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Biomedical subjects

C M Reilly

Publications and source records attributed to C M Reilly.

15 recordsLinked to original sources

Impact of different cell isolation techniques on lymphocyte viability and function.

The outcome of immunological assays is markedly influenced by the method of isolation of lymphocytes. It is, therefore, important to comparatively assess various techniques of isolation of lymphocytes, an aspect thus far not thoroughly addressed. In particular, the potential of isolation techniques to influence cell recovery, viability, and function has not yet been evaluated. These studies were designed to determine the effect of different mechanical tissue dissociation methods on the viability and function of lymphocytes. Following spleen and thymus removal, the lymphoid organs were dissociated by one of four different tissue dissociation techniques: metallic screen, sheer force slide, commercial stomacher, or plunger-screen. Cells were then enumerated and a trypan blue exclusion technique and 7-amino-actinomycin D (7-AAD) were both employed to assess viability. Mitogen-induced lymphocyte proliferation was measured using the Alamar Blue assay. Cell viability and lymphocyte surface antigen expression were assessed using flow cytometry. No significant differences in lymphocyte viability, morphology, or surface antigen expression were observed among the different techniques. Likewise, cellular apoptosis and necrosis were comparable across all the techniques. However, mitogen induced splenic T-cell proliferation was higher in cells collected using the metallic screen and plunger-screen isolation methods as compared to the sheer force slide or commercial stomacher procedures. These data suggest that cell recovery, morphology, and viability are not affected by isolation techniques. However, lymphocyte function, as assessed by mitogen induced proliferation, was negatively affected by the sheer force slide or commercial stomacher isolation techniques.

Animals↗

Complement component C3 is not required for full expression of immune complex glomerulonephritis in MRL/lpr mice.

Complement activation and tissue deposition of complement fragments occur during disease progression in lupus nephritis. Genetic deficiency of some complement components (e.g., Factor B) and infusion of complement inhibitors (e.g., Crry, anti-C5 Ab) protect against inflammatory renal disease. Paradoxically, genetic deficiencies of early components of the classical complement pathway (e.g., C1q, C4, and C2) are associated with an increased incidence of lupus in humans and lupus-like disease in murine knockout strains. Complement protein C3 is the converging point for activation of all three complement pathways and thus plays a critical role in biologic processes mediated by complement activation. To define the role of C3 in lupus nephritis, mice rendered C3 deficient by targeted deletion were backcrossed for eight generations to MRL/lpr mice, a mouse strain that spontaneously develops lupus-like disease. We derived homozygous knockout (C3(-/-)), heterozygous (C3(+/-)), and C3 wild-type (C3(+/+)) MRL/lpr mice. Serum levels of autoantibodies and circulating immune complexes were similar among the three groups. However, there was earlier and significantly greater albuminuria in the C3(-/-) mice compared with the other two groups. Glomerular IgG deposition was also significantly greater in the C3(-/-) mice than in the other two groups, although overall pathologic renal scores were similar. These results indicate that C3 and/or activation of C3 is not required for full expression of immune complex renal disease in MRL/lpr mice and may in fact play a beneficial role via clearance of immune complexes.

Albuminuria↗

Prostaglandin J(2) inhibition of mesangial cell iNOS expression.

Mesangial cells from MRL/lpr mice, a model of lupus, overproduce nitric oxide (NO) compared to controls. J series prostaglandins (PG) and thiazolidinediones block LPS stimulation of NO production via the activation of peroxisome proliferator-activator receptor-gamma (PPAR-gamma) in macrophages but utilize an alternative mechanism in microglial cells. We investigated the mechanism by which PGJ(2) inhibits NO production in LPS/IFN-gamma-stimulated MRL/lpr mesangial cells. Our results demonstrated that LPS/IFN-gamma addition to MRL/lpr mesangial cells stimulated iNOS activation, expression of p-38 kinase and p44/42 MAPK, and NF-kappaB translocation to the nucleus. Both pioglitazone, a specific PPAR-gamma agonist, and PGJ(2) blocked NO production, iNOS protein expression, and iNOS mRNA transcription. PGJ(2) failed to inhibit nuclear NF-kappaB translocation or p44/42 MAPK or p-38 kinase induction in stimulated mesangial cells. These data suggest that PGJ(2) blocks iNOS expression and subsequent NO production in mesangial cells via a PPAR-gamma-mediated mechanism either by interfering with NF-kappaB transcriptional activity or by an NF-kappaB-independent mechanism.

