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PubMed1987

Selection, generalized transmission and the evolution of modifier genes. I. The reduction principle.

Modifier gene models are used to explore the evolution of features of organisms, such as the genetic system, that are not directly involved in the determination of fitness. Recent work has shown that a general "reduction principle" holds in models of selectively neutral modifiers of recombination, mutation, and migration. Here we present a framework for models of modifier genes that shows these reduction results to be part of a more general theory, for which recombination and mutation are special cases. The deterministic forces that affect the genetic composition of a population can be partitioned into two categories: selection and transmission. Selection includes differential viabilities, fertilities, and mating success. Imperfect transmission occurs as a result of such phenomena as recombination, mutation and migration, meiosis, gene conversion, and meiotic drive. Selectively neutral modifier genes affect transmission, and a neutral modifier gene can evolve only by generating association with selected genes whose transmission it affects. We show that, in randomly mating populations at equilibrium, imperfect transmission of selected genes allows a variance in their marginal fitnesses to be maintained. This variance in the marginal fitnesses of selected genes is what drives the evolution of neutral modifier genes. Populations with a variance in marginal fitnesses at equilibrium are always subject to invasion by modifier genes that bring about perfect transmission of the selected genes. It is also found, within certain constraints, that for modifier genes producing what we call "linear variation" in the transmission processes, a new modifier allele can invade a population at equilibrium if it reduces the level of imperfect transmission acting on the selected genes, and will be expelled if it increases the level of imperfect transmission. Moreover, the strength of the induced selection on the modifier gene is shown to range up to the order of the departure of the genetic system from perfect transmission.

Biological Evolution↗
PubMed1983

Production of the modified form of human plasminogen in the plasma activated by urokinase.

Plasminogen, a precursor of proteolytic enzyme plasmin which lyses thrombi in vivo, is postulated to be adsorbed onto fibrin and is converted into a modified form by plasmin. The properties of the modified form examined in vitro support this hypothesis. Nevertheless, it has been postulated that no conversion of native plasminogen into the modified form occurs in plasma, since alpha 2-plasmin inhibitor rapidly inactivates plasmin formed. However, we suggested production of the modified form in the "post-exercise" plasma. The present study was undertaken to examine production of the modified form in a simpler system, urokinase-activated plasma. The amount of the modified form in the plasma was estimated using the previous method with modification, epsilon-aminocaproic acid-containing polyacrylamide gel disc electrophoresis. The amount in the post-exercise plasma was also re-estimated by the present method. The amount of the modified form increased with the increase in urokinase concentration added to plasma. The presence of the modified form in the post-exercise plasma was also confirmed. The modified form could be produced in the plasma where an excess amount of alpha 2-plasmin inhibitor was expected to exist. The present results indicate that conversion of native plasminogen into the modified form may occur in vivo, supporting the hypothesis mentioned above.

Adult↗
PubMed1990

Immunotherapy with monomethoxypolyethylene glycol modified allergens.

