Rural-urban differences in social and emotional protective factors and their association with child health and flourishing.

BACKGROUND: Children in rural communities experience higher mortality rates and less access to health care services than those in urban communities. Protective factors like social support also vary by geography, but their contribution to differences in child health is understudied. Understanding geographic variation in protective health factors could provide insight into their impact on health and guide future intervention strategies. RESEARCH OBJECTIVE: To examine protective factors' association with child flourishing and child health status in rural and urban communities. METHODS: Publicly available data from the National Survey of Children's Health, 2018-2021, with nonmissing geographic data (N = 150,493) were used to assess the relationship between protective factors and child flourishing and health by rurality. Multivariate survey-weighted probit models examined these relationships, adjusting for child and caregiver characteristics. FINDINGS: More than a third of children were not flourishing, according to parental report. An estimated 62% of rural children were flourishing compared to 66% of urban children (P<0.001). Urban caregivers also were more likely to report better adult mental and physical health status. Nevertheless, rural children were reported to receive more social support than urban children, while their caregivers reported more emotional support and living in supportive and safe neighborhoods (P<0.001). Rural caregivers reported more support from places of worship and less from counselors/other mental health care providers than urban caregivers. CONCLUSIONS: Despite higher reported caregiver emotional support and child social support, fewer rural children are flourishing. Health systems and community organizations able to leverage these existing social and emotional protective factors in rural communities could help close this gap.

Does ethnic-racial socialization matter? A within-person analysis of racial discrimination and sleep health among Black and Latinx emerging adults.

OBJECTIVES: Emerging work suggests that racism-related stressors may contribute to adverse sleep health, yet little is known about how culturally relevant resources may influence the relationship between racism-related stressors and adverse sleep health. The aim of this study was to examine associations between weekly reports of racial hassles and young adults' sleep health (i.e., sleep onset latency, total sleep time, sleep quality) and to determine whether various forms of parental ethnic-racial socialization would moderate these associations. METHODS: Participants were 141 college students (Mage = 20.7 years, standard deviation (SD) = 1.22, 70% female) who identified as either Black (n = 88; 62.4%) or Latinx (n = 53; 37.6%). Participants completed an initial 1.5-hour assessment in the laboratory and 4 weekly sleep diary surveys (assessed sleep health and depressive symptoms). RESULTS: Weekly racial hassles are related to greater sleep onset latency, decreased total sleep time, and poorer sleep quality. The promotion of mistrust and cultural socialization significantly moderated associations between weekly racial hassles and sleep onset latency and total sleep time, respectively. CONCLUSIONS: These results provide supportive evidence that parental ethnic-racial socialization practices, a preemptive cultural resource, may be an understudied mechanism in sleep health research. Future research is needed to clarify the role of parental ethnic-racial socialization in promoting sleep health equity among youth and young adults.

Social Needs as a Risk Factor for Positive Postpartum Depression Screens in Pediatric Primary Care.

OBJECTIVE: The goal of this study was to examine the association between self-reported social needs and postpartum depression (PPD) symptoms of mothers screened in pediatric primary care clinics. METHODS: This retrospective cohort study used electronic health record data from 3616 pediatric patients (age 0-6 months), whose mothers completed the Edinburgh Postpartum Depression Scale (EPDS) and a social needs screening in a large pediatric primary care network between April 2021 and February 2022. Mothers were screened for four self-reported social needs (food, housing, transportation, and utilities). Logistic regression evaluated the association between the report of any social need and a positive EPDS screen (≥ 10), adjusting for demographic and clinical characteristics and ZIP code-level poverty. RESULTS: Overall, 8.6% of mothers screened positive for PPD and 10.0% reported any social needs. The odds of a positive depression screen were significantly higher among mothers who reported any social need compared to those not reporting a social need (OR 4.18, 95% CI 3.11-5.61). The prevalence of all depressive symptoms on the EPDS was significantly higher among those who reported any social need, relative to those reporting no needs. Mothers reporting any social needs were significantly more likely to report thoughts of self-harm (6.9% vs 1.5%, P < .005). CONCLUSIONS: Self-report of social need was significantly associated with positive PPD screens during infant well-child visits. Social needs may be a target of future interventions addressing PPD in pediatric settings. Improving care for social needs may have added benefit of alleviating the risk of PPD.

