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Biomedical subjects

G L Freeman

Publications and source records attributed to G L Freeman.

At least 19 recordsLinked to original sources
PubMed1999

Neonatal idiotypic exposure alters subsequent cytokine, pathology, and survival patterns in experimental Schistosoma mansoni infections.

Exposure to maternal idiotypes (Ids) or antigens might predispose a child to develop an immunoregulated, asymptomatic clinical presentation of schistosomiasis. We have used an experimental murine system to address the role of Ids in this immunoregulation. Sera from mice with 8-wk Schistosoma mansoni infection, chronic (20-wk infection) moderate splenomegaly syndrome (MSS), or chronic hypersplenomegaly syndrome (HSS) were passed over an S. mansoni soluble egg antigen (SEA) immunoaffinity column to prepare Ids (8WkId, MSS Id, HSS Id). Newborn mice were injected with 8WkId, MSS Id, HSS Id, or normal mouse immunoglobulin (NoMoIgG) and infected with S. mansoni 8 wk later. Mice exposed to 8WkId or MSS Id as newborns had prolonged survival and decreased morbidity compared with mice that received HSS Id or NoMoIgG. When stimulated with SEA, 8WkId, or MSS Id, spleen cells from mice neonatally injected with 8WkId or MSS Id produced more interferon gamma than spleen cells from mice neonatally injected with HSS Id or NoMoIgG. Furthermore, neonatal exposure to 8WkId or MSS Id, but not NoMoIgG or HSS Id, led to significantly smaller granuloma size and lower hepatic fibrosis levels in infected mice. Together, these results indicate that perinatal exposure to appropriate anti-SEA Ids induces long-term effects on survival, pathology, and immune response patterns in mice subsequently infected with S. mansoni.

Animals↗
PubMed1999

Regulation of CCAAT/Enhancer binding protein, interleukin-6, interleukin-6 receptor, and gp130 expression during myocardial ischemia/reperfusion.

BACKGROUND: Interleukin (IL)-6 is elevated in myocardium after ischemia and reperfusion. The IL-6 promoter/enhancer region contains response elements for nuclear factor-kappaB, AP-1, and CCAAT/enhancer binding protein (C/EBP). Expression and regulation of C/EBP in rat myocardium after ischemia and reperfusion has not been defined, nor has the behavior of the specific IL-6 receptor (IL-6R) or the signal transducer gp130. METHODS AND RESULTS: C/EBP DNA binding activity was not detected in shams or in previously ischemic tissue at 15 minutes of reperfusion; it was detected at 30 minutes of reperfusion, increased at 1 hour of reperfusion, and declined by 6 hours of reperfusion. A supershift was observed with anti-C/EBP-beta but not with anti-alpha or anti-delta antibodies. mRNA and protein levels of IL-6 and gp130 were detected at low levels in controls, increased at 1 hour of reperfusion, and remained high until 6 hours of reperfusion. IL-6R mRNA and protein were not detected in controls, but its mRNA was induced at 1 hour of reperfusion and its protein at 2 hours of reperfusion. Although effects of reperfusion were rapid, in ischemic tissue not reperfused, low levels of C/EBP were detected at 4 hours, and at 24 hours the levels were slightly elevated. Significant upregulation in IL-6, IL-6R, and gp130 occurred only at 24 hours of sustained ischemia. CONCLUSIONS: Reperfusion after a brief period of ischemia caused induction of myocardial C/EBP (beta-subunit). The rapid and sustained production of IL-6 with concomitant expression of IL-6 receptor and gp130 suggest that these factors may participate in a local inflammatory cascade after myocardial ischemia and reperfusion.

Animals↗
PubMed1998

Inhibition of nuclear factor kappa B attenuates proinflammatory cytokine and inducible nitric-oxide synthase expression in postischemic myocardium.

