Metabolic functions of duplicate genes in Saccharomyces cerevisiae

The roles of duplicate genes and their contribution to the phenomenon of enzyme dispensability are a central issue in molecular and genome evolution. A comprehensive classification of the mechanisms that may have led to their preservation, however, is currently lacking. In a systems biology approach, we classify here back-up, regulatory, and gene dosage functions for the 105 duplicate gene families of Saccharomyces cerevisiae metabolism. The key tool was the reconciled genome-scale metabolic model iLL672, which was based on the older iFF708. Computational predictions of all metabolic gene knockouts were validated with the experimentally determined phenotypes of the entire singleton yeast library of 4658 mutants under five environmental conditions. iLL672 correctly identified 96%-98% and 73%-80% of the viable and lethal singleton phenotypes, respectively. Functional roles for each duplicate family were identified by integrating the iLL672-predicted in silico duplicate knockout phenotypes, genome-scale carbon-flux distributions, singleton mutant phenotypes, and network topology analysis. The results provide no evidence for a particular dominant function that maintains duplicate genes in the genome. In particular, the back-up function is not favored by evolutionary selection because duplicates do not occur more frequently in essential reactions than singleton genes. Instead of a prevailing role, multigene-encoded enzymes cover different functions. Thus, at least for metabolism, persistence of the paralog fraction in the genome can be better explained with an array of different, often overlapping functional roles.     

Induction of biologically active antineutrophil cytoplasmic antibodies by immunization with human apoptotic polymorphonuclear leukocytes

Translocation of intracellular components to the cell surface during the priming or apoptosis of polymorphonuclear leukocytes (PMN) is an important mechanism for interaction of antineutrophil cytoplasmic antibodies (ANCA) with these antigens. To test the capacity of apoptotic PMN to trigger production of ANCA, six groups of mice were immunized with either live or apoptotic lymphocytes, or with live, apoptotic, formalin-fixed, or lysed PMN. Mice immunized with both live and apoptotic neutrophils developed high titers of antibodies which gave a granular cytoplasmic immunofluorescent pattern. These antibodies were specific for lactoferrin and myeloperoxidase. Following a second intravenous infusion of apoptotic PMNs, mice developed anti-PR3 antibodies. Vasculitis lesions were not found in mice which developed ANCA. The ANCA-containing IgG fraction induced superoxide production by human PMNs. These results support the hypothesis that neutrophil-specific antigens presented on the cell membranes of apoptotic PMN may induce ANCA in the proper conditions.     

Grebe chondrodysplasia and brachydactyly in a family

A family is reported in which various skeletal abnormalities have been segregating over three generations. The Great-grandfather (11) of the consultand had features consistent with Grebe chondrodysplasia. The other members of the family have brachydactyly, radiologically characterised by short first metacarpals and short middle phalanges of the index and little fingers. The possibility of association of familial brachydactyly and Grebe chondrodysplasia is discussed. An attempt has been made to deal with the genetic counselling problem in this particular family.     

Caffeic Acid-Containing Medium for Identification of Cryptococcus neoformans

A new growth medium containing caffeic acid and ferric citrate is described. The pigment produced on this medium is specific for the identification of Cryptococcus neoformans and differentiates it from other cryptococci. The medium is more easily compounded and requires less time for pigment formation than the conventional Guizotia extract media. The medium is stable in the dry form as well as in the prepared form.     

The use of natural interferon alpha conjugated to a monoclonal antibody anti mammary epithelial mucin (Mc5) for the treatment of human breast cancer xenografts

Summary An immunoconjugate composed of natural interferon (nIFN) bound in a noncleavable fashion to a monoclonal antibody (MoAb) recognizing a breast epithelial membrane mucin (Mc5) was used to treat xenografts of a human mammary carcinoma cell line (MCF-7) growing in nude mice. The immunoconjugate (nIFN/Mc5) was administered as 20 intralesional (i.l.) injections to 1 of 2 xenografts in each animal. It was found that nIFN/Mc5 produced a significant enhancement of the growth inhibitory actions of nIFN on the injected tumors. Further enhancement was obtained when nIFN or nIFN together with Mc5 (at a dose 10 times larger than that present in nIFN/Mc5) were added to the immunoconjugate. Biodistribution experiments showed that the uptake of¹²⁵I-nIFN/Mc5 by the tumors was greater and its elimination slower than for¹²⁵I-nIFN alone or conjugated to irrelevant mouse IgG₁. In addition, the immunoconjugate up-regulated the antigenic expression of a breast epithelial membrane mucin by the carcinoma cells, an up-regulation which was not significantly different from that produced by nIFN alone. The contralateral noninjected tumors exposed to systemic levels of the immunoconjugate showed an enhancement of antitumor effects, but to a lesser extent than the injected tumors. These findings suggest that the enhancement of the growth inhibitory action of the immunoconjugate was related to the specific binding of Mc5 which targeted the IFN to the carcinoma cells and impeded its elimination. It is likely that the targeting was favored by the IFN-mediated up-regulation of antigenic expression by the carcinoma cells, thereby producing a cascade of interrelated effects. The results of this study point out the feasibility and potential usefulness of IFN treatment by means of immunoconjugates as well as the worth of pursuing and improving this form of therapy.     

