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Biomedical subjects

C W Roberts

Publications and source records attributed to C W Roberts.

At least 37 records · Page 2Linked to original sources
PubMed1998

The role of IL-4 in adult acquired and congenital toxoplasmosis.

The course of Toxoplasma gondii infection was studied in IL-4-deficient mice from three genetic backgrounds and their wild-type counterparts following peroral inoculation of tissue cysts. Survival rates were significantly reduced in disease-susceptible C57 BL/6 mice and F1 (C57BL/6 x 129Sv) mice deficient in IL-4 compared with wild-type controls. In contrast, this difference was not observed in T. gondii-resistant BALB/c mice. However, brain tissue cyst burdens in IL-4-deficient mice were either equivalent to (C57BL/6 and BALB/c mice) or significantly less (B6/129 mice) than similarly infected wild-type mice. Thus strain-specific differences in the course of T. gondii were demonstrated in the absence of IL-4. The course of T. gondii infection was also compared between B6/129 IL-4-deficient mice and their wild-type counterparts following peroral challenge with 20 tissue cysts on day 12 of pregnancy. Age-matched non-pregnant IL-4-/- and IL-4+/+ mice were also infected to assess the role of IL-4 on T. gondii infection during pregnancy. Disease phenotypes, as measured by mortality, were reversed if infections were initiated during pregnancy compared with non-pregnant infection. Thus significant mortality occurred immediately post partum in IL-4+/+ mothers, while all IL-4-/- mothers survived. Cyst burdens 28 days p.i. were significantly lower in IL-4-/- mothers than IL-4+/+ mothers and both IL-4-/- and IL-4+/+ non-pregnant mice. Congenital disease transmission as measured by foetal death or vertical disease transmission was independent of the presence or absence of IL-4. These studies demonstrate a role for IL-4 in pregnancy-induced immunosuppression and the associated increased susceptibility to T. gondii infection.

Animals↗
PubMed1998

A protective role for IL-6 during early infection with Toxoplasma gondii.

IL-6 deficient mice were found to be significantly more susceptible to peroral infection with Toxoplasma gondii than their wild-type counterparts as measured by survival, brain cyst burdens and brain pathology at 28 days post infection. The physical manifestations of disease, such as weight loss, were not observed in IL-6 deficient animals until at least seven days later than such changes occurred in wildtype mice. During this early stage of infection IL-6+/+ but not IL-6-/- mice mounted a peripheral blood neutrophilia. Furthermore, between 6-8 days post-infection there was a significant increase in plasma IFN-gamma levels in wild-type but not IL-6 deficient mice. Not until days 18-23 post-infection, concurrent with the majority of deaths in IL-6-/- mice, were plasma IFN-gamma levels substantially and significantly raised in IL-6-/- mice. At this time not only were these plasma IFN-gamma levels 20-fold higher than background but eight-fold greater than peak (6-8 days post-infection) IFN-gamma levels in IL-6+/+ mice. IFN-gamma dependent parasite specific IgG2a levels were also significantly higher in IL-6-/- mice over this period and thereafter. Overall the evidence suggests that in the absence of IL-6 mice are unable to initiate a rapid proinflammatory response against T. gondii, which allows increased parasite growth. Increased mortality in IL-6-/- mice may be directly due to this increased parasite burden and the excessive inflammatory response this induces three weeks post-infection.

Animals↗
PubMed1997

Mechanisms of innate resistance to Toxoplasma gondii infection.

