Angel Hernanz

Daily physical activity in patients with chronic obstructive pulmonary disease is mainly associated with dynamic hyperinflation.

RATIONALE Although the major limitation to exercise performance in patients with COPD is dynamic hyperinflation, little is known about its relation to daily physical activity. OBJECTIVES To analyze the contribution of dynamic hyperinflation, exercise tolerance, and airway oxidative stress to physical activity in patients with COPD. METHODS In a cross-sectional study, we included 110 patients with moderate to very severe COPD. Daily physical activity was measured using a triaxial accelerometer providing a mean of 1-minute movement epochs as vector magnitude units (VMU). Patients performed the 6-minute walk test, incremental exercise test with measurement of breathing pattern and operating lung volumes, and constant-work rate test at 75% of maximal work rate. MEASUREMENTS AND MAIN RESULTS Using the GOLD stage and BODE index, we determined arterial blood gases, lung volumes, diffusing capacity, and biomarkers in exhaled breath condensate. Daily physical activity was lower in the 89 patients who developed dynamic hyperinflation than in the 21 who did not (n =161 [SD 70] vs. n = 288 [SD 85] VMU; P = 0.001). Physical activity was mainly related to distance walked in 6 minutes (r = 0.72; P = 0.001), Vo(2) (r = 0.63; P = 0.001), change in end-expiratory lung volume during exercise (r = -0.73; P = 0.001), endurance time (r = 0.61; P = 0.001), and 8-isoprostane in exhaled breath condensate (r = -0.67; P = 0.001). In a multivariate linear regression analysis using VMU as a dependent variable, dynamic hyperinflation, change in end-expiratory lung volume, and distance walked in 6 minutes were retained in the prediction model (r(2) = 0.84; P = 0.001). CONCLUSIONS Daily physical activity of patients with COPD is mainly associated with dynamic hyperinflation, regardless of severity classification.

Changes in the intracellular homocysteine and glutathione content associated with aging.

Since moderate hyperhomocysteinemia is an independent risk factor for vascular disease by mean of its oxidant effect and glutathione plays a main role as intracellular redox-regulating agent, we have studied for the first time the total intracellular content of homocysteine in aging. Plasma homocysteine concentration, total intracellular and plasma glutathione, and other related thiol compounds such as cysteine and the glutathione catabolite cysteinglycine were also studied. Forty three healthy elderly subjects and twenty seven healthy young ones were studied. The total intracellular peripheral blood mononuclear cell content was higher for homocysteine, cysteine and cysteinglycine, whereas that of the total glutathione was greatly decreased in elderly people with respect to young ones. Elderly subjects showed significantly higher levels than young ones of total plasma homocysteine and cysteinglycine, but not cysteine, whereas total plasma glutathione levels were increased. In addition, elderly subjects showed significantly decreased plasma vitamin E levels and increased concentrations of serum lipid peroxides measured as TBARS (reaction product of malondialdehyde with thiobarbituric acid). The intracellular glutathione content presented significantly negative correlation with serum TBARS, and intracellular and plasma homocysteine levels. These findings show an increase of homocysteine synthesis associated with aging, which in turn can produce an augmented oxidant effect on endothelium, and an impaired intracellular antioxidant capacity leading to an enhanced lipid peroxidation and decreased total intracellular glutathione content.

Increased cerebrospinal fluid Fas (Apo-1) levels in Alzheimer’s disease: Relationship with IL-6 concentrations

Increasing lines of evidence suggest a role of apoptosis in the neurodegeneration associated with Alzheimers disease, in which it has been implicated in increasing the expression of p53 and Fas. On the other hand, inflammatory cytokines have also been implicated as important factors in the progression of neuronal damage in this disease. In an attempt to investigate the possible in vivo relationship between programmed cell death and the inflammatory response in patients with dementia of the Alzheimer type (DAT), we measured the levels of soluble Fas, interleukin-1beta (IL-lbeta) and IL-6 in cerebrospinal fluid (CSF) from ten DAT patients and ten age-matched controls. Our results show a significant increase in IL-6 and soluble Fas concentrations in the CSF of DAT patients compared with those from nondemented controls. Moreover, linear regression analysis demonstrated a significant correlation (r=0.703; P<0.05) between soluble Fas and IL-6 levels in the CSF in DAT patients. These results suggest that Fas is implicated in the inflammatory response observed in Alzheimers brains.

