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Background: Type 1 diabetes is a chronic autoimmune disease associated with insulin-producing beta cell destruction, declining insulin secretion, and elevated blood glucose. Physical activity improves glycaemic control and cardiovascular health. This study explores acute effects of maximal exhaustion induced by a cardiopulmonary exercise on macro- and microvascular parameters in type 1 diabetes. Methodology: Twenty-five participants with type 1 diabetes (14 males, 11 females), aged 41.4 ± 11.87 years, BMI 23.7 ± 3.08, completed a repeated-measure study. Measurements pre-, post-, 30- and 60-minutes post-exhaustion involved a maximal incremental cardio-pulmonary exercise test. Macro- and microvascular parameters were assessed using VICORDER® and retinal blood vessel image analysis. Repeated measures ANOVA in SPSS (Version 27.0) analysed data. Results: Post-exercise, heart rate increased (p<.001), and diastolic blood pressure decreased (p=.023). Diabetes duration correlated with pulse wave velocity (r=0.418, p=.047), diastolic blood pressure (r=0.470, p=.023), and central retinal arteriolar equivalent (r=0.492, p=.023). Conclusion: In type 1 diabetes, cardiopulmonary exercise-induced exhaustion elevates heart rate and reduces diastolic blood pressure. Future research should explore extended, rigorous physical activity protocols for greater cardiovascular risk reduction.
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Diabetes Mellitus Tipo 1 , Ejercicio Físico , Microvasos , Humanos , Diabetes Mellitus Tipo 1/fisiopatología , Masculino , Femenino , Adulto , Ejercicio Físico/fisiología , Microvasos/fisiopatología , Persona de Mediana Edad , Frecuencia Cardíaca/fisiología , Presión Sanguínea/fisiología , Prueba de Esfuerzo , Glucemia/metabolismoRESUMEN
AIM: To evaluate the relationship between breath volatile organic compounds (VOCs) and glycaemic states in individuals with type 1 diabetes (T1D), focusing on identifying specific VOCs as biomarkers for hypoglycaemia to offer a non-invasive diabetes-monitoring method. MATERIALS AND METHODS: Ten individuals with T1D underwent induced hypoglycaemia in a clinical setting. Breath samples, collected every 10-15 minutes, were analysed using gas chromatography-ion mobility spectrometry (GC-IMS). Correlation analysis and machine learning models, including Partial Least Squares Discriminant Analysis (PLS-DA) and Support Vector Machine classifiers, were used to classify glycaemic states based on VOC profiles. RESULTS: Statistical analysis revealed moderate correlations between specific VOCs (e.g. isoprene, acetone) and venous blood glucose levels. Machine learning models showed high accuracy in classifying glycaemic states, with the best performance achieved by a two-class PLS-DA model showing an accuracy of 93%, sensitivity of 92% and specificity of 94%. Key biomarkers identified included isoprene, acetone, 2-butanone, methanol, ethanol, 2-propanol and 2-pentanone. CONCLUSIONS: This study shows the potential of breath VOCs to accurately classify glycaemic states in individuals with T1D. While key biomarkers such as isoprene, acetone and 2-butanone were identified, the analysis emphasizes the importance of using overall VOC patterns rather than individual compounds, which can be markers for multiple conditions. Machine learning models leveraging these patterns achieved high accuracy, sensitivity and specificity. These findings suggest that breath analysis using GC-IMS could be a viable non-invasive method for monitoring glycaemic states and managing diabetes.
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The human microbiota-associated (HMA) mice model, especially the germ-free (GF)-humanized mice, has been widely used to probe the causal relationships between gut microbiota and human diseases such as type 1 diabetes (T1D). However, most studies have not clarified the extent to which the reconstruction of the human donor microbiota in recipient mice correlates with corresponding phenotypic reproducibility. In this study, we transplanted fecal microbiota from five patients with T1D and four healthy people into GF mice, and microbiota from each donor were transplanted into 10 mice. Mice with similar microbiota structure to the donor exhibited better phenotypic reproducibility. The characteristics of the microbial community assembly of donors also influenced the phenotypic reproducibility in mice, and individuals with a higher proportion of stochastic processes showed more severe disorders. Microbes enriched in patients with T1D had a stronger colonization potential in mice with impaired glucose metabolism, and microbiota functional features related to T1D were better reproduced in these mice. This indicates that assembly traits and colonization efficacy of microbiota influence phenotypic reproducibility in GF-humanized mice. Our findings provide important insights for using HMA mice models to explore links between gut microbiota and human diseases.
