School Nurses on the Front Lines of Healthcare: Emergencies Associated With Sport and Physical Activities (Part 4)-The Assessment of Pediatric Shoulder and Hip Injuries Utilizing the "SPASMS" Mnemonic.

Sport participation is an important part of the development, both physically and mentally, of children and adolescents in the United States. Illness and injury associated with sport and physical activities may occur in the school setting. Although most sport-related illness and injury in students are considered minor emergencies, life-threatening illnesses or injuries may occur. It is important for the school nurse to recognize potential life-threatening emergencies associated with sport and physical activity, to initiate stabilization of the student with life-threatening symptoms, and to triage these students to an appropriate level of care (back to the classroom, home with their guardian with follow up at their primary healthcare provider's office, or directly to the closest emergency department [ED] via Emergency Medical Services [EMS]). This article specifically describes the initial assessment and management of shoulder and hip injuries in pediatric athletes.

School Nurses on the Front Lines of Medicine: Emergencies Associated With Sport and Physical Activities: Part 1.

Illness and injury associated with sport and physical activities may occur in the school setting. Although most sport-related illness and injury in students are considered minor emergencies, life- and limb-threatening illnesses or injuries may occur, such as sudden cardiac arrest, heat stroke, status asthmaticus, catastrophic brain or cervical spine injuries, hypoglycemia, blunt chest/abdominal injuries, or extremity fractures requiring surgery. It is important for the school nurse to recognize potential life- and limb-threatening emergencies associated with sport and physical activity, to initiate stabilization of the student with life- and limb-threatening symptoms, and to triage these students to an appropriate level of care (back to the classroom, home with their guardian with follow up at their primary healthcare provider's office, or directly to the closest emergency department via emergency medical services). This article describes the initial assessment and management of three common emergencies associated with sport and physical activities.

Pharmacokinetic/Pharmacodynamic Correlation Analysis of Amantadine for Levodopa-Induced Dyskinesia.

Dyskinesia is a common motor complication associated with the use of levodopa to treat Parkinson's disease. Numerous animal studies in mice, rats, and nonhuman primates have demonstrated that the N-methyl-d-aspartate antagonist, amantadine, dose dependently reduces levodopa-induced dyskinesia (LID). However, none of these studies characterized the amantadine plasma concentrations required for a therapeutic effect. This study evaluates the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between amantadine plasma concentrations and antidyskinetic efficacy across multiple species to define optimal therapeutic dosing. The PK profile of amantadine was determined in mice, rats, and macaques. Efficacy data from the 6-hydroxydopamine rat and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine macaque model of LID, along with previously published antidyskinetic efficacy data, were used to establish species-specific PK/PD relationships using a direct-effect maximum possible effect model. Results from the PK/PD model were compared with amantadine plasma concentrations and antidyskinetic effect in a phase 2 study in patients with Parkinson's disease treated with ADS-5102, an extended-release amantadine capsule formulation. Outcomes from each of the species evaluated indicate that the EC50 of amantadine for reducing dyskinesia range from 1025 to 1633 ng/ml (1367 ng/ml for an all-species model). These data are consistent with the mean amantadine plasma concentrations observed in patients with Parkinson's disease (∼1500 ng/ml) treated with ADS-5102 at doses that demonstrated a statistically significant reduction in dyskinesia. These results demonstrate that the EC50 of amantadine for reducing dyskinesia is consistent across multiple species and supports a plasma concentration target of ∼1400 ng/ml to achieve therapeutic efficacy.

Motivations for Compliance With Bracing in Adolescent Idiopathic Scoliosis.

STUDY DESIGN: Cross-sectional study. OBJECTIVE: To determine motivations for compliance with bracing among female patients with adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Bracing prevents the need for surgery for the majority of girls with AIS with curves of 20° to 40° and 2 or more years of growth remaining. The main obstacle to success is compliance. The factors that either promote or impede compliance previously have not been fully clarified. METHODS: Participants were females 10 to 16 years of age who were prescribed a brace to be worn 16 hours per day for AIS. Each completed a "Scoliosis Compliance Questionnaire" composed of the SRS-22r and five original sections focused on patients' attitudes to scoliosis, situations in which they found wearing the brace to be most and least difficult, factors that motivate brace wear, and interventions that could potentially improve compliance. RESULTS: Thirty-nine subjects completed the study, mean age 13 years (range 11-15 years), at a mean of 15.4 months (range 4-39 months) of brace wear at the time of recruitment. More than 90% of patients stated that their main motivations for compliance were the desire to avoid surgery and to prevent curve progression. Compliance was most challenging during the summer and while at school. Many patients reported pain and skin irritation in the brace. The majority reported they would likely improve their hours of wear if they were able to communicate with a peer in the same situation. SRS-22r scores were similar to those of healthy adolescents. CONCLUSIONS: The most important influences promoting brace wear are the patient's desire to avoid surgery and to prevent curve progression. Peer support potentially may improve compliance. LEVEL OF EVIDENCE: Level III.