An Initial Development and Evaluation of a Culturally Responsive Police Interactions Training for Black Adolescents with Autism Spectrum Disorder.

The purpose of the current study was to conduct a qualitative and experimental analysis of a culturally informed police safety skills training for adolescents with autism spectrum disorder (ASD). The current study focused primarily on meeting the unique training needs of Black adolescents with autism spectrum disorder (ASD). A single case design was used to evaluate the initial efficacy and acceptability of a culturally responsive training method. Preliminary evidence about the physiological ramifications of police contact were also collected to begin to examine the broader behavioral and psychophysiological nature of youth's experiences. The current experimental design included in-person simulated contexts that youth, and caregivers, endorsed as relevant to their normal lives, which greatly strengthened the ecological validity of the approach.

Using Telehealth to Deliver Family-Based Cognitive Behavioral Treatment of Insomnia in a School-Aged Child With Autism Spectrum Disorder.

Chronic insomnia (>3 months) is common in children with autism. Cognitive behavioral treatment for insomnia in children (CBT-CI) holds promise for improving sleep and daytime functioning in school-aged children with autism and their parents, but typical delivery involving multiple in-person office visits limits accessibility. This case study describes telehealth delivery of CBT-CI (teleCBT-CI) with a 7-year 4-month-old biracial boy with autism spectrum disorder (ASD) and insomnia and his parents. He and his mother wore actigraphs and completed electronic sleep diaries for 2 weeks, and his mother completed the Aberrant Behavior Checklist at pre/post/1-month follow-up. He and both of his parents completed eight telehealth treatment sessions. TeleCBT-CI improved the boy's sleep (objective, subjective) and decreased irritability, lethargy, stereotypy, and hyperactivity. This case study shows that teleCBT-CI is feasible and can improve child sleep and functioning.

Within-person associations between racial microaggressions and sleep among African American and Latinx young adults.

Emerging work suggests that experiences of racial discrimination may impact overall sleep health; however, there is limited work on the link between racial microaggressions and sleep. Using weekly diary data, the current study examined young adults' weekly reports of racial microaggressions across 4 weeks, and their relation to weekly reports of sleep-onset latency, reduced total sleep time and poorer sleep quality. This design allowed us to examine how within-person fluctuations in racial microaggressions corresponded with young adults' sleep. Data were collected among 140 African American (62.1%) and Latinx (37.9%) college students attending a Midwestern University. Students were randomly selected to participate; they were, on average, 20.70 years old (SD = 1.22) and the majority were female (69.3%). Participants self-reported their racial microaggressions and sleep behaviours (i.e. sleep-onset latency, total sleep time and sleep quality) each week (across 4 weeks). Multilevel modelling showed significant within-person effects of racial microaggressions for sleep onset and sleep quality, but not for total sleep duration. Specifically, on weeks that individuals reported increases in racial microaggressions, they reported greater sleep-onset duration and poorer sleep quality. The current findings provide preliminary evidence that racial microaggressions are associated with sleep-onset durations and sleep quality among African American and Latinx young adults. Although racial microaggressions are often considered subtle, they may impact the sleep health of young adults in marginalized groups.

Lipoprotein-associated phospholipase A2 activity is increased in patients with definite familial hypercholesterolemia compared with other forms of hypercholesterolemia.