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Type 1 diabetes mellitus (T1D) is associated with cognitive impairments in humans. A well-established animal model of T1D is induced through the administration of streptozotocin (STZ), a glucose analog that induces pancreatic ß-cell death, resulting in hyperglycemia and cognitive impairment linked to neuroinflammation and oxidative stress. Tumor necrosis factor (TNF)-α, a key inflammatory mediator, is elevated in the central nervous system (CNS) of diabetic animals. In this study, we utilized TNFR1 knockout mice to investigate the role of TNFR1 signaling in short-term T1D-related cognitive impairment. Our findings showed that diabetic animals did not develop cognitive damage within the first 2 weeks of T1D but exhibited reduced exploration in all behavioral tests. Our findings suggest that this reduction in exploration was attributable to motor impairment, as there was no reduction in motivated novelty-seeking behavior. Additionally, deletion of TNFR1 signaling attenuated gait speed impairment in diabetic mice, but did not affect other motor-related or exploratory behaviors.
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BACKGROUND: Type-1 diabetes mellitus (T1DM) is one of the most dreaded chronic diseases, especially in children or youth. To help patients and their families effectively manage their disease, structured therapeutic patient education (TPE) is essential. MATERIALS AND METHOD: The purpose of this non-randomized before and after controlled study was to assess TPE program effects. In total, 200 T1DM children and adolescents, aged 8-18 years, selected from two pediatric departments, were equally assigned to the intervention and control groups. The primary endpoints were differences between groups at 3 months follow-up in measured HbA1c and health-related quality of life (QoL) assessed by a validated questionnaire. RESULTS: At 3 months follow-up of a TPE intervention for T1DM children and adolescents, although there was no significant change in HbA1c for both groups, a significant improvement was observed in the maximum pre- and postprandial blood glucose levels (r: ~0.3; variation rates: -10,47% and -3,85%, respectively) in the intervention group, whereas there was a significant increase in the maximum and minimum of preprandial blood glucose levels in the control group (r: ~0.3, variation rates: 14.29% and 25%, respectively). Global and dimensional QoL mean scores variation rates showed a significant difference between groups, with an improvement in the intervention group (r ≥ 0.7, Cohen's > 0.8) and a decrease in the control group (r ≥ 0.7). CONCLUSION: These results support the hypotheses of difference between the study groups in favor of better glycemic control and QoL for the intervention group.
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Childhood-onset type 1 diabetes (T1D) is associated with substantial psychiatric morbidity in later life, but it remains unknown whether these associations are due to common underlying biological mechanisms or the impacts of living with the condition and its treatment. Here, using Czech national register data, we identified children with T1D aged ≤14 years between 1994 and 2007 and estimated the risk of psychiatric disorders up to 24 years later. We found that children diagnosed with T1D had an elevated risk of developing substance use, mood, anxiety and personality disorders, and behavioral syndromes. Conversely, we found that children with T1D had a lower risk of developing psychotic disorders. In Mendelian randomization analysis, we found an association with schizophrenia, which, however, did not persist following multiple testing adjustment. The combined observational and Mendelian randomization evidence suggests that T1D diagnosis in childhood predisposes to far-reaching, extensive psychiatric morbidity, which is unlikely to be explicable by common underlying biological mechanisms. The findings of this study highlight that monitoring and addressing the mental health needs of children with T1D is imperative, whereas glucose dysregulation and/or inflammation implicated in schizophrenia pathogenesis warrants future research.
