Developmental activities of elite junior hockey players: an analysis of early sport specialization.

Early sport specialization is a popular and contentious topic in the scientific literature and popular media. The lure of extrinsic rewards has led to increasing rates of specialization among young athletes, while expert recommendations promote multisport participation. The purpose of this study was to describe and analyze developmental activities of a group of elite junior hockey players in Canada. Within this context, elements of specialization were investigated in accordance with existing theoretical frameworks and long-term athlete development models to enhance the literature. Fifteen participants from the Ontario Hockey League completed quantitative retrospective interviews, detailing past sport and recreational activities. Thirty-one developmental milestones were assessed. Accumulated hours of activity were categorized in accordance with Côté's (1999) Developmental Model of Sports Participation, along with the number and types of sports in which they participated during childhood. Jayanthi et al.'s (2015) continuum was utilized to determine the age at which the athletes became moderately and highly specialized. Accrued hours of deliberate practice reported by participants increased from ages 6 to 16 years, as did competition in organized hockey games. Reported hours of deliberate play peaked at 9 years of age and decreased thereafter. Participants played a combined 16 sports other than hockey, ranging from an average of 2.0 at age 6, to a maximum average of 5.6 at 12 years old, and decreasing each year to 2.3 by age 15. The greatest number of hours in other sports was accumulated at 12 years of age. Using a three-point scale, participants considered themselves "highly specialized" at 14 years old; however, other quantitative indicators suggested this may have occurred at 12 years of age. Relative to previous research on early sport specialization, participants in this study spent more time practicing hockey, while ceasing hockey-specific play and other sports at younger ages. Despite a diverse sport history, hockey competition was initiated earlier than recommended, showing high levels of sport commitment as young as 9 years old. The early specialization path remains a popular trajectory among coaches, parents, and athletes in Canadian ice hockey.

The acceptability of a directly-administered antiretroviral therapy (DAART) intervention among patients in public HIV clinics in Los Angeles, California.

Directly administered antiretroviral therapy (DAART) is an intensive adherence support strategy for highly active antiretroviral therapy (HAART) that requires patient acceptance to be effective. In one arm of a randomized adherence study, community workers (CW) delivered and observed ingestion of one HAART dose to participants five days a week for six months. We evaluated acceptability by study participation, retention, attendance and a satisfaction survey. Chi-square and nonparametric tests were used to examine differences between participants who did and did not complete DAART. Between November 2001 and March 2004, 416 eligible participants were identified; 250 were enrolled and 166 refused to participate (22 of these (13%) because of DAART specifically). Of the 82 randomized to DAART (70% Latino, 20% African American, 27% female and 69% foreign-born), 65 (79%) completed six months of DAART. Participants attended 6,953/7,390 (94%) appointments. Latinos were more likely to complete DAART compared to African Americans (OR=4.76, 95%CI=1.38, 16.44, p=0.01). In addition, foreign-born participants were more likely to complete DAART than US-born participants (OR=3.38, 95%CI=1.11-10.22, p=0.03). Participants completing DAART reported high rates of satisfaction. Retention, attendance and participant satisfaction suggest that DAART is an acceptable adherence support strategy in this public clinic population, particularly among Latino and foreign-born participants.

A pilot study of ranolazine in patients with intermittent claudication.

AIM: This pilot study provides preliminary information regarding safety and changes in exercise performance during treatment with ranolazine extended-release in patients with reproducible claudication during exercise treadmill testing (ETT). METHODS: We enrolled 45 patients with documented peripheral arterial disease, reproducible claudication on ETT, and ankle-brachial indices <0.85 at rest that decreased by at least 0.15% or 20% immediately postexercise. Randomized patients received double-blind treatment with either ranolazine 1 000 mg b.i.d. (n=22) or placebo (n=23) for 4 weeks. RESULTS: Compared with baseline, peak walking time (PWT) increased (mean+/-SEM) by 53+/-34 s with ranolazine (P=0.13) and by 41+/-33 s with placebo (P=0.22). Pain-free walking time during ETT increased by 62+/-18 s with ranolazine (P=0.002) and 36+/-18 s with placebo (P=0.045). Supplemental analyses, excluding patients with baseline exercise duration (16 min and (12 min, showed additional improvement with ranolazine on PWT. CONCLUSIONS: Ranolazine was well tolerated and these data provide a rationale for proceeding with a definitive trial.

Endothelial cell adhesion on RGD-containing methacrylate terpolymers.