Animals↗

Inhibition of mesangial cell nitric oxide in MRL/lpr mice by prostaglandin J2 and proliferator activation receptor-gamma agonists.

MRL/Mp-lpr/lpr (MRL/lpr) mice develop immune complex glomerulonephritis similar to human lupus. Glomerular mesangial cells are key modulators of the inflammatory response in lupus nephritis. When activated, these cells secrete inflammatory mediators including NO and products of cyclooxygenase perpetuating the local inflammatory response. PGJ2, a product of cyclooxygenase, is a potent in vitro inhibitor of macrophage inflammatory functions and is postulated to function as an in vivo inhibitor of macrophage-mediated inflammatory responses. We hypothesized that in lupus, a defect in PGJ2 production allows the inflammatory response to continue unchecked. To test this hypothesis, mesangial cells were isolated from MRL/lpr and BALB/c mice and stimulated with IL-1beta or LPS plus IFN-gamma. In contrast to the 2- to 3-fold increase in PGJ2 production by stimulated BALB/c mesangial cells, supernatant PGJ2 did not increase in MRL/lpr mesangial cell cultures. NO production in stimulated MRL/lpr and BALB/c mesangial cells, was blocked by PGJ2 and pioglitazone. These studies suggest that abnormalities in PGJ2 production are present in MRL/lpr mice and may be linked to the heightened activation state of mesangial cells in these mice.

Animals↗

Duration of estrogen exposure prior to follicle-stimulating hormone stimulation is critical to granulosa cell growth and differentiation in rats.

Estrogens have been reported to exert both stimulatory and inhibitory effects on granulosa cell function. Previous studies from our laboratory showed that 12 h after administration of diethylstilbestrol (DES; a synthetic estrogen), FSH-stimulated granulosa cell proliferation and aromatase activity were increased; however, 48 h after DES, FSH stimulation of both parameters was inhibited. In other experiments, exposure of rats to DES for a period of 26 h blocked ovulation in response to eCG and hCG administration, whereas the same treatment regimen without DES caused ovulation in all treated rats. Thus, DES may in some cases actually interfere with maturation and development of ovulatory follicles. The present study was designed 1) to confirm that the duration of estrogen pre-exposure determines the way granulosa cells respond to FSH and 2) to investigate the underlying mechanisms involved. While DES was used in preliminary experiments, the majority of the studies were conducted with estradiol, a natural estrogen, in order to conform as closely as possible to the normal physiology. In the experimental protocol, immature female rats received injections of DES or implants of estradiol pellets 12 h (short exposure) or 36 h (long exposure) before 36 h of FSH treatment. Rats were killed, ovaries removed, and granulosa cells collected at the end of the FSH treatment period. The results demonstrate that exposure to either of these estrogens for 12 h allowed the subsequent FSH stimulation to produce high cellular proliferation, high aromatase enzyme activity, and large amounts of FSH receptor and aromatase mRNA. Estrogen exposure for 36 h, however, resulted in significantly decreased FSH stimulation of all these parameters. These findings confirm that short exposure to estrogen enhances the response of granulosa cells to FSH while longer exposure makes granulosa cells refractory to FSH. This differential sensitivity of granulosa cells to estrogen exposure could help explain how dominant follicles survive to ovulate while others are lost to atresia during ovarian cycles.

Animals↗

Sites of androgenic regulation of cavernosal blood pressure during penile erection in the rat.