BACKGROUND AND AIM: Lipoprotein-associated phospholipase A2 (Lp-PLA2) plays a key role in atherosclerosis development. It is considered a marker of increased risk of cardiovascular disease (CVD) and plaque vulnerability. Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated plasma levels of low-density lipoprotein cholesterol and a higher prevalence of early CVD. Our aim was to evaluate the differences in Lp-PLA2 activity in a population of hypercholesterolemic patients with and without definite FH. METHODS AND RESULTS: Hypercholesterolemic patients were consecutively recruited. Definite FH was defined according to Dutch Lipid Clinic Network criteria ≥8. All patients underwent routine clinical examination and biological assessments and Lp-PLA2 activity was measured in blood samples. Among 469 patients, 118 had a definite diagnosis of FH. Lp-PLA2 activity was significantly higher in definite FH patients compared to non-definite FH patients (206.5 ± 54.5 vs. 180.8 ± 48.4 nmol/min/mL, p < 0.0001). Lp-PLA2 positively correlated with total cholesterol, LDL-C and apolipoprotein B and negatively with HDL-C and apolipoprotein A-1. In multivariate analysis, definite FH diagnosis, LDL-C, HDL-C and statin treatment remained correlates of Lp-PLA2 independently of systolic blood pressure. CONCLUSIONS: Lp-PLA2 activity was higher in definite FH than in non-definite FH patients independently of LDL-C levels and statin treatment. These results highlight the particular phenotype of FH subjects among hypercholesterolemic patients. As increased Lp-PLA2 activity suggests, FH patients exhibit higher arterial inflammation that may contribute to their high cardiovascular risk. Our results reinforce the potential beneficial role of statins pleiotropic effects and the need for proper identification and treatment of FH patients.

Retinal arteriolar remodeling evaluated with adaptive optics camera: Relationship with blood pressure levels.

AIM: To research a retinal arterioles wall-to-lumen ratio or lumen diameter cut-off that would discriminate hypertensive from normal subjects using adaptive optics camera. PATIENTS AND METHODS: One thousand and five hundred subjects were consecutively recruited and Adaptive Optics Camera rtx1™ (Imagine-Eyes, Orsay, France) was used to measure wall thickness, internal diameter, to calculate wall-to-lumen ratio (WLR) and wall cross-sectional area of retinal arterioles. Sitting office blood pressure was measured once, just before retinal measurements and office blood pressure was defined as systolic blood pressure>=140mmHg and diastolic blood pressure>=90mmHg. ROC curves were constructed to determine cut-off values for retinal parameters to diagnose office hypertension. In another population of 276 subjects office BP, retinal arterioles evaluation and home blood pressure monitoring were obtained. The applicability of retinal WLR or diameter cut-off values were compared in patients with controlled, masked, white-coat and sustained hypertension. RESULTS: In 1500 patients, a WLR>0.31 discriminated office hypertensive subjects with a 0.57 sensitivity and 0.71 specificity. Lumen diameter<78.2µm discriminated office hypertension with a 0.73 sensitivity and a 0.52 specificity. In the other 276 patients, WLR was higher in sustained hypertension vs normotensive patients (0.330±0.06 vs 0.292±0.05; P<0.001) and diameter was narrower in masked hypertensive vs normotensive subjects (73.0±11.2 vs 78.5±11.6µm; P<0.005). CONCLUSION: A WLR higher than 0.31 is in favour of office arterial hypertension; a diameter under<78µm may indicate a masked hypertension. Retinal arterioles analysis through adaptive optics camera may help the diagnosis of arterial hypertension, in particular in case of masked hypertension.

Association of dietary patterns with insulin resistance and clinically silent carotid atherosclerosis in apparently healthy people.