We have previously reported that induction of nuclear factor-kappa B (NF-kappa B) occurs in a biphasic manner in postischemic myocardium. Because interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-alpha), and inducible nitric-oxide synthase (iNOS) contain kappa B-response elements, and since transforming growth factor-beta 1 (TGF-beta 1) down-modulates both cytokine and iNOS expression, we studied their temporal expression during myocardial ischemia/reperfusion (I/R). Northern and Western analyses showed low levels of IL-6 and no signal for IL-1 beta, TNF-alpha and iNOS under basal conditions. Their expression rose significantly over sham-operated controls by 1 h reperfusion, and persisted high for various periods. Under basal conditions, low levels of TGF-beta 1 were detected, which rose significantly at 3 h reperfusion, and remained high until 24 h reperfusion. Administration of diethyldithiocarbamate (DDC) inhibited induction of NF-kappa B and concomitantly the expression of IL-1 beta, IL-6, TNF-alpha as well as iNOS. However, expression of TGF-beta was not altered. Our results indicate that ischemia/reperfusion induces NF-kappa B, and upregulates kappa B-response genes. Administration of DDC inhibits NF-kappa B levels, and attenuates expression of inflammatory cytokines and iNOS.

Animals↗
PubMed1998

Expression of apoptosis-related proteins in experimental coxsackievirus myocarditis.

OBJECTIVE: The extent to which apoptosis contributes to myocyte cell loss during acute carditic viral infection is unknown. To assess whether apoptosis occurs in acute viral myocarditis, and how it is modulated, we studied mice inoculated with coxsackievirus B3 (CVB3). METHODS: Five CD1 and C3H.HeJ (C3H) mice/group were sacrificed as saline vehicle-injected controls, and at 1, 2, and 3 weeks post-inoculation (p.i.) with 5 x 10(6) pfu CVB3. Histopathological status and terminal transferase-mediated dUTP-biotin nick end-labeling (TUNEL) assays quantified inflammation, necrosis and apoptosis in myocardium. Apoptosis-related protein immunoreactivity defined presence and location of Bax, Fas, Fas Ligand (FasL), Bcl-2, interleukin-1 beta converting enzyme (ICE), inducible nitric oxide synthase (iNOS) and the proto-oncogene p53. RESULTS: Both strains exhibited significant histopathology at all time points. Saline-injected control animals showed no signs of inflammation and no significant difference in apoptosis-related protein immunoreactivity was observed between strains. Myocardial TUNEL-positive cells were exceedingly rare though apoptosis was present in thymic medulla and spleen follicles. Pro-apoptotic proteins Bax, Fas, and FasL were present in all groups though no clear correlation with histopathology was apparent. By contrast, the anti-apoptotic protein Bcl-2 showed mild immunoreactivity in controls, which increased following infection and correlated well with histopathological scores in both strains. Myocardial iNOS immunoreactivity displayed a similar though weaker staining pattern to Bcl-2 over the 3 week study period in both strains. Neither ICE nor p53 immunoreactivity could be demonstrated in myocardium. CONCLUSION: Thus, despite marked inflammatory activity, myocyte apoptosis is rare in acute CVB3 myocarditis in CD1 and C3H.HeJ mice.

Animals↗
PubMed1998

Overexpression of cardiotrophin-1 and gp130 during experimental acute Chagasic cardiomyopathy.

Cardiotrophin-1 (CT-1), a cytokine with structural similarities to interleukin-6, has been shown to signal through gp130-dependent pathways. In vitro, CT-1 promotes the survival and induces hypertrophy of neonatal cardiomyocytes. Since acute Chagas' disease involves an inflammatory response followed by chamber dilation, with subsequent compensatory hypertrophy, we hypothesized CT-1 and gp130 may participate in this disease process. Thus, we investigated expression and localization of these moieties during acute Chagasic cardiomyopathy. Lewis rats (n = 6/group) were either inoculated with cell culture-derived T. cruzi trypomastigotes or saline, and sacrificed 15 days later. Hearts were collected for histology, immunohistochemistry (IHC), mRNA, and protein analyses. Histology showed dense myocardial infection with amastigotes and diffuse mononuclear cell infiltrate. Northern blot analysis showed low level expression of CT-1 mRNA in controls, which was markedly elevated in infected animals (2.5-fold; P < 0.001). Similarly, Western blotting showed a twofold elevation of CT-1 protein in infected animals (P < 0.025). Likewise, levels of both gp130 mRNA and protein were low in controls, but were approximately threefold higher in infected animals. IHC showed weak and diffuse staining for CT-1 in control myocardium, while intense staining especially localized to the cytoplasmic region of cardiomyocytes, was found in infected animals. Although gp130 immunoreactivity was observed in both normal and infected myocardium, more intense staining was found in infected animals. Unlike CT-1, gp130 staining was granular, and was present in both the cytoplasm as well as in the perinuclear region. These data suggest that there is substantial overexpression of both CT-1 and gp130 in the heart during acute Chagasic carditis. Their overexpression may provide a mechanism for myocyte protection, and for development of compensatory cardiac hypertrophy following myocardial damage in this form of cardiomyopathy.

