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Background: Systematic and comprehensive data acquisition from the electronic health record (EHR) is critical to the quality of data used to improve patient care. We described EHR tools, workflows, and data elements that contribute to core quality metrics in the Type 1 Diabetes Exchange Quality Improvement Collaborative (T1DX-QI)., Method: We conducted interviews with quality improvement (QI) representatives at 13 T1DX-QI centers about their EHR tools, clinic workflows, and data elements., Results: All centers had access to structured data tools, nine had access to patient questionnaires and two had integration with a device platform. There was significant variability in EHR tools, workflows, and data elements, thus the number of available metrics per center ranged from four to 17 at each site. Thirteen centers had information about glycemic outcomes and diabetes technology use. Seven centers had measurements of additional self-management behaviors. Centers captured patient-reported outcomes including social determinants of health (n = 9), depression (n = 11), transition to adult care (n = 7), and diabetes distress (n = 3). Various stakeholders captured data including health care professionals, educators, medical assistants, and QI coordinators. Centers that had a paired staffing model in clinic encounters distributed the burden of data capture across the health care team and was associated with a higher number of available data elements., Conclusions: The lack of standardization in EHR tools, workflows, and data elements captured resulted in variability in available metrics across centers. Further work is needed to support measurement and subsequent improvement in quality of care for individuals with type 1 diabetes., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JL is on the GoodRx medical advisory board, is a consultant for Tandem Diabetes Care and has participated on a Sanofi Digital Advisory Board. OE is an advisor for Medtronic Diabetes and Sanofi Diabetes. He has received research support through his institution (T1D Exchange) from Abbott, Vertex, Eli Lilly, Dexcom and Medtronic. RW receives research support through her institution (Johns Hopkins) from Novo Nordisk as the center PI of a trial. more...

Brainstem injury occurs secondary to radiation to the posterior fossa in up to 2% of pediatric patients. It may occur after months to years after treatment. It has been associated with age less than 5 years and with comorbid conditions such as cerebrovascular disease, diabetes mellitus, and hypertension. Radiation necrosis is often symptomatic and can be fatal. A pathogenic variant in RNF213 was found in a patient who suffered fatal radiation necrosis. This mutation has been associated with moyamoya disease and may predispose to radiation necrosis., (© 2023 Wiley Periodicals LLC.) more...

Objective: Transgender/non-binary (TNB) youth are at increased risk for anxiety, depression, and suicidality compared to cisgender youth. Gender affirming hormone therapy (GAHT, i.e., testosterone or estrogen) is a standard of care option for TNB youth, and we have recently shown that GAHT (testosterone) in transgender youth assigned a female sex at birth is associated with reductions in internalizing symptomatology. The current analysis explores: 1) whether these benefits are observed in both TNB youth assigned female at birth (TNB AFAB ) and TNB youth assigned male at birth (TNB AMAB ) and 2) the extent to which body image dissatisfaction and alteration in neural circuitry relate to internalizing symptoms., Method: The current study is an expansion of a previous publication from our lab that explored the association between gender-affirming testosterone and internalizing symptomatology. While participants in our previous study consisted of 42 TNB AFAB youth, participants in the current study included adolescent TNB AFAB receiving GAHT (n = 21; GAHT+) and not receiving GAHT (n = 29; GAHT-) as well as adolescent GAHT+ TNB AMAB (n = 15) and GAHT- TNB AMAB (n = 17). Participants reported symptoms of trait and social anxiety, depression, suicidality in the past year, and body image dissatisfaction. Brain activation was measured during a face processing task designed to elicit amygdala activation during functional MRI., Results: GAHT+ TNB AFAB had significantly lower rates of social anxiety, depression, and suicidality compared to GAHT- TNB AFAB . While there were no significant relationships between estrogen and depression and anxiety symptoms, longer duration of estrogen was related to less suicidality. Both testosterone and estrogen administration were related to significantly lower rates of body image dissatisfaction compared to GAHT- youth. No significant differences emerged for BOLD response in the left or right amygdala during the face processing task, however, there was a significant main effect of GAHT on functional connectivity between the right amygdala and the ventromedial prefrontal cortex, such that GAHT+ youth had stronger co-activation between the two regions during the task. Body image dissatisfaction, greater functional connectivity, their interaction effect, and age predicted depression symptomatology and body image dissatisfaction additionally predicted suicidality in the past year., Conclusion: The current study suggests that GAHT is associated with fewer short-term internalizing symptoms in TNB AFAB than in TNB AMAB , although internalizing symptoms among TNB AMAB may diminish with longer durations of estrogen treatment. Controlling for age and sex assigned at birth, our findings indicate that less body image dissatisfaction and greater functional connectivity between the amygdala and ventromedial prefrontal cortex were both predictors of fewer levels of internalizing symptoms following GAHT., Competing Interests: Declaration of Competing Interest none., (Copyright © 2023 Elsevier Ltd. All rights reserved.) more...