The present studies were designed to determine the role of reactive vascular smooth muscle in the regulation of blood flow into and out of the cavernous sinuses during penile erection in castrated and testosterone-treated animals. While the mean arterial pressure and intracavernosal pressure were continuously monitored, vasoactive drugs were injected into the aorta or into the cavernous sinuses during erection. The results show that both a NO releasing vasodilatory drug and an alpha adrenergic agonist significantly affected both mean arterial pressure and intracavernosal pressure when injected into the aorta. However, when these same drugs were injected into the cavernous sinuses, neither drug exerted a significant influence on the erectile response. Based on these studies, we conclude that the flow of blood into the cavernous sinuses during erection is regulated by reactive vascular smooth muscle but the outflow is not under the regulation of reactive vascular smooth muscle. Furthermore, the relaxation of the smooth muscle which controls the flow of blood into the cavernous sinuses during erection may be under partial androgenic control.

Androgens↗

Bioequivalence evaluation of new megestrol acetate formulations in humans.

The bioequivalence of two new investigational 160 mg tablets, one containing the regular form and the other a micronized form of megestrol acetate, was determined relative to a commercially available 40 mg tablet. The tablets were administered to 24 male subjects in a three-way crossover study, balanced for sequence, with 1 week between administrations. The 40 mg tablets were administered qid at 8 AM, 12 PM, 6 PM, and 10 PM, while the 160 mg tablets were administered once at 8 AM. Plasma samples were collected at appropriate times up to 96 hours after administration and were analyzed for megestrol acetate with a validated high-performance liquid chromatographic procedure. Based on the times to maximum plasma concentrations (2.5 to 2.8 h) the rate of absorption was the same for each of the tablets. Relative to the 40 mg qid dose, the 160 mg regular and the 160 mg micronized tablets had mean relative bioavailabilities of 97% and 118%, respectively.

Adult↗

Hypothyroidism following removal of a "thyroglossal duct cyst".

This case demonstrates how a midline ectopic thyroid gland can be misdiagnosed as a thyroglossal duct cyst. Awareness of this clinical entity is critical if the diagnosis is to be made preoperatively. Thyroid function tests and a 99mTc or 123I scintiscan of the neck should be performed when evaluating a patient with a midline anterior cervical mass. Although thyroid replacement will often cause regression of the enlarged ectopic thyroid gland, surgical intervention is required if a solid mass persists. When an ectopic thyroid gland has been excised and is subsequently found to be the child's only thyroid tissue, thyroid replacement is necessary. If biopsy of the mass established the diagnosis at the time of surgery, effective treatment consists of longitudinally dividing the tissue and placing each half laterally beneath the strap muscles. When this is done, long-term follow-up and periodic thyroid function tests are advised. If this tissue should become hypoactive, thyroid replacement is then required.

Child↗

Evaluation of two new megestrol acetate tablet formulations in humans.

The bioequivalence of two new investigational 160 mg tablets, one containing the regular form and the other a micronized form of megestrol acetate, was determined relative to a commercially available 40 mg tablet (Megace). The tablets were administered to 24 male subjects in a three-way cross-over study, balanced for sequence, with a week between administrations. The 40 mg tablets were administered q.i.d. at 08.00, 12.00, 18.00 and 22.00 h, while the 160 mg tablets were administered once at 08.00 h. Plasma samples were collected at appropriate times out to 96 h after administration and were analysed for megestrol acetate with a validated high performance liquid chromatographic procedure. Based on the times to maximum plasma concentrations (2.5 to 2.8 h), the absorption rate constant was the same for each of the tablets. Relative to the 40 mg q.i.d. dose, the 160 mg regular and the 160 mg micronized tablets had mean relative bioavailabilities of 97 per cent and 118 per cent, respectively.

Adult↗

Prospective measure of serum 3-nitrotyrosine levels in systemic lupus erythematosus: correlation with disease activity.