National health expenditures, 1988. Office of National Cost Estimates

Every year, analysts in the Health Care Financing Administration present figures on what our Nation spends for health. As the result of a comprehensive re-examination of the definitions, concepts, methods, and data sources used to prepare those figures, this year's report contains new estimates of national health expenditures for calendar years 1960 through 1988. Significant changes have been made to estimates of spending for professional services and to estimates of what consumers pay out of pocket for health care. In the first article, trends in use of and expenditure for various types of goods and services are discussed, as well as trends in the sources of funds used to finance health care. In a companion article, the benchmark process is described in more detail, as are the data sources and methods used to prepare annual estimates of health expenditures.     

Reusable instruments are more cost-effective than disposable instruments for laparoscopic cholecystectomy

Health care costs are rising rapidly, and surgeons can play a role in limiting costs of operations. Of the 600,000 cholecystectomies performed each year in the United States, approximately 80% are performed with laparoscopic technique. The purpose of this study was to compare the costs of reusable vs disposable instruments used during laparoscopic cholecystectomy. The costs to the hospital of reusable and disposable instruments were obtained. Instruments studied were the Veress needle, trocars and sleeves (two 10 mm and two 5 mm), reducers, clip appliers, and clips. In addition, the costs of sterilization and sharpening for reusable instruments were calculated. The cost of reusable instruments was based on an assumed instrument life of 100 cases. Data from three private hospitals and a Canadian university hospital were collected and examined. Data from the four hospitals revealed that the costs of reusable instruments per case were $46.92–$50.67. The comparable costs for disposable instruments were $385.28–$515.48. The advantage was thus $330.00–$460.00 per case. Theoretical advantages of disposable instruments such as safety, sterility, and better efficiency are not borne out in literature review. In addition, the environmental impact of increased refuse from disposable instruments could not be exactly defined. With the consideration of significant cost savings and the absence of data demonstrating disadvantages of their use, reusable instruments for laparoscopic cholecystectomy are strongly recommended.     

N-bisphosphonates cause gastric epithelial injury independent of effects on the microcirculation

BACKGROUND: Nitrogen-containing bisphosphonates have been shown to be effective for the treatment of osteoporosis and Paget's disease of bone. Unfortunately, these drugs also have the capacity to irritate the upper gastrointestinal mucosa. In this study we investigated the ability of alendronate and pamidronate to directly damage the gastric epithelium and attempted to determine whether these drugs caused injury through gastric microcirculatory alterations. METHODS: An ex vivo gastric chamber model was used. Effects of topically applied alendronate and pamidronate on transmucosal potential difference and epithelial integrity (histology) were determined. Also, the effects of agents capable of preventing microvascular injury in the stomach (PGE2 and two nitric oxide donors) were examined for their ability to prevent gastric injury induced by the two N-bisphosphonates. RESULTS: Alendronate and pamidronate caused a concentration-dependent decrease in transmucosal potential difference, widespread epithelial injury and infiltration of neutrophils into the mucosa. PGE2 and the two nitric oxide donors did not prevent the changes in potential difference or the epithelial injury, but did reduce neutrophil infiltration. Significant release of PGE2 into the lumen was observed following application of the two bisphosphonates, but neither drug altered mucosal blood flow. CONCLUSIONS: These results suggest that these N-bis- phosphonates directly damage the gastric epithelium independent of actions on the microvasculature.     

The mechanism of the formation of a circadian rhythm of bone marrow proliferation in rats]

Flow cytofluorimetry and statmokinetic method were used to study the circadian rhythm of bone marrow proliferation in Pliss' lymphosarcoma-bearing and intact rats. These data were compared to those obtained in the study of the mitotic activity of the bone marrow in cancer patients. It was found that, already at early stage, tumor affected the circadian rhythm of bone marrow proliferation, reducing the amplitude of oscillations. A model simulating formation of the circadian rhythm of the bone marrow was suggested basing on the possibility to arrest cells at the end of G1 phase. The rate of transition of G1 cells to S phase was determined not only by endogenous "set-points" of the rhythm which formed the basic wave of proliferation but also by conditions of animal upkeep.