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Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by various combinations of autonomic failure, parkinsonism, and cerebellar ataxia. To elucidate variants associated with MSA, we have been conducting short-read-based whole-genome sequence analysis. In the process of the association studies, we initially focused on GBA1, a previously proposed susceptibility gene for MSA, to evaluate whether GBA1 variants can be efficiently identified despite its extraordinarily high homology with its pseudogene, GBA1LP. To accomplish this, we conducted a short-read whole-genome sequence analysis with alignment to GRCh38 as well as Sanger sequence analysis and compared the results. We identified five variants with inconsistencies between the two pipelines, of which three variants (p.L483P, p.A495P-p.V499V, p.L483_M489delinsW) were the results of misalignment due to minor alleles in GBA1P1 registered in GRCh38. The miscalling events in these variants were resolved by alignment to GRCh37 as the reference genome, where the major alleles are registered. In addition, a structural variant was not properly identified either by short-read or by Sanger sequence analyses. Having accomplished correct variant calling, we identified three variants pathogenic for Gaucher disease (p.S310G, p.L483P, and p.L483_M489delinsW). Of these variants, the allele frequency of p.L483P (0.003) in the MSA cases was higher than that (0.0011) in controls. The meta-analysis incorporating a previous report demonstrated a significant association of p.L483P with MSA with an odds ratio of 2.92 (95% CI; 1.08 - 7.90, p = 0.0353).
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Orbital cavernous venous malformation (OCVM) is a sporadic vascular anomaly of uncertain etiology characterized by abnormally dilated vascular channels. Here, we identify a somatic missense mutation, c.121G > T (p.Gly41Cys) in GJA4, which encodes a transmembrane protein that is a component of gap junctions and hemichannels in the vascular system, in OCVM tissues from 25/26 (96.2%) individuals with OCVM. GJA4 expression was detected in OCVM tissue including endothelial cells and the stroma, through immunohistochemistry. Within OCVM tissue, the mutation allele frequency was higher in endothelial cell-enriched fractions obtained using magnetic-activated cell sorting. Whole-cell voltage clamp analysis in Xenopus oocytes revealed that GJA4 c.121G > T (p.Gly41Cys) is a gain-of-function mutation that leads to the formation of a hyperactive hemichannel. Overexpression of the mutant protein in human umbilical vein endothelial cells led to a loss of cellular integrity, which was rescued by carbenoxolone, a non-specific gap junction/hemichannel inhibitor. Our data suggest that GJA4 c.121G > T (p.Gly41Cys) is a potential driver gene mutation for OCVM. We propose that hyperactive hemichannel plays a role in the development of this vascular phenotype.
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Mutación con Ganancia de Función , Malformaciones Vasculares , Humanos , Células Endoteliales , Uniones Comunicantes/genética , Mutación , Venas , Malformaciones Vasculares/metabolismoRESUMEN
BACKGROUND: Postoperative pain and inflammation are significant complications following surgery. Strategies that aim to prevent excessive inflammation without hampering natural wound-healing are required for the management of postoperative pain and inflammation. However, the knowledge of the mechanisms and target pathways involved in these processes is lacking. Recent studies have revealed that autophagy in macrophages sequesters pro-inflammatory mediators, and it is therefore being recognized as a crucial process involved in regulating inflammation. In this study, we tested the hypothesis that autophagy in macrophages plays protective roles against postoperative pain and inflammation and investigated the underlying mechanisms. METHODS: Postoperative pain was induced by plantar incision under isoflurane anesthesia in mice lacking macrophage autophagy (Atg5flox/flox LysMCre +) and their control littermates (Atg5flox/flox). Mechanical and thermal pain sensitivity, changes in weight distribution, spontaneous locomotor activity, tissue inflammation, and body weight were assessed at baseline and 1, 3, and 7 days after surgery. Monocyte/macrophage infiltration at the surgical site and inflammatory mediator expression levels were evaluated. RESULTS: Atg5flox/flox LysMCre + mice compared with the control mice exhibited lower mechanical and thermal pain thresholds and surgical/non-surgical hindlimb weight-bearing ratios. The augmented neurobehavioral symptoms observed in the Atg5flox/flox LysMCre + mice were associated with more severe paw inflammation, higher pro-inflammatory mediator mRNA expression, and more monocytes/macrophages at the surgical site. CONCLUSION: The lack of macrophage autophagy augmented postoperative pain and inflammation, which were accompanied by enhanced pro-inflammatory cytokine secretion and surgical-site monocyte/macrophage infiltration. Macrophage autophagy plays a protective role in postoperative pain and inflammation and can be a novel therapeutic target.
