Novel mouse model of autosomal semidominant adult hypophosphatasia has a splice site mutation in the tissue nonspecific alkaline phosphatase gene Akp2.

Deactivating mutations in the TNSALP gene cause HPP. Akp2(-/-) mice model severe infantile HPP, but there is no model for the relatively mild adult form. Here we report on mice with an induced mutation in Akp2 that affects splicing. The phenotype of homozygotes mirror aspects of the adult form of HPP. INTRODUCTION: Hypophosphatasia (HPP) is a clinically varied skeletal disorder resulting from deficiency of tissue nonspecific alkaline phosphatase (TNSALP). Mice lacking Akp2 model infantile HPP characterized by skeletal hypomineralization, impaired growth, seizures, and perinatal mortality. No animal model exists to study the less severe forms of the disease that typically present in later life. MATERIALS AND METHODS: N-ethyl-N-nitrosourea (ENU) mutagenesis was used to generate mouse models of human disease. A mouse with low plasma alkaline phosphatase (ALP) activity was identified by our clinical chemistry screen. Its offspring were used for inheritance studies and subjected to biochemical, histological, and radiological phenotyping. DNA was extracted for mapping and osteoblasts harvested for functional studies. RESULTS: We showed semidominant inheritance of the low ALP phenotype and mapped the underlying point mutation to Akp2. Affected offspring bear the splice site mutation 862 + 5G>A-a hypomorphic allele named Akp2(Hpp). The same mutation has been reported in a patient. Akp2(Hpp/+) mice have approximately 50% of normal plasma ALP but display no other biochemical or skeletal abnormalities. Unlike Akp2(-/-) mice, Akp2(Hpp/Hpp) mice have normal initial skeletal development and growth, a normal lifespan and do not have seizures. TNSALP is low but detectable in Akp2(Hpp/Hpp) plasma. Osteoblasts display approximately 10% of normal ALP activity and reduced intracellular inorganic phosphate levels, yet are capable of normal mineralization in vitro. TNSALP substrates are significantly elevated in urine (inorganic pyrophosphate and phosphoethanolamine) and plasma (pyridoxal 5'-phosphate), whereas plasma inorganic pyrophosphate levels are normal. Akp2(Hpp/Hpp) mice develop late-onset skeletal disease, notably defective endochondral ossification and bone mineralization that leads to arthropathies of knees and shoulders. CONCLUSIONS: Akp2(Hpp/Hpp) mice mirror a number of clinical features of the human adult form of HPP. These mice provide for the first time an animal model of late onset HPP that will be valuable in future mechanistic studies and for the evaluation of therapies such as those aimed at HPP.     

Life threatening ventricular tachycardias in late survivors of surgically corrected tetralogy of Fallot.

Electrophysiological tests were performed in three patients with surgically corrected tetralogy of Fallot (mean age at evaluation 25 years, mean age at surgical correction 4 years) who had had either a cardiac arrest or transient neurological disturbances (presyncope, syncope) associated with ventricular arrhythmias. All three patients had an excellent haemodynamic result from surgery as judged by echocardiography and cardiac catheterisation. Ambulatory electrocardiographic monitoring and stress exercise testing were normal in two patients and showed complex ventricular ectopy in one. During invasive electrophysiological evaluation all three patients had inducible ventricular tachycardia (monomorphic QRS in two patients, cycle lengths 230 and 240 ms; polymorphic QRS in one patient, mean cycle length 200 ms) with adverse haemodynamic effects in all three patients. These findings suggest that rapid ventricular tachycardia with detrimental haemodynamic consequences, similar to that induced during laboratory study, was the basis for the presenting symptoms in each patient. This possibility was confirmed in one patient who had identical QRS morphology during both spontaneous ventricular tachycardia and that induced during the laboratory study. Thus sudden death or symptoms of syncope postoperatively in patients with surgically corrected tetralogy of Fallot appear to be due to rapid ventricular tachycardia, which may occur despite an apparently excellent surgical result.     

