Understanding and Parenting Children's Noncompliant Behavior: The Efficacy of an Online Training Workshop for Resource Parents.

The current study examined the effectiveness of an online training program on parenting children's noncompliant behavior. Eighty-two resource parents (foster, adoptive, and kinship) were recruited through Foster Parent College-an online training website-and randomly assigned to a treatment or wait-list control group. Parents in the treatment group participated in an online interactive workshop on noncompliant child behavior. Online assessments occurred before and after a 1-week intervention, and again 3 months later. Group differences at posttest were significant for parents' reports of children's positive behavior and parent knowledge related to children's noncompliant behavior. Only parents in the treatment group showed significant improvement from pre- to posttest on several other outcome measures of parenting noncompliant behavior. Satisfaction with the online workshop at posttest was very high. Results at the 3-month follow-up assessment showed significant group differences only for parents' knowledge about children's noncompliant behavior. Feedback on the workshop remained positive, with treatment group parents indicating that they felt the workshop had beneficially impacted their parenting and their children's behavior.

Six Weeks of Daily Abaloparatide Treatment Increased Vertebral and Femoral Bone Mineral Density, Microarchitecture and Strength in Ovariectomized Osteopenic Rats.

Abaloparatide is a novel, potent and selective activator of parathyroid hormone receptor 1 (PTHR1) under clinical development for the treatment of osteoporosis. We assessed the effect of 6 weeks of abaloparatide on bone mass, microarchitecture, quality and strength in ovariectomized (OVX) rats. After 8 weeks of post-surgical bone depletion (baseline), OVX rats (n = 20-21/group) received daily subcutaneous vehicle (OVX-Veh) or abaloparatide at 5 or 20 µg/kg. Sham-operated control rats (n = 24) received vehicle. Areal bone mineral density (aBMD) of the lumbar spine (L4), total femur and femur diaphysis was measured at baseline and after 6 weeks of treatment. Femur and vertebral bone architecture and mechanical properties were assessed at the end of the treatment phase. At baseline, OVX-Veh rats exhibited significantly lower aBMD relative to Sham controls. Treatment of OVX rats with abaloparatide at 5 or 20 µg/kg/day increased aBMD dose-dependently in the lumbar spine, total femur and femur diaphysis to levels exceeding OVX-Veh or Sham controls. The abaloparatide 5 and 20 µg/kg groups had improved trabecular microarchitecture relative to OVX vehicle, with trabecular BV/TV exceeding OVX-Veh control values by 57 and 78 % (respectively) at the lumbar spine, and by 145 and 270 % at the distal femur. Femur diaphyseal cortical volume and thickness were significantly greater in the abaloparatide 20 µg/kg group relative to OVX vehicle or Sham controls. Bone strength parameters of the femur diaphysis, femur neck and L4 vertebra were significantly improved in the OVX-ABL groups relative to OVX-Veh controls. Bone mass-strength relationships and estimated intrinsic strength properties suggested maintained or improved bone quality with abaloparatide. These data demonstrate skeletal restoration via abaloparatide treatment of osteopenic OVX rats, in association with improved trabecular microarchitecture, cortical geometry and bone strength at sites that have clinical relevance in patients with osteoporosis.

Dimorphic effects of transforming growth factor-ß signaling during aortic aneurysm progression in mice suggest a combinatorial therapy for Marfan syndrome.

