Metabolic defence against oxidative stress: the road less travelled so far.

Bacteria have survived, and many have thrived, since antiquity in the presence of the highly-reactive chalcogen-oxygen (O2 ). They are known to evoke intricate strategies to defend themselves from the reactive by-products of oxygen-reactive oxygen species (ROS). Many of these detoxifying mechanisms have been extensively characterized; superoxide dismutase, catalases, alkyl hydroperoxide reductase and the glutathione (GSH)-cycling system are responsible for neutralizing specific ROS. Meanwhile, a pool of NADPH-the reductive engine of many ROS-combating enzymes-is maintained by metabolic enzymes including, but not exclusively, glucose-6 phosphate dehydrogenase (G6PDH) and NADP-dependent isocitrate dehydrogenase (ICDH-NADP). So, it is not surprising that evidence continues to emerge demonstrating the pivotal role metabolism plays in mitigating ROS toxicity. Stemming from its ability to concurrently decrease the production of the pro-oxidative metabolite, NADH, while augmenting the antioxidative metabolite, NADPH, metabolism is the fulcrum of cellular redox potential. In this review, we will discuss the mounting evidence positioning metabolism and metabolic shifts observed during oxidative stress, as critical strategies microbes utilize to thrive in environments that are rife with ROS. The contribution of ketoacids-moieties capable of non-enzymatic decarboxylation in the presence of oxidants-as ROS scavengers will be elaborated alongside the metabolic pathways responsible for their homeostases. Further, the signalling role of the carboxylic acids generated following the ketoacid-mediated detoxification of the ROS will be commented on within the context of oxidative stress.

Aluminum-induced defective mitochondrial metabolism perturbs cytoskeletal dynamics in human astrocytoma cells.

Although aluminum (Al), a known environmental toxin, has been implicated in a variety of neurological disorders, the molecular mechanism responsible for these conditions is not fully understood. In this report, we demonstrate the ability of Al to trigger mitochondrial dysfunction and ineffective adenosine triphosphate (ATP) production. This situation severely affected cytoskeletal dynamics. Whereas the control cells had well-defined structures, the Al-exposed astrocytoma cells appeared as globular structures. Creatine kinase (CK) and profilin-2, two critical modulators of cellular morphology, were markedly diminished in the astrocytoma cells treated with Al. Antioxidants such as alpha-ketoglutarate and N-acetylcysteine mitigated the occurrence of the globular-shaped cells promoted by Al toxicity. Taken together, these data reveal an intricate link between ATP metabolism and astrocytic dysfunction and provide molecular insights into the pathogenesis of Al-induced neurological diseases.

1,25-dihydroxyvitamin D3 prevents the in vivo induction of murine experimental autoimmune encephalomyelitis.

The hormone, 1,25-dihydroxyvitamin D3 (1,25-[OH]2-D3), inhibits lymphocyte activation in vitro. We studied the ability of the vitamin D metabolite to interfere in vivo with a primary T cell-mediated model of autoimmunity, murine experimental autoimmune encephalomyelitis (EAE). Within 2 wk of antigenic challenge, immunized animals will develop acute paralysis with central nervous tissue inflammation. If mice survive, a rise in antibody titer develops within a month. The administration of 0.1 microgram 1,25-(OH)2-D3 i.p. given every other day for 15 d, starting 3 d before immunization, significantly prevented the development of EAE. The rise in antibody titer to myelin basic protein was also abrogated. Histopathologic lesions of EAE were inhibited by treatment with the sterol. These results suggest a potent immunosuppressive role for 1,25-(OH)2-D3 in vivo in the modulation of a cell-mediated model of autoimmunity.

1 alpha,25-dihydroxyvitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells.