Acute Disease↗
PubMed1998

Cloning of Syrian hamster (Mesocricetus auratus) cytokine cDNAs and analysis of cytokine mRNA expression in experimental visceral leishmaniasis.

The Syrian golden hamster (Mesocricetus auratus) is uniquely susceptible to a variety of intracellular pathogens and is an excellent model for a number of human infectious diseases. The molecular basis for this high level of susceptibility is unknown, and immunological studies related to this model have been limited by the lack of available reagents. In this report we describe the cloning and sequence analysis of portions of the Syrian hamster interleukin 2 (IL-2), IL-4, gamma interferon (IFN-gamma), tumor necrosis factor alpha, IL-10, IL-12p40, and transforming growth factor beta cDNAs. In addition, we examined the cytokine response to infection with the intracellular protozoan Leishmania donovani in this animal model. Sequence analysis of the hamster cytokines revealed 69 to 93% homology with the corresponding mouse, rat, and human nucleotide sequences and 48 to 100% homology with the deduced amino acid sequences. The hamster IFN-gamma, compared with the mouse and rat homologs, had an additional 17 amino acids at the C terminus that could decrease the biological activity of this molecule and thus contribute to the extreme susceptibility of this animal to intracellular pathogens. The splenic expression of these genes in response to infection with L. donovani, the cause of visceral leishmaniasis (VL), was determined by Northern blotting. VL in the hamster is a progressive, lethal disease which very closely mimics active human disease. In this model there was pronounced expression of the Th1 cytokine mRNAs, with transcripts being detected as early as 1 week postinfection. Basal expression of IL-4 in uninfected hamsters was prominent but did not increase in response to infection with L. donovani. IL-12 transcript expression was detected at low levels in infected animals and paralleled the expression of IFN-gamma. Expression of IL-10, a potent macrophage deactivator, increased throughout the course of infection and could contribute to the progressive nature of this infection. These initial studies are the first to examine the molecular immunopathogenesis of a hamster model of VL infection and indicate that progressive disease in this model of VL is not associated with early polarization of the splenic cellular immune response toward a Th2 phenotype and away from a Th1 phenotype.

Amino Acid Sequence↗
PubMed1998

Contractile depression and expression of proinflammatory cytokines and iNOS in viral myocarditis.

We assessed two strains of mice [CD-1 and C3H.HeJ (C3H)] with different responses to coxsackievirus B3 (CVB3) infection at 7, 14, and 21 days after inoculation with 10(5) pfu of CVB3. CD-1 mice developed inflammatory lesions at 7 days that nearly recovered by 21 days; C3H mice demonstrated persistence of infiltrates. Although there were differences in the baseline fractional shortening, it was further reduced at 7 and 14 days in both strains. It recovered in CD-1 mice but remained depressed at 21 days in C3H mice. Interleukin-6 and tumor necrosis factor-alpha transcripts were increased in both strains at 7 days. Levels dropped to near control in CD-1 mice at 21 days but remained elevated in C3H mice. Interleukin-1 beta was minimally elevated in CD-1 mice but increased progressively in C3H mice. mRNA for the inducible form of NO synthase (iNOS) was increased at 7 days in the CD-1 mice, returning to baseline by 14 days; it rose progressively in C3H mice, with a fivefold increase at 21 days. We conclude that mice infected with CVB3 show increased expression of proinflammatory cytokines as well as iNOS associated with reduced contractile performance. In more susceptible mice, contractile depression and cytokine and iNOS expression are more pronounced.