OBJECTIVE: Studies of mice with mild Marfan syndrome (MFS) have correlated the development of thoracic aortic aneurysm (TAA) with improper stimulation of noncanonical (Erk-mediated) TGFß signaling by the angiotensin type I receptor (AT1r). This correlation was largely based on comparable TAA modifications by either systemic TGFß neutralization or AT1r antagonism. However, subsequent investigations have called into question some key aspects of this mechanism of arterial disease in MFS. To resolve these controversial points, here we made a head-to-head comparison of the therapeutic benefits of TGFß neutralization and AT1r antagonism in mice with progressively severe MFS (Fbn1(mgR/mgR) mice). APPROACH AND RESULTS: Aneurysm growth, media degeneration, aortic levels of phosphorylated Erk and Smad proteins and the average survival of Fbn1(mgR/mgR) mice were compared after a ≈3-month-long treatment with placebo and either the AT1r antagonist losartan or the TGFß-neutralizing antibody 1D11. In contrast to the beneficial effect of losartan, TGFß neutralization either exacerbated or mitigated TAA formation depending on whether treatment was initiated before (postnatal day 16; P16) or after (P45) aneurysm formation, respectively. Biochemical evidence-related aneurysm growth with Erk-mediated AT1r signaling, and medial degeneration with TGFß hyperactivity that was in part AT1r dependent. Importantly, P16-initiated treatment with losartan combined with P45-initiated administration of 1D11 prevented death of Fbn1(mgR/mgR) mice from ruptured TAA. CONCLUSIONS: By demonstrating that promiscuous AT1r and TGFß drive partially overlapping processes of arterial disease in MFS mice, our study argues for a therapeutic strategy against TAA that targets both signaling pathways although sparing the early protective role of TGFß.

The somatostatin analog 188Re-P2045 inhibits the growth of AR42J pancreatic tumor xenografts.

UNLABELLED: P2045 is a peptide analog of somatostatin with picomolar affinity for the somatostatin receptor subtype 2 (SSTR2) upregulated in some pancreatic tumors. Studies were conducted in rat AR42J pancreatic tumor xenograft mice to determine whether (188)Re-P2045 could inhibit the growth of pancreatic cancer in an animal model. METHODS: (188)Re-P2045 was intravenously administered every 3 d for 16 d to nude mice with AR42J tumor xenografts that were approximately 20 mm(3) at study initiation. Tumor volumes were recorded throughout the dosing period. At necropsy, all tissues were assessed for levels of radioactivity and evaluated for histologic abnormalities. Clinical chemistry and hematology parameters were determined from terminal blood samples. The affinity of nonradioactive (185/187)Re-P2045 for somatostatin receptors was compared in human NCI-H69 and rat AR42J tumor cell membranes expressing predominantly SSTR2. RESULTS: In the 1.85- and 5.55-MBq groups, tumor growth was inhibited in a dose-dependent fashion. In the 11.1-MBq group, tumor growth was completely inhibited throughout the dosing period and for 12 d after the last administered dose. The radioactivity level in tumors 4 h after injection was 10 percentage injected dose per gram, which was 2-fold higher than in the kidneys. (188)Re-P2045 was well tolerated in all dose groups, with no adverse clinical, histologic, or hematologic findings. The nonradioactive (185/187)Re-P2045 bound more avidly (0.2 nM) to SSTR2 in human than rat tumor membranes, suggesting that these studies are relevant to human studies. CONCLUSION: (188)Re-P2045 is a promising therapeutic candidate for patients with somatostatin receptor-positive cancer.

Antisense Oligonucleotide-mediated Suppression of Muscle Glycogen Synthase 1 Synthesis as an Approach for Substrate Reduction Therapy of Pompe Disease.

Pompe disease is an autosomal recessive disorder caused by a deficiency of acid α-glucosidase (GAA; EC 3.2.1.20) and the resultant progressive lysosomal accumulation of glycogen in skeletal and cardiac muscles. Enzyme replacement therapy using recombinant human GAA (rhGAA) has proven beneficial in addressing several aspects of the disease such as cardiomyopathy and aberrant motor function. However, residual muscle weakness, hearing loss, and the risks of arrhythmias and osteopenia persist despite enzyme therapy. Here, we evaluated the relative merits of substrate reduction therapy (by inhibiting glycogen synthesis) as a potential adjuvant strategy. A phosphorodiamidate morpholino oligonucleotide (PMO) designed to invoke exon skipping and premature stop codon usage in the transcript for muscle specific glycogen synthase (Gys1) was identified and conjugated to a cell penetrating peptide (GS-PPMO) to facilitate PMO delivery to muscle. GS-PPMO systemic administration to Pompe mice led to a dose-dependent decrease in glycogen synthase transcripts in the quadriceps, and the diaphragm but not the liver. An mRNA response in the heart was seen only at the higher dose tested. Associated with these decreases in transcript levels were correspondingly lower tissue levels of muscle specific glycogen synthase and activity. Importantly, these reductions resulted in significant decreases in the aberrant accumulation of lysosomal glycogen in the quadriceps, diaphragm, and heart of Pompe mice. Treatment was without any overt toxicity, supporting the notion that substrate reduction by GS-PPMO-mediated inhibition of muscle specific glycogen synthase represents a viable therapeutic strategy for Pompe disease after further development.