BACKGROUND/OBJECTIVES: Dietary habits are important determinants of individual cardiovascular and metabolic risk. This study investigated the association between dietary patterns and asymptomatic carotid atherosclerosis, defined as the presence of plaques and/or increased intima-media thickness, and metabolic biomarkers of insulin resistance, including the homeostasis model assessment of insulin resistance (HOMA-IR) and the trygliceride/high-density lipoprotein (HDL)-cholesterol (Tg/HDL) ratio in a cohort of adults without known diabetes or atherosclerotic cardiovascular disease. SUBJECTS/METHODS: Nine hundred and twenty-nine randomly selected participants were cross-sectionally investigated. Each participant answered a food frequency questionnaire, and underwent high-resolution ultrasonographic evaluation of both carotid arteries. Laboratory blood measurements were obtained in a subsample of 507 participants. RESULTS: A dietary pattern that could be defined as unhealthy (high consumption of soft drinks, fried foods, seed oils, cured meats, butter, red meat and sweets) was identified in 21% of the cohort, whereas 34% of the cohort exhibited a dietary pattern that resembled the Mediterranean diet (high intakes of fruit, milk and cheese, olive oil, vegetables, pasta and bread). Intermediate habits characterized the remaining 45%. After adjusting for age, body mass index (BMI), waist circumference, glycated hemoglobin (HbA1c) and hypertension on treatment, the Mediterranean dietary pattern was associated with significantly lower HOMA-IR (ß-coefficient=-0.51; P=0.003). After adjusting for gender, BMI and HbA1c, the unhealthy dietary pattern was associated with a significantly higher Tg/HDL-cholesterol ratio (ß-coefficient=0.43; P=0.006). No significant association was found between dietary patterns and carotid atherosclerosis. CONCLUSIONS: This study suggests that, independent of measures of adiposity, a Mediterranean dietary pattern is associated with lower insulin resistance.

Influence of a new bicycle crank design on aerobic parameters of non-cyclists.

AIM: A well known problem in conventional cycling crank systems is the pedalling dead spot when the crank arms are in vertical position. The pedalling dead spot mitigates the power output during the propulsion phase of pedalling. The aim of this study was to verify the effects of a new design of crank system on aerobic parameters of performance in healthy non-cyclists. The mechanical concept of the new system is based on the theory that crank arms should never be perpendicularly aligned to the ground at dead spot. METHODS: The maximal aerobic capacity (VO2 max) and different parameters of cycling efficiency were measured in 14 (mean±SD of age: 26±5) non-obese (body mass index: 26.0±3.0 kg/m2) healthy men in two different occasions at intervals of 2 days using alternately and in randomized order both the traditional crank system and the system without dead spot respectively. RESULTS: The workload performed was significantly higher with the new crank system as suggested by the higher exercise duration (12.89 ±2.36 vs. 13.33±2.30 min; P=0.032). CONCLUSION: The favourable results obtained in this study using the new chainring may be in consequence of a more efficient biomechanics of pedalling that does not reflect changes in O2 consumption and CO2 produced. However, it is not possible to exclude that involuntary motivational factors may have induced the difference in the time test since it was not possible to blind subjects about the two crank systems. Further investigations are necessary to confirm the results of this exploratory study and give a more exhaustive explanation about the mechanisms that allow the possible better performance with this new chainring system.

Glycaemic variability using continuous glucose monitoring and endothelial function in the metabolic syndrome and in Type 2 diabetes.

AIMS: Subjects who are at increased risk of developing diabetes may have increased glycaemic variability associated with endothelial dysfunction and possibly subclinical atherosclerosis, which may lead to increased cardiovascular risk observed at the time of diabetes diagnosis. To investigate this hypothesis, we measured endothelial function, carotid intima-media thickness and glycaemic variability using 48-h continuous subcutaneous glucose monitoring in 3 groups of overweight or obese subjects--those without the metabolic syndrome, and those with the metabolic syndrome with or without newly diagnosed Type 2 diabetes. METHODS: Consecutive subjects, aged 30-65 years with a body mass index >or= 25 kg/m(2) were recruited. Patients were classified as with or without the metabolic syndrome,or as metabolic syndrome with newly diagnosed Type 2 DM. Glycaemic variability was calculated in terms of the coefficient of variation. Endothelial function was measured using brachial artery flow-mediated dilation. RESULTS: We identified 75 subjects. Mean flow mediated dilation decreased (P < 0.001) and carotid intima-media thickness increased (P < 0.05) across groups. Flow mediated dilation predictors included mean 48-h continuous subcutaneous glucose monitoring values (beta = -0.022; P < 0.005) and the coefficient of variation (beta = -0.10; P = 0.01). Carotid intima-media thickness predictors included age (beta = 0.009; P < 0.001) and flow mediated dilation (beta = -0.014; P = 0.076). Patients re-stratified according to cut-offs for mean 48-h glycaemia and variability demonstrated that subjects with high mean glycaemia but low coefficient of variability had similar flow mediated dilation and carotid intima-media thickness to subjects with low mean glycaemia but high coefficient of variation. CONCLUSIONS: This study suggests that glycaemic variability influences endothelial function even in non-diabetic subjects. Such variability may explain the increased cardiovascular risk observed in patients prior to developing overt Type 2 diabetes.