Articular cartilage development: a molecular perspective

In this article, development of articular cartilage and endochondral ossification is reviewed, from the perspective of both morphologic aspects of histogenesis and molecular biology, particularly with respect to key signaling molecules and extracellular matrix components most active in cartilage development. The current understanding of the roles of transforming growth factor β and associated signaling molecules, bone morphogenic proteins, and molecules of the Wnt-β catenin system in chondrogenesis are described. Articular cartilage development is a highly conserved complex biological process that is dynamic and robust in nature, which proceeds well without incident or failure in all joints of most young growing individuals.     

Cardiovascular Risk and Psoriasis: Beyond the Traditional Risk Factors

Psoriasis is an autoimmune disease resulting in plaques of the skin. Similar to atherosclerosis, inflammation is integral to the initiation and propagation of plaque development. Mounting evidence has emerged demonstrating that psoriasis not only is associated with increased prevalence of cardiovascular risk factors, but also is an independent risk factor for the development of cardiovascular disease. Systemic therapies for moderate to severe psoriasis can increase the cardiovascular risk. Despite the evidence that psoriasis is an independent risk factor for cardiovascular disease, current guidelines only address managing traditional risk factors. An interdisciplinary approach is needed to find the necessary steps beyond classic risk reduction and detection of early cardiovascular disease in patients with psoriasis, as well as to develop a cardiovascular disease preventive regimen.     

Electrophysiologic effects of theophylline in young patients with recurrent symptomatic bradyarrhythmias

In this study, both acute electrophysiologic actions of intravenously administered theophylline and clinical effects of chronic oral theophylline therapy were assessed in 10 young patients (aged 9 to 41 years) without clinically significant cardiac disease, in whom recurrent symptoms of syncope and dizziness were attributed to transient bradyarrhythmias (sinus pauses, marked sinus bradycardia or paroxysmal atrioventricular [AV] block). Intravenous theophylline infusion (serum concentration range 9.5 to 12.0 mg/liter) shortened means sinus cycle length (control 973 ± 285 ms versus theophylline 880 ± 226 ms, p <0.005) and decreased both the estimated sinoatrial conduction time (control 169 ± 56.0 ms versus theophylline 143 ± 55.3 ms, p <0.05) and the maximum corrected sinus node recovery time (control 442 ±251.0 ms versus theophylline 255 ± 146.2 ms, p <0.05). In addition, theophylline infusion shortened the minimum atrial paced cycle length with sustained 1:1 AV conduction (control 414 ± 86 ms versus theophylline 379 ± 97 ms, p <0.05) and consistently reduced AV node functional refractory periods. Subsequent chronic oral theophylline therapy (serum levels 9 to 12 mg/liter) was tolerated in 8 patients (80%). During a follow-up of 5 to 24 months, suppression of symptoms was achieved in 6 of the 8 patients. Thus, theophylline exhibits positive chronotropic and dromotropic effects in man at serum concentrations in the usual therapeutic range (10 to 15 mg/liter). Furthermore, suppression of symptoms during follow-up suggests that theophylline treatment may be a useful therapeutic consideration in some patients with recurrent symptomatic bradyarrhythmias.     

Transesophageal echocardiography in patients with mechanical circulatory assistance.

Transesophageal echocardiography was used to assess myocardial function and to detect complications after mechanical circulatory support for 8 patients with cardiogenic shock. In 3 of 8 patients, serial transesophageal echocardiography documented improvement of systolic ventricular function, and it was possible to wean these 3 patients from the ventricular assist device. In all patients, transesophageal echocardiography added clinically important information including the extent of left and right ventricular dysfunction (6 patients), presence of atrial or ventricular thrombus (5 patients), presence of pericardial effusion or clot (2 patients), and verification of the position of the intravascular device (1 patient). Thus, transesophageal echocardiography may provide clinically useful information regarding both the underlying cardiac disease and potential complications from the mechanical circulatory assistance.