Transplacental passage and breast milk concentrations of hydralazine

Summary The concentrations of real and apparent (= real hydralazine + acid-labile hydrazones) hydralazine in maternal and umbilical plasma obtained at delivery of 6 women treated with hydralazine and atenolol for pregnancy hypertension were measured by gas chromatography. In one of the patients, the concentrations of the same substances were subsequently measured in breast milk. Apparent hydralazine reached higher levels in umbilical than in maternal blood. The concentration of real hydralazine seemed to be at least as high in the fetus as in the mother. On the other hand, even though the fraction of real (i.e. presumably active) hydralazine was greater in milk than in plasma, the total concentration was smaller, and the estimated dose per milk feed of 75ml would not exceed 0.013mg. Thus, hydralazine treatment of the pregnant woman would expose her fetus to effective concentrations of the drug, but breast feeding would not result in a clinically relevant concentration in the infant.     

Motion analysis in two dimensions of radial-ulnar deviation of type I versus type II lunates

The motions of 2 different types of lunate (type I, no medial hamate facet; type II, medial hamate facet) were evaluated and compared during radial-ulnar deviation of the wrist using radiography and magnetic resonance imaging. Ten right wrists (5 type I and 5 type II lunates) were studied using posteroanterior and lateral x-rays. Six of the 10 normal volunteers (3 type I and 3 type II lunates) were studied using magnetic resonance imaging in 6 positions of radial-ulnar deviation. In the radiographic study the ulnar shift ratio of the lunate (USR), the shortest distance between the proximal ulnar tip of the lunate and the distal ulnar edge of the sigmoid notch of the radius (R-L), the closest distance between the distal ulnar tip of the lunate and the proximal pole of the hamate (L-H), the radius of curvature of the proximal head of the capitate (Cr) on posteroanterior view, and the radiolunate angle on lateral view were measured in each wrist in each of the 6 positions. There were statistically significant differences between type I and II lunates with regard to average maximum ulnar deviation of USR and R-L, total change of USR, R-L distance and L-H distance, average L-H distance and Cr distance in all positions, and average radiolunate angle in neutral and 15 degrees ulnar deviation. In the magnetic resonance imaging study the wrists with a type I lunate did not have contact between the lunate and hamate in any position; the wrists with a type II lunate did have contact between the hamate and the lunate, but only in ulnar deviation. The results of this study demonstrate that the kinematics of a type I lunate are different from those of a type II lunate during radial-ulnar deviation of the wrist.     

Exposure to perfluorooctane sulfonate during pregnancy in rat and mouse. I: maternal and prenatal evaluations.

The maternal and developmental toxicities of perfluorooctane sulfonate (PFOS, C8F17SO3-) were evaluated in the rat and mouse. PFOS is an environmentally persistent compound used as a surfactant and occurs as a degradation product of both perfluorooctane sulfonyl fluoride and substituted perfluorooctane sulfonamido components found in many commercial and consumer applications. Pregnant Sprague-Dawley rats were given 1, 2, 3, 5, or 10 mg/kg PFOS daily by gavage from gestational day (GD) 2 to GD 20; CD-1 mice were similarly treated with 1, 5, 10, 15, and 20 mg/kg PFOS from GD 1 to GD 17. Controls received 0.5% Tween-20 vehicle (1 ml/kg for rats and 10 ml/kg for mice). Maternal weight gain, food and water consumption, and serum chemistry were monitored. Rats were euthanized on GD 21 and mice on GD 18. PFOS levels in maternal serum and in maternal and fetal livers were determined. Maternal weight gains in both species were suppressed by PFOS in a dose-dependent manner, likely attributed to reduced food and water intake. Serum PFOS levels increased with dosage, and liver levels were approximately fourfold higher than serum. Serum thyroxine (T4) and triiodothyronine (T3) in the PFOS-treated rat dams were significantly reduced as early as one week after chemical exposure, although no feedback response of thyroid-stimulating hormone (TSH) was observed. A similar pattern of reduction in T4 was also seen in the pregnant mice. Maternal serum triglycerides were significantly reduced, particularly in the high-dose groups, although cholesterol levels were not affected. In the mouse dams, PFOS produced a marked enlargement of the liver at 10 mg/kg and higher dosages. In the rat fetuses, PFOS was detected in the liver but at levels nearly half of those in the maternal counterparts, regardless of administered doses. In both rodent species, PFOS did not alter the numbers of implantations or live fetuses at term, although small deficits in fetal weight were noted in the rat. A host of birth defects, including cleft palate, anasarca, ventricular septal defect, and enlargement of the right atrium, were seen in both rats and mice, primarily in the 10 and 20 mg/kg dosage groups, respectively. Our results demonstrate both maternal and developmental toxicity of PFOS in the rat and mouse.     