Inhibition of APP gamma-secretase restores Sonic Hedgehog signaling and neurogenesis in the Ts65Dn mouse model of Down syndrome.

Neurogenesis impairment starting from early developmental stages is a key determinant of intellectual disability in Down syndrome (DS). Previous evidence provided a causal relationship between neurogenesis impairment and malfunctioning of the mitogenic Sonic Hedgehog (Shh) pathway. In particular, excessive levels of AICD (amyloid precursor protein intracellular domain), a cleavage product of the trisomic gene APP (amyloid precursor protein) up-regulate transcription of Ptch1 (Patched1), the Shh receptor that keeps the pathway repressed. Since AICD results from APP cleavage by γ-secretase, the goal of the current study was to establish whether treatment with a γ-secretase inhibitor normalizes AICD levels and restores neurogenesis in trisomic neural precursor cells. We found that treatment with a selective γ-secretase inhibitor (ELND006; ELN) restores proliferation in neurospheres derived from the subventricular zone (SVZ) of the Ts65Dn mouse model of DS. This effect was accompanied by reduction of AICD and Ptch1 levels and was prevented by inhibition of the Shh pathway with cyclopamine. Treatment of Ts65Dn mice with ELN in the postnatal period P3-P15 restored neurogenesis in the SVZ and hippocampus, hippocampal granule cell number and synapse development, indicating a positive impact of treatment on brain development. In addition, in the hippocampus of treated Ts65Dn mice there was a reduction in the expression levels of various genes that are transcriptionally regulated by AICD, including APP, its origin substrate. Inhibitors of γ-secretase are currently envisaged as tools for the cure of Alzheimer's disease because they lower ßamyloid levels. Current results provide novel evidence that γ-secretase inhibitors may represent a strategy for the rescue of neurogenesis defects in DS.

Like Father, Like Son: Cleidocranial Dysplasia: A Case Report.

CASE: We present the case of a six-year-old boy who was referred to the pediatric orthopaedics division of our academic medical center by his primary care physician for a concern regarding possible fractured clavicles. He was diagnosed with cleidocranial dysplasia, a genetic condition characterized by skeletal and dental anomalies, primarily delayed ossification of midline osseous structures. On radiographs, cleidocranial dysplasia has been linked to both coxa vara and a characteristic "chef's hat" appearance of the femoral head. CONCLUSION: Cleidocranial dysplasia has multiple potential orthopaedic complications, and an awareness of this condition, its presentations, and its diagnosis is useful for all physicians.

Leucine-rich repeat kinase 2 (LRRK2)-deficient rats exhibit renal tubule injury and perturbations in metabolic and immunological homeostasis.

Genetic evidence links mutations in the LRRK2 gene with an increased risk of Parkinson's disease, for which no neuroprotective or neurorestorative therapies currently exist. While the role of LRRK2 in normal cellular function has yet to be fully described, evidence suggests involvement with immune and kidney functions. A comparative study of LRRK2-deficient and wild type rats investigated the influence that this gene has on the phenotype of these rats. Significant weight gain in the LRRK2 null rats was observed and was accompanied by significant increases in insulin and insulin-like growth factors. Additionally, LRRK2-deficient rats displayed kidney morphological and histopathological alterations in the renal tubule epithelial cells of all animals assessed. These perturbations in renal morphology were accompanied by significant decreases of lipocalin-2, in both the urine and plasma of knockout animals. Significant alterations in the cellular composition of the spleen between LRRK2 knockout and wild type animals were identified by immunophenotyping and were associated with subtle differences in response to dual infection with rat-adapted influenza virus (RAIV) and Streptococcus pneumoniae. Ontological pathway analysis of LRRK2 across metabolic and kidney processes and pathological categories suggested that the thioredoxin network may play a role in perturbing these organ systems. The phenotype of the LRRK2 null rat is suggestive of a complex biology influencing metabolism, immune function and kidney homeostasis. These data need to be extended to better understand the role of the kinase domain or other biological functions of the gene to better inform the development of pharmacological inhibitors.

Discovery of (R)-4-cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline (ELND006) and (R)-4-cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline (ELND007): metabolically stable γ-secretase Inhibitors that selectively inhibit the production of amyloid-ß over Notch.

