Cardiometabolic Changes in Different Gonadal Female States Caused by Mild Hyperuricemia and Exposure to a High-Fructose Diet.

BACKGROUND: The objective of this study is to observe if mild hyperuricemia and a high-fructose diet influence the cardiovascular and metabolic systems in hypogonadic female Wistar rats compared to normogonadic female rats. METHODS: Fifty-six (56) adult female Wistar rats were used in the present work. Animals were divided into two groups: normogonadic (NGN) and hypogonadic (HGN). These groups were also divided into four subgroups in accordance with the treatment: control with only water (C), fructose (F), oxonic acid (OA), and fructose + oxonic acid (FOA). Lipid profile, glycemia, uric acid, and creatinine determinations were assessed. Cardiovascular changes were evaluated by measuring blood pressure, myocyte volume, fibrosis, and intima-media aortic thickness. RESULTS: HGN rats had higher levels of total cholesterol (TC) (p < 0.01) and noHDLc (p < 0.01), in addition to higher levels of uric acid (p < 0.05). The OA group significantly increased myocyte volume (p < 0.0001) and the percentage of fibrosis as well as the group receiving FOA (p < 0.001) in both gonadal conditions, being greater in the HGN group. Hypogonadic animals presented a worse lipid profile. CONCLUSION: Mild hyperuricemia produces hypertension together with changes in the cardiac hypertrophy, fibrosis, and increased thickness of the intima media in hypogonadic rats fed high-fructose diet.

Alterations in biomarkers of cardiovascular disease (CVD) in active acromegaly.

OBJECTIVES: In acromegalic patients, cardiovascular and metabolic comorbidities contribute to enhance mortality. Available data on the lipoprotein profile of these patients are controversial. Our aim was to characterize the lipoprotein profile and emergent biomarkers of cardiovascular disease in active acromegalic patients in comparison with sex- and age-matched healthy controls. PATIENTS: Eighteen patients with active acromegaly and 18 controls were studied. MEASUREMENTS: Glucose levels, hormonal status, lipoprotein profile and C reactive protein (CRP) were evaluated by standardized methods. Cholesteryl ester transfer protein (CETP) and lipoprotein-associated phospholipase A(2 )(Lp-PLA(2)) were measured by radiometric techniques, endothelin-1 and vascular cell adhesion molecule (VCAM)-1 by enzyme-linked immunosorbent assay, and leucocytes CD18, CD49d and CD54 by flow cytometry. RESULTS: After adjusting for body mass index (BMI), acromegalic patients presented a more atherogenic lipoprotein profile, consisting of higher levels of triglycerides and apolipoprotein B and alterations in the ratios which estimate insulin resistance and atherogenic risk. CETP activity was significantly increased in acromegalic patients as compared to controls (168 +/- 17 vs. 141 +/- 30% per ml h, respectively; P < 0.05). Endothelin-1 levels evidenced an increase in the patients' group (0.9 +/- 0.2 vs. 0.7 +/- 0.2 ng/l, respectively; P < 0.01) and showed positive and significant correlations with GH, IGF-1 and IGFBP-3 (r = 0.45, 0.42 and 0.44, respectively; P < 0.01 for all of them; with BMI as a fixed variable). Lymphocytes from acromegalic patients showed increased CD49d content (282 +/- 59 vs. 246 +/- 48 arbitrary units, respectively; P < 0.05). CONCLUSIONS: Taken together, the alterations described seem to contribute to constituting a state of higher propensity for the development of atherosclerotic cardiovascular disease, which adds to the presence of specific cardiomyopathy.

Detection of interleukin 10 in cerebrospinal fluid of patients with subacute sclerosing panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is a neurodegenerative disorder due to persistent measles virus infection, with high level of measles-specific antibodies in cerebrospinal fluid (CSF). To analyze whether such response arises from a TH2-biased response, the authors determined TH1 (interferon [IFN]-gamma) and TH2 (interleukin [IL]-4 and IL-10) cytokines in CSF, taken at diagnosis, of eight SSPE patients (median age, 57.5 month, range 42 to 76 months). All patients presented IL-10 (median 29.3 pg/ml, range 4.3 to 162 pg/ml), but not IL-4 (<10 pg/ml); only one case showed IFN-gamma (162 pg/ml). These results are consistent with a TH2 bias or with a local, anti-inflammatory or neuroprotective mechanism involving IL-10.

Effect of ovaric hyper-stimulation on blood lymphocyte subpopulations, cytokines, leptin and nitrite among patients with unexplained infertility.

