Inter-agency indicators of out-of-home-care placement by age 13-14 years: A population record linkage study.

BACKGROUND: Cross-agency administrative data can improve cost-effective triage systems for child protection and other human service delivery. OBJECTIVE: To determine the minimum set of cross-agency indicators that could accurately classify placement in out-of-home-care (OOHC) before age 13-14 years. PARTICIPANTS AND SETTING: Participants were 72,079 Australian children (mean age = 13.16 years; SD = 0.37; 51.4% male) and their parents, for whom linked administrative records spanning the years 1994-2016 were available for analysis within the 'New South Wales Child Development Study'. METHODS: First, a series of logistic regression analyses were conducted to examine associations between cross-agency (health, justice, education) risk indicators and membership of the sub-cohort of 1239 children who had an OOHC placement prior to age 13-14 years, relative to (1) the sub-cohort of 55,473 children who had no previous contact with child protection services, and (2) the sub-cohort of 15,367 children who had been reported to child protection services but had no record of OOHC placement. We then explored the classification characteristics associated with a smaller combination of risk factors, and the utility of specific familial risk factors, for classifying membership of the OOHC subgroup. RESULTS: A combination of six risk indicators evident before OOHC placement can classify children placed in OOHC with approximately 95% accuracy, and the presence of at least four of these risk indicators provides excellent specificity (99.6%). CONCLUSIONS: A combination of risk factors observable in administrative datasets held by multiple government agencies may be used to target support services to prevent entry into OOHC for children from vulnerable families.

Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation.

Aberrant activation of matrix metalloproteinases (MMPs) is a common feature of pathological cascades observed in diverse disorders, such as cancer, fibrosis, immune dysregulation, and neurodegenerative diseases. MMP-9, in particular, is highly dynamically regulated in several pathological processes. Development of MMP inhibitors has therefore been an attractive strategy for therapeutic intervention. However, a long history of failed clinical trials has demonstrated that broad-spectrum MMP inhibitors have limited clinical utility, which has spurred the development of inhibitors selective for individual MMPs. Attaining selectivity has been technically challenging because of sequence and structural conservation across the various MMPs. Here, through a biochemical and structural screening paradigm, we have identified JNJ0966, a highly selective compound that inhibited activation of MMP-9 zymogen and subsequent generation of catalytically active enzyme. JNJ0966 had no effect on MMP-1, MMP-2, MMP-3, MMP-9, or MMP-14 catalytic activity and did not inhibit activation of the highly related MMP-2 zymogen. The molecular basis for this activity was characterized as an interaction of JNJ0966 with a structural pocket in proximity to the MMP-9 zymogen cleavage site near Arg-106, which is distinct from the catalytic domain. JNJ0966 was efficacious in reducing disease severity in a mouse experimental autoimmune encephalomyelitis model, demonstrating the viability of this therapeutic approach. This discovery reveals an unprecedented pharmacological approach to MMP inhibition, providing an opportunity to improve selectivity of future clinical drug candidates. Targeting zymogen activation in this manner may also allow for pharmaceutical exploration of other enzymes previously viewed as intractable drug targets.

Morphine Versus Methadone Treatment for Neonatal Withdrawal and Impact on Early Infant Development.

Objective. Compare developmental outcomes in infants treated with morphine versus methadone. Method. Retrospective chart review of newborns identified through use of ICD-9 code for neonatal abstinence syndrome (NAS). Thirty-six infants were evaluated-17 treated with methadone and 19 treated with morphine. Assessment was completed following treatment using the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III). Scores in Cognitive, Language, and Motor domains were compared. Results. Comparison of scores between morphine- and methadone-treated groups revealed differences in mean Cognitive Composite (91.3 vs 83.0; P = .03410) and mean Total Motor Composite Scores (96.3 vs 89.6; P = .0149). Conclusion. Newborns with NAS treated with morphine had significantly higher scores in Cognitive and Gross Motor domains compared to infants treated with methadone. Development screening should be pursued to determine if this difference persists throughout early childhood. Results may influence accepted treatment protocols for NAS.

Identification of early developmental deficits in infants with prenatal heroin, methadone, and other opioid exposure.

