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Objective: This study aimed to evaluate the effect of child-friendly dentist attire and camouflage syringes on reducing dental anxiety in children. Methods: A cross-sectional study was conducted with 120 pediatric patients aged 6 to 12 years. Participants were assigned to one of three groups: group A (child-friendly dentist attire), group B (camouflage syringe), or group C (control group). Child preference for dentist attire was assessed using a visual analog scale, while dental anxiety was measured using the Modified Child Dental Anxiety Scale and the Facial Image Scale. Results: The results showed a significant decrease in dental anxiety scores in both group 2 and group 3 compared to group 1 (P < 0.001). Children in group A exhibited a higher preference for child-friendly dentist attire [mean score: 8.7, standard deviation (SD): 1.2] compared to group 1 (mean score: 3.2, SD: 1.5) (P < 0.001). Similarly, children in group 2 showed a higher preference for a camouflage syringe (mean score: 8.5, SD: 1.3) compared to group 1 (mean score: 3.4, SD: 1.6) (P < 0.001). Conclusion: Child-friendly dentist attire and camouflage syringes were found to be effective in reducing dental anxiety among pediatric patients. These interventions were well received by children and their parents, highlighting the importance of considering child preferences in dental settings.
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The inflammasome is a multiprotein complex critical for the innate immune response to injury. Inflammasome activation initiates healthy wound healing, but comorbidities with poor healing, including diabetes, exhibit pathologic, sustained activation with delayed resolution that prevents healing progression. In prior work, we reported the allosteric P2X7 antagonist A438079 inhibits extracellular ATP-evoked NLRP3 signaling by preventing ion flux, mitochondrial reactive oxygen species generation, NLRP3 assembly, mature IL-1ß release, and pyroptosis. However, the short half-life in vivo limits clinical translation of this promising molecule. Here, we develop a controlled release scaffold to deliver A438079 as an inflammasome-modulating wound dressing for applications in poorly healing wounds. We fabricated and characterized tunable thickness, long-lasting silk fibroin dressings and evaluated A438079 loading and release kinetics. We characterized A438079-loaded silk dressings in vitro by measuring IL-1ß release and inflammasome assembly by perinuclear ASC speck formation. We further evaluated the performance of A438079-loaded silk dressings in a full-thickness model of wound healing in genetically diabetic mice and observed acceleration of wound closure by 10 days post-wounding with reduced levels of IL-1ß at the wound edge. This work provides a proof-of-principle for translating pharmacologic inhibition of ATP-induced inflammation in diabetic wounds and represents a novel approach to therapeutically targeting a dysregulated mechanism in diabetic wound impairment.
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Diabetes Mellitus Experimental , Inflamasomas , Piridinas , Tetrazoles , Ratones , Animales , Proteína con Dominio Pirina 3 de la Familia NLR , Cicatrización de Heridas , Vendajes , Seda , Adenosina TrifosfatoRESUMEN
Purpose This study aims to document the early stages of development of an unsupervised, deep learning-based clinical annotation and segmentation tool (CAST) capable of isolating clinically significant teeth in both intraoral photographs and their corresponding oral radiographs. Methods The dataset consisted of 172 intraoral photographs and 424 dental radiographs, manually annotated by two operators, augmented to yield 6258 images for training, 183 for validation, and 98 for testing. The training involved the use of an object detection model ('YOLOv8') combined with a feature extraction system ('Segment Anything Model'). This combination enabled the auto-annotation and segmentation of tooth-related features and lesions in both types of images without operator intervention. Outputs were further processed using a data relabelling tool ('X-AnyLabeling') enabling the option to manually reannotate erroneous data outputs through reinforcement learning. Results The trained object detection model achieved a mean average precision (mAP) of 77.4%, with precision and recall rates of 75.0% and 72.1%, respectively. The model was able to segment features from oral images annotated by polygonal boundaries better than radiological images annotated using bounding boxes. Conclusion The development of the auto-annotation and segmentation tool showed initial promise in automating the image labelling and segmentation process for intraoral images and radiographs. Further work is required to address the limitations.
