Long-Term Functional Outcome Following Neurosurgical Intervention for Suspected Abusive Head Trauma.

BACKGROUND: The purpose of this study was to evaluate the long-term functional and neurodevelopmental outcomes in pediatric patients who underwent neurosurgical intervention following suspected abusive head trauma (AHT). METHODS: We performed a single-center retrospective review (January 1, 2007, to December 31, 2019) of patients aged less than three years who had intracranial injury suspicious for AHT and received a neurosurgical procedure. Long-term functional outcome was measured using the Pediatric Cerebral Performance Category (PCPC), Pediatric Overall Performance Category (POPC), and the Mullen Scales of Early Learning (MSEL). RESULTS: Seventy-seven patients were identified; 53 survived to discharge and had at least one-year follow-up. To examine long-term functional outcome, PCPC at the last available visit was examined and found to be 1 or 2 (normal to mild disability) for 64% of patients and 3 or 4 (moderate to severe disability) for 36%. The last available MSEL composite score for neurodevelopmental assessment also demonstrated that 13% of patients scored in the "average" range, 17% in the "below average" range, and 70% in the "very low" range. There was no statistical difference in the last available PCPC or POPC score or the last available MSEL score for patients who received a craniotomy when compared with those who received an intracranial shunt. CONCLUSIONS: For patients with AHT who survived to discharge, functional improvements over time were noted in both patients who received craniotomy or who simply required shunt placement. These results suggest that, for patients who survive to discharge, operative management of AHT can lead to reasonable long-term functional outcomes.

The Autism Detection in Early Childhood Tool: Level 2 autism spectrum disorder screening in a NICU Follow-up program.

OBJECTIVE: Children born preterm are at increased risk for autism spectrum disorder (ASD). However, early diagnosis of ASD is challenging because conventional screening Level 1 tools are less reliable in this population. We sought to determine whether the Autism Detection in Early Childhood (ADEC) and Child Behavior Checklist (CBCL) could accurately identify children at risk for ASD in a NICU Follow-up setting and thus facilitate referral for formal ASD evaluation. METHOD: Children aged 18-36 months were recruited from a NICU Follow-up program. All children received presumptive diagnoses based on DSM-5 criteria and were screened for ASD risk with the ADEC and CBCL. Children scoring in the "at risk" range on either tool were referred for a full diagnostic ASD evaluation. RESULTS: Sixty-nine patients (median birth weight 1140 g; median gestational age 28 weeks) were included with 18 designated "at risk" for ASD. Nine (13 %) scored "at risk" on the ADEC and 12 (17 %) on the CBCL. Thirteen children underwent diagnostic ASD evaluation with 9 receiving a formal diagnosis of ASD. The ADEC demonstrated the best performance (sensitivity 89 %, specificity 98 %). The CBCL was less sensitive (sensitivity 50 %, specificity 90 %). Requiring elevated scores on both the CBCL and ADEC was specific but not sensitive (sensitivity 33 %, specificity 100 %). CONCLUSION: The ADEC performed well in identifying children at risk for ASD within this high-risk NICU cohort, adding benefit as an autism-specific screening tool over the CBCL alone.

Preoperative Panel Testing for Hereditary Cancer Syndromes Does Not Significantly Impact Time to Surgery for Newly Diagnosed Breast Cancer Patients Compared with BRCA1/2 Testing.

BACKGROUND: This study seeks to determine whether there is a delay in time to surgery in breast cancer patients with panel tests compared with traditional BRCA testing. METHODS: This study was a retrospective review of women diagnosed with breast cancer who underwent genetic evaluation from our institution's Genetic Counselor Database from January 2013 to August 2015. Patients were excluded if they were male, clinical information was unavailable, the patient underwent neoadjuvant chemotherapy, had a diagnosis of recurrent breast cancer during time of study, or had postoperative genetics evaluation. RESULTS: Included in the study were 138 patients. The time from diagnosis to surgery for BRCA1/2 tested patients was 43.5 days compared with 51.0 days in the panel group (p = 0.186). Turnaround time for genetic testing decreased during the period studied and was approximately 6 days longer for panel testing than BRCA testing. It took 12.2 days for BRCA results and 18.9 days for the panel results (p < 0.01). Turnaround time for BRCA1/2 testing in 2014 and 2015 was 12.4 and 10.5 days respectively, whereas panel testing was 20.5 and 18.2 days (p ≤ 0.001). Of the variables included in multivariable linear regression, only mastectomy significantly contributed to time to surgery (p < 0.001). DISCUSSION: Panel genetic testing did not delay time to surgery compared with BRCA testing alone. The use of panel testing has increased over time, and lab turnaround time has decreased. Mastectomy was the only clinical variable contributing to longer time to surgery.

Learning, plasticity, and atypical generalization in children with autism.

