Learning to Look for Language: Development of Joint Attention in Young Deaf Children.

Joint attention between hearing children and their caregivers is typically achieved when the adult provides spoken, auditory linguistic input that relates to the child's current visual focus of attention. Deaf children interacting through sign language must learn to continually switch visual attention between people and objects in order to achieve the classic joint attention characteristic of young hearing children. The current study investigated the mechanisms used by sign language dyads to achieve joint attention within a single modality.

Transcriptional activation of TFEB/ZKSCAN3 target genes underlies enhanced autophagy in spinobulbar muscular atrophy.

Spinobulbar muscular atrophy (SBMA) is an inherited neuromuscular disorder caused by the expansion of a CAG repeat encoding a polyglutamine tract in exon 1 of the androgen receptor (AR) gene. SBMA demonstrates androgen-dependent toxicity due to unfolding and aggregation of the mutant protein. There are currently no disease-modifying therapies, but of increasing interest for therapeutic targeting is autophagy, a highly conserved cellular process mediating protein quality control.

Finger displacement in Parkinson disease: up? down? sideways?

We previously reported that patients with tremor preponderant Parkinson disease (PD) displayed upward or lateral displacement of their more tremulous finger when they pointed both their index fingers at a target and closed their eyes for 15 seconds. In this study, we examined the phenomenon in 104 PD patients: 72 patients without tremor and 32 with minimal tremor to see if the displacement is related to the disease or the tremor. Sixty-eight of the 72 patients without tremor, 94%, exhibited finger displacement suggesting the phenomenon is related to the disease.

Pathogenic mechanisms and therapeutic strategies in spinobulbar muscular atrophy.

We review the genetic and clinical features of spinobulbar muscular atrophy (SBMA), a progressive neuromuscular disorder caused by a CAG/glutamine tract expansion in the androgen receptor. SBMA was the first polyglutamine disease to be discovered, and we compare and contrast it with related degenerative disorders of the nervous system caused by expanded glutamine tracts. We review the cellular and animals models that have been most widely used to study this disorder, and highlight insights into disease pathogenesis derived from this work.

Funding anatomic pathology research: a retrospective analysis of an intramural funding mechanism.

Context: In 2006, the department of pathology at our institution established an intramural research funding mechanism to support anatomic pathology research projects for faculty and trainee development. A review committee consisting of faculty members with diverse academic interests evaluated applications; proposals were eligible for a maximum award amount of $30 000 per project with a maximum program cost of $150 000 annually.

Objective: To report our experience based on a retrospective review of the research proposals submitted to the committee since the inception of the Anatomic Pathology Research Fund and evaluate the outcomes of the funded projects.

Radiology-pathology case report: isolated extranodal Rosai-Dorfman disease of the skull base.

Rosai-Dorfman disease is a rare pathologic entity characterized by massively enlarged painless cervical lymph nodes. Exclusive extranodal disease is much less common than the characteristic presentation with exclusive central nervous system and skull base involvement being quite rare. We present a case of exclusive extranodal Rosai-Dorfman disease of the skull base and briefly discuss the entity.

Distinguishing the tremor of Parkinson's disease from essential tremor: finger displacement.

Although, the tremor of Parkinson's disease (PD) usually, but not always, differs from essential tremor (ET), there is no simple bedside test to distinguish PD from ET. We believe we have made such an observation. We studied 50 consecutive tremor-dominant PD patients (mean age: 63.

Infants and young children in military families: a conceptual model for intervention.

Infants and young children of parents in the military deserve special attention because the first years of life are pivotal in establishing trusting attachment relationships, which are based on the developmental expectation that parents will be reliably available and protective both physically and emotionally. For young children in military families, the stresses of extended absences of mothers and/or fathers as the result of deployment abroad, recurrent separations and reunions resulting from repeated deployments, or parents struggling with the emotional sequelae of their war experiences, and the traumatic impact of parental injury and death can strain and derail the normative expectation of parental availability and protectiveness. This article describes the key features of mental health in infancy and early childhood, the developmentally expectable early anxieties that all children experience in the first years of life across cultures and circumstances, and the ways in which these normative anxieties are exacerbated by the specific circumstances of military families.