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BACKGROUND: Diabetes distress (DD) is a prevalent concern among people with type 1 diabetes (T1D) and is linked to poor clinical outcomes. Instead of targeting the elimination of DD, we propose a novel approach that empowers individuals with strategies to manage their diabetes effectively in the context of DD: Acceptance and Commitment Therapy (ACT). The purpose of this in-progress trial is to compare an ACT group intervention (ACT1VATE) with usual care in improving HbA1c, DD, quality of life, and cost-effectiveness in adults with T1D. METHODS: This is a two-arm, parallel group, randomized controlled superiority trial enrolling N = 250 adults with T1D, elevated HbA1c, and significant DD in a real-world community-based health system. Participants are randomized to receive ACT1VATE (a five-week ACT group telehealth intervention) or diabetes self-management education and support (usual care as the first-line recommended intervention for DD). The trial will examine comparative effectiveness in improving HbA1c, DD, quality of life, and cost-effectiveness over 12 months. DISCUSSION: We predict that ACT1VATE will be superior given its (1) specific focus on DD, without any expectation that difficult diabetes-related thoughts and emotions must (or can) be completely eliminated; and (2) purposeful linkage of diabetes self-care behaviors to an individual's deeply held values, thus eliciting intrinsic, patient-centric motivation for meaningful and lasting health behavior changes. This trial will provide a valuable test of real-world effectiveness, drive sustainability and scalability, and inform the future of chronic disease care. TRIAL REGISTRATION: NCT04933851 (https://clinicaltrials.gov/ct2/show/NCT04933851). CLINICAL TRIAL: Clinicaltrials.govNCT04933851https://clinicaltrials.gov/study/NCT04933851.
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It is oftentimes the case in studies of disease progression that subjects can move into one of several disease states of interest. Multistate models are an indispensable tool to analyze data from such studies. The Environmental Determinants of Diabetes in the Young (TEDDY) is an observational study of at-risk children from birth to onset of type-1 diabetes (T1D) up through the age of 15. A joint model for simultaneous inference of multistate and multivariate nonparametric longitudinal data is proposed to analyze data and answer the research questions brought up in the study. The proposed method allows us to make statistical inferences, test hypotheses, and make predictions about future state occupation in the TEDDY study. The performance of the proposed method is evaluated by simulation studies. The proposed method is applied to the motivating example to demonstrate the capabilities of the method.
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Narcolepsy type 1 (NT1) is associated with severe loss of orexin neurons and characterized by symptoms including excessive daytime sleepiness and cataplexy. Current medications indicated for NT1 often show limited efficacy, not addressing the full spectrum of symptoms, demonstrating a need for novel drugs. We discovered a parenteral orexin receptor 2 (OX2R) agonist, danavorexton, and an orally available OX2R agonist, TAK-994; both improving NT1 phenotypes in mouse models and individuals with NT1. However, danavorexton has limited oral availability and TAK-994 has a risk of off-target liver toxicity. To avoid off-target-based adverse events, a highly potent molecule with low effective dose is preferred. Here, we show that a novel OX2R-selective agonist, TAK-861 [N-{(2S,3R)-4,4-Difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide], activates OX2R with a half-maximal effective concentration of 2.5 nM and promotes wakefulness at 1 mg/kg in mice and monkeys, suggesting ~ tenfold higher potency and lower effective dosage than TAK-994. Similar to TAK-994, TAK-861 substantially ameliorates wakefulness fragmentation and cataplexy-like episodes in orexin/ataxin-3 and orexin-tTA;TetO DTA mice (NT1 mouse models). Compared with modafinil, TAK-861 induces highly correlated brain-wide neuronal activation in orexin-tTA;TetO DTA mice, suggesting efficient wake-promoting effects. Thus, TAK-861 has potential as an effective treatment for individuals with hypersomnia disorders including narcolepsy, potentially with a favorable safety profile.