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Inflamación , Macrófagos , Ratones , Animales , Macrófagos/metabolismo , Inflamación/metabolismo , Dolor Postoperatorio/tratamiento farmacológico , Autofagia , Umbral del DolorRESUMEN
AIM: Hereditary neuropathy with liability to pressure palsies (HNPP) is a peripheral neuropathy with autosomal dominant inheritance. Diagnosis can be made from the characteristic abnormalities determined by nerve conduction studies (NCS), including subclinical deficits at physiological compression sites. Heterozygous deletion of the chromosome 17p11.2-p12 region including the peripheral myelin protein 22 gene (PMP22) is the cause in the majority of cases. However, the loss of function of PMP22 due to frameshift-causing insertion/deletion, missense, nonsense, or splice-site disrupting variants cause HNPP in some patients. We report a case of a patient diagnosed with HNPP on the basis of clinical features and the results of NCS. No deletions of PMP22 were detected by fluorescence in situ hybridization. METHODS: We performed direct nucleotide sequence analysis and identified a heterozygous variant, c.78 + 3G > T, in PMP22. Since this variant is located outside the canonical splice site at the exon 2-intron 2 junction, we investigated whether the variant causes aberrant splicing and leads to the skipping of exon 2 of PMP22 by in vitro minigene splicing assay. RESULTS: We demonstrated that the c.78 + 3G > T variant causes the skipping of exon 2 and leads to loss of function of the mutant allele. CONCLUSION: Searching for sequence variants located outside the canonical splice sites should also be considered even when deletion of PMP22 is not found in a patient with a clinical diagnosis suggesting HNPP.
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Enfermedad de Charcot-Marie-Tooth , Neuropatía Hereditaria Motora y Sensorial , Enfermedades del Sistema Nervioso Periférico , Humanos , Hibridación Fluorescente in Situ , Proteínas de la Mielina/genética , Enfermedades del Sistema Nervioso Periférico/genética , Parálisis , Enfermedad de Charcot-Marie-Tooth/genéticaRESUMEN
PURPOSE: Perioperative shivering is common and can occur as a result of hypothermia or changes in the threshold of thermoregulation. Droperidol usage for anesthesia is currently limited to its sedative and antiemetic effects. We investigated the effects of high and low doses of droperidol on the shivering threshold in rabbits. METHODS: Forty-two male Japanese white rabbits were anesthetized with isoflurane and randomly assigned to the control, high-dose, or low-dose group. Rabbits in the high-dose group received a 5 mg/kg droperidol bolus followed by continuous infusion at 5 mg/kg/h, those in the low-dose group received a 0.5 mg/kg droperidol bolus, and those in the control group received the same volume of saline as the high-dose group. Body temperature was reduced at a rate of 2-3 °C/h, and the shivering threshold was defined as the subject's core temperature (°C) at the onset of shivering. RESULTS: The shivering thresholds in the control, high-dose, and low-dose groups were 38.1 °C ± 1.1 °C, 36.7 °C ± 1.2 °C, and 36.9 °C ± 1.0 °C, respectively. The shivering thresholds were significantly lower in the high-dose and low-dose groups than in the control group (P < 0.01). The thresholds were comparable between the high-dose and low-dose groups. CONCLUSIONS: Droperidol in high and low doses effectively reduced the shivering threshold in rabbits. Droperidol has been used in low doses as an antiemetic. Low doses of droperidol can reduce the incidence of shivering perioperatively and during the induction of therapeutic hypothermia.
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Hipotermia , Isoflurano , Animales , Conejos , Masculino , Tiritona/fisiología , Droperidol/farmacología , Temperatura Corporal/fisiología , Isoflurano/farmacología , Hipotermia/tratamiento farmacológicoRESUMEN
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder caused by FMR1 premutation expansion of CGG repeats. FXTAS can be misdiagnosed with many neurodegenerative disorders manifesting with cerebellar ataxias owing to their overlapping clinical and radiological features. The frequency of the FMR1 premutation allele in Japan has not been fully determined. Herein, we aimed to determine the frequency of FMR1 premutation alleles in Japanese patients with undiagnosed cerebellar ataxia and multiple system atrophy, using repeat-primed PCR in 186 patients with adult onset of undiagnosed cerebellar ataxia and 668 patients with multiple system atrophy, to identify expanded CGG repeats as well as to detect AGG interruptions within the expanded alleles. The size of expansions was estimated using fragment length analysis of PCR products obtained by conventional PCR employing a pair of unique primers flanking the repeat sequence. We identified FMR1 premutation alleles in three male patients. One patient revealed 84 repeat units with one AGG interruption and another patient showed 103 repeat units. Both had presented with sporadic cerebellar ataxia, giving an estimated frequency of 3.7% among Japanese male patients with sporadic cerebellar ataxia with age at onset above 50 years. One patient with the clinical diagnosis of multiple system atrophy harbored 60 repeat units with four AGG interruptions. FMR1 intermediate alleles were observed in two males and one female among the multiple system atrophy patients. We found that genetic tests for FMR1 premutation should be considered in Japanese male patients with cerebellar ataxia with the age at onset above 50 years.