Herein, we describe our strategy to design metabolically stable γ-secretase inhibitors which are selective for inhibition of Aß generation over Notch. We highlight our synthetic strategy to incorporate diversity and chirality. Compounds 30 (ELND006) and 34 (ELND007) both entered human clinical trials. The in vitro and in vivo characteristics for these two compounds are described. A comparison of inhibition of Aß generation in vivo between 30, 34, Semagacestat 41, Begacestat 42, and Avagacestat 43 in mice is made. 30 lowered Aß in the CSF of healthy human volunteers.

Discovery of 4-alkylamino-7-aryl-3-cyanoquinoline LRRK2 kinase inhibitors.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with familial Parkinson's disease (PD). The kinase activity of this complex protein is increased by pathogenic mutations. Inhibition of LRRK2 kinase activity has therefore emerged as a promising approach for the treatment of PD. Herein we report our findings on a series of 4-alkylamino-7-aryl-3-cyanoquinolines that exhibit kinase inhibitory activity against both wild type and G2019S mutant LRRK2. Activity was determined in both biochemical and cellular assays. Compound 14 was further evaluated in an in vivo pharmacodynamic study and found to significantly inhibit Ser935 phosphorylation after oral dosing.

Discovery of a novel [3.2.1] benzo fused bicyclic sulfonamide-pyrazoles as potent, selective and efficacious γ-secretase inhibitors.

Structure-activity relationship (SAR) of a novel, potent and metabolically stable series of benzo [3.2.1] bicyclic sulfonamide-pyrazoles as γ-secretase inhibitors are described. Compounds that are efficacious in reducing the cortical Aßx-40 levels in FVB mice via oral dose, as well as those with high selectivity over Notch, are highlighted.

The ß-secretase-derived C-terminal fragment of ßAPP, C99, but not Aß, is a key contributor to early intraneuronal lesions in triple-transgenic mouse hippocampus.

Triple-transgenic mice (3xTgAD) overexpressing Swedish-mutated ß-amyloid precursor protein (ßAPP(swe)), P310L-Tau (Tau(P301L)), and physiological levels of M146V-presenilin-1 (PS1(M146V)) display extracellular amyloid-ß peptides (Aß) deposits and Tau tangles. More disputed is the observation that these mice accumulate intraneuronal Aß that has been linked to synaptic dysfunction and cognitive deficits. Here, we provide immunohistological, genetic, and pharmacological evidences for early, age-dependent, and hippocampus-specific accumulation of the ß-secretase-derived ßAPP fragment C99 that is observed from 3 months of age and enhanced by pharmacological blockade of γ-secretase. Notably, intracellular Aß is only detectable several months later and appears, as is the case of C99, in enlarged cathepsin B-positive structures, while extracellular Aß deposits are detected ~12 months of age and beyond. Early C99 production occurs mainly in the CA1/subicular interchange area of the hippocampus corresponding to the first region exhibiting plaques and tangles in old mice. Furthermore, the comparison of 3xTgAD mice with double-transgenic mice bearing the ßAPP(swe) and Tau(P301L) mutations but expressing endogenous PS1 (2xTgAD) demonstrate that C99 accumulation is not accounted for by a loss of function triggered by PS1 mutation that would have prevented C99 secondary cleavage by γ-secretase. Together, our work identifies C99 as the earliest ßAPP catabolite and main contributor to the intracellular ßAPP-related immunoreactivity in 3xTgAD mice, suggesting its implication as an initiator of the neurodegenerative process and cognitive alterations taking place in this mouse model.

Development of ALZET® osmotic pump compatible solvent compositions to solubilize poorly soluble compounds for preclinical studies.

CONTEXT: Hydrophilic, non-aqueous solvents are frequently used to solubilize poorly water soluble compounds for use in ALZET® osmotic pumps used during the discovery and preclinical stages. Though these solvents exhibit the potential to solubilize several poorly soluble compounds, the solubilized compounds are prone to crystallization up on contact with aqueous fluids in vitro and in vivo. Crystallization of a compound can potentially cause pain at the release site, erratic blood levels, and uneven or delayed pharmacokinetic profiles. OBJECTIVE: In this study, we discussed the development of ALZET® pump compatible hydrophilic, non-aqueous vehicles that solubilized two poorly soluble model compounds (ELND006 and ELN 481594) and prevented their crystallization from solutions in vitro and in vivo. METHODS: The selected formulations were filled into the pumps at three concentrations for each model compound and investigated for their compatibility with the pumps and the subcutaneous tissue of mice where the pump was inserted. RESULTS AND DISCUSSION: The results showed that the formulations were stable physically with no crystallization and chemically with no degradation and were compatible with the pump and animal tissue. The plasma concentration of ELND006 decreased with time at each dose. The extent of the time-dependent decrease in ELND006 plasma levels increased as the amount of dose delivered increased. This time and dose dependent decrease in ELND006 plasma concentrations was attributed to the known auto-induction of hepatic enzymes by the compound. In contrast, the plasma concentration of ELN 481594 increased significantly at higher dose, likely due to accumulation of the compound.