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Modelos Animales de Enfermedad , Narcolepsia , Receptores de Orexina , Vigilia , Animales , Narcolepsia/tratamiento farmacológico , Receptores de Orexina/agonistas , Receptores de Orexina/metabolismo , Vigilia/efectos de los fármacos , Ratones , Administración Oral , Fenotipo , Masculino , HumanosRESUMEN
OBJECTIVE: Diabetic kidney disease (DKD) is influenced by multiple factors, yet its precise progression mechanisms remain largely unclear. This study aimed to create a clinical risk-scoring system based on genetic polymorphisms in the AFF3, CARS, CERS2, ERBB4, GLRA3, RAET1L, TMPO, and ZMIZ1 genes. METHODS: The study included a DKD group diagnosed with diabetic kidney disease before age 18 and a WDC group matched by age, gender, and age at diabetes diagnosis. Genetic data and clinical data from diabetes diagnosis to moderately increased albuminuria (MIA) detection were compared between the groups. RESULTS: Among 43 DKD cases, 22 were girls and 21 were boys. At MIA diagnosis, mean body weight SDS was -0.24 ± 0.94, height SDS was 0.34 ± 1.15, and BMI SDS was -0.26 ± 0.94. Systolic blood pressure was at the 72nd percentile (2-99), and diastolic blood pressure was at the 74th percentile (33-99). Significant differences in rs267734, rs267738, and rs942263 polymorphisms were found between DKD and non-complication diabetic groups (13[30.2 %] vs 5[11.6 %], p = 0.034; 14[32.6 %] vs 5[11.6 %], p = 0.019; 26[60.5 %] vs 40[93 %], p < 0.001). CONCLUSION: Several factors were identified as significant in DKD onset, including low follow-up weight SDS, elevated diastolic blood pressure, presence of rs267734, and absence of rs942263 polymorphisms. The model demonstrated a specificity of 81.4 % and a sensitivity of 74.4 %.
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AIMS: To examine the association of daily PA levels and sedentary behaviour with body composition, estimated insulin sensitivity, and arterial stiffness in adults with type 1 diabetes (T1D). METHODS: Cross-sectional study in adults with T1D (nâ¯=â¯54). PA levels (daily steps, and time in moderate-to-vigorous intensity PA (MVPA)) and sedentary behaviour were measured using accelerometry for 7â¯days (McRoberts® DynaPort MoveMonitor). Cardiopulmonary exercise test for VO2max. Anthropometrics were collected, and body composition (total and % of fat mass (FMtot, FM%), total and % of lean mass (LMtot, LM%), and estimated visceral adipose tissue (VAT)) volume was assessed with dual energy X-ray-absorptiometry (DXA). Estimates of insulin sensitivity were determined (estimated glucose disposal rate (eGDR) and total daily insulin dose). Arterial stiffness was assessed with carotid-femoral pulse wave velocity (cf-PWV (m/s); SphygmoCor®). RESULTS: Lower 10-years HbA1c associated moderately with all PA measures. Favourable moderate associations were also found between PA measures and BMI, waist, VAT but not FM and LM. PA measures were favourably associated with a lower total daily insulin dose and higher eGDR. All PA parameters associated moderately with cf-PWV however not independent from traditional risk factors. VO2max inversely associated with cf-PWV independent of age, T1D duration and 24-hour mean blood pressure. CONCLUSIONS: Higher levels of PA, lower sedentary behaviour and greater exercise capacity are favourably associated with long-term glycaemic control, body composition, insulin dosage, estimated insulin sensitivity and arterial stiffness in adults with T1D. Therefore, regular PA and limiting sedentary time should be encouraged to improve metabolic and cardiovascular health in this population. Future longitudinal studies should explore mutual interactions and synergistic effects of PA on these outcomes.