Hexyl methacrylate (HMA), methyl methacrylate (MMA), and methacrylic acid (MAA) were used as comonomers to produce a low glass transition temperature material, potentially useful in fabricating a small diameter vascular graft. Because it has been shown that grafts seeded with endothelial cells have better resistance to thrombosis, RGD-based peptide sequences were incorporated into the terpolymer. The two methods used for incorporating peptide sequences were a chain transfer reaction during polymerization, and a coupling reaction between the amine terminus of the peptide and the carboxyl groups of the MAA. Polymers were synthesized using the chain transfer reaction with peptide concentrations ranging from 1.7 to 7.0 micromol/g. Weight-average molecular weights decreased with increasing peptide concentration from 310,000 g/mol for the terpolymer without peptide, to 110,000 g/mol for a peptide concentration of 7.0 micromol/g. As a result, Young's modulus decreased with increasing peptide concentration. Terpolymers with peptides attached through a coupling reaction showed no decrease in molecular weight or mechanical properties. Confocal microscopy showed cells seeded on the RGD surfaces adhered and spread, while terpolymers with RGE sequences showed cells that were rounded and not spreading. Cell density on RGD surfaces increased with increasing peptide concentration up to a bulk peptide concentration of approximately 5 micromol/g and reached a plateau, which indicated the minimum peptide concentration necessary for maximum cell adhesion.

Synthesis and characterization of acrylic terpolymers with RGD peptides for biomedical applications.

The goal of this research was to design a biomaterial, using acrylic terpolymers, which could support endothelial cells and function in small diameter vascular graft applications. Hexyl methacrylate (HMA) and octyl methacrylate (OMA) were used as comonomers to produce a material with a low glass transition temperature (T(g)). Methacrylic acid (MAA) was used to provide ionic character, and methyl methacrylate (MMA) was selected because of its wide usage in biomedical applications. Cation neutralization was employed to modify the mechanical properties. RGD-based peptide sequences were attached to promote endothelial cell adhesion, because vascular grafts seeded with endothelial cells have fewer problems with thrombosis. The two methods used to incorporate peptide sequences were a chain transfer reaction during polymerization, and a coupling reaction attaching the peptides to carboxyl groups on the polymer after polymerization. The compositions that produced T(g)s of approximately 0 degrees C were 75 mol% OMA and 92 mol% HMA. The Young's modulus of the HMA copolymer was approximately 0.37 MPa, well below the desired value of 0.9 MPa. Likewise, the Young's modulus of approximately 0.50 MPa for the OMA copolymer was also below the desired value. After partial neutralization with sodium cations, the Young's moduli increased to approximately 0.93 and 0.99 MPa, respectively. The chain transfer reaction lowered the molecular weights and mechanical properties of the copolymers, while the coupling reaction method had little effect on these properties. The chain transfer method appears to be a promising one-step method to produce polymers with a wide range of peptide concentrations.

A multicenter dose-escalation trial with denileukin diftitox (ONTAK, DAB(389)IL-2) in patients with severe psoriasis.

BACKGROUND: Denileukin diftitox, a fusion protein targeting both malignant and normal activated lymphocytes, has been shown previously to have antipsoriatic activity. However, the ideal dosing regimen for treating psoriasis was not established. OBJECTIVE: We examined the safety and efficacy of denileukin diftitox in patients with severe plaque-type psoriasis. METHODS: This was a cohort dose-escalation trial. Patients were administered denileukin diftitox on 3 consecutive days every other week. Patients were evaluated for toxicity, improvement in psoriasis, immunogenicity, and serum levels. RESULTS: Thirty-five patients were treated at 3 dose levels. Eight patients had a 50% decrease or more in Psoriasis Area and Severity Index score from baseline (0/10 at 0.5 microg/kg per day, 1/10 at 1.5 microg/kg per day, and 7/15 at 5 microg/kg per day). Adverse events primarily consisted of constitutional events and skin reactions. CONCLUSIONS: The potential antipsoriatic activity of denileukin diftitox demonstrated in this study was comparable to that observed in other psoriasis studies with this agent. However, this dosing regimen was better tolerated than the dosing regimen used in the last study with denileukin diftitox in psoriasis patients.

CPI-1189 attenuates effects of suspected neurotoxins associated with AIDS dementia: a possible role for ERK activation.

Individuals infected with the human immunodeficiency virus (HIV) often experience a dementia characterized by mental slowing and memory loss. Motor dysfunction may also accompany this condition. The pathogenesis of the dementia is not known, but microscopic examination of brain tissue from those afflicted shows evidence of chronic inflammation, reactive gliosis and cell death. Neurotoxic factors produced from activated macrophage or microglial cells such as tumor necrosis factor-alpha (TNFalpha), gp120 and quinolinic acid have been implicated as agents for the cell death which often appears to occur by an apoptotic mechanism. CPI-1189, a drug currently undergoing clinical evaluation as a treatment for the dementia associated with AIDS, is shown in this paper to mitigate apoptosis induced by TNFalpha, gp120, and necrosis induced by quinolinic acid. In addition, CPI-1189 mitigates the cell death produced by supernatants from cultured macrophages obtained from patients with AIDS dementia. The exact mechanism by which CPI-1189 prevents neurotoxicity is not known; however, protection from TNFalpha and supernatant-induced toxicity does not appear to involve NFkappaB translocation, and appears to be associated with an increase in activated ERK-MAP kinase. These findings may have implications for other neurological diseases where apoptotic cell death contributes to neurodegeneration.