Activated B and T lymphocytes from normal human subjects are known to have the specific high-affinity receptor for 1,25-dihydroxyvitamin D3 (1,25-(OH)2-D3). In an attempt to determine a functional role for the sterol in such cells, we studied the effect of 1,25-(OH)2-D3 on DNA synthesis and Ig production by normal human peripheral blood mononuclear (PBM) cells activated in vitro by the polyclonal lymphocyte activators pokeweed mitogen and phytohemagglutinin, and the specific antigen dermatophyton O. A dose-dependent inhibition of [3H]thymidine incorporation was observed in cells incubated with 1,25-(OH)2-D3 in concentrations ranging from 10(-10) to 10(-7) M. Production of IgG and IgM, determined by enzyme-linked immunosorbent assay, was similarly inhibited by increasing concentrations of 1,25-(OH)2-D3. Half-maximal inhibition of DNA and Ig synthesis was found at 10(-10) to 10(-9) M 1,25-(OH)2-D3. This suppressive effect was specific for 1,25-(OH)2-D3; of the other vitamin D metabolites examined, only 10(-7) M 24R,25 dihydroxyvitamin D3 (24,25-(OH)2-D3) had a similar inhibitory effect. 1,25-(OH)2-D3 was not cytotoxic and did not affect unactivated PBMs. These data demonstrate that 1,25-(OH)2-D3 is a potent inhibitor of human PBM Ig production in vitro and suggest that this action is mediated through the hormone's antiproliferative effect on Ig-producing B cells and/or helper T cells.

Physiological control of repressible acid phosphatase gene transcripts in Saccharomyces cerevisiae.

We have examined the regulation of repressible acid phosphatase (APase; orthophosphoric-monoester phosphohydrolase [acid optimum], EC 3.1.3.2) in Saccharomyces cerevisiae at the physiological and molecular levels, through a series of repression and derepression experiments. We demonstrated that APase synthesis is tightly regulated throughout the growth phase and is influenced by exogenous and endogenous Pi pools. During growth in a nonlimiting Pi medium, APase is repressed. When external Pi becomes limiting, there is a biphasic appearance of APase mRNA and enzyme. Our data on APase mRNA half-lives and on the flux of intracellular Pi and polyphosphate during derepression are consistent with a mechanism of transcriptional autoregulation for the biphasic appearance of APase mRNA. Accordingly, preculture concentrations of Pi control the level of corepressor generated from intracellular polyphosphate degradation. When cells are fully derepressed, APase mRNA levels are constant, and the maximal linear accumulation rate of APase is observed. A scheme to integrate phosphorus metabolism and phosphatase regulation in S. cerevisiae is proposed.

Synthesis of repressible acid phosphatase in Saccharomyces cerevisiae under conditions of enzyme instability.

The synthesis of repressible acid phosphatase in Saccharomyces cerevisiae was examined under conditions of blocked derepression as described by Toh-e et al. (Mol. Gen. Genet. 162:139-149, 1978). Based on a genetic and biochemical analysis of the phenomenon these authors proposed a new regulatory model for acid phosphatase expression involving a simultaneous interaction of regulatory factors in the control of structural gene transcription. We demonstrate here that under growth conditions that fail to produce acid phosphatase the enzyme is readily inactivated. Furthermore, we demonstrate under these conditions the production of acid phosphatase mRNA which is active both in vitro and in vivo in the synthesis of enzyme. This eliminates any step prior to translation of acid phosphatase polypeptide as an explanation for the phenomenon. We interpret our results for the block in appearance of acid phosphatase as a result of both deaccelerated growth and cellular biosynthesis during derepression, accompanied by an enhanced instability of the enzyme.

Regulation of repressible acid phosphatase gene transcription in Saccharomyces cerevisiae.

We examined the genetic system responsible for transcriptional regulation of repressible acid phosphatase (APase; orthophosphoric-monoester phosphohydrolase [acid optimum, EC 3.1.3.2]) in Saccharomyces cerevisiae at the molecular level by analysis of previously isolated and genetically well-defined regulatory gene mutants known to affect APase expression. These mutants identify numerous positive- (PHO4, PHO2, PHO81) and negative-acting (PHO80, PHO85) regulatory loci dispersed throughout the yeast genome. We showed that the interplay of these positive and negative regulatory genes occurs before or during APase gene transcription and that their functions are all indispensible for normal regulation of mRNA synthesis. Biochemical evidence suggests that the regulatory gene products they encode are expressed constitutively. More detailed investigation of APase synthesis is a conditional PHO80(Ts) mutant indicated that neither PHO4 nor any other protein factor necessary for APase mRNA synthesis is transcriptionally regulated by PHO80. Moreover, in the absence of PHO80, the corepressor, presumed to be a metabolite of Pi, did not inhibit their function in the transcriptional activation of APase.