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Protein folding in the endoplasmic reticulum (ER) requires a high ratio of oxidized to reduced glutathione (GSSG/rGSH). Since the GSSG/rGSH depends on total glutathione (tGSH = GSSG + rGSH) levels, we hypothesized that limiting GSH biosynthesis will ameliorate protein misfolding by enhancing the ER oxidative milieu. As a proof-of-concept, we used DL-buthionine-(S,R)-sulfoximine (BSO) to inhibit GSH biosynthesis in Akita mice, which are prone to proinsulin misfolding. We conducted a 2-week intervention to investigate if BSO was safe and a 6-week intervention to find its effect on glucose intolerance. In both cohorts, male heterozygous Akita (AK) and wild-type (WT) mice were continuously administered 15 mM BSO. No adverse effects were observed on body weight, food intake, and water intake in either cohort. Unaltered levels of plasma aspartate and alanine aminotransferases, and cystatin-C, indicate that BSO was safe. BSO-induced decreases in tGSH were tissue-dependent with maximal effects in the kidneys, where it altered the expression of genes associated with GSH biosynthesis, redox status, and proteostasis. BSO treatment decreased random blood glucose levels to 80% and 67% of levels in untreated mice in short-term and long-term cohorts, respectively, and 6-h fasting blood glucose to 82% and 74% of levels in untreated mice, respectively. BSO also improved glucose tolerance by 37% in AK mice in the long-term cohort, without affecting insulin tolerance. Neither glucose tolerance nor insulin tolerance were affected in WT. Data indicate that BSO might treat misfolded proinsulin-induced glucose intolerance. Future studies should investigate the effect of BSO on proinsulin misfolding and if it improves glucose intolerance in individuals with Mutant Insulin Diabetes of Youth.
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The development of automated insulin delivery (AID) systems, which connect continuous glucose monitoring (CGM) systems with algorithmic insulin delivery from an insulin pump (continuous subcutaneous insulin infusion, [CSII]), has led to improved glycaemia and quality of life benefits in those with insulin-treated diabetes. This review summarizes the benefits gained by the connectivity between insulin pumps and CGM devices. It details the technical requirements and advances that have enabled this, and highlights the clinical and user benefits of such systems. Clinical trials and real-world outcomes from the use of AID systems in people with type 1 diabetes (T1D) will be the focus of this article; outcomes in people with type 2 diabetes (T2D) and other diabetes subtypes will also be discussed. We also detail the limitations of current technological approaches for connectivity between insulin pumps and CGM devices. While recognizing the barriers, we discuss opportunities for the future.
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Chiari Malformation Type I (CMI) is a prevalent neurosurgical condition characterized by the descent of cerebellar tonsils below the foramen magnum. Surgery, aimed at reducing symptomatology and syrinx size, presents risks, making intraoperative neuromonitoring (IONM) a potentially vital tool. Despite its widespread use in cervical spine surgery, the utility of IONM in CMI surgery remains controversial, with concerns over increased operative time, cost, restricted anesthetic techniques and tongue lacerations. This systematic review and meta-analysis followed the Cochrane Group standards and PRISMA framework. It encompassed an extensive search through PubMed, Embase, and Web of Science up to December 2023, focusing on clinical and surgical outcomes of IONM in CMI surgery. Primary outcomes included the use of various IONM techniques, complication rates, clinical improvement, reoperation, and mortality. The review, registered at PROSPERO (CRD42024498996), included both prospective and retrospective studies, with rigorous selection and data extraction processes. Statistical analysis was conducted using R software. The review included 16 studies, comprising 1358 patients. It revealed that IONM techniques predominantly involved somatosensory evoked potentials (SSEPs), followed by motor evoked potentials (MEPs) and Brainstem auditory evoked potentials (BAEPs). The estimated risk of complications with IONM was 6% (95% CI: 2-11%; I2 = 89%), lower than previously reported rates without IONM. Notably, the clinical improvement rate post-surgery was high at 99% (95% CI: 98-100%; I2 = 56%). The analysis also showed lower reoperation rates in surgeries with IONM compared to those without. Interestingly, no mortality was observed in the included studies. This systematic review and meta-analysis indicate that intraoperative neuromonitoring in Chiari I malformation surgery is associated with favorable clinical outcomes, including lower complication and reoperation rates, and high rates of clinical improvement.
