RESUMEN
Although the amygdala plays an important part in the pathogenesis of anxiety and generation of exteroceptive fear, recent discoveries have challenged the directionality of this brain-behavior relationship with respect to interoceptive fear. Here we highlight several paradoxical findings including: (1) amygdala lesion patients who experience excessive fear and panic following inhalation of carbon dioxide (CO2), (2) clinically anxious patients who have significantly smaller (rather than larger) amygdalae and a pronounced hypersensitivity toward CO2, and (3) epilepsy patients who exhibit apnea immediately following stimulation of their amygdala yet have no awareness that their breathing has stopped. The above findings elucidate an entirely novel role for the amygdala in the induction of apnea and inhibition of CO2-induced fear. Such a role is plausible given the strong inhibitory connections linking the central nucleus of the amygdala with respiratory and chemoreceptive centers in the brainstem. Based on this anatomical arrangement, we propose a model of Apnea-induced Anxiety (AiA) which predicts that recurring episodes of apnea are being unconsciously elicited by amygdala activation, resulting in transient spikes in CO2 that provoke fear and anxiety, and lead to characteristic patterns of escape and avoidance behavior in patients spanning the spectrum of anxiety. If this new conception of AiA proves to be true, and activation of the amygdala can repeatedly trigger states of apnea outside of one's awareness, then it remains possible that the chronicity of anxiety disorders is being interoceptively driven by a chemoreceptive system struggling to maintain homeostasis in the midst of these breathless states.
Asunto(s)
Apnea , Dióxido de Carbono , Amígdala del Cerebelo/fisiología , Ansiedad , Trastornos de Ansiedad , Apnea/etiología , Apnea/patología , HumanosRESUMEN
BACKGROUND: PURA syndrome is rare autosomal dominant condition characterized by moderate to severe neurodevelopmental delay with absence of speech in nearly all patients and lack of independent ambulation in many. Early-onset problems include excessive hiccups, hypotonia, hypersomnolence, hypothermia, feeding difficulties, recurrent apneas, epileptic seizures, and abnormal nonepileptic movements. Other less common manifestations comprise congenital heart defects, urogenital malformations, and various skeletal, ophthalmological, gastrointestinal, and endocrine anomalies. Up to now, 78 individuals with PURA syndrome and 64 different pathogenic variants have been reported, but no clear-cut genotype-phenotype correlations have emerged so far. Herein, we report the clinical and molecular characterization of a 3-year-old girl with severe hypotonia, global developmental delay, and soft, loose skin, who came to our attention with a suspicion of cutis laxa (CL), which denotes another condition with variable neurodevelopmental problems. METHODS: Amplicon-based whole exome sequencing was performed, and an in-house pipeline was used to conduct filtering and prioritization of variants. New prediction algorithms for indels were used to validate the pathogenicity of the PURA variant, and results were confirmed with the Sanger method. Finally, we collected clinical and mutational data of all PURA syndrome patients reported yet and compared the clinical features with those of our patient. RESULTS: Clinical evaluation and biochemical investigations excluded CL and prompted to perform whole exome sequencing, which confirmed the absence of pathogenic variants in all CL-related genes and revealed the known PURA c.697_699del, p.(Phe233del) variant, identified hitherto in seven additional children with PURA syndrome. CONCLUSIONS: Our data expand the phenotypic spectrum of PURA syndrome by showing that it can be regarded as a differential diagnosis for cutis laxa in early infancy. Our patient and literature review emphasize that a wide clinical variability exists not only between individuals with different PURA variants, but also among patients with the same causal mutation.
Asunto(s)
Apnea/genética , Cutis Laxo/genética , Proteínas de Unión al ADN/genética , Discapacidades del Desarrollo/genética , Epilepsia/genética , Fenotipo , Factores de Transcripción/genética , Apnea/patología , Preescolar , Cutis Laxo/patología , Discapacidades del Desarrollo/patología , Diagnóstico Diferencial , Epilepsia/patología , Femenino , Eliminación de Gen , Humanos , SíndromeRESUMEN
The opioid-induced analgesia is associated with a number of side effects such as addiction, tolerance and respiratory depression. The involvement of neuropeptide FF (NPFF) in modulation of pain perception, opioid-induced tolerance and dependence was well documented in contrast to respiratory depression. Therefore, the aim of the present study was to examine the potency of NPFF to block post-opioid respiratory depression, one of the main adverse effects of opioid therapy. Urethane-chloralose anaesthetized Wistar rats were injected either intravenously (iv) or intracerebroventricularly (icv) with various doses of NPFF prior to iv endomorphin-1 (EM-1) administration. Iv NPFF diminished the number of EM-1-induced apneas without affecting their length and without influence on the EM-1 induced blood pressure decline. Icv pretreatment with NPFF abolished the occurrence of post-EM-1 apneas and reduced also the maximal drop in blood pressure and heart rate. These effects were completely blocked by the NPFF receptor antagonist RF9, which was given as a mixture with NPFF before systemic EM-1 administration. In conclusion, our results showed that centrally administered neuropeptide FF is effective in preventing apnea evoked by stimulation of µ-opioid receptors and the effect was due to activation of central NPFF receptors. Our finding indicates a potential target for reversal of opioid-induced respiratory depression.
