Insulin resistance is unrelated to circulating retinol binding protein and protein C inhibitor

CONTEXT: Recent data suggest that circulating retinol-binding protein (RBP) might be involved in the pathogenesis of insulin resistance. Moreover, protein C inhibitor (PCI), which specifically binds retinoic acid, was found to be increased in myocardial infarction survivors who are also insulin resistant. OBJECTIVE: The objective of this study was to investigate the association of insulin resistance with RBP factors and PCI active antigen. DESIGN AND SETTING: This was a clinical study. PATIENTS: Nondiabetic humans with high (IS; n = 20, 14 females, six males, aged 47.2 +/- 1.9 yr, body mass index 26 +/- 1 kg/m(2)) and low (IR; n = 20, 14 females, six males, aged 45.5 +/- 1.7 yr, body mass index 28 +/- 1 kg/m(2)) insulin-stimulated glucose-disposal (M) participated in this study. MAIN OUTCOME MEASURES: M was measured by 2-h hyperinsulinemic (40 mU.min(-1).m(-2))-isoglycemic clamp tests. Measurements of RBP were performed using a nephelometric method and validated using quantitative Western blotting. RESULTS: M (80-120 min) was higher in IS (10.9 +/- 0.6 mg.min(-1).kg(-1)) than IR (4.0 +/- 0.2; P < 10(-12)). Fasting plasma RBP concentrations were comparable between IS and IR measured by both nephelometry (IS: 4.4 +/- 0.3; IR: 4.6 +/- 0.3 mg/dl, P = 0.6) and quantitative Western blot (IS 7.9 +/- 0.5, IR 8.3 +/- 0.6 mg/dl; P = 0.6). Fasting plasma PCI active antigen was similar in both groups. Plasma RBP and PCI were not significantly related to M. RBP was positively correlated with uric acid (r = 0.488, P = 0.003), triglycerides (r = 0.592, P < 0.001), prealbumin (r = 0.63, P < 0.0001), and vitamin A (r = 0.75, P < 10(-6)). CONCLUSIONS: Our data demonstrate that healthy, insulin-resistant humans do not show altered plasma retinol binding factors, such as RBP and PCI. Both do not significantly correlate with insulin sensitivity. Thus, our findings do not support the hypothesis of insulin sensitivity modulation by proteins involved in retinol transport.     

Staphylococcal superantigen-like 5 binds PSGL-1 and inhibits P-selectin-mediated neutrophil rolling

Staphylococcus aureus secretes several virulence factors interfering with host-cell functions. Staphylococcal superantigen-like (SSL) proteins are a family of 11 exotoxins with structural homology to superantigens but with generally unknown functions. Recently, we described that chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS(31-121)), a potent inhibitor of C5a-induced responses, is structurally homologous to the C-terminal domain of SSL5. Here, we identify P-selectin glycoprotein ligand-1 (PSGL-1), involved in the initial rolling of neutrophils along the endothelium, as a target for SSL5. SSL5 specifically bound to Chinese hamster ovary cells stably expressing PSGL-1 (CHO-PSGL-1), which was dependent of sulfation and sialylation. Furthermore, SSL5 bound to PSGL-1/Ig fusion protein immobilized on a biosensor chip. SSL5 affected binding of soluble P-selectin/Fc chimera, the principle ligand of PSGL-1, to CHO-PSGL-1 cells and inhibited adhesion of neutrophils to immobilized P-selectin under static conditions. Under flow conditions SSL5 strongly decreased neutrophil rolling on immobilized P-selectin/Fc and activated human endothelial cells. In conclusion, SSL5 interferes with the interaction between PSGL-1 and P-selectin, suggesting that S aureus uses SSL5 to prevent neutrophil extravasation toward the site of infection. This makes SSL5 a potential lead for the development of new anti-inflammatory compounds for disorders characterized by excessive recruitment of leukocytes.     

Using step activity monitoring to characterize ambulatory activity in community-dwelling older adults

OBJECTIVES: To explore the potential of using step activity monitoring to detect differences in ambulatory activity associated with advancing age and declining function in community-dwelling seniors. DESIGN: Cross-sectional pilot study. SETTING: General communities of Seattle, Washington; Catonsville, Maryland; and Durham, North Carolina. PARTICIPANTS: Thirty healthy younger adults, 28 healthy older adults, and 12 older adults reporting functional limitations. MEASUREMENTS: Ambulatory activity data were collected over 6 days with the StepWatch 3. Average daily values were calculated for number of steps, number of minutes of activity, number of activity bouts, variability of minute-to-minute activity, and randomness of minute-to-minute activity fluctuations. RESULTS: Healthy older adults engaged in fewer bouts of activity (P=.03) and displayed less-variable activity (P=.02) than younger adults. Older adults reporting functional limitations not only engaged in fewer bouts of activity (P=.009) and less variable activity (P<.001) than younger adults, but also accumulated fewer total steps (P=.003) and minutes of activity (P=.008) and had less-random minute-to-minute activity fluctuations (P=.02). CONCLUSION: Step activity monitoring data were useful for detecting differences in ambulatory activity according to age and functional limitation. Monitor-based measures reflecting patterns of ambulatory activity show promise for use in studies of physical functioning.     