Acute effects of coffee on endothelial function in healthy subjects.

BACKGROUND/OBJECTIVES: Coffee is the most widely consumed beverage in the world, but its effect on the cardiovascular system has not been fully understood. Coffee contains caffeine and antioxidants, which may influence endothelial function, both of which have not yet been investigated. The objective of this study was to investigate the acute effects of coffee on endothelial function measured by brachial artery flow-mediated dilation (FMD). SUBJECTS/METHODS: A total of 20 (10 males and 10 females) healthy non-obese subjects underwent a double-blind, crossover study. Subjects ingested one cup of caffeinated (CC) and one cup of decaffeinated (DC) Italian espresso coffee in random order at 5- to 7-day intervals. RESULTS: Following CC ingestion, FMD decreased progressively and significantly (mean+/-s.e.m.: 0 min, 7.7+/-0.6; 30 min, 6.3+/-0.7; 60 min, 6.0+/-0.8%; ANOVA (analysis of variance), P<0.05), but it did not significantly increase after DC ingestion (0 min, 6.9+/-0.6; 30 min, 8.1+/-0.9; 60 min, 8.5+/-0.9%; P=0.115). Similarly, CC significantly increased both systolic and diastolic blood pressure; this effect was not observed after DC ingestion. Blood glucose concentrations remained unchanged after ingestion of both CC and DC, but insulin (0 min, 15.8+/-0.9; 60 min, 15.0+/-0.8 muU/ml; P<0.05) and C-peptide (0 min, 1.25+/-0.09; 60 min, 1.18+/-0.09 ng/ml; P<0.01) blood concentrations decreased significantly only after CC ingestion. CONCLUSIONS: CC acutely induced unfavorable cardiovascular effects, especially on endothelial function. In the fasting state, insulin secretion is also likely reduced after CC ingestion. Future studies will determine whether CC has detrimental clinically relevant effects, especially in unhealthy subjects.

Dose-dependent effects of decaffeinated coffee on endothelial function in healthy subjects.

BACKGROUND/OBJECTIVES: Coffee is known to contain antioxidant substances whose effects may be blunted because of caffeine that may unfavorably affect the cardiovascular system. This study was designed to investigate the acute dose-dependent effects of decaffeinated coffee (DC) on endothelial function measured by the brachial artery flow-mediated dilation (FMD). SUBJECTS/METHODS: A total of 15 (8 men and 7 women) healthy nonobese subjects underwent a single-blind, crossover study. Subjects ingested one and two cups of decaffeinated Italian espresso coffee in random order at 5- to 7-day intervals. RESULTS: In the hour following the ingestion of two cups of DC, FMD increased (mean+/-s.e.m.): 0 min, 7.4+/-0.7%; 30 min, 8.0+/-0.6%; 60 min, 10.8+/-0.8%; P<0.001) as compared to consumption of one cup of DC (0 min, 6.9+/-0.7%; 30 min, 8.4+/-1.2%; 60 min, 8.5+/-1.1%; 3 x 2 repeated-measures analysis of variance: P=0.037 for time x treatment effect). Blood pressure did not differ between groups, and basal heart rate was lower in the two-cup group at baseline and 60 min. CONCLUSIONS: The present study demonstrated a significant acute favorable dose-dependent effect of decaffeinated espresso coffee on endothelial function. Further studies are needed to investigate the effects of chronic use of DC especially with respect to caffeinated coffee and in subjects with cardiovascular diseases.

A low reported energy intake is associated with metabolic syndrome.

