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Biomedical subjects

E M Smith

Publications and source records attributed to E M Smith.

At least 163 records · Page 9Linked to original sources
PubMed1988

ACTH receptor-mediated induction of leukocyte cyclic AMP.

Studies were conducted to determine whether lymphocyte ACTH receptors behave as their structurally similar adrenal cell counterparts, in terms of adenylate cyclase activation and cyclic AMP (cAMP) production in the presence of ACTH. Treatment of mouse mononuclear splenocytes with ACTH (10(-5) to 10(-10) M) induced a consistent rise in cAMP. ACTH treatment of more homogenous cell populations, represented by Molt 4 T lymphoblast and S49A T cell lymphoma lines, yielded a dramatic, dose-related increase in cAMP levels for S49A cells but not for Molt 4 cells. Immunofluorescence assays, employing an antiserum to the adrenal cell ACTH receptor, indicated that 45% of splenocytes, 69% of S49A cells, and less than 1% of Molt 4 cells possess ACTH receptors. Radioligand binding studies confirmed that Molt 4 cells possess many fewer receptors than S49A cells, and probably fail to respond to ACTH because they lack the appropriate receptor. This is the first report of ACTH induction of leukocyte cAMP, evidence important to understanding the mechanisms by which this neuroendocrine hormone influences immune responses.

Adenylyl Cyclases↗
PubMed1988

Decreased mononuclear leukocyte TSH responsiveness in patients with major depression.

A subgroup of individuals with major depressive disorder have an impaired thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH). The molecular relationship between the mechanism of this "blunted" TSH response and depression is unknown. Numerous recent studies have characterized similarities and interactions between the immune and neuroendocrine systems. As the immune system both produces and responds to TSH, we utilized a peripheral blood leukocyte system to compare immunoreactive (ir)-TSH responsiveness in 10 adult patients (1 man, 9 women) with Research Diagnostic Criteria for major depressive disorder to that of 9 control subjects. All subjects had normal baseline serum TSH and T4 concentrations. Isolated mononuclear leukocytes were treated in vitro with either 0.5 micrograms/ml staphylococcal enterotoxin A (SEA), 50 micrograms/ml TRH, or no stimulant. After incubation, the cells were monitored for ir-TSH production by indirect immunofluorescence and reverse hemolytic plaque assay using antisera to TSH-beta. The culture supernates were analyzed by TSH radioimmunoassay. SEA- and TRH-treated cell cultures from depressed individuals had significantly fewer immunofluorescent positive cells, as well as significantly fewer and smaller plaques, than did similarly treated leukocytes from control subjects. The increase in supernatant ir-TSH was significantly less in TRH-treated cultures from depressed patients as compared to normals (p less than 0.05). These results suggest that examination of mononuclear leukocyte TSH production may reflect an altered state of neuroendocrine function and may thus be a useful marker for major depressive disorder.

Adult↗
PubMed1988

Rat hepatic glutaminase: purification and immunochemical characterization.

A method for the purification of phosphate-activated glutaminase from the liver of streptozotocin-diabetic rats is described. The procedure involves solubilization of glutaminase activity from isolated mitochondria by sonication, followed by ammonium sulfate precipitation, polyethylene glycol precipitation, and sequential chromatography on DEAE, hydroxylapatite, and zinc-chelated resins. The enzyme was purified 600-fold to a specific activity of 31-57 U/mg protein. The purified enzyme has an apparent subunit molecular mass of 58,000-Da and is greater than 80% pure by scanning densitometry of sodium dodecyl sulfate-polyacrylamide gels. The purified enzyme has an apparent Km for glutamine of 17 mM and a pH optimum between 7.8 and 8.2. The physical and kinetic properties of this enzyme are similar to those of the enzyme from normal rat liver. Polyclonal antibodies raised against the enzyme specifically inhibit hepatic glutaminase activity and react primarily with a 58,000-Da peptide in liver fractions on immunoblots. These antibodies were used in equivalence point titrations and immunoblots to provide evidence for increased concentration of glutaminase protein in the liver of diabetic rats with no change in specific activity of the enzyme. In addition, the antibodies cross-react, at low affinity, with kidney-type glutaminases. On immunoblots, the antibodies did not react with fetal liver, mammary gland, or lung. Antibodies to rat hepatic glutaminase should prove useful as tools to study the long-term regulation of the enzyme.

Ammonium Sulfate↗
PubMed1988

Synthesis and pharmacological activity of angiotensin converting enzyme inhibitors: N-(mercaptoacyl)-4-substituted-(S)-prolines.

