RESUMO
Metabolic dysfunctions are among the best documented hallmarks of ageing. Cardiovascular disease, Alzheimer's disease, cancer, type 2 diabetes mellitus, metabolic-dysfunction-associated steatosis liver disease, and fragility fractures are diseases of hyperinsulinaemia that reduce life and healthspan. We studied the effect of suppressing ketosis in 10 lean (BMI 20.5 kg/m2 ± 1.4), metabolically healthy, pre-menopausal women (age 32.3 ± 8.9 years) maintaining nutritional ketosis (NK) for an average of 3.9 years (± 2.3) who underwent three 21-day phases: nutritional ketosis (NK; P1), suppressed ketosis (SuK; P2), and returned to NK (P3). Ketosis suppression significantly increased insulin, 1.83-fold (p = 0.0006); glucose, 1.17-fold (p = 0.0088); homeostasis model assessment for insulin resistance (HOMA-IR), 2.13-fold (p = 0.0008); leptin, 3.35-fold (p = 0.0010); total osteocalcin, 1.63-fold (p = 0.0138); and uncarboxylated osteocalcin, 1.98-fold (p = 0.0417) and significantly decreased beta-hydroxybutyrate, 13.50-fold (p = 0.0012) and glucagon-like peptide-1 (GLP-1), 2.40-fold (p = 0.0209). Sustained NK showed no adverse health effects and may mitigate hyperinsulinemia. All biomarkers returned to basal P1 levels after removing the intervention for SuK, indicating that metabolic flexibility was maintained with long-term euketonaemia.
RESUMO
Most studies on ketosis have focused on short-term effects, male athletes, or weight loss. Hereby, we studied the effects of short-term ketosis suppression in healthy women on long-standing ketosis. Ten lean (BMI 20.5 ± 1.4), metabolically healthy, pre-menopausal women (age 32.3 ± 8.9) maintaining nutritional ketosis (NK) for > 1 year (3.9 years ± 2.3) underwent three 21-day phases: nutritional ketosis (NK; P1), suppressed ketosis (SuK; P2), and returned to NK (P3). Adherence to each phase was confirmed with daily capillary D-beta-hydroxybutyrate (BHB) tests (P1 = 1.9 ± 0.7; P2 = 0.1 ± 0.1; and P3 = 1.9 ± 0.6 pmol/L). Ageing biomarkers and anthropometrics were evaluated at the end of each phase. Ketosis suppression significantly increased: insulin, 1.78-fold from 33.60 (± 8.63) to 59.80 (± 14.69) pmol/L (p = 0.0002); IGF1, 1.83-fold from 149.30 (± 32.96) to 273.40 (± 85.66) µg/L (p = 0.0045); glucose, 1.17-fold from 78.6 (± 9.5) to 92.2 (± 10.6) mg/dL (p = 0.0088); respiratory quotient (RQ), 1.09-fold 0.66 (± 0.05) to 0.72 (± 0.06; p = 0.0427); and PAI-1, 13.34 (± 6.85) to 16.69 (± 6.26) ng/mL (p = 0.0428). VEGF, EGF, and monocyte chemotactic protein also significantly increased, indicating a pro-inflammatory shift. Sustained ketosis showed no adverse health effects, and may mitigate hyperinsulinemia without impairing metabolic flexibility in metabolically healthy women.