Efficacy of Blended Preservice Training for Resource Parents.

To evaluate a new way of meeting the growing demand for training prospective resource parents, our study compared the efficacy of a blended online and in-person approach with a traditional classroom-only approach. Findings based on a sample of 111 resource parent prospects showed significantly greater gains in knowledge from pre- to posttest for the blended approach over the classroom-only approach. The blended approach also produced dramatically lower dropout rates during preservice training. Both groups made significant gains in parenting awareness from pre to post, but those gains were greater for the classroom-only approach. Post hoc analyses examined this finding more closely. Satisfaction with training was comparably high for both groups. Gains in knowledge and awareness were sustained at a 3-month follow-up assessment.

Systemic delivery of a Peptide-linked morpholino oligonucleotide neutralizes mutant RNA toxicity in a mouse model of myotonic dystrophy.

Expansions of CUG trinucleotide sequences in RNA transcripts provide the basis for toxic RNA gain-of-function that leads to detrimental changes in RNA metabolism. A CTG repeat element normally resides in the 3' untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene, but when expanded it is the genetic lesion of myotonic dystrophy type 1 (DM1), a hereditary neuromuscular disease. The pathogenic DMPK transcript containing the CUG expansion is retained in ribonuclear foci as part of a complex with RNA-binding proteins such as muscleblind-like 1 (MBNL1), resulting in aberrant splicing of numerous RNA transcripts and consequent physiological abnormalities including myotonia. Herein, we demonstrate molecular and physiological amelioration of the toxic effects of mutant RNA in the HSA(LR) mouse model of DM1 by systemic administration of peptide-linked morpholino (PPMO) antisense oligonucleotides bearing a CAG repeat sequence. Intravenous administration of PPMO conjugates to HSA(LR) mice led to redistribution of Mbnl1 protein in myonuclei and corrections in abnormal RNA splicing. Additionally, myotonia was completely eliminated in PPMO-treated HSA(LR) mice. These studies provide proof of concept that neutralization of RNA toxicity by systemic delivery of antisense oligonucleotides that target the CUG repeat is an effective therapeutic approach for treating the skeletal muscle aspects of DM1 pathology.

Web-Enhanced Preservice Training for Prospective Resource Parents: A Randomized Trial of Effectiveness and User Satisfaction.

Traditionally, prospective resource parents must attend all preservice training in person. While live sessions are necessary for activities such as screening applicants, instructional portions of training could be enhanced by web-based sessions. This pilot study compares the effectiveness of online and classroom versions of one session from a widely used preservice training program. Ninety-two individuals who volunteered to complete the program in two states were randomly assigned to a treatment group that viewed an online version of the class on child abuse and neglect or a comparison group that took the same class in person. Written questionnaires were completed before and after the class. Significant group differences on knowledge of child maltreatment and empathy toward birth parents, plus high user satisfaction, were hypothesized. ANCOVA results showed the online training was more effective than the live training at increasing knowledge. MANCOVA findings on empathy were not significant but trended toward greater empathy for the online group. Feedback indicated high satisfaction with the online course. If supported by future research, the finding that online instruction is more effective than live has positive implications for practice, because web-based training offers advantages like standardizing instruction, cutting agency and trainee costs, and providing greater flexibility.

Inhibiting TGF-ß activity improves respiratory function in mdx mice.