The synthesis of a series of N-(mercaptoacyl)-4-substituted-(S)-prolines (2 and 3) is described. These compounds were evaluated in vitro for inhibition of angiotensin-converting enzyme (ACE), and selected compounds were evaluated in vivo for ACE inhibition. The most potent compounds in vitro are 108, 109, 111, 114, and 116, having relative potencies of 1.0, 1.0, 1.3, 1.1, and 2.6 as compared to the potency of captopril. The most potent compounds in vivo intravenously are 108, 111, 114, 116, 117, and 97.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1988

The OVEIA assay, a simultaneous measurement of oestrone and pregnanediol glucuronides, for studying the treatment of infertility patients.

A new simple assay developed for establishing the limits of the fertile period was evaluated in infertility patients. This assay is a colorimetric method for measuring the oestrone glucuronide/pregnanediol glucuronide ratio. Steroid levels were assayed simultaneously and an index of their ratio was obtained in this dual analyte assay (DAA). Twenty subfertile women, receiving clomiphene citrate for ovulation induction, were monitored for the DAA index using early morning urine samples. Ten of these women were also monitored in a pretreatment cycle. A further 10 patients on an in-vitro fertilization (IVF) programme were assessed with the same assay. DAA ratios were found to correlated with follicular phase serum oestradiol levels. Peak DAA ratios dropped dramatically when significant rises in urinary luteinizing hormone concentrations occurred prior to ovulation. An association between high DAA ratios and adequate luteal phase activity was also established. In addition, the total volume of the three largest ovarian follicles, as measured by ultrasound, in IVF patients was found to correlate with DAA measurements.

Adult↗
PubMed1988

A molecular basis for interactions between the immune and neuroendocrine systems.

Homeostatic and psychologic alterations associated with infections and tumors are very interesting yet poorly understood pathophysiologic responses. Numerous anecdotal and indirect examples suggest that these responses occur through a link between the central nervous and immune systems (for review see Blalock, Bost, & Smith, 1985; Spector & Korneva, 1981; Maestroni & Pierpaoli, 1981; Felton et al., 1985; Jankovic, 1985). Interactions between the two systems are just now being described. One possible mechanism is direct modulation of the immune system by the sympathetic nervous system. This could occur in innervated immune organs such as spleen, thymus, and bone marrow (Felton et al., 1985). The evidence for this is that sympathectomy and lesioning of specific regions of the brain can be shown to both enhance and/or suppress immune responses (Miles et al., 1985; Roszman et al., 1985). Also, the firing rate of hypothalamic neurons is altered during an immune response (Besedovsky et al., 1977). Alternatively, hormonal involvement in immune reactions has been known for some time, in particular the immunosuppressive effects of glucocorticoids (for review see Cupps & Fauci, 1982). Recently, we and others found that neuroendocrine peptide hormones will modulate T and B lymphocytes plus other immunocyte responses (Besedovsky et al., 1977; Cupps & Fauci, 1982; Johnson et al., 1982; Wybran et al., 1979; Hazum, Chang & Cuatrecasas, 1979; O'Dorisio et al., 1981; Gilman et al., 1982; McCain et al., 1982; Mathews et al., 1983; Plotnikoff et al., 1985; Johnson et al., 1984). Furthermore, lymphocytes themselves can synthesize biologically active neuroendocrine hormones (Blalock & Smith, 1980; O'Dorisio et al., 1980; Smith & Blalock, 1981; Smith et al., 1983; Lolait et al., 1984; Ruff & Pert, 1984), as well as possess specific hormone receptors (Blalock et al., 1985; Johnson et al., 1982; Wybran et al., 1979; Hazum et al., 1979; O'Dorisio et al., 1981; Lopker et al., 1980; Payan, Brewster & Goetzl, 1984; Pert et al., 1985). Immune responses (Besedovsky, del Rey & Sorkin, 1981), thymic hormones (Healy et al., 1983), and lymphokines (Lotze et al., 1985; Woloski et al., 1985) have all been shown to exert hormonal effects. Thus, another method for communication between the immune and neuroendocrine systems seems to be through soluble factors such as neuroendocrine hormones. This review will concentrate on the latter topic, in particular on work this laboratory has done over the past few years to show the lymphocyte production and immunoregulatory actions of neuroendocrine hormones.

Animals↗
PubMed1987

The regulation of glutamine and ketone-body metabolism in the small intestine of the long-term (40-day) streptozotocin-diabetic rat.