Multiple alpha-fetoprotein RNAs in adult rat liver: cell type-specific expression and differential regulation.

Multiple alpha-fetoprotein (AFP) RNAs are expressed in the rat liver and are differentially regulated during development. We examined the expression and cellular distribution of the full-length AFP RNA (major form, 2.1 kilobases highly expressed in fetal liver) and 3 variants of 1.7, 1.4, and 1.0 kilobases in normal rat liver, during fetal development, in regeneration, and in carcinogenesis. The 1.7-kilobase variant is expressed only in developing liver (by 15 days of gestation) and is much less abundant than the major form. In adult normal liver the 1.4- and 1.0-kilobase RNAs are the predominant forms. By cell separation studies we show that these variants are produced by parenchymal and nonparenchymal cells in normal rat liver, and that the full-length AFP mRNA is detectable in normal nonparenchymal cells. We demonstrate by in situ hybridization that the 2.1-kilobase mRNA is expressed by some ductular cells and a few nondividing hepatocytes (approximately 1 in 20,000). Further studies revealed that (a) the 2.1-kilobase AFP mRNA encodes translation products of molecular weight 68,000 and 70,000, and probably has multiple sites for translation initiation; (b) the 1.4-kilobase AFP RNA variant in adult rat liver encodes translation products of molecular weight 58,000, 54,000 and 44,000; (c) the 2.1-kilobase AFP RNA increases in liver nonparenchymal cells after CCl4 injury (20-30-fold) and in galactosamine-injured liver (60-100-fold), while the 1.4- and 1.0-kilobase variants change much less; and (d) after partial hepatectomy there are only small changes in any of the AFP RNAs, while during carcinogenesis oval cells contain large amounts of 2.1-kilobase AFP RNA and levels of the 1.4- and 1.0-kilobase species which are lower than those in normal liver. We suggest that after development synthesis of the full-length RNA is not shut off in a small proportion of rat liver cells and that ductular cells that express this RNA may constitute a facultative liver stem cell compartment.

Cell lineages and oval cell progenitors in rat liver development.

We determined whether the formation of the hepatic primordium in the rat is associated with the expression of liver-specific markers. Further, we examined the origin of intra- and extrahepatic bile ducts and tried to establish whether there are cell types in the developing liver that might correspond to "stem-like" cells ("oval cells") that proliferate during carcinogenesis and toxic injury in adult livers. Using in situ hybridization and immunohistochemical methods, we show that alpha-fetoprotein (AFP) mRNA is detected in cells of the ventral foregut at 10.5 days of development and that the protein is first detected 1 day later. Thus, AFP transcription occurs before liver morphogenesis, and translation of the protein is first detected when liver cords are being formed, indicating that AFP expression in endodermal cells signals their commitment toward the liver lineage. Although albumin is considered a trait of differentiated hepatocytes, its mRNA was first detected just 1 day later than the AFP message. An analysis of the expression of lineage-specific cytokeratins (cytokeratins 7, 9, 18, and 19), surface markers, and histochemical determination of gamma-glutamyl transferase activity and glycogen revealed that (a) hepatoblasts undergo gradual maturation throughout liver development, (b) AFP- and albumin-containing hepatoblasts gave rise to intra- and extrahepatic bile ducts, and (c) hepatoblasts forming primitive intrahepatic bile ducts during liver development have markers similar to those expressed by stem-like cells that proliferate during liver carcinogenesis.

Homology between rat liver RNA populations during development, regeneration, and neoplasia.