Respiratory function is the main cause of mortality in patients with Duchenne muscular dystrophy (DMD). Elevated levels of TGF-ß play a key role in the pathophysiology of DMD. To determine whether therapeutic attenuation of TGF-ß signaling improves respiratory function, mdx mice were treated from 2 weeks of age to 2 months or 9 months of age with either 1D11 (a neutralizing antibody to all three isoforms of TGF-ß), losartan (an angiotensin receptor antagonist), or a combination of the two agents. Respiratory function was measured in nonanesthetized mice by plethysmography. The 9-month-old mdx mice had elevated Penh values and decreased breathing frequency, due primarily to decreased inspiratory flow rate. All treatments normalized Penh values and increased peak inspiratory flow, leading to decreased inspiration times and breathing frequency. Additionally, forelimb grip strength was improved after 1D11 treatment at both 2 and 9 months of age, whereas, losartan improved grip strength only at 2 months. Decreased serum creatine kinase levels (significant improvement for all groups), increased diaphragm muscle fiber density, and decreased hydroxyproline levels (significant improvement for 1D11 only) also suggested improved muscle function after treatment. For all endpoints, 1D11 was equivalent or superior to losartan; coadministration of the two agents was not superior to 1D11 alone. In conclusion, TGF-ß antagonism may be a useful therapeutic approach for treating DMD patients.

Pediatric submersion events in portable above-ground pools in the United States, 2001-2009.

OBJECTIVE: The goal of this study was to describe the epidemiology of pediatric submersion events occurring in portable pools in the United States. METHODS: A retrospective analysis of fatal and nonfatal submersion events involving children younger than 12 years in portable pools was conducted using injury and fatality data compiled by the US Consumer Product Safety Commission from 2001 through 2009. RESULTS: There were 209 fatal and 35 nonfatal submersion cases reported to the commission from 2001 through 2009. The majority (94%) involved children younger than 5 years, 56% involved boys, 73% occurred in the child's own yard, and 81% occurred during the summer months. The number of submersion events increased rapidly from 2001 to 2005 and then leveled off from 2005 to 2009. CONCLUSIONS: The use of portable pools in residential settings poses a significant risk of submersion-related morbidity and mortality to children, especially in the <5-year-old age group. No single strategy will prevent all submersion deaths and injuries; therefore, layers of protection are recommended. Industry is advised to engage in development of protective devices that are effective and affordable for portable pools, including isolation fencing, pool alarms, and safety covers. A strong and pervasive consumer education campaign is needed to make consumers aware of the dangers of portable pools, because these small, inexpensive, consumer-installed pools may not generate the same sense of risk as an in-ground pool.

Homeostatic role of transforming growth factor-beta in the oral cavity and esophagus of mice and its expression by mast cells in these tissues.

Transforming growth factor-beta (TGF-beta) is a pleiotropic growth factor; its overexpression has been implicated in many diseases, making it a desirable target for therapeutic neutralization. In initial safety studies, mice were chronically treated (three times per week) with high doses (50 mg/kg) of a murine, pan-neutralizing, anti-TGF-beta antibody. Nine weeks after the initiation of treatment, a subset of mice exhibited weight loss that was concurrent with decreased food intake. Histopathology revealed a unique, nonneoplastic cystic epithelial hyperplasia and tongue inflammation, as well as dental dysplasia and epithelial hyperplasia and inflammation of both the gingiva and esophagus. In an effort to determine the cause of this site-specific pathology, we examined TGF-beta expression in these tissues and saliva under normal conditions. By immunostaining, we found higher expression levels of active TGF-beta1 and TGF-beta3 in normal tongue and esophageal submucosa compared with gut mucosal tissues, as well as detectable TGF-beta1 in normal saliva by Western blot analysis. Interestingly, mast cells within the tongue, esophagus, and skin co-localized predominantly with the TGF-beta1 expressed in these tissues. Our findings demonstrate a novel and restricted pathology in oral and esophageal tissues of mice chronically treated with anti-TGF-beta that is associated with basal TGF-beta expression in saliva and by mast cells within these tissues. These studies illustrate a previously unappreciated biological role of TGF-beta in maintaining homeostasis within both oral and esophageal tissues.

Isolation, characterization, and biological evaluation of syn and anti diastereomers of [(99m)Tc]technetium depreotide: a somatostatin receptor binding tumor imaging agent.