Assuntos
Doenças dos Bovinos , Dieta Cetogênica , Hiperinsulinismo , Cetose , Animais , Bovinos , Humanos , Masculino , Feminino , Adulto Jovem , Adulto , Doenças dos Bovinos/metabolismo , Insulina/farmacologia , Ácido 3-Hidroxibutírico/metabolismoRESUMO
Patients with type 2 diabetes mellitus (T2DM) and/or cardiovascular disease (CVD), conditions of hyperinsulinaemia, have lower levels of osteocalcin and bone remodelling, and increased rates of fragility fractures. Unlike osteoporosis with lower bone mineral density (BMD), T2DM bone fragility "hyperinsulinaemia-osteofragilitas" phenotype presents with normal to increased BMD. Hyperinsulinaemia and insulin resistance positively associate with increased BMD and fragility fractures. Hyperinsulinaemia enforces glucose fuelling, which decreases NAD+-dependent antioxidant activity. This increases reactive oxygen species and mitochondrial fission, and decreases oxidative phosphorylation high-energy production capacity, required for osteoblasto/cytogenesis. Osteocytes directly mineralise and resorb bone, and inhibit mineralisation of their lacunocanalicular space via pyrophosphate. Hyperinsulinaemia decreases vitamin D availability via adipocyte sequestration, reducing dendrite connectivity, and compromising osteocyte viability. Decreased bone remodelling and micropetrosis ensues. Trapped/entombed magnesium within micropetrosis fossilisation spaces propagates magnesium deficiency (MgD), potentiating hyperinsulinaemia and decreases vitamin D transport. Vitamin D deficiency reduces osteocalcin synthesis and favours osteocyte apoptosis. Carbohydrate restriction/fasting/ketosis increases beta-oxidation, ketolysis, NAD+-dependent antioxidant activity, osteocyte viability and osteocalcin, and decreases excess insulin exposure. Osteocalcin is required for hydroxyapatite alignment, conferring bone structural integrity, decreasing fracture risk and improving metabolic/endocrine homeodynamics. Patients presenting with fracture and normal BMD should be investigated for T2DM and hyperinsulinaemia.
RESUMO
Unlike bolus insulin secretion mechanisms, basal insulin secretion is poorly understood. It is essential to elucidate these mechanisms in non-hyperinsulinaemia healthy persons. This establishes a baseline for investigation into pathologies where these processes are dysregulated, such as in type 2 diabetes (T2DM), cardiovascular disease (CVD), certain cancers and dementias. Chronic hyperinsulinaemia enforces glucose fueling, depleting the NAD+ dependent antioxidant activity that increases mitochondrial reactive oxygen species (mtROS). Consequently, beta-cell mitochondria increase uncoupling protein expression, which decreases the mitochondrial ATP surge generation capacity, impairing bolus mediated insulin exocytosis. Excessive ROS increases the Drp1:Mfn2 ratio, increasing mitochondrial fission, which increases mtROS; endoplasmic reticulum-stress and impaired calcium homeostasis ensues. Healthy individuals in habitual ketosis have significantly lower glucagon and insulin levels than T2DM individuals. As beta-hydroxybutyrate rises, hepatic gluconeogenesis and glycogenolysis supply extra-hepatic glucose needs, and osteocalcin synthesis/release increases. We propose insulin's primary role is regulating beta-hydroxybutyrate synthesis, while the role of bone regulates glucose uptake sensitivity via osteocalcin. Osteocalcin regulates the alpha-cell glucagon secretory profile via glucagon-like peptide-1 and serotonin, and beta-hydroxybutyrate synthesis via regulating basal insulin levels. Establishing metabolic phenotypes aids in resolving basal insulin secretion regulation, enabling elucidation of the pathological changes that occur and progress into chronic diseases associated with ageing.
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Risk factors for COVID-19 patients with poorer outcomes include pre-existing conditions: obesity, type 2 diabetes mellitus, cardiovascular disease (CVD), heart failure, hypertension, low oxygen saturation capacity, cancer, elevated: ferritin, C reactive protein (CRP) and D-dimer. A common denominator, hyperinsulinaemia, provides a plausible mechanism of action, underlying CVD, hypertension and strokes, all conditions typified with thrombi. The underlying science provides a theoretical management algorithm for the frontline practitioners.Vitamin D activation requires magnesium. Hyperinsulinaemia promotes: magnesium depletion via increased renal excretion, reduced intracellular levels, lowers vitamin D status via sequestration into adipocytes and hydroxylation activation inhibition. Hyperinsulinaemia mediates thrombi development via: fibrinolysis inhibition, anticoagulation production dysregulation, increasing reactive oxygen species, decreased antioxidant capacity via nicotinamide adenine dinucleotide depletion, haem oxidation and catabolism, producing carbon monoxide, increasing deep vein thrombosis risk and pulmonary emboli. Increased haem-synthesis demand upregulates carbon dioxide production, decreasing oxygen saturation capacity. Hyperinsulinaemia decreases cholesterol sulfurylation to cholesterol sulfate, as low vitamin D regulation due to magnesium depletion and/or vitamin D sequestration and/or diminished activation capacity decreases sulfotransferase enzyme SULT2B1b activity, consequently decreasing plasma membrane negative charge between red blood cells, platelets and endothelial cells, thus increasing agglutination and thrombosis.Patients with COVID-19 admitted with hyperglycaemia and/or hyperinsulinaemia should be placed on a restricted refined carbohydrate diet, with limited use of intravenous dextrose solutions. Degree/level of restriction is determined by serial testing of blood glucose, insulin and ketones. Supplemental magnesium, vitamin D and zinc should be administered. By implementing refined carbohydrate restriction, three primary risk factors, hyperinsulinaemia, hyperglycaemia and hypertension, that increase inflammation, coagulation and thrombosis risk are rapidly managed.
