Cytokines and chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) patients show evidence of immune activation, as demonstrated by increased numbers of activated T lymphocytes, including cytotoxic T cells, as well as elevated levels of circulating cytokines. Nevertheless, immune cell function of CFS patients is poor, with low natural killer cell cytotoxicity (NKCC), poor lymphocyte response to mitogens in culture, and frequent immunoglobulin deficiencies, most often IgG1 and IgG3. Immune dysfunction in CFS, with predominance of so-called T-helper type 2 and proinflammatory cytokines, can be episodic and associated with either cause or effect of the physiological and psychological function derangement and/or activation of latent viruses or other pathogens. The interplay of these factors can account for the perpetuation of disease with remission/exacerbation cycles. A T-helper type 2 predominance has been seen among Gulf War syndrome patients and this feature may also be present in other related disorders, such as multiple chemical sensitivity. Therapeutic intervention aimed at induction of a more favorable cytokine expression pattern and immune status appears promising.

Benzalkonium salts: effects on G protein-mediated processes and surface membranes.

Benzalkonium salts comprise a group of positively charged surface-active alkylamine biocides with the general formula alkyldimethylbenzylammonium chloride or bromide. They interact with guanine nucleotide triphosphate-binding proteins (G proteins), thereby affecting signal transduction in a variety of cell types and processes. This article reviews the known and potential basic science research and clinical applications and manifestations of benzalkonium salts. Benzalkonium salts have antiproliferative effects on a variety of cells (including T cells) through G protein-dependent pathways, affect cytokine gene expression (downregulate tumor necrosis factor expression), and are also effective bactericidal, fungicidal, and virucidal agents with multisite (direct and immunologically mediated) inhibitory activity against many pathogens, including the human immunodeficiency virus (HIV), papillomavirus, and herpesviruses. Therefore, benzalkonium salts not only appear to be effective as disinfectants and spermicides but may also prove useful in the prevention and treatment of neoplasias and other disease, particularly those linked to viruses and originating at the skin or mucosal surface.

DNA viruses and oncogenesis.

This review addresses the biology and role of DNA viruses in oncogenesis.

Acute retroviruses and oncogenesis.

This review addresses the role of acute retroviruses in oncogenesis and the molecular mechanisms of viral carcinogenesis.

Endogenous proviruses.

Sequences related to different retroviruses are present in the mammalian genome, being inherited through the germ line, and some of these sequences are expressed as RNA and protein products. The ubiquitous presence of these viral sequences suggests that they are related to some essential cellular functions. However, these functions remain to be defined. The possible role of endogenous provirus expression in cell differentiation and proliferation as well as in tumorigenic processes remains enigmatic. Available evidence strongly suggests that endogenous retroviruses present in the human and nonhuman mammalian genome are not oncogenic.

Hydrochlorothiazide-induced pulmonary edema and associated immunologic changes.

OBJECTIVE: To describe a patient with noncardiogenic acute pulmonary edema induced by hydrochlorothiazide and to investigate the possible involvement of an immunologic mechanism in this adverse reaction. CASE SUMMARY: A 66-year-old Hispanic woman developed acute pulmonary edema 30 minutes after the ingestion of one tablet of triamterene 75 mg/hydrochlorothiazide 50 mg. The reaction was associated with hemoconcentration; a decreased white blood cell count with a shift to a predominance of polymorphonuclear cells; decreased serum immunoglobulin (Ig) G, IgG1, and IgG4; and increased serum IgM and complement 3 concentrations. DISCUSSION: Although there have been 35 reports of cases of hydrochlorothiazide-induced pulmonary edema, the etiology of this adverse reaction remains unknown. The observations presented in this case report, along with commonalities with previously reported cases, suggest that granulocytic infiltration into the lungs and IgG deposition in alveolar membranes may play a role in hydrochlorothiazide-induced pulmonary edema. CONCLUSIONS: Noncardiogenic pulmonary edema may be an immunologically mediated rare idiosyncratic reaction to hydrochlorothiazide.

DNA replication and cancer.

Current knowledge of the mechanisms of DNA replication and their implications in oncogenesis is reviewed. Progress in this area will continue to provide new tools in the clinical characterization and treatment of a variety of neoplasms.

Soluble immune mediators in POEMS syndrome with pulmonary hypertension: case report and review of the literature.

