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1.
Diabetes Obes Metab ; 2020 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-32991046

RESUMEN

AIM: To investigate the effects of L-phenylalanine on gastroenteropancreatic hormone release, glucose levels, subjective appetite and energy intake in humans, and to determine whether these effects were stereoisomer-specific by comparing them with D-phenylalanine. MATERIALS AND METHODS: A dose-finding, non-randomized, unblinded, crossover study was conducted during October-December 2017 at the NIHR Imperial Clinical Research Facility in five participants, in which the tolerability of escalating doses of oral L-phenylalanine was assessed (0, 3, 6 and 10 g). Also, an acute, randomized, double-blind, placebo-controlled crossover study was conducted during January-May 2018 at the NIHR Imperial Clinical Research Facility in 11 participants, in which the effects of oral 10 g L-phenylalanine relative to D-phenylalanine and placebo on gastroenteropancreatic hormone (insulin, glucagon, glucose-dependent insulinotropic polypeptide [GIP], peptide tyrosine tyrosine [PYY], glucagon-like peptide-1) and glucose concentrations, visual analogue scales for subjective appetite and energy intake at an ad libitum meal served 70 minutes postingestion, were investigated. RESULTS: L-phenylalanine was well-tolerated and increased insulin and glucagon concentrations prior to meal ingestion at several time points relative to placebo and D-phenylalanine (P < .05). L-phenylalanine also increased GIP concentrations relative to D-phenylalanine (P = .0420) and placebo (P = .0249) 70 minutes following ingestion. L-phenylalanine reduced postprandial glucose area under the curve (AUC)70-150mins relative to placebo (P = .0317) but did not affect subjective appetite or energy intake (P > .05). D-phenylalanine increased postprandial PYY AUC70-150mins concentrations relative to placebo (P = .0002). CONCLUSIONS: Ingestion of L-phenylalanine, but not D-phenylalanine, increases insulin, glucagon and GIP concentrations without appearing to have a marked effect on appetite.

2.
J Anal Toxicol ; 2020 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-32986094

RESUMEN

Baclofen (BLF) has been prescribed in the UK since 1972 for the alleviation of spasticity. However, evidence suggests BLF is also recreationally misused. It has been associated with ethanol, gamma-hydroxybutyric acid (GHB), pregabalin (PGL) and gabapentin (GBP) use/abuse and deaths have been reported. With current postmortem (PM) toxicological screening approaches, BLF is not routinely included in the general drugs screen, and is only screened for if specifically mentioned in the case documents. The extent of BLF misuse is thus unclear. This study was carried out to determine the prevalence and concentrations of BLF in Coroners' toxicology, to investigate whether BLF misuse with ethanol, GHB, PGL and GBP is causing death and to determine the potential extent of the under-reporting of BLF-associated deaths. Between 01/01/2016 to 31/12/2017, 3750 PM femoral vein bloods were screened for BLF; all positive cases were quantified. Only 0.56% of samples screened positive for BLF, with concentration ranging from 0.08 to 102.00 µg/mL (median = 0.28). It was determined that routine analysis without additional screening of BLF had been performed, 43% of BLF positives cases would have been missed. However, given the low incidence of detection, this only represents 0.25% of the cohort. Likely illicit use of BLF with GHB was seen in one case only. Death from the recreational use of BLF with PGL and GBP was not observed. Only two cases positive for BLF had an ethanol concentration of ≥ 50 mg%. Two cases of presumed intentional overdose of BLF were observed. This study highlights that although BLF abuse may be occurring, deaths are rare. It is therefore not cost or time effective to screen for BLF in all PM cases. With BLF currently being investigated for the treatment of alcoholism and withdrawal symptoms of illicit drug use, BLF-related deaths may rise in the future.