Animals↗
PubMed1998

Temporal expression of pro-inflammatory cytokines and inducible nitric oxide synthase in experimental acute Chagasic cardiomyopathy.

To characterize the kinetics of myocardial cytokine and inducible nitric oxide synthase (iNOS) expression in acute Chagasic cardiomyopathy, we studied a rat model of acute Trypanosoma cruzi infection. Rats were euthanized 36 hours and 5, 10, and 15 days after infection, and hearts were collected for histology, mRNA, and protein analyses. Histological analysis of myocardium showed a progressive increase in the number of amastigotes and mononuclear inflammatory cells. Organisms were first detected 5 days after intraperitoneal inoculation as isolated nests and became numerous by day 15. Northern blot analysis of total RNA revealed no signal for interleukin (IL)-1beta or tumor necrosis factor (TNF)-alpha and a weak signal for IL-6 in control hearts. High levels of expression for the three genes were detected in the infected animals at 36 hours after infection. Although IL-1beta and IL-6 levels increased steadily up to 10 days, TNF-alpha levels were the highest at 5 days, remained high at 10 days, and declined thereafter. Western blot analysis showed similar results to that of mRNA expression. No signal was detected for iNOS in the controls, but both its mRNA and protein were found in the infected animals, with levels being highest at 15 days after infection. Immunohistochemistry revealed no iNOS immunoreactivity in uninfected animals, but intense iNOS staining was detected in blood vessels of infected animals, which decreased progressively with period of infection. Positive staining for iNOS in cardiomyocytes was first detected at 36 hours after infection (at a time when there was no histological inflammatory reaction), which steadily increased, being the highest at 15 days after infection. These results indicate that, in addition to mechanical damage by T. cruzi, substantial pro-inflammatory cytokine production within the myocardium is likely to participate in the pathophysiology of acute Chagasic cardiomyopathy.

Animals↗
PubMed1997

Immunoregulatory idiotypes stimulate T helper 1 cytokine responses in experimental Schistosoma mansoni infections.

Inbred male CBA/J mice with chronic Schistosoma mansoni infections develop two distinct syndromes. Hypersplenomegaly syndrome (HSS) demonstrates pathologic similarities to the hepatosplenic form of chronic human schistosomiasis, and moderate splenomegaly syndrome (MSS) resembles the asymptomatic intestinal form. Immunoaffinity-purified Abs against S. mansoni soluble egg Ags (SEA) from infected patients' sera differ idiotypically according to the donor's clinical form of the disease. We now show that immunoaffinity-purified anti-SEA Abs (Id) from MSS or HSS mice parallel idiotypic preparations of the analogous human clinical form by their differential ability to stimulate the proliferation of anti-Id T cells. MSS Id preparations stimulate spleen cells from either MSS or HSS animals. In contrast, HSS Id does not stimulate spleen cells from either group. In an anti-SEA ELISA, MSS and HSS Id preparations contained comparable levels of IgM and IgG1. However, the MSS Id preparation had higher levels of SEA-specific IgG2a and IgG2b than did HSS Id. The Ig isotypes of these Id preparations suggested differences in cytokine expression patterns. Studies of the cytokine profiles of the spleen cells responding to anti-SEA Id preparations demonstrated that while Id preparations from acutely infected mice stimulate IL-4 and IL-10 production, Id preparations from chronic MSS mice stimulate IFN-gamma production. HSS Id did not stimulate the production of any of these cytokines. The possibility that distinct immunoregulatory environments may contribute to the development of MSS and HSS correlates with earlier hypotheses that hepatosplenic pathology results at least in part from a lack of development or expression of appropriate regulatory Ids.

Adjuvants, Immunologic↗
PubMed1997

Induction of nuclear factor kappaB and activation protein 1 in postischemic myocardium.