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BACKGROUND: Developmental dysplasia of the hip (DDH) is a condition where there is an abnormal relationship between the femoral head and acetabulum. DDH is prevalent in Jordan, where late presentations of complicated cases are common due to the absence of a national screening program and cultural behaviors that can exacerbate DDH progression. The study aims to prove that the absence of a nationwide screening program and low awareness of the population about DDH are the primary reasons for the high incidence of late-presenting DDH in Jordan. The study highlights the need for addressing modifiable risk factors like swaddling and correcting common misconceptions such as using multiple diapers as a treatment option. METHODS: The cross-sectional study evaluated the awareness level of DDH among Jordan residents above the age of 18. An online questionnaire was used, containing two sections. The Chi-square test was used to analyze the level of awareness scores according to demographic variables and cultural norms such as tight swaddling and using multiple diapers. The sample was categorized into three groups based on their scores: low awareness (0-4), moderate awareness (5-8), and high awareness (9-12). RESULTS: The study included 1013 participants. The results indicated that 48.9% had moderate awareness, 37.8% had low awareness, and 13.3% had high awareness of DDH. Gender and place of residence had no significant relationship with the level of awareness. However, the majority of participants with high and moderate levels of awareness were in the 25-40 years age group, and healthcare workers had the highest levels of awareness. The study showed that 33.9% of participants gained their knowledge from either relatives or self-experience, while awareness campaigns were the least assessed source of information with only 2.9% of participants getting their information from them. The study also revealed misconceptions regarding DDH, such as the belief that tight swaddling and wearing many diapers reduced the risk of developing DDH. Additionally, about half of the participants were unaware of the presence of screening guidelines for DDH. CONCLUSION: The study underscores the urgent need to establish a national screening program and awareness campaigns to increase knowledge about DDH and prevent late presentations of complicated cases in Jordan. The study findings provide essential information for the development of future DDH campaigns and screening protocols.
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Objectives: To examine the impact of dental students' usage patterns within an adaptive learning platform (ALP), using ALP-related indicators, on their final exam performance. Methods: Track usage data from the ALP, combined with demographic and academic data including age, gender, pre- and post-test scores, and cumulative grade point average (GPA) were retrospectively collected from 115 second-year dental students enrolled in a blended learning review course. Learning performance was measured by post-test scores. Data were analyzed using correlation coefficients and linear regression tests. Results: The ALP-related variables (without controlling for background demographics and academic data) accounted for 29.6% of student final exam performance (R2=0.296, F(10,104)=4.37, p=0.000). Positive significant ALP-related predictors of post-test scores were improvement after activities (ß=0.507, t(104)=2.101, p=0.038), timely completed objectives (ß=0.391, t(104)=2.418, p=0.017), and number of revisions (ß=0.127, t(104)=3.240, p=0.002). Number of total activities, regardless of learning improvement, negatively predicted post-test scores (ß= -0.088, t(104)=-4.447, p=0.000). The significant R2 change following the addition of gender, GPA, and pre-test score (R2=0.689, F(13, 101)=17.24, p=0.000), indicated that these predictors explained an additional 39% of the variance in student performance beyond that explained by ALP-related variables, which were no longer significant. Inclusion of cumulative GPA and pre-test scores showed to be the strongest and only predictors of post-test scores (ß=18.708, t(101)=4.815, p=0.038) and (ß=0.449, t(101)=6.513, p=0.038), respectively. Conclusions: Track ALP-related data can be valuable indicators of learning behavior. Careful and contextual analysis of ALP data can guide future studies to examine practical and scalable interventions.
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Instrucción por Computador , Humanos , Estudios Retrospectivos , Estudiantes de Odontología , Aprendizaje , Modelos LinealesRESUMEN
OBJECTIVE: To develop two-dimensional (2D) upper airway normative values in pediatric patients and correlate upper airway measurements with age. METHODS: Cone beam computed tomography scans of 3738 patients were examined, and a sample of 61 patients, divided into two age groups (7-11 and 12-17 years), was used to reconstruct lateral cephalograms. RESULTS: The mean adenoid-nasopharynx (A/N) ratio was 0.45 and 0.44 for age groups 1 and 2, respectively. The mean PNS-ad1 and PNS-ad2 were 24 and 18.7 mm, respectively, for age group 1, and 26.7 and 21.2 mm, respectively, for age group 2. Additional normative values for the hyoid bone, airway space, uvula, and tongue are presented. The highest correlation with age was the upper airway length (r = 0.557, p < 0.001). CONCLUSION: Although cephalometric radiographs remain 2D reconstructions of three-dimensional structures, they have significant value and can aid clinicians in the screening process for pediatric sleep apnea.
