Conformational preferences in a benzodiazepine series of potent nonpeptide fibrinogen receptor antagonists

Previously, we reported the direct design of highly potent nonpeptide 3-oxo-1,4-benzodiazepine fibrinogen receptor antagonists from a constrained, RGD-containing cyclic semipeptide. The critical features incorporated into the design of these nonpeptides were the exocyclic amide at the 8-position which overlaid the Arg carbonyl, the phenyl ring which maintained an extended Gly conformation, and the diazepine ring which mimicked the gamma-turn at Asp. In this paper, we investigate conformational preferences of the 8-substituted benzodiazepine analogues by examining structural modifications to both the exocyclic amide and the seven-membered diazepine ring and by studying the conformation of the benzodiazepine ring using molecular modeling, X-ray crystallography, and NMR. We found that the directionality of the amide at the 8-position had little effect on activity and the (E)-olefin analogue retained significant potency, indicating that the trans orientation of the amide, and not the carbonyl or NH groups, made the largest contribution to the observed activity. For the diazepine ring, with the exception of the closely analogous 3-oxo-2-benzazepine ring system described previously, all of the modifications led to a significant reduction in activity compared to the potent 3-oxo-1, 4-benzodiazepine parent ring system, implicating this particular type of ring system as a desirable structural feature for high potency. Energy minimizations of a number of the modified analogues revealed that none could adopt the same low-energy conformation as the one shared by the active (S)-isomer of the 3-oxo-1, 4-benzodiazepines and 3-oxo-2-benzazepines. The overall data suggest that the features contributing to the observed high potency in this series are the orientation of the 3-4 amide and the conformational constraint imposed by the seven-membered ring, both of which position the key acidic and basic groups in the proper spatial relationship.     

A feminist case against euthanasia. Women should be especially wary of arguments for "the freedom to die"

Feminists, among others, should not be too quick to hail assisted suicide and euthanasia as extensions of human freedom. Indeed, there are good reasons why women should be especially suspicious of such "reforms." First, it is not clear that a person has a moral right to end his or her existence. Feminists understand that suicide and murder are irretrievably linked, and that a person is not a monad. We often hear of suicide attempts in which the person's body--by vomiting up poison, for instance--overrules his or her mind. If there can be such miscommunication between a mind and a body, how are we to trust the communication between a person and the physician ready to assist his or her suicide? Ambivalent motivation and ambiguous meanings have always characterized human relations. In the past, however, an absolute taboo against suicide or euthanasia cemented a patient's right to expect the care of his or her physician, family, and community. If we were to discard that taboo, we would subtly alter these relationships and make each other more vulnerable. History suggests that women, minorities, the ill, the old, and the handicapped would be most at risk. Finally, the assisted-suicide debate has even larger social implications. Unconditional respect for the gift of life is eroding in the United States. The suicide rate is already climbing at all levels of society, especially among teenagers. Wouldn't the acceptance of suicide and euthanasia make it even more acceptable for people to check out of all kinds of uncomfortable situations--marriages or life?     

Tissue cultures from cerebrospinal fluid specimens in the study of human brain tumors.

The authors report a study in which 109 cerebrospinal fluid (CSF) specimens from patients with varying neurological disorders were incubated in tissue culture medium for 1, 3, and sometimes 7 days. Strict criteria for malignancy were applied to cells found at these intervals. In 35 patients with verified central nervous system neoplasms, eight cases had malignant cells and 11 others had "doubtful" cells by tissue-culture analysis. Thirty-three of these cases were also examined with standard millipore cytological techniques: six had malignant cells and four had "doubtful" cells. Of 50 cases with inflammatory or other non-neoplastic conditions, cells were cultured in 13. None was considered malignant by our criteria. Tissue culture of CSF has several potential benefits. Even with stringent criteria, it is possible to demonstrate the presence of unequivocally malignant cells in CSF by tissue culture. The systemic application of such criteria may eventually increase the positive identification of malignancies. Further, since these cells are growing, the degree of malignancy may be more accurately determined by a study of growth in culture. Such a study could not be done by conventional methods. Finally, tissue culture can help to guide therapy in certain instances in which a surgical biopsy cannot be obtained.     

Prolonged travel time to neonatal intensive care unit does not affect content of parental visiting: a controlled prospective study.

Decreased local obstetric care appears to be increasing the rate of premature births to rural populations. With increased numbers of premature and complicated births in rural populations, understanding the impact of the Neonatal Intensive Care Unit (NICU) environment on the development of parent-child relationships becomes critical. NICU infants appear to be at increased risk for failure to thrive, child abuse, and neglect. Some reports suggest that the frequency of parental visits to the NICU can predict infants likely to be at risk. Because rural parents visiting infants hospitalized in urban centers are likely to visit less often, understanding this possible relationship is critical. In this controlled prospective study, three groups of parents were observed visiting their hospitalized infants: (1) those visiting "in house" while the mother was still hospitalized; (2) those whose visits required one hour or less in travel time; and (3) those whose visits required more than one hour in travel time. Results showed that travel time influenced the frequency of visits, with fewer visits from those living furthest from the NICU. However, those visiting from greater distances stayed with their infants longer so that there was no difference in the total visiting time over a two-week period. Direct observations of the visits by both mothers and fathers showed no differences in the content of parent-child interactions among groups. Thus, visit frequency alone must be viewed cautiously as a potential indicator of failure to bond with a hospitalized infant, especially in settings serving rural populations.     

The abortion debate: can this chronic public illness be cured?

Abortion has provided one of the most noxious, disturbing, and unending of all American moral and legal struggles. The issue forces us to think about the most difficult kind of ethical issues, e.g., the moral status of the fetus and the meaning of human "life" and "personhood." The win-at-all-costs attitude among the leading advocacy groups has created gross stereotypes. While most arguments heard today were also heard prior to the Roe vs. Wade decision, the tone has radically changed. Better organization has meant hotter rhetoric and a nastier public style. We need to move the abortion debate along; it is now as stagnate as it is nasty. We need creative discussion and realistic compromise. The pre-Roe arguments in favor of choice have changed. Then, the movement to legalize abortion rested on the following: 1) illegal abortions were killing and maiming women; 2) women should have a backup to ineffective contraception; 3) the number of unwanted pregnancies should be reduced; only wanted children should be born, as a matter of child welfare; 4) women should have the right to make the abortion decision; 5) everything possible should be done to change the economic and domestic circumstances forcing women into unwanted pregnancies. The argument benefited women, children, and society. The many abortion myths that have since taken prominence cloud an already difficult issue. The ongoing tension rests with the conflict between the moral and legal issues. Is it possible to combine legal freedom and seriousness about the moral questions? Only if we recognize the equality of both positions' moral traditions, accept public discussion, the need for compromise, the need to do everything possible to change the economic and social circumstance leading to the abortion choice, and the need for meaningful counseling of women considering abortion.     

"Congenital" hematic cyst of the orbit.

A case of true hematic cyst of the orbit in a 10-year-old girl, apparently resulting from birth trauma, is presented. Ultrasonic and clinical features believed to aid the examiner in correctly diagnosing such a lesion are presented. While apparently unique among reported cases, "congenital" hematic cysts of the orbit undoubtedly occur occasionally and the possibility of this entity should be considered in appropriate circumstances.