To investigate the degree of homology which may exist between rat liver RNA populations during development, regeneration, and neoplasia, we hybridized polyadenylated RNAs from (a) normal adult, (b) 24-h regenerating, (c) 20-day fetal livers, and (d) the transplantable Morris hepatoma 5123tc to homologous and heterologous complementary DNAs and to cDNAs enriched for sequences preferentially transcribed in either adult or fetal liver. We also compared the in vitro translation products of these RNAs. Analyses of normal adult, regenerating, and fetal liver RNA populations and their translation products show that the overall pattern of gene expression during liver regeneration differs little from that of normal adult rat liver and that mature hepatocytes do not appear to revert to an "immature" state upon reentering the cell cycle. Comparisons between fetal, normal adult, and tumor RNA populations revealed that RNA populations from fetal liver and the 5123tc tumor lack sequences normally expressed in the mature adult liver. However, the tumor does not "reexpress" sequences which are preferentially expressed in fetal livers.

1,25-Dihydroxyvitamin-D3 regulation of interleukin-2 and interleukin-2 receptor levels and gene expression in human T cells.

1,25-Dihydroxyvitamin-D3 (1,25-D3) is known to inhibit DNA synthesis, immunoglobulin and lymphokine production [interleukin-2 (IL-2), gamma interferon (G-IFN), and granulocyte-monocyte colony-stimulating factor (GM-CSF)] by mitogen-stimulated human peripheral blood mononuclear cells (PBMCs). Recent data suggest these inhibitory effects are mediated at the gene level through inhibition of mRNA accumulation of specific lymphokines in the activated cells. In previous studies, we have demonstrated the CD8+ T cell population was less sensitive to the anti-proliferative actions of 1,25-D3 than CD4+ T cells. The purpose of this investigation was to further assess ability of 1,25-D3 to regulate CD4+ and CD8+ T cell functions. Initial experiments showed that 1,25-D3 inhibited both IL-2 production and mRNA accumulation in mitogen-stimulated PBMC. However, IL-2 receptor (IL-2R) expression and mRNA accumulation in stimulated PBMC was not affected by 1,25-D3. Both FACS sorted CD4+ and CD8+ T cells expressed IL-2R equally upon stimulation and neither showed an inhibitory effect on this expression by 1,25-D3. Human CD4+ and CD8+ T cells showed a stimulus-specific production of IL-2. CD4+ cells stimulated with mitogen and HLA-DR positive accessory cells produced measurable levels of IL-2 that were completely inhibited by 1,25-D3. CD8+ T cells did not generate measurable amounts of IL-2 in this system. However, CD4+ and CD8+ T cells produced large amounts of IL-2 when stimulated with mitogen and a protein kinase C activator, phorbol myristate acetate (PMA). Under these circumstances, both CD4+ and CD8+ T cell IL-2 production was inhibited completely by 1,25-D3. These data suggest that IL-2R expression in PBMCs and T cell subsets is equal and unaffected by 1,25-D3 while IL-2 production in T cell subsets is stimulus-specific and completely inhibited by 1,25-D3.

Exogenous interleukin-2 does not reverse the immunoinhibitory effects of 1,25-dihydroxyvitamin D3 on human peripheral blood lymphocyte immunoglobulin production.

1,25-Dihydroxyvitamin D3 (1,25-D3) is known to have potent inhibitory effects on human peripheral blood mononuclear cell (PBMC) functions. Previous experiments suggest that addition of interleukin-2 (IL-2) to cell cultures can reverse the antiproliferative action of 1,25-D3. Previous studies have also shown that the CD4+ T-cell subset is more sensitive to the antiproliferative actions of 1,25-D3 than are the CD8+ T-cells. The objective of this study was to determine whether exogenous IL-2 could reverse the antiproliferative and immunoinhibitory action (inhibition of Ig production) in mitogen-activated PBMC cultures and in fluorescein-activated cell sorting (FACS) experiments where CD8+ T-cells were removed from PBMCs before mitogen stimulation with/without exogenous IL-2 added. In these studies, addition of IL-2 to mitogen-activated, 1,25-D3-treated PBMCs allowed the cells to overcome the 1,25-D3 suppressive effect on cell proliferation. However, exogenous IL-2 did not overcome the 1,25-D3-mediated inhibitory effect on PBMC Ig production. Using FACS lymphocyte populations (CD4+, CD8+ and B-cells), we showed that CD4+ T-cell-directed Ig synthesis in co-culture with autologous B-cells was inhibitable by incubation of cells with 1,25-D3, but Ig synthesis was restored to near-normal levels by addition of exogenous IL-2. This clearly contrasts with the inability of Il-2 to reverse the 1,25-D3 inhibitory effect on Ig synthesis in PBMCs. In other experiments, when CD8+ cells were removed from mitogen-stimulated, 1,25-D3-treated PBMCs, addition of exogenous IL-2 resulted in a full reversal of the 1,25-D3-mediated Ig inhibition. These data suggest that the inability of IL-2 to reverse the inhibitory effects of 1,25-D3 on PBMC Ig production is probably a result of a lack of sensitivity of CD8+ T-cells to the antiproliferative and immunoregulatory actions of 1,25-D3. This is possibly because of a differential expression of 1,25-D3 receptors on CD4+ and CD8+ T-cells.

