Hypophosphatasia: molecular testing of 19 prenatal cases and discussion about genetic counseling

OBJECTIVE: We studied hypophosphatasia (HP) mutations in 19 cases prenatally detected by ultrasonography without familial history of HP. We correlated the mutations with the reported ultrasound signs, and discussed genetic counseling with regard to the particular dominantly inherited prenatal benign form of HP. METHOD: The coding sequence of the tissue nonspecific alkaline phosphatase (TNSALP) gene was analyzed by DNA sequencing, and 3D modeling was used to locate the mutated amino acids with regard to the functional domains of TNSALP. RESULTS: Although reported ultrasound signs were heterogeneous, two mutated alleles were found in 18 of the 19 cases studied, indicating recessive transmission of the disease. Functional domains of TNSALP were affected by 74% of missense mutations. In all the cases, including one with only a heterozygous mutation, molecular, biological, and familial data do not corroborate the hypothesis of prenatal benign HP. The mutation c.1133A>T observed in the prenatal benign form of HP and common in USA was not found in this series. CONCLUSION: The results point out the prenatally detectable allelic heterogeneity of HP. The nature of the detected mutations and the evidence of recessive inheritance do not support these cases being affected with prenatal benign HP.     

Surgical sperm retrieval: what not to do

Surgical sperm retrieval has revolutionized the treatment of azoospermia. However, the ease with which it could be performed meant that it is perhaps being used where not indicated. Here are the potential pitfalls to be avoided.     

Practical tips and tricks for the measurement of fractional flow reserve

Coronary pressure measurement has emerged as one of the most promising tool to assist interventional cardiologist to make accurate clinical decisions. Fractional flow reserve (FFR) is a simple way of reliably assessing the functional consequences of coronary atherosclerosis. The training in FFR is easy, and coronary pressure measurements can be obtained swiftly in the catheterization laboratory. This review outlines the practical set up of FFR in the catheterization laboratory and also discusses the potential pitfalls in the measurement of FFR. © 2010 Wiley‐Liss, Inc.     

Complete heart block in a patient with acute lymphoblastic leukaemia: teicoplanin as a possible cause and review of literature

What is known and Objective:  Teicoplanin is a glycopeptide antibiotic used against documented or presumed methicillin‐resistant infections. We report a 31‐month‐old boy with acute lymphocytic leukaemia who developed permanent complete atrioventricular block (CAVB) necessitating pacemaker insertion after receiving teicoplanin for Staphylococcus epidermidis bacteremia. Case summary:  Clinical assessment of the child revealed febrile neutropenia. After thorough assessment and work‐up, the patient was started on teicoplanin intravenously after which he had sudden onset of bradycardia. Electrocardiography showed CAVB that eventually required permanent pacemaker insertion. Twenty‐nine months from the incident, the patient is doing well. What is new and Conclusion:  We report on a case of teicoplanin‐associated CAVB in a child with acute lymphoblastic leukaemia (ALL). This is one of only two similar cases reported in the literature. Teicoplanin remains the most probable cause. The use of teicoplanin should be approached cautiously in the setting of immunosuppression. Whether VZV contributed and teicoplanin triggered remains speculative. Physicians should be aware of this possible complication.     

Differential effects of combined Ad5- delta 24RGD and radiation therapy in in vitro versus in vivo models of malignant glioma.

PURPOSE: The integrin-targeted conditionally replicating adenovirus Ad5-delta 24RGD has been shown to possess strong oncolytic activity in experimental tumors and is currently being developed toward phase I clinical evaluation for ovarian cancer and malignant glioma. Previously, we reported that combination therapy of Ad5-delta 24RGD with irradiation led to synergistic antitumor activity in s.c. glioma xenografts. In the current study, the underlying mechanism of action to this synergy was studied and the effects of combined therapy were assessed in an orthotopic glioma model. EXPERIMENTAL DESIGN AND RESULTS: Sequencing studies in U-87 monolayers showed that delivery of irradiation before Ad5-delta 24RGD infection led to a greater oncolytic effect than simultaneous delivery or infection before irradiation. This effect was not due to enhanced virus production or release. Experiments using a luciferase-encoding vector revealed a small increase in transgene expression in irradiated cells. In tumor spheroids, combination therapy was more effective than Ad5-delta 24RGD or irradiation alone. Staining of spheroid sections showed improved penetration of virus to the core of irradiated spheroids. Mice bearing intracranial tumors received a combination of Ad5-delta 24RGD with 1 x 5 Gy total body irradiation or with 2 x 6 Gy whole brain irradiation. In contrast to the in vitro data and reported results in s.c. tumors, addition of radiotherapy did not significantly enhance the antitumor effect of Ad5-delta 24RGD. CONCLUSIONS: Combined treatment with Ad5-delta 24RGD and irradiation shows enhanced antitumor activity in vitro and in s.c. tumors, but not in an orthotopic glioma model. These differential results underscore the significance of the selected tumor model in assessing the effects of combination therapies with oncolytic adenoviruses.