Cardiac valve replacement in elderly patients.

Cardiac valve replacement in 65 consecutive elderly patients (aged 65 years and older) revealed that the indications for cardiac valve replacement in the elderly should be the same as those in the general population. These 65 patients represented 16% of the patients undergoing valve replacement. The mortality in the first 30 days after operation was 4.6% in the elderly group, compared with 0.9% in the group under 65 years of age. There were 26 significant but nonfatal early complications in the elderly patients, but their long-term functional status was excellent, most of the survivors ending up in either class I or class II of the New York Heart Association functional classification. The late mortality was 3.9% per patient year for aortic valve replacement and 15.1% for mitral with or without aortic valve replacement. The actuarial survival rates were 88% at 24 months and 55% at 54 months for the total elderly group, 86% at 36 months for those with aortic valve replacement, 85% at 24 months and 64% at 36 months for those with mitral valve replacement, 90% at 24 months and 77% at 42 months for the men, and 82% at 24 months and 68% at 42 months for the women. Aortic valve replacement was more common in the elderly than in the younger group because of the higher prevalence of congenital calcific aortic stenosis in the former, and this operation provided more gratifying results than mitral valve replacement in the elderly patients.     

Antigen-specific T-cell factor in cell cooperation and genetic control of the immune response.

Cell interactions between thymus-derived (T) and bone marrow-derived (B) lymphocytes in the antibody response appear to involve soluble T-cell mediators known as 'factors.' This paper describes the properties of a T-cell factor that has specificity for the inducing antigen, a synthetic polypeptide (T, G)-A--L, and is able to replace T cells in the thymus-dependent antibody response to (T, G)-A--L. Besides antigen specificity, the main features of the molecule are that it is nonimmunoglobulin; it has a molecular weight of about 50,000; and it is a product of the I-A subregion of the H-2 complex (the mouse major histocompatibility complex). These properties suggest that the factor is closely related to the T-cell receptor, which may, by inference, also be a product of the H-2 complex. The factor cooperates well with allogeneic B cells. It can also be absorbed by bone marrow cells and B cells. Studies on the genetic control of the immune response to (T, G)-A--L using the T-cell factor indicate that two immune response genes in the H-2 complex are involved in genetic control, one expressed in T cells and the other in B cells. This two gene hypothesis has been confirmed by showing that an F1 between two low responders to (T, G)-A--L can be a high responder.     

SP62, a Viable Mutant of Bacteriophage T4D Defective in Regulation of Phage Enzyme Synthesis

SP62 is a mutant of bacteriophage T4D that was discovered because it produces fewer phage than the wild type in the presence of 5-fluorodeoxyuridine. In the absence of phage DNA synthesis, SP62 solubilizes host DNA slower than normal; this may explain the sensitivity to 5-fluorodeoxyuridine. In Escherichia coli B at 37 C in the absence of drugs, SP62 makes DNA at a normal rate and the kinetics of appearance of phage are nearly normal. Under the same conditions, SP62 produces T4 lysozyme (gene e) at a normal rate until 20 min, but then produces it at twice the normal rate until at least 60 min. It has long been known that, when T4 DNA synthesis is blocked (DNA⁻ state) in an otherwise normal infection, the synthesis of a number of early enzymes continues beyond the shutoff time of about 12 min seen in the DNA⁺ state, but still stops at about 20 min. We have termed the 12-min shutoff event S1 and the 20-min shutoff event S2. We show here that, in the DNA⁺ state, SP62 makes four early enzymes normally, i.e., S1 occurs. However, in the DNA⁻ state (where S1 is missing), SP62 continues to make dCTPase (gene 56), dCMP hydroxymethylase (gene 42), and deoxynucleotide kinase (gene 1) for at least an hour; this results in production of up to 13 times the normal level of dCTPase at 60 min after infection, or 6 times the DNA⁻ level. We conclude that SP62 is defective in the second shutoff mechanism, S2, for these three enzymes. In contrast, SP62 causes premature cessation of dTMP synthetase production in the DNA⁻ state; the result is a twofold underproduction of dTMP synthetase. Autoradiograms of pulse-labeled proteins separated by slab-gel electrophoresis in the presence of sodium dodecyl sulfate show that a number of other T4 early proteins, including the products of genes 45, 46, and rIIA, are synthesized longer than normal by SP62 in the DNA⁻ state. Few late proteins are made in the DNA⁻ state, but in autoradiograms examining the DNA⁺ state there is little or no effect of the SP62 mutation on the synthesis of T4 late or early proteins. Circumstantial evidence is presented favoring a role for the gene of SP62 in translation of certain mRNAs. At very high temperatures (above 43 C) in the absence of drugs, phage production, but not DNA synthesis, is much reduced in SP62 infections relative to wild-type T4 infections; this temperature sensitivity is greater on E. coli CR63 than on E. coli B. This property has facilitated recognition of the SP62 genotype and aided in complementation testing and genetic mapping. A later publication will provide evidence that SP62 defines a new T4 gene named regA, which maps between genes 43 and 62.     