Design, synthesis and structure-activity relationship of novel [3.3.1] bicyclic sulfonamide-pyrazoles as potent γ-secretase inhibitors.

The structure-activity relationship (SAR) of a novel, potent and metabolically stable series of sulfonamide-pyrazoles that attenuate ß-amyloid peptide synthesis via γ-secretase inhibition is detailed herein. Sulfonamide-pyrazoles that are efficacious in reducing the cortical Aßx-40 levels in FVB mice via a single PO dose, as well as sulfonamide-pyrazoles that exhibit selectivity for inhibition of APP versus Notch processing by γ-secretase, are highlighted.

Amino-caprolactam γ-secretase inhibitors showing potential for the treatment of Alzheimer's disease.

Herein we describe the structure-activity relationship (SAR) of amino-caprolactam analogs derived from amino-caprolactam benzene sulfonamide 1, highlighting affects on the potency of γ-secretase inhibition, selectivity for the inhibition of APP versus Notch processing by γ-secretase and selected pharmakokinetic properties. Amino-caprolactams that are efficacious in reducing the cortical Aß(x-40) levels in FVB mice via a single 100 mpk IP dose are highlighted.

Design and synthesis of a novel, orally active, brain penetrant, tri-substituted thiophene based JNK inhibitor.

The SAR of a series of tri-substituted thiophene JNK3 inhibitors is described. By optimizing both the N-aryl acetamide region of the inhibitor and the 4-position of the thiophene we obtained single digit nanomolar compounds, such as 47, which demonstrated an in vivo effect on JNK activity when dosed orally in our kainic acid mouse model as measured by phospho-c-jun reduction.

Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease.

INTRODUCTION: Inhibition of gamma-secretase presents a direct target for lowering Aß production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a safety perspective for AD therapy. METHODS: In vitro assays monitoring inhibitor potencies at APP γ-site cleavage (equivalent to Aß40), and Notch ε-site cleavage, in conjunction with a single cell assay to simultaneously monitor selectivity for inhibition of Aß production vs. Notch signaling were developed to discover APP selective gamma-secretase inhibitors. In vivo efficacy for acute reduction of brain Aß was determined in the PDAPP transgene model of AD, as well as in wild-type FVB strain mice. In vivo selectivity was determined following seven days x twice per day (b.i.d.) treatment with 15 mg/kg/dose to 1,000 mg/kg/dose ELN475516, and monitoring brain Aß reduction vs. Notch signaling endpoints in periphery. RESULTS: The APP selective gamma-secretase inhibitors ELN318463 and ELN475516 reported here behave as classic gamma-secretase inhibitors, demonstrate 75- to 120-fold selectivity for inhibiting Aß production compared with Notch signaling in cells, and displace an active site directed inhibitor at very high concentrations only in the presence of substrate. ELN318463 demonstrated discordant efficacy for reduction of brain Aß in the PDAPP compared with wild-type FVB, not observed with ELN475516. Improved in vivo safety of ELN475516 was demonstrated in the 7d repeat dose study in wild-type mice, where a 33% reduction of brain Aß was observed in mice terminated three hours post last dose at the lowest dose of inhibitor tested. No overt in-life or post-mortem indications of systemic toxicity, nor RNA and histological end-points indicative of toxicity attributable to inhibition of Notch signaling were observed at any dose tested. CONCLUSIONS: The discordant in vivo activity of ELN318463 suggests that the potency of gamma-secretase inhibitors in AD transgenic mice should be corroborated in wild-type mice. The discovery of ELN475516 demonstrates that it is possible to develop APP selective gamma-secretase inhibitors with potential for treatment for AD.

Design of an orally efficacious hydroxyethylamine (HEA) BACE-1 inhibitor in a preclinical animal model.

In this Letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing 16 which lowers Αß by 28% and 32% in the cortex and CSF, respectively, in the preclinical wild type Hartley guinea pig animal model when dosed orally at 30mpk BID for 2.5days.