OBJECTIVE: Study aims to examine development in infants following prenatal heroin, methadone, and opioid exposure, which adversely affects central and autonomic nervous systems. Abrupt discontinuation results in neurologic and behavioral findings as Neonatal Abstinence Syndrome (NAS). METHOD: Following NAS treatment, 28 infants (mean age 55 days [range 21-98 days], 57% male) were assessed using Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) Cognitive, Language, and Motor subscales. Outcomes were compared with a historical control. RESULTS: Mean Language and Cognition scores were significantly lower (P < .001) in the NAS group. Distributions of scores for Language (P < .001) and Cognition (P = .022) were also significantly different between NAS and historical control groups. CONCLUSION: Prenatal heroin, methadone, and other opioid exposure is associated with weaknesses in language and cognition. This information has important public health implications, drawing attention to an otherwise healthy infant population which may benefit from early intervention services.

Podcasting in undergraduate nursing programs.

Little information is available regarding the value of podcasting in nursing education. This mixed-methods study described nursing students' (n=101) perceptions of podcasted materials, the benefits of podcasting, and when and where students used podcasted materials. Students (86%) believed podcasts enriched their learning, and 95% reported podcasts as valuable tools in the learning environment. Most students (94%) would recommend podcasting in other courses and accessed podcast materials 3 times per week. More than half of the students (55%) accessed podcast materials in multiple places (ie, in the car, in the home, and at school).

Pediatric post-acute care hospital transitions: an evaluation of current practice.

OBJECTIVES: After discharge from an acute care hospital, some children require ongoing care at a post-acute care hospital. Care transitions occur at both admission to the post-acute care hospital and again at discharge to the home/community. Our objective was to report the current practices used during the admission to and discharge from 7 pediatric post-acute care hospitals in the United States. METHODS: Participants from 7 pediatric post-acute care hospitals completed a survey and rated the frequency of use of 20 practices to prepare and support children and their families during both admission to the hospital and at time of discharge to the home/community. For consistency with existing literature, practices were grouped into 4 previously reported categories: assessment, communication, education, and logistics. Descriptive statistics were used to report the frequency of use within practices and between hospitals. RESULTS: Only 2 of 10 admission practices and 3 of 10 discharge practices were reportedly "always" used by all hospitals. Assessment and communication practices were reported to be more frequently used (57%-100% of the time) than education and logistic procedures. Between hospitals, only the reported frequency of use of the discharge practices was statistically significantly different (P = .03). CONCLUSIONS: Variability exists in transition practices among 7 post-acute care pediatric hospitals. This report is the first known to detail the frequency of use of admission and discharge practices for pediatric post-acute care hospitals in the United States.

Glutamate transporters: a key piece in the glutamate puzzle of major depressive disorder.

Glutamatergic therapies are emerging as the new path for the treatment of Major Depression Disorder. Recent reports reviewing the use of glutamate activity modulators in the treatment of resistant depression advocate the importance of understanding the alterations of the diverse components of this complex system in mood disorders. In this postmortem study we used in situ hybridization and microarray analysis to evaluate the gene expression of the membrane transporters SLC1A2 and SLCA3 and the vesicular transporter SLCA17A7 in the hippocampus of Major Depressive Disorder (MDD) and Bipolar Disorder (BPD) subjects. Samples from 8 controls, 11 MDD and 6 BPD subjects were processed for in situ hybridization using cRNA probes for SLC1A2, SLC1A3 and SLC17A7. Laser capture microdissection was used to collect tissue from adjacent sections for microarray analysis. The results showed that the expression of the membrane transporters SLC1A2 and SLC1A3 was diminished in the MDD group compared to controls. The expression of the vesicular glutamate transporter SLC17A7 on the other hand was increased in MDD subjects. As for the BPD group, all three transporters showed trends similar to those observed in MDD, but the changes observed did not reach significance. We hypothesize that the decreased expression of the membrane glutamate transporters and the increased expression of the vesicular transporter in the hippocampus would affect the balance of the glutamatergic circuitry of the hippocampus, and that this effect may be a major contributor to depressive symptoms.

Glucocorticoid and mineralocorticoid receptor expression in the human hippocampus in major depressive disorder.