On the basis of the results of experiments in naive mice, i.e., in mice which had not been presensitized, it was anticipated that mPEG-modified allergens would suppress the specific IgE response in allergic humans. However, only minor or no suppression of IgE antibodies was induced on administration of mPEG conjugates in allergic patients with a longstanding IgE response. This observation was later confirmed in pre-sensitized animals. The mPEG-modified allergens can be synthesized in a reproducible manner. This makes mPEG-modified allergens suitable for production and quality control. There is indirect evidence, i.e., identification of IgE and IgG antibody stimulation against all identified allergens, that the relevant determinants are available for processing by the immune system. By contrast, the polymerization of allergens by formaldehyde or glutaraldehyde leads to ill-defined, cross-linked high molecular weight materials. As in the case of other modified allergens, mPEG-modified allergens have been developed primarily because of their lower allergenicity than the original allergen preparations. However, they also retain clinical efficacy of the same magnitude as that induced by unmodified allergen preparations, which is a prerequisite for clinical use. IT with mPEG-modified pollen allergen preparations has been proven to be as effective as IT with unmodified allergens, when these preparations are given in similar doses. Furthermore, a more pronounced beneficial effect can be obtained with higher doses of mPEG-modified allergen, without the risk of side effects which are often precipitated by unmodified allergens. Therefore, it seems reasonable to suggest that children and young adults with developing sensitivity to perennial allergens, and without chronic changes of the bronchial mucosa, are the most suitable candidates for IT with mPEG-modified allergen preparations. Mite asthma, which always includes bronchial inflammation and nonspecific hyperresponsiveness, represents a more complicated model. In mite asthmatics mPEG-modified mite allergen preparations were safer than the corresponding unmodified preparation. Although bronchial sensitivity to allergen and histamine did not change significantly in mite asthmatics during the observation time, it appears that IT with mPEG-modified mite allergen led to a decrease in the releasability of histamine from skin mast cells, as measured by SPT, to a similar degree as observed in pollinosis patients. Therefore, it may be inferred that the allergic component of asthma might be influenced by IT with mPEG allergens. As a consequence, before the start of IT, the degree of reversibility of pathophysiological changes in the bronchial wall should be considered.(ABSTRACT TRUNCATED AT 400 WORDS)

Allergens↗
PubMedDate not supplied

Modified radical neck dissection in cancer of the mouth, pharynx, and larynx.

A retrospective analysis of 390 determinate radical neck dissections (RND) performed for cancers of the mouth, pharynx, and larynx was carried out. There were 75 patients (19%) who had a modified RND. These were separately analyzed and the outcome was compared to those who had a standard total RND. Our goal was to assess the effectiveness of modified RND in controlling disease in the neck, and to identify its impact on survival and quality of life. Overall neck recurrence rate in the entire modified RND group was 28%, 35% in the partial RND, and 25% in the comprehensive modified RND. Neck recurrence rate was no worse in the comprehensive modified RND for N0 and N1 cases, but increased significantly (as compared to the group of patients with standard RND) in the N2 and N3 cases (52% vs. 33%). Treatment of neck recurrences following modified RND was primarily by surgery, with a 48% 3-year disease-free survival. Overall survival was the same for modified RND (68%) and for standard total RND (63%). This was true for all N stages individually. The morbidity of standard total RND is discussed and the goals of modified RND are analyzed. Definitions and a standardized nomenclature for the various types of modified RND are suggested for uniformity of reporting.

Carcinoma, Squamous Cell↗
PubMed1979

H-2-linked genetic control of murine T-cell-mediated lympholysis to autologous cells modified with low concentrations of trinitrobenzene sulfonate.

Spleen cells from B10.BR and C57BL/10 (B10) mice were compared for their ability to generate primary in vitro cytotoxic responses to syngeneic cells modified with different concentrations (from 10 to 0.031 mM) of trinitrobenzene sulfonate (TNBS) (TNP-self). Although both strains generated effector cells to TNP-self in the range of 10-0.25 mM TNBS modification, effector activity of B10 cells was weaker than that of B10.BR cells. B10 spleen cells did not respond to syngeneic stimulating cells modified at 0.1 mM or lower, whereas B10.BR cells generated effector activity even when stimulated by TNP-self modified with as low as 0.031 mM TNBS. Fluorescence analysis of the modified cells using the FACS II indicated that equivalent quantities of TNP were conjugated to the surfaces of B10.BR and B10 spleen cells for any given concentration of TNBS modification. Similar strain-dependent differences were observed when the TNP was diluted out in the cultures by reducing the number of stimulating cells modified with 10 mM TNBS. These response patterns were verified by stimulating cultures of B10.BR and B10 spleen cells either with TNP conjugated to bovine serum albumin or bovine gamma globulin (B10.BR but not B10 cells responded to TNP-conjugated proteins) or with TNBS-modified glass-adherent spleen cells. The strain-dependent differences could also be detected at the effector phase, because optimally stimulated B10.BR, but not B10 effector cells, could lyse 0.1 mM TNBS-modified syngeneic target cells. The genetic parameters associated with the response and nonresponse patterns of B10.BR and B10 mice were further investigated by comparing the cytotoxic responses to low doses of TNP-self of spleen cells from the following strains: (a) C3H/HeJ (H-2k) and C3H.SW (H-2b); (b) BALB.K (H-2k) and BALb.b (h-2b); and (c) B10.A (H-2a) and B10.D2 (H-2d). The H-2k and H-2a, but not the H-2b and H-2d, strains generated cytotoxic responses to TNP-self when the syngeneic stimulators were modified with 0.1 mM TNBS. Further studies using (B10 X B10.BR)F1 responding cells and parental or F1-modified stimulating cells, indicated that the F1 cells generated cytotoxic activity to low doses of TNP in association with H-2k but not in association with H-2b self products. The results of this study indicate that H-2-linked genetic factors, expressed in the target as well as in the responding and/or stimulating cell populations, control the ability of inbred mouse strains to generate cytotoxic effector cells to low doses of TNP-self. Such dose-dependent genetic effects may be important in the regulation of immune responses activated in vivo by chronic exposure to infectious agents.