Individuals with autism spectrum disorder (ASD) show accelerated learning in some tasks, degraded learning in others, and distinct deficits when generalizing to novel situations. Recent simulations with connectionist models suggest that deficits in cortical plasticity mechanisms can account for atypical patterns of generalization shown by some children with ASD. We tested the surprising theoretical prediction, from past simulations, that the children with ASD who show atypical generalization in perceptual categorization tasks will benefit more from training with a single prototypical member of the category than from training with multiple examples, but children with ASD who generalize normally will be comparatively harmed. The experimental results confirmed this prediction, suggesting that plasticity deficits may well underlie the difficulties that some children with ASD have generalizing skills, and these deficits are not specific to the acquisition of social skills, but rather reflect a more general perceptual learning deficit that may impact many abilities.

Differential contribution of CBP:CREB binding to corticotropin-releasing hormone expression in the infant and adult hypothalamus.

Corticotropin-releasing hormone (CRH) contributes crucially to the regulation of central and peripheral responses to stress. Because of the importance of a finely tuned stress system, CRH expression is tightly regulated in an organ- and brain region-specific manner. Thus, in the hypothalamus, CRH is constitutively expressed and this expression is further enhanced by stress; however, the underlying regulatory mechanisms are not fully understood. The regulatory region of the crh gene contains several elements, including the cyclic-AMP response element (CRE), and the role of the CRE interaction with the cyclic-AMP response element binding protein (CREB) in CRH expression has been a focus of intensive research. Notably, whereas thousands of genes contain a CRE, the functional regulation of gene expression by the CRE:CREB system is limited to ∼100 genes, and likely requires additional proteins. Here, we investigated the role of a member of the CREB complex, CREB binding protein (CBP), in basal and stress-induced CRH expression during development and in the adult. Using mice with a deficient CREB-binding site on CBP, we found that CBP:CREB interaction is necessary for normal basal CRH expression at the mRNA and protein level in the nine-day-old mouse, prior to onset of functional regulation of hypothalamic CRH expression by glucocorticoids. This interaction, which functions directly on crh or indirectly via regulation of other genes, was no longer required for maintenance of basal CRH expression levels in the adult. However, CBP:CREB binding contributed to stress-induced CRH expression in the adult, enabling rapid CRH synthesis in hypothalamus. CBP:CREB binding deficiency did not disrupt basal corticosterone plasma levels or acute stress-evoked corticosterone release. Because dysregulation of CRH expression occurs in stress-related disorders including depression, a full understanding of the complex regulation of this gene is important in both health and disease.

Digital family histories for data mining.

As we move closer to ubiquitous electronic health records (EHRs), genetic, familial, and clinical information will need to be incorporated into EHRs as structured data that can be used for data mining and clinical decision support. While the Human Genome Project has produced new and exciting genomic data, the cost to sequence the human personal genome is high, and significant controversies regarding how to interpret genomic data exist. Many experts feel that the family history is a surrogate marker for genetic information and should be part of any paper-based or electronic health record. A digital family history is now part of the Meaningful Use Stage 2 menu objectives for EHR reimbursement, projected for 2014. In this study, a secure online family history questionnaire was designed to collect data on a unique cohort of Vietnam-era repatriated male veterans and a comparison group in order to compare participant and family disease rates on common medical disorders with a genetic component. This article describes our approach to create the digital questionnaire and the results of analyzing family history data on 319 male participants.

Forebrain CRF1 modulates early-life stress-programmed cognitive deficits.

Childhood traumatic events hamper the development of the hippocampus and impair declarative memory in susceptible individuals. Persistent elevations of hippocampal corticotropin-releasing factor (CRF), acting through CRF receptor 1 (CRF1), in experimental models of early-life stress have suggested a role for this endogenous stress hormone in the resulting structural modifications and cognitive dysfunction. However, direct testing of this possibility has been difficult. In the current study, we subjected conditional forebrain CRF1 knock-out (CRF1-CKO) mice to an impoverished postnatal environment and examined the role of forebrain CRF1 in the long-lasting effects of early-life stress on learning and memory. Early-life stress impaired spatial learning and memory in wild-type mice, and postnatal forebrain CRF overexpression reproduced these deleterious effects. Cognitive deficits in stressed wild-type mice were associated with disrupted long-term potentiation (LTP) and a reduced number of dendritic spines in area CA3 but not in CA1. Forebrain CRF1 deficiency restored cognitive function, LTP and spine density in area CA3, and augmented CA1 LTP and spine density in stressed mice. In addition, early-life stress differentially regulated the amount of hippocampal excitatory and inhibitory synapses in wild-type and CRF1-CKO mice, accompanied by alterations in the neurexin-neuroligin complex. These data suggest that the functional, structural and molecular changes evoked by early-life stress are at least partly dependent on persistent forebrain CRF1 signaling, providing a molecular target for the prevention of cognitive deficits in adults with a history of early-life adversity.

Correlated memory defects and hippocampal dendritic spine loss after acute stress involve corticotropin-releasing hormone signaling.