Assuntos
Infecções por Coronavirus/terapia , Dieta com Restrição de Carboidratos , Suplementos Nutricionais , Hiperinsulinismo/terapia , Insulina/sangue , Magnésio/uso terapêutico , Pneumonia Viral/terapia , Trombose/terapia , Vitamina D/uso terapêutico , Betacoronavirus/patogenicidade , Biomarcadores/sangue , Glicemia/metabolismo , COVID-19 , Infecções por Coronavirus/sangue , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Suplementos Nutricionais/efeitos adversos , Interações Hospedeiro-Patógeno , Humanos , Hiperinsulinismo/sangue , Hiperinsulinismo/epidemiologia , Cetonas/sangue , Magnésio/sangue , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Prognóstico , Fatores de Risco , SARS-CoV-2 , Trombose/sangue , Trombose/epidemiologia , Trombose/virologia , Vitamina D/sangue , Zinco/uso terapêuticoRESUMO
Hearing loss (HL) is an extra-skeletal manifestation of the connective tissue disorder osteogenesis imperfecta (OI). Systematic evaluation of the prevalence and characteristics of HL in COL1A1/COL1A2-related OI will contribute to a better clinical management of individuals with OI. We collected and analyzed pure-tone audiometry data from 312 individuals with OI who were enrolled in the Linked Clinical Research Centers and the Brittle Bone Disorders Consortium. The prevalence, type, and severity of HL in COL1A1/COL1A2-related OI are reported. We show that the prevalence of HL in OI is 28% and increased with age in Type I OI but not in Types III and IV. Individuals with OI Types III and IV are at a higher risk to develop HL in the first decade of life when compared to OI Type I. We also show that the prevalence of SNHL is higher in females with OI compared to males. This study reveals new insights regarding prevalence of HL in OI including a lower general prevalence of HL in COL1A1/COL1A2-related OI than previously reported (28.3 vs. 65%) and high prevalence of SNHL in females. Our data support the need in early routine hearing evaluation in all types of OI that can be adjusted to the severity of the skeletal disease.
Assuntos
Colágeno Tipo I/genética , Perda Auditiva/epidemiologia , Mutação , Osteogênese Imperfeita/fisiopatologia , Adolescente , Adulto , Criança , Cadeia alfa 1 do Colágeno Tipo I , Feminino , Genótipo , Perda Auditiva/genética , Perda Auditiva/patologia , Humanos , Masculino , Pessoa de Meia-Idade , América do Norte/epidemiologia , Fenótipo , Adulto JovemRESUMO
OBJECTIVE: To describe the use of electronic health records (EHR) among members of the American Neurotology Society (ANS). STUDY DESIGN: Cross-sectional. SETTING: Active ANS members in November 2017. INTERVENTION: Internet-based survey. MAIN OUTCOME MEASURE: Survey that assessed the use of EHR in practice, types of EHR programs, different elements of EHR employed, and respondents' satisfaction and efficiency with EHR. RESULTS: One hundred twenty-seven ANS members responded to the survey with 67 (52.8%) respondents working in academic practice and 60 (47.2%) respondents working in private practice. Epic was the most commonly used EHR with 89 (70.1%) respondents using this system. Among all respondents, 84 (66.1%) respondents reported their efficiency was reduced by EHR use, and there was an even split between respondents who reported they were satisfied versus dissatisfied with their EHR (â¼40% each). We found that younger members were more likely to feel EHR increased their efficiency compared with the older members (pâ=â0.04). In all other analyses, we found no significant difference in efficiency and satisfaction between age groups, practice settings, presence of residents or fellows, or specific EHR used. The main challenges reported by ANS members related to the EHR were increased time burden, poor user interface, lack of customizability, and the focus away from patients. CONCLUSIONS: The majority of ANS members felt their efficiency decreased as a result of EHR. These findings provide specific changes to the EHR that would improve efficiency and satisfaction among neurotologists.