Animals↗
PubMed1992

Inactivation of batrachotoxin-modified Na+ channels in GH3 cells. Characterization and pharmacological modification.

Batrachotoxin (BTX)-modified Na+ currents were characterized in GH3 cells with a reversed Na+ gradient under whole-cell voltage clamp conditions. BTX shifts the threshold of Na+ channel activation by approximately 40 mV in the hyperpolarizing direction and nearly eliminates the declining phase of Na+ currents at all voltages, suggesting that Na+ channel inactivation is removed. Paradoxically, the steady-state inactivation (h infinity) of BTX-modified Na+ channels as determined by a two-pulse protocol shows that inactivation is still present and occurs maximally near -70 mV. About 45% of BTX-modified Na+ channels are inactivated at this voltage. The development of inactivation follows a sum of two exponential functions with tau d(fast) = 10 ms and tau d(slow) = 125 ms at -70 mV. Recovery from inactivation can be achieved after hyperpolarizing the membrane to voltages more negative than -120 mV. The time course of recovery is best described by a sum of two exponentials with tau r(fast) = 6.0 ms and tau r(slow) = 240 ms at -170 mV. After reaching a minimum at -70 mV, the h infinity curve of BTX-modified Na+ channels turns upward to reach a constant plateau value of approximately 0.9 at voltages above 0 mV. Evidently, the inactivated, BTX-modified Na+ channels can be forced open at more positive potentials. The reopening kinetics of the inactivated channels follows a single exponential with a time constant of 160 ms at +50 mV. Both chloramine-T (at 0.5 mM) and alpha-scorpion toxin (at 200 nM) diminish the inactivation of BTX-modified Na+ channels. In contrast, benzocaine at 1 mM drastically enhances the inactivation of BTX-modified Na+ channels. The h infinity curve reaches minimum of less than 0.1 at -70 mV, indicating that benzocaine binds preferentially with inactivated, BTX-modified Na+ channels. Together, these results imply that BTX-modified Na+ channels are governed by an inactivation process.

Batrachotoxins↗
PubMed1972

Dominance modifiers in neurospora crassa: phenocopy selection and influence of certain ascus mutants.