Purpose: We aimed to examine the concurrent associations of gender-affirming hormonal interventions (i.e., puberty blockers, testosterone, estrogen), as well as family and friend social support, on transgender and nonbinary (TNB) adolescents' reports of anxiety symptoms, depressive symptoms, nonsuicidal self-injury (NSSI), and suicidality. We hypothesized that gender-affirming hormonal interventions and greater social support would be associated with lower levels of mental health concerns., Methods: Participants (n = 75; aged 11-18; M age  = 16.39 years) were recruited for this cross-sectional study from a gender-affirming multidisciplinary clinic. Fifty-two percent were receiving gender-affirming hormonal interventions. Surveys assessed anxiety and depressive symptoms, NSSI and suicidality in the past year, and social support from family, friends, and significant others. Hierarchical linear regression models examined associations between gender-affirming hormonal interventions and social support (i.e., family, friend) with mental health while accounting for nonbinary gender identity., Results: Regression models explained 15%-23% of variance in TNB adolescents' mental health outcomes. Gender-affirming hormonal interventions were associated with fewer anxiety symptoms (β = -0.23; p < .05). Family support was associated with fewer depressive symptoms (β = -0.33; p = .003) and less NSSI (β = -0.27; p = .02). Friend support was associated with fewer anxiety symptoms (β = -0.32; p = .007) and less suicidality (β = -0.25; p = .03)., Discussion: TNB adolescents had better mental health outcomes in the context of receiving gender-affirming hormonal interventions and having greater support from family and friends. Findings highlight the important role of quality family and friend support for TNB mental health. Providers should aim to address both medical and social factors to optimize TNB mental health outcomes., (Copyright © 2023 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.) more...

This article describes how the T1D Exchange Quality Improvement Collaborative leverages an innovative web platform, the QI Portal, to gather and store electronic medical record (EMR) data to promote benchmarking and population health improvement in a type 1 diabetes learning health system. The authors explain the value of the QI Portal, the process for mapping center-level data from EMRs using standardized data specifications, and the QI Portal's unique features for advancing population health., (© 2022 by the American Diabetes Association.) more...

Introduction: Efficient methods to obtain and benchmark national data are needed to improve comparative quality assessment for children with type 1 diabetes (T1D). PCORnet is a network of clinical data research networks whose infrastructure includes standardization to a Common Data Model (CDM) incorporating electronic health record (EHR)-derived data across multiple clinical institutions. The study aimed to determine the feasibility of the automated use of EHR data to assess comparative quality for T1D., Methods: In two PCORnet networks, PEDSnet and OneFlorida, the study assessed measures of glycemic control, diabetic ketoacidosis admissions, and clinic visits in 2016-2018 among youth 0-20 years of age. The study team developed measure EHR-based specifications, identified institution-specific rates using data stored in the CDM, and assessed agreement with manual chart review., Results: Among 9,740 youth with T1D across 12 institutions, one quarter (26%) had two or more measures of A1c greater than 9% annually (min 5%, max 47%). The median A1c was 8.5% (min site 7.9, max site 10.2). Overall, 4% were hospitalized for diabetic ketoacidosis (min 2%, max 8%). The predictive value of the PCORnet CDM was > 75% for all measures and >90% for three measures., Conclusions: Using EHR-derived data to assess comparative quality for T1D is a valid, efficient, and reliable data collection tool for measuring T1D care and outcomes. Wide variations across institutions were observed, and even the best-performing institutions often failed to achieve the American Diabetes Association HbA1C goals (<7.5%)., Competing Interests: K.E.W., within the past 36 months, has served as a consultant for Sanofi and Research Triangle Institute. The other authors have no financial interest to declare in relation to the content of this article., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.) more...