Asunto(s)
Apnea/tratamiento farmacológico , Enfermedades Cardiovasculares/tratamiento farmacológico , Oligopéptidos/farmacología , Receptores Opioides mu/genética , Analgesia/efectos adversos , Analgésicos Opioides/efectos adversos , Animales , Apnea/inducido químicamente , Apnea/genética , Apnea/patología , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/genética , Modelos Animales de Enfermedad , Humanos , Infusiones Intraventriculares , Oligopéptidos/efectos adversos , Oligopéptidos/genética , Percepción del Dolor/efectos de los fármacos , Ratas , Receptores de Neuropéptido/antagonistas & inhibidores , Receptores de Neuropéptido/genética , Receptores Opioides mu/antagonistas & inhibidores , Activación Transcripcional/efectos de los fármacosRESUMEN
Pharmacogenetics, the genetic influence on the interpersonal variability in drug response, has enabled tailored pharmacotherapy and emerging 'personalized medicine.' Although oncology spearheaded the clinical implementation of personalized medicine, other specialties are rapidly catching up. In anesthesia, classical examples of genetically mediated idiosyncratic reactions have been long known (e.g., malignant hyperthermia and prolonged apnea after succinylcholine). The last two decades have witnessed an expanding body of pharmacogenetic evidence in anesthesia. This review highlights some of the prominent pharmacogenetic associations studied in anesthesia and pain management, with special focus on pediatric anesthesia.
Asunto(s)
Anestesia/métodos , Manejo del Dolor/métodos , Dolor/tratamiento farmacológico , Succinilcolina/uso terapéutico , Anestesiología/tendencias , Apnea/inducido químicamente , Apnea/genética , Apnea/patología , Niño , Preescolar , Humanos , Hipertermia Maligna/etiología , Hipertermia Maligna/genética , Hipertermia Maligna/patología , Dolor/genética , Dolor/patología , Pediatría , Medicina de Precisión , Succinilcolina/efectos adversosRESUMEN
The possible relationship between lung cancer and nocturnal intermittent hypoxia, apnea and daytime sleepiness, especially the possible relationship between the occurrence and progression of lung cancer and obstructive sleep apnea syndrome (OSAS) was explored. Forty-five cases of primary lung cancer suitable for surgical resection at the Third Affiliated Hospital of Kunming Medical University between January 2017 and December 2017 were recruited (lung cancer group), and there were 45 patients in the control group who had no significant differences in age, sex and other general data from lung cancer group. The analyzed covariates included general situation, snore score, the Epworth Sleeping Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), apnea and hypopneas index (AHI), oxygen desaturation index 4 (ODI4), lowest arterial oxygen saturation [LSpO2 (%)], oxygen below 90% of the time [T90% (min)], the percentage of the total recorded time spend below 90% oxygen saturation (TS90%), to explore the possible relationship between lung cancer and above indicators. The participants were followed up for one year. The results showed that: (1) There was significant difference in body mass index (BMI), ESS, AHI, T90% (min), TS90%, ODI4, snore score and LSpO2 (%) between lung cancer group and control group (P<0.05). There was no statistically significant difference in age, gender, PSQI score, incidence of concurrent hypertension, diabetes and coronary heart disease (CHD), and smoking history between the two groups (P>0.05); (2) Patients in the lung cancer group were divided into OSAS subgroup and non-OSAS subgroup according to the international standard for the diagnosis of OSAS. There was significant difference in BMI, age, staging, incidence of concurrent hypertension and concurrent CHD, snore score, ESS score, T90% (min), TS90%, ODI4 and LSpO2 (%) between OSAS subgroup and non-OSAS subgroup (P<0.05). There was no statistically significant difference in gender, PSQI score, incidence of concurrent diabetes, smoking history and lung cancer type between the two groups (P>0.05); (3) AHI was strongly negatively correlated with the LSpO2 (%) and positively with ESS, staging, snoring score, T90% (min), TS90%, ODI4 and BMI (P<0.05); (4) There were 3 deaths, 5 cases of recurrence, and 4 cases of metastasis in OSAS subgroup; and there was 1 death, 4 cases of recurrence and 2 cases of metastasis in non-OSAS subgroup during the follow-up period of one year, respectively. There was no significant difference in mortality, recurrence rate and metastasis rate between the two subgroups, and the total rate of deterioration in OSAS subgroup was significantly increased compared to the non-OSAS subgroup (P<0.05). It was concluded that the patients with lung cancer are prone to nocturnal hypoxemia, apnea, snoring and daytime sleepiness compared to control group. The incidence of OSAS in patients with lung cancer was higher, and the difference in the hypoxemia-related indicators was statistically significant. The mortality, recurrence rate, and metastasis rate increases in lung cancer patients with OSAS during the one-year follow-up period, suggesting that OSAS may be a contributing factor to the occurrence and progression of lung cancer.