1,25-Dihydroxyvitamin D3 inhibits the passive transfer of cellular immunity by a myelin basic protein-specific T cell clone.

1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] and related analogs have been shown to exert immunoinhibitory effects on activated lymphocytes in vitro. However, the effects of the hormone on the mammalian immune response in vivo have not been well studied. To examine the possible immunoactions of 1,25-(OH)2D3 in vivo, we employed a murine model of experimental autoimmune encephalomyelitis (EAE). In this model, T helper lymphocyte clones developed from lines of lymphocytes reactive to myelin basic protein (MBP) confer MBP immunoreactivity and demyelinating central nervous system disease on syngeneic, naive recipients of the T cell clone. Similar to peripheral blood mononuclear cells incubated with mitogen, the T cell clone evaluated in this study expressed a high-affinity specific receptor for 1,25-(OH)2D3 (VDR; K(in) = 0.03 nM) upon exposure to MBP. The MBP-stimulated clone elicited a ninefold enhancement of the local delayed hypersensitivity (DTH) response when as few as 0.5 x 10(5) cells of the T cell clone were injected into the foot pad of recipient mice. The DTH response in the recipient was completely blocked when the clone was preincubated with greater than or equal to 10(-8) M 1,25-(OH)2D3 before transfer; the half-maximal inhibitory concentration of hormone (EC50) was 5 x 10(-9) M. These data indicate that exposure of antigen-reactive T helper lymphocytes to a VDR saturating concentration of 1,25-(OH)2D3 can dramatically lessen the expression of immunoreactivity in vivo.

1,25-Dihydroxy-24-OXO-16ene-vitamin D3, a renal metabolite of the vitamin D analog 1,25-dihydroxy-16ene-vitamin D3, exerts immunosuppressive activity equal to its parent without causing hypercalcemia in vivo.

The hormone, 1,25-(OH)2D3, is metabolized into 1,25-(OH)2-24-OXO-D3, in kidney prior to conversion to its final inactive product, calcitroic acid. Similarly, 1,25-(OH)2-24OXO-16eneD3, is produced in the kidney from the Vitamin D analog, 1,25-(OH)2-16eneD3, but resists further hydroxylation. The analog's metabolite was synthesized and its biologic activity compared to the parent compound. Naive SJL/J mice, 4 weeks old, were immunized with neuroantigen in adjuvant to induce experimental autoimmune encephalomyelitis [EAE]. Treatment with 1,25-(OH)2-24OXO-16eneD3 was given at 0.05, 0.15 and 0.3 microgram I.P., on alternate days, starting 3 days prior and for up to 5 days post immunization and compared to a similar treatment with 0.1 microgram 1,25-(OH)2D3 or 1,25-(OH)2-16eneD3. Suppression of EAE was observed with 0.15 microgram 1,25-(OH)2-24OXO-16eneD3, comparable to the suppression induced with the parent compound and more potent than 1,25-(OH)2D3. However, no hypercalcemia was seen in mice treated with 0.15 microgram of OXO-metabolite (9.7 +/- 0.6 vs 9.3 +/- 1.1 mg/dl, treated vs controls), in contrast to 1,25-(OH)2D3 and 1,25-(OH)2-16eneD3 (11.2 +/- 1.0 and 11.0 +/- 0.9 mg/dl respectively; p < 0.001). In summary, our results suggest that 1,25-(OH)2-24OXO-16eneD3, a stable intermediary metabolite of the vitamin D analog, 1,25-(OH)2-16eneD3 exerts immunosuppressive activity equal to its parent without causing hypercalcemia in vivo.

