Increased monocyte activation in elderly patients after surgical stress.

OBJECTIVE: To investigate age-related changes in the host response to surgical stress. The clinical course, serum interleukin-6 (IL-6) levels, monocyte production of tumor necrosis factor-alpha (TNF-alpha), and monocyte expression of CD11b/CD18 were used as markers of the systemic response. METHODS: Patients with gastric cancer, undergoing distal gastrectomy were divided into 2 groups: >75 years of age (elderly group) and < or =75 years of age (young group). Serum IL-6 levels, TNF-alpha production and CD11b/CD18 expression by monocytes, and the postoperative clinical course were compared between the 2 groups. RESULTS: TNF-alpha production by lipopolysaccharide-stimulated monocytes and CD11b/CD18 expression on monocytes after surgical stress were significantly higher in the elderly than in the young group. Moreover, serum IL-6 levels on the first postoperative day in the elderly group were significantly higher than those in the young group. The incidence and duration of systemic inflammatory response syndrome (SIRS) were significantly greater in the elderly than in the young group. CONCLUSIONS: The activation of monocytes and hypercytokinemia occur readily after surgical stress in the elderly and may therefore contribute to SIRS and increased susceptibility to postoperative complications.

Mechanism of the inhibitory effect of protease inhibitor on tumor necrosis factor alpha production of monocytes.

If the inflammatory response becomes excessive or uncontrolled by some stimuli, inappropriate inflammatory responses occur. Monocytes are extremely important cells for regulating the cytokine network and tumor necrosis factor alpha (TNFalpha) and interleukin- (IL) 10, which are mainly synthesized by monocytes, are representative cytokines that play a central role in the cytokine network. Protease inhibitors such as gabexate mesilate (GM) and ulinastatin (UTI) have been shown to have various beneficial effects by inhibiting the activation of leukocytes, but the mechanism for this has yet to be fully elucidated. In this study we investigated the mechanism of the inhibitory effect of protease inhibitors on the proinflammatory cytokine production of lipopolysaccharide- (LPS) stimulated monocytes. LPS-stimulated monocytes were treated with GM or UTI. The value of TNFalpha and IL-10 in the culture medium of monocytes was measured and each mRNA expression was assayed. The inhibitory effect of protease inhibitors on the activity of intracellular signal transduction pathways such as protein kinase C (PKC) and nuclear factor kappa B (NFkappaB) were also evaluated. GM decreased the TNFalpha production of LPS-stimulated monocytes as shown by the inhibition of mRNA expression and increased the IL-10 production of LPS-stimulated monocytes. GM also suppressed the NFkappaB activity of LPS-stimulated monocytes. UTI decreased the TNFalpha production of LPS-stimulated monocytes, but did not inhibit the TNFalpha mRNA expression. The present study shows that the inhibitory effect of GM on the TNFalpha production of activated human monocytes is mediated by the suppression of NFkappaB activation, while the mechanism of UTI inhibiting TNFalpha production of human monocytes may be due to the inhibition of either the translation or secretion of TNFalpha.

Severe sepsis induces deficient interferon-gamma and interleukin-12 production, but interleukin-12 therapy improves survival in peritonitis.

BACKGROUND: After severe sepsis, there is an increase of Th2 cytokine and a decrease in Th1 cytokine that may account for impaired cellular immunity. The aim of this study is to evaluate the Th1, Th2 cytokine balance in the serum, peritoneal lavage fluid (PLF) and liver mononuclear cells (MNC) of experimental peritonitis mice, and determine the effect of interleukin-12 (IL-12), a cytokine stimulating Th1 cytokine production, when administered to septic mice. METHODS: Experimental bacterial peritonitis mice was induced by cecal ligation and puncture (21-gauge needle, mild peritonitis) or cut (5 mm, severe peritonitis). Serum and PLF levels and liver MNC production of interferon (IFN)-gamma, IL-10, and IL-12 were measured after the procedure. Mild and severe peritonitis mice were treated intraperitoneally with recombinant IL-12 (r-IL-12) either 6 hours before or 6 and 24 hours after the procedure. The survival rates were then compared with nontreated mice. RESULTS: Serum and PLF IFN-gamma, IL-12 levels in severe peritonitis mice were significantly lower than those in mild peritonitis mice at 6 and 12 hours after the procedure. On the other hand, serum and PLF IL-10 levels in severe peritonitis mice were significantly higher than those in mild peritonitis mice at 6 hours after the procedure. Furthermore, liver MNC IFN-gamma production in severe peritonitis mice was significantly higher than that in mild peritonitis mice at 6 hours after the procedure, but liver MNC IL-12 production in severe peritonitis mice was significantly lower than that in mild peritonitis mice at 12 hours after the procedure. Severe peritonitis mice treated with r-IL-12 at 6 hours before the procedure improved survival rate, and mild peritonitis mice treated with r-IL-12 at 24 hours after the procedure showed significantly improved survival rates. CONCLUSIONS: Change in the Th1, Th2 cytokine balance in peritonitis mice might induce a shift toward a Th2 dominant phenotype according to the severity of peritonitis, and the capacity to produce IFN-gamma and IL-12 by liver MNC is reduced. Therapies designed to augment the production of Th1 cytokines, such as IL-12, may thus prove to be beneficial in the treatment of severe sepsis after peritonitis.