Asunto(s)
Apnea/epidemiología , Hipoxia/epidemiología , Neoplasias Pulmonares/epidemiología , Apnea Obstructiva del Sueño/epidemiología , Adulto , Anciano , Apnea/complicaciones , Apnea/metabolismo , Apnea/patología , Índice de Masa Corporal , Progresión de la Enfermedad , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/epidemiología , Hipertensión/metabolismo , Hipertensión/patología , Hipoxia/metabolismo , Hipoxia/patología , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Oxígeno/metabolismo , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/metabolismo , Apnea Obstructiva del Sueño/patología , SomnolenciaRESUMEN
Cardiorespiratory recovery from apneas requires dynamic responses of brainstem circuitry. One implicated component is the raphe system of Pet1-expressing (largely serotonergic) neurons, however their precise requirement neonatally for homeostasis is unclear, yet central toward understanding newborn cardiorespiratory control and dysfunction. Here we show that acute in vivo perturbation of Pet1-neuron activity, via triggering cell-autonomously the synthetic inhibitory receptor hM4Di, resulted in altered baseline cardiorespiratory properties and diminished apnea survival. Respiratory more than heart rate recovery was impaired, uncoupling their normal linear relationship. Disordered gasp recovery from the initial apnea distinguished mice that would go on to die during subsequent apneas. Further, the risk likelihood of apnea-related mortality associated with suppression of Pet1 neurons was higher for animals with baseline elevated ventilatory equivalents for oxygen. These findings establish that Pet1 neurons play an active role in neonatal cardiorespiratory homeostasis and provide mechanistic plausibility for the serotonergic abnormalities associated with SIDS.
Asunto(s)
Apnea/patología , Tronco Encefálico/patología , Frecuencia Cardíaca , Neuronas/patología , Frecuencia Respiratoria , Factores de Transcripción/análisis , Animales , Animales Recién Nacidos , Homeostasis , Ratones , Análisis de SupervivenciaRESUMEN
Primary blast traumatic brain injury (bTBI) accounts for a significant proportion of wartime trauma. Previous studies have demonstrated direct brain injury by blast waves, but the effect of the location of the blast epicenter on the skull with regard to brain injury remains poorly characterized. In order to investigate the role of the blast epicenter location, we modified a previously established rodent model of cranium-only bTBI to evaluate two specific blast foci: a rostrally focused blast centered on bregma (B-bTBI), which excluded the foramen magnum region, and a caudally focused blast centered on the occipital crest, which included the foramen magnum region (FM-bTBI). At all blast overpressures studied (668-1880 kPa), rats subjected to FM-bTBI demonstrated strikingly higher mortality, increased durations of both apnea and hypoxia, and increased severity of convexity subdural hematomas, than rats subjected to B-bTBI. Together, these data suggest a unique role for the foramen magnum region in mortality and brain injury following blast exposure, and emphasize the importance of the choice of blast focus location in experimental models of bTBI.