Interlaboratory variability of rotational chair test results II: analysis of simulated data.

Standardization of rotational chair testing across laboratories has not been achieved because of differences in test protocol and analysis algorithms. The Interlaboratory Rotational Chair Study Group was formed to investigate these differences. Its first study demonstrated significant variability in calculated results using actual patient data files. No estimation of accuracy could be made, however, because the "true" values of response parameters were unknown. In this study we used simulated "patient" data files to further explore the differences among analysis algorithms. We found a high degree of agreement and accuracy across laboratories using automated analysis of high signal-to-noise/low-artifact data for gain, phase, and asymmetry. Variability increased significantly for the lower signal-to-noise ratio/higher artifact files. Operator intervention generally improved accuracy and decreased variability, but there were cases in which operator intervention reduced accuracy.     

Synergistic activity of recombinant human endostatin in combination with adriamycin: analysis of in vitro activity on endothelial cells and in vivo tumor progression in an orthotopic murine mammary carcinoma model.

PURPOSE: Current combination treatment strategies in malignancy are designed to evaluate the use of cytotoxic drugs and antiangiogenic agents. Endostatin, a fragment of collagen XVIII, specifically inhibits proliferation, migration, and differentiation of endothelial cells in vitro as well as angiogenesis and tumor progression in in vivo models. In this study, we determine the antitumor effect of rhEndostatin administered alone or in combination with Adriamycin against established orthotopic murine mammary carcinoma. EXPERIMENTAL DESIGN: Mice bearing orthotopically established DA-3 mammary adenocarcinoma tumors received varying doses of rhEndostatin alone and in combination with Adriamycin to assess tumor growth inhibition. Additional studies of this in vivo combination included a determination of Adriamycin-induced cardiotoxicity and in vitro effects on human umbilical vein endothelial cell proliferation and cord formation. RESULTS: For single-agent activity, optimal tumor growth inhibition was observed after s.c. administration of 50 mg/kg/day rhEndostatin or 5 mg/kg Adriamycin injected i.v. every 4 days. Combination of Adriamycin with optimal or suboptimal doses of rhEndostatin resulted in synergistic inhibition of DA-3 tumor growth. Importantly, unlike other antiangiogenic agents, rhEndostatin did not exacerbate the cardiotoxicity of Adriamycin. The synergistic interaction between rhEndostatin and Adriamycin was also observed in vitro for inhibition of human umbilical vein endothelial cell proliferation and inhibition of cord formation. CONCLUSIONS: These data suggest that the synergy observed with rhEndostatin in combination with Adriamycin is exerted at the level of the endothelial cell and can result in enhanced tumor growth inhibition. The potential benefit of Adriamycin used in combination with rhEndostatin is being considered for clinical evaluation.     

An obstetric and gynecologic clerkship''s influence on a medical community: The Washington, Alaska, Montana, and Idaho Anchorage obstetric and gynecologic clerkship

OBJECTIVES: Our purpose was to explore the influences of an obstetric and gynecologic medical student clerkship on a remote medical community. Return of physicians to Alaska and faculty perceptions of their experience were central foci.STUDY DESIGN: Data were obtained on former clerks to determine choice of speciality and location of practice. Data regarding all physicians new to Alaska was correlated with the University of Washington Medical School graduate data. Additionally, a questionnaire with a Likert-type scale evaluated the 10 clinical faculty members participating in the clerkship.RESULTS: Between 1978 and 1991 we trained 266 clerks. A total of 77 of 374 (21%) new physicians in Alaska (1978 to 1991) were graduates of the University of Washington; 26 of those 77 (34%) were our former Anchorage obstetrics and gynecology clerks. The clinical faculty reported both positive and negative effects of their participation in the clerkship.CONCLUSION: The desired benefit, the return of new physicians to Alaska, seemed supported. Questionnaire results hinted at additional benefits for the supervising faculty physicians in this isolated community. The formal affiliation effected by the clerkship seemed to have a positive impact on patient care, communication, consultation, and shared action among the participating physicians. (Am J Obstet Gynecol 1997;176:1363-7.)     

