Dihydropyridine-insensitive calcium currents contribute to function of small cerebral arteries

Although dihydropyridines are widely used for the treatment of vasospasm, their effectiveness is questionable, suggesting that other voltage-dependent calcium channels (VDCCs) contribute to control of cerebrovascular tone. This study therefore investigated the role of dihydropyridine-insensitive VDCCs in cerebrovascular function. Using quantitative PCR and immunohistochemistry, we found mRNA and protein for L-type (Ca_V1.2) and T-type (Ca_V3.1 and Ca_V3.2) channels in adult rat basilar and middle cerebral arteries and their branches. Immunoelectron microscopy revealed both L- and T-type channels in smooth muscle cell (SMC) membranes. Using patch clamp electrophysiology, we found that a high-voltage-activated calcium current, showing T-type channel kinetics and insensitivity to nifedipine and nimodipine, comprised ∼20% of current in SMCs of the main arteries and ∼45% of current in SMCs from branches. Both components were abolished by the T-type antagonists mibefradil, NNC 55-0396, and efonidipine. Although nifedipine completely blocked vasoconstriction in pressurized basilar arteries, a nifedipine-insensitive constriction was found in branches and this increased in magnitude as vessel size decreased. We conclude that a heterogeneous population of VDCCs contributes to cerebrovascular function, with dihydropyridine-insensitive channels having a larger role in smaller vessels. Sensitivity of these currents to nonselective T-type channel antagonists suggests that these drugs may provide a more effective treatment for therapy-refractory cerebrovascular constriction.     

Short-term exposure of Chinook salmon (Oncoryhnchus tshawytscha) to o,p-DDE or DMSO during early life-history stages causes long-term humoral immunosuppression

We evaluated the effect of short-term exposures to a xenobiotic chemical during early life-history stages on the long-term immune competence of chinook salmon (Oncoryhnchus tshawytscha). Immersion of chinook salmon eggs in a nominal concentration of o,p-dichlorodiphenyldichloroethylene (o,p-DDE; 10 ppm) for 1 hr at fertilization followed by immersion in the same dose for 2 hr at hatch resulted in a significant reduction in the ability of splenic leukocytes from fish 1 year after treatment to undergo blastogenesis upon in vitro stimulation with lipopolysaccharide. We also observed that the vehicle, dimethyl sulfoxide (DMSO), caused a significant reduction in the ability of the splenic leukocytes to express surface immunoglobin M (SIgM) at this time. The concentration of o,p-DDE in a pooled sample of whole fry from this treatment was 0.53 microg/g lipid 1 month after first feeding but was undetectable in all other treatments. Mortality rate, time to hatch, fish length, and weight were unaffected by treatment with o,p-DDE. Similarly, sex ratios, gonadal development, and concentrations of plasma estradiol and 11-ketotestosterone were not affected by the treatment. In addition, we found no evidence that plasma lysozyme concentrations or the mitogenic responses of splenic leukocytes to concanavalin A or polyinosinic-polycytidylic acid were influenced by the treatment. In this experiment, a brief period of exposure to o,p-DDE or DMSO during early development was able to induce long-term effects on humoral immune competence of chinook salmon. Such immunosuppression may increase susceptibility to disease, which may in turn be critical to regulating the population.     

Calreticulin has opposing effects on the migration of human trophoblast and myometrial endothelial cells

Calreticulin is a calcium binding, endoplasmic reticulum resident protein best known for its roles in intracellular calcium homeostasis and the quality control processes of the endoplasmic reticulum. There is evidence for a range of activities for calreticulin outside the endoplasmic reticulum, including in the cytosol, on the surface of different cells types and in the extracellular matrix. Recent evidence indicates that human pregnancy is a condition of elevated circulating calreticulin. Calreticulin was increased in the plasma of women throughout pregnancy compared to the non-pregnant state. Calreticulin was also further increased during the hypertensive disorder of human pregnancy, pre-eclampsia. To clarify the roles of circulating calreticulin in pregnancy and pre-eclampsia, the aim of this study was to determine the effects of exogenous calreticulin on two cell types that are relevant to normal human pregnancy and to pre-eclampsia. Human primary myometrial microvascular endothelial cells (UtMVEC-Myo) and the human trophoblast cell line, HTR8/SVneo, were cultured with exogenous calreticulin at concentrations (2 μg/ml and 5 μg/ml) comparable to that measured in maternal blood. The higher concentration of calreticulin significantly increased the migration of the UtMVEC-Myo cells, but significantly reduced the migration of the HTR8/SVneo cells. In the presence of only FGF, FBS and antibiotics calreticulin at 5 μg/ml significantly reduced the number of UtMVEC-Myo cells during in vitro culture for 120 h. These results demonstrate that exogenous calreticulin can alter both HTR8/SVneo and UtMVEC-Myo cell functions in vitro at a (patho-) physiologically relevant concentration. Increased calreticulin may also contribute to altered functions of both cell types during pre-eclampsia.     