Asunto(s)
Traumatismos por Explosión/patología , Lesiones Traumáticas del Encéfalo/patología , Foramen Magno/lesiones , Foramen Magno/patología , Animales , Apnea/etiología , Apnea/patología , Traumatismos por Explosión/mortalidad , Lesiones Traumáticas del Encéfalo/mortalidad , Modelos Animales de Enfermedad , Hematoma Subdural/patología , Hipoxia Encefálica/etiología , Hipoxia Encefálica/patología , Masculino , Hueso Occipital/lesiones , Ratas , Ratas Long-Evans , Insuficiencia Respiratoria/etiologíaAsunto(s)
Sistemas de Registro de Reacción Adversa a Medicamentos , Baclofeno/efectos adversos , Bases de Datos Farmacéuticas , Farmacovigilancia , Síndromes de la Apnea del Sueño/complicaciones , Administración Oral , Alcoholismo/tratamiento farmacológico , Apnea/patología , Control de Medicamentos y Narcóticos , Femenino , Hospitalización , Humanos , Inyecciones Espinales , Masculino , Espasticidad Muscular/tratamiento farmacológico , Enfermedades del Sistema Nervioso/complicaciones , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Síndromes de la Apnea del Sueño/inducido químicamente , Ácido gamma-Aminobutírico/químicaAsunto(s)
Anestesia Raquidea/métodos , Apnea/inducido químicamente , Dexmedetomidina/administración & dosificación , Hipnóticos y Sedantes/administración & dosificación , Anciano , Anciano de 80 o más Años , Apnea/patología , Dexmedetomidina/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hipnóticos y Sedantes/efectos adversos , Masculino , Persona de Mediana Edad , Proyectos PilotoRESUMEN
Two critical parameters that influence breathing stability are the levels of arterial pCO2 at which breathing ceases and subsequently resumes - termed the apneic and recruitment thresholds (AT and RT, respectively). Reduced respiratory neural activity elicits a chemoreflex-independent, long-lasting increase in phrenic burst amplitude, a form of plasticity known as inactivity-induced phrenic motor facilitation (iPMF). The physiological significance of iPMF is unknown. To determine if iPMF and neural apnea have long-lasting physiological effects on breathing, we tested the hypothesis that patterns of neural apnea that induce iPMF also elicit changes in the AT and RT. Phrenic nerve activity and end-tidal CO2 were recorded in urethane-anesthetized, ventilated rats to quantify phrenic nerve burst amplitude and the AT and RT before and after three patterns of neural apnea that differed in their duration and ability to elicit iPMF: brief intermittent neural apneas, a single brief "massed" neural apnea, or a prolonged neural apnea. Consistent with our hypothesis, we found that patterns of neural apnea that elicited iPMF also resulted in changes in the AT and RT. Specifically, intermittent neural apneas progressively decreased the AT with each subsequent neural apnea, which persisted for at least 60min. Similarly, a prolonged neural apnea elicited a long-lasting decrease in the AT. In both cases, the magnitude of the AT decrease was proportional to iPMF. In contrast, the RT was transiently decreased following prolonged neural apnea, and was not proportional to iPMF. No changes in the AT or RT were observed following a single brief neural apnea. Our results indicate that the AT and RT are differentially altered by neural apnea and suggest that specific patterns of neural apnea that elicit plasticity may stabilize breathing via a decrease in the AT.
Asunto(s)
Potenciales de Acción/fisiología , Apnea/fisiopatología , Dióxido de Carbono/metabolismo , Neuronas Motoras/fisiología , Nervio Frénico/fisiología , Umbral Sensorial/fisiología , Potenciales de Acción/efectos de los fármacos , Análisis de Varianza , Anestesia , Animales , Apnea/patología , Análisis de los Gases de la Sangre , Presión Sanguínea/efectos de los fármacos , Dióxido de Carbono/farmacología , Modelos Animales de Enfermedad , Masculino , Neuronas Motoras/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder that is primarily caused by mutations in the methyl CpG binding protein 2 gene (MECP2). RTT is the second most prevalent cause of intellectual disability in girls and there is currently no cure for the disease. The finding that the deficits caused by the loss of Mecp2 are reversible in the mouse has bolstered interest in gene therapy as a cure for RTT. In order to assess the feasibility of gene therapy in a RTT mouse model, and in keeping with translational goals, we investigated the efficacy of a self-complementary AAV9 vector expressing a codon-optimized version of Mecp2 (AAV9-MCO) delivered via a systemic approach in early symptomatic Mecp2-deficient (KO) mice. Our results show that AAV9-MCO administered at a dose of 2×1011 viral genome (vg)/mouse was able to significantly increase survival and weight gain, and delay the occurrence of behavioral deficits. Apneas, which are one of the core RTT breathing deficits, were significantly decreased to WT levels in Mecp2 KO mice after AAV9-MCO administration. Semi-quantitative analysis showed that AAV9-MCO administration in Mecp2 KO mice resulted in 10 to 20% Mecp2 immunopositive cells compared to WT animals, with the highest Mecp2 expression found in midbrain regions known to regulate cardio-respiratory functions. In addition, we also found a cell autonomous increase in tyrosine hydroxylase levels in the A1C1 and A2C2 catecholaminergic Mecp2+ neurons in treated Mecp2 KO mice, which may partly explain the beneficial effect of AAV9-MCO administration on apneas occurrence.