POEMS syndrome is a plasma cell dyscrasia that presents with numerous complications, one of which is rarely pulmonary hypertension. Here we present a case of POEMS syndrome with pulmonary hypertension who improved with steroids and six rounds of plasmapheresis done over 1 month, and we document the baseline immune mediator status and the changes associated with the therapeutic intervention. Serum levels of soluble immune mediators such as interleukin (IL)-5, IL-8, IL-10, and eotaxin were normal at baseline and throughout therapy, whereas those of tumor necrosis factor (TNF)-alpha, soluble TNF-receptor type I (sTNF-RI), IL-6, interferon (IFN)-gamma, IL-2, and sIL-2R, which were abnormally high at baseline normalized with steroids and plasmapheresis. Serum levels of sIL-6R, which were abnormally low at baseline, increased to normal after therapy. The latter results pinpoint not only potential mediators of the systemic manifestations of POEMS syndrome with pulmonary hypertension but also relevant markers in patient follow-up. In this respect, IL-6 has been involved in the pathogenesis of multiple myeloma and Castleman's disease, and the interplay between abnormally high levels of IL-6 and abnormally low levels of its soluble receptor, deficiencies that corrected with therapy in this patient, appears to be particularly relevant to the pathogenic manifestations of POEMS syndrome with pulmonary hypertension. These findings are discussed in the context of our current knowledge of the pathogenesis of pulmonary hypertension and of potential new therapeutic modalities for POEMS syndrome with pulmonary hypertension.

Altered cell-mediated immunity in asymptomatic Colombian natives with positive or indeterminate serology for HTLV-I.

Although HTLV-I infection has been associated with immunosuppression in symptomatic patients, no controlled study has been done in asymptomatic carriers. We evaluated delayed-type hypersensitivity (DTH) to seven antigens by multitest cell-mediated immunity (CMI) in 40 Colombian Indians, 10 HTLV-I-seropositive asymptomatic patients, and 30 matched controls. Multitest CMI was placed in the forearm and was read 48 hours later by the same physician. A positive reaction was defined as > or =2 mm. Hypoergic response was defined as <2 of 7 positive reactions per case or control. We found that HTLV-I-seropositive people had fewer positive reactions than matched controls (50% versus 64%, respectively; p < .04) but no significant difference was found in these populations in the evaluation of hypoergic responses. This study suggests the presence in asymptomatic HTLV-I-positive Colombian Indians of a marginal alteration of cell-mediated immunity that cannot be classified as hypoergic.

Enteropathy-associated T-cell lymphoma and its immunocarcinogenic correlates: case report and review of the literature.

We report a case of enteropathy-associated T-cell lymphoma (EATL), diagnosed by small intestine and gastric biopsies, who presented with manifestations of hypocalcemia and malabsorption. Immunological assessment revealed increased expression levels of tumor necrosis factor system components and eotaxin, an observation that is consistent with the cytotoxic T-cell phenotype characteristic of EATL, and decreased numbers of circulating activated (CD8+CD38+ and CD4+CD25+) and suppressor (CD11b+) T cells, a feature which can contribute to lymphomagenesis in patients with celiac disease. The acute clinical presentation of the patient resolved with mineral and vitamin supplementation and a gluten-free diet. The novel immunological findings described are discussed in the context of a review of our current knowledge of the immunopathogenesis of celiac disease and associated intestinal neoplasia.

Serum neopterin and somatization in women with chemical intolerance, depressives, and normals.

The symptom of intolerance to low levels of environmental chemicals (CI, chemical intolerance) is a feature of several controversial polysymptomatic conditions that overlap symptomatically with depression and somatization, i.e., chronic fatigue syndrome, fibromyalgia, multiple chemical sensitivity, and Persian Gulf syndrome. These syndromes can involve many somatic symptoms consistent with possible inflammation. Immunological or neurogenic triggering might account for such inflammation. Serum neopterin, which has an inverse relationship with l-tryptophan availability, may offer a marker of inflammation and macrophage/monocyte activation. This study compared middle-aged women with CI (who had high levels of affective distress; n = 14), depressives without CI (n = 10), and normals (n = 11). Groups did not differ in 4 p.m. resting levels of serum neopterin. However, the CI alone had strong positive correlations between neopterin and all of the scales measuring somatization. These preliminary findings suggest the need for additional research on biological correlates of 'unexplained' multiple somatic symptoms in subtypes of apparent somatizing disorders.

Reduction of water permeability by anisotonic solutions in frog corneal epithelium.