BACKGROUND AND AIMS: Metabolic syndrome (MS) may be associated with the presence of an energy-sparing metabolism that predisposes to the excess accumulation of body fat. This study examined the relationship between reported energy intake and obesity in individuals with and without MS. METHODS AND RESULTS: Ninety consecutive non-diabetic obese subjects were divided into 2 groups based on the presence (MS+: no.=50) or absence (MS-: no.=40) of MS. The study design was cross-sectional. The 3-day food record method was used to assess the subjects' usual energy intake and the Diet Readiness Test (DRT) was also administered. Compared to the MS- group, the MS+ group had a significantly higher body weight, body mass index (mean+/-SEM: 39.1+/-1.3 vs 31.5+/-0.9, p<0.001) and fat mass. The absolute energy intake of the MS+ group (8629+/-331 kJ/24h) did not differ from that of the MS- group (8571+/-515 kJ/24h; p=ns). The daily energy intake normalized for the fat-free mass (FFM) size was higher in the MS- group (163+/-8 kJ/kg-FFM x 24h) than in the MS+ group (138+/-4 kJ/kg-FFM x 24h; p<0.03). The DRT test results were similar in both groups except that section 6 (exercise patterns and attitudes) score was lower in the MS+ group (10.0+/-0.5) than in the MS- group (11.9+/-0.5; p<0.01). CONCLUSION: The results of this study support the hypothesis that subjects with MS have an energy-sparing metabolism.

Metabolic parameters and adipokine profile during GH replacement therapy in children with GH deficiency.

OBJECTIVE: GH replacement therapy in children with GH deficiency (GHD) mainly promotes linear growth. Not only have very few studies fully analyzed the metabolic consequences of GH therapy, but also the question as to whether GH may affect adipokine secretion has been insufficiently investigated. Our aim was to study the effects of GH replacement therapy on auxological data, lipid and glycemic profiles, insulin homeostasis (HOMA-IR) and serum adipokines in children. METHODS: This was a 1-year prospective study. Thirty-four GHD children (11.6 +/- 2.6 years) and thirty healthy matched controls were enrolled. Children affected by GHD were studied both before beginning continuous GH replacement therapy and again at 12 months. RESULTS: At the beginning of the study, total and LDL cholesterol were higher in GHD children than in controls (P<0.001), whereas HDL cholesterol, triglycerides, insulin, HOMA-IR, leptin, and adiponectin were similar. At 12 months of continuous GH replacement therapy in the GHD group, there was a significant increase in both auxological data and IGF-I (P<0.001); total cholesterol (P<0.001), LDL (P<0.001), triglycerides (P<0.005), and leptin (P<0.001) decreased significantly; HDL (P<0.003), insulin (P<0.001), HOMA-IR (P<0.001) increased while adiponectin was unmodified. Furthermore, IGF-IDelta showed an inverse correlation with leptin Delta (rho = -0.398, P = 0.02). CONCLUSIONS: In GHD children, the evaluation of metabolic parameters proves to be a useful tool for the evaluation of auxological parameters during GH replacement therapy. In our study, GH replacement therapy in GHD children improved final height, restored IGF-I levels, reduced leptin levels, and improved the lipid profile, without producing any unfavorable effects on glucose metabolism.

CD4(+)IL-13(+) cells in peripheral blood well correlates with the severity of atopic dermatitis in children.