PROBLEM: To determine the effect of ovarian stimulation on TH1, TH2 and natural killer (NK) lymphocytes, plasma cytokines, leptin and nitrite levels. METHODS: Women with reproductive failure were studied during the implantation window, at baseline (n = 18) and under ovarian stimulation (gonadotropins + progesterone, n = 6). CONTROLS: eight fertile women. Lymphocyte subpopulations and NK function were determined by flow cytometry. Interleukin-2 (IL-2), IL-4, IL-10, IFN-gamma, TNF-alpha, TGF-beta1 and leptin were measured by enzyme immunoassay (EIA); nitrite by the Griess reaction. RESULTS: At baseline, patients had higher values of NK effectors, NK activity and plasma IFN-gamma and IL-2 than controls. Conversely, TGF-beta1 values were lower. Hormones induced leukocytosis. Under stimulation, THI CD4+ cells, NK effectors and function and plasma IFN-gamma and IL-2 decreased, while transforming growth factor (TGF)-beta1 increased. Other variables did not change. CONCLUSION: The abnormal distribution of leukocytes, high TH1 cytokines and a low TGF-beta1 associated with reproductive failure, respond to ovarian stimulation, achieving total or partial normalization.

High serum interleukin-10 and tumor necrosis factor alpha levels in chronic paracoccidioidomycosis.

In patients with chronic paracoccidioidomycosis (n = 10), levels of tumor necrosis factor alpha, interleukin-10, and interleukin-2 in serum, measured by enzyme-linked immunosorbent assay (in picograms per milliliter, as mean +/- standard error of the mean), were higher than in normal controls (n = 8): 186 +/- 40 versus 40 +/- 7 (P < 0.05), 203 +/- 95 versus 20 +/- 8 (P = 0.001), and 96.3 +/- 78.57 versus 1.19 +/- 1.19 (P = 0.045), respectively. Gamma interferon and interleukin-4 levels were similar in patients and controls.

Neutrophil respiratory burst activity and pro- and anti-inflammatory cytokines in AAA surgery: conventional versus endoluminal treatment.

PURPOSE: To examine the inflammatory impact of endovascular and conventional surgery of abdominal aortic aneurysm (AAA) as assessed by the activation of neutrophils and serum levels of pro- and anti-inflammatory cytokines. METHODS: Twenty-four patients undergoing AAA exclusion were treated with either endovascular (n = 14) or conventional (n=10) techniques. Clinical and hematological data, respiratory burst of neutrophils, and the expression of adhesion and activation molecules (CD18, CD11b, CD69, and HLA-DR) were analyzed by flow cytometry. The enzyme-linked immunosorbent assay technique was used to measure proinflammatory cytokine interleukin (IL)-8 and anti-inflammatory cytokines IL-1 receptor antagonist (IL-1RA) and transforming growth factor beta1 (TGF-beta1). RESULTS: All patients, most of whom had normal cytokine values before surgery, were successfully treated. No significant changes were found in surface antigens. Basal respiratory burst was quite heterogeneous; in all cases respiratory burst activity decreased after surgery and remained low throughout the observation period. Despite marked interpatient differences, IL-1RA and IL-8 increased after surgery, whereas TGF-beta1 decreased, although the variation achieved statistical significance only in the conventional group. Elevated IL-1RA returned to normal within 48 hours in the endoluminal group, whereas the level remained high in the conventional group in the last sample. CONCLUSIONS: Despite heterogeneity before surgery, the respiratory burst decreased for most of the patients regardless of the approach, and both techniques increased IL-1RA. Although both procedures seemed to decrease TGF-beta1, the difference was significant only with the conventional approach. IL-1RA levels fell toward basal values quicker in the endograft patients, suggesting that the endoluminal approach was less aggressive.

In vivo effect of snake phospholipase A2 (crotoxin+cardiotoxin) on serum IL-1alpha, TNF-alpha and IL-1ra level in humans.

VRCTC-310-Onco (crotoxin, a secretory phospholipase A2+cardiotoxin) is under development as an anti-neoplastic agent. Pro-inflammatory cytokines TNF-alpha and interleukin 1 alpha (IL-1alpha) and anti-inflammatory cytokine IL-1 receptor antagonist (IL-1ra) were measured with commercial ELISA kits in sera corresponding to 23 cycles with doses between 0.0025 and 0.023 microg/kg body weight, obtained during the phase I trial of VRCTC-310-Onco. Neither serum TNF-alpha nor IL-1alpha did change significantly after VRCTC-310-Onco. Basal IL-1ra was 794 +/- 97 pg/ml, by 3 h it was similar, 651 +/- 99 pg/ml and at 24 h p.i. it increased to 1197 +/- 122 pg/ml (P<0.001). The increase was dose-dependent. The addition of dexamethasone (required to reduce pain with the highest doses) inhibited IL-1alpha and enhanced the induction of IL-1ra by VRCTC-310-Onco. Summing up, in vivo, in humans, in the dose range tested, VRCTC-310-Onco induces IL-1ra, and does not consistently modify IL-1alpha or TNF-alpha serum levels.

Guillain-Barre syndrome following 2-chlorodeoxyadenosine treatment for Hairy Cell Leukemia.