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Malformación de Arnold-Chiari , Monitorización Neurofisiológica Intraoperatoria , Humanos , Malformación de Arnold-Chiari/cirugía , Monitorización Neurofisiológica Intraoperatoria/métodos , Potenciales Evocados Somatosensoriales/fisiología , Procedimientos Neuroquirúrgicos/métodos , Potenciales Evocados Motores/fisiología , Potenciales Evocados Auditivos del Tronco Encefálico/fisiologíaRESUMEN
BACKGROUND: To investigate the mechanism of Golgi matrix protein 130(GM130) regulating the antiviral immune response of TLR3 after herpes simplex virus type 1(HSV-1) infection of microglia cells. We explored the regulatory effects of berberine on the immune response mediated by GM130 and TLR3. METHODS: An in vitro model of HSV-1 infection was established by infecting BV2 cells with HSV-1. RESULTS: Compared to the uninfected group, the Golgi apparatus (GA) fragmentation and GM130 decreased after HSV-1 infection; TLR3 increased at 6 h and began to decrease at 12 h after HSV-1 infection; the secretion of interferon-beta(IFN-ß), tumour necrosis factor alpha(TNF-α), and interleukin-6(IL-6) increased after infection. Knockdown of GM130 aggravated fragmentation of the GA and caused TLR3 to further decrease, and the virus titer also increased significantly. GM130 knockdown inhibits the increase in TLR3 and inflammatory factors induced by TLR3 agonists and increases the viral titer. Overexpression of GM130 alleviated fragmentation of the GA induced by HSV-1, partially restored the levels of TLR3, and reduced viral titers. GM130 overexpression reversed the reduction in TLR3 and inflammatory cytokine levels induced by TLR3 inhibitors. Therefore, the decrease in GM130 levels caused by HSV-1 infection leads to increased viral replication by inhibiting TLR3-mediated innate immunity. Berberine can protect the GA and reverse the downregulation of GM130, as well as the downregulation of TLR3 and its downstream factors after HSV-1 infection, reducing the virus titer. CONCLUSIONS: In microglia, one mechanism of HSV-1 immune escape is disruption of the GM130/TLR3 pathway. Berberine protects the GA and enhances TLR3-mediated antiviral immune responses.
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Regulación hacia Abajo , Herpesvirus Humano 1 , Inmunidad Innata , Microglía , Receptor Toll-Like 3 , Herpesvirus Humano 1/inmunología , Herpesvirus Humano 1/efectos de los fármacos , Herpesvirus Humano 1/fisiología , Receptor Toll-Like 3/metabolismo , Receptor Toll-Like 3/genética , Microglía/virología , Microglía/inmunología , Microglía/efectos de los fármacos , Animales , Ratones , Línea Celular , Evasión Inmune , Berberina/farmacología , Citocinas/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Herpes Simple/inmunología , Herpes Simple/virologíaRESUMEN
INTRODUCTION & OBJECTIVES: To evaluate whether cardiovascular risk factors and their management differ in primary prevention between adult males and females with type 1 diabetes (T1D) in two European countries in 2020-2022 and sex inequalities in achievement of standards of care in diabetes. METHODS: We used 2020-2022 data of patients without a cardiovascular history in the Prospective Diabetes Follow-up registry (DPV) centres, in Germany, and the Société Francophone du Diabète- Cohorte Diabète de Type 1 cohort (SFDT1), in France. RESULTS: We included 2,657 participants from the DPV registry and 1,172 from the SFDT1 study. Body mass indexes were similar in females and males with similar proportions of HbA1c < 7% (DPV: 36.6 vs 33.0%, p = 0.06, respectively; SFDT1: 23.4 vs 25.7%, p = 0.41). Females were less overweight compared to men in DPV (55.4 vs 61.0%, p < 0.01) but not in SFDT1 (48.0 vs 44.9%, p = 0.33) and were less prone to smoke (DPV: 19.7 vs 25.8%, p < 0.01; SFDT1: 21.0 vs 26.0%, p = 0.07). Systolic blood pressure was lower in females than males with a higher rate of antihypertensive therapy in case of hypertension in females in DPV (70.5 vs 63.7%, p = 0.02) but not in SFDT1 (73.3 vs 68.6%, p = 0.64). In the case of microalbuminuria, ACEi-ARB were less often prescribed in women than men in DPV (21.4 vs 37.6%, p < 0.01) but not SFDT1 (73.3 vs 67.5.0%, p = 0.43). In females compared to males, HDL-cholesterol levels were higher; triglycerides were lower in both countries. In those with LDL-cholesterol > 3.4 mmol/L (DPV: 19.9 (females) vs 23.9% (males), p = 0.01; SFDT1 17.0 vs 19.2%, p = 0.43), statin therapy was less often prescribed in females than males in DPV (7.9 vs 17.0%, p < 0.01), SFDT1 (18.2 vs 21.0%, p = 0.42). CONCLUSION: In both studies, females in primary prevention have a better cardiovascular risk profile than males. We observed a high rate of therapeutic inertia, which might be higher in females for statin treatment and nephroprotection with ACEi-ARB, especially in Germany. Diabetologists should be aware of sex-specific differences in the management of cardiorenal risk factors to develop more personalized prevention strategies.