Human and mouse neuroinflammation markers in Niemann-Pick disease, type C1.

Niemann-Pick disease, type C1 (NPC1) is an autosomal recessive lipid storage disorder in which a pathological cascade, including neuroinflammation occurs. While data demonstrating neuroinflammation is prevalent in mouse models, data from NPC1 patients is lacking. The current study focuses on identifying potential markers of neuroinflammation in NPC1 from both the Npc1 mouse model and NPC1 patients.

Npc1 acting in neurons and glia is essential for the formation and maintenance of CNS myelin.

Cholesterol availability is rate-limiting for myelination, and prior studies have established the importance of cholesterol synthesis by oligodendrocytes for normal CNS myelination. However, the contribution of cholesterol uptake through the endocytic pathway has not been fully explored. To address this question, we used mice with a conditional null allele of the Npc1 gene, which encodes a transmembrane protein critical for mobilizing cholesterol from the endolysosomal system.

C9ORF72 expansion in a family with bipolar disorder.

Objective: To investigate the role in bipolar disorder of the C9ORF72 hexanucleotide repeat expansion responsible for frontotemporal lobe dementia and amyotrophic lateral sclerosis.

Methods: Eighty-nine subjects from a previously described panel of individuals with bipolar disorder ascertained for genetic studies were screened to detect expansion of the C9ORF72 repeat. One two-generation family with bipolar disorder and an expanded repeat was characterized in depth using molecular diagnostics, imaging, histopathology, and neurological and neuropsychological evaluation.

Maternal symptomatology and parent-child relationship functioning in a diverse sample of young children exposed to trauma.

Children under the age of 6 years are disproportionately exposed to interpersonal trauma. Research describing type and frequency of exposure to trauma among this young population is limited. Additionally, few studies have assessed the role of multiple indicators of parental functioning on children's behavior following trauma exposure.

Sources of technical variability in quantitative LC-MS proteomics: human brain tissue sample analysis.

To design a robust quantitative proteomics study, an understanding of both the inherent heterogeneity of the biological samples being studied as well as the technical variability of the proteomics methods and platform is needed. Additionally, accurately identifying the technical steps associated with the largest variability would provide valuable information for the improvement and design of future processing pipelines. We present an experimental strategy that allows for a detailed examination of the variability of the quantitative LC-MS proteomics measurements.

The calcineurin-NFAT pathway negatively regulates megakaryopoiesis.

The calcium regulated calcineurin-nuclear factor of activated T cells (NFAT) pathway modulates the physiology of numerous cell types, including hematopoietic. Upon activation, calcineurin dephosphorylates NFAT family transcription factors, triggering their nuclear entry and activation or repression of target genes. NFATc1 and c2 isoforms are expressed in megakaryocytes.

Is there room for non-dopaminergic treatment in Parkinson disease?

Although levodopa and dopaminergic drugs remain the mainstay of therapy for the motor symptoms of Parkinson disease (PD), they fail to address many of the non-motor symptoms of PD including orthostatic hypotension, freezing of gait (FOG) and difficulty with balance, drug-induced paranoia and hallucinations, and drug-induced dyskinesias. Droxidopa, a drug that increases norepinephrine, treats orthostatic hypotension, cholinomimetic drugs sometimes help with FOG and difficulty with balance, pimavanserin, a drug that blocks serotonin receptors, treats paranoia and hallucinations, and anti-glutaminergic drugs treat dyskinesias. Thus, there are ample opportunities for non-dopaminergic drugs in PD.

Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation.

We sought new strategies to reduce amounts of the polyglutamine androgen receptor (polyQ AR) and achieve benefits in models of spinobulbar muscular atrophy, a protein aggregation neurodegenerative disorder. Proteostasis of the polyQ AR is controlled by the heat shock protein 90 (Hsp90)- and Hsp70-based chaperone machinery, but mechanisms regulating the protein's turnover are incompletely understood. We demonstrate that overexpression of Hsp70 interacting protein (Hip), a co-chaperone that enhances binding of Hsp70 to its substrates, promotes client protein ubiquitination and polyQ AR clearance.

