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The American Thoracic Society (ATS) published guidelines for the treatment and management of community-acquired pneumonia in 2001, but the impact of adherence on outcomes such as mortality and length of stay is not well defined. A study of 780 patients with community-acquired pneumonia consecutively admitted to hospital over 1 yr was carried out. Nursing home patients were excluded. Overall adherence to antibiotics recommended in the ATS guidelines was 84%. The lowest adherence was found in patients admitted to an intensive care unit (52%), especially those at risk of infection with Pseudomonas aeruginosa (ATS group IVb). However, very few patients from this group were indeed infected with P. aeruginosa. This could be explained by the exclusion of the nursing home patients. There was a difference in mortality between patients that received adherent and nonadherent regimens (3 versus 10.6%). There was a difference in length of stay between patients receiving adherent and nonadherent regimens (7.6 versus 10.4 days). This result was confirmed on multivariate analysis. Adherence to the 2001 American Thoracic Society guidelines was high except in community-acquired pneumonia patients admitted to an intensive care unit. Length of stay was shorter in patients who received adherent rather than nonadherent antibiotic regimens.

Hematological disturbances that develop during linezolid treatment are a major concern when linezolid is administered for prolonged periods of time. The aim of this study was to evaluate the influences of pyridoxine, rifampin, and renal function on hematological adverse events. From January 2002 to April 2006, 52 patients received a long-term course of linezolid. Blood cell counts were monitored weekly. Thrombocytopenia was defined as a decrease to <75% of the baseline platelet count, and anemia was defined when the hemoglobin concentration decreased by > or =2 g/liter from the baseline value. Twenty-four patients received linezolid alone, and 28 patients received linezolid plus 200 mg of pyridoxine. The Kaplan-Meier survival method, followed by the log-rank test, was used to estimate the cumulative probability of adverse events, and Cox regression analysis was performed to evaluate the independent predictors of toxicity. The baseline characteristics of the patients in both groups were similar. The cumulative probability of thrombocytopenia and anemia in patients who received pyridoxine was not different from that in patients who did not receive it. Hematological adverse events were less frequent in patients taking rifampin and were more frequent in patients with renal failure. However; the Cox regression analysis showed that rifampin was the only independent predictor associated with a lower risk of thrombocytopenia (hazard ratio, 0.37; 95% confidence interval, 0.14 to 0.98; P = 0.045). In conclusion, pyridoxine did not prevent linezolid-related hematological adverse events, and the coadministration of rifampin was associated with a lower risk of thrombocytopenia.

Background: The role of viruses in community-acquired pneumonia may have been previously underestimated. We aimed to study the incidence and clinical characteristics of community-acquired pneumonia (CAP) due to respiratory viruses in adults adding PCR to routine conventional laboratory tests., Methods: Consecutive adult patients diagnosed of CAP from January 2003 to March 2004 were included. Conventional tests including cultures of blood, sputum, urine antigen detection of Streptococcus pneumoniae and Legionella pneumophila, and paired serologies were routinely performed. Nasopharyngeal swabs were processed for study of respiratory viruses through antigen detection by indirect immunofluorescence assay, isolation of viruses in cell culture and detection of nucleic acids by two independent multiplex RT-PCR assays. According to the aetiology, patients were categorized in 4 groups: group 1, only virus detected; group 2, only bacteria detected; group 3, viral and bacterial; and group 4, unkown aetiology., Results: Of 340 patients diagnosed with CAP, 198 had nasopharyngeal swabs available and were included in this study. Aetiology was established in 112 (57%) patients: group 1, n=26 (13%); group 2, n=66 (33%); group 3, n=20 (10%). The most common aetiological agent was S. neumoniae (58 patients, 29%), followed by respiratory viruses (46 patients, 23%). Forty-eight respiratory viruses were identified: influenza virus A (n=16), respiratory syncytial virus A (n=5), adenovirus (n=8), parainfluenza viruses (n=5), enteroviruses (n=1), rhinoviruses (n=8) and coronavirus (n=5). There were two patients coinfected by two respiratory viruses. Serology detected 6 viruses, immunofluorescence 8, viral culture 12, and PCR 45. For the viruses that could be diagnosed with conventional methods, the sensitivity and specificity of RT-PCR was 85% and 92%, respectively. The only clinical characteristic that significantly distinguished viral from bacterial aetiology was a lower number of leukocytes (P=0.004)., Conclusion: PCR revealed that viruses represent a common aetiology of CAP. There is an urgent need to reconsider routine laboratory tests for an adequate diagnosis of respiratory viruses, as clinical characteristics are unable to reliably distinguish viral from bacterial aetiology.