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 1 , Disparidades en el Estado de Salud , Disparidades en Atención de Salud , Factores de Riesgo de Enfermedad Cardiaca , Prevención Primaria , Sistema de Registros , Humanos , Masculino , Femenino , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/terapia , Francia/epidemiología , Adulto , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/diagnóstico , Alemania/epidemiología , Factores Sexuales , Persona de Mediana Edad , Medición de Riesgo , Resultado del Tratamiento , Factores de Tiempo , Biomarcadores/sangre , Hipoglucemiantes/uso terapéutico , Estudios ProspectivosRESUMEN
Recently, nanovaccine-based immunotherapy has been robustly investigated due to its potential in governing the immune response and generating long-term protective immunity. However, the presentation of a tumor peptide-major histocompatibility complex to T lymphocytes is still a challenge that needs to be addressed for eliciting potent antitumor immunity. Type 1 conventional dendritic cell (cDC1) subset is of particular interest due to its pivotal contribution in the cross-presentation of exogenous antigens to CD8+ T cells. Here, the DC-derived nanovaccine (denoted as Si9GM) selectively targets cDC1s with marginal loss of premature antigen release for effective stimulator of interferon genes (STING)-mediated antigen cross-presentation. Bone marrow dendritic cell (BMDC)-derived membranes, conjugated to cDC1-specific antibody (αCLEC9A) and binding to tumor peptide (OVA257-264), are coated onto dendrimer-like polyethylenimine (PEI)-grafted silica nanoparticles. Distinct molecular weight-cargos (αCLEC9A-OVA257-264 conjugates and 2'3'-cGAMP STING agonists) are loaded in hierarchical center-radial pores that enables lysosome escape for potent antigen-cross presentation and activates interferon type I, respectively. Impressively, Si9GM vaccination leads to the upregulation of cytotoxic T cells, a reduction in tumor regulatory T cells (Tregs), M1/M2 macrophage polarization, and immune response that synergizes with αPD-1 immune checkpoint blockade. This nanovaccine fulfills a dual role for both direct T cell activation as an artificial antigen-presenting cell and DC subset maturation, indicating its utility in clinical therapy and precision medicine.
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The transplantation of islet beta cells offers an alternative to heterotopic islet transplantation for treating type 1 diabetes mellitus (T1DM). However, the use of systemic immunosuppressive drugs in islet transplantation poses significant risks to the body. To address this issue, we constructed an encapsulated hybrid scaffold loaded with islet beta cells. This article focuses on the preparation of the encapsulated structure using 3D printing, which incorporates porcine pancreas decellularized extracellular matrix (dECM) to the core scaffold. The improved decellularization method successfully preserved a substantial proportion of protein (such as Collagen I and Laminins) architecture and glycosaminoglycans in the dECM hydrogel, while effectively removing most of the DNA. The inclusion of dECM enhanced the physical and chemical properties of the scaffold, resulting in a porosity of 83.62% ± 1.09% and a tensile stress of 1.85 ± 0.16 MPa. In teams of biological activity, dECM demonstrated enhanced proliferation, differentiation, and expression of transcription factors such as Ki67, PDX1, and NKX6.1, leading to improved insulin secretion function in MIN-6 pancreatic beta cells. In the glucose-stimulated insulin secretion experiment on day 21, the maximum insulin secretion from the encapsulated structure reached 1.96 ± 0.08 mIU ml-1, representing a 44% increase compared to the control group. Furthermore, conventional capsule scaffolds leaverage the compatibility of natural biomaterials with macrophages to mitigate immune rejection. Here, incorporating curcumin into the capsule scaffold significantly reduced the secretion of pro-inflammatory cytokine (IL-1ß, IL-6, TNF-α, IFN-γ) secretion by RAW264.7 macrophages and T cells in T1DM mice. This approach protected pancreatic islet cells against immune cell infiltration mediated by inflammatory factors and prevented insulitis. Overall, the encapsulated scaffold developed in this study shows promise as a natural platform for clinical treatment of T1DM.