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Ataxia Cerebelosa , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Síndrome del Cromosoma X Frágil , Atrofia de Múltiples Sistemas , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Alelos , Ataxia Cerebelosa/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/diagnóstico , Síndrome del Cromosoma X Frágil/genética , Japón , Atrofia de Múltiples Sistemas/diagnóstico , Atrofia de Múltiples Sistemas/genética , Expansión de Repetición de TrinucleótidoRESUMEN
While multiple system atrophy (MSA) has been considered a sporadic disease, there were previously reported multiplex families with MSA. Furthermore, several families with multiple patients with MSA and Parkinson's disease (PD) have been reported. As genetic risk factors for MSA, functionally impaired variants in COQ2 and Gaucher-disease-causing GBA variants have been reported. While it has been established that GBA variants are associated with PD, COQ2 may also be associated with PD. In 672 patients with MSA, we identified 12 multiplex families of patients with MSA and PD in first-degree relatives. We conducted a detailed analysis of the clinical presentations of these patients and genetic analyses of GBA and COQ2. In the multiplex families, a patient with MSA with predominant parkinsonism (MSA-P) was observed in nine families, while a patient with MSA cerebellar subtype (MSA-C) was observed in three families. Six families had siblings with MSA and PD, five families had a parent-offspring pair with MSA and PD, and in one family, a sibling and a parent of an MSA patient had PD. In genetic analyses of these patients, GBA variants were identified in one of the 12 MSA patients and two of the seven PD patients. Functionally impaired variants of COQ2 were identified in two of the 12 MSA patients and not identified in the seven PD patients. This study further emphasizes the occurrence of MSA and PD in first-degree relatives, raising the possibility that a common genetic basis underlies MSA and PD. Even though variants of COQ2 and GBA were identified in some patients in multiplex families with MSA and PD, it is necessary to further explore as yet unidentified genetic risk factors shared by MSA and PD.
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BACKGROUND: During cardiopulmonary resuscitation, the brain becomes ischemic. Adrenaline and vasopressin have been recommended for use during cardiopulmonary resuscitation. We aimed to investigate the direct effects of adrenaline and vasopressin on the cerebral microvasculature at baseline and during ischemia and reperfusion in rabbits. METHODS: The closed cranial window method was used to visualize the cerebral microcirculation and changes in the pial arteriole diameter in rabbits. Adrenaline and vasopressin were administered topically on the brain tissue. First, the effects of adrenaline and vasopressin on pial arterioles were evaluated in 7 rabbits that were given 4 different concentrations of adrenaline, and another 7 rabbits that received 4 different concentrations of vasopressin. Second, the effects of adrenaline and vasopressin were determined during the global brain ischemia and reperfusion, which was induced by clamping the brachiocephalic, left common carotid, and left subclavian arteries for 15 min. An additional 21 rabbits were randomly assigned to receive artificial cerebrospinal fluid (aCSF) (n = 7), adrenaline 10-5 mol/L (n = 7), or vasopressin 10-7 mol/L (n = 7). Each drug was continuously infused from 5 min after the initiation of ischemia until 120 min after reperfusion. The pial arteriole diameters were recorded before and during ischemia, and after reperfusion. RESULTS: At baseline, adrenaline and vasopressin did not affect the cerebral pial arterioles. During ischemia, vasopressin, but not aCSF and adrenaline constricted the pial vessels. Late in the reperfusion phase, pial diameter became reduced in the vasopressin and aCSF groups whereas pial diameter was higher in the animals treated with adrenaline. CONCLUSIONS: Adrenaline and vasopressin did not affect pial arterioles at baseline. During reperfusion, adrenaline may counteract the cerebral vasoconstriction.
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Isquemia Encefálica , Epinefrina , Animales , Conejos , Epinefrina/farmacología , Vasopresinas/farmacología , Isquemia Encefálica/tratamiento farmacológico , IsquemiaRESUMEN
BACKGROUND: Accidental dural puncture (ADP), which is a complication of epidural anesthesia, still exists and leads to worse outcomes in surgical patients. While residency training is important for epidural competency, it remains unknown whether anesthetic experience reduces ADP in surgical patients. Using an incident reporting system along with anesthetic records, this case-controlled study retrospectively investigated risk factors associated with ADP in surgical patients. METHODS: Patients who experienced ADP during epidural anesthesia who were registered in the incident reporting system of our institution between April 2012 and March 2019 were enrolled. Patients with ADP were control-matched with those who without ADP in a 1:3 ratio, to compare the potential risk factors and calculated odds ratios (ORs) for ADP. The primary hypothesis was that anesthesiologists' experience reduces the incidence of ADP. The secondary hypothesis was that there are risk factors for ADP. Between-group differences in anesthesiologists' experience were compared using the Mann-Whitney U test. Significance was set at P < 0.05. RESULTS: Thirty-five patients who experienced ADP were identified from the incident reporting system. These were matched with 69 patients who did not experience ADP. There was no difference in the years of experience of anesthesiologists between the groups that did and did not experience ADP (8 [3-20] vs. 9 [3-18] years, respectively; P = 0.65). CONCLUSIONS: Having an experienced anesthesiologist did not guarantee the prevention of ADP. Daily individual training and briefings would be needed to reduce the incidence of ADP.