3.
J Prosthet Dent ; 124(3): 274-349, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32811666

RESUMEN

This comprehensive review of the 2019 restorative dental literature is offered to inform busy dentists regarding remarkable publications and noteworthy progress made in the profession. Developed by the Scientific Investigation Committee of the American Academy of Restorative Dentistry, each author brings discipline-specific expertise to 1 of 8 sections of the report: (1) prosthodontics; (2) periodontics, alveolar bone, and peri-implant tissues; (3) implant dentistry; (4) dental materials and therapeutics; (5) occlusion and temporomandibular disorders; (6) sleep-related breathing disorders; (7) oral medicine and oral and maxillofacial surgery; and (8) dental caries and cariology. The report targets important information likely to influence day-to-day dental treatment decisions. Each review is not intended to stand alone but to update interested readers so that they may visit source material when greater detail is desired. As the profession moves toward evidence-based clinical decision-making, an incredible volume of potentially valuable dental literature continues to increase. It is the intention of this review and its authors to provide assistance in negotiating the extensive dental literature published in 2019. It is our hope that readers find this work useful in the clinical management of dental patients.


Asunto(s)
Caries Dental , Materiales Dentales , Oclusión Dental , Humanos , Periodoncia , Prostodoncia , Estados Unidos
4.
Nat Metab ; 2(9): 840-848, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32694821

RESUMEN

A key metabolic activity of the gut microbiota is the fermentation of non-digestible carbohydrate, which generates short-chain fatty acids (SCFAs) as the principal end products. SCFAs are absorbed from the gut lumen and modulate host metabolic responses at different organ sites. Evidence suggests that these organ sites include skeletal muscle, the largest organ in humans, which plays a pivotal role in whole-body energy metabolism. In this Review, we evaluate the evidence indicating that SCFAs mediate metabolic cross-talk between the gut microbiota and skeletal muscle. We discuss the effects of three primary SCFAs (acetate, propionate and butyrate) on lipid, carbohydrate and protein metabolism in skeletal muscle, and we consider the potential mechanisms involved. Furthermore, we highlight the emerging roles of these gut-derived metabolites in skeletal muscle function and exercise capacity, present limitations in current knowledge and provide suggestions for future work.

5.
J Esthet Restor Dent ; 32(6): 545-553, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32613725

RESUMEN

OBJECTIVE: The aim of this report is to present an interdisciplinary treatment involving periodontics, orthodontics, dental implant placement, and prosthodontics with a fully digital dentistry approach. CLINICAL CONSIDERATIONS: The patient presented with an edentulous ridge on the area of the lower left lateral incisor as well as gingival recession on the adjacent teeth. After performing a digital orthodontic setup and indirect bonding bracket placement, a dental implant placement was carried out before orthodontic treatment in combination with guided bone regeneration (GBR), connective tissue graft (CTG) and periodontal accelerated osteogenic orthodontics (PAOO). In a 6-month period, orthodontic treatment was fully completed and the dental implant was restored at 8 months. Following one-and-a-half years, significant gingival recession reduction was accomplished and soft tissue augmentation around the dental implant appeared stable with a good functional and esthetic result. CONCLUSION: The use of the digital POIP concept with a proper diagnosis and careful planning is crucial for reducing treatment time and enhancing precision.


Asunto(s)
Aumento de la Cresta Alveolar , Implantes Dentales de Diente Único , Implantes Dentales , Recesión Gingival , Implantación Dental Endoósea , Estética Dental , Humanos , Maxilar/cirugía
6.
Sci Rep ; 10(1): 1703, 2020 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-32015477

RESUMEN

The nuclear hormone receptor Dax1 functions during development as a testes-determining gene. However, the phenotype of male mice lacking Dax1 is strain-dependent due to the background-specific abundance of male-determining Sry gene-transcripts. We hypothesised that inter-individual variation in Sry mRNA-abundance would result in a spectrum of phenotypes even within-strain. We found that while all XY C57BL/6J mice lacking Dax1 presented as phenotypic females, there was a marked inter-individual variability in measures of fertility. Indeed, we report rare occasions where sex-reversed mice had measures of fertility comparable to those in control females. On two occasions, these sex-reversed XY mice were able to give birth to live offspring following mating to stud-males. As such, this work documents within-strain variability in phenotypes of XY mice lacking Dax1, and reports for the first time a complete sex-reversal capable of achieving live birth in these mice.