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Tonsila Faríngea , Hueso Hioides , Síndromes de la Apnea del Sueño , Niño , Humanos , Tonsila Faríngea/diagnóstico por imagen , Cefalometría/métodos , Tomografía Computarizada de Haz Cónico/métodos , Hueso Hioides/diagnóstico por imagenRESUMEN
BACKGROUND: Dentofacial problems have a definitive impact on patients' psychological well-being, quality of life, and satisfaction. Therefore, patients' satisfaction with their dentition should be an essential goal for dental caregivers. AIM: To compare parental satisfaction with their children's rapid palatal expansion treatment outcome provided by orthodontists and pediatric dentists. MATERIALS AND METHODS: The authors reviewed 605 medical records and contacted 134 parents whose children received early orthodontic treatment from orthodontists and pediatric dentists using a rapid palatal expander. Eighty-eight parents (65.7%) responded to a validated questionnaire about patients' satisfaction with orthodontic treatment outcomes. RESULTS: At baseline; there were no significant differences in relation to parent-related demographic variables. However, there were statistically significant differences between patients' ages and treatment duration (p < 0.001). Independent t-tests showed statistically significant differences in the means for the subscales of doctor-patient relationship and situational aspects (p < 0.05). Spearman's rho correlation coefficients and multivariate linear regression analysis showed that the overall satisfaction is significantly related to, and can be predicted by, parents' educational level, child's gender, and the specialty of the dentist who provided the treatment (p < 0.05). CONCLUSION: Overall parental satisfaction with their children's rapid palatal expansion treatment is significantly higher when provided by pediatric dentists as compared with orthodontists. Factors related to doctor-patient relationship and situational aspects (ie, office location and design, appointment waiting, and treatment duration) significantly impacted parental satisfaction.
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There is a great deal of excitement in higher education about the value of adaptive learning to personalize learning paths according to students' individual needs. The authors explored the impact of an Adaptive Learning Platform (ALP) on learning, by comparing learning effectiveness between dental students who used the ALP in a blended learning environment formatively and summatively compared with students who did not use the ALP (i.e., face-to-face), as measured by students' performance on the final exam in a single review preparatory course during the academic years 2013-2018. Paired t-tests showed significant improvement in post-test scores across different course instructional modalities (P < 0.01). The learning gain was greater for students who studied using the ALP summatively (t = 26.20) than those who used it formatively or studied using a face-to-face format (t = 13.10 and 14.13, respectively). Controlling for pre-test scores, analysis of covariance tests indicate that: (1) intervention groups (formative and summative ALP) scored significantly higher than the traditional group (B = 9.34 points, P < 0.01, for summative ALP group) and (B = 4.47 points, P < 0.05, for formative ALP group), and (2) summative ALP group scored significantly higher than formative ALP group (B = 4.84 points, P < 0.05). This study provides empirical evidence that an adaptive learning intervention can have a significant impact on student learning performance. The success of any adaptive learning system relies mainly on sound instructional design. Technology will continue to grow at an overwhelming pace; the cautionary note the authors highlight is that conceptions of pedagogy, complemented by technology, must guide the development of adaptive learning systems.
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Instrucción por Computador , Curriculum , Evaluación Educacional , Humanos , Aprendizaje , Estudiantes de OdontologíaRESUMEN
OBJECTIVE: To develop and compare pediatric upper airway three-dimensional normative values using the two most commonly used cone beam computed tomography (CBCT) software: Invivo5 (fixed threshold) and Dolphin 3D (interactive threshold). STUDY DESIGN: Out of 3738 CBCT scans, scans of 81 pediatric patients were utilized after applying strict exclusion criteria. The sample was grouped into two age groups (7-11 and 12-17 years). Intra-class correlation coefficient was used to test intra-rater and inter-rater reliability and showed coefficients greater than 0.9 indicating good reliability of the methods used. RESULTS: Paired t tests showed that volumetric and area measurements obtained using Dolphin 3D were significantly larger than those obtained using Invivo5 (p < 0.05). The mean minimal cross-sectional areas (MCSA) for Dolphin 3D were 151 mm2 and 177 mm2 for age groups 1 and 2, respectively. The mean MCSA values for Invivo5 for age groups 1 and 2 were 120 mm2 and 145 mm2, respectively. CONCLUSION: Pediatric upper airway volumetric, area, and linear measurements were reported after applying strict exclusion criteria including a validated sleep questionnaire. Our goal is that clinicians utilize the proposed-here normative values for screening and assist in the timely diagnosis and management of pediatric sleep apnea.
