Molecular genetics and transfusion management in a child with Bernard Soulier syndrome.

We present a case of Bernard Soulier syndrome in a 9-year-old boy caused by a novel genetic mutation. This child was shown to be homozygous for a single nucleotide deletion (c.1077delG) in the GP1BA gene not previously reported. Clinically, the boy has become refractory to platelet transfusions with both allo-antibodies and iso-antibodies and a massive transfusion requirement for ongoing haemorrhage. We describe the critical role that the blood product transfusion continues to play in the management of Bernard Soulier syndrome and discuss therapeutic options in these patients.     

Deformation behaviour of bovine cancellous bone.

Repetitive cyclic loading from daily activities is reported to induce fatigue damage and microcracking in bone structures. In terms of osteoporotic structures or in cases of serious damage of skeleton segments and the replacement by metallic implants the degree of damage due to cyclic loading will be even more pronounced. It is generally assumed that fatigue induced cracking and crack propagation essentially act as driving forces for complex physiological phenomena such as remodelling processes of bones and the adaptation to applied loads. In cases where the crack propagation rate exceeds the remodelling velocity, sudden and unexpected fracture of the bone is observed. Especially for implant reinforced structures the deviation in stiffness to the bone material can induce high peak stresses and accelerate crack propagation. Whereas, for cortical bone the mechanical behaviour under cyclic loading is sufficiently described, only rough data are available for trabaecular structures. In this study the deformation behaviour of bovine vertebra trabecular bone specimens is investigated under cyclic compressive loading. A powerlaw relationship was found between the applied load ratio and cycles to failure. A linear decrease of maximum, integral strains at failure with increasing applied load ratio was observed. Optical deformation measurement of the surface strains revealed that low strains (0-1 increasing applied load ratio whereby the higher strains behave directly opposite. This indicates that different failure mechanisms are acting at low cycle and high cycle fatigue, respectively.     

In-vitro/in-vivo correlation of pulsatile drug release from press-coated tablet formulations: a pharmacoscintigraphic study in the beagle dog.

The aim of the current study was to investigate the in-vitro and in-vivo performance of a press-coated tablet (PCT) intended for time delayed drug release, consisting of a rapidly disintegrating theophylline core tablet, press-coated with barrier granules containing glyceryl behenate (GB) and low-substituted hydroxypropylcellulose (L-HPC). The PCTs showed pulsatile release with a lag time dependent upon the GB and L-HPC composition of the barrier layer. In-vivo gamma-scintigraphic studies were carried out for PCTs containing GB:L-HPC at 65:35 w/w and 75:25 w/w in the barrier layer in four beagle dogs, in either the fed or fasted state. The in-vivo lag time in both the fed and fasted states did not differ significantly (p>0.05) from the in-vitro lag time. Additionally, no significant difference (p<0.05) between in-vivo fed and fasted disintegration times was observed, demonstrating that in-vivo performance of the PCT was not influenced by the presence or absence of food in the gastrointestinal tract. A distinct lag time was obtained prior to the appearance of drug in plasma and correlated (R2=0.98) with disintegration time observed from scintigraphic images. However, following disintegration, no difference in pharmacokinetic parameters (AUC(0-6 dis), K(el), Cmax) was observed. The current study highlighted the potential use of these formulations for chronopharmaceutical drug delivery.     

Estimation of average flow in ungated 3D phase contrast angiograms

Three dimensional (3D) phase contrast angiograms contain velocity data, which is discarded after the reconstruction of the projections. In extension to earlier work on velocity quantification with ungated 2D phase data, this paper shows that a useful estimate of the average velocity and flow rate can be extracted from ungated 3D phase contrast angiograms. Simulations and experiments in a phantom and in vivo were performed. For pulsatile flow and strong spin saturation, an over-estimation of the flow rate at the net in-flow end of the imaging volume and underestimation at the net out-flow end was observed. Imaging at lower RF tip angles yielded flow rates close to the correct value within the entire imaging volume. In contrast to ungated 2D experiments, the flow rates determined by repeated 3D experiments showed no variation.     