Approximately 50% of mood disorder patients exhibit hypercortisolism. Cortisol normally exerts its functions in the CNS via binding to mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Both MR and GR are highly expressed in human hippocampus and several studies have suggested that alterations in the levels of MR or GR within this region may contribute to the dysregulation in major depressive disorder (MDD). Studies have also shown functional heterogeneity across the hippocampus, with posterior hippocampus preferentially involved in cognitive processes and anterior hippocampus involved in stress, emotion and affect. We therefore hypothesize that GR and MR expression in hippocampus of control and MDD patients may vary not only with disease, but also with regional specificity along the anterior/posterior axis. Student's t-test analysis showed decreased expression of MR in the MDD group compared to controls in the anterior, but not the posterior hippocampus, with no significant changes in GR. Linear regression analysis showed a marked difference in MR:GR correlation between suicide and non-suicide patients in the posterior hippocampus. Our findings are consistent with previous reports of hippocampal corticosteroid receptor dysregulation in mood disorders, but extend those findings by analysis across the anterior/posterior axis of the hippocampus. A decrease in MR in the anterior but not posterior hippocampus of MDD patients emphasizes the important functional role of the anterior hippocampus in neuroendocrine regulation in humans.

Discovery of novel Cobactin-T based matrix metalloproteinase inhibitors via a ring closing metathesis strategy.

The discovery of potent N-hydroxyl caprolactam matrix metalloproteinase (MMP) inhibitors (6) based on the natural product Cobactin-T (2) is described. The synthetic method, which utilizes the ring closing metathesis reaction, is compatible to provide complementary (R) and (S) enantiomers. These compounds tested against MMP-2 and 9, show that the R stereochemistry (i.e., 16), which is opposite for that found in the natural product Cobactin-T is >1000-fold more active with IC(50) values of 0.2-0.6nM against both enzymes. The variation in the incorporation of the sulfonamide enzyme recognition element (Ar(2)XAr(1)SO(2)N(R(1)), 6), along with alterations in the RCM/double bond chemistry (R(2)) provided a series of sub nanomolar MMP inhibitors. For example, compounds 16 and 34 were found to be the most potent with IC(50) values against MMP-2 and MMP-9 found to be between 0.2 and 0.6nM with 34 being the most potent compound discovered (MMP-2 IC(50)=0.39nM and MMP-9 IC(50)=0.22nM). Compounds 16 and 34 showed acceptable drug-like properties in vivo with compound 34 showing oral bioavailability.

Region-specific in situ hybridization-guided laser-capture microdissection on postmortem human brain tissue coupled with gene expression quantification.

This chapter describes the procedure of in situ hybridization-guided laser-capture microdissection performed on postmortem human brain tissue. This procedure permits the precise collection of brain tissue within anatomically defined brain nuclei that is enriched with mRNA. The chapter emphasizes the specific handling of postmortem tissue and preservation of RNA integrity to ensure high-quality gene profiling. Downstream procedures including mRNA amplification, gene profiling using high-density microarray chips, and confirmation with quantitative real-time polymerase chain reaction (qPCR) are described. PCR primer design and cDNA quantification required for qPCR are delineated.

A novel fluorogenic substrate for the measurement of endothelial lipase activity.

Endothelial lipase (EL) is a phospholipase A1 (PLA1) enzyme that hydrolyzes phospholipids at the sn-1 position to produce lysophospholipids and free fatty acids. Measurement of the PLA1 activity of EL is usually accomplished by the use of substrates that are also hydrolyzed by lipases in other subfamilies such as PLA2 enzymes. In order to distinguish PLA1 activity of EL from PLA2 enzymatic activity in cell-based assays, cell supernatants, and other nonhomogeneous systems, a novel fluorogenic substrate with selectivity toward PLA1 hydrolysis was conceived and characterized. This substrate was preferred by PLA1 enzymes, such as EL and hepatic lipase, and was cleaved with much lower efficiency by lipases that exhibit primarily triglyceride lipase activity, such as LPL or a lipase with PLA2 activity. The phospholipase activity detected by the PLA1 substrate could be inhibited with the small molecule esterase inhibitor ebelactone B. Furthermore, the PLA1 substrate was able to detect EL activity in human umbilical vein endothelial cells in a cell-based assay. This substrate is a useful reagent for identifying modulators of PLA1 enzymes, such as EL, and aiding in characterizing their mechanisms of action.