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Tomografía Computarizada de Haz Cónico , Nariz , Niño , Humanos , Reproducibilidad de los Resultados , Programas InformáticosAsunto(s)
Antirreumáticos/efectos adversos , Hidroxicloroquina/efectos adversos , Tamizaje Masivo/métodos , Enfermedades de la Retina/diagnóstico , Adulto , Antirreumáticos/administración & dosificación , Niño , Diagnóstico por Imagen/métodos , Humanos , Hidroxicloroquina/administración & dosificación , Oftalmología/normas , Guías de Práctica Clínica como Asunto , Pautas de la Práctica en Medicina , Retina/efectos de los fármacos , Enfermedades de la Retina/inducido químicamente , Medición de RiesgoRESUMEN
OBJECTIVE: To determine the prevalence and associated features of demoralization in Parkinson disease (PD). METHODS: Participants with PD and controls were prospectively recruited from outpatient movement disorder clinics and the community. Demoralization was defined as scoring positively on the Diagnostic Criteria for Psychosomatic Research, Demoralization questionnaire or Kissane Demoralization Scale score ≥24. Depression was defined as Patient Health Questionnaire-9 score ≥10. Forward stepwise logistic regression was used to determine the odds of having demoralization in the overall, control, and PD cohorts. RESULTS: Demoralization occurred in 18.1% of 94 participants with PD and 8.1% of 86 control participants (p = 0.05). These 2 groups were otherwise comparable in age, sex, education, economics, race, and marital status. Although demoralization was highly associated with depression, there were individuals with one and not the other. Among participants with PD, 7 of 19 (36.8%) depressed individuals were not demoralized, and 5 of 17 (29.4%) demoralized individuals were not depressed. In the overall cohort, having PD (odds ratio 2.60, 95% confidence interval 1.00-6.80, p = 0.051) was associated with demoralization, along with younger age and not currently being married. In the PD cohort, younger age and Unified Parkinson's Disease Rating Scale, part III score (per score 1) were associated with demoralization (odds ratio 1.06, 95% confidence interval 1.01-1.12, p = 0.02). CONCLUSIONS: Demoralization is common in PD and is associated with motor dysfunction. In demoralization, there is a prominent inability to cope, making it somewhat distinct from depression. Treatment approaches are also different, making it important to identify demoralization in patients with PD.
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Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/psicología , Anciano , Estudios Transversales , Depresión/epidemiología , Femenino , Humanos , Masculino , Salud Mental , Prevalencia , Estudios Prospectivos , AutoimagenRESUMEN
Restless legs syndrome (RLS) is a common, chronic neurologic condition, which causes a persistent urge to move the legs in the evening that interferes with sleep. Human and animal studies have been used to study the pathophysiologic state of RLS and much has been learned about the iron and dopamine systems in relation to RLS. Human neuropathologic and imaging studies have consistently shown decreased iron in different brain regions including substantia nigra and thalamus. These same areas also demonstrate a state of relative dopamine excess. While it is not known how these changes in dopamine or iron produce the symptoms of RLS, genetic and hormone studies of RLS have identified other biologic systems or genes, such as the endogenous opioid and melanocortin systems and BTBD9 and MEIS1, that may explain some of the iron or dopamine changes in relation to RLS. This manuscript will review what is known about the pathophysiology of RLS, especially as it relates to changes in iron, dopamine, genetics, and hormonal systems.