Recent prospective studies indicate endothelial dysfunction and increased risk for cardiovascular events in patients with serological evidence of multiple infections. Soluble CD14 (sCD 14) plays a key role in the neutralization of lipopolysaccharide (LPS), a well-established bacterial product inducing endothelial dysfunction. Insulin resistance was recently identified as a significant factor influencing circulating sCD 14 concentration. Thus, we investigated the association of circulating sCD14 and endothelial dysfunction in subjects with well-established insulin resistance (patients with type 2 diabetes, n = 40) compared to control non-diabetic subjects (n = 100). To further explore the underlying mechanisms, we also analysed C-reactive protein and circulating NO2-/NO3- and cyclic GMP in the diabetic group. Serum sCD 14 concentration (ELISA) was found to be differently associated with endothelium-dependent vasodilatation (EDVD, high-resolution ultrasound) in diabetic and non-diabetic subjects. In nondiabetic subjects, serum sCD14 and C-reactive protein correlated negatively with EDVD (r = -0.21, p = 0.03, and r = -0.21, p = 0.03, respectively). In a partial correlation analysis, these associations remained significant after controlling for age and weight (sCD 14 and EDVD, r = -0.23, p = 0.023; C-reactive protein and EDVD, r = -0.21, p = 0.03; sCD14 and C-reactive protein, r = 0.30, p = 0.002). In contrast, sCD 14 was positively associated with EDVD in type 2 diabetic patients (r = 0.37, p = 0.019,). Interestingly, sCD14 was also associated with NO2-/NO3- in this group (r = 0.62, p = 0.001, n = 22). EDVD also correlated with cyclic GMP (r = 0.47, p = 0.03, n = 22). In summary, circulating sCD 14 is associated with endothelial function. While in non-diabetic subjects sCD14 behaves as an acute phase reactant, its role in type 2 diabetic patients should be further clarified. These findings need to be confirmed in further studies with larger number of patients.

Objective: Adiponectin has been proposed to play important roles in the regulation of energy homeostasis and insulin sensitivity. In experimental studies, adiponectin has also been found to inhibit vascular smooth muscle cell proliferation. Decreased adiponectin levels have been described in patients with coronary artery disease, and circulating adiponectin predicts cardiovascular death in patients with renal failure. Because adiponectin appears to influence both insulin sensitivity and vessel wall physiology, we examined insulin sensitivity and vascular function in relation with circulating adiponectin., Research Design and Methods: We studied brachial artery vascular reactivity (high-resolution external ultrasound) and insulin sensitivity (minimal model) in 68 healthy subjects. Brachial artery vascular reactivity was also determined in 52 patients with altered glucose tolerance: 30 subjects with impaired fasting glucose (IFG) or glucose intolerance (GIT) and 22 patients with type 2 diabetes., Results: Circulating adiponectin concentration was significantly associated with insulin sensitivity (r=0.29, P=0.02) and with fasting serum triglycerides (r=-0.29, P=0.02) in healthy subjects. In the latter, adiponectin levels were positively associated with arterial vasodilation in response to nitroglycerin (endothelium-independent vasodilation [EIVD], r=0.41, P=0.002) but not with flux-induced, endothelium-dependent vasodilation (EDVD) (r=0.007, P=NS). In contrast, EIVD was not significantly associated with adiponectin in subjects with IFG, GIT, or type 2 diabetes (r < or =0.10, P=NS). In a multiple linear regression analysis to predict EIVD in healthy subjects, age (P=0.012), sex (P=0.042), and adiponectin concentration (P=0.045), but not BMI, insulin sensitivity, or fasting triglycerides, contributed to 39% of EIVD variance., Conclusions: Serum adiponectin concentration appears to be significantly associated with vascular function in apparently healthy humans. This association seems to be independent of its link with insulin sensitivity.