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Analgesia Epidural , Anestésicos , Cefalea Pospunción de la Duramadre , Humanos , Analgesia Epidural/efectos adversos , Cefalea Pospunción de la Duramadre/epidemiología , Punciones/efectos adversos , Estudios RetrospectivosRESUMEN
BACKGROUND: With recent advances in robot-assisted techniques, an increasing number of surgeries are being performed with pneumoperitoneum and head-down maneuver (HDM) that may affect the cerebral microcirculation. For the first time, this study investigated the direct influence of pneumoperitoneum and HDM on the cerebral microvasculature in rabbits. METHODS: Adult male rabbits were randomly allocated to the following groups (n = 7 each): control, pneumoperitoneum alone (P), and pneumoperitoneum with HDM (P + HDM) for 120 min. A closed cranial window was installed above the parietal bone to visualize the pial microvasculature. Pial arteriolar diameter and hemodynamic and blood gas parameters were measured during the 140-min observation period. Brain edema was assessed by evaluation of the brain water content at the end of the experiment. RESULTS: Rabbits in the P and P + HDM groups exhibited a similar degree of immediate pial arteriolar dilation following the initiation of both P and P + HDM (P: 1.11 ± 0.03, p = 0.0044 and P + HDM: 1.07 ± 0.02, p = 0.0004, relative changes from the baseline value by defining the baseline as one). In the P + HDM group, pial arteriole diameter returned to the baseline level following the discontinuation of pneumoperitoneum and HDM (1.05 ± 0.03, p = 0.0906, vs. baseline). In contrast, the pial arterioles remained dilated as compared to the baseline level in the P group after discontinuation of pneumoperitoneum. There were no changes in pial arteriole diameter in the animals in the control group. Heart rate, blood gas parameters, and brain water content were not significantly different between the groups. CONCLUSION: The pial arterioles dilated immediately after pneumoperitoneum with or without HDM. The pial arterioles remained dilated 20 min after discontinuation of pneumoperitoneum alone but constricted upon discontinuation of pneumoperitoneum plus HDM. Pneumoperitoneum and HDM for 2 h did not cause brain edema.
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Edema Encefálico , Neumoperitoneo , Masculino , Animales , Conejos , Inyecciones Intraperitoneales , Microvasos , MicrocirculaciónRESUMEN
Our objective was to investigate the frequency of KIF5A variants in amyotrophic lateral sclerosis (ALS) and the clinical characteristics of familial ALS (FALS) associated with variants in KIF5A. Whole-exome sequence analysis was performed for a Japanese series of 43 families with FALS and 444 patients with sporadic ALS (SALS), in whom causative variants had not been identified. We compared the frequencies of rare variants (MAF < 0.01) in KIF5A, including missense and loss of function (LoF) variants, between ALS and control subjects (n = 1163). Clinical characteristics of patients with FALS carrying pathogenic variants in KIF5A were also described. LoF variants were identified only in the probands of two families with FALS, both of which were 3' splice-site variants leading to exon skipping and an altered C-terminal domain, located in the mutational hotspot causing FALS, and were considered to be pathogenic for FALS. Rare missense variants in KIF5A were identified in five patients with SALS (1.13%) and 11 control subjects (0.95%, carrier frequency), which were not significantly different. Consequently, the pathogenic LoF variants in KIF5A accounted for 2.1% of all FALS families in this study. These patients suffered from ALS characteristically associated with the predominant involvement of upper motor neuron. In conclusion, we identified two pathogenic splice-site variants in KIF5A in the probands in two Japanese families with FALS, which altered the C-terminal region of KIF5A. Our findings broaden the phenotype spectrum of ALS associated with variants in KIF5A in the Japanese series.
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Esclerosis Amiotrófica Lateral/genética , Predisposición Genética a la Enfermedad/genética , Cinesinas/genética , Mutación/genética , Adulto , Esclerosis Amiotrófica Lateral/diagnóstico , Pueblo Asiatico/genética , Femenino , Estudios de Asociación Genética , Humanos , Japón , Masculino , Persona de Mediana EdadRESUMEN
Adrenoleukodystrophy (ALD) is an X-linked disease that affects primarily the white matter of the central nervous system and adrenal cortex. A correlation between genotypes and phenotypes has not been observed. Here, we present two Japanese siblings with a novel missense variant (c.1887T > G) in the ABCD1 gene who presented with different clinical phenotypes, i.e., adolescent cerebral and cerebello-brainstem types. We also review the literature focusing on the variation in the clinical phenotypes within ALD families. In our review, 61.9% of sibling pairs presented with the same clinical type of ALD and 59.1% of sibling pairs presented with a similar age of onset. Conversely, 15.4% of sibling pairs had a similar age of onset, but different clinical types of ALD. To observe the correlation between genotypes and phenotypes, it is important to diagnose early and to accumulate reports describing age of onset, first onset symptom, and progression of the symptom.
