David B. P. Goodman

Captopril and lisinopril suppress production of interleukin-12 by human peripheral blood mononuclear cells

Angiotensin converting enzyme (ACE) inhibitors have immunomodulatory functions and can suppress a number of proinflammatory, monocyte/macrophage-derived cytokines. Interleukin-12 is a cytokine produced primarily by monocytes and macrophages, which plays an essential role in cell mediated immunity and stimulates the development of T helper type 1 immune responses. In this study, we investigated the ability of ACE inhibitors, captopril and lisinopril, to suppress IL-12 production by human peripheral blood mononuclear cells (PBMC). We show that both ACE inhibitors significantly inhibit production of IL-12 by PBMC stimulated with bacterial lipopolysaccharide (LPS) or Staphylococcus aureus Cowan (SAC). Although both ACE inhibitors also suppressed IFN-gamma production by human anti-CD3/anti-CD28-stimulated T-cells, the addition of exogenous IFN-gamma to the PBMC stimulation medium does not abrogate the ability of ACE inhibitors to suppress IL-12 production. Inhibition of IL-12 was not associated with inhibition of IL-1beta, but correlated with the suppression of ACE. Therefore, suppression of IL-12 may contribute to the immunomodulatory effect of ACE inhibitors and may be responsible for the beneficial effect of captopril and other ACE inhibitors in inflammatory or autoimmune conditions in which IL-12 is involved.

Purification and characterization of chick intestine brush border membrane Effects of 1α(OH) vitamin D3 treatment

A new technique has been developed for the isolation of membrane vesicles from the vitamin D-deficient and vitamin D-treated chick intestinal brush border membrane. The technique involves removal of nuclei from a low speed pellet by discontinuous sucrose gradient centrifugation. The resulting intact brush borders are then homogenized in 0.5 M Tris and the membrane fragments purified on a glycerol gradient. This preparation represents a 20-fold purification of the brush border marker sucrase. After 1alpha-hydroxyvitamin D3 treatment there is a significant increase in membrane phospholipid phosphorous, an alteration in the fatty acid composition of the phosphatidylcholine fraction of membrane phospholipid, and a decrease in sucrase specific activity.

Positive and negative acute phase proteins in affective subtypes

BACKGROUNDnPatients with affective disorders show evidence of increased positive acute phase proteins (e.g., C-reactive protein [CRP], alpha-1-acid glycoprotein, haptoglobin) and decreased negative acute phase proteins (e.g., albumin, transferrin [TFN]). CRP reductions have been reported to be greater in patients who later respond to lithium augmentation, and these patients also demonstrate higher CRP levels on the failed antidepressant, prior to the addition of lithium. However, association of such systemic immune changes with affective subtypes, mood state, psychotropic medications, age and gender has not been extensively explored.nnnMETHODSnThe present study assessed levels of CRP and TFN in 79 bipolar I, 24 bipolar II, and 46 unipolar depressed outpatients in comparison to 22 healthy controls.nnnRESULTSnPatients on lithium monotherapy were significantly less likely to demonstrate elevated CRP, and a similar trend was noted in those patients taking lithium in combination with an antidepressant. The frequency of elevated CRP levels did not significantly vary for different psychotropic medications, affective subgroups, or mood states. TFN levels were not influenced by diagnosis, affective state or psychotropic medications.nnnLIMITATIONSnDue to the retrospective nature of this analysis, the affective subgroups were heterogeneous with regard to medications and affective state, and differed significantly in age. Due to limitations in subgroup sample size, significant effects of clinical variables may have been masked by interactions of medications, age, affective subtype, and mood state.nnnCONCLUSIONSnThe results imply that lithium may play a role in normalizing systemic immune activation associated with depression. Whether such immune changes may be restricted to lithium-responsive subgroups deserves further evaluation.

Breast enlargement during chronic antidepressant therapy.

Recent reports of mammoplasia during selective serotonin re-uptake inhibitor (SSRI) therapy suggested that this side effect may be more common than previously reported. We examined 59 women receiving > or = 2 months treatment with an SSRI or venlafaxine for changes in breast size in relation to menopausal status, weight gain and duration of drug therapy. Serum prolactin, estradiol and beta-hCG were also measured before and during treatment in a subgroup of patients. Twenty-three out of 59 patients (39%) reported some degree of mammoplasia. Significantly more SSRI vs. venlafaxine patients reported mammoplasia (p < 0.01). Eighty-four percent with mammoplasia had weight gain vs. 30% without mammoplasia (p < 0.001). The rate of mammoplasia was unrelated to age, menopausal status or duration of treatment. Serum prolactin increased during treatment in the paroxetine subgroup (p < 0.03). In conclusion, antidepressant-induced mammoplasia may be more common than previously expected.

Vitamin D3 induced alteration of microvillar membrane lipid composition

The lipid composition of microvillar membranes prepared from vitamin D3-treated and vitamin D3-deficient chick intestine has been investigated. Vitamin treatment results in an increase in the proportion of phospholipid in this target membrane as well as an alteration in the fatty acid composition of both membrane phospholipids and cholesterol esters. An increase in the weight percentage of several classes of phospholipid long chain polyunsaturated fatty acids results from vitamin treatment. The primary effect of vitamin treatment on cholesterol ester fatty acids appears to be in shorter chain species.

Autoantibody disturbances in affective disorders: a function of age and gender?