Asunto(s)
Terapia Genética , Proteína 2 de Unión a Metil-CpG/administración & dosificación , Síndrome de Rett/terapia , Aminas , Animales , Apnea/metabolismo , Apnea/patología , Apnea/prevención & control , Codón , Ácidos Ciclohexanocarboxílicos , Dependovirus , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Gabapentina , Vectores Genéticos , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Masculino , Mesencéfalo/metabolismo , Mesencéfalo/patología , Proteína 2 de Unión a Metil-CpG/genética , Proteína 2 de Unión a Metil-CpG/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Respiración , Síndrome de Rett/metabolismo , Síndrome de Rett/patología , Análisis de Supervivencia , Tirosina 3-Monooxigenasa/metabolismo , Aumento de Peso , Ácido gamma-AminobutíricoRESUMEN
Inhalation of capsaicin-based sprays can cause central respiratory depression and lethal apneas. There are contradictory reports regarding the sites of capsaicin action. Furthermore, an understanding of the neurochemical mechanisms underlying capsaicin-induced apneas and the development of pharmacological interventions is lacking. The main objectives of this study were to perform a systematic study of the mechanisms of action of capsaicin-induced apneas and to provide insights relevant to pharmacological intervention. In vitro and in vivo rat and transient receptor potential vanilloid superfamily member 1 (TRPV1)-null mouse models were used to measure respiratory parameters and seizure-like activity in the presence of capsaicin and compounds that modulate glutamatergic neurotransmission. Administration of capsaicin to in vitro and in vivo rat and wild-type mouse models induced dose-dependent apneas and the production of seizure-like activity. No significant changes were observed in TRPV1-null mice or rat medullary slice preparations. The capsaicin-induced effects were inhibited by the TRPV1 antagonist capsazepine, amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonists CNQX, NBQX, perampanel, and riluzole, a drug that inhibits glutamate release and increases glutamate uptake. The capsaicin-induced effects on breathing and seizure-like activity were accentuated by positive allosteric modulators of the AMPA receptors, CX717 and cyclothiazide. To summarize, capsaicin-induced apneas and seizure-like behaviors are mediated via TRPV1 activation acting at lung afferents, spinal cord-ascending tracts, and medullary structures (including nucleus tractus solitarius). AMPA receptor-mediated conductances play an important role in capsaicin-induced apneas and seizure-like activity. A pharmaceutical strategy targeted at reducing AMPA receptor-mediated glutamatergic signaling may reduce capsaicin-induced deleterious effects.
Asunto(s)
Apnea/inducido químicamente , Apnea/patología , Animales , Animales Recién Nacidos , Apnea/metabolismo , Tronco Encefálico/efectos de los fármacos , Capsaicina/análogos & derivados , Capsaicina/farmacología , Ratones Endogámicos C57BL , Pletismografía , Ratas Sprague-Dawley , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transducción de Señal/efectos de los fármacos , Médula Espinal/efectos de los fármacos , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/metabolismoRESUMEN
The neuromuscular junction (NMJ) is one of the best-studied cholinergic synapses. Inherited defects of peripheral neurotransmission result in congenital myasthenic syndromes (CMSs), a clinically and genetically heterogeneous group of rare diseases with fluctuating fatigable muscle weakness as the clinical hallmark. Whole-exome sequencing and Sanger sequencing in six unrelated families identified compound heterozygous and homozygous mutations in SLC5A7 encoding the presynaptic sodium-dependent high-affinity choline transporter 1 (CHT), which is known to be mutated in one dominant form of distal motor neuronopathy (DHMN7A). We identified 11 recessive mutations in SLC5A7 that were associated with a spectrum of severe muscle weakness ranging from a lethal antenatal form of arthrogryposis and severe hypotonia to a neonatal form of CMS with episodic apnea and a favorable prognosis when well managed at the clinical level. As expected given the critical role of CHT for multisystemic cholinergic neurotransmission, autonomic dysfunctions were reported in the antenatal form and cognitive impairment was noticed in half of the persons with the neonatal form. The missense mutations induced a near complete loss of function of CHT activity in cell models. At the human NMJ, a delay in synaptic maturation and an altered maintenance were observed in the antenatal and neonatal forms, respectively. Increased synaptic expression of butyrylcholinesterase was also observed, exposing the dysfunction of cholinergic metabolism when CHT is deficient in vivo. This work broadens the clinical spectrum of human diseases resulting from reduced CHT activity and highlights the complexity of cholinergic metabolism at the synapse.