Asunto(s)
Receptor Nuclear Huérfano DAX-1/genética , Trastornos del Desarrollo Sexual/genética , Procesos de Determinación del Sexo/fisiología , Proteína de la Región Y Determinante del Sexo/genética , Testículo/fisiología , Animales , Variación Biológica Individual , Femenino , Fertilidad , Antecedentes Genéticos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Parto , Fenotipo
7.
PLoS Biol ; 17(12): e3000482, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31805040

RESUMEN

Better understanding of feeding behaviour will be vital in reducing obesity and metabolic syndrome, but we lack a standard model that captures the complexity of feeding behaviour. We construct an accurate stochastic model of rodent feeding at the bout level in order to perform quantitative behavioural analysis. Analysing the different effects on feeding behaviour of peptide YY3-36 (PYY3-36), lithium chloride, glucagon-like peptide 1 (GLP-1), and leptin shows the precise behavioural changes caused by each anorectic agent. Our analysis demonstrates that the changes in feeding behaviour evoked by the anorectic agents investigated do not mimic the behaviour of well-fed animals and that the intermeal interval is influenced by fullness. We show how robust homeostatic control of feeding thwarts attempts to reduce food intake and how this might be overcome. In silico experiments suggest that introducing a minimum intermeal interval or modulating upper gut emptying can be as effective as anorectic drug administration.


Asunto(s)
Ingestión de Alimentos/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Conducta Alimentaria/fisiología , Animales , Depresores del Apetito/farmacología , Ingestión de Alimentos/fisiología , Péptido 1 Similar al Glucagón/farmacología , Homeostasis/efectos de los fármacos , Leptina/farmacología , Masculino , Ratones , Obesidad , Fragmentos de Péptidos/farmacología , Péptido YY/farmacología , Ratas
8.
J Anal Toxicol ; 43(7): 564-570, 2019 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-31062862

RESUMEN

Due to the rise in their misuse and associated mortality, the UK government is reclassifying gabapentin (GBP) and pregabalin (PGL) to Class C controlled drugs from April 2019. However, it is impossible to gauge the extent of their use with current post-mortem toxicological screening, where GBP and PGL are only screened for if they are mentioned in the case documents. This study determines the prevalence of GBP and PGL, the potential extent of their under-reporting and poly-drug use in a post-mortem population. Between 1 January 2016 and 31 December 2017, 3,750 deceased from Coroners' cases in London and South East England underwent a routine drugs screen and a specific screen for GBP and PGL. The prevalence of both drugs was determined in the cohort and the subcategories of heroin users and non-heroin-users. The prevalence of both drugs was compared to tramadol (Class C drug). Case documents were reviewed to investigate the under-reporting of GBP and PGL and poly-drug use. Of 3,750 samples analyzed, 118 (3.1%) were positive for GBP, 229 (6.1%) for PGL and 120 (3.2%) were positive for tramadol. If routine analysis without additional screening of GBP and PGL had been performed in this cohort, GBP would have been under-reported by 57.6% (P < 0.0001) and PGL by 53.7% (P < 0.0001) in deaths. The most common drug group observed with GBP and PGL was non-heroin-related opioids at 60.2% and 64.6%, respectively. In total 354 deceased (9.4%) were heroin users. GBP was positive in 23 (6.5%) of these cases and PGL was positive in 69 (19.5%). The prevalence of PGL in heroin users (19.5%) was 4.1 times greater than in non-heroin users (4.7%) (P < 0.0001). GBP and PGL are being significantly under reported in fatalities. Both drugs are extensively used with opioids. The prevalence of PGL in heroin users is highly significant.


Asunto(s)
Toxicología Forense/métodos , Gabapentina/análisis , Pregabalina/análisis , Trastornos Relacionados con Sustancias , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Inglaterra/epidemiología , Femenino , Dependencia de Heroína/diagnóstico , Dependencia de Heroína/mortalidad , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Prevalencia , Trastornos Relacionados con Sustancias/diagnóstico , Trastornos Relacionados con Sustancias/mortalidad
9.
Gut ; 68(8): 1430-1438, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30971437

