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Studies have linked childhood anxiety and depression with parenting characterized by high control and low warmth. However, few studies have examined how control and warmth may work together to influence internalizing symptoms in children. Therefore, the goal of this study was to examine the moderating effect of warmth on the relationship between overcontrol and anxiety and depressive symptoms, as well as whether negative thoughts serve as a mediator of these pathways. A total of 182 fourth and fifth grade children completed measures of maternal parenting behavior, negative thoughts, and anxiety and depressive symptoms. Results showed an interaction between overcontrol and warmth for depressive but not anxiety symptoms. Furthermore, low warmth increased the strength of the mediating relationship between overcontrol and depression via thoughts of personal failure. Findings may signal a need for early interventions to address parenting behaviors, such as controlling behaviors, in parents of children at risk for internalizing difficulties., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In vivo genetic manipulation is used to study the impact of gene deletion or re-expression on β-cell function and organism physiology. Cre-LoxP is a system wherein LoxP sites flanking a gene are recognized by Cre recombinase. Cre transgenic mice are the most prevalent technology used to deliver Cre but many models have caveats of off-target recombination, impaired β-cell function, and high cost of animal production. Inducible estrogen receptor conjugated Cre models face leaky recombination and confounding effects of tamoxifen. As an alternative, we characterize an adeno associated virus (AAV) with a rat insulin 1 promoter driving Cre recombinase (AAV8 Ins1-Cre) that is economical and rapid to implement, and has limited caveats. Intraperitoneal AAV8 Ins1-Cre produced efficient β-cell recombination, alongside some hepatic, exocrine pancreas, α-cell, δ-cell, and hypothalamic recombination. Delivery of lower doses via the pancreatic duct retained good rates of β-cell recombination and limited rates of off-target recombination. Unlike inducible Cre in transgenic mice, AAV8 Ins1-Cre required no tamoxifen and premature recombination was avoided. We demonstrate the utility of this technology by inducing hyperglycemia in inducible insulin knockout mice (Ins1 -/- ;Ins2 f/f ). AAV-mediated expression of Cre in β-cells provides an effective alternative to transgenic approaches for inducible knockout studies.

Evidence suggests that Social Anxiety Disorder (SAD) is less responsive to cognitive behavioral treatment (CBT) compared to other anxiety disorders. Therefore, exploring what might facilitate clinical benefit is essential. Social threat cognitions, characterized by exaggerated perceptions of negative evaluation by others, may be one important avenue to examine. The current study investigated whether youths' social threat cognitions decreased with Skills for Academic and Social Success (SASS), a group, school-based CBT designed for SAD, and whether decreases predicted SAD severity and treatment response. Participants included 138 high school students with SAD randomly assigned to SASS, or a nonspecific school counseling intervention. SASS participants showed significantly decreased social threat cognitions at 5-month follow-up. Treatment responders had significantly greater reductions in social threat cognitions compared to nonresponders at post-intervention and follow-up. These findings suggest that social threat cognitions may be important to assess and monitor when treating youth with SAD., (© Copyright 2019 Springer Publishing Company, LLC.)

We investigated the impact of emotions on learning vocabulary in an unfamiliar language to better understand affective influences in foreign language acquisition. Seventy native English speakers learned new vocabulary in either a negative or a neutral emotional state. Participants also completed two sets of working memory tasks to examine the potential mediating role of working memory. Results revealed that participants exposed to negative stimuli exhibited difficulty in retrieving and correctly pairing English words with Indonesian words, as reflected in a lower performance on the prompted recall tests and the free recall measure. Emotional induction did not change working memory scores from pre to post manipulation. This suggests working memory could not explain the reduced vocabulary learning in the negative group. We argue that negative mood can adversely affect language learning by suppressing aspects of native-language processing and impeding form-meaning mapping with second language words.

The Clinical Global Impressions of Improvement (CGI-I) scale is widely used in clinical trials to monitor clinically meaningful change during treatment. Although it is standard practice in research to have independent evaluators (IEs) complete the CGI-I, this approach is not practical in school and community settings. Few studies have explored the potential utility of other informants, such as youth and parents. Therefore, this study aimed to investigate agreement between IEs and both adolescents and parents in CGI-I improvement ratings in the context of a randomized controlled trial of cognitive-behavioral therapy for social anxiety disorder, as delivered by psychologists and school counselors. Multilevel growth models indicated that IEs were generally more conservative in their ratings of positive treatment response across time and treatment conditions, though greater agreement was observed between parents and IEs by post-intervention and 5-month follow-up. Possible explanations for these findings and suggestions for alternative approaches are discussed.

