Absence of relaxation to lactate in human placental vessels of pregnancies with severe preeclampsia

OBJECTIVE: Our objective was to determine whether the observed relaxation to lactate and other agents in placental vessels of normal pregnancies is altered in severe preeclampsia.STUDY DESIGN: Isolated placental arteries and veins from women with severe preeclampsia and uncomplicated term pregnancies were precontracted with prostaglandin F_2α under 5% oxygen and 5% carbon dioxide with the balance nitrogen (Po₂ 35 to 38 torr) and then exposed to lactate (1 to 10 mmol/L, pH 7.4, n = 8 to 15), arachidonic acid (0.01 to 10 μmol/L, n = 6 to 13), nitroglycerin (1 nmol to 1 μmol/L, n = 4 to 12), or forskolin (0.01 to 10 μmol/L, n = 6 to 9). The response to lactate was also examined in placental vessels from appropriate-for-gestational-age preterm deliveries (n = 8) for comparison with a similar group with severe preeclampsia (n = 8). The t test and analysis of variance statistics were used.RESULTS: Relaxation to lactate was markedly inhibited in both placental arteries and veins of women with severe preeclampsia compared with vessels from uncomplicated term or preterm pregnancies. Responses to the other relaxing agents were not altered in the severely preeclampsia vessels.CONCLUSIONS: In severe preeclampsia absence of lactate-induced dilatation of placental vessels may contribute to the fetal complications associated with impaired blood flow and vasospasm.     

A novel 37-Kd adhesive membrane protein from cloned murine bone marrow stromal cells and cloned murine hematopoietic progenitor cells

The adhesion of hematopoietic progenitor cells to bone marrow stromal cells is critical to hematopoiesis and involves multiple effector molecules. Stromal cell molecules that participate in this interaction were sought by analyzing the detergent-soluble membrane proteins of GBI/6 stromal cells that could be adsorbed by intact FDCP-1 progenitor cells. A single-chain protein from GBI/6 cells having an apparent molecular weight of 37 Kd was selectively adsorbed by FDCP-1 cells. This protein, designated p37, could be surface-radiolabeled and thus appeared to be exposed on the cell membrane. An apparently identical 37- Kd protein was expressed by three stromal cell lines, by Swiss 3T3 fibroblastic cells, and by FDCP-1 and FDCP-2 progenitor cells. p37 was selectively adsorbed from membrane lysates by a variety of murine hematopoietic cells, including erythrocytes, but not by human erythrocytes. Binding of p37 to cells was calcium-dependent, and was not affected by inhibitors of the hematopoietic homing receptor or the cell-binding or heparin-binding functions of fibronectin. It is proposed that p37 may be a novel adhesive molecule expressed on the surface of a variety of hematopoietic cells that could participate in both homotypic and heterotypic interactions of stromal and progenitor cells.     

The heat shock/oxidative stress connection

Involvement of free-radical oxidations in the aging process has been a topic of interest since Harman's original contribution. Because of the close association between aging and Alzheimer disease (AD) and the qualitative similarity in the neuropathology of both conditions, it has been proposed by many investigators that oxidative stress may be important in AD. If such modality of injury was indeed involved, one should expect to find markers of oxidation and heat shock (since free radicals are key mediators of heat-shock induction) in brains of patients with AD. In fact, several studies documented abnormal expression of antioxidant enzymes and heat-shock proteins (HSP) along with other markers of oxidation in AD brains. We showed that abnormally expressed antioxidant enzymes are topographically associated with senile plaques and neurofibrillary tangles, and that the activity of these enzymes is (contrary to what one would expect) markedly reduced. These findings have recently been confirmed by other investigators. Despite a large amount of evidence that suggests an association between oxidative stress and the pathogenesis of AD, it is not yet known whether oxidative stress is a cause or consequence of the disorder. Future research efforts regarding the oxidative stress hypothesis of AD should include attempts, at generating AD pathology by oxidative means in laboratory animals, determining the role and integrity of the heat-shock response in AD, as well as that of various antioxidant systems, growth factors, and hormones with antioxidant and neuroprotective properties.     

In Uruguay, an ethic of care for the dying

The ethics of care for the terminally ill in Uruguay spring from deeply rooted attitudes which invest the physician with sole power to determine the course of treatment, even to prescribe painkilling drugs and to hasten death actively or passively, without collaboration from the patient's family. The paternal function attributed to the physician has not been questioned by any systematic reflection on biomedical ethics. However, conscientious physicians are interested in these issues and are well informed about the concerns of their foreign colleagues.     

Chlorinated hydrocarbon levels in human serum: Effects of fasting and feeding

Twenty healthy adult humans had serum samples drawn on four occasions within a 24-hr period: after a 12 hr overnight fast, 4–5 hr after a high fat breakfast, at midafternoon, and the next morning after another 12 hr fast. Nonfasting samples had 22% to 29% higher mean concentrations (p < 0.05) than did fasting samples for polychlorinated biphenyls (PCBs, 4.81 vs 3.74 ng/g serum wt), hexachlorobenzene (HCB, 0.163 vs 0.134 ng/g serum wt), andp,p-dichlorodiphenyldichloroethylene (p,p-DDE, 6.74 vs 5.37 ng/g serum wt) measured by electron capture gas liquid chromatography. Total serum lipids were estimated from measurements of total cholesterol, free cholesterol, triglycerides, and phospholipids and were 20% higher in nonfasting samples than in fasting samples (7.05 g/L vs 5.86 g/L). When PCBs, HCB, andp,p-DDE concentrations were corrected by total serum lipids, results from fasting and nonfasting samples were not statistically different. Because of the differences in these chlorinated hydrocarbon concentrations observed with different sample collection regimens, meaningful comparison of analytical results requires standardizing collection procedures or correcting by total serum lipid levels.     