RESUMEN

OBJECTIVE: To investigate the underlying mechanisms behind changes in glucose homeostasis with delivery of propionate to the human colon by comprehensive and coordinated analysis of gut bacterial composition, plasma metabolome and immune responses. DESIGN: Twelve non-diabetic adults with overweight and obesity received 20 g/day of inulin-propionate ester (IPE), designed to selectively deliver propionate to the colon, a high-fermentable fibre control (inulin) and a low-fermentable fibre control (cellulose) in a randomised, double-blind, placebo-controlled, cross-over design. Outcome measurements of metabolic responses, inflammatory markers and gut bacterial composition were analysed at the end of each 42-day supplementation period. RESULTS: Both IPE and inulin supplementation improved insulin resistance compared with cellulose supplementation, measured by homeostatic model assessment 2 (mean±SEM 1.23±0.17 IPE vs 1.59±0.17 cellulose, p=0.001; 1.17±0.15 inulin vs 1.59±0.17 cellulose, p=0.009), with no differences between IPE and inulin (p=0.272). Fasting insulin was only associated positively with plasma tyrosine and negatively with plasma glycine following inulin supplementation. IPE supplementation decreased proinflammatory interleukin-8 levels compared with cellulose, while inulin had no impact on the systemic inflammatory markers studied. Inulin promoted changes in gut bacterial populations at the class level (increased Actinobacteria and decreased Clostridia) and order level (decreased Clostridiales) compared with cellulose, with small differences at the species level observed between IPE and cellulose. CONCLUSION: These data demonstrate a distinctive physiological impact of raising colonic propionate delivery in humans, as improvements in insulin sensitivity promoted by IPE and inulin were accompanied with different effects on the plasma metabolome, gut bacterial populations and markers of systemic inflammation.


Asunto(s)
Microbioma Gastrointestinal/fisiología , Insulina/metabolismo , Inulina , Metaboloma/fisiología , Obesidad , Sobrepeso , Adulto , Índice de Masa Corporal , Estudios Cruzados , Suplementos Dietéticos , Método Doble Ciego , Heces/microbiología , Femenino , Humanos , Inflamación/metabolismo , Resistencia a la Insulina/fisiología , Inulina/administración & dosificación , Inulina/metabolismo , Masculino , Persona de Mediana Edad , Obesidad/diagnóstico , Obesidad/dietoterapia , Obesidad/metabolismo , Sobrepeso/diagnóstico , Sobrepeso/dietoterapia , Sobrepeso/metabolismo , Propionatos/administración & dosificación , Propionatos/metabolismo , Resultado del Tratamiento
10.
Obesity (Silver Spring) ; 26(11): 1721-1726, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30358156

RESUMEN

OBJECTIVE: The satiating effect of protein compared with other nutrients has been well described and is thought to be mediated, in part, by gut hormone release. Previously, it has been shown that oral L-arginine acts as a GLP-1 secretagogue both in vitro and in vivo in rodents. Here, the effect of L-arginine on gut hormone release in humans was investigated. METHODS: The hypothesis was tested in two separate studies. The first study assessed the tolerability of oral L-arginine in healthy human subjects. The second study assessed the effect of oral L-arginine on gut hormone release following an ad libitum meal. Subjects were given L-arginine, glycine (control amino acid), or vehicle control in a randomized double-blind fashion. RESULTS: At a dose of 17.1 mmol, L-arginine was well tolerated and stimulated the release of plasma GLP-1 (P < 0.05) and PYY (P < 0.001) following an ad libitum meal. Food diaries showed a trend toward lower energy intake and particularly fat intake following L-arginine treatment. CONCLUSIONS: L-arginine can significantly elevate GLP-1 and PYY in healthy human volunteers in combination with a meal. Further work is required to investigate whether L-arginine may have utility in the suppression of appetite and food intake.


Asunto(s)
Depresores del Apetito/uso terapéutico , Arginina/uso terapéutico , Ingestión de Alimentos/efectos de los fármacos , Péptido 1 Similar al Glucagón/efectos de los fármacos , Péptido YY/efectos de los fármacos , Periodo Posprandial/efectos de los fármacos , Adulto , Depresores del Apetito/farmacología , Arginina/farmacología , Método Doble Ciego , Femenino , Péptido 1 Similar al Glucagón/sangre , Humanos , Masculino , Péptido YY/sangre
11.
PLoS One ; 13(1): e0192014, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29370263

RESUMEN

[This corrects the article DOI: 10.1371/journal.pone.0176821.].