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Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP/genética , Adrenoleucodistrofia/genética , Edad de Inicio , Sustitución de Aminoácidos , Mutación Missense , Mutación Puntual , Adrenoleucodistrofia/clasificación , Adrenoleucodistrofia/complicaciones , Adrenoleucodistrofia/patología , Tronco Encefálico/diagnóstico por imagen , Tronco Encefálico/patología , Cerebelo/diagnóstico por imagen , Cerebelo/patología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Resultado Fatal , Humanos , Lipoma/complicaciones , Masculino , Trastornos de la Memoria/genética , Neuroimagen , Linaje , Fenotipo , Hermanos , Neoplasias de los Tejidos Blandos/complicaciones , Disrafia Espinal/complicaciones , Estrabismo/genética , Adulto JovenRESUMEN
Loss-of-function (LoF) variants in NEK1 have recently been reported to be associated with amyotrophic lateral sclerosis (ALS). In this study, we investigated the association of NEK1 LoF variants with an increased risk of sporadic ALS (SALS) and the clinical characteristics of patients with SALS carrying LoF variants in a Japanese case series. Whole-exome sequencing analysis was performed for a series of 446 SALS patients in whom pathogenic variants in familial ALS-causative genes have not been identified and 1163 healthy control subjects in our Japanese series. We evaluated LoF variants, defined as nonsense, splice-site disrupting single-nucleotide variants (SNVs), or short insertion/deletion (indel) variants predicted to cause frameshifts in NEK1. We identified seven NEK1 LoF variants in patients with SALS (1.57%), whereas only one was identified in control subjects (0.086%) (P = 0.00073, Fisher's exact test). This finding is consistent with those in recent reports from other regions in the world. In conclusion, we demonstrated that NEK1 LoF variants are also associated with an increased risk of SALS in the Japanese population.
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Esclerosis Amiotrófica Lateral/genética , Pueblo Asiatico/genética , Mutación con Pérdida de Función , Quinasa 1 Relacionada con NIMA/deficiencia , Edad de Inicio , Anciano , Esclerosis Amiotrófica Lateral/etnología , Esclerosis Amiotrófica Lateral/psicología , Codón sin Sentido , Trastornos del Conocimiento/genética , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Mutación INDEL , Masculino , Persona de Mediana Edad , Mutación , Quinasa 1 Relacionada con NIMA/genética , Quinasa 1 Relacionada con NIMA/fisiología , Polimorfismo de Nucleótido Simple , Isoformas de Proteínas/genética , Sitios de Empalme de ARN/genética , Secuenciación del ExomaRESUMEN
PURPOSE: Intranasal insulin administration may improve cognitive function in patients with dementia and may prevent cognitive problems after surgery. Although the metabolic effects of intranasal insulin in non-surgical patients have been studied, its influence on glucose concentration during surgery is unknown. METHODS: We conducted a randomized, double-blind, placebo-contolled trial in patients scheduled for elective cardiac surgery. Patients with type 2 diabetes mellitus (T2DM) and non-T2DM patients were randomly allocated to one of three groups (normal saline, 40 international units [IU] of intranasal insulin, and 80 IU intranasal insulin). Insulin was given after the induction of general anesthesia. Glucose and plasma insulin concentrations were measured in ten-minute intervals during the first hour and every 30 min thereafter. The primary outcome was the change in glucose concentration 30 min after intranasal insulin administration. RESULTS: A total of 115 patients were studied, 43 of whom had T2DM. In non-T2DM patients, 40 IU intranasal insulin did not affect glucose concentration, while 80 IU intranasal insulin led to a statistically significant but not clinically important decrease in blood glucose levels (mean difference, 0.4 mMol·L-1; 95% confidence interval, 0.1 to 0.7). In T2DM patients, neither 40 IU nor 80 IU of insulin affected glucose concentration. No hypoglycemia (< 4.0 mMol·L-1) was observed after intranasal insulin administration in any patients. In non-T2DM patients, changes in plasma insulin were similar in the three groups. In T2DM patients, there was an increase in plasma insulin concentrations ten minutes after administration of 80 IU of intranasal insulin compared with saline. CONCLUSIONS: In patients with and without T2DM undergoing elective cardiac surgery, intranasal insulin administration at doses as high as 80 IU did not cause clinically important hypoglycemia. TRIAL REGISTRATION: www.ClinicalTrials.gov (NCT02729064); registered 5 April 2016.