Enhanced efficacy of nilvadipine in hypertensives whose raised ambulatory blood pressure is sustained during sleep.

This study was designed to clarify the relationship between the antihypertensive effects of the calcium antagonist nilvadipine, and circadian changes in blood pressure. Based on measurements using an ambulatory blood pressure monitoring system (ABPM), 17 outpatients with untreated essential hypertension were divided into two groups: a sustained hypertensive group (with a fall in blood pressure during sleep < 10%, n = 7) and a waking time hypertensive group (with a fall in blood pressure during sleep > or = 10%, n = 10). During treatment with nilvadipine (8 mg/day, > or = 2 weeks), patients were reexamined by ABPM. The antihypertensive effect of nilvadipine was significantly and negatively correlated with the night time fall in blood pressure: this effect was significantly greater in the sustained hypertensive group than in the waking time hypertensive group. These data suggest that the long acting calcium antagonist nilvadipine has more potent antihypertensive effects in patients with sustained hypertension ("nondippers") than in those whose hypertension lessens during sleep ("dippers").

Liver biopsy in neonatal cholestasis: a review on statistical grounds.

The aim of this study was to improve the accuracy of the histopathologic diagnosis in the differential diagnosis between obstructive and nonobstructive forms of neonatal cholestasis, using this clinical situation as a model for a mathematical approach. The study was blind, and we performed it in two steps. In the first step, 49 histologic parameters were visually estimated and were scored on a scale of 0 to 4+ in 100 liver biopsy specimens obtained between 1980 and 1985 from 78 patients with neonatal cholestasis. Forty-eight of these 100 specimens were from patients with final diagnosis of obstructive cholestasis (Group I), and 52 were from patients with nonobstructive cholestasis (Group II). The age range was 3 to 24 weeks (median, 12.5 wk). Twelve histologic variables were selected by chi 2 and Fisher's exact test (P < .05). Next, a series of combinations among these variables were submitted to statistical analysis by logistic regression method, defining a six-variable model that had the most powerful predictive value to classify the type of cholestasis. The variables were portal ductal proliferation, bile plugs in portal bile ductules, portoportal bridges, neutrophils, hepatocyte swelling, and multinucleated giant hepatocytes. The score obtained by this model correspond to the probability of a case belonging to Group I. The accuracy, sensitivity, and specificity rates were 94.0%. In the second step, the model was applied to a new sample of 74 needle-liver biopsy specimens obtained between 1990 and 1995, 45 from patients in Group I and 29 from patients in Group II. The age range was 3 to 15 weeks (median, 8 wk). The accuracy, sensitivity, and specificity rates were 90.5%, 100%, and 75.9%, respectively. In our diagnostic routine, this score has been systematically reported and has been helpful in orienting the therapeutic decision in this group of patients.

Cold activation of complement in sera from patients with persistent hepatitis C virus infection on interferon therapy.

The loss of haemolytic activity in sera during storage at low temperature (the cold activation of complement) was observed in 136 of 184 (74%) patients with chronic liver disease associated with hepatitis C virus (HCV) infection. This was more frequent than observed in the three of 40 (8%) patients with chronic hepatitis B (P < 0.001) or none in 43 normal controls (P < 0.001). Of 103 patients with chronic hepatitis C who had completed a full course of recombinant interferon-alpha 2a therapy (total dose: 516 x 10(6) U), 40 responded completely and 21 responded partially, as judged by the normalization or decrease of alanine aminotransferase levels 6 months after the completion of therapy; 42 patients did not respond at all. The cold activation of complement persisted in five (13%) complete responders, less often than in 33 (79%) non-responders (P < 0.001). At the completion of interferon therapy, the cold activation of complement persisted in 12 of 54 patients despite the normalization of alanine aminotransferase. Spontaneous exacerbation of hepatitis occurred in seven of 12 (58%) patients with cold activation, which was more frequent than in the four of 42 patients (10%) without it (P < 0.01). The cold activation of complement disappeared along with the loss of HCV-RNA in five of six responders during the 6 month period after the completion of interferon therapy, while both cold activation and HCV-RNA persisted in all eight non-responders. These results indicate that the cold activation of complement may be useful as a marker of HCV viraemia for monitoring the response to interferon in patients with HCV infection.

Immunosuppression in dogs naturally infected with Babesia gibsoni.

We examined lymphoproliferative response to phytohemagglutinin and anti-parasite antibody level in dogs naturally infected with Babesia gibsoni. The dogs with subclinical B. gibsoni infection exhibited suppressed lymphocyte blastogenesis. Prominent depression of lymphocyte blastogenesis and anti-parasite antibody production was observed in dogs suffering from relapses of clinical B. gibsoni infection.

Inherited thermostability variants of seven enzymes in a Japanese population.

The frequency of inherited variations in thermostability was investigated in a series of seven enzymes in a Japanese population. Among a total of 5930 determinations, nine variants were encountered. In each instance one parent exhibited a similar finding. It is suggested that this procedure should detect a high proportion of the variants of these enzymes characterized by amino acid substitutions not altering molecular charge. Failure to detect more such thermostability variants is interpreted to mean that electrophoresis not only detects amino acid substitutions altering molecular charge but also a considerable proportion of those that do not alter charge.