Asunto(s)
Apnea/genética , Mutación/genética , Miastenia Gravis/genética , Terminales Presinápticos/metabolismo , Simportadores/genética , Simportadores/metabolismo , Adolescente , Apnea/complicaciones , Apnea/metabolismo , Apnea/patología , Artrogriposis/complicaciones , Artrogriposis/genética , Butirilcolinesterasa/metabolismo , Niño , Preescolar , Neuronas Colinérgicas/metabolismo , Neuronas Colinérgicas/patología , Análisis Mutacional de ADN , Exoma/genética , Femenino , Genes Recesivos/genética , Células HEK293 , Heterocigoto , Homocigoto , Humanos , Lactante , Recién Nacido , Masculino , Hipotonía Muscular/genética , Debilidad Muscular/complicaciones , Debilidad Muscular/genética , Debilidad Muscular/patología , Mutación Missense/genética , Miastenia Gravis/complicaciones , Miastenia Gravis/metabolismo , Miastenia Gravis/patología , Unión Neuromuscular/enzimología , Unión Neuromuscular/metabolismo , Unión Neuromuscular/patología , Terminales Presinápticos/patología , Simportadores/deficiencia , Transmisión SinápticaRESUMEN
Despite numerous reports of relationships between weight gain and butyrylcholinesterase (BChE), this enzyme's role in the genesis of obesity remains unclear, but recent research points to strong links with ghrelin, the "hunger hormone." The availability of BChE knockout (KO) mice provides an opportunity to clarify the causal relationship between BChE and obesity onset. We now find that young KO mice have abnormally high plasma ghrelin levels that slowly decline during long-term high-fat feeding and ultimately drop below those in wild-type mice. On such a diet, the KO mice gained notably more weight, more white fat, and more hepatic fat than wild-type animals. In addition to a greater burden of hepatic triglycerides, the livers of these KO mice show distinctly higher levels of inflammatory markers. Finally, their energy expenditure proved to be lower than in wild-type mice despite similar activity levels and increased caloric intake. A gene transfer of mouse BChE with adeno-associated virus vector restored nearly all aspects of the normal phenotype. Our results indicate that BChE strongly affects fat metabolism, has an important impact on fat accumulation, and may be a promising tool for combating obesity.
Asunto(s)
Tejido Adiposo/metabolismo , Apnea/metabolismo , Butirilcolinesterasa/deficiencia , Butirilcolinesterasa/genética , Dieta Alta en Grasa , Metabolismo de los Lípidos/genética , Hígado/metabolismo , Errores Innatos del Metabolismo/metabolismo , Tejido Adiposo/patología , Adiposidad/genética , Animales , Apnea/patología , Butirilcolinesterasa/metabolismo , Células HEK293 , Humanos , Hígado/patología , Masculino , Errores Innatos del Metabolismo/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Tamaño de los Órganos , Regulación hacia Arriba/genéticaRESUMEN
The purpose of the study was to provide insight in diaphragmatic involuntary breathing movements (IBM) during struggle phase of apnea at total lung capacity (TLC) and functional residual capacity (FRC) using magnetic resonance imaging along with measurements of hemodynamics and arterial oxygenation. The study was performed in eight elite breath-hold divers. There was a similar increase in diaphragmatic cranio-caudal excursions towards the end of TLC and FRC apnea. The greatest diaphragmatic excursion in both apneas and during tidal breathing was in the middle and posterior part of the diaphragm. Diaphragm thickness in elite BHD was within the reference range of normal values suggesting no diaphragmatic hypertrophy in this population. We found that the range of diaphragmatic excursions increases toward the end of apneas. Additionally, our data suggest that the diaphragm participates in IBM occurrence and that various segments of the diaphragm behave nonhomogenously both in tidal breathing and IBMs.