RéSUMé: OBJECTIF: L'administration intranasale d'insuline pourrait améliorer la fonction cognitive des patients souffrant de démence et pourrait prévenir les problèmes cognitifs après une chirurgie. Bien que les effets métaboliques de l'insuline intranasale chez les patients non chirurgicaux aient été étudiés, son influence sur la glycémie pendant une chirurgie est inconnue. MéTHODE: Nous avons réalisé une étude randomisée, à double insu, contrôlée par placebo auprès de patients devant subir une chirurgie cardiaque non urgente. Des patients atteints de diabète de type 2 et des patients non diabétiques ont été randomisés dans l'un de trois groupes (solution physiologique salée, 40 unités internationales [UI] d'insuline intranasale et 80 UI d'insuline intranasale). La solution intranasale a été administrée après l'induction de l'anesthésie générale. Les concentrations de glucose et d'insuline plasmatique ont été mesurées à des intervalles de dix minutes pendant la première heure et toutes les 30 minutes par la suite. Le critère d'évaluation principal était le changement de glycémie 30 min après l'administration intranasale d'insuline. RéSULTATS: Un total de 115 patients ont été étudiés, dont 43 souffraient de diabète de type 2. Chez les patients non diabétiques, 40 UI d'insuline intranasale n'ont pas affecté la glycémie, alors que 80 UI d'insuline intranasale ont entraîné une réduction statistiquement significative mais non cliniquement importante de la glycémie (différence moyenne, 0,4 mMol·L−1; intervalle de confiance de 95 %, 0,1 à 0,7). Chez les patients diabétiques, ni 40 UI ni 80 UI d'insuline n'ont affecté la glycémie. Aucune hypoglycémie (< 4,0 mMol·L−1) n'a été observée après administration intranasale d'insuline chez les patients diabétiques ou non diabétiques. Chez les patients non diabétiques, les changements de l'insuline plasmatique étaient semblables dans les trois groupes. Chez les patients diabétiques, une augmentation des concentrations d'insuline plasmatique a été observée dix minutes après l'administration de 80 UI d'insuline intranasale comparée à la solution saline. CONCLUSION: Chez les patients diabétiques et non diabétiques subissant une chirurgie cardiaque non urgente, l'administration intranasale d'insuline à des doses allant jusqu'à 80 UI n'a pas causé d'hypoglycémie cliniquement importante. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT02729064); enregistrée le 5 avril 2016.
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Procedimientos Quirúrgicos Cardíacos , Diabetes Mellitus Tipo 2 , Hipoglucemia , Administración Intranasal , Glucemia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Método Doble Ciego , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemia/prevención & control , Hipoglucemiantes , Insulina/uso terapéuticoRESUMEN
PURPOSE: To evaluate changes in cerebral regional oxygen saturation (rSO2) after spinal anesthesia and compare the changes in rSO2 and systemic oxygenation between dexmedetomidine sedation and propofol sedation. METHODS: Thirty-six patients scheduled to undergo transurethral surgery under spinal anesthesia were randomly assigned to the dexmedetomidine (n = 18) and propofol groups (n = 18). We used near-infrared spectroscopy sensors to measure rSO2, and obtained data from each side were averaged. After oxygen insufflation, baseline measurements of mean arterial blood pressure (MAP), heart rate, rSO2, pulse oximetry saturation (SpO2), bispectral index, and body temperature were made. After spinal anesthesia, we measured these parameters every 5 min. Twenty minutes after spinal injection, dexmedetomidine or propofol administration was started. We measured each parameter at 10, 25, and 40 min after the administration of dexmedetomidine or propofol. RESULTS: The baseline rSO2 in the dexmedetomidine group was 71.3 ± 7.3%, and that in the propofol group was 71.8 ± 5.6%. After spinal anesthesia, rSO2 in both groups decreased significantly (dexmedetomidine group: 65.4 ± 6.9%; propofol group: 64.3 ± 7.4%). After administering sedatives, rSO2 was equivalent after spinal anesthesia. rSO2 was comparable between the two groups. MAP and SpO2 were significantly higher in the dexmedetomidine group than in the propofol group. CONCLUSION: Spinal anesthesia decreased rSO2; however, the decline was not severe. Dexmedetomidine and propofol did not compromise cerebral oxygenation under spinal anesthesia. Nevertheless, MAP and SpO2 were more stable in dexmedetomidine sedation than in propofol sedation. Dexmedetomidine may be suitable for spinal anesthesia.