Ischemia/reperfusion induces nuclear factor kappaB (NF-kappaB) and AP-1 in rat hearts after 15 min of ischemia followed by reperfusion (R) for various periods of time (15 and 30 min, 1, 2, 3, 6, 12, and 24 h). Low levels of NF-kappaB and no signal for AP-1 were detected in shams and in non-ischemic tissue distant from the ischemic zone. In postischemic tissue, NF-kappaB levels increased biphasically with peak levels at 15 min and again at 3 h R. Immunoblotting showed minimal NF-kappaB p50 subunit at all times, with changes in p65 similar to EMSA results. Northern blots showed low p50 and increased p65 expression levels at both 2 and 3 h R. By contrast, AP-1 increased monophasically, with peak levels at 15 min R, which dropped steadily thereafter. These results indicate that NF-kappaB and AP-1 are differentially regulated during reperfusion, which may be a control mechanism for gene expression in reperfused myocardium.

Animals↗
PubMed1997

Schistosoma mansoni: susceptibility differences between male and female mice can be mediated by testosterone during early infection.

In murine Schistosoma mansoni infections, fewer adult worms develop in male than in female mice infected with the same number of cercariae. To evaluate a potential role for testosterone in this phenomenon, testosterone levels were manipulated in groups of CBA/J mice that were then infected and monitored for survival rates, worm burdens, organomegaly, and egg production. By 16 weeks of infection, more than 80% of mice in groups with low levels of testosterone (untreated females, castrated males, or carrier-treated castrates) were dead, while less than 40% of those in groups with high levels of testosterone (sham-castrated males, testosterone-treated castrates, or testosterone-treated female mice) succumbed to infection. The mean number of worms recovered from mice in the low testosterone level groups was comparable among groups, and significantly greater than that from those in high-testosterone-level groups. The degree of organomegaly observed correlated strongly with worm burden, but the number of hepatic eggs per female worm did not differ significantly between groups. When male mice were castrated or sham-castrated 5 weeks after S. mansoni infection, no significant differences in host survival occurred. Furthermore, female mice treated with testosterone demonstrated reduced worm burdens if the testosterone was given 10 days prior to infection but not if the testosterone was given 10 days or 5 weeks after infection. Thus, the host sex bias observed in parallel-infected male and female mice appears to be related to the presence of male gonadal tissue or testosterone early in infection, during the development of immature schistosomules.

Animals↗
PubMed1997

Induction of proinflammatory cytokine and antioxidant enzyme gene expression following brief myocardial ischaemia.

The purpose of this study was to determine if proinflammatory cytokines are up-regulated during reperfusion following sublethal ischaemia, and whether concurrent up-regulation of antioxidant enzymes occurs. Open-chest rats were subjected to 15 min of ischaemia followed by 1 or 3 h reperfusion (R). Myocardium from the ischaemic zone showed a significantly higher (P<0.01) generation of thiobarbituric acid-reactive substances at 1 h and 3 h R. Northern blots showed a weak signal in controls for IL-6 mRNA (0.13 +/- 0.01); this was elevated to 0.68 +/- 0.12 at 1 h and 0.69 +/- 0.10 at 3 h R. Neither IL-1beta nor tumour necrosis factor-alpha (TNF-alpha) were detectable in controls. IL-1beta rose to 0.78 +/- 0.07 at 1 h and 0.51 +/- 0.08 at 3 h R, and TNF-alpha rose to 0.69 +/- 0.10 at 1 h and 0.38 +/- 0.15 at 3 h R. Western blotting showed no signals in the control, but readily detectable signals at 1 h R; these remained high (IL-6) or decreased (IL-1beta and TNF-alpha at 3h R. mRNA analysis for antioxidant enzymes revealed a weak signal in controls for catalase (CAT; 0.16 +/- 0.08), glutathione peroxidase (GSH-Px; 0.15 +/- 0.06) and superoxide dismutase (SOD; 0.21 +/- 0.05). After 1 h R, levels increased significantly for CAT (0.46 +/- 0.10; P < 0.025) and GSH-Px (0.51 +/- 0.13; P < 0.01), but remained similar to controls for SOD (0.26 +/- 0.15). At 3 h R the mRNA levels were significantly elevated for the three enzymes (CAT 0.48 +/- 0.13; GSH-Px 0.47 +/- 0.10; SOD 0.54 +/- 0.08). We conclude that mRNA for proinflammatory cytokines is expressed early in reperfusion, and that the proteins are present in heart tissue. Also, reperfusion is associated with rapid expression of genes for antioxidant enzymes, which may enhance reactive oxygen intermediate (ROI) scavenging.