BACKGROUNDnNumerous investigators have reported increased autoantibodies to a wide variety of native antigens in patients with affective disorders. However, association of autoimmunity with affective subtypes, mood state, psychotropic medications, age, and gender has not been extensively explored.nnnMETHODSnThe present study assessed 79 bipolar I, 24 bipolar II, and 46 unipolar major depression patients along with 22 healthy, nonpsychiatric controls for the presence of serum antinuclear (ANA), anti-double stranded DNA, antithyroid microsomal, antithyroglobulin, anticardiolipin (ACA) IgM, and ACA IgG antibodies.nnnRESULTSnConsistent with their higher prevalence of autoimmune disease, women exhibited increased levels of ANA and ACA IgM compared to men. ACA IgG antibody titers also increased significantly with age. Contrary to prior reports of general, overall increases in autoantibodies and specific increases in ANA and antithyroid antibodies in depressed patients, we did not see a significant association between any of the autoantibodies and affective subtype, mood state, or psychotropic medications.nnnLIMITATIONSnAffective subgroups were heterogeneous with respect to psychotropic medications, affective state, age, and gender in this retrospective analysis. Subgroup sample size was insufficient to determine whether interactions of these clinical variables may have influenced results.nnnCONCLUSIONnThese results suggest that gender and age may have more influence on autoantibodies than affective diagnosis, affective state, or medications.

Phenytoin hypersensitivity: A case of severe acute rhabdomyolysis

A 22-year-old black man was hospitalized with fever, rash, myalgias, and marked periorbital and facial edema three months after beginning phenytoin therapy. His hospital course was marked by an initial serum creatine phosphokinase level of 85,000 IU/liter, which rose to a peak value of 242,000 IU/liter on the third hospital day and a striking eosinophilia (8,400/microliter). Muscle biopsy revealed only early fiber necrosis with partial dissolution of the sarcoplasm without evidence of inflammation, vasculitis, regeneration, or parasitic infection. When therapy with phenobarbital, a structural congener of phenytoin, was begun, the patient had an exacerbation of his rash and became febrile again.

CALCIUM AND CAMP AS INTERRELATED INTRACELLULAR MESSENGERS

In several of the papers presented in this volume, either Ca2+ and/or cyclic AMP (CAMP) have been discussed as possible regulators of microtubule form and function. Our major interest has not been primarily to define the biochemistry of microtubule function but to develop a fundamental understanding of the interrelationships between Ca2+ and cAMP in the control of a variety of animal-cell functions, including secretion, contraction, and metabolism., From our own work, as well as that of many others, it has become clear that Ca2+ and cAMP are interrelated second messengers in the action of a large number of peptide and amine hormones, as well as other small-molecule first messengers. It seems clear, even at this stage of our knowledge, that Ca2+ and cAMP are two of the general second messengers involved in translating events at the cell surface into altered activity within the cell. It is not surprising that in many different cell types their relationships appear to be basically similar, i.e., they act as an integrating system of interacting second messengers to control cell response. Also, considered from the perspective of biologic evolution, it is not surprising that there are several variations upon the basic theme of their relatedness. Given this variability and the evident relationship of CaZt and cAMP to microtubule form and function, it is worth outlining the extent of our knowledge about these variations in cAMP-Ca2+ relationships.

Murine macrophages stimulated with central and peripheral nervous system myelin or purified myelin proteins release inflammatory products

Macrophage inflammatory products including tumor necrosis factor (TNF) and interleukin-12/p40 are implicated in demyelinating diseases such as multiple sclerosis (MS), Guillain-Barré syndrome, and animal models experimental autoimmune encephalomyelitis and neuritis. The macrophage product angiotensin converting enzyme (ACE) is released during inflammation. ACE can also be elevated in MS. We investigated the ability of central (CNS) and peripheral nervous system (PNS) myelin to stimulate TNF, interleukin-12, and ACE production by murine macrophages. Both CNS and PNS myelin and purified myelin basic protein and P2 protein induced release of these products. Direct stimulation by myelin may represent a mechanism of inducing release of macrophage products in inflammatory demyelination or neural injury.

t-Butyl hydroperoxide alters fatty acid incorporation into erythrocyte membrane phospholipid

Because the ability of cells to replace oxidized fatty acids in membrane phospholipids via deacylation and reacylation in situ may be an important determinant of the ability of cells to tolerate oxidative stress, incorporation of exogenous fatty acid into phospholipid by human erythrocytes has been examined following exposure of the cells to t-butyl hydroperoxide. Exposure of human erythrocytes to t-butyl hydroperoxide (0.5-1.0 mM) results in oxidation of glutathione, formation of malonyldialdehyde, and oxidation of hemoglobin to methemoglobin. Under these conditions, incorporation of exogenous [9,10-3H]oleic acid into phosphatidylethanolamine is enhanced while incorporation of [9,10-3H]oleic acid into phosphatidylcholine is decreased. These effects of t-butyl hydroperoxide on [9,10-3H]oleic acid incorporation are not affected by dissipating transmembrane gradients for calcium and potassium. When malonyldialdehyde production is inhibited by addition of ascorbic acid, t-butyl hydroperoxide still decreases [9,10-3H]oleic acid incorporation into phosphatidylcholine but no stimulation of [9,10-3H]oleic acid incorporation into phosphatidylethanolamine occurs. In cells pre-treated with NaNO2 to convert hemoglobin to methemoglobin, t-butyl hydroperoxide reduces [9,10-3H]oleic acid incorporation into phosphatidylcholine by erythrocytes but does not stimulate [9,10-3H]oleic acid incorporation into phosphatidylethanolamine. Under these conditions oxidation of erythrocyte glutathione and formation of malonyldialdehyde still occur. These results indicate that membrane phospholipid fatty acid turnover is altered under conditions where peroxidation of membrane phospholipid fatty acids occurs and suggest that the oxidation state of hemoglobin influences this response.