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Anestesia Raquidea , Dexmedetomidina , Propofol , Humanos , Hipnóticos y Sedantes , Inyecciones Espinales , OxígenoRESUMEN
Intermediate-length CAG repeats in ATXN2 have been widely shown to be a risk factor for sporadic amyotrophic lateral sclerosis (SALS). To evaluate the association of ATXN2 intermediate-length CAG repeat alleles with an increased risk of SALS, we investigated distributions of CAG repeat alleles in 394 patients with SALS and 490 control individuals in the Japanese population. In the intermediate-length repeat units of 29 or more, we identified one SALS patient with 31 repeat units and two control individuals with 30 repeat units. Thus, no significant differences in the carrier frequency of intermediate-length CAG repeat alleles were detected between patients with SALS and control individuals. When we investigated the distribution of "large normal alleles" defined as ATXN2 CAG repeats ranging from 24 up to 33 in the Japanese population compared with those in other populations in previous studies, the frequency of large normal alleles was significantly higher in the European and North American series than in the Japanese series. Moreover, these frequencies in the Turkish, Chinese, Korean, and Brazilian (Latin American) series were also higher than that in the Japanese series. These results raise the possibility that the frequencies of large normal alleles in individual populations underlie the frequencies of ALS risk alleles in the corresponding populations.
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Alelos , Esclerosis Amiotrófica Lateral/etnología , Esclerosis Amiotrófica Lateral/genética , Ataxina-2/genética , Adulto , Anciano , Pueblo Asiatico , Estudios de Casos y Controles , Análisis Mutacional de ADN , Etnicidad , Femenino , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Japón , Masculino , Persona de Mediana Edad , Secuencias Repetitivas de Ácidos NucleicosRESUMEN
BACKGROUND: Sodium ion transportation plays a crucial role in the pathogenesis of hypoxic-ischemic brain injury. Amiodarone, a Vaughan-Williams class III antiarrhythmic drug, has been widely used to treat life-threatening arrhythmia and cardiac arrest worldwide. In addition to its inhibitory effects on the potassium channel, amiodarone also blocks various sodium ion transporters, including the voltage-gated sodium channel, sodium pump, and Na+/Ca+ exchanger. Considering these pharmacological profile, amiodarone may affect the influx-efflux balance of sodium ion in the hypoxic-ischemic brain. Previous studies suggest that the blockade of the voltage-gated sodium channel during hypoxic-ischemic brain injury exerts neuroprotection. On the contrary, the blockade of sodium pump or Na+/Ca+ exchanger during hypoxia-ischemia may cause further intracellular sodium accumulation and consequent osmotic cell death. From these perspectives, the effects of amiodarone on sodium ion balance on the hypoxic-ischemic brain can be both protective and detrimental depending on the clinical and pathophysiological conditions. In this study, we therefore investigated the effect of amiodarone on hypoxic-ischemic brain injury using a murine experimental model. RESULTS: Compared with the control group mice, mice that received amiodarone after induction of 40-min hypoxic-ischemic brain injury exhibited lower survival rates over 7 days and worse neurological function. After 25-min hypoxic-ischemic brain injury, amiodarone treated mice exhibited larger infarct volumes (16.0 ± 6.9 vs. 24.2 ± 6.8 mm3, P < 0.05) and worse neurological function. In addition, the brains harvested from the amiodarone-treated mice contained larger amounts of sodium (194.7 ± 45.1 vs. 253.5 ± 50.9 mEq/kg dry weight, P < 0.01) and water (259.3 ± 8.9 vs. 277.2 ± 12.5 mg, P < 0.01). There were no significant differences in hemodynamic parameters between groups. CONCLUSIONS: Amiodarone exacerbated brain injuries and neurological outcomes after hypoxic-ischemic insults. Severe brain sodium accumulation and brain edema were associated with the detrimental effects of amiodarone. Amiodarone at the clinical dose can exacerbate brain injury after hypoxic-ischemic insult by affecting sodium ion transportation and facilitate intracellular sodium accumulation in the brain.