Autophagic dysfunction in a lysosomal storage disorder due to impaired proteolysis.

Alterations in macroautophagy (hereafter referred to as "autophagy") are a common feature of lysosomal storage disorders, and have been hypothesized to play a major role in the pathogenesis of these diseases. We have recently reported multiple defects in autophagy contributing to the lysosomal storage disorder Niemann-Pick type C (NPC). These include increased formation of autophagosomes, slowed turnover of autophagosomes secondary to impaired lysosomal proteolysis, and delivery of stored lipids to the lysosome via autophagy.

Apolipoprotein E genotype and neurological disease onset in Niemann-Pick disease, type C1.

Niemann-Pick disease, type C1 (NPC1) is a lipid storage disorder that results in progressive neurological impairment. The NPC1 phenotype is extremely variable and at the individual level is likely influenced by other genetic traits. In addition to residual function of NPC1 protein, we hypothesize that modifier genes, as frequently observed with other autosomal recessive diseases, influence the NPC phenotype.

Guidelines for the use and interpretation of assays for monitoring autophagy.

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding.

DSM-V diagnostic criteria for bereavement-related disorders in children and adolescents: developmental considerations.

Two bereavement-related disorders are proposed for the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V): Adjustment Disorder Related to Bereavement, to be located in the main body of the text as an official diagnostic entity; and Bereavement-Related Disorder, including a Traumatic Death Specifier, to be located in the Appendix as an invitation for further research. These diagnoses currently do not include developmentally informed criteria, despite the importance of developmental processes in the ways children and adolescents grieve. In this article, we draw upon a selective review of the empirical literature and expert clinical knowledge to recommend developmentally informed modifications and specifiers of the proposed criteria for both bereavement disorders and strategies to improve future research.

Impaired proteolysis underlies autophagic dysfunction in Niemann-Pick type C disease.

Niemann-Pick type C disease (NPC) is a childhood onset neurodegenerative disorder arising from lipid-trafficking defects caused by mutations in the NPC1 or NPC2 gene. Marked accumulation of autophagosomes is a prominent feature of NPC cells, yet a detailed understanding of the disease-associated alterations in autophagy and their role in pathogenesis has been lacking. Prior studies have shown that lipid storage in NPC disease induces autophagy.

A simple question about falls to distinguish balance and gait difficulties in Parkinson's disease.

Although gait and balance difficulties often occur together in Parkinson's disease (PD) patients, it is believed that they are actually two eparate symptoms. However, there are no simple tests to distinguish them. We have developed the self-administered Barrow Neurological Institute (BNI) question to distinguish between gait and balance issues in PD and it was tested in 102 consecutive PD patients.

A polyglutamine expansion disease protein sequesters PTIP to attenuate DNA repair and increase genomic instability.

Glutamine (Q) expansion diseases are a family of degenerative disorders caused by the lengthening of CAG triplet repeats present in the coding sequences of seemingly unrelated genes whose mutant proteins drive pathogenesis. Despite all the molecular evidence for the genetic basis of these diseases, how mutant poly-Q proteins promote cell death and drive pathogenesis remains controversial. In this report, we show a specific interaction between the mutant androgen receptor (AR), a protein associated with spinal and bulbar muscular atrophy (SBMA), and the nuclear protein PTIP (Pax Transactivation-domain Interacting Protein), a protein with an unusually long Q-rich domain that functions in DNA repair.

Autophagy in lysosomal storage disorders.

Lysosomes are ubiquitous intracellular organelles that have an acidic internal pH, and play crucial roles in cellular clearance. Numerous functions depend on normal lysosomes, including the turnover of cellular constituents, cholesterol homeostasis, downregulation of surface receptors, inactivation of pathogenic organisms, repair of the plasma membrane and bone remodeling. Lysosomal storage disorders (LSDs) are characterized by progressive accumulation of undigested macromolecules within the cell due to lysosomal dysfunction.