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Dopamina/metabolismo , Hormonas/metabolismo , Hierro/metabolismo , Síndrome de las Piernas Inquietas/genética , Síndrome de las Piernas Inquietas/fisiopatología , Animales , Humanos , Síndrome de las Piernas Inquietas/tratamiento farmacológicoRESUMEN
Assessment of the network of toxicity pathways by Omics technologies and bioinformatic data processing paves the road toward a new toxicology for the twenty-first century. Especially, the upstream network of responses, taking place in toxicant-treated cells before a point of no return is reached, is still little explored. We studied the effects of the model neurotoxicant 1-methyl-4-phenylpyridinium (MPP(+)) by a combined metabolomics (mass spectrometry) and transcriptomics (microarrays and deep sequencing) approach to provide unbiased data on earliest cellular adaptations to stress. Neural precursor cells (LUHMES) were differentiated to homogeneous cultures of fully postmitotic human dopaminergic neurons, and then exposed to the mitochondrial respiratory chain inhibitor MPP(+) (5 µM). At 18-24 h after treatment, intracellular ATP and mitochondrial integrity were still close to control levels, but pronounced transcriptome and metabolome changes were seen. Data on altered glucose flux, depletion of phosphocreatine and oxidative stress (e.g., methionine sulfoxide formation) confirmed the validity of the approach. New findings were related to nuclear paraspeckle depletion, as well as an early activation of branches of the transsulfuration pathway to increase glutathione. Bioinformatic analysis of our data identified the transcription factor ATF-4 as an upstream regulator of early responses. Findings on this signaling pathway and on adaptive increases of glutathione production were confirmed biochemically. Metabolic and transcriptional profiling contributed complementary information on multiple primary and secondary changes that contribute to the cellular response to MPP(+). Thus, combined 'Omics' analysis is a new unbiased approach to unravel earliest metabolic changes, whose balance decides on the final cell fate.
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1-Metil-4-fenilpiridinio/toxicidad , Neuronas Dopaminérgicas/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Células-Madre Neurales/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Transcripción Genética/efectos de los fármacos , Factor de Transcripción Activador 4/genética , Factor de Transcripción Activador 4/metabolismo , Adaptación Fisiológica , Adenosina Trifosfato/metabolismo , Línea Celular , Biología Computacional , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica , Glucosa/metabolismo , Glutatión/metabolismo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Espectrometría de Masas , Metabolómica/métodos , Mitocondrias/metabolismo , Mitocondrias/patología , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Síndromes de Neurotoxicidad/genética , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Fosfocreatina/metabolismo , Interferencia de ARN , Factores de Tiempo , TransfecciónRESUMEN
OBJECTIVE: To determine the incidence and pattern of thyroid dysfunction (TD) in patients on chronic amiodarone therapy. METHODS: A retrospective study which evaluated 59 patients who had received amiodarone therapy regularly for at least 12 months from a period of 3 years from October 2007 to October 2010. The patients were followed-up at the cardiac clinic at Sultan Qaboos University Hospital, Muscat, Oman. RESULTS: The mean age of the cohort was 63 ± 13 years ranging from 27 to 98 years. Fifty-one percent (n = 30) of the patients were female. There were 11 (19%) cases of thyroid dysfunction (TD). Seven (12%) patients were hypothyroid, 3 (5%) had hyperthyroidism and 1 (2%) patient had sub-clinical hypothyroidism; no cases of sub-clinical hyperthyroidism were noted. Female gender and presence of anti-thyroid peroxidase antibodies were significantly associated with amiodarone-induced hypothyroidism (p = 0.001) while age, amiodarone dose and duration of therapy were not correlated with the development of TD (all p-values > 0.05). CONCLUSION: Amiodarone-induced thyroid dysfunction is prevalent. Hypothyroidism was more frequent and seen more in female patients and those who had positive anti-thyroid peroxidase antibodies. Initial screening and periodic monitoring of thyroid function is mandatory for all patients on amiodarone therapy.