CPI-1189 inhibits interleukin 1beta-induced p38-mitogen-activated protein kinase phosphorylation: an explanation for its neuroprotective properties?

The p38 mitogen-activated protein kinase (p38-MAPK) is a central enzyme in one of the major protein kinase cascades that regulate proapoptotic and proinflammatory signal transduction. p38-MAPK is activated by receptor/ligand recognition events or by exposure to extracellular stressors, including oxidative stress. Activation of p38-MAPK is affected by dual phosphorylation on a specific inhibitory domain. Dual phosphorylation causes a structural change in the p38-MAPK enzyme which allows binding of ATP and target substrate. Agents which block ATP docking to phosphoactivated p38-MAPK are being investigated for treatment of inflammatory diseases and neurodegenerative pathologies. An alternative strategy for p38-MAPK antagonism would be the inhibition of p38-MAPK phosphoactivation. We now report potent inhibition of p38-MAPK phosphorylation by a synthetic benzamide (CPI-1189) which displays protective action against tumor necrosis factor-alpha (TNFalpha)-induced neurodegeneration. In primary astrocytes treated with interleukin 1beta (IL1beta), CPI-1189 inhibits p38-MAPK phosphorylation at concentrations of 10 nM or less. While the precise molecular target of CPI-1189 remains unknown, these findings suggest a novel mechanism for the neuroprotective properties of the compound. These findings also indicate that antagonism of the p38-MAPK may be achieved through pharmacological inhibition of p38-MAPK phosphorylation, a strategy that is conceptually distinct from direct inhibition of ATP binding to the active enzyme.

CPI-1189 prevents apoptosis and reduces glial fibrillary acidic protein immunostaining in a TNF-alpha infusion model for AIDS dementia complex.

AIDS dementia complex (ADC) is characterized by increased apoptosis, gliosis, and oxidative stress in the CNS, as well as a compromised blood-brain barrier. TNF-alpha has been shown to be elevated in AIDS dementia complex brains and may contribute to AIDS dementia complex. To model elevated TNF-alpha in AIDS dementia complex, TNF-alpha was infused ICV bilaterally into rats for 3 days. TNF-alpha treatment increased apoptosis around the infusion site and selectively in the septum and corpus callosum. Co-administration of the synthetic antioxidant CPI-1189 prevented TNF-alpha induced apoptosis. Both TNF-alpha and CPI-1189 treatment suppressed glial fibrillary acidic protein (GFAP) staining at the infusion site. TNF-alpha did not significantly affect the integrity of the blood-brain barrier, but CPI-1189 treatment increased blood-brain barrier integrity at the infusion site. No effect of TNF-alpha or CPI-1189 treatment was found on measures of oxidative stress. These results support TNF-alpha as a key agent for increasing apoptosis in AIDS dementia complex. Additionally, CPI-1189 treatment may protect against TNF-alpha induced apoptosis and astrogliosis in AIDS dementia complex. Lastly, the toxic effect of TNF-alpha and the protective effect of CPI-1189 may not be mediated primarily through manipulation of classic reactive oxygen species.

Administration of DAB389IL-2 to patients with recalcitrant psoriasis: a double-blind, phase II multicenter trial.

BACKGROUND: Current therapies for recalcitrant psoriasis focus on immunoregulation and targeting of activated T-lymphocytes rather than keratinocytes. Previous studies with low doses of the lymphocyte-selective fusion protein DAB389IL-2 have shown benefit to patients with psoriasis. OBJECTIVE: We examined the safety and efficacy of DAB389IL-2 in 41 volunteers receiving more frequent and higher doses than in a previous trial. METHODS: Patients were randomized to receive either placebo or 5, 10, or 15 microg/kg daily of DAB389IL-2 intravenously for 3 consecutive days each week for 4 consecutive weeks with a subsequent 4-week observation period. RESULTS: Of the placebo group, 17% (2 of 12) exhibited at least 50% improvement from baseline Psoriasis Area and Severity Index scores at the end of the study, whereas 24% of all treated patients (7 of 29) showed the same improvement. Overall, 3 of 12 (25%) patients given placebo as opposed to 12 of 29 (41%) patients treated with DAB389IL-2 improved to this same extent at some point during the study. The rate of improvement for treated patients was significantly greater than for placebo patients (p = 0.04; repeated measures ANOVA). Among treated patients, decreases in Psoriasis Area and Severity Index scores were paralleled by changes in the Physician's Global Assessment and the Dermatology Life Quality Index. Treatment in ten patients was discontinued because of adverse events. Flu-like symptoms were the most common with severity increasing at the two higher doses. Only one serious adverse event was reported. This occurred in a patient receiving 5 microg/kg daily who experienced vasospasm and a coagulopathy resulting in arterial thrombosis. CONCLUSION: Our findings are consistent with the potential antipsoriatic activity of DAB389IL-2 demonstrated in an earlier study. However, DAB389IL-2 was less well tolerated at this dosing regimen, particularly at the highest dose, and it was too toxic at these doses and schedules to be considered in the routine treatment of psoriasis.