The interaction of protozoan parasites with innate host defences is critical in determining the character of the subsequent infection. The initial steps in the encounter of Toxoplasma gondii with the vertebrate immune system provide a striking example of this important aspect of the host-parasite relationship. In immuno-competent individuals this intracellular protozoan produces an asymptomatic chronic infection as part of its strategy for transmission. Nevertheless, T. gondii is inherently a highly virulent pathogen. The rapid induction by the parasite of a potent cell-mediated immune response that both limits its growth and drives conversion to a dormant cyst stage explains this apparent paradox. Studies with gene-deficient mice have demonstrated the interleukin-12 (IL-12)-dependent production of interferon gamma (IFN-gamma) to be of paramount importance in controlling early parasite growth. However, this seems to be independent of nitric oxide production as mice deficient in inducible nitric oxide synthase (iNOS) and tumour necrosis factor receptor were able to control early growth of T. gondii, although, they later succumbed to infection. Nitric oxide does, however, seem to be important in controlling persistent infection; treating chronic infection with iNOS metabolic inhibitors results in disease reactivation. Preliminary evidence implicates neutrophils in effector pathways against this parasite distinct from that described for macrophages. Once initiated, IL-12-dependent IFN-gamma production in synergy with other proinflammatory cytokines can positively feed back on itself to induce 'cytokine shock'. Regulatory cytokines, particularly IL-10, are essential to down-regulate inflammation and limit host pathology.

Animals↗
PubMed1997

On the key role of secondary lymphoid organs in antiviral immune responses studied in alymphoplastic (aly/aly) and spleenless (Hox11(-)/-) mutant mice.

The role of the spleen and of other organized secondary lymphoid organs for the induction of protective antiviral immune responses was evaluated in orphan homeobox gene 11 knockout mice (Hox11(-/-)) lacking the spleen, and in homozygous alymphoplastic mutant mice (aly/aly) possessing a structurally altered spleen but lacking lymph nodes and Peyer's patches. Absence of the spleen had no major effects on the immune response, other than delaying the antibody response by 1-2 d. In aly/aly mice, the thymus-independent IgM response against vesicular stomatitis virus (VSV) was delayed and reduced, whereas the T-dependent switch to the protective IgG was absent. Therefore, aly/aly mice were highly susceptible to VSV infection. Since aly/aly spleen cells yielded neutralizing IgM and IgG after adoptive transfer into recipients with normally structured secondary lymphoid organs, these data suggest that the structural defect was mainly responsible for inefficient T-B cooperation. Although aly/aly mice generated detectable, but reduced, CTL responses after infection with vaccinia virus (VV) and lymphocytic choriomeningitis virus (LCMV), the elimination of these viruses was either delayed (VV) or virtually impossible (LCMV); irrespective of the dose or the route of infection, aly/aly mice developed life-long LCMV persistence. These results document the critical role of organized secondary lymphoid organs in the induction of naive T and B cells. These structures also provide the basis for cooperative interactions between antigen-presenting cells, T cells, and B cells, which are a prerequisite for recovery from primary virus infections via skin or via blood.

Adoptive Transfer↗
PubMed1997

Solutions containing miotic agents: effects on corneal transendothelial electrical potential difference.

BACKGROUND: Anterior chamber miotic solutions are widely used during anterior chamber surgery. We examined the effects of solutions containing miotic agents such as carbachol and/or acetylcholine on corneal endothelial pumping activity. METHODS: We monitored, in vitro, the transendothelial electrical potential difference of isolated rabbit corneal endothelial preparations. As controls, we used solutions without miotics. RESULTS: We found that a solution containing 55 mM acetylcholine and minimal amounts of salts (Miochol E) maintains transendothelial electrical potential difference some 30% above control levels for up to 4 h. Two other solutions, one including balanced salts and 0.55 mM carbachol (Miostat), the other a mixture of 0.19 mM carbachol and 55 mM acetylcholine plus minimal salts, are adequate to maintain the potential difference at control levels. Lastly, a solution with acetylcholine but without any salts (Miochol) greatly decreases the potential difference, to 30% of the control level, in 100 min. CONCLUSION: Our results indicate that: (1) 55 mM (1%) acetylcholine stimulates the endothelial electrical potential difference; (2) addition of 0.19 mM (0.003%) carbachol negates the stimulatory effect of acetylcholine; and (3) absence of electrolytes severely depresses the endothelial electrical activity.

Administration, Topical↗
PubMed1997

Effects of acetylcholine, carbachol, and mannitol on rabbit corneal endothelial function as assessed by corneal deturgescence.