When homozygous in zygotes, mutant alleles at the peak locus in linkage group V of Neurospora crassa initiate aberrant asci that are nonlinear, in contrast to the linear asci characteristic of wild type. Most mutant alleles are recessive, inasmuch as crosses of the mutant strains with wild type give linear asci. However, five different mutant alleles, when heterozygous with the wild-type allele, act in varying degrees as zygote dominants, initiating both linear and nonlinear asci, the relative proportions depending on the allele. Five modifiers that act on the dominance relationships of at least one of the five possible heterozygotes of a dominant peak and its wild-type allele have been characterized, four of them having been obtained by selection directed against a phenocopy of these mutants induced by treatment of wild type with l-sorbose. The pattern of modifier specificity observed among the various dominant peak heterozygotes indicates that the phenotypic effects are produced by a complex relationship between the modifiers and the dominant peak alleles in relation to their wild-type allele. In all but two cases the direction of modification, where present, is towards decreasing the dominance of the mutant allele in the heterozygote, evidenced by an increase in the percentage of linear asci when compared with control data. The modifiers exert their maximum modification when they themselves are heterozygous with their wild-type alleles and when the dominant peak allele is heterozygous with its wild-type allele. No modification occurs when heterozygous modifiers are included in zygotes homozygous for a dominant peak allele, reinforcing the notion that the modifiers act on the dominance relationship existent between a dominant peak allele and its wild-type allele, rather than influencing some activity of the mutant allele itself. The modifiers have no detectable effect of their own on ascus morphology, since homozygous modifier zygotes initiate entirely linear asci when only wild-type alleles of peak are present in the zygotes. Their only detectable effect, other than dominance modification, appears to be in conferring sorbose resistance to the mycelium. The modifiers are unlinked to the peak locus, and, except for two of them, they are nonallelic.

Crosses, Genetic↗
PubMed1978

Studies on delayed hypersensitivity to protein antigen. Induction of delayed hypersensitivity by chemically modified antigen.

it was shown in our previous paper that mice primed with chemically modified bacterial alpha-amylase (BaA), which was neither cross-reactive with anti-BaA antibody nor able to induce a humoral anti-BaA response, developed enhanced responses to a subsequent challenge with native BaA and that the magnitude of the immunological memory was closely related to the priming dose of modified BaA. This paper describes the experimental conditions for induction of delayed hypersensitivity (DH) by modified BaA in relation to the development of immunological memory for antibody response to native BaA. Mice primed with either an intraperitoneal (i.p.) or subcutaneous (s.c.) injection of modified BaA in complete Freunds adjuvant (CFA) developed enhanced anti-BaA as the immunogen and modified BaA as the eliciting antigen, the relationship of anti-BaA responses to a subsequent challenge with BaA. In contrast, when mice were immunized with an s.c. injection of the modified BaA only, a significant level of DH to native BaA could be induced, as measured by the footpad reaction (FPR). The highest degree of DH was observed in mice given 50 micrograms of modified BaA. DH was detectable within 5 days and persisted for 25 days after immunization. In the reciprocal combination of native BaA as the immunogen and modified BaA as the eliciting antigen, the relationship of anti-BaA responses to DH was examined. The primary anti-BaA responses induced by an i.p. injection of large doses of BaA was markedly higher than those induced by an s.c. injection, while DH was exhibited only in mice given s.c. injection of BaA in CFA. With respect to DH to native BaA induced by the modified BaA, it was shown that C3H/He mice were high and C57BL/6 mice were low responders.

Amylases↗
PubMed1992

Modified latex agglutination test for antibodies to Toxoplasma gondii in eluates from Guthrie cards.

AIMS: To determine whether the Eiken particle agglutination test could be modified to make it sufficiently sensitive to screen blood samples collected on Guthrie cards for the presence of antibodies to Toxoplasma gondii; to evaluate the specificity of the modified system; and to compare seroepidemiological data on the prevalence of T gondii in pregnant women. METHODS: Simulated dried blood spots were prepared from sera from pregnant women booking for antenatal care. Eluates from the simulated dried blood spot cards and sera were tested in parallel using the modified test (1 in 5 dilution of latex) and the standard assay (neat latex particles) and endpoints determined. Guthrie card eluates, from neonates in three Thames regions, were then tested using the modified test. RESULTS: The modified test produced a 4.21-fold increase in antibody titre in 85 sera when tested in parallel with the standard test. Eluates of 168/170 from simulated dried blood spots derived from seropositive patients gave a positive result in the modified test. The two eluates which gave a negative result were derived from patients with an equivocal titre of 1/16 in the standard serum test. Of the eluates derived from serum negative patients all 103 were negative at a dilution of 1 in 4 in the modified test. The seroprevalence of antibodies to T gondii in pregnancy was 21.8% using the standard test. A similar value of 20.5% was obtained when dried blood spots from neonates in a similar region of London were tested by the modified test. CONCLUSIONS: The modified Eiken Toxo-reagent test is sensitive, simple, and economic for screening large numbers of dried blood spots. The procedure could be easily semiautomated and the technique applied to the mass screening of neonatal blood samples collected on Guthrie cards to determine the seroprevalence of T gondii in pregnant women.

