Axial tissue diffusion can account for the disparity between current models of hepatic elimination for lipophilic drugs

An assumption of previous models of hepatic elimination is that there is negligible axial diffusion in the liver. We show, by construction of a stochastic model and analysis of published data, that compounds which are readily diffusible and partitioned into hepatocytes may undergo axial tissue diffusion. The compounds most likely to be affected by axial tissue diffusion are the lipophilic drugs for which the cell membranes provide little resistance and which are highly extracted, thereby creating steep concentration gradients along the sinusoid at steady state. This phenomenon greatly modifies the availability of the compound under conditions of altered hepatic blood flow and protein binding. For moderately diffusible compounds, these relationships are similar to those predicted by the simplistic venous-equilibrium model. Hence, the paradoxical ability of the venous-equilibrium model to describe the steady-state kinetics of lipophilic drugs such as lidocaine, meperidine, and propranolol may be finally resolved. The effects of axial tissue diffusion and vascular dispersion on hepatic availability of drugs are compared. Vascular dispersion is of major importance to the availability of poorly diffusible compounds, whereas axial tissue diffusion becomes increasingly dominant for highly diffusive and partitioned substances.This study was supported by the National Health and Medical Research Council of Australia.     

Autoimmune diseases in pregnancy.

Autoimmune diseases are a significant problem in women of reproductive age. This article reviews some of the more common autoimmune disorders and discusses their diagnosis and management during pregnancy. The effects of the autoimmune disorder on pregnancy and the effects of pregnancy on the course of the autoimmune disorder are also discussed with an emphasis on the implications for clinical management.     

Return to training and competition after deep venous calf thrombosis.

A 25-yr-old female triathlete presented with 4 d of increasing left calf pain that started 1 d after an elective termination of pregnancy during the eighth week of gestation. She had been training with running, bicycling, and swimming but did not recall any injury to the calf muscle. Deep venous thrombosis of the calf and popliteal veins was diagnosed, and she was treated with intravenous heparin and oral warfarin anticoagulation. Her major concern was return to training and competition. A protocol was developed based on experience with less active patients and animal studies to allow a progressive return to training activities over 5 wk, followed by running in the sixth week. After release from the hospital, she accelerated the return-to-training protocol and progressed to running within 3 wk. She developed the post-phlebitic syndrome that resolved within 2 yr. The diagnosis and treatment of deep venous thrombosis are reviewed, with specific attention to the needs of athletic patients.     

Maturational changes in retinal excitatory amino acid receptors

The appearance, kinetics and pharmacological properties of receptors for n-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), kainate (KA), L-glutamate (Glu) and L-aspartate (Asp) was investigated using 3H-ligand binding during the development of chick embryo retina. Receptors for AMPA are maximally concentrated at embryonic day 7 (ED 7) and decline 50% in subsequent days; L-Glu receptors are low until ED 11, and the same is true for Asp and NMDA receptors which increase at ED 14 and 18 respectively. All receptors studied underwent an increase in pharmacological specificity, whereas only AMPA-receptors showed an important change in affinity during ontogeny. Results demonstrate that receptors for excitatory amino acids in the retina suffer maturational changes and suggest that while NMDA and aspartate could interact with the same receptor, AMPA and glutamate seem to bind to different sites.     

Combined thoracic aortic dissection and abdominal aortic fusiform aneurysm.

Certain clinical and autopsy findings are described in 13 patients who had both aortic dissection (AD) and fusiform abdominal aortic aneurysm (AAA). All 13 patients had severe and extensive aortic atherosclerosis. The AAA was diagnosed clinically in 9 patients, and 5 had the AAA resected. The AD was diagnosed clinically in 5 patients, and 2 underwent attempted operative repair. Two patients who had the AAA resected because of suspected rupture were found later to have ruptured a more proximal AD. Thus, AD occurs occasionally in patients who have AAA. In older persons with suspected rupture of an AAA, a more proximal rupture of an AD should be ruled out. When both AAA and AD are present in the same patient, the AD is more likely the cause of cardiovascular collapse than is rupture of the AAA.     

Gender differences in the effect of age on adrenergic neurotransmission in the heart.