Expression patterns of corticotropin-releasing factor, arginine vasopressin, histidine decarboxylase, melanin-concentrating hormone, and orexin genes in the human hypothalamus.

The hypothalamus regulates numerous autonomic responses and behaviors. The neuroactive substances corticotropin-releasing factor (CRF), arginine-vasopressin (AVP), histidine decarboxylase (HDC), melanin-concentrating hormone (MCH), and orexin/hypocretins (ORX) produced in the hypothalamus mediate a subset of these processes. Although the expression patterns of these genes have been well studied in rodents, less is known about them in humans. We combined classical histological techniques with in situ hybridization histochemistry to produce both 2D and 3D images and to visually align and quantify expression of the genes for these substances in nuclei of the human hypothalamus. The hypothalamus was arbitrarily divided into rostral, intermediate, and caudal regions. The rostral region, containing the paraventricular nucleus (PVN), was defined by discrete localization of CRF- and AVP-expressing neurons, whereas distinct relationships between HDC, MCH, and ORX mRNA-expressing neurons delineated specific levels within the intermediate and caudal regions. Quantitative mRNA signal intensity measurements revealed no significant differences in overall CRF or AVP expression at any rostrocaudal level of the PVN. HDC mRNA expression was highest at the level of the premammillary area, which included the dorsomedial and tuberomammillary nuclei as well as the dorsolateral hypothalamic area. In addition, the overall intensity of hybridization signal exhibited by both MCH and ORX mRNA-expressing neurons peaked in distinct intermediate and caudal hypothalamic regions. These results suggest that human hypothalamic neurons involved in the regulation of the HPA axis display distinct neurochemical patterns that may encompass multiple local nuclei.

Promoting and developing a trail network across suburban, rural, and urban communities.

BACKGROUND: The Wyoming Valley Wellness Trails Partnership received an Active Living by Design grant late in 2003 for a project centered on a growing trail network linking urban, suburban, and rural communities in northeast Pennsylvania, a former coal region, in order to increase physical activity among residents. INTERVENTION: The partnership conducted research, collected information, created promotional documents, worked with partners on events and programs, and participated in trail planning. Local trail organizations continued planning and construction toward developing a trail network. Other partners spearheaded policy change in schools and worksites and worked toward downtown revitalization. The partnership assisted these efforts by providing a forum in which organizations could meet. RESULTS: The partnership became a central resource for information about local parks, trails, and outdoor recreational activities. The partnership increased awareness and use of recreational facilities. Trail partners constructed 22 miles of walking and biking trails. The partnership took advantage of an allied effort that created organizational capacity for wellness in schools and worksites. LESSONS LEARNED: Messages promoting social and entertainment benefits of physical activity were more successful than those promoting health benefits. The existence of multiple small, independent trail organizations can help advance trail development through concurrent development efforts. Urban, suburban, and rural residents' conceptions of walkability may differ. CONCLUSIONS: Trails provide options for recreational and transportation-related physical activity across urban, suburban, and rural landscapes that are supported by all constituents. Trail builders can be strong allies in bringing active living to suburban and rural places.

Evolutionary sequence modeling for discovery of peptide hormones.

There are currently a large number of "orphan" G-protein-coupled receptors (GPCRs) whose endogenous ligands (peptide hormones) are unknown. Identification of these peptide hormones is a difficult and important problem. We describe a computational framework that models spatial structure along the genomic sequence simultaneously with the temporal evolutionary path structure across species and show how such models can be used to discover new functional molecules, in particular peptide hormones, via cross-genomic sequence comparisons. The computational framework incorporates a priori high-level knowledge of structural and evolutionary constraints into a hierarchical grammar of evolutionary probabilistic models. This computational method was used for identifying novel prohormones and the processed peptide sites by producing sequence alignments across many species at the functional-element level. Experimental results with an initial implementation of the algorithm were used to identify potential prohormones by comparing the human and non-human proteins in the Swiss-Prot database of known annotated proteins. In this proof of concept, we identified 45 out of 54 prohormones with only 44 false positives. The comparison of known and hypothetical human and mouse proteins resulted in the identification of a novel putative prohormone with at least four potential neuropeptides. Finally, in order to validate the computational methodology, we present the basic molecular biological characterization of the novel putative peptide hormone, including its identification and regional localization in the brain. This species comparison, HMM-based computational approach succeeded in identifying a previously undiscovered neuropeptide from whole genome protein sequences. This novel putative peptide hormone is found in discreet brain regions as well as other organs. The success of this approach will have a great impact on our understanding of GPCRs and associated pathways and help to identify new targets for drug development.

beta-N-Biaryl ether sulfonamide hydroxamates as potent gelatinase inhibitors: part 1. Design, synthesis, and lead identification.