Animals↗
PubMed1989

Platelet-modified low density lipoprotein induces macrophage cholesterol accumulation and platelet activation.

Low density lipoprotein (LDL), modified by chemical or biological means, was shown to induce macrophage cholesterol accumulation. The cholesterol and protein contents of LDL were decreased (by 10 and 15%, respectively) by incubation of the LDL for 2 h at 37 degrees C with normal washed platelet suspension or with platelet-conditioned medium; these decreases were not affected by platelet activation. The platelet-modified LDL caused a greater increase (by up to 15%) in collagen-induced, in vitro platelet aggregation than control LDL. Incubation of mouse peritoneal macrophages with platelet-modified LDL for 18 h at 37 degrees C resulted in an elevation of the macrophage cholesterol ester content (by 35-50%) as well as an increase in the cholesterol esterification rate (by 40-70%), compared with the effect of control LDL. Macrophage cholesterol synthesis, however, was significantly decreased (by 40-50%), compared with the effect of control LDL. The effect of LDL treated by platelet-conditioned medium was similar to that of platelet-modified LDL. The effect of platelet-modified LDL on macrophage cholesterol esterification was maximal within 24 h of incubation, and it was not significantly affected by inhibition of cholesterol synthesis. The platelet-modified LDL was taken up by the macrophages in a saturable fashion and its uptake was competitively inhibited by LDL, but not by acetylated LDL. We conclude that platelet-modified LDL interacts with the LDL receptor and induces macrophage cholesterol accumulation. Since the modified lipoprotein induces in vitro foam cell formation and platelet activation, platelet-modified LDL could be considered to be pro-atherogenic.

Animals↗
PubMed1992

Immunization of colorectal cancer patients with modified ovine submaxillary gland mucin and adjuvants induces IgM and IgG antibodies to sialylated Tn.

Tn and sialylated Tn (sTn) are blood group-related epitopes expressed on mucins of colon carcinoma and other epithelial tumors and are, therefore, potential targets for immunological control. We have immunized 20 colorectal cancer patients at high risk for recurrence with a vaccine consisting of partially desialylated ovine submaxillary gland mucin (modified OSM) which contains both Tn and sTn determinants. Six patients were treated with modified OSM alone (group 1), eight patients were treated with modified OSM and the immunological adjuvant DETOX (group 2), and six patients were treated with modified OSM and Bacillus Calmette-Guérin (group 3). Pre- and postvaccination sera were tested by enzyme-linked immunosorbent assay and dot blot immune stains for antibodies reactive with modified OSM. Antibody titers increased in 4 of 8 patients immunized with modified OSM and DETOX, in 5 of 6 patients immunized with modified OSM and B. Calmette-Guérin, and in 0 of 6 patients receiving modified OSM without adjuvant. The specificity of induced IgM and IgG antibodies was confirmed by demonstrating reactivity with OSM, bovine submaxillary mucin, and synthetic glycoconjugates sTn-human serum albumin (HSA) and Tn-HSA in enzyme-linked immunosorbent assay and immune stains. Median IgM pre-postvaccination reciprocal titers were 20/80 for Tn-HSA and 10/320 for sTn-HSA. Low level IgG antibody titers against sTn-HSA were detected after vaccination in 7 patients. Toxicity was limited to inflammatory skin reactions at the site of vaccination resulting from the adjuvants. No inflammatory infiltrates were seen in the skin when the modified OSM vaccine was administered in the absence of an immunological adjuvant. These results demonstrate that sTn and Tn can be recognized by the human immune system and that vaccines containing these structures can be administered safely with immunological adjuvants. Attempts to augment the immunogenicity of these carbohydrate antigens by covalent attachment to immunogenic carrier proteins and the use of more potent immunological adjuvants are now being pursued.

