Craniomaxillofacial trauma: synopsis of 14,654 cases with 35,129 injuries in 15 years.

Craniomaxillofacial (CMF) trauma occurs in isolation or in combination with other serious injuries, including intracranial, spinal, and upper- and lower-body injuries. It is a major cause of expensive treatment and rehabilitation requirements, temporary or lifelong morbidity, and loss of human productivity. The aim of this study was to evaluate patterns of CMF trauma in a large patient sample within a 15-year time frame. Between 1991 and 2005, CMF trauma data were collected from 14,654 patients with 35,129 injuries at the Department of Cranio-Maxillofacial and Oral Surgery in Innsbruck, assessing a plethora of parameters such as injury type and mechanism as well as age and gender distribution over time. Three main groups of CMF trauma were evaluated: facial bone fractures, dentoalveolar trauma, and soft tissue injuries. Statistical comparisons were carried out using a chi-square test. This was followed by a logistic regression analysis to determine the impact of the five main causes for CMF injury. Older people were more prone to soft tissue lesions with a rising risk of 2.1% per year older, showing no significant difference between male and female patients. Younger patients were at higher risk of suffering from dentoalveolar trauma with an increase of 4.4% per year younger. This number was even higher (by 19.6%) for female patients. The risk of sustaining facial bone fractures increased each year by 4.6%. Male patients had a 66.4% times higher risk of suffering from this type of injury. In addition, 2550 patients (17.4%) suffered from 3834 concomitant injuries of other body parts. In summary, we observed changing patterns of CMF trauma over the last 15 years, paralleled by advances in refined treatment and management options for rehabilitation and reconstruction of patients suffering from CMF trauma.

New insights into tetrahydrobiopterin pharmacodynamics from Pah enu1/2, a mouse model for compound heterozygous tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency.

Phenylketonuria (PKU), an autosomal recessive disease with phenylalanine hydroxylase (PAH) deficiency, was recently shown to be a protein misfolding disease with loss-of-function. It can be treated by oral application of the natural PAH cofactor tetrahydrobiopterin (BH(4)) that acts as a pharmacological chaperone and rescues enzyme function in vivo. Here we identified Pah(enu1/2) bearing a mild and a severe mutation (V106A/F363S) as a new mouse model for compound heterozygous mild PKU. Although BH(4) treatment has become established in clinical routine, there is substantial lack of knowledge with regard to BH(4) pharmacodynamics and the effect of the genotype on the response to treatment with the natural cofactor. To address these questions we applied an elaborate methodological setup analyzing: (i) blood phenylalanine elimination, (ii) blood phenylalanine/tyrosine ratios, and (iii) kinetics of in vivo phenylalanine oxidation using (13)C-phenylalanine breath tests. We compared pharmacodynamics in wild-type, Pah(enu1/1), and Pah(enu1/2) mice and observed crucial differences in terms of effect size as well as effect kinetics and dose response. Results from in vivo experiments were substantiated in vitro after overexpression of wild-type, V106A, and F263S in COS-7 cells. Pharmacokinetics did not differ between Pah(enu1/1) and Pah(enu1/2) indicating that the differences in pharmacodynamics were not induced by divergent pharmacokinetic behavior of BH(4). In conclusion, our findings show a significant impact of the genotype on the response to BH(4) in PAH deficient mice. This may lead to important consequences concerning the diagnostic and therapeutic management of patients with PAH deficiency underscoring the need for individualized procedures addressing pharmacodynamic aspects.

Pahenu1 is a mouse model for tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency and promotes analysis of the pharmacological chaperone mechanism in vivo.

The recent approval of sapropterin dihydrochloride, the synthetic form of 6[R]-l-erythro-5,6,7,8-tetrahydrobiopterin (BH(4)), for the treatment of phenylketonuria (PKU) as the first pharmacological chaperone drug initiated a paradigm change in the treatment of monogenetic diseases. Symptomatic treatment is now replaced by a causal pharmacological therapy correcting misfolding of the defective phenylalanine hydroxylase (PAH) in numerous patients. Here, we disclose BH(4) responsiveness in Pah(enu1), a mouse model for PAH deficiency. Loss of function resulted from loss of PAH, a consequence of misfolding, aggregation, and accelerated degradation of the enzyme. BH(4) attenuated this triad by conformational stabilization augmenting the effective PAH concentration. This led to the rescue of the biochemical phenotype and enzyme function in vivo. Combined in vitro and in vivo analyses revealed a selective pharmaceutical action of BH(4) confined to the pathological metabolic state. Our data provide new molecular-level insights into the mechanisms underlying protein misfolding with loss of function and support a general model of pharmacological chaperone-induced stabilization of protein conformation to correct this intracellular phenotype. Pah(enu1) will be essential for pharmaceutical drug optimization and to design individually tailored therapies.