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease. Overproduction of nitric oxide (NO) has been implicated in its pathogenesis. Several retrospective studies have indicated a correlation between serum nitrate and nitrite (NOx) and disease activity. This measure of NO production can be falsely elevated by exogenous dietary and medication sources of NOx and variably reduced by serum thiols. These variables can make NOx a less reliable tool for studying the role of NO in SLE. Peroxynitrite, a by-product of NO and superoxide, nitrates tyrosine moieties. The resulting 3-nitrotyrosine (3NT) serves as a long-term indicator of NO-mediated protein modifications that is not affected by exogenous sources of NOx or serum thiols. We hypothesized that for these reasons serum 3NT levels would correlate with lupus disease activity more significantly than serum NOx. To address this hypothesis, we prospectively evaluated lupus disease activity, serum protein 3NT levels, and NOx levels in a cohort of lupus patients at 3-month intervals. Serum 3NT correlated with disease activity among African-Americans, while NOx correlated with disease activity among Caucasians. Subjects with active lupus nephritis had higher levels of serum 3NT than those without renal disease. Immunohistochemical analysis of renal biopsies from subjects with active proliferative lupus nephritis revealed renal expression of inducible NO synthase. The results of this study suggest that overproduction of NO may play a pathogenic role in SLE and lupus nephritis. Serum 3NT may be a useful, new tool for studying the contributions of NO to the pathogenesis of SLE.

Autoantibodies↗

Androgens modulate the alpha-adrenergic responsiveness of vascular smooth muscle in the corpus cavernosum.

Rat penile erection is an androgen-dependent process with castration leading to a loss of potency. The present study was designed to determine if one of the mechanisms by which androgens maintain the erectile response is the regulation of the alpha-adrenergic responsiveness of cavernosal smooth muscle. Electrical stimulation of the major pelvic ganglion (MPG) was used to elicit erection in untreated, castrated rats (CASTRATE) or castrated rats given testosterone replacement (TESTO). The effects of phenylephrine (an alpha 1-adrenergic agonist) and prazosin (an alpha 1-adrenergic antagonist) on the erectile response were investigated. Phenylephrine, when administered to both TESTO and CASTRATE animals during erection, resulted in a dose-dependent decrease in the intracavernosal pressure (CCP) with an ED50 value of 1.8 +/- 0.48 micrograms/kg BW for TESTO rats; in the CASTRATE animals, the ED50 was significantly reduced to 0.29 +/- 0.08 microgram/kg BW. The increases in mean arterial pressure (MAP) resulting from phenylephrine injection in TESTO and CASTRATE animals were of similar magnitude and were not significantly different. Prazosin administration resulted in an enhancement of the erectile response in CASTRATE but not in TESTO animals. Taken together these results demonstrate that the cavernosal vasculature in CASTRATE animals possesses increased reactivity to alpha-adrenergic stimulation as compared to the sensitivity in TESTO rats. Based on these findings, we conclude that one of the mechanisms by which androgens maintain erectile function is by regulating the alpha 1-adrenergic responsiveness of the cavernosal smooth muscle.

Adrenergic alpha-Agonists↗

Androgenic regulation of NO availability in rat penile erection.

Prior studies from this laboratory, using untreated castrated (CASTRATE) rats and testosterone-treated castrated (TESTO) rats, have shown that the magnitude of the intracavernosal pressure increase during erection is androgen dependent. Studies from this and other laboratories have also presented evidence suggesting that penile erection is mediated principally by nitric oxide (NO). The present report was designed to confirm that androgens maintain the availability of cavernosal NO and to determine if this androgenic action is exerted at the genomic level modulating the expression of the neuronal form of the nitric oxide synthase gene (nNOS). The results showed that administration of supplemental L-arginine failed to augment the erectile response in either group, suggesting that substrate availability is not a cause of the reduced response in CASTRATE animals. Inhibition of NO synthesis with a nitro-arginine competitive inhibitor of nitric oxide synthase enzyme protein (NOS) resulted in strong inhibition of erection in both TESTO and CASTRATE rats. When given in conjunction with ganglionic stimulation to induce erection, the NO releasing drug, sodium nitro-prusside (SNP), increased intracavernosal pressure in CASTRATE rats but not in TESTO rats, suggesting a deficiency of the available NO in CASTRATE-animals. Finally, reverse transcription-polymerase chain reaction (RT-PCR) demonstrated that mRNA levels for the enzyme nNOS in the penis were greater in TESTO animals than in CASTRATE rats. These results support the hypothesis that androgens mediate the erectile response in the rat penis by stimulating the expression of the neuronal isoform of nitric oxide synthase, thus maintaining an adequate supply of NO.