A common polymorphism (825 C/T) in exon 10 of the GNB3 gene, that encodes for the beta-3 subunit, has been associated with different degrees of activation of heterotrimeric guanine nucleotide binding proteins (G proteins). Many hormones and neurotransmitters use specific receptors that interact noncovalently with G proteins in the transmembrane signaling process. Among them, insulin uses an inhibitory G protein-sensitive mechanism that is involved in metabolic and vascular events, leading to enhanced glucose transport and vasodilation. We hypothesized differences in peripheral and vascular insulin sensitivity according to GNB3 gene polymorphism in type 2 diabetic patients. To address this issue, we used an intervention-optimization protocol to examine whether diabetic patients with the variant show a different response in terms of insulin-sensitivity. Interindividual differences in baseline insulin sensitivity and vascular dysfunction (vasodilatory response to glyceryl trinitrate) were not attributable to this polymorphism of the GNB3 gene. However, in contrast to normal homozygotes, insulin sensitivity (S(I)) significantly improved (P=0.01) in carriers of the 825T variant. Parallel to these findings, stimulated C-peptide tended to decrease, and the response to glyceryl trinitrate significantly improved (P=0.004) among 825T carriers. Body mass index, systolic and diastolic blood pressure, heart rate, or serum lipid levels did not significantly change in either group. Our findings suggest an effect of GNB3 gene polymorphism on important phenotypic variations in type 2 diabetes mellitus. The GNB3 gene polymorphism might be an example of pharmacogenetics, with the underlying etiological genetic defect altering the response to treatment.

Objective: In a recent study, iron chelation with deferoxamine led to improvement of endothelial dysfunction in patients with coronary artery disease. We tested the hypothesis that decreasing circulating iron stores might improve vascular dysfunction in patients with type 2 diabetes and increased serum ferritin concentration., Research Design and Methods: A total of 28 type 2 diabetic male patients with serum ferritin levels >200 ng/ml ( approximately 18% of consecutive type 2 diabetic men attending our outpatient clinic) were randomized to iron depletion (three extractions of 500 ml blood at 2-week intervals; group 1A) or to observation (group 1B). C282Y mutation was absent in all patients. Vascular reactivity (high-resolution external ultrasound) was evaluated at baseline and at 4 and 12 months thereafter. The two groups of patients were matched for age, BMI, pharmacological treatment, and chronic diabetic complications., Results: Endothelium-dependent vasodilation remained essentially unchanged in both groups of patients. In contrast, the vasodilation induced by glyceryl trinitrate (GTN) improved significantly after iron depletion (P = 0.006). These changes occurred in parallel to decreases in transferrin saturation index and HbA(1c) levels (-0.6%, P < 0.05) only in group 1A patients. The best predictor of the modifications in endothelium-independent vasodilation was the change in HbA(1c) levels. Changes in endothelium-independent vasodilation also correlated with the change in serum ferritin (r = -0.45, P = 0.04). At 12 months, transferrin saturation index and GTN-induced vasodilation returned to values similar to those at baseline in both groups of subjects., Conclusions: Iron depletion improves vascular dysfunction in type 2 diabetic patients with high ferritin concentrations. The mechanisms by which these changes occur should be further investigated.