This study investigated the relationship of medical and non-medical fears to children's anxiety, pain, and distress during an invasive medical procedure, the voiding cystourethrogram. Parents of 34 children completed the Fear Survey Schedule-II prior to their child's procedure. Child distress behaviors during the procedure were audiotaped and coded using the Child-Adult Medical Procedure Interaction Scale-Revised. Ratings of child procedural anxiety and pain were obtained from children, parents, and examining technologists within minutes following the procedure. Associations were observed between medical fears, procedural anxiety (parent and staff reports), and coded distress behaviors. Findings may inform preparation efforts to reduce anxiety around invasive medical procedures., (© The Author(s) 2014.)

Pancreatic progenitors derived from human embryonic stem cells (hESCs) are a potential source of transplantable cells for treating diabetes and are currently being tested in clinical trials. Yet, how the milieu of pancreatic progenitor cells, including exposure to different factors after transplant, may influence their maturation remains unclear. Here, we examined the effect of thyroid dysregulation on the development of hESC-derived progenitor cells in vivo. Hypothyroidism was generated in SCID-beige mice using an iodine-deficient diet containing 0.15% propyl-2-thiouracil, and hyperthyroidism was generated by addition of L-thyroxine (T4) to drinking water. All mice received macroencapsulated hESC-derived progenitor cells, and thyroid dysfunction was maintained for the duration of the study ("chronic") or for 4 weeks posttransplant ("acute"). Acute hyperthyroidism did not affect graft function, but acute hypothyroidism transiently impaired human C-peptide secretion at 16 weeks posttransplant. Chronic hypothyroidism resulted in severely blunted basal human C-peptide secretion, impaired glucose-stimulated insulin secretion, and elevated plasma glucagon levels. Grafts from chronic hypothyroid mice contained fewer β-cells, heterogenous MAFA expression, and increased glucagon(+) and ghrelin(+) cells compared to grafts from euthyroid mice. Taken together, these data suggest that long-term thyroid hormone deficiency may drive the differentiation of human pancreatic progenitor cells toward α- and ε-cell lineages at the expense of β-cell formation., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Pluripotent human embryonic stem cells (hESCs) are a potential source of transplantable cells for treating patients with diabetes. To investigate the impact of the host recipient on hESC-derived pancreatic progenitor cell maturation, cells were transplanted into immunodeficient SCID-beige mice or nude rats. Following the transplant, basal human C-peptide levels were consistently higher in mice compared with rats, but only rats showed robust meal- and glucose-responsive human C-peptide secretion by 19-21 weeks. Grafts from rats contained a higher proportion of insulin:glucagon immunoreactivity, fewer exocrine cells, and improved expression of mature β cell markers compared with mice. Moreover, ECM-related genes were enriched, the collagen network was denser, and blood vessels were more intricately integrated into the engrafted endocrine tissue in rats relative to mice. Overall, hESC-derived pancreatic progenitor cells matured faster in nude rats compared with SCID-beige mice, indicating that the host recipient can greatly influence the fate of immature pancreatic progenitor cells post-transplantation., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Human embryonic stem cell (hESC)-derived pancreatic progenitor cells effectively reverse hyperglycemia in rodent models of type 1 diabetes, but their capacity to treat type 2 diabetes has not been reported. An immunodeficient model of type 2 diabetes was generated by high-fat diet (HFD) feeding in SCID-beige mice. Exposure to HFDs did not impact the maturation of macroencapsulated pancreatic progenitor cells into glucose-responsive insulin-secreting cells following transplantation, and the cell therapy improved glucose tolerance in HFD-fed transplant recipients after 24 weeks. However, since diet-induced hyperglycemia and obesity were not fully ameliorated by transplantation alone, a second cohort of HFD-fed mice was treated with pancreatic progenitor cells combined with one of three antidiabetic drugs. All combination therapies rapidly improved body weight and co-treatment with either sitagliptin or metformin improved hyperglycemia after only 12 weeks. Therefore, a stem cell-based therapy may be effective for treating type 2 diabetes, particularly in combination with antidiabetic drugs., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