Stress affects the hippocampus, a brain region crucial for memory. In rodents, acute stress may reduce density of dendritic spines, the location of postsynaptic elements of excitatory synapses, and impair long-term potentiation and memory. Steroid stress hormones and neurotransmitters have been implicated in the underlying mechanisms, but the role of corticotropin-releasing hormone (CRH), a hypothalamic hormone also released during stress within hippocampus, has not been elucidated. In addition, the causal relationship of spine loss and memory defects after acute stress is unclear. We used transgenic mice that expressed YFP in hippocampal neurons and found that a 5-h stress resulted in profound loss of learning and memory. This deficit was associated with selective disruption of long-term potentiation and of dendritic spine integrity in commissural/associational pathways of hippocampal area CA3. The degree of memory deficit in individual mice correlated significantly with the reduced density of area CA3 apical dendritic spines in the same mice. Moreover, administration of the CRH receptor type 1 (CRFR(1)) blocker NBI 30775 directly into the brain prevented the stress-induced spine loss and restored the stress-impaired cognitive functions. We conclude that acute, hours-long stress impairs learning and memory via mechanisms that disrupt the integrity of hippocampal dendritic spines. In addition, establishing the contribution of hippocampal CRH-CRFR(1) signaling to these processes highlights the complexity of the orchestrated mechanisms by which stress impacts hippocampal structure and function.

Retrospective comparison of patient outcomes after in-person and telephone results disclosure counseling for BRCA1/2 genetic testing.

Telephone disclosure of BRCA1/2 molecular genetic test results has been proposed as a feasible alternative to traditional in-person results disclosure. The purpose of this study was to investigate the relationship between method of result disclosure with the patient outcome variables of knowledge, cancer worry, cancer risk perception, satisfaction, and cancer screening and prophylactic surgery behaviors. Study participants included 228 women who completed retrospective, self-administered, mailed surveys regarding their pre-test genetic counseling and results disclosure. No significant relationships were found between result disclosure method and the outcome variables investigated. A majority (90%) of individuals who received positive results by telephone returned for follow up visits. Factors which genetic counselors believed influenced their clinical decision to offer telephone disclosure, such as history of breast cancer, a priori risk of genetic mutation and family history of known mutation were not shown to significantly impact the actual disclosure method. This study suggests that telephone results disclosure is clinically appropriate when counselors utilize their clinical judgment to determine which patients are appropriate candidates.

A novel mouse model for acute and long-lasting consequences of early life stress.

Chronic early-life stress (ES) exerts profound acute and long-lasting effects on the hypothalamic-pituitary-adrenal system, with relevance to cognitive function and affective disorders. Our ability to determine the molecular mechanisms underlying these effects should benefit greatly from appropriate mouse models because these would enable use of powerful transgenic methods. Therefore, we have characterized a mouse model of chronic ES, which was provoked in mouse pups by abnormal, fragmented interactions with the dam. Dam-pup interaction was disrupted by limiting the nesting and bedding material in the cages, a manipulation that affected this parameter in a dose-dependent manner. At the end of their week-long rearing in the limited-nesting cages, mouse pups were stressed, as apparent from elevated basal plasma corticosterone levels. In addition, steady-state mRNA levels of CRH in the hypothalamic paraventricular nucleus of ES-experiencing pups were reduced, without significant change in mRNA levels of arginine vasopressin. Rearing mouse pups in this stress-provoking cage environment resulted in enduring effects: basal plasma corticosterone levels were still increased, and CRH mRNA levels in paraventricular nucleus remained reduced in adult ES mice, compared with those of controls. In addition, hippocampus-dependent learning and memory functions were impaired in 4- to 8-month-old ES mice. In summary, this novel, robust model of chronic early life stress in the mouse results in acute and enduring neuroendocrine and cognitive abnormalities. This model should facilitate the examination of the specific genes and molecules involved in the generation of this stress as well as in its consequences.

Rapid loss of dendritic spines after stress involves derangement of spine dynamics by corticotropin-releasing hormone.

Chronic stress causes dendritic regression and loss of dendritic spines in hippocampal neurons that is accompanied by deficits in synaptic plasticity and memory. However, the responsible mechanisms remain unresolved. Here, we found that within hours of the onset of stress, the density of dendritic spines declined in vulnerable dendritic domains. This rapid, stress-induced spine loss was abolished by blocking the receptor (CRFR(1)) of corticotropin-releasing hormone (CRH), a hippocampal neuropeptide released during stress. Exposure to CRH provoked spine loss and dendritic regression in hippocampal organotypic cultures, and selective blockade of the CRFR(1) receptor had the opposite effect. Live, time-lapse imaging revealed that CRH reduced spine density by altering dendritic spine dynamics: the peptide selectively and reversibly accelerated spine retraction, and this mechanism involved destabilization of spine F-actin. In addition, mice lacking the CRFR(1) receptor had augmented spine density. These findings support a mechanistic role for CRH-CRFR(1) signaling in stress-evoked spine loss and dendritic remodeling.