The small intestine is the major site of glutamine utilization in the mammalian body. During prolonged (40-day) streptozotocin-diabetes in the rat there is a marked increase in both the size and the phosphate-activated glutaminase activity of the small intestine. Despite this increased capacity, intestinal glutamine utilization ceases in diabetic rats. Mean arterial glutamine concentration fell by more than 50% in diabetic rats, suggesting that substrate availability is responsible for the decrease in intestinal glutamine use. When arterial glutamine concentrations in diabetic rats were elevated by infusion of glutamine solutions, glutamine uptake across the portal-drained viscera was observed. The effect of other respiratory fuels on intestinal glutamine metabolism was examined. Infusions of ketone bodies did not affect glutamine use by the portal-drained viscera of non-diabetic rats. Prolonged diabetes had no effect on the activity of 3-oxoacid CoA-transferase in the small intestine or on the rate of ketone-body utilization in isolated enterocytes. Glutamine (2 mM) utilization was decreased in enterocytes isolated from diabetic rats as compared with those from control animals. However, glutaminase activity in homogenates of enterocytes was unchanged by diabetes. In enterocytes isolated from diabetic rats the addition of ketone bodies or octanoate decreased glutamine use. It is proposed that during prolonged diabetes ketone bodies, and possibly fatty acids, replace glutamine as the major respiratory fuel of the small intestine.

Animals↗
PubMed1987

Novel processing pathway for proopiomelanocortin in lymphocytes: endotoxin induction of a new prohormone-cleaving enzyme.

We have discovered that the immune system processes proopiomelanocortin (POMC) products differently depending on the stimulus for induction. We have shown that corticotropin-releasing factor (CRF) induces the lymphocytes from C3HeB/FeJ lipopolysaccharide (LPS)-sensitive mice to produce adrenocorticotropin (ACTH) 1-39 and beta-endorphin, whereas LPS induces these lymphocytes to produce ACTH 1-23 to 26 and alpha- or gamma-endorphin. We have proposed that the smaller species of ACTH and endorphin are proteolytic cleavage products from ACTH 1-39 and beta-endorphin. Analysis of C3HeB/FeJ LPS-treatment B lymphocyte lysates showed an enzymatic activity at pH 5 but not pH 7 that cleaved ACTH 1-39 into a smaller ACTH 1-23 to 26. The B lymphocytes from C3H/HeJ (LPS-resistant) mice expressed but did not process proopiomelanocortin after LPS or CRF treatment, nor did their B cells express the aforementioned enzymatic activity. Taken together, these data suggest a unique processing pathway in LPS-treated B lymphocytes and one in which immunoreactive (ir)-endorphins may play a role in the pathophysiology of endotoxic shock.

Adrenocorticotropic Hormone↗
PubMed1987

Have we reduced the risk of getting cancer or of dying from cancer? An update.

We have examined trends in cancer mortality, incidence and survival in the United States to update our earlier work and respond to criticisms. [Bailar, J.C., Smith, E.M.: New Engl. J. Med. 314, 1226 (1986).] Here we concentrate on the years 1975-1984, and show that overall cancer mortality has increased, incidence has increased and case survival is virtually unchanged. This generally unfavorable picture is scarcely changed when lung cancer is excluded from the trends. While trends for individual cancers have been mixed, overall progress in both curative treatment and prevention has been minimal. This evaluation does not deny the marked progress in treating some uncommon forms of cancer, improved palliation, reduced extent or severity of treatment, or benefits of cancer research that can be applied in other areas of medicine. While our finding of limited progress is not new, we believe that it requires increased attention in setting the course of future research initiatives, demonstration programs, medical training and clinical practice.

Humans↗
PubMed1987

Splenic lymphocyte production of an endorphin during endotoxic shock.

Endogenous opioids have been reported to elicit some of the pathophysiologic responses to endotoxic shock by binding to the delta-opiate receptor. We have previously reported the production of immunoreactive (ir)-endorphin by B lymphocytes treated with bacterial lipopolysaccharide (LPS). We postulated that this lymphocyte-derived ir-endorphin may be an extrapituitary source of the endogenous opioid component associated with the pathophysiology of endotoxic shock. To test this hypothesis, we chose to study the LPS-sensitive (C3HeB/FeJ) and -resistant (C3H/HeJ) inbred mouse model. We treated these mice with intraperitoneal injections of LPS or B-lymphocyte-derived ir-endorphin. The LPS-sensitive mice presented with a severe hypothermic and pathophysiologic response pattern when treated with LPS or with ir-endorphin. The LPS-resistant mice, which were unresponsive to the LPS, however, presented with the typical hypothermic and pathophysiologic responses to the ir-endorphin. Immunofluorescence on the splenic leukocytes in the LPS-treated mice showed significant ir-endorphin present only in the LPS-sensitive mice at a time point preceding onset of the pathophysiologic response pattern. Taken together, this evidence strongly suggests a role for B-lymphocyte-derived ir-endorphin in the pathophysiology of endotoxic shock. The implications of immune system regulation of neuroendocrine function are discussed.