Tumor necrosis factor-alpha (TNF-alpha) is increasingly recognized as a key component in the development of insulin resistance and increased blood pressure. In a sample of 368 individuals, the ratio of soluble TNF-alpha receptors (sTNFR2/sTNFR1) correlated positively with systolic and diastolic blood pressure (P < 0.01). This ratio was significantly greater in type 2 diabetic subjects (DM-2) than in type 1 diabetic patients and was greater than in control nondiabetic subjects (P < 0.00001). The TNF-alpha receptor 1 (TNFR1) density in peripheral blood monocytes was similar in DM-2 patients and in nondiabetic subjects. After phorbol 12-myristate 13-acetate, TNFR1 shedding was significantly decreased in DM-2 compared with control subjects, and it was directly associated with insulin sensitivity (r = 0.54, P = 0.03). Serum sTNFR1 concentration was also linked to the vasodilatory response to glyceryltrinitrate (P = 0.01). Conversely, TNF-alpha receptor 2 shedding was negatively associated with insulin sensitivity (r = -0.54, P = 0.03), whereas shedding of L-selectin showed no significant association. After exercise-induced lowering of blood pressure, a parallel decrease in sTNFR2/sTNFR1 was observed in DM-2 patients. Our findings suggest that insulin resistance and blood pressure are linked to altered shedding of TNF-alpha receptors in DM-2. The latter seems reversible and is not genetically determined.

Iron-related insulin-resistance is improved by iron depletion or treatment with iron chelators. The aim of this study was to evaluate insulin sensitivity and insulin secretion after blood letting in patients who had high-ferritin type 2 diabetes and were randomized to blood letting (three phlebotomies [500 ml of blood] at 2-week intervals, group 1) or to observation (group 2). Insulin secretion and sensitivity were tested at baseline and 4 and 12 months thereafter. The two groups were matched for age, BMI, pharmacologic treatment, and chronic diabetic complications. All patients were negative for C282Y mutation of hereditary hemochromatosis. Baseline glycated hemoglobin (6.27 +/- 0.9% vs. 6.39 +/- 1.2%), insulin sensitivity (2.75 +/- 1.8 vs. 3.2 +/- 2.1 mg.dl(-1).min(-1)), and area under the curve for C-peptide (AUC(C-peptide); 38.7 +/- 11.6 vs. 37.6 +/- 14.1 ng.ml(-1).min(-1)) were not significantly different between the two groups of patients. Body weight, blood pressure, blood hematocrit levels, and drug treatment remained essentially unchanged during the study period. As expected, serum ferritin, transferrin saturation index, and blood hemoglobin decreased significantly at 4 months only in patients who received blood letting. In parallel to this changes, blood HbA(1c) decreased significantly only in group 1 subjects (mean differences, -0.61; 95% CI, -0.17 to -1.048; P = 0.01). AUC(C-peptide) decreased by -10.2 +/- 6.3% after blood letting. In contrast, a 10.4 +/- 6.4% increase in AUC(C-peptide) was noted in group 2 subjects at 4 months (P = 0.032). At 12 months, AUC(C-peptide) returned to values not significantly different from baseline in the two groups of subjects. At 4 months, the change in insulin sensitivity from baseline was significantly different between the two groups (80.6 +/- 43.2% vs. -8.6 +/- 9.9% in groups 1 and 2, respectively, P = 0.049). At 12 months, the differences between the two groups were even more marked (55.5 +/- 24.8% vs. -26.8 +/- 9.9%; P = 0.005). When the analysis was restricted to those subjects who completed the follow-up until 12 months, results did not show differences compared with the changes observed at 4 months, except for insulin sensitivity. A statistically significant increase in insulin sensitivity was observed in the blood-letting group (from 2.30 +/- 1.81 to 3.08 +/- 2.55 mg.dl(-1).min(-1) at 4 months, to 3.16 +/- 1.85 mg.dl(-1).min(-1) at 12 months; P = 0,045) in contrast with group 2 subjects (from 3.24 +/- 1.9 to 3.26 +/- 2.05 mg.dl(-1).min(-1) at 4 months, to 2.31 +/- 1.35 mg.dl(-1).min(-1) at 12 months). In summary, blood letting led simultaneously to decreased blood HbA(1c) levels and to changes in insulin secretion and insulin resistance that were significantly different from those observed in a matched observational group of subjects with high-ferritin type 2 diabetes. The mechanisms for improvement in peripheral insulin sensitivity after blood letting should be investigated further.