BACKGROUND: Anterior chamber miotic solutions are widely used in ophthalmic surgery to induce pupillary contraction. We investigated whether the acetylcholine, carbachol, or mannitol present in perfusing solutions can affect corneal endothelial function. METHODS: Freshly dissected deepithelized rabbit corneas were mounted in a Dikstein-Maurice chamber at 36 degrees C. The endothelial sides were perfused with six solutions: (A) 55 mM (1%) acetylcholine Cl plus modified balanced salts; (B) control for A, with acetylcholine Cl replaced by sucrose; (C) 0.55 mM (0.01%) carbachol Cl plus balanced salts; (D) balanced salts solution (BS; control for C); (E) 3% mannitol plus modified balanced salts; and (F) modified balanced salts (control for E, with mannitol replaced by sucrose). Corneal thickness was followed for 3 h in each experiment. The effect of solution E did not differ from that of solution F. RESULTS: The carbachol-containing solution produced a small increase in corneal thickness compared to the control solution, while the acetylcholine-containing solution resulted in corneal thickness lower than that in control preparations. CONCLUSION: From these data, acetylcholine is harmless to the endothelium, and may actually stimulate its fluid pump mechanism. Carbachol, on the other hand, appears to have a detrimental effect.

Acetylcholine↗
PubMed1997

Innate immunity to Toxoplasma gondii is influenced by gender and is associated with differences in interleukin-12 and gamma interferon production.

Given that differences between the sexes in relative susceptibility to parasitic infections have been noted, this study further elucidates the mechanisms responsible by demonstrating that male SCID mice are more resistant than female mice to infection with Toxoplasma gondii and that this difference correlates with enhanced innate immune responses in these animals. Male SCID mice exhibited longer survival times, lower parasite burdens, and less severe pathological changes postinfection. An immunological basis for these differences is demonstrated in that these animals produced interleukin-12 more rapidly and exhibited higher levels of gamma interferon earlier postinfection.

Animals↗
PubMed1996

Base-specific recognition of the nontemplate strand of promoter DNA by E. coli RNA polymerase.

RNA polymerase recognizes its promoters through base-specific interaction between defined segments of DNA and the sigma subunit of the enzyme. This interaction leads to separation of base pairs and exposure of the template strand for RNA synthesis. We show that base-specific recognition by the sigma 70 holoenzyme in this process involves primarily nontemplate strand bases in the -10 promoter region. We suggest that melting involves the persistence of these contacts as the bound duplex (closed) form is converted to the single-stranded (open) form of the enzyme-promoter complex.

Base Sequence↗
PubMed1996

Enzymes of energy metabolism in the bradyzoites and tachyzoites of Toxoplasma gondii.

The bradyzoite and tachyzoite forms of Toxoplasma gondii, purified from infected animals, were analysed for their activities of phosphofructokinase, pyruvate kinase, lactate dehydrogenase, NAD(+)- and NADH-linked isocitrate dehydrogenases, and succinic dehydrogenase. Both developmental stages contained high activities of phosphofructokinase (specific for pyrophosphate rather than ATP), pyruvate kinase and lactate dehydrogenase, suggesting that energy metabolism in both forms may centre around a high glycolytic flux linked to lactate production. The markedly higher activity of the latter two enzymes in bradyzoites suggests that lactate production is particularly important in this developmental form. NAD(+)-specific isocitrate dehydrogenase was not detectable in either stage of the parasite (and proved useful as a measure of the purity of the bradyzoite preparation), whereas both parasite forms contained low activities of NADP(+)-linked isocitrate dehydrogenase. The results are consistent with the bradyzoites lacking a functional TCA cycle and respiratory chain and are suggestive of a lack of susceptibility of this developmental stage to atovaquone.

Animals↗
PubMed1996

Sex steroids, pregnancy-associated hormones and immunity to parasitic infection.