Animals↗
PubMed1987

Topical ocular hypotensive effects of the novel angiotensin converting enzyme inhibitor SCH 33861 in conscious rabbits.

SCH 33861 is a novel, non-sulfhydryl angiotensin converting enzyme (ACE) inhibitor. Topical administration of the compound to the eye of conscious rabbits was employed to examine actions on intraocular pressure (IOP). Falls in IOP resulted from SCH 33861 (0.001-0.01%) administration. Ocular hypotensive responses were sustained for as long as 24 hrs following a single application of 0.001% SCH 33861. The RSS isomer of SCH 33861, which is 200-fold weaker an ACE inhibitor than SCH 33861, caused only transient falls in IOP at 0.1% concentration. The magnitude of the fall in IOP induced by 0.001% SCH 33861 (4.8 +/- 0.5 mmHg) was comparable to that produced by 0.5% timolol (4.5 +/- 0.3 mmHg). Other ACE inhibitors such as captopril (0.1%) and enalaprilic acid (0.01%) also reduced IOP by 4.0 +/- 0.4 and 4.7 +/- 0.4 mmHg, respectively. These findings indicate that SCH 33861 is 500-fold more potent on a weight basis than is timolol in lowering IOP. No loss of ocular hypotensive activity was observed when SCH 33861 was administered twice daily for 5 days suggesting little, if any, potential for tolerance development. SCH 33861, as well as the other ACE inhibitors, caused neither ocular irritation nor alteration of pupil diameter. These findings suggest that inhibition of ocular ACE may represent an effective means of reducing IOP.

Administration, Topical↗
PubMed1987

In vivo immunoreactive adrenocorticotropin (ACTH) production by human mononuclear leukocytes from normal and ACTH-deficient individuals.

Mononuclear leukocytes from 25 children (16 with normal pituitary ACTH production and 9 with ACTH deficiency) were examined for in vivo ACTH production by immunofluorescence with antiserum to ACTH-(1-13) amide. The protocol included 3 study periods: control, after administration of insulin, and after administration of typhoid vaccine (an interferon-alpha inducer). Plasma cortisol and mononuclear leukocyte ACTH immunofluorescence were measured before (0900 h) and 1, 2, 4, 6, 8, and 10 h after treatment on each of the 3 study days. In vitro studies with human leukocytes from normal subjects incubated with ACTH, insulin, or typhoid vaccine were also performed. Patients with normal pituitary ACTH production had an increase in the number of ACTH immunofluorescence-positive cells 1 h after insulin administration [25 +/- 5% (+/- SEM) to 44 +/- 6% P less than 0.05], and no change after typhoid administration. ACTH-deficient patients had no change after insulin administration and a significant rise 6 h after typhoid vaccine treatment (24 +/- 12% to 50 +/- 6%; P less than 0.05). The number of ACTH immunofluorescence-positive cells did not increase when mononuclear leukocytes were incubated in vitro with ACTH or insulin (with or without glucose deprivation). However, typhoid antigen enhanced this response from 8% to 55%. These data suggest that the number of human mononuclear leukocytes containing immunoreactive ACTH is increased by at least 2 stimuli: 1) a central factor(s), such as CRH, accounting for the in vivo rise 1 h after insulin administration in patients with an intact hypothalamic-pituitary axis, and 2) an interferon inducer (e.g. typhoid antigen), accounting for the typhoid antigen-induced rise in the number of ACTH-positive cells in vivo in ACTH-deficient patients and in vitro.

Adolescent↗
PubMed1987

Comparison of gynecologic health care problems between lesbians and bisexual women. A survey of 2,345 women.

A survey of reproductive system problems was conducted in a large group of lesbians (n = 1,921) and bisexual women (n = 424) in a nonclinical setting. Demographically the groups were similar: the majority of respondents were white, urban and well educated. A history of heterosexual coitus was common in both groups (bisexuals, 95%; lesbians, 77%). Bisexuals were more likely than lesbians to report an abnormal Papanicolaou smear, cystitis, genital herpes, gonorrhea and vaginal infections. When sexual orientation was controlled for, most, but not all, of these differences were associated with a difference in reported frequency of (prior) coitus. Despite the lower risk of certain problems, however, the lesbians who reported no previous coitus did report the occurrence of vaginitis, abnormal Papanicolaou smears and genital herpes. There were no differences in past oral contraceptive use, endometriosis, menstrual dysfunction or breast disease. The lesbian group reported a greater percentage of hysterectomies. These data suggest that, overall, the sexual behaviors of lesbians are associated with a lower risk of most sexually transmitted diseases.

Adult↗