Assuntos
Registros Eletrônicos de Saúde , Neuro-Otologia , Estudos Transversais , Eficiência , Humanos , Inquéritos e Questionários , Estados UnidosRESUMO
Bone remodeling disorders have been identified as potential candidates for the etiology underlying some forms of otologic disease. Here, four clinical cases are presented to demonstrate a novel approach to tinnitus management that focuses on two fundamental etiologic bases. First, is the effect of bone remodeling abnormalities of the otic capsule and second, the effect of blood sugar and insulin abnormalities upon the function of the inner ear and self-reports of tinnitus. This report presents the effect of treatment directed at bone remodeling abnormalities of the otic capsule and abnormalities of blood sugar and insulin. The treatment effects led to a substantial reduction in subjective tinnitus. These findings suggest a potential convergence between bone pathophysiology and some forms of tinnitus.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Hipoglicemia/complicações , Doenças do Labirinto/complicações , Osteoporose/complicações , Zumbido/terapia , Adulto , Dietoterapia , Feminino , Humanos , Hipoglicemia/dietoterapia , Doenças do Labirinto/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Osteoporose/tratamento farmacológico , Fluoreto de Sódio/uso terapêutico , Zumbido/etiologiaRESUMO
INTRODUCTION: Despite improvement in the computational capabilities of visual displays in flight simulators, intersensory visual-vestibular conflict remains the leading cause of simulator sickness (SS). By using galvanic vestibular stimulation (GVS), the vestibular system can be synchronized with a moving visual field in order to lessen the mismatch of sensory inputs thought to result in SS. METHODS: A multisite electrode array was used to deliver combinations of GVS in 21 normal subjects. Optimal electrode combinations were identified and used to establish GVS dose-response predictions for the perception of roll, pitch, and yaw. Based on these data, an algorithm was then implemented in flight simulator hardware in order to synchronize visual and GVS-induced vestibular sensations (oculo-vestibular-recoupled or OVR simulation). Subjects were then randomly exposed to flight simulation either with or without OVR simulation. A self-report SS checklist was administered to all subjects after each session. An overall SS score was calculated for each category of symptoms for both groups. RESULTS: The analysis of GVS stimulation data yielded six unique combinations of electrode positions inducing motion perceptions in the three rotational axes. This provided the algorithm used for OVR simulation. The overall SS scores for gastrointestinal, central, and peripheral categories were 17%, 22.4%, and 20% for the Control group and 6.3%, 20%, and 8% for the OVR group, respectively. CONCLUSIONS: When virtual head signals produced by GVS are synchronized to the speed and direction of a moving visual field, manifestations of induced SS in a cockpit flight simulator are significantly reduced.
