Increased activity of tyrosine hydroxylase in the cerebellum of the X-irradiated dystonic rat

The exposure of the cephalic end of rats to repeated doses of X-irradiation (150 rad) immediately after birth induces a long-term increase in the noradrenaline (NA), content of cerebellum (CE) (+37.8%), and a decrease in cerebellar weight (65.2% of controls), which results in an increased NA concentration (+109%). This increase in the neurotransmitter level is accompanied by a dystonic syndrome and histological abnormalities: Purkinje cells (the target cells for NA afferents to CE) fail to arrange in a characteristic monolayer, and their primary dendritic tree appears randomly oriented. The injection of reserpine 0.9 and 1.2 mg/kg ip to adult rats for 18 h depletes cerebellar NA content in both controls (15.7±4 ng/CE and 2.8±1.5 ng/CE, respectively) and X-irradiated rats (17.1±1 ng/CE and 8.3±2 ng/CE, respectively). The activity of tyrosine hydroxylase (TH) in CE of adult rats, measured by an in vitro assay, is significantly increased in neonatally X-irradiated animals when compared to agematched controls (16.4±1.4 vs 6.32±0.6 nmol CO₂/h/mg prot.,p<0.01). As observed for NA levels, a net increase in TH activity induced by the ionizing radiation is also measured: 308.9±23.8 vs 408.2±21.5 nmol CO₂/h/CE,p<0.01 (controls and X-treated, respectively). These results suggest that X-irradiation at birth may induce an abnormal sprouting of noradrenergic afferents to CE. The possibility that these changes represent a response of the NA system to the dystonic syndrome is discussed.     

Familial hypertrophic cardiomyopathy: the same mutation, different prognosis. Comparison of two families with a long follow-up.

The gene encoding the beta-myosin heavy chain is one of the most frequently implicated in familial hypertrophic cardiomyopathy. Several mutations have been identified and some genotype-phenotype relationships have been assumed, particularly with regard to prognosis. Nevertheless, phenotypic expression is variable even in affected members of the same family carrying the same mutation. We identified the Ile263Thr mutation in several members of two unrelated Portuguese families. Penetrance, clinical behavior and prognosis were quite different between the two families, particularly concerning the occurrence of sudden death. Additional factors probably exist which account for the differences found. The complexity of hypertrophic cardiomyopathy makes it difficult to accurately determine genotype-phenotype relationships, and the screening and comparison of large affected families carrying the same mutation is warranted.     

Visual system abnormalities in adrenomyeloneuropathy

We studied the visual system in 59 men with adrenomyeloneuropathy. Pattern-reversal visual evoked potentials, magnetic resonance imaging, and clinical examination revealed that visual pathways are affected in 63% of patients, involving the optic discs, optic nerves, lateral geniculate bodies, optic radiations, and parietooccipital cortex. This indicates both primary demyelination of the optic nerves and discs, and more diffuse involvement of postchiasmal structures.     

Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man

Aims Saquinavir is a potent HIV protease inhibitor whose effectiveness is limited in vivo by its low bioavailability. Since saquinavir is metabolized by CYP3A4, the effect of grapefruit juice, an inhibitor of CYP3A4, was investigated on its bioavailability.
Methods After an overnight fast, eight healthy volunteers were treated with either 400  ml grapefruit juice or water before intravenous (12  mg) or oral saquinavir (600  mg) was administered. Serial blood samples were obtained over the following 24  h and standardized meals were served 5 and 10  h after the administration of saquinavir. The plasma concentrations of saquinavir were determined by high-performance liquid chromatography and pharmacokinetic parameters were calculated by routine methods.
Results The AUC was not affected by grapefruit juice after intravenous administration, but it increased significantly from 76±96 (water, mean (s.d.) to 114±70 (μg  l⁻¹  h (grapefruit juice) after oral saquinavir. Similarly, the oral bioavailability of saquinavir increased by a factor of 2 with grapefruit juice (from 0.7% to 1.4%). In contrast, clearance, volume of distribution and elimination half-life of saquinavir were not affected by grapefruit juice. After oral, but not after intravenous administration, the plasma concentration-time curve showed a second peak after lunch irrespective of pretreatment, suggesting enhancement of absorption by food.
Conclusions The studies demonstrate that grapefruit juice increases the bioavailability of saquinavir without affecting its clearance, suggesting that inhibition of intestinal CYP3A4 may contribute. Since the antiretroviral effect of saquinavir is dose-dependent, inhibition of CYP3A4 may represent a way to enhance its effectiveness without increasing the dose.     

Three-dimensional structure of the transthyretin-retinol-binding protein complex.

Transthyretin (TTR), formerly called prealbumin, one of the transporters of the hormone thyroxine and retinol-binding protein (RBP), the specific carrier of vitamin A, forms, under physiological conditions, a macromolecular complex that prevents glomerular filtration of the low-molecular-weight RBP in the kidneys. This paper describes briefly the three-dimensional structure of the two proteins as determined by X-ray diffraction analysis of single crystals and that of the complex that the two molecules form in plasma and discusses the non-crystallographic evidence that supports the model of the macromolecular complex.