Adjuvants, Immunologic↗
PubMed1983

Comparison of urinary modified nucleosides and bases in rats with hepatomas and nephroblastomas.

Hepatomas were induced in rats with aflatoxin B1, and nephroblastomas with dimethylnitrosamine. Microscopic examination of livers of aflatoxin-treated rats revealed multinodular hepatocyte hyperplasia at 8 months, and by 13 months all rats had hepatomas. Nephroblastomas were observed by 4 months and by 8 months all rats had developed them. The urinary excretion of several modified nucleosides and bases by normal rats is dependent on body weight and reflects, to a certain extent, their concentrations in tissue tRNA. Increased levels of several modified nucleosides and bases were found in all rats that had cancer. Rats with hepatomas excreted essentially the same modified nucleosides and bases as did those with nephroblastomas; the quantitative patterns of excretion were different, however, suggesting that the urinary modified nucleosides and bases may be used to differentiate between neoplasms. Although the increase in urinary modified nucleosides and bases by tumor-bearing animals results primarily from more rapid turnover of neoplastic tRNAs, the data indicate that increased turnover of mRNA and possibly rRNA may occur in neoplastic tissue. Preliminary data suggest that increases in urinary modified nucleosides and bases may occur during a precancerous stage. The urinary pattern of modified nucleosides and bases by rats with hepatomas is altered if another primary tumor is present. The results obtained from these studies support the use of modified nucleosides and bases in urine as biochemical markers of cancer.

Aflatoxin B1↗
PubMed1987

Modified versus classical Blalock-Taussig shunts for congenital cyanotic heart diseases: a comparison of long-term results.

Between March 1977 and December 1984, 103 Blalock-Taussig shunts were performed on 88 patients. Included in this study were 40 patients who underwent the modified BT shunt and 63 patients who underwent the classical BT shunt. 13 of the modified BT shunts (33 per cent) and 18 of the classical BT shunts (29 per cent) were performed during infancy and 10 of the modified BT shunts (25 per cent) were performed on patients under the age of 3 months. EPTFE grafts of varying sizes were used in the patients who underwent modified BT shunts--4 mm in 14 cases, 5 mm in 15 cases and 6 mm in 11 cases, respectively. The early mortality rate was 11 per cent (3 deaths) in the group who had modified BT shunts and 8 per cent (5 deaths) in the group who had classical BT shunts. Over a follow-up period of 6 years, 6 shunt failures were diagnosed in the modified BTS group by auscultation and/or angiographic study, and during a follow-up period of 8 years, 12 shunt failures were diagnosed in the classical BTS group. The patency rate 3 years after surgery was 88.8 per cent in the modified BTS group and 78.0 per cent in the classical BTS group. The patency rate 5 years after surgery was 88.8 per cent in the modified BTS group and 75 per cent in the classical BTS group.(ABSTRACT TRUNCATED AT 250 WORDS)

Anastomosis, Surgical↗
PubMed1988

Role of disease-modifying antirheumatic drugs versus cytotoxic agents in the therapy of rheumatoid arthritis.