Differential effects of gastrin-releasing peptide, neuropeptide Y, somatostatin and vasoactive intestinal peptide on interleukin-1β, interleukin-6 and tumor necrosis factor-α production by whole blood cells from healthy young and old subjects

In the present study, we have investigated the effect in vitro of gastrin-releasing peptide (GRP, 10(-10) M), neuropeptide Y (NPY, 10(-10) M), somatostatin (10(-10) M) and vasoactive intestinal peptide (VIP, 10(-9) M) on the production of IL-1 beta, IL-6 and TNF alpha by peripheral whole blood cells from healthy young and old people. We have found that GRP, NPY, somatostatin and VIP stimulated the production of IL-1 beta in old subjects, and NPY, somatostatin and VIP in young ones. In addition, the production of IL-6 was enhanced by GRP, NPY and VIP in young and old people. The TNF alpha production was stimulated by NPY and somatostatin in young subjects, and by NPY, somatostatin and VIP in old ones, whereas GRP produced a decrease of TNF alpha in young persons. GRP in old subjects and VIP in young and old subjects stimulated in a great degree the LPS-induced IL-6 production by whole blood cells. On the contrary, GRP and VIP inhibited highly the LPS-induced TNF alpha production in young controls. Our results show that these neuropeptides, when added to whole blood cells at physiological concentrations, are able to stimulate the production of IL-1 beta, IL-6 and TNF alpha in a differential way according to the subject age.

INCREASED PLASMA LEVELS OF HOMOCYSTEINE AND OTHER THIOL COMPOUNDS IN RHEUMATOID ARTHRITIS WOMEN

OBJECTIVES Since moderate hyperhomocysteinemia is an independent risk factor for vascular disease and physiological thiol compounds mediate Cu2+- and Fe3+-dependent low-density lipoprotein (LDL) oxidation, we have studied the total plasma concentrations of thiol compounds including methionine as precursor of homocysteine in rheumatoid arthritis patients, in which the high mortality found is associated with cardiovascular disease. DESIGN AND METHODS Thirty-eight women with rheumatoid arthritis and 25 age-matched control women were studied. Plasma was used to measure thiol compounds and amino acids by HPLC. RESULTS Rheumatoid arthritis patients showed significantly higher levels than healthy controls of total plasma homocysteine (17.3 +/- 7.8 vs. 7.6 +/- 1.9; p <0.001), cysteine (293 +/- 61 vs. 201 +/- 45; p < 0.001), cysteinglycine (32.7 +/- 8.3 vs. 22.3 +/- 4.7; p < 0.001) and methionine (25 +/- 9 vs. 18 +/- 3; p < 0.01), whereas total glutathione levels were not increased (4.7 +/- 2.0 vs. 4.1 +/- 1.6). CONCLUSIONS The increased levels of thiol compounds found in rheumatoid. arthritis patients may be implicated in the increased incidence of cardiovascular disease found in these patients by means of the toxic effect of homocysteine on endothelium and the increased susceptibility of LDL to oxidation by increased plasma amounts of thiol compounds such as cysteine.

Bombesin, gastrin-releasing peptide, and neuromedin C modulate murine lymphocyte proliferation through adherent accessory cells and activate protein kinase C

Recent data have shown the ability of bombesin-related peptides to stimulate murine macrophage functions. In the present study, we have investigated the effect of bombesin, gastrin-releasing peptide (GRP), and neuromedin C on the proliferative response of lymphocytes from murine axillary nodes, spleen, and thymus. The results show that these neuropeptides at 10(-9), 10(-10), and 10(-11) M concentrations modulate the lymphoproliferative response, stimulating to a small but significant extent the spontaneous proliferation and inhibiting to a great extent the lymphoproliferative response to the mitogen concanavalin A (Con A). This regulation is probably mediated through adherent accessory cells, since their presence for the neuropeptides to produce their effect. The increased interleukin-1 beta production by Con A in cultures of peritoneal macrophages (a model of adherent accessory cells) decreased after the addition of bombesin, GRP, and neuromedin C; this diminution is a possible mechanism for their inhibitory action on the lymphoproliferative response to Con A. In addition, these neuropeptides caused a significant protein kinase C activation in total leukocyte population and T-enriched lymphocytes from axillary nodes, as well as in peritoneal macrophages.