In vivo and in vitro analysis of chloroquine resistance in Plasmodium falciparum isolates from Senegal

To determine the predictive value of chloroquine (CQ) resistance markers in Senegal, Plasmodium falciparum DNA polymorphisms in pfmdr1and pfcrt were examined in relation to clinical outcome. Despite CQ treatment, 17% of patients had parasitemia after 28 days. Examination of molecular markers of CQ resistance revealed that 64% of all isolates had the T76 resistant allele at the pfcrt locus, while 30% carried the Y86 resistant allele at the pfmdr1 locus. The pfcrt T76 allele was present not only in all in vivo resistant isolates, 89% of in vitro resistant isolates, but also in 35% of in vitro sensitive isolates. The pfmdr1 N86Y polymorphism did not correlate with in vitro or in vivo CQ resistance. Our data suggest that the pfcrt T76 allele alone is required but not a sufficient predictor for in vivo CQ resistance.     

Coxsackievirus B3 replication and persistence in intestinal cells from mice infected orally and in the human CaCo-2 cell line

Although the transmission of coxsackievirus B3 occurs mainly via the oral route, little is known about the primary replication and persistence of this agent in the intestine. To address this question, BALB/c mice were inoculated by gavage with coxsackievirus B3, Nancy strain. The mice were killed from 1 hr to 90 days after infection. The viral markers were detected in the small intestine using RT-PCR, cell culture and detection of VP1 protein. Coxsackievirus B3 was detected positive by the three methods from hr 2 to day 45 after infection. By using monoclonal antibodies directed towards VP1, CD40 and CD26, the virus was shown to be present in the lymphocytes of the mucosa as soon as 2 hr after infection; in contrast, no virus was detected in the epithelial cells lining the intestinal lumen. Further experiments were performed to evaluate the capacity of coxsackievirus B3 to establish a persistent infection in two intestinal cell lines. In contrast to HT29 cells, the CaCo-2 cells were shown to develop a persistent infection for up to 20 passages, as demonstrated by the detection of viral RNA and VP1 protein. This study provides further evidence that, after infection by the oral route, the viral particles are concentrated in the lymphocytes of the mucosal layer. In addition, the results suggest that coxsackievirus B3 is capable of establishing a persistent infection in the small intestine that may act as a reservoir of viral particles for the delayed spread of the virus to other target organs.     

Evidence of oxidative stress and in vivo neurotoxicity of beta-amyloid in a transgenic mouse model of Alzheimer's disease: a chronic oxidative paradigm for testing antioxidant therapies in vivo.

Increased expression of antioxidant enzymes and heat-shock proteins are key markers of oxidative stress. Such proteins are abnormally present within the neuropathological lesions of Alzheimer's disease (AD), suggesting that oxidative stress may play significant but yet undefined roles in this disorder. To gain further insight into the role of oxidative stress in AD, we studied the expression of CuZn superoxide dismutase (SOD) and hemoxygenase-1 (HO-1), two established markers of oxidative stress, in a transgenic mouse model of AD. Immunohistochemistry with anti-SOD and anti-HO-1 antibodies revealed a very pronounced increase of these proteins only in aged transgene-positive mice. Interestingly, the distribution of the oxidative burden was largely overlapping with dystrophic neuritic elements in the mice as highlighted with anti-ubiquitin antibodies. Because the most conspicuous alterations were identified around amyloid (Abeta) deposits, our results provide strong support for the hypothesis that Abeta is neurotoxic in vivo and that such toxicity is mediated by free radicals. To obtain additional experimental evidence for such an interpretation (ie, a cause-effect relationship between Abeta and oxidative neurotoxicity), PC12 cells were exposed to increasing concentrations of Abeta or to oxidative stress. In agreement with the in vivo findings, either treatment caused marked induction of SOD or HO-1 in a dose-dependent fashion. These results validate the transgenic approach for the study of oxidative stress in AD and for the evaluation of antioxidant therapies in vivo.     

Muscle strength, volume and activation following 12-month resistance training in 70-year-old males

In elderly males muscle plantar flexor maximal voluntary contraction (MVC) torque normalised to muscle volume (MVC/VOL) is reduced compared to young males as a result of incomplete muscle activation in the elderly. The aim of the present study was to determine the influence of a 12-month resistance training programme on muscle volume, strength, MVC/VOL, agonist activation and antagonist coactivation of the plantarfexors in elderly males. Thirteen elderly males aged 70 years and over (range 70–82 years), completed a 12-month whole body resistance-training programme (TRN), training three times a week. Another eight males (range 18–30 years), who maintained their habitual physical activity for the same 12-month period as the TRN group acted as controls (CTRL). Isometric plantarflexor maximal voluntary contraction (MVC) torque increased in the TRN group by 20% (P<0.01), from 113.1±22.0 Nm to 141.5±19.2 Nm. Triceps surae volume (TS VOL) assessed using MRI, increased by 12%, from 796.3±78.9 cm³ to 916.8±144.4 cm³ . PF activation, measured using supramaximal double twitch interpolation, increased from 83.6±11.0% pre training, to 92.1±7.6% post training (P<0.05). Dorsiflexion MVC and antagonist coactivation (assessed using surface electromyography) did not change with training. Plantarflexor MVC torque normalized for triceps surae muscle volume (MVC/VOL) was 142.6±32.4 kN m^–2 before training and 157.0± 27.9 kN m^–2 after training (a non-significant increase of 8%). No significant change in any measurement was observed in the CTRL group. This study has shown that the gain in muscle strength in response to long-term (12-month) training in older men is mostly accounted for by an increased muscle volume and activation.