Asunto(s)
Apnea/fisiopatología , Contencion de la Respiración , Diafragma/fisiopatología , Buceo/fisiología , Movimiento/fisiología , Contracción Muscular/fisiología , Adulto , Apnea/patología , Análisis de los Gases de la Sangre , Diafragma/patología , Hemodinámica/fisiología , Humanos , Imagen por Resonancia Magnética , Masculino , Fatiga Muscular/fisiología , Tamaño de los Órganos , Capacidad Pulmonar Total/fisiologíaRESUMEN
INTRODUCTION: Insufficient pre-oxygenation before emergency intubation, and hyperventilation after intubation are mistakes that are frequently observed in and outside the operating room, in clinical practice and in simulation exercises. Physiological parameters, as appearing on standard patient monitors, do not alert to the deleterious effects of low oxygen saturation on coronary perfusion, or that of low carbon dioxide concentrations on cerebral perfusion. We suggest the use of HumMod, a computer-based human physiology simulator, to demonstrate beneficial physiological responses to pre-oxygenation and the futility of excessive minute ventilation after intubation. METHODS: We programmed HumMod, to A.) compare varying times (0-7 minutes) of pre-oxygenation on oxygen saturation (SpO2) during subsequent apnoea; B.) simulate hyperventilation after apnoea. We compared the effect of different minute ventilation rates on SpO2, acid-base status, cerebral perfusion and other haemodynamic parameters. RESULTS: A.) With no pre-oxygenation, starting SpO2 dropped from 98% to 90% in 52 seconds with apnoea. At the other extreme, following full pre-oxygenation with 100% O2 for 3 minutes or more, the SpO2 remained 100% for 7.75 minutes during apnoea, and dropped to 90% after another 75 seconds. B.) Hyperventilation, did not result in more rapid normalization of SpO2, irrespective of the level of minute ventilation. However, hyperventilation did cause significant decreases in cerebral blood flow (CBF). CONCLUSIONS: HumMod accurately simulates the physiological responses compared to published human studies of pre-oxygenation and varying post intubation minute ventilations, and it can be used over wider ranges of parameters than available in human studies and therefore available in the literature.
Asunto(s)
Hiperventilación , Hipoxia/prevención & control , Hipoxia/terapia , Oxígeno/administración & dosificación , Adulto , Apnea/patología , Calibración , Dióxido de Carbono/química , Circulación Cerebrovascular , Simulación por Computador , Humanos , Intubación Intratraqueal , Masculino , Modelos Teóricos , Oxígeno/química , Perfusión , Respiración , Programas Informáticos , Factores de TiempoRESUMEN
BACKGROUND: The supply of unregulated "new psychoactive substances" (NPS) has shown a steady increase over the past six years. This report from the Swedish STRIDA project describes analytically confirmed non-fatal intoxications involving butyrfentanyl (butyrylfentanyl) or 4-fluorobutyrfentanyl (para-fluorobutyrfentanyl), two fentanyl analogues recently introduced as NPS opioids. STUDY DESIGN: Observational case series of consecutive patients with suspected acute NPS exposure and requiring hospital care from all over Sweden. PATIENTS AND METHODS: From May 2014 to January 2015, blood and urine samples were obtained from four intoxication cases involving butyrfentanyl and one case involving 4-fluorobutyrfentanyl (men, 19-30 years) presenting in emergency departments (ED) or intensive care units (ICU). Laboratory analysis of serum and/or urine samples was performed by multi-component liquid chromatography-mass spectrometry methods. Data on clinical features were collected during consultations with the Poisons Information Centre and retrieved from medical records. CASE DETAILS: Of the five patients, two were discharged home from the ED and three were admitted to the ICU, of whom two required intubation and mechanical ventilation. Clinical features included typical opioid symptoms such as unconsciousness, respiratory depression, and apnea. In one case, naloxone successfully countered the effects. All patients were discharged the same or the following day. Butyrfentanyl was detected in two serum (0.6 and 0.9 ng/mL) and three urine (2.0-65.6 ng/mL) samples from three of four cases; three cases also contained fentanyl. In the 4-fluorobutyrfentanyl case, the substance was detected in serum (â¼15 ng/mL) and urine (â¼10 ng/mL). In four cases, other NPS and/or classical drugs were also detected. Analysis of two "butyrfentanyl" NPS products (nasal spray and powder) brought to hospital by patients showed that the 10-fold more potent fentanyl was the main active ingredient (â¼7.5-10-fold higher amount) in both. CONCLUSION: Typical and potentially life-threatening opioid toxicity was seen in acute intoxications involving butyrfentanyl, 4F-butyrfentanyl, and fentanyl. The incorrect labelling of butyrfentanyl NPS products which instead mainly contained fentanyl is alarming, given the narrow range between a safe and a lethal dose for opioids.