BACKGROUND: In atopic dermatitis (AD) a Th1/Th2 imbalance has been reported, and interleukin (IL)-13 seems to play a pivotal role in the inflammatory network. We tried to assess the correlation between the immunological marker CD4(+)IL-13(+) and the clinical phase of extrinsic AD in children. METHODS: Twenty children with AD were studied. Assessed parameters were: clinical severity (SCORAD index), total serum immunoglobulin E (IgE), blood eosinophil count, and percentage of CD4(+)IFNgamma(+), CD4(+)IL-4(+), CD4(+)IL-13(+) T cells. Determinations were carried out in the acute phase and after clinical remission were achieved. Ten nonatopic-matched children served as controls. RESULTS: At baseline, AD was mild in 25%, moderate in 50% and severe in 25% of children. In the acute phase a significant relationship between the eosinophil count and the SCORAD index was found (P = 0.0001). Blood CD4(+)IL-4(+) were significantly higher in the AD group (median 17.0, range: 13.7-21.4) than in controls (12.6, 6.4-17.2, P < 0.0001). CD4(+)IL-13(+) cells in the AD group well correlated (P = 0.0007) with SCORAD index. At remission, a significant correlation between SCORAD index and eosinophil count was found (P < 0.03) and the percentage of CD4(+)IL-13(+) cells globally decreased (P < 0.0001), while no difference was found among SCORAD classes. CONCLUSION: This study confirms the Th2 profile predominance in the peripheral blood of children with AD, and evidences close relationship between the number of CD4(+)IL-13(+) T cells and the disease's severity.

Up-regulation of c-FLIPshort and reduction of activation-induced cell death in T-cells from patients with Type 1 diabetes.

AICD of T-cells is an efficient way of removing activated T-lymphocytes. In this study we investigated the molecular basis of AICD upon reactivation in peripheral T-lymphocytes from newly diagnosed T1DM patients and age-matched healthy controls. In an in vitro model system, PHA-stimulated T-cells, upon prolonged culture in IL-2, acquire a sensitive phenotype to Fas-mediated apoptosis. This phenomenon is less pronounced in T1DM T-cells. Moreover, the restimulation of activated T-cells via TCR/CD3 and/or via CD28 inhibits Fas-mediated apoptosis in T1DM in comparison to control T-cells. After Fas triggering, the generation of the active sub-units of caspase-8 is significantly reduced in T1DM T-cells restimulated via TCR/CD3 and/or CD28. In parallel, we found that the amount of c-FLIPshort protein is significantly increased in the DISC only in T1DM T-cells restimulated via TCR/CD3 and via CD28. These data suggest that increased levels of c-FLIPshort may prevent recruitment of pro-caspase-8 in T1DM CD3-treated T-cells and provide new insight into the molecular mechanisms of apoptosis resistance in stimulated T-cells from T1DM patients.

Differential regulation of Fas-mediated apoptosis in both thyrocyte and lymphocyte cellular compartments correlates with opposite phenotypic manifestations of autoimmune thyroid disease.

Several mechanisms are probably involved in determining the evolution of autoimmune thyroid disease (AITD) towards either hypothyroidism and the clinical syndrome known as Hashimoto's thyroiditis (HT) or toward hyperthyroidism and the symptoms of Graves' disease (GD). To gain further insight into such mechanisms we performed an exhaustive comparative analysis of the expression of key molecules regulating cell death (Fas, Fas ligand [FasL], Bcl-2) and apoptosis in both thyrocytes and thyroid infiltrating lymphocytes (TILs) from patients with either GD or HT. GD thyrocytes expressed less Fas/FasL than HT thyrocytes, whereas GD TILs had higher levels of Fas/FasL than HT TILs. GD thyrocytes expressed increased levels of the antiapoptotic molecule Bcl-2 compared to the low levels detected in HT thyrocytes. The opposite pattern was observed in GD (low Bcl-2) and HT (high Bcl-2) TILs. The patterns of apoptosis observed were consistent with the regulation of Fas, FasL, and Bcl-2 described above. Our findings suggest that in GD thyroid the regulation of Fas/FasL/Bcl2 favors apoptosis of infiltrating lymphocytes, possibly limiting their autoreactive potential and impairing their ability to mediate tissue damage. Moreover, the reduced levels of Fas/FasL and increased levels of Bcl-2 should favor thyrocyte survival and favor the thyrocyte hypertrophy associated with immunoglobulins stimulating the thyrotropin (TSH) receptor. In contrast, the regulation of Fas/FasL/Bcl2 expression in HT promotes thyrocyte apoptosis, tissue damage, and a gradual reduction in thyrocyte numbers leading to hypothyroidism. These findings help define key molecular mechanisms contributing to the clinical outcome of thyroid autoimmunity.