Objective: To assess health-related quality of life (HRQoL), psychosocial adjustment, and family functioning of children with differences of sex development (DSD) or cleft lip and/or palate (CL/P)., Methods: In this cross-sectional study, parents of children with DSD (n = 67), CL/P (n = 121), and a comparison group of unaffected youth (n = 126) completed standardized measures assessing family functioning and their children's HRQoL and psychosocial adjustment. Medical charts were abstracted for youth with either congenital condition., Results: Children with DSD were rated as having significantly lower HRQoL and greater internalizing problems compared to youth with CL/P and unaffected youth. Children in the DSD group were also significantly more likely to fall into the clinical risk categories for total and internalizing problems relative to the CL/P and unaffected groups. Caregivers of children with DSD were significantly more likely to endorse items about child suicidality compared with caregivers in the CL/P and unaffected groups. No significant differences were found between groups for externalizing problems or the expressiveness domain of family functioning; parents of children with DSD reported significantly less family conflict relative to the other groups and greater cohesion relative to the unaffected group. Conclusions Youth with DSD appear to be at greater risk for psychosocial problems relative to children with CL/P and unaffected peers. Results underscore the need for integrated interdisciplinary care and ongoing psychosocial risk monitoring in youth with DSD., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.) more...

Introduction: Patient outcomes resulting from optimal type 1 diabetes (T1D) care have historically focused on driving a single metric, hemoglobin A 1c . Our objectives were to design, build, and launch an aggregate clinical indicator that comprehensively reflects patient management status beyond hemoglobin A 1c alone. This project aimed to show proof of principle that an aggregate score comprised of T1D outcome metrics could be built to track quality performance., Methods: We established an electronic medical record-based diabetes registry and utilized its population health modules to design and build this diabetes care metric. Elements representing optimal diabetes management, as defined by current guidelines and expert opinion, were identified. Nine elements fall into categories of management tools, care assessments, and complications risk. The Type 1 Diabetes Composite Score (T1DCS) aggregates these outcome measures to reflect the overall diabetes care status for each patient. Higher scores suggest better management and overall improved patient health., Results: We launched this metric build in November 2018 and applied the scoring to our T1D population (≈1,900 patients). The T1DCS quickly provides a summary of current diabetes management status. T1DCS viewed over the registry cohort demonstrates a normal distribution, and scores improved from March to September 2019, reflecting better care and outcomes, and illustrating the potential to track program effectiveness., Conclusions: The T1DCS is a useful metric to evaluate the clinical status of T1D patients, assess the capability of a clinical program to achieve optimal diabetes outcomes, identify patient diversity opportunities, and document outcome improvement as a novel comprehensive quality measure., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.) more...

Objectives: The American Diabetes Association (ADA) and the International Society for Pediatric and Adolescent Diabetes (ISPAD) have outlined standards for best practices in providing optimal diabetes care to children with type 1 diabetes (T1D). Our objectives were to design a metric that evaluated delivery of optimal diabetes care and to use this metric to drive improvement within our diabetes program., Methods: Using published guidelines, we identified 11 elements of optimal diabetes care that should be reliably delivered at our institution as standard-of-care. We utilized our electronic medical record to aid in data collection and to notify staff when to deliver specific care elements (eg, lipid collection, depression screening, etc.). We designed the T1D Care Index (T1DCI), a metric which aggregates missed opportunities to deliver elements of optimal diabetes care over a given period into a cumulative score, with a lower T1DCI reflecting better care delivery and improved program performance., Results: Tracking the T1DCI permitted recognition of areas to focus on quality improvement efforts, guided interventions to improve processes for care delivery, and helped determine the allocation of time and resources. Interventions resulted in improvement of care delivery across some elements of care. Overall, we observed a 26% reduction in the T1DCI after 12 months of utilization., Conclusions: The T1DCI is a powerful metric to evaluate the ability of our diabetes program to standardize, quantify, and monitor delivery of optimal diabetes care to children with T1D, and to drive our program toward zero missed opportunities for quality care delivery., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.) more...