Asunto(s)
Analgésicos Opioides/envenenamiento , Fentanilo/envenenamiento , Adulto , Apnea/inducido químicamente , Apnea/tratamiento farmacológico , Apnea/patología , Cromatografía Liquida , Relación Dosis-Respuesta a Droga , Servicio de Urgencia en Hospital , Humanos , Drogas Ilícitas/orina , Unidades de Cuidados Intensivos , Masculino , Espectrometría de Masas , Naloxona/farmacología , Insuficiencia Respiratoria/inducido químicamente , Insuficiencia Respiratoria/tratamiento farmacológico , Insuficiencia Respiratoria/patología , Estudios Retrospectivos , Suecia , Inconsciencia/inducido químicamente , Inconsciencia/tratamiento farmacológico , Inconsciencia/patología , Adulto JovenRESUMEN
No disponible
Asunto(s)
Humanos , Recién Nacido , Virus Sincitiales Respiratorios/genética , Virus Sincitiales Respiratorios/metabolismo , Cuidado Intensivo Neonatal , Cuidado Intensivo Neonatal/métodos , Apnea/metabolismo , Infección Hospitalaria/genética , Infección Hospitalaria/patología , Virus Sincitiales Respiratorios/fisiología , Virus Sincitiales Respiratorios/patogenicidad , Cuidado Intensivo Neonatal/psicología , Cuidado Intensivo Neonatal/tendencias , Apnea/patología , Infección Hospitalaria/complicaciones , Infección Hospitalaria/metabolismoRESUMEN
We investigated the role of the autonomic nervous system to cardiovascular responses to obstructive apnea in awake, unrestrained rats, and measured expression of Fos induced by apnea in the brainstem. We implanted a tracheal balloon contained in a rigid tube to allow the induction of apnea without inducing pain in the trachea. During bouts of 15s of apnea, heart rate fell from 371±8 to 161±11bpm (mean±SEM, n=15, p<0.01) and arterial pressure increased from 115±2 to 131±4mmHg (p<0.01). Bradycardia was due to parasympathetic activity because it was blocked by the muscarinic antagonist, methylatropine. The pressor response was due to vasoconstriction caused by sympathetic activation because it was blocked by the α1 antagonist, prazosin. Apnea induced Fos expression in several brainstem areas involved in cardiorespiratory control such as the nucleus of the solitary tract (NTS), ventrolateral medulla (VLM), and pons. Ligation of the carotid body artery reduced apnea-induced bradycardia, blocked heart rate responses to i.v. injection of cyanide, reduced Fos expression in the caudal NTS, and increased Fos expression in the rostral VLM. In conclusion, apnea activates neurons in regions that process signals from baroreceptors, chemoreceptors, pulmonary receptors, and regions responsible for autonomic and respiratory activity both in the presence and absence of carotid chemoreceptors.
Asunto(s)
Apnea/patología , Apnea/fisiopatología , Tronco Encefálico/fisiopatología , Vigilia , Análisis de Varianza , Animales , Derivados de Atropina/farmacología , Presión Sanguínea/efectos de los fármacos , Tronco Encefálico/efectos de los fármacos , Cuerpo Carotídeo/citología , Células Quimiorreceptoras/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Proteínas Oncogénicas v-fos/metabolismo , Parasimpatolíticos/farmacología , Prazosina/farmacología , Ratas , Ratas Wistar , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Pial artery adjustments to changes in blood pressure (BP) may last only seconds in humans. Using a novel method called near-infrared transillumination backscattering sounding (NIR-T/BSS) that allows for the non-invasive measurement of pial artery pulsation (cc-TQ) in humans, we aimed to assess the relationship between spontaneous oscillations in BP and cc-TQ at frequencies between 0.5 Hz and 5 Hz. We hypothesized that analysis of very short data segments would enable the estimation of changes in the cardiac contribution to the BP vs. cc-TQ relationship during very rapid pial artery adjustments to external stimuli. BP and pial artery oscillations during baseline (70s and 10s signals) and the response to maximal breath-hold apnea were studied in eighteen healthy subjects. The cc-TQ was measured using NIR-T/BSS; cerebral blood flow velocity, the pulsatility index and the resistive index were measured using Doppler ultrasound of the left internal carotid artery; heart rate and beat-to-beat systolic and diastolic blood pressure were recorded using a Finometer; end-tidal CO2 was measured using a medical gas analyzer. Wavelet transform analysis was used to assess the relationship between BP and cc-TQ oscillations. The recordings lasting 10s and representing 10 cycles with a frequency of ~1 Hz provided sufficient accuracy with respect to wavelet coherence and wavelet phase coherence values and yielded similar results to those obtained from approximately 70cycles (70s). A slight but significant decrease in wavelet coherence between augmented BP and cc-TQ oscillations was observed by the end of apnea. Wavelet transform analysis can be used to assess the relationship between BP and cc-TQ oscillations at cardiac frequency using signals intervals as short as 10s. Apnea slightly decreases the contribution of cardiac activity to BP and cc-TQ oscillations.