The role of glucagon in the pathological condition of diabetes is gaining interest, and it has been recently reported that its action is essential for hyperglycemia to occur. Glucagon levels, which are elevated in some diabetic models, are reduced following leptin therapy. Likewise, hyperglycemia is corrected in type 1 diabetic mice treated with leptin, although the mechanisms have not been fully determined. A direct inhibitory effect of leptin on mouse and human α-cells has been demonstrated at the levels of electrical activity, calcium signaling, and glucagon secretion. In the present study we employed the Cre-loxP strategy to generate Lepr(flox/flox) Gcg-cre mice, which specifically lack leptin receptors in glucagon-secreting α-cells, to determine whether leptin resistance in α-cells contributes to hyperglucagonemia, and also whether leptin action in α-cells is required to improve glycemia in type 1 diabetes with leptin therapy. Immunohistochemical analysis of pancreas sections revealed Cre-mediated recombination in ∼ 43% of the α-cells. We observed that in vivo Lepr(flox/flox) Gcg-cre mice display normal glucose and lipid homeostasis. In addition, leptin administration in streptozotocin-induced diabetic Lepr(flox/flox) Gcg-cre mice restored euglycemia similarly to control mice. These findings suggest that loss of leptin receptor signaling in close to one-half of α-cells does not alter glucose metabolism in vivo, nor is it sufficient to prevent the therapeutic action of leptin in type 1 diabetes.

Human embryonic stem cells (hESCs) are considered a potential alternative to cadaveric islets as a source of transplantable cells for treating patients with diabetes. We previously described a differentiation protocol to generate pancreatic progenitor cells from hESCs, composed of mainly pancreatic endoderm (PDX1/NKX6.1-positive), endocrine precursors (NKX2.2/synaptophysin-positive, hormone/NKX6.1-negative), and polyhormonal cells (insulin/glucagon-positive, NKX6.1-negative). However, the relative contributions of NKX6.1-negative versus NKX6.1-positive cell fractions to the maturation of functional β-cells remained unclear. To address this question, we generated two distinct pancreatic progenitor cell populations using modified differentiation protocols. Prior to transplant, both populations contained a high proportion of PDX1-expressing cells (~85%-90%) but were distinguished by their relatively high (~80%) or low (~25%) expression of NKX6.1. NKX6.1-high and NKX6.1-low progenitor populations were transplanted subcutaneously within macroencapsulation devices into diabetic mice. Mice transplanted with NKX6.1-low cells remained hyperglycemic throughout the 5-month post-transplant period whereas diabetes was reversed in NKX6.1-high recipients within 3 months. Fasting human C-peptide levels were similar between groups throughout the study, but only NKX6.1-high grafts displayed robust meal-, glucose- and arginine-responsive insulin secretion as early as 3 months post-transplant. NKX6.1-low recipients displayed elevated fasting glucagon levels. Theracyte devices from both groups contained almost exclusively pancreatic endocrine tissue, but NKX6.1-high grafts contained a greater proportion of insulin-positive and somatostatin-positive cells, whereas NKX6.1-low grafts contained mainly glucagon-expressing cells. Insulin-positive cells in NKX6.1-high, but not NKX6.1-low grafts expressed nuclear MAFA. Collectively, this study demonstrates that a pancreatic endoderm-enriched population can mature into highly functional β-cells with only a minor contribution from the endocrine subpopulation., (© AlphaMed Press.)

Aims/hypothesis: Islet transplantation is a promising cell therapy for patients with diabetes, but it is currently limited by the reliance upon cadaveric donor tissue. We previously demonstrated that human embryonic stem cell (hESC)-derived pancreatic progenitor cells matured under the kidney capsule in a mouse model of diabetes into glucose-responsive insulin-secreting cells capable of reversing diabetes. However, the formation of cells resembling bone and cartilage was a major limitation of that study. Therefore, we developed an improved differentiation protocol that aimed to prevent the formation of off-target mesoderm tissue following transplantation. We also examined how variation within the complex host environment influenced the development of pancreatic progenitors in vivo., Methods: The hESCs were differentiated for 14 days into pancreatic progenitor cells and transplanted either under the kidney capsule or within Theracyte (TheraCyte, Laguna Hills, CA, USA) devices into diabetic mice., Results: Our revised differentiation protocol successfully eliminated the formation of non-endodermal cell populations in 99% of transplanted mice and generated grafts containing >80% endocrine cells. Progenitor cells developed efficiently into pancreatic endocrine tissue within macroencapsulation devices, despite lacking direct contact with the host environment, and reversed diabetes within 3 months. The preparation of cell aggregates pre-transplant was critical for the formation of insulin-producing cells in vivo and endocrine cell development was accelerated within a diabetic host environment compared with healthy mice. Neither insulin nor exendin-4 therapy post-transplant affected the maturation of macroencapsulated cells., Conclusions/interpretation: Efficient differentiation of hESC-derived pancreatic endocrine cells can occur in a macroencapsulation device, yielding glucose-responsive insulin-producing cells capable of reversing diabetes.