Short Introduction/background: Children affected by differences/disorders of sex development (DSDs) and their families are vulnerable to significant risks across developmental stages that threaten quality of life and psychosocial functioning. Accordingly, both experts in DSD treatment and patient advocacy groups have endorsed the incorporation of psychosocial care into interdisciplinary management of DSD conditions., Objective: This study assessed psychosocial needs and received services reported by parents of children with DSD treated at two large US academic medical centers. Specifically, differences in parents' perceptions of psychosocial service needs were compared between those who received or did not receive interdisciplinary care that included psychology/social work professionals., Study Design: In a cross-sectional study, sixty-four parents of children with DSD aged 0-19 years attending two major academic centers with interdisciplinary teams completed a questionnaire about their receipt and perception of 12 individual psychosocial services throughout their child's DSD treatment., Results: Receipt of individual psychosocial services ranged from 27 to 81%. Most commonly, parents reported having a psychosocial provider explain medical terms and answer questions after talking with a doctor (81%), assist with words and terms to describe the condition and treatment (69%), and help navigate the hospital system (63%). Families positively endorsed psychosocial services, with 91-100% of services received rated as helpful. Parents of children who received care as part of an interdisciplinary team were significantly more likely to receive psychosocial services than those treated by single providers (e.g., urologists). Specific gaps in psychosocial care were noted in regard to access to mental health providers familiar with DSD, fertility counseling, and support with community advocacy (e.g., arranging for accommodations at the school or advocating on patient's behalf with the insurance company). Among families who had not received them, services most desired were assistance with words and terms to describe condition or treatment; explanation of medical terms and answering questions after meeting with a doctor; connection to resources such as books, pamphlets, websites, and support groups; and a central care coordinator for the medical team., Discussion and Conclusion: Families value psychosocial services but are far less likely to receive services if they are not seen in an interdisciplinary clinic visit that includes a psychosocial provider. Families desire but often lack mental health, advocacy, and fertility-related support. This study highlights the need for sustained psychosocial follow-up across development, even in the absence of pressing medical concerns, to provide support and anticipatory guidance as needs and issues evolve., (Copyright © 2019 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.) more...

The term transgender youth commonly refers to those whose gender identity, or personal core sense of self as a particular gender, differs from their assigned sex at birth; this is often designated by what external genitalia are present. These youths are presenting to multidisciplinary clinics worldwide at exponentially higher rates than in decades past, and clinics themselves have grown in number to meet the specialized demands of these youth. Additionally, the scientific and medical community has moved towards understanding the construct of gender dimensionally (i.e., across a spectrum from male to female) as opposed to dichotomous or binary "male or female" categories. This is reflected in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM 5); in this publication, the diagnostic classification of gender dysphoria, GD, (which has two subtypes: childhood and adolescence/adulthood) provides a set of criteria that many transgender people meet. GD describes the affective distress that arises as a result of the incongruence between gender identity and sex anatomy. The DSM uses language to indicate that a person may identify as another gender instead of the other gender, which further captures the complexity of the human experience of gender. Also, research regarding how current adolescents are describing their identity development and experience along this spectrum within today's society is only now being addressed in the literature. Therefore, the clinical needs of the transgender population have outpaced medical training and scientific advancement, which has opened up gaps on how to define best practices. This article provides current concepts of evaluation and management for transgender persons with emphasis on hormonal therapy (i.e., puberty blockers and gender affirming hormone therapy). Other management issues are briefly considered including gender confirming surgery and changes in the face as well as voice., (Copyright © 2019. Published by Elsevier Inc.) more...

Introduction: Patients with gonadal dysgenesis (GD) with a Y chromosome have an increased risk of gonadal neoplasm. Few data exist on the ability of imaging to detect malignancy in intra-abdominal gonads in these patients., Objective: We aimed to determine the correlation between preoperative imaging findings and gonadal pathology in GD patients with Y chromosome material., Methods: A retrospective review was performed of patients with XY or XO/XY GD who underwent gonadectomy at our institution from 2003 to 2017. Patients were assessed preoperatively with ultrasonography; some additionally underwent MRI., Results: The series consisted of 10 patients, all with female gender and non-palpable gonads. Median age was 13.1 years (range 2.4-18.3 years). Overall, four of the ten patients (40%) had a tumor (gonadoblastoma or dysgerminoma) on final pathology. Four patients had a gonad or gonads that were definitively seen on ultrasonography. All visualized gonads were described as "normal" or "small" with the exception of one patient, who had a normal MRI. Three of the four patients in this group had a tumor on final pathology. The remaining six patients had a gonad or gonads that were not definitively visualized on ultrasound; one patient in this group had a tumor on final pathology. Overall, five of seven gonads (71%) definitively visualized on ultrasound had tumor on final pathology, and two of thirteen gonads (15%) not visualized on ultrasound had tumor on final pathology; this difference was statistically significant (p = 0.012). Three patients were imaged with MRI. Of the gonads that could be visualized on MRI, no definitive abnormalities were seen. All patients imaged with MRI had tumors on final pathology., Discussion: Both ultrasound and MRI are relatively poor at identifying and characterizing intra-abdominal gonads in GD patients. The majority of patients who had a neoplasm had normal imaging findings. Gonads that were definitively visualized on ultrasound were more likely to contain neoplasms that could not be visualized, which perhaps because of tumor growth. No other consistent imaging findings of malignancy were found. Our study included ultrasound evaluations that were completed over 10 years ago and not performed by pediatric ultrasonographers, which may have biased the results. However, results suggest that when discussing gonadectomy with GD patients, one should not be reassured by "normal" imaging findings. Neither ultrasound nor MRI should be relied on for surveillance in GD patients who decide against gonadectomy., Conclusion: A normal ultrasound or MRI does not rule out neoplasm in GD patients with intra-abdominal gonads., (Copyright © 2017 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.) more...