In male rats, there is an age-associated decline in the capacity of cardiac sympathetic nerves to release norepinephrine. To investigate whether this phenomenon also occurs in female rats, we examined adrenergic neurochemical transmission in the hearts of female and male Fischer 344 rats. Rats aged 6, 12, and 24 months were employed. Hearts with the right cardiac sympathetic nerve intact were isolated and perfused with Krebs-Ringer solution. Stimulations were performed following the administration of cocaine or metanephrine separately and in combination or following the combination of cocaine, metanephrine, and yohimbine. Cocaine (1 microM) was used to block uptake 1, metanephrine (1 x 10(-5) M) to block uptake 2, and yohimbine (3 microM) to block alpha 2 receptor presynaptically. The nerve was stimulated with frequencies of 2, 6, and 12 Hz, and norepinephrine amount in the effluent was determined by high performance liquid chromatography/electrochemical detection methods. Neither norepinephrine release nor the effects of yohimbine, cocaine, or metanephrine were found to be affected in older female rats (24 month). This suggests that age-related changes in adrenergic neurochemical transmission in the heart of female rats differ from those seen in older male rats.     

Patterns of CD16 and CD56 expression in persistent expansions of CD3+NKa+ lymphocytes are predictive for clonal T-cell receptor gene rearrangements

Phenotypic characteristics, and correlations between the expression of membrane NK-associated (NKa) determinants (CD11b, CD16, CD56 and CD57) and T cell receptor (TCR) genotypic patterns, were examined in 25 patients with persistent (greater than 6 months) expansions of CD3+WT31+NKa+ (CD8+ and CD8dim+) lymphocytes. These studies showed that distinct NKa phenotypic profiles were restricted to cases with rearranged TCR configurations and that clonal CD3+NKa+ components could be predicted in most cases by assessing relationships between membrane CD16 and CD56 expression. For all normal NKa subpopulations, there was a high correlation (P less than 0.0001; n = 31) between the expression of these two membrane determinants. Markedly increased CD16 expression by CD3+NKa+ cells, in relation to CD56 (i.e. a high CD16:CD56 ratio), was found exclusively in cases with rearranged TCR (13/16 cases); 2/3 of the remaining cases showing significantly reduced CD16:CD56 ratios and high (greater than 2.0) CD3+CD56+ absolute numbers. In contrast, 7/9 of the germline TCR cases had a normal CD16:CD56 ratio and 2/9 a decreased ratio with low (less than 1.0) CD3+CD56+ absolute numbers. A high ratio of CD16:CD56 expression by CD3+NKa+ lymphocytes was therefore informative for 82% of TCR rearrangements in this series; and analysis of CD16 and CD56 expression was predictive for germline and rearranged TCR configurations in 24/25 persistent CD3+NKa+ expansions.     

Interleukin-1-inhibitor activity induced by respiratory syncytial virus: abrogation of virus-specific and alternate human lymphocyte proliferative responses

Respiratory syncytial virus (RSV) infection has been shown to induce human mononuclear leukocyte (MNL) production of net interleukin-1 (IL-1)-inhibitor activity. In the current studies of IL-1-inhibitor effects, RSV-exposed cells were compared with autologous MNL that were sham-exposed or exposed to inactivated RSV or influenza virus (which induces net IL-1 activity and commonly elicits effective homotypic immunity). Exposure of MNL to influenza virus or inactivated RSV resulted in increased expression of human leukocyte antigen-DR, the IL-2 receptor, and the transferrin receptor and increased progression through the cell cycle by 3 days. In contrast, exposure to infectious RSV resulted in decreased marker expression and cell cycle arrest, with abrogation of proliferation in response to the virus or other stimuli. These data raise the possibility that a contributing mechanism for recurrence of RSV infection is early suppression of the clonal expansion of virus-specific lymphocytes due to net IL-1-inhibitor activity.     

The Role of Energy Expenditure in Energy Regulation: Findings from a Decade of Research

The role of energy expenditure in energy regulation remains a subject of continuing controversy. New data have emerged from studies conducted over the last decade demonstrating that energy expenditure is a critical factor contributing to successful energy regulation in normal individuals, as well as to the disregulation of energy balance that characterizes obesity. Reduced energy expenditure appears to facilitate weight gain in individuals susceptible to obesity and also appears to reduce the extent of body energy loss during undereating in both lean and obese individuals. The magnitude of the reduction in energy expenditure during, and perhaps after, weight loss is greater than expected on the basis of the reduction in body weight and appears to occur in response to undefined underlying determinants of energy regulation. In addition, exercise intervention studies and cross-sectional investigations of the relationship between energy expenditure for physical activity and body composition demonstrate an apparent equilibration between physical activity and body fat content. This equilibration is suggestive of a direct influence of physical activity on the underlying metabolic determinants of energy balance.