A wealth of evidence has accumulated that illustrates the ability of sex-associated hormones to influence directly a variety of diverse immunological functions. Thus, it is not surprising that differences have also been noted between the sexes in their relative susceptibility to parasitic infections. Furthermore, during pregnancy, much of the observed maternal immunomodulation, essential for fetal survival, has been attributed to changes in the levels of steroid hormones. These pregnancy-induced alterations in immune function can also have profound effects on the course of parasitic infection. In this article, Craig Roberts, Abhay Satoskar and James Alexander review the immunological basis for differences in the relative susceptibilities of males, non-pregnant females and pregnant females to parasitic infection, particularly leislumaniasis and toxoplasmosis. They also discuss the role of the major sex- and pregnancy-associated hormones in mediating these effects.

Journal Article↗
PubMed1996

Pretreatment with topical diclofenac sodium to decrease postoperative inflammation.

PURPOSE: Anti-inflammatory medications are traditionally administered to the eye only postoperatively for control of inflammation. Because the presumed mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) is to inhibit the formation of prostaglandin mediators of inflammation, the author studied the effect that pretreatment with an NSAID had on postoperative inflammation. METHODS: In a prospective study, 60 patients scheduled for phacoemulsification with silicone lens implantation were randomly assigned to receive either (1) pretreatment with one drop of diclofenac sodium 0.1% four times per day for the 3 days before surgery plus one drop of diclofenac sodium 0.1% every 15 minutes for four doses, beginning 1 hour before surgery along with the dilating drops; (2) no pretreatment, but one drop of diclofenac sodium 0.1% every 15 minutes for four doses beginning 1 hour before surgery along with the dilating drops; or (3) no diclofenac sodium drops at all before surgery. No anti-inflammatory medications were given either during or immediately after surgery, and all patients were begun on a regimen of one drop of diclofenac sodium 0.1% to the operated eye four times per day after being examined on the first postoperative day. Postoperative inflammation was measured on the first postoperative day and at 1 week with a laser cell and flare meter. RESULTS: On the first postoperative day, the mean flare score for group A was 25.59 photons/millisecond; for group B, 29.69 photons/millisecond; and for group C, 33.07 photons/millisecond. The difference between groups A and C was statistically significant. The differences between groups A and B and between groups B and C were not statistically significant. There was no statistically significant difference for cell scores at 1 day or for cell or flare scores at 1 week. CONCLUSIONS: The pretreatment with an NSAID before cataract surgery can reduce the amount of initial postoperative inflammation.

Administration, Topical↗
PubMed1996

Comparison of diclofenac sodium and flurbiprofen for inhibition of surgically induced miosis.

PURPOSE: To compare the efficacy of two topical nonsteroidal anti-inflammatory drugs, diclofenac sodium and flurbiprofen, commonly used prior to cataract surgery to inhibit surgically induced miosis. SETTING: Department of Ophthalmology, Cornell University Medical College, The New York Hospital, New York, New York. METHODS: Fifty-one patients having phacoemulsification were randomly assigned to receive topical treatment with either diclofenac sodium 0.1% or flurbiprofen 0.03% every 15 minutes for four doses along with their dilating drops beginning 1 hour before surgery. All surgeries were videotaped, with the magnification calibrated. The videotapes were analyzed and the horizontal and vertical diameters of the pupil were measured just before the initial conjunctival incision (baseline) and then every 5 minutes during the procedure. Measurements were also made at the beginning of capsulorhexis, the beginning of phacoemulsification, the end of phacoemulsification, the end of cortical cleanup, and before and after implantation of an intraocular lens. RESULTS: There was no statistically significant difference between the two treatment groups in baseline pupil dilation; however, regardless of the drug received, the light irides were, on average, more dilated at baseline than the dark ones. After surgery began, there were no statistically significant differences between the two groups at any time or surgical interval except at the start of phacoemulsification, at which point the flurbiprofen-treated eyes were more dilated than the diclofenac-treated eyes. CONCLUSION: Diclofenac sodium and flurbiprofen were equally effective in maintaining intraoperative mydriasis during cataract surgery.

