Adiponectin in renal disease: relationship to phenotype and genetic variation in the gene encoding adiponectin

BACKGROUND: The prevalence of cardiovascular disease (CVD) and inflammation is high in patients with end-stage renal disease (ESRD). Adiponectin is an adipocytokine that may have significant anti-inflammatory and anti-atherosclerotic effects. Low adiponectin levels have previously been found in patients with high risk for CVD. METHODS: In a cohort of 204 (62% males) ESRD patients aged 52 +/- 1 years the following parameters were studied: presence of CVD, body composition, plasma adiponectin (N= 107), cholesterol, triglycerides, HDL-cholesterol, serum leptin, high-sensitivity C-reactive protein (hs-CRP), urinary albumin excretion (UAE), and single-nucleotide polymorphisms (SNPs) in the apM1 gene at positions -11391, -11377, 45, and 276. Thirty-six age- (52 +/- 2 years) and gender-matched (64% males) healthy subjects served as control subjects. RESULTS: Markedly (P < 0.0001) elevated median plasma adiponectin levels were observed in ESRD patients (22.2 microg/mL), especially type 1 diabetic patients (36.8 microg/mL), compared to control subjects (12.2 microg/mL). Log plasma adiponectin correlated to visceral fat mass (R=-0.29; P < 0.01) and Log hs-CRP (R=-0.26; P < 0.01). In a stepwise (forward followed by backward) multiple regression model only type-1 diabetes (P < 0.001) and visceral fat mass (P < 0.05) were independently associated with plasma adiponectin levels. The adiponectin gene -11377 C/C genotype was associated with a lower prevalence of CVD (25 vs. 42%) compared to the G/C genotype. CONCLUSION: The present cross-sectional study demonstrates that, whereas genetic variations seem to have a minor impact on circulating adiponectin levels, lower visceral fat mass and type 1 diabetes mellitus are associated with elevated plasma adiponectin levels in ESRD patients. Furthermore, low levels of adiponectin are associated with inflammation in ESRD.     

Chronic systemic inflammation in dialysis patients: an update on causes and consequences

Despite marked improvements in dialysis technology during the last 20 years, the age-adjusted mortality rate in end-stage renal disease (ESRD) patients treated by dialysis is still unacceptably high and comparable to that of many cancer patients with metastases. The main cause of the increased mortality in ESRD patients is cardiovascular disease (CVD), which is twice as common and advances at twice the rate already in patients with early stages of chronic kidney disease as compared to the general population. Although traditional risk factors for CVD are common in dialysis patients, they can only in part explain the very high prevalence of CVD in this patient group. Recent evidence demonstrates that chronic inflammation, a non-traditional risk factor which is a commonly observed in dialysis patients, may cause progressive atherosclerotic CVD and malnutrition, itself an important risk factor for the development of CVD, by several pathogenetic mechanisms. The causes of inflammation in dialysis are multifactorial and include both dialysis-related and unrelated factors. While the long-term effects of chronic inflammation may be most important in the pathogenesis of CVD, the acute-phase reaction may also cause vascular damage by several pathogenic mechanisms. Indeed, it seems logical to speculate that suppression of the vicious cycle of malnutrition, inflammation, and atherosclerosis (MIA syndrome) in ESRD would improve survival and decrease co-morbidity in dialysis patients. As there are currently no established guidelines for the treatment of chronic inflammation in ESRD patients, more studies on the long-term effects of various anti-inflammatory treatment strategies on the nutritional and cardiovascular status, as well as outcome in this patient group, are clearly warranted and will be helpful in identifying precisely which pathways are most involved in the pathogenic process.     

Tumor-infiltrating lymphocytes and interleukin-2: dose and schedules of administration in the treatment of metastatic cancer

PURPOSE: The potential for therapeutic use of tumor-infiltrating lymphocytes (TIL), as adoptive cellular therapy has been touted for many years with some encouraging reports in patients with metastatic melanoma. MATERIALS AND METHODS: We previously described methodologies for TIL production and phenotypic characterization of TIL generated in our laboratory between 1991 and 1995 in semipermeable bags and between 1996 and 2000 in bioreactors. Patients treated in the earlier era were to have received a hybrid bolus and a 12-hour continuous infusion of interleukin (IL)-2 (total, 48 MIU), while in the latter era 4 days of interferon- alpha preceded the TIL and IL-2; which was given by a hybrid schedule that included bolus and 72- hour continuous IL-2 (total, 96 MIU). There were 55 patients, including 23 patients with melanoma, 9 patients with renal cell carcinoma, and 8 patients with colorectal cancer. There was only 1 objective tumor response, which was noted in a patient with renal cell carcinoma. The 55 patients who received these products were grouped in cohorts by treatment era, quantity of TIL received, amount of IL-2 intended, and different combinations of TIL and IL-2. RESULTS: There was no difference in survival by production method (treatment era), or amount of IL-2 given with TIL, but 33 patients who received an intermediate or higher dose of TIL (mean = 54.4 x 10(9)) had a median survival of 11.8 months, compared to 6.4 months for 22 patients who received 1 low-dose TIL (mean = 6.48 x 10(9)) (p = 0.059, log rank test). The objective response rate in this heterogeneous group of patients was not encouraging. The data suggest there may be a dose/benefit relationship between the total number of TIL infused and survival.     