Assuntos
Medicina Aeroespacial , Terapia por Estimulação Elétrica , Enjoo devido ao Movimento/prevenção & controle , Interface Usuário-Computador , Vestíbulo do Labirinto , Adulto , Feminino , Humanos , Masculino , Orientação , Reflexo Vestíbulo-OcularRESUMO
Galvanic stimulation has long been used as a nonmechanical means of activating the vestibular apparatus through direct action on the vestibular nerve endings. This stimulation has been reported to be safe, but no studies have examined the potential changes in the corresponding cochlear receptors. The aim of the present study was to evaluate the effect of galvanic vestibular stimulation (GVS) on distortion product otoacoustic emissions (DPOAEs). Fourteen subjects underwent DPOAEs during several conditions of GVS. The DPOAEs ranged from â¼ 1 kHz to â¼ 8 kHz at 65/55 dB for f1/f2 and with an f2/f1 ratio of 1.2. The subjects were evaluated at 10 stimulation conditions that ranged from -2.0 mA to +2.0 mA for each frequency. Statistical analysis showed no significant differences in DPOAE amplitudes for all conditions with and without GVS. Results also showed no significant differences between DPOAE amplitudes before and after GVS. Multivariate analysis found subject variability in DPOAE amplitude, which was not thought to be GVS related. Results indicated that GVS produced neither temporary nor permanent changes in DPOAEs.
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Estimulação Acústica , Emissões Otoacústicas Espontâneas/fisiologia , Vestíbulo do Labirinto/fisiologia , Estimulação Acústica/métodos , Adulto , Fenômenos Biomecânicos/fisiologia , Cóclea/fisiologia , Fenômenos Eletrofisiológicos/fisiologia , Feminino , Resposta Galvânica da Pele/fisiologia , Humanos , Masculino , Análise Multivariada , Adulto JovemAssuntos
Orelha , Cefaleia/diagnóstico , Náusea/diagnóstico , Neurologia/métodos , Otolaringologia/métodos , Dor/diagnóstico , Vertigem/diagnóstico , Criança , Ritmo Circadiano , Dieta com Restrição de Gorduras , Tontura/complicações , Tontura/diagnóstico , Feminino , Cefaleia/complicações , Cefaleia/fisiopatologia , Humanos , Hiperinsulinismo/complicações , Hiperinsulinismo/diagnóstico , Hiperinsulinismo/dietoterapia , Náusea/complicações , Náusea/fisiopatologia , Otosclerose/complicações , Otosclerose/diagnóstico , Dor/complicações , Dor/fisiopatologia , Vertigem/complicações , Vertigem/fisiopatologiaAssuntos
Mergulho , Tontura/etiologia , Doenças do Labirinto/etiologia , Doenças Metabólicas/complicações , Osso Temporal/diagnóstico por imagem , Conservadores da Densidade Óssea/uso terapêutico , Diagnóstico Diferencial , Tontura/tratamento farmacológico , Humanos , Doenças do Labirinto/tratamento farmacológico , Masculino , Doenças Metabólicas/tratamento farmacológico , Pessoa de Meia-Idade , RadiografiaAssuntos
Perda Auditiva Neurossensorial/diagnóstico , Hiperacusia/diagnóstico , Otosclerose/diagnóstico , Zumbido/diagnóstico , Conservadores da Densidade Óssea/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ácido Etidrônico/análogos & derivados , Ácido Etidrônico/uso terapêutico , Perda Auditiva Neurossensorial/tratamento farmacológico , Perda Auditiva Neurossensorial/patologia , Humanos , Hiperacusia/tratamento farmacológico , Hiperacusia/patologia , Hiperparatireoidismo/complicações , Masculino , Pessoa de Meia-Idade , Otosclerose/tratamento farmacológico , Otosclerose/patologia , Ácido Risedrônico , Zumbido/tratamento farmacológico , Zumbido/patologiaRESUMO
Presented here is a first-person account of the evolution of the practice of surgical neurootology to that of medical neurootology shaped mainly by results of treatment directed at underlying otosclerosis-like lesions of the otic capsule and metabolic factors. With new technologies and rapidly evolving concepts, the changing treatment algorithms did not remain constant to provide the usual evidence-based outcome analyses. However, the majority of the patients presenting with neurootological symptoms had undergone previous medical or surgical treatment before undergoing the medical management herein described. The underlying ongoing basic science findings over this period were linked to the clinical observations. On the basis of the more effective results of treating neurootological disorders, recommendations are made for future areas of investigation-mostly basic science-into developing an investigative foundation for future effective management of patients with a variety of neurootological disorders.