Administration, Topical↗
PubMed1996

Preoperative and postoperative use of nonsteroidal antiinflammatory drugs in cataract surgery.

Nonsteroidal antiinflammatory drugs have unique properties that aid the cataract surgeon. In phacoemulsification surgery, patients routinely receive nonsteroidal antiinflammatory drugs along with their dilating drops to inhibit intraoperative miosis. After surgery, these drugs can control inflammation and inhibit the development of cystoid macular edema. We present two prospective randomized studies. In the first, diclofenac sodium was compared with prednisolone acetate for control of postoperative inflammation. In the second, diclofenac sodium was compared with flurbiprofen for inhibition of intraoperative miosis. Diclofenac sodium was found to be as effective as prednisolone acetate for control of postoperative inflammation and as effective as flurbiprofen for inhibition of intraoperative miosis. Thus, whereas in the past we used a nonsteroidal antiinflammatory drug before surgery for inhibition of intraoperative miosis and a steroid drop in the postoperative period to control postsurgical inflammation, we now have equal efficacy using the same drug in the entire perioperative period.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1996

Different roles for interleukin-4 during the course of Toxoplasma gondii infection.

The course of Toxoplasma gondii infection from initiation of disease perorally until day 28 postinfection was compared between interleukin-4 (IL-4) gene knockout (IL-4-/-) mice and their wild-type (IL-4+/+) counterparts on a disease-susceptible genetic background. The rate of mortality was significantly greater in mice deficient in Il-4 than in the immunocompetent controls. Although levels of T. gondii-specific spleen cell proliferation measured in vitro were similar between groups at all time points examined throughout infection, the quantities of cytokines released into the culture supernatant differed. Culture supernatants from spleen cells derived from IL-4-deficient mice contained significantly more gamma interferon than those derived from IL-4+/+ mice at day 7 postinfection. Conversely, IL-10 production was significantly greater from the spleen cells derived from wild-type mice at day 28 postinfection. Splenocytes from both groups of mice had a marked inhibition of proliferation in response to soluble tachyzoite antigen as well as reduced proliferation in response to concanavalin A between days 7 and 14 postinfection and marked proliferation on days 21 and 28 postinfection. At day 28 postinfection, histological examination of the brains indicated that IL-4+/+ mice had more severe pathological changes and more cysts than IL-4-/- mice. In addition, although many nonencysted single organisms were present in IL-4+/+ mice within both necrotic lesions and microglial nodules, few nonencysted parasites were found, and no necrotic lesions were present in IL-4-deficient animals. These results suggest that the observed reduction in mortality during the early acute phases of infection may be due to the down-regulatory effects of Il-4 or associated Th2-derived products on proinflammatory cytokines such as gamma interferon. However, the long-term effects of IL-4 are detrimental, possibly because of the ability of this cytokine to inhibit proinflammatory antiparasitic products. This may explain the increased parasite multiplication with cysts observed in the brains of IL-4+/+ mice.

Animals↗
PubMed1995

A comparison of topical diclofenac with prednisolone for postcataract inflammation.

OBJECTIVE: To compare diclofenac sodium with prednisolone acetate for the control of postoperative inflammation after cataract surgery. DESIGN: Fifty-two patients undergoing phacoemulsification with posterior chamber intraocular lens implantation were randomly assigned to receive either 0.1% diclofenac eye drops or 1% prednisolone eye drops as their postoperative anti-inflammatory medication. The patients were examined 1 day (baseline), 1 week, and 1 month after surgery. Postoperative inflammation was evaluated subjectively by slit-lamp assessment of cell and flare and objectively by measurement of cell and flare with a laser cell and flare meter. RESULTS: At each visit, there was no statistically significant difference in postoperative inflammation either by slit-lamp assessment or with the laser cell and flare meter for the two treatment groups. CONCLUSION: In the dosage used, diclofenac was as effective an anti-inflammatory agent for uncomplicated post-cataract inflammation as prednisolone.

Administration, Topical↗