12.
J R Soc Interface ; 15(138)2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29367240

RESUMEN

Obesity is a major global public health problem. Understanding how energy homeostasis is regulated, and can become dysregulated, is crucial for developing new treatments for obesity. Detailed recording of individual behaviour and new imaging modalities offer the prospect of medically relevant models of energy homeostasis that are both understandable and individually predictive. The profusion of data from these sources has led to an interest in applying machine learning techniques to gain insight from these large, relatively unstructured datasets. We review both physiological models and machine learning results across a diverse range of applications in energy homeostasis, and highlight how modelling and machine learning can work together to improve predictive ability. We collect quantitative details in a comprehensive mathematical supplement. We also discuss the prospects of forecasting homeostatic behaviour and stress the importance of characterizing stochasticity within and between individuals in order to provide practical, tailored forecasts and guidance to combat the spread of obesity.


Asunto(s)
Metabolismo Energético , Glucosa/metabolismo , Homeostasis , Aprendizaje Automático , Modelos Biológicos , Obesidad/metabolismo , Bases de Datos Factuales , Humanos
13.
Mol Metab ; 7: 71-79, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29122559

RESUMEN

OBJECTIVE: Brain insulin-induced improvement in glucose homeostasis has been proposed to be mediated by the parasympathetic nervous system. Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) activating afferent branches of the vagus nerve may prevent hyperglycemia in diabetes models. We examined the effects of 14-min taVNS vs sham stimulation by Cerbomed Nemos® on glucose metabolism, lipids, and hepatic energy homeostasis in fasted healthy humans (n = 10, age 51 ± 6 yrs, BMI 25.5 ± 2.7 kg/m2). METHODS: Heart rate variability (HRV), reflecting sympathetic and parasympathetic nerve activity, was measured before, during and after taVNS or sham stimulation. Endogenous glucose production was determined using [6,6-2H2]glucose, and hepatic concentrations of triglycerides (HCL), adenosine triphosphate (ATP), and inorganic phosphate (Pi) were quantified from 1H/31P magnetic resonance spectroscopy at baseline and for 180 min following stimulation. RESULTS: taVNS did not affect circulating glucose, free fatty acids, insulin, glucagon, or pancreatic polypeptide. Rates of endogenous glucose production (P = 0.79), hepatic HCL, ATP, and Pi were also not different (P = 0.91, P = 0.48 and P = 0.24) between taVNS or sham stimulation. Hepatic HCL, ATP, and Pi remained constant during prolonged fasting for 3 h. No changes in heart rate or shift in cardiac autonomic function from HRV towards sympathetic or parasympathetic predominance were detected. CONCLUSION: Non-invasive vagus stimulation by Cerbomed Nemos® does not acutely modulate the autonomic tone to the visceral organs and thereby does not affect hepatic glucose and energy metabolism. This technique is therefore unable to mimic brain insulin-mediated effects on peripheral homeostasis in humans.


Asunto(s)
Adenosina Trifosfato/metabolismo , Metabolismo Energético , Ayuno/metabolismo , Hígado/metabolismo , Sistema Nervioso Parasimpático/fisiología , Estimulación del Nervio Vago , Adulto , Ayuno/fisiología , Femenino , Glucosa/metabolismo , Frecuencia Cardíaca , Humanos , Masculino , Persona de Mediana Edad , Triglicéridos/metabolismo
15.
Curr Opin Pharmacol ; 37: 16-23, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28802874

RESUMEN

Gut hormones have important roles in the regulation of appetite and glucose homeostasis. Understanding how macronutrient sensing in the gastrointestinal tract modulates gut hormone release may reveal novel pharmacological or dietary approaches to metabolic disease. In this short review we discuss the mechanisms by which the gut senses macronutrients and the products of macronutrient digestion, and their putative utility in treating obesity and related conditions.