The early and later eluting [(99m)TcO]depreotide products on RP-HPLC were confirmed to be the anti and syn diastereomers, respectively, based on proton NMR and circular dichroism spectroscopy. NMR provided evidence of a folded, conformationally constrained structure for the syn diastereomer. The syn diastereomer is predominant (anti/syn approximately 10:90) in the [(99m)TcO]depreotide preparation and shows a slightly higher affinity (IC50 = 0.15 nM) for the somatostatin receptor than the anti diastereomer (IC50 = 0.89 nM). Both diastereomers showed higher binding affinities than the free peptide (IC(50) = 7.4 nM). Biodistribution studies in AR42J tumor xenograft nude mice also showed higher tumor uptake for syn [(99m)TcO]depreotide (6.58% ID/g) than for the anti [(99m)TcO]depreotide (3.38% ID/g). Despite the differences in biological efficacy, the favorable binding affinity, tumor uptake, and tumor-to-background ratio results for both diastereomeric species predict that both are effective for imaging somatostatin receptor-positive tumors in vivo.

Somatostatin receptor-binding peptides suitable for tumor radiotherapy with Re-188 or Re-186. Chemistry and initial biological studies.

Somatostatin derivative peptides previously designed for radiodiagnostic purposes (99mTc P829 or 99mTc depreotide) were reoptimized for radiotherapy of tumors with rhenium radioisotopes. An optimized pharmacophore peptide P1839 was derived by in vitro binding affinity assay to AR42J rat pancreatic tumor cell membranes. Peptides with chelating domains and their oxorhenium(V) complexes were tested in vitro for binding to NCI H69 human SCLC tumor membranes. Further optimization entailed radiolabeling with 99mTc and biodistribution in an AR42J xenograft mouse model. Kidney uptake was decreased substantially by removing positively charged residues. Neutral N3S diamide amine thiol chelators with no adjacent positive charges had the best overall properties. Substituting an aromatic amino acid into the chelator approximately doubled the tumor uptake. The final optimized peptide P2045 (39) radiolabeled with 99mTc exhibited increased tumor uptake ( approximately 25 %ID/g at 1.5 h), lower kidney uptake ( approximately 4.8 %ID/g at 1.5 h), and extensive urinary excretion (59 %ID at 1.5 h). Finally, comparison biodistribution studies between 99mTc and 188Re (39) showed a good correlation between the two metal complexes and demonstrated prolonged tumor retention (> or =24 h).

Parents of preschool fire setters: perceptions of the child-play fire hazard.

The present study sought to learn about risk perceptions held by parents of preschool fire-setters. A 41-item survey was distributed to 60 parents whose children, aged 6 years and younger, had previously set fires and who were involved in intervention programmes throughout the US. Most parents did not think their children would play with matches/lighters, or knew how to use these items, although some had witnessed their children playing with matches/lighters previously. Most parents reported having taken precautions to keep matches/lighters out of reach and also educating their children about fire. Regardless, children not only set fires, but in 40% of cases climbed to access the match/lighter. Parents' perceptions of their children's proclivity for fire play were not consistent with their actual fire-play behaviour. Parents underestimated the likelihood that their children would play with matches/lighters. Although most reportedly undertook preventative measures aimed at thwarting fire play, these strategies were ineffective. Traditionally relied upon precautionary techniques, such as storing lighters out of reach and discussing the dangers of fire, were not sufficient to stem interest and resultant fire play.

Vstreet.com: a web-based community for at-risk teens.

Most teens leaving the care of an agency are woefully unprepared and unsupported. Current approaches to aftercare are expensive and difficult to implement. This study evaluated a prototype version of Vstreet.com, an innovative website for at-risk youth designed to teach lifeskills and build community. Findings from a sample of youth in the Job Corps showed that the website was highly effective in increasing their knowledge of apartment hunting skills, feelings of peer social support, and intentions of staying in touch with their agency.

Epigenetic abnormalities associated with a chromosome 18(q21-q22) inversion and a Gilles de la Tourette syndrome phenotype.