Analysis of Variance↗

Androgenic maintenance of the rat erectile response via a non-nitric-oxide-dependent pathway.

Prior studies have demonstrated that the erectile response in the rat penis is androgen dependent and is mediated by nitric oxide (NO), the neurotransmitter synthesized by the enzyme nitric oxide synthase (NOS). The present studies used L-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOS, to determine if androgens also regulate alternative pathways leading to the erectile response but not mediated by NO. Castrated rats that were treated with L-NAME (L-NAME CASTRATE) exhibited little or no increase in intracavernosal pressure in response to stimulation of the major pelvic ganglion. This ganglion controls blood flow into the penis and, when stimulated, normally leads to erection. However, when castrated animals were treated with testosterone along with L-NAME (L-NAME TESTO), the animals responded to the ganglionic stimulation with increased intracavernosal pressure. This finding suggests that there are other androgen-dependent pathways that lead to penile erection but are not mediated by NO. Erection occurred in both L-NAME CASTRATE and L-NAME TESTO rats in response to intracavernosal injection of sodium nitroprusside (an NO donor drug), proving that the NO responsive mechanisms were unaffected by the inhibition of NOS activity. To investigate further the nature of this NO independent pathway, L-NAME CASTRATE and L-NAME TESTO rats were treated with either zaprinast (a specific phosphodiesterase 5 inhibitor), which would block the breakdown of cGMP to 5'GMP, or methylene blue (an inhibitor of guanylate cyclase) to prevent the synthesis of cGMP. Zaprinast treatment led to increased erectile response in L-NAME TESTO rats but not in L-NAME CASTRATE rats, demonstrating that androgen-sensitive alternative pathways increased guanylate cyclase activity. Methylene blue inhibited the erectile response in all treatment groups, showing that cyclic GMP is critical to the NO-independent pathway as well as the NO-dependent pathway. Taken together, these results support the hypothesis that androgens maintain the erectile response by alternate pathways, including one that is independent of NO but involves the synthesis of cyclic GMP.

Androgens↗

The loss of alpha-adrenergic effect during the erectile response in the long-term diabetic rat.

The present study was designed to investigate the effect of long-term, streptozotocin-induced diabetes on the erectile response in the laboratory rat. Mean arterial blood pressure (MAP) and intracavernosal blood pressure within the erectile tissue (CCP) were continuously monitored during erection elicited by stimulation of the autonomic innervation of the penis. MAP and CCP were also measured during administration of two drugs: nitroglycerin, a nitric oxide donor drug and phenylephrine, an alpha-adrenergic agonist. The results of these studies show that during graded electrical stimulation of the ganglion, the overall magnitude of the erectile response was greater in the diabetic rats than in untreated control animals. Neither diabetic nor control animals responded significantly to infusion of nitroglycerin. However, diabetic rats and control rats responded very differently to administration of phenylephrine; in the control rats, this alpha agonist caused a sharp decline in CCP as the cavernosal vessels constricted in response to the drug. The same dose of phenylephrine had no discernible effect on CCP in the diabetic animals. This loss of alpha responsiveness may be confined to the penile circulation because MAP was elevated to approximately the same extent in both groups. Taken together, these results show that long-term diabetes leads to a failure of alpha-adrenergic responsiveness in the cavernosal circulation. The greater erectile response to ganglionic stimulation in the diabetic animals is likely due to the loss of response to endogenous norepinephrine.

Adrenergic alpha-Agonists↗