Women with heart failure due to nonischemic causes had significantly better survival than men with or without coronary disease as their primary cause of heart failure.

Constitutive activation of the RET receptor tyrosine kinase underlies the genesis and progression of multiple endocrine neoplasia type 2 (MEN 2), a dominantly inherited cancer predisposition. Importantly, although kinase activation represents a common theme in neoplasias, not all activating mutations are functionally equivalent. Consistent with this, we ascertained a patient with classical features of MEN 2B, but lacking either of the classical mutations in RET (M918T or A883F). Instead, the patient harbors a novel pair of germ line missense mutations in cis at codons 804 and 805. We evaluated the potential physiochemical effects of these substitutions in silico, predicting both to be moderately deleterious in isolation, but severely deleterious in combination. Consistent with this postulate, we show that the identified tandem mutations (V804M/E805K) are biologically active, transforming cells in culture and that their transforming capacity in combination is distinctly synergistic. Furthermore, the V804M/E805K tandem lesion confers resistance to the small molecule receptor tyrosine kinase inhibitor, PP1, suggesting a mode of action distinct from that known for classical MEN 2B mutations. To address this question, we used homology molecular modeling in silico to model the active site of RET. We predict that RET804 constitutes a critical gatekeeper residue that, when mutated in combination with RET805, induces a conformational change in the hinge region that locks the active site in a position permissive for ATP hydrolysis. Our findings have implications both in the clinic and in the successful development of novel kinase-targeted anticancer drugs.

Disillusionment with the therapeutic ideal has led to the current movement to reduce the jurisdiction of juvenile courts to cases in which they can exercise a crime-prevention function and to emphasize a fair, adversarial court procedure including representation by a lawyer. Two North Carolina juvenile courts were studied in 1975-1976 to determine their degree of concern about rehabilitation, crime prevention, and adversarial procedure. These courts showed a trend toward reducing their intake of cases with a less serious prior record and current offense and becoming more punitive with regard to the remaining cases. The dominant factors associated with disposition—particularly with the decision to commit the child to training school—were prior court record and seriousness of current offense. Other factors found to be of some importance were the child's family structure, support by the family as shown by court attendance, and whether the complainant in the case was a parent or probation officer. Race, family income, and the sex of the child had little or no effect on decisions to commit. Differences in individual judges' commitment rates were explained largely by differences in the cases they handled. Being held in detention before the court hearing made commitment more likely. The type of counsel a child had—private, individually assigned, or specialized Juvenile Defender—made no difference in whether he was adjudicated delinquent or committed. In fact, children represented by counsel were somewhat more likely to be committed than those without counsel. This and other findings of the study suggest that the participation of lawyers in juvenile court may be largely a formality, a token compliance with due process requirements rather than an integral part of court fact-finding.

Dysprothrombinaemia is a rare, congenital cause of bleeding. Fewer than 25 families who express a functional prothrombin (factor II) defect have been reported. The original patient with prothrombin Denver had a severe haemophilia-like bleeding disorder treated with weekly prophylactic factor replacement. Analysis of factor II activity and antigen in the patient showed a factor II activity of 5 units/dl and factor II antigen of 21 units/dl. Genomic DNA from the patient, mother and brother was obtained from peripheral blood white cells. Oligonucleotides were constructed, and prothrombin exons were amplified via polymerase chain reaction (PCR). The entire sequence of the thrombin portion of the molecule (exons VIII-XIV) and that of exons I-II and IV-VII was determined. This moderately severe dysprothrombinaemia was found to be associated with compound heterozygosity for two different Glu-->Lys point mutations, at amino acid positions 300 and 309. Assays of plasma from the prothrombin Denver proband suggested that the functional defect was in the activation of zymogen to enzyme.

SUMMARYSix interspecific hybridomas (heterohybridomas) secreting bovine monoclonal antibodies (MAbs) against respiratory syncytial (RS) virus were produced. Four of the heterohybridomas were formed using the mouse myeloma cell line NS1 as the fusion partner, one using NS0, and the remaining heterohybridoma was formed using a bovine × murine hybridoma as the fusion partner. Five heterohybridomas secreted bovine IgG1 and one secreted IgG2. All six MAbs recognized human subtype A and B viruses as well as bovine RS virus. They were specific for the fusion glycoprotein and reacted with a 140K dimer and a 70K monomer in a Western blot of native antigen; three also bound to the 46K F~ component and its 22K cleavage product in a blot of reduced antigen. Two of these MAbs neutralized RS virus infectivity, inhibited virusinduced fusion, lysed RS virus-infected cells in the presence of complement and protected mice against RS virus challenge.