PURPOSE: To study the effects of bathing solution osmolarity and Cl- secretagogues on the diffusional water permeability (Pdw) of the isolated frog corneal epithelium. METHODS: Isolated frog corneas, with the endothelium scraped off, were mounted as a partition between Ussing-type hemichambers. Unidirectional diffusional water fluxes (Jdw) were measured by adding 3H2O to one hemichamber and sampling from the other. Electrical parameters were measured simultaneously. Jdw was determined in control isosmotic conditions and after either changes in osmolarity of the bathing solutions or the additions of amphotericin B, epinephrine, Ca2+ ionophore, and other agents. RESULTS: Apical addition of 0.5 mM HgCl2 elicited an 11-fold increase in paracellular conductance and inhibited Jdw by 36%, suggesting that Jdw was predominantly transcellular and that there was a negligible contribution of the paracellular pathway. Pretreatment of corneas with 2-mercaptoethanol prevented the effects of Hg2+ on the paracellular conductance and Jdw. A hypotonic medium on the basolateral side reversibly reduced Jdw proportionately to the reduction in osmolarity, with 40 mOsm exerting a 29% decrease. Results from an Arrhenius plot suggest that water channels closed under this condition. Apical hypertonicity (350 mOsm) reduced Jdw by approximately 12%. Basolateral hypertonicity (450 mOsm), after permeabilization of the apical membrane with amphotericin B, reduced Jdw by 15%. Epinephrine was the only Cl- secretagogue that reduced Jdw, on average by 12%. This effect, which was also observed with amphotericin B-treated corneas, was not mediated by classical beta-receptors based on the results obtained with isoproterenol and propranolol. CONCLUSIONS: Changes in basolateral osmolarity or the presence of an apical hypertonic solution decreased the diffusional water permeability (Pdw) of the corneal epithelium. Epinephrine also decreased Pdw, and this effect was localized to the basolateral membrane. The similarities, of a sequence motif found in potassium channels and beta-adrenergic receptor kinases that are regulated by the beta gamma subunit of G proteins with that found in aquaporins 2 and 5, could explain the link with epinephrine. Regardless of the mechanism, these results indicate that corneal epithelial water permeability can be regulated, presumably to protect cell volume from changes in solution osmolarity.

Chronic retroviruses and oncogenesis.

Chronic retroviruses are associated with both malignant and nonmalignant diseases in vertebrates. This review addresses the pathogenetic basis of neoplastic processes that have been directly or indirectly associated with chronic retroviruses.

Primate retroviruses and oncogenesis.

This review summarizes the current knowledge and role of human and nonhuman primate retroviruses in the pathogenesis of neoplasia.

General biological aspects of oncogenesis.

Both genetic and epigenetic events play an important role in oncogenic processes. This review discusses the four hypothesis for the origin of neoplastic transformation (mutational genetic, nonmutational genetic, viral, and epigenetic) in the context of a summary of our current knowledge of the pathobiology of cancer.

Individual differences in neural sensitization and the role of context in illness from low-level environmental chemical exposures.

This paper summarizes the clinical phenomenology of multiple chemical sensitivity (MCS), outlines the concepts and evidence for the olfactory-limbic, neural sensitization model for MCS, and discusses experimental design implications of the model for exposure-related research. Neural sensitization is the progressive amplification of responsivity by the passage of time between repeated, intermittent exposures. Initiation of sensitization may require single toxic or multiple subtoxic exposures, but subsequent elicitation of sensitized responses can involve low or nontoxic levels. Thus, neural sensitization could account for the ability of low levels of environmental chemicals to elicit clinically severe, adverse reactions in MCS. Different forms of sensitization include limbic kindling of seizures (compare temporal lobe epilepsy and simple partial seizures) and time-dependent sensitization of behavioral, neurochemical, immunological, and endocrinological variables. Sensitized dysfunction of the limbic and mesolimbic systems could account in part for many of the cognitive, affective, and somatic symptoms in MCS. Derealization (an alteration in perception making familiar objects or people seem unfamiliar or unreal) is a common MCS symptom and has been linked with limbic dysfunction in clinical neuroscience research. Sensitization is distinct from, but interactive with, other neurobiological learning and memory processes such as conditioning and habituation (compare adaptation or tolerance). In previous studies, hypotheses for MCS involving sensitization, conditioning, and habituation (adaptation) have often been considered in isolation from one another. To design more appropriate chemical exposure studies, it may be important to integrate the various theoretical models and empirical approaches to MCS with the larger scientific literature on individual differences in these potentially interactive phenomena.

Immunological correlates of disease severity in pediatric slow progressors with human immunodeficiency virus type 1 infection.

Pediatric slow progressors are a group of HIV-1-infected individuals who are homogeneous for route and length of infection and standard of care and are therefore amenable to cross-sectional population studies on the immunological correlates of disease progression. We report here that both clinical and immunological categorizations of pediatric slow progressors based on the 1994 CDC criteria for symptom and immunosupression severity levels yield similar immunological findings: declining proportions of CD4 T cells are associated with increasing proportions of CD8 and CD4-CD8- T cells and with declining IL-2, -5, and -10 production levels by peripheral blood cells in response to the T cell-dependent mitogen, phytohemagglutinin, but not to the T and B cell-dependent mitogen from pokeweed. The latter cross-sectional results point to potential prognostic and nosologic markers and therapeutic targets among HIV-infected pediatric slow progressors. Longitudinal studies will help to assess further the relevance of these findings.