Gilles de la Tourette syndrome (GTS) is a potentially debilitating neuropsychiatric disorder defined by the presence of both vocal and motor tics. Despite evidence that this and a related phenotypic spectrum, including chronic tics (CT) and Obsessive Compulsive Disorder (OCD), are genetically mediated, no gene involved in disease etiology has been identified. Chromosomal abnormalities have long been proposed to play a causative role in isolated cases of GTS spectrum phenomena, but confirmation of this hypothesis has yet to be forthcoming. We describe an i(18q21.1-q22.2) inversion in a patient with CT and OCD. We have fine mapped the telomeric aspect of the rearrangement to within 1 Mb of a previously reported 18q22 breakpoint that cosegregated in a family with GTS and related phenotypes. A comprehensive characterization of this genomic interval led to the identification of two transcripts, neither of which was found to be structurally disrupted. Analysis of the epigenetic characteristics of the region demonstrated a significant increase in replication asynchrony in the patient compared to controls, with the inverted chromosome showing delayed replication timing across at least a 500-kb interval. These findings are consistent with long-range functional dysregulation of one or more genes in the region. Our data support a link between chromosomal aberrations and epigenetic mechanisms in GTS and suggest that the study of the functional consequences of balanced chromosomal rearrangements is warranted in patients with phenotypes of interest, irrespective of the findings regarding structurally disrupted transcripts.

Suction-type suffocation incidents in infants and toddlers.

OBJECTIVES: To describe the danger of upper airway obstruction associated with semirigid hollow objects in infants and toddlers and to define a minimum frequency with which episodes involving these products have occurred and propose a model defining the potentially hazardous characteristics of these objects. METHODS: A retrospective study of incidents reported to the US Consumer Product Safety Commission from January 1983 to March 2000, involving children younger than 5 years, was conducted. The medical literature (Medline) was searched for similar cases. The resulting case series was analyzed. RESULTS: A total of 17 incidents were identified in which a semirigid, hollow hemispherical/ellipsoidal object was described as having "cupped" the face, simultaneously covering the nose and the mouth. Of the 17 incidents, 13 involved toys; the remaining 4 incidents involved 2 different consumer products. All of these incidents involved children aged 4 to 36 months. Eight incidents resulted in death; 9 were nonfatal because of parental intervention. In all cases investigated, the infant was found with the semirigid object strongly adhering to his or her face. In 16 incidents, significant physical effort reportedly was required to remove the objects from the child's face. The fatal incidents involved children aged 4 to 24 months, whereas the age range of the children in nonfatal incidents was 7 to 36 months. In all but 1 of the fatal cases, the victim was found dead in a crib or playpen. The cross-sectional diameter of the products involved in suffocation incidents was in the range of 6.4 to 9.7 cm. The depths of the products ranged from 4.2 to 5.1 cm. The approximate volume of containers ranged between 100 and 170 mL. These dimensions are compatible with the range of anthropometric measurements that allow the product to fit snugly over the mouth and the nose of a young child, resulting in complete airway obstruction. CONCLUSIONS: Children between the ages of 4 and 36 months are at risk from suffocation by hollow, semirigid hemispherical/ellipsoidal objects through suction formation and complete airway obstruction. Shallow containers with dimensions ranging from approximately 6.0 to 11.0 cm seem to be especially hazardous. Several recommendations may be proposed to lessen the hazard to young children. These include product design changes that limit the amount of contact with the perimeter and reduce the chance of forming a seal between the container and the face and ventilation holes to prevent a seal from forming. Although design change alone may be very helpful in products that are intended for use by children who are younger than 3 years, products that have similar dimensions and are not intended for infants present additional challenges. Thus, a very important additional prevention strategy is education. Pediatricians and other health care providers should alert parents and caregivers to the dangers of leaving such products in an infant's crib or playpen or allowing infants to play with these objects while unattended.

Supervision of children aged two through six years.

Manufacturers of household products--including appliances, exercise equipment, and even some children's toys--expect consumers to supervise their children to prevent product-related injuries. This approach to hazard prevention places the burden of safety on parents and caretakers. This study examined actual supervision practices of parents of children between the ages of two and six years. 59 parents, aged 31 to 40 years, residing in Montgomery County, Maryland, completed a 24-item self-administered questionnaire, consisting of multiple choice and open-ended questions. Nearly all respondents reported that there are times when their children are in a different room from them. When the children are out of sight, parents reported checking on their children periodically, with increasingly longer periods between observations, as the child gets older. Nearly half of the children got out of bed in the morning always or often before a parent. Ninety-five percent of parents perceived that their child was at no risk or slight risk of injury when getting up in the morning before them. In conclusion, it can be said that many parents supervise their children by being close-by and on-hand as needed, rather than being directly involved in the child's activities. Manufacturers are encouraged to employ passive measures and sound designs, rather than rely on close parental supervision for injury prevention.