Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson's disease

Recent evidence indicates that cyclin-dependent kinases (CDKs, cdks) may be inappropriately activated in several neurodegenerative conditions. Here, we report that cdk5 expression and activity are elevated after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that damages the nigrostriatal dopaminergic pathway. Supporting the pathogenic significance of the cdk5 alterations are the findings that the general cdk inhibitor, flavopiridol, or expression of dominant-negative cdk5, and to a lesser extent dominant-negative cdk2, attenuates the loss of dopaminergic neurons caused by MPTP. In addition, CDK inhibition strategies attenuate MPTP-induced hypolocomotion and markers of striatal function independent of striatal dopamine. We propose that cdk5 is a key regulator in the degeneration of dopaminergic neurons in Parkinson's disease.     

Defining the domains of type I collagen involved in heparin- binding and endothelial tube formation

Cell surface heparan sulfate proteoglycan (HSPG) interactions with type I collagen may be a ubiquitous cell adhesion mechanism. However, the HSPG binding sites on type I collagen are unknown. Previously we mapped heparin binding to the vicinity of the type I collagen N terminus by electron microscopy. The present study has identified type I collagen sequences used for heparin binding and endothelial cell–collagen interactions. Using affinity coelectrophoresis, we found heparin to bind as follows: to type I collagen with high affinity (K_d ≈ 150 nM); triple-helical peptides (THPs) including the basic N-terminal sequence α1(I)87–92, KGHRGF, with intermediate affinities (K_d ≈ 2 μM); and THPs including other collagenous sequences, or single-stranded sequences, negligibly (K_d 10 μM). Thus, heparin–type I collagen binding likely relies on an N-terminal basic triple-helical domain represented once within each monomer, and at multiple sites within fibrils. We next defined the features of type I collagen necessary for angiogenesis in a system in which type I collagen and heparin rapidly induce endothelial tube formation in vitro. When peptides, denatured or monomeric type I collagen, or type V collagen was substituted for type I collagen, no tubes formed. However, when peptides and type I collagen were tested together, only the most heparin-avid THPs inhibited tube formation, likely by influencing cell interactions with collagen–heparin complexes. Thus, induction of endothelial tube morphogenesis by type I collagen may depend upon its triple-helical and fibrillar conformations and on the N-terminal heparin-binding site identified here.     

Risk factors for complications and readmission after operative fixation of pediatric femur fractures

Purpose

Operative fixation of pediatric femur fractures with intramedullary implants has grown in popularity in recent decades. However, risk factors for short-term adverse events and readmission have not been well studied.

Methods

Pediatric patients who underwent intramedullary nailing of a femur fracture between 2012 and 2013 were identified from the American College of Surgeons National Surgical Quality Improvement Program database. Risk factors for any adverse event (AAE) and readmission after intramedullary nailing were evaluated using univariate and multivariate analysis.

Results

A total of 522 pediatric patients who underwent intramedullary nailing of the femur during the study period were identified. The mean age of this patient cohort was 10.2 ± 3.8 years. Review of the cases revealed that 18 (3.4 %) patients had AAE and that 20 (3.8 %) patients were readmitted, of whom 13 (2.5 %) underwent a reoperation. Independent risk factors for AAE were a cardiac comorbidity [odds ratio (OR) 12.7, 95 % confidence interval (CI) 1.5, 103.7], open fracture (OR 10.2, 95 % CI 1.4, 74.4), and prolonged operative time (OR 17.5, 95 % CI 6.1, 50.5). Independent risk factors for readmission were a central nervous system disorder (OR 4.5, 95 % CI 1.3, 16.2) and a seizure disorder (OR 4.9, 95 % CI 1.0, 23.5).

Conclusions

The results of the multivariate analysis suggest that cardiac comorbidities, open fractures, and prolonged operative time increase the risk for AAE and that central nervous system disorders and seizure disorders may increase the risk for readmission. Surgeons should be aware of these risk factors and counsel the families of pediatric patients who undergo intramedullary nailing of femur fractures.