Citations

Ongoing communication with cancer patients about their treatment preferences is important. A survey assessing treatment preferences was distributed to 100 cancer patients who were newly diagnosed, 100 in remission after therapy, and 60 who had failed therapy/ relapsed; 100 cancer caregivers, and 100 noncancer patients attending the cancer center for benign hematologic problems. Almost 59% of respondents preferred treatment even if the chance of cure was less than 10%. Among subjects who did not have cancer, less than 50% wanted treatment under these circumstances, whereas over 70% of cancer patients who had failed treatment or relapsed wanted treatment ( P = .0994). Multiple logistic regression analysis revealed that the adjusted odds of preferring aggressive treatment were less for those without cancer and those with newly diagnosed cancer than for respondents who had failed treatment or were in relapse. The preference for aggressive cancer treatment is related to medical condition.

The trafficking of leukocytes from the blood to sites of inflammation is the cumulative result of receptor-ligand-mediated signaling events associated with the leukocytes themselves as well as with the underlying vascular endothelium. Our data show that Gα i signaling pathways in the vascular endothelium regulate a critical step required for leukocyte diapedesis. In vivo studies using knockout mice demonstrated that a signaling event in a non-lymphohematopoietic compartment of the lung prevented the recruitment of proinflammatory leukocytes. Intravital microscopy showed that blockade was at the capillary endothelial surface and ex vivo studies of leukocyte trafficking demonstrated that a Gα i -signaling event in endothelial cells was required for transmigration. Collectively, these data suggest that specific Gα i2 -mediated signaling between endothelial cells and leukocytes is required for the extravasation of leukocytes and for tissue-specific accumulation.

AbstractContext: Retinol binding protein (RBP4), secreted primarily from the liver and adipose tissues, was recently proposed as a link between obesity and insulin resistance. The role of RBP4 in pediatric obesity, its relationship with subclinical inflammation, and its response to lifestyle changes are not elucidated.Objective: The objective of the study was to determine in children: 1) the status of RBP4 levels in lean vs. obese; 2) the relationship between RBP4 levels and subclinical inflammation; and 3) the effect of lifestyle-only intervention on RBP4 levels.Design, Setting, and Patients: Lean and obese children (n = 21) matched for age (>14 yr to < 18 yr) and maturity stage (Tanner IV) were studied at baseline and with lifestyle intervention in obese subjects only (n = 15).Intervention: Patients received 3 months of randomized and controlled physical activity-based lifestyle intervention.Main Outcome Measure: RBP4 levels in children before and after intervention and the relationship between RBP4 and subclinical inflammation were measured.Results: Higher RBP4 levels were found in the obese group vs. lean group (P = 0.005). RBP4 correlated with not only indices of obesity and insulin resistance but also inflammatory factors (r = 0.63 and 0.64 for C-reactive protein and IL-6, respectively, P < 0.01). Intervention reduced RBP4 levels by approximately 30% (P = 0.001), and RBP4 reduction was correlated with the magnitude of decrease in inflammatory factors (P = 0.01).Conclusion: Alterations in serum RBP4 occur at an early age in the clinical course of obesity and appear to correlate with subclinical inflammation. Lifestyle intervention almost entirely reversed the raised RBP4 levels in obese children. Future studies should determine whether elevation of RBP4 is a direct trigger for the insulin resistance and subclinical inflammation implicated in the premature development of cardiovascular disease and diabetes.

This study identifies the actin-binding protein, coronin-1a, as a novel and effective immunohistochemical marker for microglia in both cell cultures and in formaldehyde-fixed, paraffin-embedded tissue. Antibodies to coronin-1a effectively immunostained microglia in human, monkey, horse, rat, and mouse tissues, even in tissues stored for long periods of time. The identity of coronin-1a-immunoreactive cells as microglia was confirmed using double immunolabeling with cell type-specific markers as well as by morphological features and the distribution of immunoreactive cells. These properties are shared by another actin-binding protein, IBA-1. Unlike IBA-1, coronin-1a immunoreactivity was also detected in lymphocytes and certain other hematopoietic cells. The results indicate that both coronin-1a and IBA-1 are robust markers for microglia that can be used in routinely processed tissue of humans and animals. Because both coronin-1a and IBA-1 are actin-binding proteins that play a role in rearrangement of the membrane cytoskeleton, it suggests that these proteins are critical to dynamic properties of microglia.