Spontaneous anti-tubular-basement-membrane antibody production by lymphocytes isolated from a rejected allograft.

The immunological events mediated by, and antigen specificity of, allograft-bound lymphocytes (ABLs) are poorly understood. To further define the role of antibody-mediated rejection, a rejected allograft from a patient with primary anti-TBM disease was sterilely minced and pressed through a microscreen. The ABLs were isolated by density gradient centrifugation. Using this technique, 8.5 X 10(6) ABLs were isolated. Then 1 X 10(6) washed ABLs/ml were suspended in RPMI 1640 with 20% fetal calf serum and cultured in microtiter plates with media only, or with pokeweed mitogen (PWM) (100 micrograms/culture). The cells were incubated for 7 days and supernatants were collected and assayed for total IgG and IgM by a solid-phase enzyme immunoassay (EIA) and reactivity with normal human kidney targets by indirect immunofluorescence (IF) and immunoperoxidase (IP) techniques. Total IgG production was 500 ng/ml for both spontaneous and PWM stimulated cells. No IgM production was detected. IF and IP studies demonstrated IgG-anti-TBM antibodies in the spontaneous supernatants only. IgG antibodies reactive with peritubular capillaries (anti-PTC) were also noted. IgG-anti-TBM anti-bodies and antibodies reactive with arterioles were subsequently demonstrated by direct immunofluorescence techniques in the rejected allograft. Analysis of serum samples obtained at the time of allograft rejection showed no IF or IP reactivity with the kidney targets. Subsequent analysis of anti-TBM production by the patient's peripheral blood mononuclear cells (PBMs) showed IgM-anti-TBM only. These studies suggest that the IgG-anti-TBM and IgG-anti-PTC antibodies reactive with the allograft resulted from in situ antibody production by ABLs; the role of anti-TBM antibodies in mediating the AR is unclear, but their presence suggests recurrence of the original disease in the allograft. Anti-PTC antibodies could be important in mediation of the vascular AR.

Hemodynamic and coronary effects of intravenous labetalol in coronary artery disease.

Labetalol, an alpha and beta receptor blocking agent, was evaluated in 11 patients with documented coronary artery disease and stable angina. The mean dose of labetalol was 1.5 (range 1 to 2) mg/kg. Cardiovascular effects began within 1 minute after injection and were maximal within 10 minutes. Mean arterial pressure decreased from 105 +/- 13 to 81 +/- 10 mm Hg (p less than 0.0001), heart rate from 70 +/- 10 to 66 +/- 7 beats/min (p less than 0.05) and the pressure-rate product from 10,322 +/- 2,344 to 7,171 +/- 1,650 (p less than 0.001). Cardiac output and pulmonary wedge pressure did not change significantly. Mean pulmonary arterial pressure decreased from 20 +/- 3 to 16 +/- 2 mm Hg (p less than 0.005). Systemic and pulmonary resistances also decreased significantly (p less than 0.0001 and p less than 0.01, respectively). Coronary sinus flow increased from 107 +/- 26 to 118 +/- 25 ml/min (p less than 0.01) and coronary vascular resistance decreased from 1.0 +/- 0.2 to 0.77 +/- 0.1 mm Hg/ml per min (p less than 0.001). Labetalol may be a useful adjunct in the treatment of angina not only because it diminishes myocardial oxygen requirements but also because it improves coronary hemodynamics. Thus, labetalol appears to have some advantage compared with the usual beta blocking agents with their potentially detrimental effects on coronary hemodynamics.

1,25-Dihydroxyvitamin D3 attenuates the expression of experimental murine lupus of MRL/l mice.