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Over the coming decades, new energy production technologies and the policies that oversee them will affect human health, the vitality of our ecosystems, and the stability of the global climate. The GLIMPSE decision model framework provides insights about the implications of technology and policy decisions on these outcomes. Using GLIMPSE, decision makers can identify alternative techno-policy futures, examining their air quality, health, and short- and long-term climate impacts. Ultimately, GLIMPSE will support the identification of cost-effective strategies for simultaneously achieving performance goals for these metrics. Here, we demonstrate the utility of GLIMPSE by analyzing several future energy scenarios under existing air quality regulations and potential CO2 emission reduction policies. We find opportunities for substantial cobenefits in setting both climate change mitigation and health-benefit based air quality improvement targets. Though current policies which prioritize public health protection increase near-term warming, establishing policies that also reduce greenhouse gas emissions may offset warming in the near-term and lead to significant reductions in long-term warming.
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Fuentes Generadoras de Energía , Política Ambiental , Modelos Teóricos , Salud Pública , Aire , Dióxido de Carbono , Clima , Cambio Climático , Toma de Decisiones en la Organización , Ecosistema , Humanos , Estados UnidosRESUMEN
Acylation stimulating protein (ASP) is a potent lipogenic factor produced from adipocytes. Plasma ASP levels were shown to increase in obesity, diabetes mellitus type II and dyslipidemia, and decrease after weight loss and fasting. Growing evidence suggests that ASP may significantly contribute to subcutaneous fat storage in females. In vitro, ASP stimulated triglyceride synthesis to a larger extent in subcutaneous compared with omental adipocytes. The ASP receptor binding affinity to plasma membranes prepared from adipose tissue showed higher binding affinity to plasma membranes from female adipose tissue compared with male adipose tissue, and was more pronounced to subcutaneous compared with omental plasma membranes. Human studies demonstrated that postprandial triglyceride clearance predicted by ASP levels was more efficient in women than in men. In mice, postprandial triglyceride clearance, with intraperitoneal ASP administration, was faster in females compared with males. The ASP deficient mice were resistant to weight gain and had reduced fat mass that was more pronounced in females. Recent findings in humans and mice point to a significant association between progesterone and ASP variations in females. In this review, we highlight findings, to date, linking ASP to physiological and hormonal alterations that may contribute to subcutaneous fat distribution typical to females.
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Péptidos y Proteínas de Señalización Intercelular/sangre , Lipogénesis , Acilación , Adipocitos/metabolismo , Animales , Complemento C3 , Femenino , Hormonas Esteroides Gonadales/metabolismo , Humanos , Masculino , Ratones , Periodo Posprandial , Factores Sexuales , Grasa Subcutánea Abdominal/metabolismo , Triglicéridos/sangre , Aumento de PesoRESUMEN
AIMS/HYPOTHESIS: We assessed whether per-arnt-sim (PAS) domain-containing protein kinase (PASK) is involved in the regulation of glucagon secretion. METHODS: mRNA levels were measured in islets by quantitative PCR and in pancreatic beta cells obtained by laser capture microdissection. Glucose tolerance, plasma hormone levels and islet hormone secretion were analysed in C57BL/6 Pask homozygote knockout mice (Pask-/-) and control littermates. Alpha-TC1-9 cells, human islets or cultured E13.5 rat pancreatic epithelia were transduced with anti-Pask or control small interfering RNAs, or with adenoviruses encoding enhanced green fluorescent protein or PASK. RESULTS: PASK expression was significantly lower in islets from human type 2 diabetic than control participants. PASK mRNA was present in alpha and beta cells from mouse islets. In Pask-/- mice, fasted blood glucose and plasma glucagon levels were 25 ± 5% and 50 ± 8% (mean ± SE) higher, respectively, than in control mice. At inhibitory glucose concentrations (10 mmol/l), islets from Pask-/- mice secreted 2.04 ± 0.2-fold (p < 0.01) more glucagon and 2.63 ± 0.3-fold (p < 0.01) less insulin than wild-type islets. Glucose failed to inhibit glucagon secretion from PASK-depleted alpha-TC1-9 cells, whereas PASK overexpression inhibited glucagon secretion from these cells and human islets. Extracellular insulin (20 nmol/l) inhibited glucagon secretion from control and PASK-deficient alpha-TC1-9 cells. PASK-depleted alpha-TC1-9 cells and pancreatic embryonic explants displayed increased expression of the preproglucagon (Gcg) and AMP-activated protein kinase (AMPK)-alpha2 (Prkaa2) genes, implying a possible role for AMPK-alpha2 downstream of PASK in the control of glucagon gene expression and release. CONCLUSIONS/INTERPRETATION: PASK is involved in the regulation of glucagon secretion by glucose and may be a useful target for the treatment of type 2 diabetes.
