Age-related changes in lung collagen metabolism. A role for degradation in regulating lung collagen production

Lung collagen levels are determined by a balance between synthesis and degradation, processes known to have rapid rates in young animals. Here, we report age-related changes in lung collagen synthesis and degradation in rats at five ages from 1 month to 2 yr. Synthesis rates were determined after injection of [14C]proline with a flooding dose of unlabeled proline, and its appearance as hydroxy-[14C]proline in protein. To determine degradation of newly synthesized collagen, the appearance of hydroxy-[14C]proline, either free or in low-molecular-weight peptides, was compared with hydroxy-[14C]proline in protein. Fractional collagen synthesis rates decreased from 13.51 +/- 0.54%/day at 1 month to 0.97 +/- 0.14%/day at 2 yr of age (p less than 0.05). Total lung collagen production also fell, but only after 15 months, when it decreased from 2.01 +/- 0.16 mg/day at 15 months to 0.54 +/- 0.10 mg/day at 2 yr of age (p less than 0.05). Fractional rates of total collagen degradation, calculated from the difference between rates of synthesis and rates of collagen deposition, decreased 20-fold from 1 month to 2 yr of age. The proportion of newly synthesized collagen degraded increased from 27.6 +/- 3.2% at 1 month to a maximum of 82.3 +/- 1.1% at 15 months. These results suggest that lung collagen synthesis and degradation occur throughout life, and that degradative pathways may play important roles in regulating collagen production during growth and ageing.     

Increasing Maternal Blood Pressure with Ephedrine Increases Uterine Artery Blood Flow Velocity during Uterine Contraction

Background: During labor, ephedrine is widely used to prevent or to treat maternal arterial hypotension and restore uterine perfusion pressure to avoid intrapartum fetal asphyxia. However, the effects of ephedrine on uterine blood flow have not been studied during uterine contractions. The purpose of the study was to assess the effects of ephedrine on uterine artery velocities and resistance index using the Doppler technique during the active phase of labor.

Methods: Ten normotensive, healthy parturients with uncomplicated pregnancies at term received intravenous ephedrine during labor to increase mean arterial pressure up to a maximum of 20% above their baseline pressure. Peak systolic and end-diastolic Doppler flow velocities and resistance indices were measured in the uterine artery before and immediately after administration of bolus intravenous ephedrine and after ephedrine washout. Umbilical and fetal middle cerebral arterial resistance indices and fetal heart rate were also calculated.

Results: After ephedrine administration, mean arterial pressure increased by 17 +/- 4%. End-diastolic flow velocity in the uterine artery at peak amplitude of uterine contraction was restored to 74% of the value observed in the absence of contraction. The systolic velocity was totally restored, and the uterine resistance index was significantly decreased, compared with the values in the absence of contraction. Between uterine contractions, ephedrine induced similar but less marked effects. Fetal hemodynamic parameters were not altered by ephedrine administration.     

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.     

In vitro metabolism of ferroquine (SSR97193) in animal and human hepatic models and antimalarial activity of major metabolites on Plasmodium falciparum.

Ferroquine (SSR97193) has been shown to be a promising antimalarial, both on laboratory clones and on field isolates. So far, no resistance was documented in Plasmodium falciparum. In the present work, the metabolic pathway of ferroquine, based on experiments using animal and human hepatic models, is proposed. Ferroquine is metabolized mainly via an oxidative pathway into the major metabolite mono-N-demethyl ferroquine and then into di-N,N-demethyl ferroquine. Some other minor metabolic pathways were also identified. Cytochrome P450 isoforms 2C9, 2C19, and 3A4 and, possibly in some patients, isoform 2D6, are mainly involved in ferroquine oxidation. The metabolites were synthesized and tested against the 3D7 (chloroquine-sensitive) and W2 (chloroquine-resistant) P. falciparum strains. According to the results, the activity of the two main metabolites decreased compared with that of ferroquine; however, the activity of the mono-N-demethyl derivative is significantly higher than that of chloroquine on both strains, and the di-N-demethyl derivative remains more active than chloroquine on the chloroquine-resistant strain. These results further support the potential use of ferroquine against human malaria.     