Urocortin 2 infusion in healthy humans: hemodynamic, neurohormonal, and renal responses.

OBJECTIVES: We sought to examine the effects of urocortin (UCN) 2 infusion on hemodynamic status, cardiovascular hormones, and renal function in healthy humans. BACKGROUND: Urocortin 2 is a vasoactive and cardioprotective peptide belonging to the corticotrophin-releasing factor peptide family. Recent reports indicate the urocortins exert important effects beyond the hypothalamo-pituitary-adrenal axis upon cardiovascular and vasohumoral function in health and cardiac disease. METHODS: We studied 8 healthy unmedicated men on 3 separate occasions 2 to 5 weeks apart. Subjects received placebo, 25-microg low-dose (LD), and 100-microg high-dose (HD) of UCN 2 intravenously over the course of 1 h in a single-blind, placebo-controlled, dose-escalation design. Noninvasive hemodynamic indexes, neurohormones, and renal function were measured. RESULTS: The administration of UCN 2 dose-dependently increased cardiac output (mean peak increments +/- SEM) (placebo 0.5 +/- 0.2 l/min; LD 2.1 +/- 0.6 l/min; HD 5.0 +/- 0.8 l/min; p < 0.001), heart rate (placebo 3.3 +/- 1.0 beats/min; LD 8.8 +/- 1.8 beats/min; HD 17.8 +/- 2.1 beats/min; p < 0.001), and left ventricular ejection fraction (placebo 0.6 +/- 1.4%; LD 6.6 +/- 1.5%; HD 14.1 +/- 0.8%; p < 0.001) while decreasing systemic vascular resistance (placebo -128 +/- 50 dynes x s/cm(5); LD -407 +/- 49 dynes x s/cm(5); HD -774 +/- 133 dynes.s/cm(5); p < 0.001). Activation of plasma renin activity (p = 0.002), angiotensin II (p = 0.001), and norepinephrine (p < 0.001) occurred only with the higher 100-mug dose. Subtle decreases in urine volume (p = 0.012) and natriuresis (p = 0.001) were observed. CONCLUSIONS: Brief intravenous infusions of UCN 2 in healthy humans induced pronounced dose-related increases in cardiac output, heart rate, and left ventricular ejection fraction while decreasing systemic vascular resistance. Subtle renal effects and activation of plasma renin, angiotensin II, and norepinephrine (at high-dose only) were observed. These findings warrant further investigation of the role of UCN 2 in circulatory regulation and its potential therapeutic application in heart disease.     

Novel mutations in two unrelated Italian patients with SSADH deficiency

Metabolic Brain Disease - Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive disorder of γ-aminobutyric acid (GABA) catabolism caused by mutations in the...     

Association between waist circumference and waist-to-height ratio with insulin resistance biomarkers in normal-weight adults working in a private educational institution

AimTo assess the association between elevated waist circumference (WC) and high waist-to-height ratio (WHtR) with insulin resistance biomarkers.MethodsWe conducted an analytical cross-sectional study in normal-weight adults. Participants were divided in two groups according to WC or WHtR levels. We considered values of WC ≥ 90 in male participants and WC ≥ 80 in adult women as elevated, and values of WHtR≥0.50 as high, for both genders. Our outcomes were high triglycerides to HDL-cholesterol (TG/HDL-C) ratio and elevated triglycerides and glucose index (TGI). We considered values of TG/HDL-C ratio ≥ 3 as high and TGI values ≥ 8.37 as elevated. We elaborated crude and adjusted Poisson generalized linear models to evaluate the proposed associations and explored the gender interaction using stratified models. We reported the prevalence ratio (PR) with their respective 95% confidence intervals (95%CI).ResultsWe analyzed 355 participants. The prevalence of elevated WC and high WHtR was 17.2% (n = 61) and 33.2% (n = 118), respectively, while the prevalence of high TG/HDL-C ratio and elevated TGI was 24.8% (n = 88) and 12.7% (n = 45), respectively. In the adjusted regression model, elevated WC was associated with high TG/HDL-C ratio only in female participants (aPR = 3.61; 95%CI: 1.59–8.20). Similarly, high WHtR was associated with high TG/HDL-C ratio in women (aPR = 2.54; 95%CI:1.08–5.97). We found an association with statistically marginal significance between elevated WC and elevated TGI in women (aPR = 1.54; 95%CI: 0.95–2.50); as well as for the association between high WHtR and elevated TGI in male participants (aPR = 1.87; 95%CI: 1.00–3.50).ConclusionElevated WC and high WHtR were associated with a high TG/HDL-C ratio in women. It is necessary to perform prospective follow-up studies in the Peruvian population in order to corroborate our results.     