Asunto(s)
Amiodarona/efectos adversos , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Hipoxia-Isquemia Encefálica/fisiopatología , Bloqueadores de los Canales de Sodio/efectos adversos , Animales , Antiarrítmicos/efectos adversos , Encéfalo/patología , Edema Encefálico/patología , Edema Encefálico/fisiopatología , Modelos Animales de Enfermedad , Hipoxia-Isquemia Encefálica/patología , Masculino , Ratones Endogámicos C57BL , Neuroprotección/efectos de los fármacos , Bloqueadores de los Canales de Potasio/efectos adversos , Sodio/metabolismoRESUMEN
OBJECTIVES: To evaluate the burden of rare variants in the causative genes for amyotrophic lateral sclerosis (ALS) on the age at onset of ALS in a Japanese case series. METHODS: We conducted whole-exome sequencing analysis of 89 families with familial ALS (FALS) and 410 patients with sporadic ALS (SALS) to identify known pathogenic mutations or rare functionally predicted deleterious variants in the causative genes for ALS. Rare variants (minor allele frequency <1%) with scaled Combined Annotation-Dependent Depletion score >20 were defined as rare functionally predicted deleterious variants. The patients with ALS were classified on the basis of the number of pathogenic and/or rare functionally predicted deleterious variants, and the age at onset was compared among the classified groups. RESULTS: Whole-exome sequencing analysis revealed known pathogenic mutations or rare functionally predicted deleterious variants in causative genes for ALS in 56 families with FALS (62.9%) and 87 patients with SALS (21.2%). Such variants in multiple genes were identified in seven probands with FALS and eight patients with SALS. The ages at onset in the patients with ALS with multiple variants were significantly earlier than those in other patients with ALS. Even when the patients with known pathogenic mutations were excluded, a significantly earlier onset of the disease was still observed in patients with multiple rare functionally predicted deleterious variants. CONCLUSIONS: A substantial number of patients carried rare variants in multiple genes, and the burden of rare variants in the known causative genes for ALS affects the age at onset in the Japanese ALS series.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Mutación/genética , Adulto , Edad de Inicio , Estudios de Casos y Controles , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Secuenciación del ExomaRESUMEN
BACKGROUND: We previously reported that each 100 mg dL- 1 reduction in blood glucose over the range from ≈90 to > 300 mg dL- 1 decreases the shivering threshold (triggering core temperature) in rabbits by 1 °C. However, the effects of lower blood glucose concentrations has yet to be evaluated. We thus evaluated the relationship between the shivering threshold and blood glucose concentration over the mild-to-severe hypoglycemic range. METHODS: Thirty-nine rabbits were lightly anaesthetized with isoflurane and randomly assigned to one of the three groups: 1) severe hypoglycemia, insulin and dextrose infusions titrated to achieve blood glucose concentration at 45-75 mg dL- 1; 2) mild hypoglycemia, insulin and dextrose infusions titrated to achieve blood glucose concentration at 75-100 mg dL- 1; and 3) saline infusion. Cooling by colonic perfusion of water at 10 °C was continued until shivering occurred or esophageal core temperatures reached to 34 °C. RESULTS: The shivering threshold in the severe hypoglycemic rabbits was 35.7 ± 1.1 °C (mean ± SD); the thresholds in the mild hypoglycemic rabbits was 37.0 ± 0.7 °C; and the threshold in the control rabbits was 37.9 ± 1.0 °C. The shivering threshold increased linearly with blood glucose concentration: shivering threshold (°C) = 0.032 â [blood glucose concentration (mg dL- 1)] + 34.1, R2 = 0.45. The shivering threshold thus decreased by approximately 1 °C for each 31 mg dL- 1 decrease in blood glucose concentration. CONCLUSIONS: There was a linear relationship between blood glucose and the shivering threshold over the range from severe hypoglycemia to normoglycemia. Blood glucose perturbations in the hypoglycemic range reduced the shivering threshold about three times as much as previously reported for the hyperglycemic range.
Asunto(s)
Hipoglucemia , Umbral Sensorial , Tiritona , Anestésicos por Inhalación/administración & dosificación , Animales , Glucemia/análisis , Hipoglucemia/inducido químicamente , Isoflurano/administración & dosificación , Modelos Animales , Conejos , Distribución Aleatoria , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: We evaluated the change of cerebral regional tissue oxygen saturation (rSO2) along with the pneumoperitoneum and the Trendelenburg position. We also assessed the relationship between the change of rSO2 and the changes of mean arterial blood pressure (MAP), heart rate (HR), arterial carbon dioxide tension (PaCO2), arterial oxygen tension (PaO2), or arterial oxygen saturation (SaO2). METHODS: Forty-one adult patients who underwent a robotic assisted endoscopic prostatic surgery under propofol and remifentanil anesthesia were involved in this study. During the surgery, a pneumoperitoneum was established using carbon dioxide. Measurements of rSO2, MAP, HR, PaCO2, PaO2, and SaO2 were performed before the pneumoperitoneum (baseline), every 5 min after the onset of pneumoperitoneum, before the Trendelenburg position. After the onset of the Trendelenburg position, rSO2, MAP, HR were recorded at 5, 10, 20, 30, 45, and 60 min, and PaCO2, PaO2, and SaO2 were measured at 10, 30, and 60 min. RESULTS: Before the pneumoperitoneum, left and right rSO2 were 67.9 ± 6.3% and 68.5 ± 7.0%. Ten minutes after the onset of pneumoperitoneum, significant increase in the rSO2 was observed (left: 69.6 ± 5.9%, right: 70.6 ± 7.4%). During the Trendelenburg position, the rSO2 increased initially and peaked at 5 min (left: 72.2 ± 6.5%, right: 73.1 ± 7.6%), then decreased. Multiple regression analysis showed that change of rSO2 correlated with MAP and PaCO2. CONCLUSIONS: Pneumoperitoneum and the Trendelenburg position in robotic-assisted endoscopic prostatic surgery did not worsen cerebral oxygenation. Arterial blood pressure is the critical factor in cerebral oxygenation. TRIAL REGISTRATION: Japan Primary Registries Network (JPRN); UMIN-CTR ID; UMIN000026227 (retrospectively registered).