A 68-year-old man, with Hairy Cell Leukemia developed a Guillain-Barré syndrome (G-B), 32 days after a single course of 2-Chlorodeoxyadenosine (CDA) at 0,14 mg/k/d, for five days in a two-hour-i.v. infusion and following a febrile neutropenia episode. In order to clarify whether this G-B case was related to an infection or to CDA neurotoxicity, we screened for infection-related autoimmune G-B and for antibodies (abs.) against gangliosides of peripheral nerves. Blood and urinary cultures were negative as well as serum anti-virus abs. However, serum anti-ganglioside abs. were positive for anti-asialo GM1 and anti-Gd1b. This latter finding was consistent with an autoimmune mechanism, not described until now as CDA neurotoxicity. In the present case, we do not have enough evidence to link CDA administration to the G-B syndrome. We think that it is necessary to exclude other causes of neurotoxicity before considering CDA adverse effect.

Pre- and post-treatment serum levels of cytokines IL-1beta, IL-6, and IL-1 receptor antagonist in celiac disease. Are they related to the associated osteopenia?

OBJECTIVE: Decreased bone mineral density is a common finding in untreated celiac disease patients. However, the precise pathophysiology of osteopenia remains incompletely understood. Pathological features of gluten sensitivity are associated with local release of proinflammatory and antiinflammatory cytokines. We investigated the serum levels of IL-1beta, IL-6, and IL-1 receptor antagonist in celiac patients and correlated them with bone density measurements. METHODS: We assessed serum samples of 16 female patients at the time of diagnosis (on an unrestricted diet) and after a mean time of 37 months on a gluten-free diet. At the same time, bone mineral density in the lumbar spine and total skeleton was determined by DEXA. RESULTS: Untreated patients had high serum levels of IL-1beta and IL-6 and normal IL-1-RA. Treatment produced a decrease in median IL-1beta levels (p = NS) and a significant diminution of IL-6 (p < 0.05). On the contrary, IL-1-RA increased significantly after treatment (p < 0.05). Baseline lumbar spine Z-score and IL-6 levels exhibited a significant inverse correlation (r = -0.61; p < 0.01). Patients with more severe baseline osteopenia (< -2 Z-scores) had a significantly lower IL-1-RA than those with less bone compromise (> -2 Z-scores). CONCLUSIONS: Our data demonstrate that the inflammatory process observed in active celiac disease is associated with high serum levels of IL-1beta and IL-6 and normal levels of IL-1-RA. Treatment significantly reduces both proinflammatory cytokines and significantly increases the antiinflammatory one. We also suggest that these cytokines might have a role in the osteopenia associated with celiac disease.

Growth hormone inhibits normal B-cell differentiation and neutrophils' chemotaxis in vitro.

In acromegalic patients we have previously described a low ability of B-lymphocytes to differentiate into plasma cells under PWM stimulation, and a decreased chemotaxis of polymorphonuclear leukocytes (PMN) towards N-formylmethionylphenilalanine (FMP). In this study we examined the effect of exogenous GH over these immune functions in normal cells. PMN were purified by dextran sedimentation, incubated with recombinant human GH (0 to 20 ng/ml) and subjected to stimulation with FMP. PBMC were cultured with or without PWM, in the presence of GH (between 0 and 100 ng/ml). Plasma cells were determined as hemolysis plaque forming cells and also by immunofluorescence. GH, in a dose-dependent way, decreased directed migration of PMN (5 ng/ml: 1.787 +/- 148 microns; 10 ng/ml: 1.581 +/- 221 microns; 20 ng/ml: 1.569 +/- 149 microns, all as mean +/- S.E.M.), when compared to similar values of untreated PMN (0 ng/ml 2.085 +/- 139 microns). GH treatment did not modify spontaneous migration. Net migration showed the same pattern as directed migration. GH decreased dose-dependently the PWM-driven differentiation of B-lymphocytes into plasma cells to 60% of the basal level. Although not significantly, GH tended to increase spontaneous B-cell differentiation. These results could account for the already described defect in B-cell differentiation and PWN chemotaxis in acromegaly, emphasizing the relationship between the endocrine and immune systems.

Decreased chemotaxis of neutrophils in acromegaly and hyperprolactinemia.

Both growth hormone (GH) and prolactin (PRL) modulate immune responses in vitro. We studied chemotaxis under agarose of polymorphonuclear cells from patients with acromegaly or hyperprolactinemia. Polymorphonuclear cells were purified by dextran sedimentation and subjected to stimulation with N-formylmethionyl-phenylalanine. The results showed a decrease in both directed migration (acromegaly: 971 +/- 155 microns; hyperprolactinemia: 1123 +/- 137 microns, expressed as mean +/- SEM) and spontaneous migration (acromegaly: 270 +/- 77 microns; hyperprolactinemia: 298 +/- 77 microns) when compared to similar features from normal controls (directed migration: 2019 +/- 99 microns; spontaneous migration: 590 +/- 49 microns) and from patients with non-GH/PRL-secreting pituitary tumours (directed migration: 1633 +/- 282 microns; spontaneous migration: 562 +/- 116 microns), suggesting that this defect is selective for acromegaly and hyperprolactinemia. Our results point to a putative direct or indirect effect of GH and PRL on polymorphonuclear cell chemotaxis.