Opposing actions of prostaglandins and oxytocin determine the onset of murine labor

Prostaglandins (PGs) have been recently proven essential for parturition in mice. To dissect the contributions of the two cyclooxygenase (COX) isoforms to the synthesis of PGs during pregnancy, we have characterized the parturition phenotype of COX-1-deficient mice. We find that mice with targeted disruption of the COX-1 gene have delayed parturition resulting in neonatal death. Results of matings of COX-1-deficient females with COX-1 intact males, and blastocyst transfer of COX-1-deficient or -intact embryos into wild-type foster mothers, proved necessity and sufficiency of maternal COX-1 for the normal onset of labor. COX-1 expression is induced in gravid murine uterus and by in situ hybridization; this induction is localized to the decidua. Measurement of uterine PGs further confirmed that COX-1 accounted for the majority of PGF2alpha production. To evaluate the interaction of PGs with oxytocin during murine labor, we generated mice deficient in both oxytocin and COX-1. Surprisingly, the combined oxytocin and COX-1-deficient mice initiated labor at the normal time. COX-1-deficient mice demonstrated impaired luteolysis, as evidenced by elevated serum progesterone concentration and ovarian histology late in gestation, and delayed induction of uterine oxytocin receptors. In contrast, simultaneous oxytocin and COX-1 deficiency restored the normal onset of labor by allowing luteolysis in the absence of elevated PGF2alpha production. These findings demonstrate that COX-1 is essential for normal labor in the mouse, with a critical function being to overcome the luteotrophic action of oxytocin in late gestation.     

Differential membrane localization and intermolecular associations of alpha-dystrobrevin isoforms in skeletal muscle

alpha-Dystrobrevin is both a dystrophin homologue and a component of the dystrophin protein complex. Alternative splicing yields five forms, of which two predominate in skeletal muscle: full-length alpha-dystrobrevin-1 (84 kD), and COOH-terminal truncated alpha-dystrobrevin-2 (65 kD). Using isoform-specific antibodies, we find that alpha-dystrobrevin-2 is localized on the sarcolemma and at the neuromuscular synapse, where, like dystrophin, it is most concentrated in the depths of the postjunctional folds. alpha-Dystrobrevin-2 preferentially copurifies with dystrophin from muscle extracts. In contrast, alpha-dystrobrevin-1 is more highly restricted to the synapse, like the dystrophin homologue utrophin, and preferentially copurifies with utrophin. In yeast two-hybrid experiments and coimmunoprecipitation of in vitro-translated proteins, alpha-dystrobrevin-2 binds dystrophin, whereas alpha-dystrobrevin-1 binds both dystrophin and utrophin. alpha-Dystrobrevin-2 was lost from the nonsynaptic sarcolemma of dystrophin-deficient mdx mice, but was retained on the perisynaptic sarcolemma even in mice lacking both utrophin and dystrophin. In contrast, alpha-dystrobrevin-1 remained synaptically localized in mdx and utrophin-negative muscle, but was absent in double mutants. Thus, the distinct distributions of alpha-dystrobrevin-1 and -2 can be partly explained by specific associations with utrophin and dystrophin, but other factors are also involved. These results show that alternative splicing confers distinct properties of association on the alpha-dystrobrevins.     

Feminism: a perspective for the 21st century

This article details some of the key elements related to feminism in American society. It suggests that the meaning and significance of a feminist perspective need to be reexamined for their importance and utility in this dynamic and rapidly changing society. A discussion of the meaning of feminism provides a framework for the article. Issues related to cultural diversity and the need for competent health care delivery for all people are some major themes. The other emphasis is related to research and women. Numerous challenges are outlined. A feminist perspective is recommended as a conceptual model through which health care reform can be enhanced. If feminism were embraced, the health status of people would be improved.     

An early comparison between endoscopic ultrasound-guided fine-needle aspiration and mediastinoscopy for diagnosis of mediastinal malignancy

Precise mediastinal lymph node staging is essential in non-small cell lung cancer for proper evaluation and treatment. In addition to CT, mediastinoscopy is routinely used for staging and diagnosis of mediastinal malignancy. Recently, endoscopic ultrasound (EUS) combined with fine-needle aspiration (FNA) biopsy has been used to evaluate mediastinal disease. The purpose of this study was to assess and compare mediastinoscopy with EUS/FNA in the evaluation of mediastinal masses. From August 1995 to July 1997, 21 patients with suspected mediastinal malignancy underwent cervical mediastinoscopy with biopsy. During this same period, seven patients with suspected mediastinal malignancy were evaluated using EUS/FNA. All patients were retrospectively studied. Both mediastinoscopy and EUS/FNA were highly sensitive in diagnosing mediastinal malignancy (100% and 86%, respectively). Specificity and positive predictive value were 100 per cent for both procedures. Mediastinoscopy and EUS/FNA are highly accurate methods of staging mediastinal malignancy. Mediastinoscopy provides better access to the upper and anterior mediastinum, whereas EUS/FNA can safely be used to biopsy subcarinal and posterior mediastinal masses. Mediastinoscopy and EUS/FNA target different areas of the mediastinum and may be complimentary in the evaluation of mediastinal malignancy and staging of bronchogenic carcinoma.     