Self-administered questionnaire compared with a personal diary for assessment of current use of hormone therapy: an analysis of 16,060 women

A personal diary may be more appropriate than a questionnaire for assessing self-reported current use of hormone therapy (estrogens, progestagens, or their combination); however, use of a questionnaire is more feasible and less expensive. The authors compared both methods for 16,060 Swedish women aged 45-73 years from the Malmo Diet and Cancer Study (baseline, 1991-1996). In a reliability analysis, the authors investigated the agreement (kappa value) between the questionnaire and the diary regarding current hormone therapy use (yes vs. no), studying the ability to replicate results whether or not they were correct. They also explored associations between discrepancy and individual characteristics. A validity analysis was conducted to determine whether use of the questionnaire achieved an outcome without systematic error (i.e., high specificity and sensitivity); the personal diary was considered the "gold standard." Agreement between both methods was high: 95.5% (kappa = 0.840). The sensitivity was 84.9% and the specificity 97.7%. Higher body mass index and being a widow were associated with agreement, whereas age (50-59 years), use of anxiolytics/hypnotics or opiates, high alcohol consumption, past smoking, and higher educational level were associated with discrepancy. Compared with a personal diary, a simple self-administered questionnaire is a valid method for assessing current use of hormone therapy.     

Type 2 diabetes and low birth weight: the role of paternal inheritance in the association of low birth weight and diabetes

Lower birth weight is associated with an increased occurrence of type 2 diabetes in later life. Whether this relationship is explained by environmental or genetic factors is unknown. We have examined the potential for genetic influences by determining whether parental diabetes is associated with lower birth weight in 1,608 children of known birth weight and gestational age born between 1941 and 1993 in the Gila River Indian Community in Arizona. The previously described relationships of maternal diabetes to increased birth weight and offspring diabetes were observed. In contrast to this we have determined novel relationships between low birth weight and paternal diabetes. The offspring of diabetic fathers were, on average, 78 g lighter than the offspring of nondiabetic fathers. For fathers, lower birth weight in their offspring was associated with an increased risk of later diabetes, i.e., fathers of offspring in the lowest quintile of birth weight, who were not diabetic at the time of birth of their child, had a 1.8-fold increased risk of developing diabetes later in life (95% CI 1.2-2.7; P = 0.004). For children, lower birth weight predicted diabetes in the offspring if paternal but not maternal diabetes was present, but it was not associated with higher plasma glucose if neither parent had diabetes. We conclude that the risk of diabetes associated with low birth weight is strongly related to the development of paternal diabetes, suggesting a genetic link between lower birth weight and later diabetes.     

Targeting the mevalonate pathway inhibits the function of the epidermal growth factor receptor.

PURPOSE: The epidermal growth factor receptor (EGFR) is a key regulator of growth, differentiation, and survival of epithelial cancers. In a small subset of tumors, the presence of activating mutations within the ATP binding site confers increased susceptibility to gefitinib, a potent tyrosine kinase inhibitor of EGFR. Agents that can inhibit EGFR function through different mechanisms may enhance gefitinib activity in patients lacking these mutations. Mevalonate metabolites play significant roles in the function of the EGFR; therefore, mevalonate pathway inhibitors may potentiate EGFR-targeted therapies. EXPERIMENTAL DESIGN: In this study, we evaluated the effect of lovastatin on EGFR function and on gefitinib activity. Effects on EGFR function were analyzed by Western blot analysis using phosphospecific antibodies to EGFR, AKT, and extracellular signal-regulated kinase. Cytotoxic effects of lovastatin and/or gefitinib were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry. RESULTS: Lovastatin treatment inhibited EGF-induced EGFR autophosphorylation by 24 hours that was reversed by the coadministration of mevalonate. Combining lovastatin and gefitinib treatments showed enhanced inhibition of AKT activation by EGF in SCC9 cells. The combination of 10 mumol/L lovastatin and 10 mumol/L gefitinib treatments showed cooperative cytotoxicity in all 8 squamous cell carcinomas, 4 of 4 non-small cell lung carcinoma and 4 of 4 colon carcinoma cell lines tested. Isobologram and flow cytometric analyses of three representative cell lines with wild-type EGFR ATP binding sites confirmed that this combination was synergistic inducing a potent apoptotic response. CONCLUSIONS: Taken together, these results show that targeting the mevalonate pathway can inhibit EGFR function. They also suggest the potential utility of combining these clinically relevant therapeutic approaches.