The murine strain MRL/l spontaneously develops a systemic lupus erythematosus (SLE)-like syndrome. An increased number of T cells and polyclonal T helper cell activity has been described in these mice suggesting a potential role for 1,25-dihydroxyvitamin-D3 [1,25-D3], an antiproliferative hormone selecting the T-helper lymphocyte subset. One month old MRL/l mice were submitted or not to 1,25-D3 0.1 microgram for 4 weeks, then 0.15 microgram given i.p. every other day for 18 weeks while maintained on a low calcium chow. Dermatologic lesions, i.e. alopecia, necrosis of the ear and scab formation, were completely inhibited by 1,25-D3 therapy. By 20 weeks, all mice had developed proteinuria. However, the degree of proteinuria was somewhat reduced in treated mice as assessed by urine protein/creatine ratios (less than 4 vs greater than 4 in treated vs untreated mice respectively). Moreover, a trend for a reduction in serum titers for anti-ssDNA antibodies was observed at 18 weeks. The active vitamin D metabolite had no effect on the development of the generalized lymphoid hyperplasia. Hypercalcemia developed when 1,25-D3 was increased to 0.15 microgram (2.62 +/- 0.12 vs 1.97 +/- 0.07 mmol/l, treated vs untreated mice respectively). These results suggest a beneficial role of 1,25-D3 in the prevention or attenuation of some manifestations of murine SLE, a model sharing many immunologic features with human SLE.

False aneurysm of the ascending aorta presenting as an acute myocardial infarction: a late complication of aortocoronary bypass.

After coronary bypass surgery, a 40-year-old man developed disruption of the site of cannulation of the ascending aorta. The false aneurysm which ensued presented as recurrent episodes of spontaneous angina and myocardial infarction ending in coronary death 48 days after surgery. the aortic origin of all three permeable coronary bypasses were strangulated by the hematoma. Awareness of this unusual potential hazard is essential, since an early suspicion would lead to proper diagnostic interventions and reoperation.

Combined hemodynamic effects of dobutamine and IV nitroglycerin in congestive heart failure.

The combined and separate hemodynamic effects of dobutamine and IV nitroglycerin were compared in 12 patients with chronic congestive heart failure (nine with ischemic heart disease, two with idiopathic congestive cardiomyopathy, and one with valvular heart disease). Dobutamine (7.1 micrograms/kg/min) increased cardiac index from 2.4 +/- 0.4 to 3.4 +/- 0.9 L/min/m2 (P < 0.001) and decreased pulmonary wedge pressure from 28 +/- 5 to 16 +/- 4 mm Hg (P < 0.001) while nitroglycerin (127 micrograms/min) alone increased cardia index to 2.8 L/min/m2 (P < 0.001) and decreased wedge pressure to 14.3 mm Hg (P < 0.001). With both drugs, cardiac index increased to 3.5 +/- 0.6 L/min/m2; (NS compared to dobutamine alone) wedge pressure decreased to 11 +/- 4L/min/m2 (P < 0.05 compared to dobutamine alone). Those beneficial hemodynamic effects occurred without a significant change in the double product of heart rate and blood pressure, and were associated with an improvement in the transmyocardial gradient. Thus, the greatly enhanced ventricular performance with dobutamine + nitroglycerin was associated with a better relationship between myocardial oxygen demand and supply.

Immunomodulatory actions of 1,25-dihydroxyvitamin D3.

The sterol, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), has immunosuppressive activity. The hormone inhibits the production of lymphokines (IL-2, IFN-gamma) and monocyte-derived cytokine (IL-12) leading to inhibition of helper T cell subset type 1 (Th1). When given in vivo, the hormone prevents the development of spontaneous and induced models of autoimmunity. Analogs of 1,25(OH)2D3, with reduced hypercalcemic effects, display an enhanced activity in autoimmunity compared to the sterol and prolong graft survival in experimental transplantation. This paper reviews our understanding of the cellular actions of the hormone and the therapeutic application of 1,25(OH)2D3 and analogs in autoimmunity and transplantation.