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Diabetes Mellitus Tipo 2/enzimología , Islotes Pancreáticos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Línea Celular , Células Cultivadas , Diabetes Mellitus Tipo 2/metabolismo , Glucagón/metabolismo , Células Secretoras de Glucagón/efectos de los fármacos , Células Secretoras de Glucagón/metabolismo , Glucosa/farmacología , Humanos , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Islotes Pancreáticos/efectos de los fármacos , Ratones , Ratones Mutantes , Modelos Biológicos , Reacción en Cadena de la Polimerasa , Proteínas Serina-Treonina Quinasas/genética , RatasRESUMEN
Glutamate transporter associated protein 3-18 (GTRAP3-18) is an endoplasmic reticulum (ER)-localized protein belonging to the prenylated rab-acceptor-family interacting with small Rab GTPases, which regulate intracellular trafficking events. Its impact on secretory trafficking has not been investigated. We report here that GTRAP3-18 has an inhibitory effect on Rab1, which is involved in ER-to-Golg trafficking. The effects on the early secretory pathway in HEK293 cells were: reduction of the rate of ER-to-Golgi transport of the vesicular stomatitis virus glycoprotein (VSVG), slowed accumulation of a Golgi marker plasmid in pre-Golgi structures after Brefeldin A treatment and inhibition of cargo concentration of the neuronal glutamate transporter excitatory amino-acid carrier 1 (EAAC1) into transpor complexes in HEK293 cells, an effect that could be completely reversed in the presence of an excess of Rab1. In accordance with the known role of Rab1 in neurite formation, overexpression of GTRAP3-18 significantly inhibited the length of outgrowing neurites in differentiated CAD cells. The inhibitory effect of GTRAP3-18 on neurite growth was rescued by co-expression with Rab1, supporting the conclusion that GTRAP 3-18 acted by inhibiting Rab1 action. Finally, we hypothesized that expression of GTRAP3-18 in the brain shoul be lower at stages of active synaptogenesis compared to early developmental stages. This was the case as expression of GTRAP3-18 declined from E17 to P0 and adult rat brains. Thus, we propose a model where protein trafficking and neuronal differentiation are directly linked by the interaction of Rab1 and its regulator GTRAP3-18.
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Proteínas Portadoras/metabolismo , Diferenciación Celular/fisiología , Neuronas/fisiología , Transporte de Proteínas/fisiología , Proteínas de Unión al GTP rab1/metabolismo , Animales , Biomarcadores/metabolismo , Brefeldino A/metabolismo , Proteínas Portadoras/genética , Línea Celular , Retículo Endoplásmico/metabolismo , Aparato de Golgi/metabolismo , Humanos , Neuronas/citología , Inhibidores de la Síntesis de la Proteína/metabolismo , Interferencia de ARN , Ratas , Ratas Sprague-Dawley , Proteínas de Unión al GTP rab1/genéticaRESUMEN
As the ear has dual functions for audition and balance, the eye has a dual role in detecting light for a wide range of behavioral and physiological functions separate from sight. These responses are driven primarily by stimulation of photosensitive retinal ganglion cells (pRGCs) that are most sensitive to short-wavelength ( approximately 480 nm) blue light and remain functional in the absence of rods and cones. We examined the spectral sensitivity of non-image-forming responses in two profoundly blind subjects lacking functional rods and cones (one male, 56 yr old; one female, 87 yr old). In the male subject, we found that short-wavelength light preferentially suppressed melatonin, reset the circadian pacemaker, and directly enhanced alertness compared to 555 nm exposure, which is the peak sensitivity of the photopic visual system. In an action spectrum for pupillary constriction, the female subject exhibited a peak spectral sensitivity (lambda(max)) of 480 nm, matching that of the pRGCs but not that of the rods and cones. This subject was also able to correctly report a threshold short-wavelength stimulus ( approximately 480 nm) but not other wavelengths. Collectively these data show that pRGCs contribute to both circadian physiology and rudimentary visual awareness in humans and challenge the assumption that rod- and cone-based photoreception mediate all "visual" responses to light.