The initial management of the neonate with ambiguous genitalia can be a very stressful and anxious time for families, as well as for the general practitioner or neonatologist. A timely approach must be sensitive and attend to the psychosocial needs of the family. In addition, it must also effectively address the diagnostic dilemma that is frequently seen in the care of patients with disorders of sex development (DSDs). One great challenge is assigning a sex of rearing, which must take into account a variety of factors including the clinical, biochemical and radiologic clues as to the etiology of the atypical genitalia (AG). However, other important aspects cannot be overlooked, and these include parental and cultural views, as well as the future outlook in terms of surgery and fertility potential. Achieving optimal outcomes requires open and transparent dialogue with the family and caregivers, and should harness the resources of a multidisciplinary team. The multiple facets of this approach are outlined in this review., Competing Interests: Conflicts of Interest: The author has no conflicts of interest to declare. more...

Regular physical activity is an important component in the management of both type 1 and type 2 diabetes mellitus (T1DM and T2DM), as it has the potential to improve glycemic control, delay cardiovascular complications, and increase overall well-being. Unfortunately, many children and adolescents with diabetes do not partake in regular exercise and physical activity for multiple reasons. This review identifies the barriers to participation from the aspect of the patient, caregiver, and the healthcare provider. The management of physical activity of children and adolescents with diabetes mellitus is unique and requires an understanding of exercise physiology and how it differs in these children and adolescents from those without the condition. These individuals are at risk for important and potentially life threatening complications including, but not limited to, severe or delayed nocturnal hypoglycemia. It is essential to identify these risks as well as, monitor and manage adjustments to carbohydrate intake and insulin dosing through basal-bolus regimen or insulin pump adjustments appropriately before, during, and after the exercise activity. This review discusses these issues and also outlines differences in management between patients with T1DM and T2DM., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare. more...

Background/aims: The diagnostic criteria for critical illness-related corticoid insufficiency (CIRCI) are not well established, particularly for children. In addition to alterations in adrenal function, cellular resistance to glucocorticoid action could contribute to CIRCI due to alterations in the functioning of the intracellular receptor protein for corticosteroids, the glucocorticoid receptor (GR)., Methods: We have therefore undertaken a pilot, prospective study to assess whether cellular GR activity can be measured in peripheral blood mononuclear cells (PBMCs) from critically ill children., Results: Total and cytoplasmic, but not nuclear GR levels were significantly lower in PBMCs from critically ill children (i.e. sepsis/septic shock and traumatic brain injury) compared to healthy controls . While total cortisol concentrations did not differ between test groups, salivary and serum-free cortisol concentrations were significantly greater in both groups of children with critical illness. Cortisol-binding globulin levels were significantly lower in patients with sepsis/septic shock., Conclusions: The lower total and cytoplasmic receptor levels in critically ill children suggest that the GR-mediated response to exogenous glucocorticoid therapy may be limited. However, the nuclear transport of GR in critically ill patients suggests that residual receptors in these patients retain functionality and may be accessible to therapeutic treatments that maximize their activity., (Copyright © 2013 S. Karger AG, Basel.) more...

Background: Whereas thyroid nodules are less common among children than among adults, the anxiety generated by the finding of a thyroid nodule is high because 20% of nodules found in children contain thyroid cancer. Discovery of a nodule in the context of hyperthyroidism is usually comforting due to the presumption that the nodule represents a benign toxic adenoma., Summary: An 11-year-old girl presented with heavy menses, fatigue, and a right thyroid mass. Laboratory evaluation revealed elevated triiodothyronine and undetectable thyroid-stimulating hormone. Thyroid ultrasonography revealed a 3.5 cm nonhomogenous nodule, and scintigraphy was consistent with an autonomous hyper-functioning nodule. Fine-needle aspiration biopsy could not rule out malignancy, and patient underwent right hemithyroidectomy and isthmusectomy. Pathology was consistent with papillary thyroid carcinoma., Conclusions: We report the discovery of papillary thyroid carcinoma in an autonomously hyperfunctioning nodule in an 11-year-old girl. Detection of an autonomously functioning thyroid nodule in children and adolescents does not exclude the possibility of thyroid carcinoma and warrants careful evaluation and appropriate therapy. more...