Viral cysteine proteinases

Summary Dozens of novel cysteine proteinases have been identified in positive single-stranded RNA viruses and, for the first time, in large double-stranded DNA viruses. The majority of these proteins are distantly related to papain or chymotrypsin and may be direct descendants of primordial proteolytic enzymes. Virus genome synthesis and expression, virion formation, virion entry into the host cell, as well as cellular architecture and functioning can be under the control of viral cysteine proteinases during infection. RNA virus proteinases mediate their liberation from giant multidomain precursors in which they tend to occupy conserved positions. These proteinases possess a narrow substrate specificity, can cleave in cis and in trans, and may also have additional, nonproteolytic functions. The mechanisms of catalysis, substrate recognition and RNA binding were highlighted by the recent analysis of the three-dimensional structure of the chymotrypsin-like cysteine proteinases of two RNA viruses.     

Tamoxifen and kallikrein in therapy of oligoasthenozoospermia: results of a randomized study

Because of the good results achieved with tamoxifen in the treatment of oligozoospermia and with kallikrein in the treatment of asthenozoospermia, a randomized study of the combined treatment of oligoasthenozoospermia suggested itself. 67 patients with idiopathic normogonadotropic oligoasthenozoospermia were treated with 30 mg tamoxifen/day (n = 33) or with 30 mg tamoxifen/day and additionally 600 IU kallikrein/day (n = 34). It was shown that, apart from a significant increase in sperm density in both groups, the combination therapy also resulted in an overall significant increase (p less than 0.02) in sperm motility. Sperm morphology and the swell test remained unaffected. After 3 months of therapy, 4 pregnancies occurred in each group. In ejaculates with a sperm density of less than 10 million/ml not even one sperm parameter was significantly affected in any of the groups, while with an initial value of more than 10 million/ml the increase in motility was more significant (p less than 0.008) in the group with additional kallikrein therapy (n = 18). In the monotherapy group, no significant therapeutic effect on sperm motility was seen even in patients with a sperm density of more than 10 million. The combination of tamoxifen and kallikrein therefore seems to constitute an improvement of the systemic therapy of male subfertility in patients with moderately severe oligoasthenozoospermia.     

A Comparison of Oral and Rectal Absorption of L-Dopa Esters in Rats and Mice

Short-chain alkyl esters of L-dopa were administered to rats and mice via oral and rectal routes. Plasma L-dopa esters and L-dopa were determined in the systemic and portal circulation by HPLC. A comparison of isopropyl, butyl, and 4-hydroxybutyl esters of L-dopa demonstrated significantly higher levels of the esters in both systemic and portal blood samples following rectal administration than following oral administration. In most cases, oral administration resulted in nondetectable (<0.01 µg/ml) levels of the esters in plasma. Correspondingly, the plasma levels of L-dopa itself were consistently higher following rectal administration. At very high oral doses (500 mg L-dopa equivalents/kg body weight), systemic plasma levels of the butyl ester could be detected (1.25 µg/ml at 10 min), which might indicate saturation of the esterase activity of the small intestine. These studies indicate that the systemic availability of L-dopa from short-chain alkyl esters of L-dopa may be best optimized by rectal administration, which avoids the relatively high esterase activity characteristic of the small intestine.     

Investigations of a novel ferrocene-containing lipid by cyclic voltammetry and cryogenic transmission electron microscopy

A novel chiral redox-active ferrocene compound (FcVI) with amphiphilic properties has been synthesized. Cryogenic Transmission Electron Microscopy (cryo-TEM) has been used to estimate the shape and size of the FcVI aggregates in solution. Uni- and multi-lamellar vesicles (between 40 and 300 nm in diameter) were observed in water. Large particles (of more than 1 μm in diameter) with a hexagonal fine structure were found in 50 mM aqueous Na₂SO₄ solution. Sonication transformed the latter into ‘rosette’-like structures. Cyclic voltammetry has been employed to investigate the electrochemical properties of FcVI. The amphiphile adsorbed on graphite electrodes and a reversible electrochemical behaviour, characteristic of ferrocene, was observed with redox potentials between 330 and 350 mV.     

Acro-pectoro-renal field defect with contralateral ureteropelvic junction obstruction

Ureteropelvic junction obstruction was noted in a newborn male infant with acro-pectoro-renal field defect. To our knowledge, this association has not previously been reported. Ultrasonography of the urinary tract should be performed on all children with aplasia of the pectoralis major muscle.