Nondigestible carbohydrates in the diets of infants and young children: a commentary by the ESPGHAN Committee on Nutrition

The consumption of nondigestible carbohydrates is perceived as beneficial by health professionals and the general public, but the translation of this information into dietary practice, public health recommendations, and regulatory policy has proved difficult. Nondigestible carbohydrates are a heterogeneous entity, and their definition is problematic. Without a means to characterize the dietary components associated with particular health benefits, specific attributions of these cannot be made. Food labeling for "fiber" constituents can be given only in a general context, and the development of health policy, dietary advice, and education, and informed public understanding of nondigestible carbohydrates are limited. There have, however, been several important developments in our thinking about nondigestible carbohydrates during the past few years. The concept of fiber has expanded to include a range of nondigestible carbohydrates. Their fermentation, fate, and effects in the colon have become a defining characteristic; human milk, hitherto regarded as devoid of nondigestible carbohydrates, is now recognized as a source for infants, and the inclusion of nondigestible carbohydrates in the diet has been promoted for their "prebiotic" effects. Therefore, a review of the importance of nondigestible carbohydrates in the diets of infants and young children is timely. The aims of this commentary are to clarify the current definitions of nondigestible carbohydrates, to review published evidence for their biochemical, physiologic, nutritional, and clinical effects, and to discuss issues involved in defining dietary guidelines for infants and young children.     

Metformin rapidly increases insulin receptor activation in human liver and signals preferentially through insulin-receptor substrate-2

Metformin decreases endogenous glucose production by the liver. Few studies have examined the effect of metformin on the insulin-signaling pathway in liver models, and none have presented data on the effect in normal human liver. Huh7 human hepatoma cells and primary human hepatocytes were used. Insulin receptor (IR) and IR substrates (IRS)-1 and -2 were assessed by immunoprecipitation and immunoblot. Normal human liver was used to assay IR kinase activity (IR-KA). Tyrphostin AG1024 was used to inhibit IR-KA and examine effects on deoxyglucose uptake. Metformin (1 micro g/ml) increased IR tyrosine phosphorylation by 78% (P = 0.0007) in 30 min in human hepatocytes and Huh7 cells and increased IRS-2 but not IRS-1 activation, and the downstream increase in deoxyglucose uptake was mediated via increased translocation of GLUT-1 to the plasma membrane. Metformin did not augment maximal or submaximal insulin-stimulated IR activation. Metformin increased basal IR-KA by 150% (P = 0.0001). AG1024 inhibited metformin-induced IR-beta phosphorylation in a concentration-dependent manner and abolished metformin-induced 2-deoxyglucose uptake. This study demonstrates that the mechanism of action of metformin in liver involves IR activation, followed by selective IRS-2 activation, and increased glucose uptake via increased GLUT-1 translocation. The effect of metformin was completely blocked by an IR inhibitor.     

Elevation of biochemical markers for myocardial damage prior to hospital admission in patients with acute chest pain or other symptoms raising suspicion of acute coronary syndrome

Abstract. Svensson L, Axelsson C, Nordlander R, Herlitz J (South Hospital, Stockholm; and Sahlgrenska University Hospital, Göteborg; Sweden). Elevation of biochemical markers for myocardial damage prior to hospital admission in patients with acute chest pain or other symptoms raising suspicion of acute coronary syndrome. J Intern Med 2003; 253: 311–319. Objectives. To evaluate the occurrence of elevation of serum biochemical markers for myocardial damage in the prehospital setting amongst patients who called for an ambulance due to a suspected acute coronary syndrome (ACS). Design. Prospective observational study. Subjects. All the patients who called for an ambulance due to suspected ACS. Setting. South Hospital's catchment area in Stockholm and in the Municipality of Göteborg, Sweden between January and November in the year 2000, were included. Interventions. On arrival of the ambulance crew, a blood sample was drawn for bedside analysis of serum myoglobin, creatine kinase MB and troponin I. A 12‐lead electrocardiogram (ECG) was simultaneously recorded. Main outcome measures. Elevation of biochemical markers prior to hospital admission. Results. In all, 511 patients participated on 538 occasions. Elevation of any biochemical marker was observed in 11% of all patients. The corresponding figure for patients developing myocardial infarction was 21%; for patients with myocardial ischaemia 8%; for patients with a possible myocardial ischaemia 4% and for patients with other diagnoses 5%. Amongst those who had a final diagnosis of acute myocardial infarction (AMI), 47% had ST‐elevation on initial ECG and 57% had either ST‐elevation or elevation of any biochemical marker. Conclusion. Bedside analysis of biochemical markers in serum is already feasible prior to hospital admission amongst patients with a suspected ACS. About 20% of patients with AMI have elevated biochemical markers at that stage. When found this data might increase the possibility of diagnosing an AMI very early in the course. However, false positives were found and whether this strategy will improve the triage of these patients in the prehospital setting remains to be proven.     

Glutathione-S-transferase pi expression and activity is increased in colonic neoplasia

Glutathione-S-transferase (GST) isoenzymes are involved in the conjugation of glutathione to electrophilic carcinogens. Recent studies have shown increased levels and activities of GST in different tumors suggesting their role in carcinogen detoxification. This study compared GST activity levels and GST-pi protein expression in paired samples of colorectal cancer, adenoma and adjacent normal mucosa from a total of thirteen patients. GST was isolated from human colorectal specimens and assayed spectrophotometrically; Western immunoblot analysis was used to quantify GST-pi levels. GST activity was greater in both colorectal cancer and adenomas than in adjacent normal colonic tissue, although statistical significance was achieved only when comparing colorectal cancer to normal tissue. Based on these observations, we conclude that increased GST activity may be a useful marker of colonic neoplasia.