We studied the arachidonic acid (AA)-mediated modulation of large-conductance Ca2+-activated K+ (BK) channels in coronary arterial smooth myocytes from lean control and Zucker Diabetic Fatty (ZDF) rats. A total of 1 μmol/l AA enhanced BK current by 274% in lean and by 98% in ZDF rats. After incubation with 10 μmol/l indomethacin, 1 μmol/l AA increased BK currents by 80% in lean and by 70% in ZDF rats. Vasoreactivity studies showed that the dilation of small coronary arteries produced by 1 μmol/l AA was reduced by 44% in ZDF rats. [3H]6-keto-prostagladin F1α ([3H]6-keto-PGF1α,), the stable metabolite of prostacyclin (PGI2), was the major [3H]AA metabolite produced by coronary arteries of lean vessels, but ZDF vessels produced only 15% as much [3H]6-keto-PGF1α. BK channel activation and vasorelaxation by iloprost were similar in lean and ZDF rats. Immunoblots showed a 73% reduction in PGI2 synthase (PGIS) expression in ZDF vessels compared with lean vessels, and there was no change in cyclooxygenase (COX) and BK channel expressions. Real-time PCR studies showed that mRNA levels of PGIS, COX-1, and COX-2 were similar between lean and ZDF vessels. We conclude that PGI2 is the major AA metabolite in lean coronaries, and AA-mediated BK channel activation is impaired in ZDF coronaries due to reduced PGIS activity.

To determine whether the hepatic insulin resistance of obesity and type 2 diabetes is due to impaired insulin-induced suppression of glycogenolysis as well as gluconeogenesis, 10 lean nondiabetic, 10 obese nondiabetic, and 11 obese type 2 diabetic subjects were studied after an overnight fast and during a hyperinsulinemic-euglycemic clamp. Gluconeogenesis and glycogenolysis were measured using the deuterated water method. Before the clamp, when glucose and insulin concentrations differed among the three groups, gluconeogenesis was higher in the diabetic than in the obese nondiabetic subjects (P < 0.05) and glycogenolysis was higher in the diabetic than in the lean nondiabetic subjects (P < 0.05). During the clamp, when glucose and insulin concentrations were matched and glucagon concentrations were suppressed, both glycogenolysis and gluconeogenesis were higher (P < 0.01) in the diabetic versus the obese and lean nondiabetic subjects. Furthermore, glycogenolysis and gluconeogenesis were higher (P < 0.01) in the obese than in the lean nondiabetic subjects. Plasma free fatty acid concentrations correlated (P < 0.001) with glucose production and gluconeogenesis both before and during the clamp and with glycogenolysis during the clamp (P < 0.01). We concluded that defects in the regulation of glycogenolysis as well as gluconeogenesis cause hepatic insulin resistance in obese nondiabetic and type 2 diabetic humans.

Lipolysis of adipose tissue triglycerides releases glycerol. Twenty-four volunteers, of whom 6 were obese and 13 were women, received a primed-constant infusion of 2H5-glycerol for 120 min during postabsorptive steady-state conditions. Arterial, abdominal venous, and interstitial (microdialysis) samples were taken, and a four-compartment model was applied to assess subcutaneous abdominal adipose tissue glycerol kinetics. Adipose tissue blood flow was measured using 133Xe washout. Venous glycerol concentrations (median 230 μmol/l [interquartile range 210–268]) were consistently greater than those of arterial blood (69.1 μmol/l [56.5–85.5]), while glycerol isotopic enrichments (tracer-to-tracee ratio) were greater in arterial blood (8.34% [7.44–10.1]) than venous blood (2.34% [1.71–2.69], P < 0.01). Microdialysate glycerol enrichment was 1.44% (1.11–1.79), indicating incomplete permeability of glycerol between capillary blood and interstitium. Calculated interstitial glycerol concentrations were between 270 μmol/l (256–350) and 332 μmol/l (281–371) (examining different boundary conditions). The calculated capillary diffusion capacity (ps) was between 2.21 ml · 100 g tissue−1 · min−1 (1.31–3.13) and 3.09 ml · 100 g tissue−1 · min−1 (1.52–4.90) and correlated inversely with adiposity (Rs ≤ −0.45, P < 0.05). Our results support previous estimates of interstitial glycerol concentration within adipose tissue and reveal capillary diffusion capacity is reduced in obesity.