Effect of nucleoside triphosphate and magnesium ion concentration on the stability and function of rat liver polysomes in vitro

The effects of different concentrations of ATP, GTP, UTP and CTP on polysome stability and function in a cell-free protein-synthesizing system prepared from rat liver were studied. Increasing the concentration of ATP in the incubation medium to 15mm resulted in progressive disaggregation of the polysomes; at ATP concentrations above 2mm their capacity to incorporate amino acids into peptide chains diminished. The same disaggregation phenomenon could be produced by incubating polysomes in a buffered medium containing 5mm-Mg(2+) and increasing concentrations of ATP. Although the disaggregating action of ATP could be prevented by increasing Mg(2+) concentration, the amino acid incorporation in the cell-free protein-synthesizing system remained impaired. The effects of different concentrations of GTP, UTP and CTP on polysome stability were similar to those of ATP. Increasing the concentrations of each nucleoside triphosphate also inhibited the hydrolysis of GTP in the cell-free protein-synthesizing system.     

Detection of human papillomavirus DNA in skin warts from immunocompromised patients but not in semen from men whose wives have abnormal cervical cytology.

The epidemiology of human papillomaviruses (HPV) was studied in 61 immunocompromised patients (e.g. renal and cardiac transplants; Bowen's disease; genital cancer) undergoing therapy at the University Hospital of Wales at Cardiff U.K. Warts from various sites of these patients were studied for the presence of HPV types 6, 11, 16 and 18 using the dot-blot DNA hybridization technique. Four HPV-16 and one HPV-11 was detected. The presence of HPV-16 in our study is quite significant since it suggests the potential occurrence of genital HPV types in skin warts in immunocompromised patients and hence the need for screening such patients against HPV types. HPV, mainly types 16 and 18 are usually associated with genital cancer, cervical malignancies and cervical intraepithelial neoplasia. The semen of the husband of 30 women with cervical abnormalities and the semen of 30 husbands (control) of wives with normal cervix were tested for HPV-6, 11, 16 and 18. No HPV-DNA could be detected in all of the 60 specimen. This suggests that specimens were either truly negative for any of those types or because virus DNA could present in a small amount less than 5 pg/microliters in some patients. Whether semen plays a role in transmitting HPV is still controversial.     

Use of peptide tagging to detect proteins expressed from cloned genes: deletion mapping functional domains of Drosophila hsp 70.

We have developed a technique which allows specific detection of proteins expressed from cloned genes. The method involves fusion of an oligonucleotide coding for part of the neuropeptide substance P to the 3' end of the gene; the protein can then be detected with a monoclonal antibody that recognises this peptide. We have used this method to determine the properties of deletion mutants of the major Drosophila heat shock protein, hsp70, expressed in monkey COS cells. The results suggest that this protein has two distinct domains. Both are capable of accumulating in the nucleus of unstressed cells, but only the more highly conserved N-terminal domain is able to bind to nucleoli following a heat shock. This implies that nucleolar binding and nuclear migration are distinct properties of the protein, and suggests that the former may be of functional importance. In addition, we observed a novel effect of heat shock on cellular metabolism: protein fragments that are normally rapidly degraded are stabilized. The effect persists for several hours after the heat shock, but does not require expression of heat shock proteins. Together with previously published data, these results suggest an intimate relationship between protein degradation and the heat shock response.     

Conservation in rat liver of light and heavy subunit sequences of mammalian ferritin. Presence of unique octopeptide in the light subunit

Ferritin, an iron-storage protein found in all life forms examined, is composed of varying proportions of two subunits of different molecular weight, heavy (H) and light (L). Using cDNA clones, we have determined the nucleotide sequence corresponding to the mRNA of the L-subunit of rat liver ferritin. The coding region of 546 nucleotides (182 amino acids) is flanked by 5'- and 3' -untranslated regions of approximately 130 and 150 nucleotides, respectively. The rat liver L-subunit amino acid sequence derived from the reading frame of the cDNA showed 88% and 82% homology, respectively, with the amino acid sequences of horse spleen ferritin (Heusterspreute, M., and Crichton, R. R. (1981) FEBS Lett. 129, 322-327), and human spleen ferritin (Wustefeld, C., and Crichton, R. R. (1982) FEBS Lett. 150, 43-48), thus demonstrating evolutionary conservation of the L-subunit sequence. However, a major difference between the rat and the horse and human sequences is the insertion of an octopeptide near the COOH-terminus of the rat protein resulting in a slightly longer peptide chain in this species. The reading frame and parts of the derived amino acid sequence including the octopeptide sequence were confirmed by direct amino acid sequencing of cyanogen bromide peptides from rat liver ferritin. Minor fragments of rat liver ferritin, presumably derived from the H-subunit, were also isolated after cyanogen bromide treatment. On sequencing, these H-peptides showed limited homology with regions of the L-sequence but extensive homology with published H-sequences from human liver and spleen. The H-subunit sequence did not contain the octopeptide found as part of the L-subunit sequence.     

A model for generalization and specification by single neurons

A rule for environmentally dependent modification of the neuronal state is examined. Under the rule, the neuron selects a trigger feature that matches either a particular pattern in the stimulus set, or the most common pattern component, depending on a certain parameter. Thus a neuron may evolve to respond to its stimulus environment in one of two capacities, namely specification or generalization. Neurons of the former variety are labelled S-cells; and those of the latter, G-cells. In the model, synaptic modification is modulated by two postsynaptic mechanisms which act antagonistically to strengthen or weaken the synaptic connectivities. The functional dependence of these mechanisms on the postsynaptic activity is shown to determine whether the neuron acts as an S-cell or a G-cell. A circuit is proposed for a module that consists of a G-cell and several S-cells sharing a common set of inputs. By inhibiting the G-cells, the S-cell acts as a contrast-enhancing element, increasing their specificities for individual patterns in the stimulus set. The output from the module is a recoded representation of the environment with respect to its general and distinctive features.This work was supported in part by United States Office of Naval Research Contract N00014-81-K-0136