An epidemiologic study of smoking and primary infertility in women.

OBJECTIVE: To determine the relationship between cigarette smoking and primary female infertility. DESIGN: Retrospective, case-control study. SETTING: Population-based and randomly selected from eight geographic areas in the United States. PARTICIPANTS: Women, 20 to 54 years of age, who were randomly selected to serve as the control group of the Cancer and Steroid Hormone Study were used for this study. Within this group, there were 483 women who were classified as having experienced primary infertility and 2,231 women eligible to serve as controls. Primary infertility, defined as 24 consecutive months of unprotected intercourse without conception, was documented from a calendar of each women's reproductive and contraceptive history. RESULTS: Smoking one pack of cigarettes per day (odds ratio = 1.36) and starting to smoke before 18 years of age (odds ratio = 1.30) were significantly associated with increased risk of infertility. Life table and proportional hazards analysis indicated that smoking did not significantly increase the time required to conceive among infertile women. CONCLUSIONS: Number of cigarettes smoked and age when the women began smoking contributed to infertility in this study. It is reasonable, therefore, to recommend that women stop smoking when they are attempting to become pregnant.     

Postamputation Pain and Sensory Changes in Treatment-naive Patients: Characteristics and Responses to Treatment with Tramadol, Amitriptyline, and Placebo

Background: Pain after amputation is common but difficult to treat, and few controlled treatment studies exist.

Methods: In the current study, 94 treatment-naive posttraumatic limb amputees with phantom pain (intensity: mean visual analog scale score [0-100], 40 [95% confidence interval, 38-41]) were randomly assigned to receive individually titrated doses of tramadol, placebo (double-blind comparison), or amitriptyline (open comparison) for 1 month. Nonresponders were crossed over to the alternative active treatment.

Results: After 1 month, phantom pain intensity was 1 (0-2) in the 48 tramadol responders (mean dose, 448 mg [95% confidence interval, 391-505 mg]), 0 (0-0) in the 40 amitriptyline responders (55 [50-59] mg), and 0 (0-0) in the 2 placebo responders, with similar effects on stump pain. Cytochrome P-450 2D6 slow metabolizers derived greater analgesia from tramadol and less from amitriptyline compared with fast metabolizers in the first treatment week (P < 0.01). Electrical pain thresholds increased and pain during suprathreshold stimulation decreased markedly on the stump and, to a lesser extent, on the contralateral limb after 1 month of treatment with amitriptyline or tramadol. Adverse effects were minor in all groups, but more common with tramadol.     

Automated three-dimensional analysis of histological and autoradiographic rat brain sections: application to an activation study.

Besides the newly developed positron emission tomography scanners (microPET) dedicated to the in vivo functional study of small animals, autoradiography remains the reference technique widely used for functional brain imaging and the gold standard for the validation of in vivo results. The analysis of autoradiographic data is classically achieved in two dimensions (2D) using a section-by-section approach, is often limited to few sections and the delineation of the regions of interest to be analysed is directly performed on autoradiographic sections. In addition, such approach of analysis does not accommodate the possible anatomical shifts linked to dissymmetry associated with the sectioning process. This classic analysis is time-consuming, operator-dependent and can therefore lead to non-objective and non-reproducible results. In this paper, we have developed an automated and generic toolbox for processing of autoradiographic and corresponding histological rat brain sections based on a three-step approach, which involves: (1) an optimized digitization dealing with hundreds of autoradiographic and histological sections; (2) a robust reconstruction of the volumes based on a reliable registration method; and (3) an original 3D-geometry-based approach to analysis of anatomical and functional post-mortem data. The integration of the toolbox under a unified environment (in-house software BrainVISA, http://brainvisa.info) with a graphic interface enabled a robust and operator-independent exploitation of the overall anatomical and functional information. We illustrated the substantial qualitative and quantitative benefits obtained by applying our methodology to an activation study (rats, n=5, under unilateral visual stimulation).