Laminins are extracellular matrix proteins that participate in neuronal development, survival, and regeneration. During excitotoxin challenge in the mouse hippocampus, neuron interaction with laminin-10 (alpha5,beta1,gamma1) protects against neuronal death. To investigate how laminin is involved in neuronal viability, we infused laminin-1 (alpha1,beta1,gamma1) into the mouse hippocampus. This infusion specifically disrupted the endogenous laminin layer. This disruption was at least partially due to the interaction of the laminin-1 gamma1 chain with endogenous laminin-10, because infusion of anti-laminin gamma1 antibody had the same effect. The disruption of the laminin layer by laminin-1 1) did not require the intact protein because infusion of plasmin-digested laminin-1 gave similar results; 2) was posttranscriptional, because there was no effect on laminin mRNA expression; and 3) occurred in both tPA(-/-) and plasminogen(-/-) mice, indicating that increased plasmin activity was not responsible. Finally, although tPA(-/-) mice are normally resistant to excitotoxin-induced neurodegeneration, disruption of the endogenous laminin layer by laminin-1 or anti-laminin gamma1 antibody renders the tPA(-/-) hippocampal neurons sensitive to kainate. These results demonstrate that neuron interactions with the deposited matrix are not necessarily recapitulated by interactions with soluble components and that the laminin matrix is a dynamic structure amenable to modification by exogenous molecules. more...

Laminins are important components of the extracellular matrix, and participate in neuronal development, survival and regeneration. The tissue plasminogen activator/plasmin extracellular protease cascade and downstream laminin degradation are implicated in excitotoxin-induced neuronal degeneration. To determine which specific laminin chains are involved, we investigated the expression of laminins in the hippocampus, and the cell types expressing them. Reverse transcription-PCR demonstrated that the messenger RNAs for all laminin chains could be detected in the hippocampus. To determine the localization of laminin chain expression, immunostaining was used. This method showed that alpha5, beta1 and gamma1 are most highly expressed in the neuronal cell layers. Immunoblotting confirmed the hippocampal expression of the chains alpha5, beta1 and gamma1, and RNA in situ hybridization showed a neuronal expression pattern of alpha5, beta1 and gamma1. At early time points following intrahippocampal injection of kainate, alpha5, beta1 and gamma1 chain immunoreactivities were lost. In addition, tissue plasminogen activator-deficient mice, which are resistant to kainate-induced neuronal death, show no significant change in laminins alpha5, beta1 and gamma1 after intrahippocampal kainate injection. Taken together, these results suggest that laminin-10 (alpha5-beta1-gamma1) comprises a major neuronal laminin in the mouse hippocampus, and is degraded before neuronal death during excitotoxic injury by the tissue plasminogen activator/plasmin protease cascade. By identifying a neuronal laminin (laminin-10) that participates in neuronal degeneration after excitotoxic injury, this study clarifies the molecular definition of the extracellular matrix in the hippocampus and further defines a pathway for mechanisms of neuronal death., (Copyright 2003 IBRO) more...

Neuronal damage in the CNS after excitotoxic injury is correlated with blood-brain barrier (BBB) breakdown. We have used a glutamate analog injection model and genetically altered mice to investigate the relationship between these two processes in the hippocampus. Our results show that BBB dysfunction occurs too late to initiate neurodegeneration. In addition, plasma infused directly into the hippocampus is not toxic and does not affect excitotoxin-induced neuronal death. To test plasma protein recruitment in neuronal degeneration, we used plasminogen-deficient (plg(-/-)) mice, which are resistant to excitotoxin-induced degeneration. Plasminogen is produced in the hippocampus and is also present at high levels in plasma, allowing us to determine the contribution of each source to cell death. Intrahippocampal delivery of plasminogen to plg(-/-) mice restored degeneration to wild-type levels, but intravenous delivery of plasminogen did not. Finally, although the neurons in plg(-/-) mice do not die after excitotoxin injection, BBB breakdown occurs to a similar extent as in wild-type mice, indicating that neuronal death is not necessary for BBB breakdown. These results indicate that excitotoxin-induced neuronal death and BBB breakdown are separable events in the hippocampus. more...