Cloning of the rat ADAMTS‐1 gene and its down regulation in endothelial cells in cirrhotic rats

Abstract: Aims: This study was undertaken in order to identify genes which are regulated during the process of liver fibrosis. Methods: The differential display method and RNA from rat endothelial cells before and after induction of cirrhosis were used. Results: A 496bp fragment, which was down regulated in liver endothelial cells from a cirrhotic animal, was cloned. The cloned fragment showed a 95% homology with the newly cloned mouse ADAMTS‐1 gene (a disintegrin and metalloproteinase with thrombospondin motifs), which is implicated in inflammation. The fragment was found to span the 3′ of exon 6, the whole exon 7 and the 5′ of exon 8. Sequencing of the entire coding region of the rat gene showed a 94% homology at the nucleic acid level and 96% homology at the amino acid level. The sequences responsible for the function of the protein were conserved. Northern blot analysis, using the cloned fragment as a probe, confirmed the finding that the gene was down‐regulated in endothelial cells derived from livers of cirrhotic animals. In situ PCR analysis localised the ADAMTS‐1 gene in the liver endothelial cells from normal animals. Conclusions: Regulation of the expression of genes which belong to the metalloproteinase family in liver endothelial cells might be important in the development of liver cirrhosis.     

Peripheral blood biomarkers of early immune reconstitution in newly diagnosed multiple myeloma

Peripheral blood biomarkers of tumor microenvironment and immune surveillance are independent prognostic factors in multiple myeloma. The timing and prognostic impact of immune reconstitution has been studied after autologous hematopoietic stem cell transplantation, less is known about its significance in newly diagnosed multiple myeloma. We studied absolute lymphocyte (ALC) and absolute monocyte (AMC) counts at the time of treatment initiation and 1 month thereafter in 771 newly diagnosed patients. Two hundred and thirty-four patients (31%) had evidence of immune dysregulation at baseline (abnormal biomarkers). Eighty-seven of these patients (37%) recovered normal biomarkers at 1 month (early immune reconstitution). The absence of immune dysregulation at baseline (compared to the presence thereof) was associated with better overall survival (HR 0.77, 95% CI 0.61-0.97, P = 0.025, n = 771). The absence of immune dysregulation at 1 month (compared to the persistence or development thereof) was associated with better overall survival (HR 0.63, 95% CI 0.50-0.80, P < 0.001, n = 771). Early immune reconstitution (compared to the persistence or development of immune dysregulation) was associated with better overall survival (HR 0.62, 95% CI 0.43-0.92, P = 0.016, n = 771). Cytogenetic high-risk disease was negatively, and treatment with immunomodulators positively, associated with early immune reconstitution. The presence or development of immune dysregulation in newly diagnosed multiple myeloma is an independent risk factor. The favorable impact of early immune reconstitution suggests immune dysregulation to be a potentially modifiable risk factor that may be exploited for therapeutic benefit.     

Interference with T cell receptor-HLA-DR interactions by Epstein-Barr virus gp42 results in reduced T helper cell recognition

Epstein-Barr virus (EBV) persists lifelong in infected hosts despite the presence of antiviral immunity. Many viral antigens are expressed during lytic infection. Thus, for EBV to spread, it must have evolved effective ways to evade immune recognition. Here, we report that HLA class II-restricted antigen presentation to T helper cells is hampered in the presence of the lytic-phase protein gp42. This interference with T cell activation involves association of gp42 with class II peptide complexes. Using HLA-DR tetramers, we identify a block in T cell receptor (TCR)-class II interactions imposed by gp42 as the underlying mechanism. EBV gp42 sterically clashes with TCR Valpha-domains as visualized by superimposing the crystal structures for gp42-HLA-DR1 and TCR-MHC class II complexes. Blocking TCR recognition provides a previously undescribed strategy for viral immune evasion.