Animals↗
PubMed1997

IL-10 deficit correlates with chronic, hypersplenomegaly syndrome in male CBA/J mice infected with Schistosoma mansoni.

Twenty weeks after moderate level infections with Schistosoma mansoni, approximately 20% of male CBA/J mice develop hypersplenomegaly syndrome (HSS) while the rest present with moderate splenomegaly syndrome (MSS). HSS and MSS mice differ pathophysiologically (degree of splenomegaly, anaemia, ascites, periportal fibrosis, portal hypertension) and immunologically with regard to antibodies (idiotypic expression, isotype levels) to schistosome soluble egg antigens (SEA), and spleen cell phenotypic profiles. This study compared in vitro proliferative responses and IL-2, IFN gamma, IL-4, and IL-10 production by spleen cells from uninfected mice and mice with acute (8 wk), MSS or HSS schistosomiasis mansoni, upon exposure to anti-CD3 epsilon or SEA, Spleen cells from uninfected mice produce Il-2 to anti-CD3 epsilon but exposure of cells from all three groups of infected mice to anti-CD3 epsilon or SEA led to only very low levels of supernatant IL-2. Anti-CD3 epsilon- or SEA-stimulated production of IFN gamma or Il-4, and anti-CD3 epsilon-stimulated production of IL-10, displayed similar patterns: highest cytokine production by cells from mice with acute infections and lower levels of production that did not differ between the two chronic groups. In contrast, while SEA-stimulated IL-10 production was again highest with cells from mice with acute infections, spleen cells from mice with MSS produced significantly more IL-10 than did those from mice with HSS. This association of low levels of antigen-induced IL-10 with severe pathology is consistent with the theory that IL-10 plays a role in the immunoregulation that occurs in chronic schistosomiasis.

Animals↗
PubMed1997

Flow cytometric study of blood leucocytes in clinical forms of human schistosomiasis.

The aim of this study was to examine three distinct groups of schistosomiasis patients and to determine whether cell phenotype profiles could be correlated with the different clinical forms of the disease. The data obtained indicate that Schistosoma mansoni infected patients have a lower percentage of CD3+ T cells than do non-infected individuals. Interestingly, infected patients presented more than twice the mean percentage of circulating activated T cells (CD3+HLA-DR+) when compared to the control group. Examination of T lymphocyte subpopulations showed that patients with the severe hepatosplenic form (HS) of the disease had lower levels of both CD8High+ and CD8Low+ cells when compared to the other groups of patients. All infected individuals had a higher percentage of circulating B cells, with an increase in the CD5+ B cell population that was more evident in the HS group. The data presented here are evidence to support a relationship between the hepatosplenic form of the disease, a decrease on the CD8+ cell population and an elevation on CD5+ B cells.

Adolescent↗
PubMed1997

Ryanodine and left ventricular function in intact dogs: dissociation of force-based and velocity-based indexes.