Obesity is a major risk factor for diabetes and is typically associated with hyperleptinemia and a state of leptin resistance. The impact of chronically elevated leptin levels on the function of insulin-secreting β-cells has not been elucidated. We previously generated mice lacking leptin signaling in β-cells by using the Cre-loxP strategy and showed that these animals develop increased body weight and adiposity, hyperinsulinemia, impaired glucose-stimulated insulin secretion and insulin resistance. Here, we performed several in vitro studies and observed that β-cells lacking leptin signaling in this model are capable of properly metabolizing glucose, but show impaired intracellular Ca(2+) oscillations and lack of synchrony within the islets in response to glucose, display reduced response to tolbutamide and exhibit morphological abnormalities including increased autophagy. Defects in intracellular Ca(2+) signaling were observed even in neonatal islets, ruling out the possible contribution of obesity to the β-cell irregularities observed in adults. In parallel, we also detected a disrupted intracellular Ca(2+) pattern in response to glucose and tolbutamide in control islets from adult transgenic mice expressing Cre recombinase under the rat insulin promoter, despite these animals being glucose tolerant and secreting normal levels of insulin in response to glucose. This unexpected observation impeded us from discerning the consequences of impaired leptin signaling as opposed to long-term Cre expression in the function of insulin-secreting cells. These findings highlight the need to generate improved Cre-driver mouse models or new tools to induce Cre recombination in β-cells.

Islet transplantation is an effective method to obtain long-term glycemic control for patients with type 1 diabetes, yet its widespread use is limited by an inadequate supply of donor islets. The hormone leptin has profound glucose-lowering and insulin-sensitizing action in type 1 diabetic rodent models. We hypothesized that leptin administration could reduce the dose of transplanted islets required to achieve metabolic control in a mouse model of type 1 diabetes. We first performed a leptin dose-response study in C57Bl/6 mice with streptozotocin (STZ)-induced diabetes to determine a leptin dose insufficient to reverse hyperglycemia. Subsequently, we compared the ability of suboptimal islet transplants of 50 or 125 syngeneic islets to achieve glycemic control in STZ-induced diabetic C57Bl/6 mice treated with or without this dose of leptin. The dose-response study revealed that leptin reverses STZ-induced diabetes in a dose-dependent manner. Supraphysiological leptin levels were necessary to restore euglycemia but simultaneously increased risk of hypoglycemia, and also lost efficacy after 12 days of administration. In contrast, 1 µg/day leptin only modestly reduced blood glucose but maintained efficacy throughout the study duration. We then administered 1 µg/day leptin to diabetic mice that underwent transplantation of 50 or 125 islets. Although these islet doses were insufficient to ameliorate hyperglycemia alone, coadministration of leptin with islet transplantation robustly improved control of glucose and lipid metabolism, without increasing circulating insulin levels. This study reveals that low-dose leptin administration can reduce the number of transplanted islets required to achieve metabolic control in STZ-induced diabetic mice.

Type 1 diabetes is a progressive autoimmune disease that is largely silent in its initial stages. Yet, sensitive methods for detection of β-cell death and prediction and prevention of diabetes are lacking. Micro-RNAs (miRNAs) have been found at high concentrations in body fluids. Here in this study we sought to determine whether an islet enriched miRNA, miR-375, is a suitable blood marker to detect β-cell death and predict diabetes in mice. We measured miR-375 levels by quantitative RT-PCR in plasma samples of streptozotocin (STZ)-treated C57BL/6 mice and nonobese diabetic (NOD) mice. We also measured miR-375 levels in media samples of cytokine- or STZ-treated islets in the presence or absence of cell-death inhibitors. High-dose STZ administration dramatically increased circulating miR-375 levels, prior to the onset of hyperglycemia. Similarly, in the NOD mouse model of autoimmune diabetes, circulating miR-375 levels were significantly increased 2 weeks before diabetes onset. Moreover, cytokine- and STZ-induced cell death in isolated mouse islets produced a striking increase in extracellular miR-375 levels, which was reduced by cell death inhibitors. These data suggest that circulating miR-375 can be used as a marker of β-cell death and potential predictor of diabetes.