Asunto(s)
Tracto Gastrointestinal/metabolismo , Obesidad/tratamiento farmacológico , Animales , Metabolismo de los Hidratos de Carbono , Humanos , Metabolismo de los Lípidos , Obesidad/metabolismo , Proteínas/metabolismo
16.
PLoS One ; 12(8): e0182659, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28796827

RESUMEN

BACKGROUND: Patients with multiple injuries or sepsis requiring intensive care treatment invariably develop a catabolic state with resultant loss of lean body mass, for which there are currently no effective treatments. Recovery can take months and mortality is high. We hypothesise that treatment with the orexigenic and anti-inflammatory gastric hormone, ghrelin may attenuate the loss of body mass following critical illness and improve recovery. METHODS: Male Wistar rats received an intraperitoneal injection of the fungal cell wall derivative zymosan to induce a prolonged peritonitis and consequent critical illness. Commencing at 48h after zymosan, animals were randomised to receive a continuous infusion of ghrelin or vehicle control using a pre-implanted subcutaneous osmotic mini-pump, and continued for 10 days. RESULTS: Zymosan peritonitis induced significant weight loss and reduced food intake with a nadir at Day 2 and gradual recovery thereafter. Supra-physiologic plasma ghrelin levels were achieved in the treated animals. Ghrelin-treated rats ate more food and gained more body mass than controls. Ghrelin increased adiposity and promoted carbohydrate over fat metabolism, but did not alter total body protein, muscle strength nor muscle morphology. Muscle mass and strength remained significantly reduced in all zymosan-treated animals, even at ten days post-insult. CONCLUSIONS: Continuous infusion of ghrelin increased body mass and food intake, but did not increase muscle mass nor improve muscle function, in a long-term critical illness recovery model. Further studies with pulsatile ghrelin delivery or additional anabolic stimuli may further clarify the utility of ghrelin in survivors of critical illness.


Asunto(s)
Composición Corporal/efectos de los fármacos , Caquexia/tratamiento farmacológico , Ghrelina/farmacología , Músculo Esquelético/fisiopatología , Peritonitis/metabolismo , Animales , Peso Corporal , Caquexia/etiología , Caquexia/metabolismo , Evaluación Preclínica de Medicamentos , Ingestión de Energía , Humanos , Masculino , Contracción Muscular , Fuerza Muscular , Peritonitis/complicaciones , Peritonitis/fisiopatología , Ratas Wistar
17.
PLoS One ; 12(5): e0176821, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28464043

RESUMEN

Kisspeptins regulate the mammalian reproductive axis by stimulating release of gonadotrophin releasing hormone (GnRH). Different length kisspeptins (KP) are found of 54, 14, 13 or 10 amino-acids which share a common C-terminal 10-amino acid sequence. KP-54 and KP-10 have been widely used to stimulate the reproductive axis but data suggest that KP-54 and KP-10 are not equally effective at eliciting reproductive hormone secretion after peripheral delivery. To confirm this, we analysed the effect of systemic administration of KP-54 or KP-10 on luteinizing hormone (LH) secretion into the bloodstream of male mice. Plasma LH measurements 10 min or 2 hours after kisspeptin injection showed that KP-54 can sustain LH release far longer than KP-10, suggesting a differential mode of action of the two peptides. To investigate the mechanism for this, we evaluated the pharmacokinetics of the two peptides in vivo and their potential to cross the blood brain barrier (BBB). We found that KP-54 has a half-life of ~32 min in the bloodstream, while KP-10 has a half-life of ~4 min. To compensate for this difference in half-life, we repeated injections of KP-10 every 10 min over 1 hr but failed to reproduce the sustained rise in LH observed after a single KP-54 injection, suggesting that the failure of KP-10 to sustain LH release may not just be related to peptide clearance. We tested the ability of peripherally administered KP-54 and KP-10 to activate c-FOS in GnRH neurons behind the blood brain barrier (BBB) and found that only KP-54 could do this. These data are consistent with KP-54 being able to cross the BBB and suggest that KP10 may be less able to do so.