Effect of calcitonin gene-related peptide, neuropeptide Y, substance P, and vasoactive intestinal peptide on interleukin-1β, interleukin-6 and tumor necrosis factor-alpha production by peripheral whole blood cells from rheumatoid arthritis and osteoarthritis patients

In the present study, we have investigated the in vitro effect of calcitonin-related peptide (CGRP), neuropeptide Y (NPY), substance P (SP) and vasoactive intestinal peptide (VIP) at concentrations of 10(-8), 10(-9) and 10(-10) M on the production of different proinflammatory cytokines or chemokines such as IL-1beta, IL-6 and TNFalpha by peripheral whole blood cells from patients with rheumatoid arthritis, as well as from osteoarthritis patients studied as a control group without immunoinflammatory background. We have found that CGRP, NPY, SP and VIP stimulated significantly the production of those cytokines and chemokines in rheumatoid arthritis patients. In general, the stimulation was higher at the 10(-9) M concentration, with SP and VIP, and in rheumatoid arthritis patients compared to osteoarthritis ones. Neuropeptides did not significantly modify the LPS-induced cytokine production by whole blood cells. The results indicate that physiological concentrations of the neuropeptides studied can modulate the inflammatory and immunological response, stimulating significantly the production of inflammatory cytokines by human whole blood cells in rheumatoid arthritis patients, as well as, in a minor way, in osteoarthritis patients.

Serum concentrations of tumour necrosis factor‐alpha (TNF‐α) and soluble TNF‐α receptor p55 in patients with hypothyroidism and hyperthyroidism before and after normalization of thyroid function

backgbound Tumour necrosis factor‐α (TNF‐α) is a cytokine with numerous immunological and metabolic activities. Receptors for TNF‐α have been demonstrated in thyroid follicular cells and TNF‐α and its receptors have been implicated in the cytotoxic mechanisms that characterize the thyroid destruction in autoimmune thyroid disease. In patients with Graves’ disease, serum levels of TNF‐α have been reported to be elevated and administration of TNF‐α to humans has been shown to induce hormonal alterations resembling those seen in the nonthyroidal illness syndrome.

Alterations in plasma and cerebrospinal fluid levels of neuropeptides in idiopathic senile anorexia.

Plasma and cerebrospinal fluid (CSF) concentrations of three well-known satiety neuropeptides, cholecystokinin (CCK), somatostatin and calcitonin gene-related peptide (CGRP), along with two powerful orexigenic neuropeptides, neuropeptide Y (NPY) and beta-endorphin have been measured in elderly persons with idiopathic anorexia and normal weight healthy subjects in a similar age range. Plasma and CSF immunoreactivity levels of the two main fractions of CCK (CCK8s and CCK33) after being separated by HPLC were measured by a radioimmunoassay (RIA) developed in our laboratory, whereas the other neuropeptides were assayed by commercially available RIA kits. Elderly underweight anorectic patients had significantly lower levels of beta-endorphin but increased concentrations of NPY in both plasma and CSF when compared to controls. In addition to significantly higher levels of CCK8s but not CCK33 in plasma, we found a trend to higher CSF concentrations of CCK8s and a positive correlation between the body mass index and either beta-endorphin (r = 0.58, P < 0.05) or CCK8s (r = 0.69, P < 0.01) concentrations in CSF in the anorectic group. CSF somatostatin concentrations were decreased significantly, but plasma somatostatin levels and plasma and CSF concentrations of CGRP were similar in senile anorectics and controls. Treatment of five anorectic patients with megestrol acetate, 480 mg daily for 6 months, reversed only the decrease in CSF beta-endorphin levels but did not normalize the body weight or the fat body mass. On the basis of our findings, we hypothesize that a decrease in CSF beta-endorphin concentration along with a rise in plasma levels of CCK8s might be accounted for the primary anorexia of aging.

Increased cerebrospinal fluid cAMP levels in Alzheimer's disease

Since increasing evidence suggests that upregulation of the cAMP-second messenger system may be implicated in Alzheimers disease neurodegeneration, we have compared the cAMP and cGMP levels in cerebrospinal fluid (CSF) from patients with dementia of the Alzheimer type (DAT, n=10) with those from nondemented age-matched controls (n=10). Our results show that cAMP levels, but not cGMP, are significantly (p<0.01) elevated in CSF from patients with DAT compared to those from nondemented controls. Moreover, a linear regression analysis demonstrated a significant correlation (r=0.62; p<0.01) between cAMP and tau protein levels in CSF when controls and patients with DAT were studied together. These results suggest that upregulation of cAMP-signaling pathway is implicated in Alzheimers disease physiopathology.