Purpose: We investigated the relationship between parental anxiety/coping strategies and girls' distress during VCUGs., Methods: Parents of 32 girls (age 4-10, mean 5.8 years) completed a trait anxiety measure and a measure of parental reactions to children's distress. Post procedure, children, parents and radiology staff rated the level of anxiety, fear, pain and discomfort., Results: Trends indicated that parents who reported increased anxiety rated their children as experiencing increased distress (r = 0.27, p = 0.071), similarly for medical staff ratings (r = 0.28, p = 0.061). Parents with lower trait anxiety scores reported using more emotion- and problem-focused coping strategies (r = -0.37 and r = -0.40, p < 0.05, respectively). These were related to children experiencing less procedural distress (r = -0.30, p = 0.054; r = -0.33, p = 0.037, respectively) and parents rated as less anxious by staff (r = -0.40, p = 0.014; r = -0.31, p = 0.047, respectively)., Conclusions: There was a trend toward parental anxiety being related to their child's distress during VCUG. Parental coping strategies resulted in less distress among children and parents. Teaching coping techniques might obviate the need for sedation and help children deal with future stressors., (Published by Elsevier Ltd.)

The high prevalence and early onset of anxiety disorders have inspired innovative prevention efforts targeting young at-risk children. With parent-child prevention models showing success for older children and adolescents, the goal of this study was to evaluate a parent-child indicated preventive intervention for preschoolers with mild to moderate anxiety symptoms. Sixteen children (ages 3-5) and at least one of their parents participated in Strengthening Early Emotional Development (SEED), a new 10-week intervention with concurrent groups for parents and children. Outcome measures included clinician-rated and parent-rated assessments of anxiety symptoms, as well as measures of emotion knowledge, parent anxiety, and parental attitudes about children's anxiety. Participation in SEED was associated with reduced child anxiety symptoms and improved emotion understanding skills. Parents reported decreases in their own anxiety, along with attitudes reflecting enhanced confidence in their children's ability to cope with anxiety. Reductions in child and parent anxiety were maintained at 3-month follow-up. Findings suggest that a parent-child cognitive-behavioral preventive intervention may hold promise for young children with mild to moderate anxiety. Improvements in parent anxiety and parental attitudes may support the utility of intervening with parents. Fostering increased willingness to encourage their children to engage in new and anxiety-provoking situations may help promote continued mastery of new skills and successful coping with anxiety.

Anxiety disorders are the most common class of psychopathology among youth, yet many of these youngsters do not receive treatment. This is particularly concerning given the chronic course of anxiety disorders, which often lead to mood disorders, substance abuse, and serious impairment. Schools are an optimal venue for identifying anxious students and delivering mental health treatment given access to youth and ability to overcome various barriers to treatment. This article reviews four school-based treatments for anxiety disorders that have been evaluated in controlled trials. Discussion centers on feasibility, challenges to school-based implementation, and future research directions for this critical area.

Although the tripartite model reliably distinguishes anxiety and depression in adolescents, it remains unclear how negative affectivity (NA) and positive affectivity (PA) influence developmental pathways to internalizing problems. Based on models which propose that affectivity shapes how youth react to stress, the present study attempted to investigate the relative roles of NA, PA, and stressful life events in characterizing and differentiating adolescent anxiety and depression. A sample of adolescent females (N=63), including a sub-sample of adolescent mothers, completed measures of NA, PA, negative life event (NLE) occurrence, anxiety, and depression. Findings supported the tripartite model as a "temperamental reactivity to stress" approach. Anxious and depressive symptoms were predicted by a combination of high NA and high NLE occurrence. However, a combination of low PA and high NLE occurrence was uniquely linked to greater depressive symptoms. Implications of these findings for early identification and prevention programs are discussed., (Copyright (c) 2009 The Association for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.)