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Curcumina , Matriz Extracelular Descelularizada , Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Andamios del Tejido , Animales , Diabetes Mellitus Tipo 1/terapia , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/citología , Andamios del Tejido/química , Curcumina/farmacología , Curcumina/química , Ratones , Matriz Extracelular Descelularizada/química , Matriz Extracelular Descelularizada/farmacología , Porcinos , Trasplante de Islotes Pancreáticos , Cápsulas/química , Insulina/metabolismo , Diabetes Mellitus Experimental/terapia , Línea Celular , Matriz Extracelular/metabolismo , Matriz Extracelular/químicaRESUMEN
Hereditary Tyrosinemia Type 1 (HT1) is a genetic disorder characterized by an autosomal recessive inheritance pattern, caused by mutations in the fumarylacetoacetate hydrolase (FAH) gene, which results in a deficiency of fumarylacetoacetase. In our study, we identified a total of 15 mutations, including 12 newly discovered and 3 previously reported pathogenic mutations, in a cohort of 19 Iranian patients with the acute form of HT1. Out of the 12 novel variants identified, 11 were missense variants: p.Asp126His, p.Gln75Glu, p.Leu385Pro, p.Ser92Thr, p.Leu96Arg, p.Val167Glu, p.Ala94Asp, p.Gly353Trp, p.Ser164Pro, p.Glu86His and p.Ala163Pro. Additionally, there was one nonsense variant, p.Try244X, that had not been previously reported. Interestingly, the Arg237X variant was found to be particularly prevalent in this study. Notably, three exons, namely exons 9, 3, and 6, exhibited a higher frequency of mutations. All of the identified variants are presumed to result in loss of function, impacting the clinical signs, disease progression, increasing tyrosine level, and the specific location of the mutation. Our study has provided valuable insights into the mutation spectrum of variants associated with HT1 disease which is reported for the first time from Iran. This information can facilitate the development of targeted mutation screening protocols, focusing on the most prevalent mutations within specific regions or ethnic groups.
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Hidrolasas , Tirosinemias , Humanos , Tirosinemias/genética , Tirosinemias/patología , Masculino , Femenino , Irán , Lactante , Hidrolasas/genética , Preescolar , Mutación , Niño , Mutación Missense , AdolescenteRESUMEN
Glutaric aciduria type I (GA-1) is a rare metabolic disorder caused by an autosomal, recessive, inherited deficiency of glutaryl-CoA dehydrogenase. Reports on the anesthetic management of patients with GA-1 are limited. It has been suggested that inhalation anesthesia is safer than propofol due to the mitochondrial dysfunction inherent in GA-1. However, inhalation anesthesia poses a risk, albeit rare, of malignant hyperthermia, which can result in severe neurological damage in GA-1 patients. Therefore, we considered that management using remimazolam might be effective and, provided a successful general anesthesia using it for a pediatric patient with GA-1. We report a case of a four-year-old girl with GA-1 who underwent a laparoscopic gastrostomy under general anesthesia. Remimazolam was used for both induction and maintenance of anesthesia. Our perioperative management also included measures to prevent a hypercatabolic condition such as adequate hydration and blood glucose control. The patient had an uneventful perioperative course and was discharged on postoperative day 7. Thus, remimazolam is proposed as a new option for anesthetic management in patients with GA-1. Additionally, tailored perioperative management that addresses the unique characteristics of GA-1 is crucial for favorable outcomes.