The injured drunk driver in central Texas: incidence, demographics, and legal ramifications

Reconstructed images in digital tomosynthesis (DTS) are affected by artifacts due to blur from planes other than the fulcrum plane. A wavelet-based method has been developed for the discrimination and subsequent removal of unrelated structures from the reconstructed plane. The approach exploits both the specific pattern of noise in DTS and the spatial locality of the wavelet transformation. The technique was implemented on a DTS clinical protoype system. Experimental evaluation on angiographic types of images demonstrated excellent noise differentiation and elimination. The method is therefore particularly useful for certain medical imaging applications such as vascular DTS imaging.     

N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 2. Structure-activity relationship and optimization of the phenyl alkyl ether moiety

We previously reported the identification of (2S)-((2-benzoylphenyl)amino)-3-?4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl?propanoic acid (2) (PPARgamma pKi = 8.94, PPARgamma pEC50 = 9.47) as a potent and selective PPARgamma agonist. We now report the expanded structure-activity relationship around the phenyl alkyl ether moiety by pursuing both a classical medicinal chemistry approach and a solid-phase chemistry approach for analogue synthesis. The solution-phase strategy focused on evaluating the effects of oxazole and phenyl ring replacements of the 2-(5-methyl-2-phenyloxazol-4-yl)ethyl side chain of 2 with several replacements providing potent and selective PPARgamma agonists with improved aqueous solubility. Specifically, replacement of the phenyl ring of the phenyloxazole moiety with a 4-pyridyl group to give 2(S)-((2-benzoylphenyl)amino)-3-?4-[2-(5-methyl-2-pyridin-4-yloxazol+ ++- 4-yl)ethoxy]phenyl?propionic acid (16) (PPARgamma pKi = 8.85, PPARgamma pEC50 = 8.74) or a 4-methylpiperazine to give 2(S)-((2-benzoylphenyl)amino)-3-(4-?2-[5-methyl-2-(4-methylpiperazin+ ++- 1-yl)thiazol-4-yl]ethoxy?phenyl)propionic acid (24) (PPARgamma pKi = 8.66, PPARgamma pEC50 = 8.89) provided two potent and selective PPARgamma agonists with increased solubility in pH 7.4 phosphate buffer and simulated gastric fluid as compared to 2. The second strategy took advantage of the speed and ease of parallel solid-phase analogue synthesis to generate a more diverse set of phenyl alkyl ethers which led to the identification of a number of novel, high-affinity PPARgamma ligands (PPARgamma pKi's 6.98-8.03). The combined structure-activity data derived from the two strategies provide valuable insight on the requirements for PPARgamma binding, functional activity, selectivity, and aqueous solubility.     

Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1

BACKGROUND: Hereditary breast cancer has been associated with mutations in the BRCA1 and BRCA2 genes and has a natural history different from sporadic breast cancer. We investigated disease-free and overall survival for patients with a proven BRCA1 alteration. METHODS: We estimated disease-free and overall survival for 49 Dutch patients from 19 consecutive families with a proven specific BRCA1 mutation and one family with strong evidence for linkage to the BRCA1 gene. We compared clinical outcome and data on tumour size, histology, axillary nodal status, contralateral breast cancer, and oestrogen-receptor and progesterone-receptor status with those of 196 patients with sporadic breast cancer, matched for age and year of diagnosis. FINDINGS: Disease-free survival for BRCA1 and sporadic patients at 5 years was 49% (95% CI 33-64) and 51% (43-59), respectively (p=0.98). Overall survival at 5 years was 63% (47-76) and 69% (62-76), respectively (p=0.88). Recurrence and death rates did not differ significantly between groups. Hazard ratios for recurrence and death among BRCA1 patients were 1.00 (0.65-1.55) and 1.04 (0.63-1.71) relative to sporadic patients (p=0.88), and these did not differ significantly after adjustment for prognostic factors. Patients with BRCA1-associated breast cancer had twice as many progesterone-receptor-negative tumours (p<0.005) and development of contralateral breast cancer was four to five times as frequent as in the sporadic group (p<0.001). INTERPRETATION: We showed that disease-free and overall survival were similar for sporadic and hereditary breast cancer in the presence of different tumour characteristics, which has implications for screening prophylactic therapy, and different treatments of hereditary breast cancer.     

Essential carbamoyl-amino acids formed in vivo in patients with end-stage renal disease managed by continuous ambulatory peritoneal dialysis: isolation, identification, and quantitation

Drugs of various classes are prescribed for intermittent claudication. However, there is some discrepancy between medical practice and the scientific basis for drug selection. We have developed a quantitative criteria-based decision analysis to evaluate all implications of drug treatment choices for intermittent claudication. Pentoxifylline, buflomedil, naftidrofuryl and ticlopidine were the drugs selected for analysis. The evaluation criteria were 1) therapeutic efficacy, 2) safety, 3) patient acceptance and 4) cost. A review panel of experts determined the relative importance of each criterion by assigning points (or utility values) to each one. The points were 48, 20, 14 and 18, respectively, for criteria 1, 2, 3 and 4. A probability value, or numerical estimate of how well a drug meets a criterion, was assigned to each drug for each of the 4 criteria. The probability value was multiplied by the utility value to determine the score for each drug and criterion. The criteria points for each drug were added for a total score for the drug. The drug with the highest overall score was pentoxifylline, with 69 points out of an ideal score of 100. The rank order for the other drugs was buflomedil, ticlopidine and naftidrofuryl. A sensitive analysis showed that the relative ranking of the drugs remained unchanged over a series of data modifications.