After anesthesia and autonomic blockade, nine dogs chronically instrumented with left ventricular (LV) micromanometers and piezoelectric dimension crystals were studied before and after the intravenous administration of 4 micrograms/kg ryanodine, a specific inhibitor of the sarcoplasmic reticulum Ca2+ release channel. Ryanodine prolonged LV contraction and relaxation (P < 0.001) without changing heart rate, end-diastolic volume (EDV), or end-systolic pressure. Velocity-dependent mechanical parameters were significantly depressed, including the maximal rate of LV pressure rise (dP/dtmax; P < 0.002), the mean velocity of circumferential fiber shortening (P < 0.002), the slope of the dP/dtmax-EDV relation (P < 0.05), and the time constant of LV relaxation (P < 0.01). In contrast, the slopes of the end-systolic pressure-volume (PES-VES) and stroke work (SW)-EDV relations, both force-based parameters, were increased (P < 0.05) or maintained, respectively. Ryanodine reduced overall LV contractile performance, evidenced by significant rightward shifts of the PES-VES, dP/dtmax-EDV, and SW-EDV relations and reduced SW at constant preload (P < 0.02). Thus, in the closed-chest dog, low-dose ryanodine resulted in 1) generalized slowing of LV mechanical events without changes in heart rate or load, 2) dissociation of velocity-based and force-based measures of LV function, with depression of the former but enhancement or maintenance of the latter, and 3) reduced overall LV inotropic performance. These effects are consistent with ryanodine-induced alterations of the Ca2+ transient and altered sarcoplasmic reticulum Ca2+ availability.

Animals↗
PubMed1997

Effect of long-term food restriction on cardiac mechanics.

Food restriction (FR) is the only known intervention capable of increasing mammalian life span. It not only increases longevity, but reduces the incidence of a broad spectrum of age-related pathologies, including cardiomyopathy, and retards the physiological decline associated with aging. Previous work from this laboratory has shown that long-term FR affects the contractile machinery of the heart, shifting the cardiac myosin profile from the fast, V1 isoform to the slow, V3 isoform. The aim of the present study was to determine whether FR also induces changes in cardiac mechanics. Isolated, isovolumically beating hearts were examined from four groups of rats: 1) ad libitum-fed rats killed at 10-13 mo of age, 2) FR rats offered only 60% of the calories consumed by ad libitum-fed rats and killed at the same age, 3) young ad libitum-fed rats having the same heart weights as the FR rats, and 4) ad libitum-fed rats subjected to short-term FR, i.e., for the last 3 wk of life, and also killed at 10-13 mo of age. Both short- and long-term FR profoundly and to approximately the same extent affected cardiac mechanics. Hearts from FR rats developed much higher pressures than hearts from the ad libitum-fed rats under conditions of low-calcium perfusate. This difference disappeared, however, when contractility was enhanced by either calcium or isoproterenol. FR prolonged both contraction and relaxation times. Long-term ad libitum-fed rats (adult, 10-13 mo of age) had a lower isoproterenol sensitivity than the young ad libitum-fed rats (10 wk of age). Both short- and long-term FR restored the sensitivity to isoproterenol. In summary, FR profoundly affects many aspects of cardiac mechanics, enhancing some age-related changes (prolongation of the contraction and relaxation times), attenuating another (increasing the isoproterenol sensitivity), and, finally, inducing some unique changes unrelated to age (increased pressure development under low-calcium perfusate).

Aging↗
PubMed1996

Immunopathogenesis and immunoregulation in schistosomiasis. Distinct chronic pathologic syndromes in CBA/J mice.

Inbred CBA/J mice with chronic (20-week) Schistosoma mansoni infections demonstrate two distinct syndromes. Hypersplenomegaly syndrome (HSS), characterized by a massive spleen, liver fibrosis, ascites, and anemia, resembles hepatosplenic human schistosomiasis, complete with portal hypertension and shunting. Moderate splenomegaly (MSS) syndrome, with less severe pathology, parallels most chronic human infections. Phenotypic analyses of spleen cells for CD44, CD62L, CD45RB, Ia, and CD25 indicate that HSS mice have more activated and memory CD4+ T cells than do MSS mice. HSS animals also have more B cells that highly express B7-2. Anti-CD3 stimulated spleen cells from 8-week or chronically infected mice produce IL-4 and IL-10 in a manner that appears not to involve the CD28/B7-2 costimulation pathway. By contrast IFN-gamma production is augmented in the presence of anti-CD28 and decreased in the presence of anti-B7-2. Infected mice make very little IL-2 to anti-CD3, even with added anti-CD28. As cytokines affect resultant B-cell responses and HSS and MSS mice display distinctive isotypes, differential regulatory or anergy hypotheses may best explain MSS/HSS differences.

Animals↗