Asunto(s)
Fármacos del Sistema Nervioso Central/farmacología , Kisspeptinas/farmacología , Análisis de Varianza , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Permeabilidad Capilar/efectos de los fármacos , Permeabilidad Capilar/fisiología , Fármacos del Sistema Nervioso Central/farmacocinética , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Humanos , Hipotálamo/citología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Inmunohistoquímica , Kisspeptinas/farmacocinética , Hormona Luteinizante/sangre , Hormona Luteinizante/metabolismo , Masculino , Ratones de la Cepa 129 , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo
18.
Forensic Sci Int ; 270: 93-97, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27936427

RESUMEN

BACKGROUND: Gamma-hydroxybutyrate (GHB) is the drug most linked to acute harm out of those used in chemsex, the incidence of which is reported to be increasing. However, there have been few systematic studies of the harms associated with GHB use. We investigated GHB-associated deaths from London coroners' jurisdictions between 2011 and 2015. METHODS: Blood and urine samples were collected by pathologists and submitted for toxicological analysis at the request of coroners. Data from the Toxicology Unit, Imperial College London was retrospectively analysed. This comprised of 6633 cases from seven out of eight coroners' jurisdictions in London that underwent toxicological analysis between January 2011 and December 2015. RESULTS: A total of 61 GHB-associated deaths (0.92% of total cases), 184 cocaine-associated deaths (2.8% of total cases) and 83 MDMA-associated deaths (1.3% of total cases) were identified. There was a 119% increase in the proportion of GHB-associated deaths detected in 2015 compared to 2014. Over the same time period there was a 25% increase in cocaine-associated deaths and a 10% decrease in MDMA-associated deaths. CONCLUSIONS: Our data suggest that GHB-associated deaths are increasing in London, and that this is likely at least in part due to increasing use of GHB for chemsex. Further studies on the use of GHB are urgently required to understand the extent of its use, whether this is as prevalent in other major urban areas in the UK, and the full extent of the harms it causes.


Asunto(s)
Drogas Ilícitas/envenenamiento , Conducta Sexual , Oxibato de Sodio/envenenamiento , Trastornos Relacionados con Sustancias/mortalidad , Adulto , Anciano , Femenino , Toxicología Forense , Cromatografía de Gases y Espectrometría de Masas , Infecciones por VIH/epidemiología , Homosexualidad Masculina , Humanos , Drogas Ilícitas/análisis , Londres/epidemiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Oxibato de Sodio/análisis , Cuerpo Vítreo/química , Adulto Joven
19.
Obesity (Silver Spring) ; 24(8): 1723-30, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27460713

RESUMEN

OBJECTIVE: To assess appetite and gut hormone levels in patients following partial (PR) or total resection (TR) of the large bowel. METHODS: A comparative cross sectional study was carried out with healthy controls (n = 99) and patients who had undergone PR (n = 64) or TR (n = 12) of the large bowel. Participants consumed a standard (720 kcal) breakfast meal at 0830 (t = 0) h followed by lactulose (15 g) and a buffet lunch (t = 210 min). Participants rated the subjective feelings of hunger at t = -30, 0, 30, 60, 120, and 180 min. Breath hydrogen (BH) concentrations were also evaluated. In a matched subset (11 controls, 11 PR and 9 TR patients) PYY and GLP-1 concentrations were measured following breakfast. The primary outcome measure was appetite, as measured using visual analogue scales and the buffet lunch. The secondary outcome was BH concentrations following a test meal. RESULTS: PR and TR participants had lower hunger and energy intake at the buffet lunch meal compared to controls. PR subjects had higher BH concentrations compared to controls and TR subjects. BH levels correlated with circulating GLP-1 levels at specific time points. CONCLUSIONS: PR or TR of the large bowel reduced feelings of hunger and energy intake, and PR increased gastrointestinal fermentation.


Asunto(s)
Apetito , Ingestión de Alimentos , Hormonas Gastrointestinales/metabolismo , Hambre , Intestino Delgado/metabolismo , Intestino Delgado/cirugía , Adulto , Desayuno , Estudios Transversales , Ingestión de Energía , Femenino , Gastrectomía , Polipéptido Inhibidor Gástrico/metabolismo , Humanos , Almuerzo , Masculino , Obesidad/cirugía
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