OS088. First trimester triple vascular test for pre-eclampsia prediction

IntroductionAlthough PE represents a major cause of maternal and fetal morbidity and mortality, the vascular mechanisms underlying this disorder have not been clearly identified. During the past three decades, while numerous clinical, biophysical, and biochemical screening tests have been proposed for the early detection of preeclampsia, maternal circulation changes during early pregnancy have yet to be fully evaluated for their contribution to PE prediction.ObjectivesThe aim of this study was to examine a combination of maternal risk factors, mean arterial blood pressure, uterine artery Doppler, brachial artery flow-mediated dilatation (FMD), and ophthalmic artery Doppler for pre-eclampsia prediction during the first trimester of pregnancy.MethodsProspective study with singleton pregnancies examined at 11–14 weeks of gestation, presenting consecutively for antenatal care in a tertiary Brazilian hospital. The base-cohort population constituted of 487 singleton pregnancies, including 9 case subjects who developed pre-eclampsia (PE) requiring delivery before 34 weeks (early PE) and 22 with late PE, 47 with gestational hypertension, and 409 cases subjects (84%) who were unaffected by PE or gestational hypertension. Maternal history (nulliparity, previous and family history of PE), body mass index (BMI), mean arterial pressure (MAP), uterine artery pulsatility index, brachial artery FMD and ophthalmic artery Doppler were recorded in all of the cases. Univariate and logistic regression analysis was used to derive algorithms for the prediction of hypertensive disorders.ResultsUterine artery percentile of mean PI was higher in the PE than in the control group (p < 0.01). The mean brachial artery FMD was 7.4% ± 8.2% in the control group and 7.3% ± 8.2% in the PE group. Logistic regression analysis determined that FDM was not a predictor of PE (OR = 0.99, CI 95% 0.94–1.04; p = 0.90) and this test was withdrawn from the predictive model. The average of the first diastolic peak velocity in the ophthalmic artery was higher in the PE group compared with controls (24.56 cm/s × 21.13 cm/s; p < 0.01).It was estimated that, with the prediction algorithm for PE, a combination of maternal factors + MAP + uterine artery Doppler or ophthalmic artery Doppler can detect 78% of early-onset PE with 10% false-positive rate.ConclusionMaternal ophthalmic artery Doppler in the first trimester of pregnancy is a novel predictive parameter for PE (especially early-onset PE), it has the same detection rate contribution in a multi-parameter predictive model as would be the case uterine artery Doppler was used instead.     

An Australian twin study of the genetic basis of preeclampsia and eclampsia

OBJECTIVE: We investigated maternal versus fetal genetic causes of preeclampsia and eclampsia by assessing concordance between monozygotic and dizygotic female co-twins, between female partners of male monozygotic and dizygotic twin pairs, and between female twins and partners of their male co-twins in dizygotic opposite-sex pairs. STUDY DESIGN: Two large birth cohorts of volunteer Australian female twin pairs (N = 1504 pairs and N = 858 pairs) were screened and interviewed, and available medical and hospital records were obtained and reviewed where indicated, with diagnoses assigned according to predetermined criteria. RESULTS: With strict diagnostic criteria used for preeclampsia and eclampsia, no concordant female twin pairs were found. Collapsing diagnoses of definite, probable, or possible preeclampsia or eclampsia resulted in very low genetic recurrence risk estimates. CONCLUSION: Results from these two cohorts of female twin pairs do not support clear, solely maternal genetic influences on preeclampsia and eclampsia. Numbers of parous female partners of male twins were too low for conclusions to be drawn regarding paternal transmission.     

Accuracy of SRM and power tap power monitoring systems for bicycling

PURPOSE:: Although manufacturers of bicycle power monitoring devices SRM and Power Tap (PT) claim accuracy to within 2.5%, there are limited scientific data available in support. The purpose of this investigation was to assess the accuracy of SRM and PT under different conditions. METHODS:: First, 19 SRM were calibrated, raced for 11 months, and retested using a dynamic CALRIG (50-1000 W at 100 rpm). Second, using the same procedure, five PT were repeat tested on alternate days. Third, the most accurate SRM and PT were tested for the influence of cadence (60, 80, 100, 120 rpm), temperature (8 and 21 degrees C) and time (1 h at ~300 W) on accuracy. Finally, the same SRM and PT were downloaded and compared after random cadence and gear surges using the CALRIG and on a training ride. RESULTS:: The mean error scores for SRM and PT factory calibration over a range of 50 - 1000 W were 2.3 +/- 4.9% and -2.5 +/- 0.5%, respectively. A second set of trials provided stable results for 15 calibrated SRM after 11 months (-0.8 +/- 1.7%), and follow-up testing of all PT units confirmed these findings (-2.7 +/- 0.1%). Accuracy for SRM and PT was not largely influenced by time and cadence; however, power output readings were noticeably influenced by temperature (5.2% for SRM and 8.4% for PT). During field trials, SRM average and max power were 4.8% and 7.3% lower, respectively, compared with PT. CONCLUSIONS:: When operated according to manufacturers instructions, both SRM and PT offer the coach, athlete, and sport scientist the ability to accurately monitor power output in the lab and the field. Calibration procedures matching performance tests (duration, power, cadence, and temperature) are, however, advised as the error associated with each unit may vary.     

The preoperative evaluation: use the history and physical rather than routine testing

The history and physical examination, rather than routine laboratory, cardiovascular, and pulmonary testing, are the most important components of the preoperative evaluation. The history should include a complete review of systems (especially cardiovascular and pulmonary), medication history, allergies, surgical and anesthetic history, and functional status.