A new series of beta-N-biaryl ether sulfonamide hydroxamates as novel gelatinase inhibitors is described. These compounds exhibit good potency for MMP-2 and MMP-9 without inhibiting MMP-1. The structure-activity relationships (SAR) reveal the biaryl ether type P1' moiety together with methanesulfonamide is the optimal combination that provides inhibitory activity of MMP-9 in the single-digit nanomolar range.

beta-N-Biaryl ether sulfonamide hydroxamates as potent gelatinase inhibitors: part 2. Optimization of alpha-amino substituents.

The introduction and the optimization of an alpha-amino substituent based on a series of alpha-hydroxy-beta-N-biaryl ether sulfonamide hydroxamates is described. The modification leads to a new series of MMP-2/MMP-9 inhibitors with enhanced inhibitory activities and improved ADME properties. An efficacy study on reducing the ischemia-induced brain edema in the rat transient middle cerebral artery occlusion (tMCAo) model is also demonstrated.

1-Hydroxy-2-pyridinone-based MMP inhibitors: synthesis and biological evaluation for the treatment of ischemic stroke.

Matrix metalloproteinase-9 (MMP-9) has been implicated in the breakdown of the blood-brain barrier during cerebral ischemia. As a result, inhibition of MMP-9 may have utility as a therapeutic intervention in stroke. Towards this end, we have synthesized a series of 1-hydroxy-2-pyridinones that have excellent in vitro potency in inhibiting MMP-9 in addition to MMP-2. Representative compounds also demonstrate good efficacy in the mouse transient mid-cerebral artery occlusion (tMCAO) model of cerebral ischemia.

Syntheses and in vitro evaluation of arylsulfone-based MMP inhibitors with heterocycle-derived zinc-binding groups (ZBGs).

Several classes of arylsulfone-based MMP-2/-9 inhibitors utilizing 6- to 8-membered heterocyclic rings as zinc-binding groups (ZBGs) have been synthesized and their enzyme inhibitory activities were evaluated. Although a number of 6- and 7-membered heterocycles were effective, the most potent arylsulfone inhibitors are based on the rigid 1- or 3-hydroxypyridone ZBG.

Outcomes of post-acute hospital episodes for young children requiring airway support.

In this descriptive study, we examined changes in invasive and non-invasive airway support; studied the rates of home discharge vs. long-term care or acute hospitalization; and examined the relationship between the level of airway support and discharge to home for 92 children (<3 years of age) with 104 admission-discharge episodes to a consortium of pediatric rehabilitation hospitals over a one-year period. We found a significant reduction (p < 0.001) in the level of airway support between admission and discharge. In 21 of 47 (45%) episodes, children weaned from mechanical ventilation to a less restrictive type of support. Sixty percent of the children had final discharges to home. There was a significant, though fair correlation (Spearman Rho = -0.344, p = 0.001) between home discharge and level of airway support. These outcomes data provide a multi-site baseline for understanding expected changes in airway support and home discharge rates of young children who are admitted to a post-acute inpatient program.

Ventilator weaning outcomes in chronic respiratory failure in children.

The purpose of this study was to describe mechanical ventilation weaning outcomes for children with chronic respiratory failure discharged from one of six post-acute rehabilitation facilities. Demographic, clinical and outcome data were collected from the medical record. Forty-four children were included in this prospective series; 20 (45%) were weaned off the ventilator at discharge. Children required significantly lower levels of ventilatory support at discharge than admission. Hourly use on the ventilator decreased from admission to discharge for the full cohort and for the subgroup who required a ventilator at discharge. Seventy-five percent of the children discharged with a ventilator had a portable unit. We conclude that nearly half of the children using mechanical ventilation achieve weaning during a postacute rehabilitation admission, whereas others have positive outcomes in severity, hours off the ventilator or portability of equipment.