exceeded by glucocorticoid output in patients with clinically overt adrenal Cushing syndrome. Several surrogate parameters of metabolic risk correlated significantly with glucocorticoid but not mineralocorticoid output. Intratumoral CYP11B1 expression was significantly associated with the corresponding in vivo glucocorticoid excretion. Unilateral adrenalectomy resolved both mineralocorticoid and glucocorticoid excess. Postoperative evidence of adrenal insufficiency was found in 13 (29%) of 45 consecutively tested patients. CONCLUSION: Our data indicate that glucocorticoid cosecretion is frequently found in primary aldosteronism and contributes to associated metabolic risk. Mineralocorticoid receptor antagonist therapy alone may not be sufficient to counteract adverse metabolic risk in medically treated patients with primary aldosteronism. FUNDING: Medical Research Council UK, Wellcome Trust, European Commission.
RESUMO
Glucocorticoids are widely prescribed for their anti-inflammatory properties, but have 'Cushingoid' side effects including visceral obesity, muscle myopathy, hypertension, insulin resistance, type 2 diabetes mellitus, osteoporosis, and hepatic steatosis. These features are replicated in patients with much rarer endogenous glucocorticoid (GC) excess (Cushing's syndrome), which has devastating consequences if left untreated. Current medical therapeutic options that reverse the tissue-specific consequences of hypercortisolism are limited. In this article, we review the current evidence that local GC metabolism via the enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) plays a central role in mediating the adverse metabolic complications associated with circulatory GC excess - challenging our current view that simple delivery of active GCs from the circulation represents the most important mode of GC action. Furthermore, we explore the potential for targeting this enzyme as a novel therapeutic strategy for the treatment of both endogenous and exogenous Cushing's syndrome.