Disease-modifying antirheumatic drugs are used to modify or alter the rheumatoid arthritis disease process. Disease-modifying antirheumatic drugs do not demonstrate the characteristic analgesic, antipyretic, and anti-inflammatory actions of the nonsteroidal anti-inflammatory drugs, since weeks or months of treatment are required before clinical benefit is observed. Although they have not been proved to delay, prevent, or reverse articular damage, therapy with disease-modifying antirheumatic drugs, when successful, is associated with decreased pain and joint swelling and improved function. Disease-modifying antirheumatic drugs and cytotoxic agents should not be considered as routine treatment for patients with rheumatoid arthritis. Before disease-modifying antirheumatic drug therapy is implemented, an optimal basic program of physical therapy, rest, and nonsteroidal anti-inflammatory drugs should be implemented, and it must be documented that the patient still has sufficient disease to justify the costs, risks, and benefits of these treatments. Drugs that are approved by the Food and Drug Administration (FDA) are preferred over nonapproved drugs. Hydroxychloroquine, parenteral gold salts, oral gold, D-penicillamine, and the cytotoxic drug azathioprine are the FDA-approved disease-modifying antirheumatic drugs for use in rheumatoid arthritis. Many, not all, rheumatologists would employ hydroxychloroquine as the first-choice disease-modifying antirheumatic drug in patients who have early, mild, and nonerosive disease; treatment should be continued for six months before being abandoned for lack of efficacy, and appropriate ophthalmologic examination every four to six months is indicated. An alternative would be auranofin, whose efficacy approaches that of parenteral gold, yet may be safer. For patients who have severe active rheumatoid arthritis, especially with erosive changes, parenteral gold salts are usually a first choice. D-penicillamine is also effective in controlling the signs and symptoms of rheumatoid arthritis, but serious toxicity may occur. Azathioprine might be considered a competitor to D-penicillamine, although the FDA approval restricts its use to patients who have failed gold therapy. Two cytotoxic drugs that are not FDA approved are methotrexate and cyclophosphamide. Methotrexate can be very effective, but its side effects, particularly pulmonary and hepatic, must be carefully monitored. Cyclophosphamide is generally considered too toxic for use in patients with rheumatoid arthritis, although it may be helpful in patients with systemic rheumatoid vasculitis or patients who have failed all other therapies.(ABSTRACT TRUNCATED AT 400 WORDS)

Anti-Inflammatory Agents↗
PubMed1986

Different characteristics of allogeneic and trinitrophenyl-modified H-2-restricted cell-mediated lympholysis: analysis of differences in interleukin-2 dependency using an ontogenical approach.

Ontogenical development of in vitro allogeneic cell-mediated lympholysis (CML) and in vitro trinitrophenyl (TNP)-modified CML was studied mainly in correlation with helper cell activity, using C3H/HeN and C57BL/6 mice. Allogeneic and TNP-modified CML were not detected in the spleen of these mice at 1 week after birth. Allogeneic CML was detectable, in parallel with increases in age. This activity in 5-week-old mice was much the same as in the 8-week-old mice but the TNP-modified CML did not appear until 8 weeks after birth. Exogenous interleukin-2 (IL-2) induced sufficient activity of TNP-modified CML, even in spleen cells from 1-week-old mice, while the same treatment had a weak but significant effect on the induction of allogeneic CML in these same cells. Experiments on the mixed lymphocyte reaction (MLR) in the presence of exogenous IL-2 showed that lymphocyte proliferation in response to TNP-modified cells was higher than that in response to allogeneic cells. These results suggest different dependencies on IL-2 between allogeneic and TNP-modified killer precursor cells. Endogenous IL-2 production and proliferative response in MLR showed that helper cells contributing to the TNP-modified CML matured later, compared to allogeneic CML. Different sensitivities to IL-2 in two types of CML, in addition to different ontogenical developments, suggest that cytotoxic T lymphocytes to allogeneic cells differ quantitatively and qualitatively from TNP-modified H-2-restricted killer cells.

Aging↗
PubMedDate not supplied

Mutational and recombinational events in carcinogen-modified plasmid DNA. Influence of host-cell repair genes.