In health, insulin is secreted in discrete pulses into the portal vein, and the regulation of the rate of insulin secretion is accomplished by modulation of insulin pulse mass. Several lines of evidence suggest that the pattern of insulin delivery by the pancreas determines hepatic insulin clearance. In previous large animal studies, the amplitude of insulin pulses was related to the extent of insulin clearance. In humans (and in large animals), the amplitude of insulin oscillations is ∼100-fold higher in the portal vein than in the systemic circulation, despite only a fivefold dilution, implying preferential hepatic extraction of insulin pulses. In the present study, by direct hepatic vein sampling in healthy humans, we sought to establish the extent of first-pass hepatic insulin extraction and to determine whether the pattern of insulin secretion (insulin pulse mass and amplitude) dictates the hepatic insulin clearance and thereby delivery of insulin to extrahepatic insulin-responsive tissues. Five nondiabetic subjects (two men and three women, mean age 32 years [range 25–39], BMI 24.9 kg/m2 [21.2–27.1]) participated. Insulin and C-peptide delivery from the splanchnic bed was measured in basal overnight-fasted state and during a glucose infusion of 2 mg · kg−1 · min−1 by simultaneous sampling from the hepatic vein and an arterialized vein along with direct estimation of splanchnic blood flow. Fractional insulin extraction was calculated from the difference between the C-peptide and insulin delivery rates from the liver. The time patterns of insulin concentrations and hepatic insulin clearance were analyzed by deconvolution and Cluster analysis, respectively. Cross-correlation analysis was used to relate C-peptide secretion and insulin clearance. Glucose infusion increased peripheral glucose concentrations from 5.4 ± 0.1 to 6.4 ± 0.4 mmol/l (P < 0.05). Likewise, insulin and C-peptide concentrations increased during glucose infusion (P < 0.05). Hepatic insulin clearance increased with glucose infusion (1.06 ± 0.18 vs. 2.55 ± 0.38 pmol · kg−1 · min−1; P < 0.01), but fractional hepatic insulin clearance was stable (78.2 ± 4.4 vs. 84 0. ± 3.9%, respectively; P = 0.18). Insulin secretory–burst mass rose during glucose infusion (P < 0.05), whereas the interburst interval remained unchanged (4.4 ± 0.2 vs. 4.5 ± 0.3 min; P = 0.36). Cluster analysis identified an oscillatory pattern in insulin clearance, with peaks occurring approximately every 5 min. Cross-correlation analysis between prehepatic C-peptide secretion and hepatic insulin clearance demonstrated a significant positive association without detectable (<1 min) time lag. Insulin secretory–burst mass strongly predicted insulin clearance (r = 0.81, P = 0.0043). In conclusion, in humans, ∼80% of insulin is extracted during the first liver passage. The liver rapidly responds to fluctuations in insulin secretion, preferentially extracting insulin delivered in pulses. The mass (and therefore amplitude) of insulin pulses traversing the liver is the predominant determinant of hepatic insulin clearance. Therefore, through this means, the pulse mass of insulin release dictates both hepatic (directly) as well as extra-hepatic (indirectly) insulin delivery. These findings emphasize the dual role of the liver and pancreas and their relationship mediated through magnitude of insulin pulse mass in regulating the quantity and pattern of systemic insulin delivery.

DHEA (dehydroepiandrosterone) replacement is not part of the current standard of care in hypoadrenal subjects. Animal studies have shown that DHEA administration prevents diabetes. To determine the physiological effect of DHEA replacement on insulin sensitivity in adrenal-deficient women, we performed a single-center, randomized, double-blind, placebo-controlled, crossover study in 28 hypoadrenal women (mean age 50.2 ± 2.87 years) who received a single 50-mg dose of DHEA daily or placebo. After 12 weeks, insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp. DHEA replacement significantly increased DHEA-S (sulfated ester of DHEA), bioavailable testosterone, and androstenedione and reduced sex hormone−binding globulin levels. Fasting plasma insulin and glucagon were lower with DHEA (42 ± 4.94 vs. 53 ± 6.58 pmol/l [P = 0.005] and 178 ± 11.32 vs. 195.04 ± 15 pmol/l [P = 0.02], respectively). The average amount of glucose needed to maintain similar blood glucose levels while infusing the same insulin dosages was higher during DHEA administration (358 ± 24.7 vs. 320 ± 24.6 mg/min; P < 0.05), whereas endogenous glucose production was similar. DHEA also reduced total cholesterol (P < 0.005), triglycerides (P < 0.011), LDL cholesterol (P < 0.05), and HDL cholesterol (P < 0.005). In conclusion, replacement therapy with 50 mg of DHEA for 12 weeks significantly increased insulin sensitivity in hypoadrenal women, thereby suggesting that DHEA replacement could have a potential impact in preventing type 2 diabetes.