A plasmid containing the STR operon has been modified in vitro (i) by irradiation with UV light, (ii) by reaction with ethyl methanesulphonate (EMS), (iii) by reaction with N-acetoxy-2-acetylaminofluorene (AcO-AAF), (iv) by reaction with (+/-)trans-benzo[a]pyrene-7, 8-dihydrodiol-9,10-epoxide (BPDE), and (v) by heating at 70 degrees C to produce apurinic sites. Suitably modified plasmid DNA was then used to transform both repair-proficient and repair-deficient strains of Escherichia coli, and the mutation frequency in the plasmid-encoded rspL+ gene measured. The influence of host mutations in the uvrB+, recA+, umuC+ and lexA+, genes on the mutation frequency have been investigated. Transformation into a uvrB strain significantly decreased survival and increased the level of mutations observed for UV- and AcO-AAF-modified plasmid DNA, while only a small increase in mutation frequency was seen with EMS-modified DNA and no increase in mutation frequency with plasmid DNA containing apurinic sites. Mutagenesis in UV- and BPDE-modified DNA (and probably also DNA containing apurinic sites) was totally dependent on he recA+ gene product, while EMS and AcO-AAF induced mutagenesis was only partially independent on the recA+ gene. Transformation of UV- or BPDE-modified DNA into a umuC or lexA strain, on the other hand, showed no change in mutation frequency from that observed with wild-type strain. Pre-irradiation of the wild-type host with UV light before transformation led to a significant increase in mutation frequency for UV- and BPDE-modified plasmid DNA. These results are discussed in terms of mutational or recombinational pathways which may be available to act on modified plasmid DNA, and suggest that the majority of the mutational events measured in this system are due to recombination between homologous regions on the plasmid and chromosomal DNA.

Carcinogens↗
PubMed1987

The Blalock-Taussig shunt in infants: standard versus modified.

In recent years, the modified Blalock-Taussig shunt--a polytetrafluoroethylene graft from the subclavian artery to the pulmonary artery--has been preferred over the standard shunt by some surgeons because (1) it requires less dissection and (2) length of native vessels is not critical. From January, 1979, to June, 1985, we operated on 51 infants less than 1 year of age, including 26 less than 1 week of age, to palliate severe complex cyanotic congenital cardiac malformations. Twenty-four modified Blalock-Taussig shunts and 29 standard Blalock-Taussig shunts were created. The groups were concurrent. We reviewed all available cineangiograms and measured branch pulmonary and subclavian arteries. Pulmonary artery index was not different preoperatively in patients given a modified versus a standard Blalock-Taussig shunt (144 +/- 118 and 118 +/- 59 mm2/m2, respectively), but it was greater postoperatively in patients with a modified shunt (431 +/- 188 and 189 +/- 106 mm2/m2) (p = 0.07). Distortion of the pulmonary artery occurred less often after a modified Blalock-Taussig shunt (4/11) than a standard Blalock-Taussig shunt (6/8) (p = 0.06), though none of the distortions was severe. Early and late shunt failure occurred less often with a modified shunt (5/24) than with a standard shunt (15/29) (p less than 0.05). The modified Blalock-Taussig shunt had advantages over the standard Blalock-Taussig shunt in our series: pulmonary artery growth was greater, distortion of pulmonary arteries was less commonly seen, and shunt failure occurred less often. Thus, in infants, we believe the modified Blalock-Taussig shunt should be considered a reasonable alternative to the standard Blalock-Taussig shunt.

Blood Vessel Prosthesis↗
PubMed1990

Genetic variation in a modifier system affecting the expression of bare mutant of Drosophila subobscura.

Genetic variation affecting the expression of Bare (Ba), a morphological mutant of Drosophila subobscura that reduces the number of bristles and is located on the O chromosome of this species, is reported. Our results show that O chromosomes extracted from a natural population (El Pedroso, Santiago de Compostela, Spain) show considerable genetic variation in modifier effect upon Ba expression. The amount of modifier variability is dependent on the chromosomal arrangement (OST and O3 + 4 + 7), since modifier variation is higher in OST than in O3 + 4 + 7 chromosomes. Investigations of the genetic architecture of this modifier system on the O chromosome carried out using biometrical methods indicate that a relatively small number of genetic "factors" can explain the differences in modifier effect between a wild O chromosome of high modifier effect and a marker chromosome of low score. In addition, the modifier effects show a non-uniform distribution along the O chromosome and some indication of clustering of modifier "factors" around the major locus (Ba) is also observed.

Analysis of Variance↗