PET Imaging of the AT1 receptor with [11C]KR31173

AIM: The goal of this study was to investigate the binding characteristics of [(11)C]KR31173 and its applicability for PET studies of the AT(1) receptor (AT(1)R). METHODS: Ex vivo biodistribution and pharmacology were tested in mice. PET imaging was performed in mice, beagle dogs and a baboon. To assess nonspecific binding, PET imaging was performed both before and after pretreatment with a potent AT(1)R antagonist. In the baboon, PET imaging was also performed with the previously developed radioligand [(11)C]L-159,884 for comparison. RESULTS: Ex vivo biodistribution studies in mice showed specific binding rates of 80-90% in the adrenals, kidneys, lungs and heart. Specific binding was confirmed in mice using small animal PET. In dogs, renal cortex tissue concentration at 75-95 min postinjection (pi) was 63 nCi/ml per millicurie at a specific binding rate of 95%. In the baboon renal cortex, tissue activity at 55-75 min pi was 345 nCi/ml per millicurie. In the baboon the specific binding of [(11)C]KR31173 was higher (81%) than the specific binding of [(11)C]L-159,884 (34%). CONCLUSION: [(11)C]KR31173 shows accumulation and significant specific binding to the AT(1)R in the kidneys of mice, dogs and baboon. These findings suggest that this radioligand is suited for imaging the renal cortical AT(1)R in multiple species.     

Improved insulin sensitivity and resistance to weight gain in mice null for the Ahsg gene

Fetuin inhibits insulin-induced insulin receptor (IR) autophosphorylation and tyrosine kinase activity in vitro, in intact cells, and in vivo. The fetuin gene (AHSG) is located on human chromosome 3q27, recently identified as a susceptibility locus for type 2 diabetes and the metabolic syndrome. Here, we explore insulin signaling, glucose homeostasis, and the effect of a high-fat diet on weight gain, body fat composition, and glucose disposal in mice carrying two null alleles for the gene encoding fetuin, Ahsg (B6, 129-Ahsg(tm1Mbl)). Fetuin knockout (KO) mice demonstrate increased basal and insulin-stimulated phosphorylation of IR and the downstream signaling molecules mitogen-activated protein kinase (MAPK) and Akt in liver and skeletal muscle. Glucose and insulin tolerance tests in fetuin KO mice indicate significantly enhanced glucose clearance and insulin sensitivity. Fetuin KO mice subjected to euglycemic-hyperinsulinemic clamp show augmented sensitivity to insulin, evidenced by increased glucose infusion rate (P = 0.077) and significantly increased skeletal muscle glycogen content (P < 0.05). When fed a high-fat diet, fetuin KO mice are resistant to weight gain, demonstrate significantly decreased body fat, and remain insulin sensitive. These data suggest that fetuin may play a significant role in regulating postprandial glucose disposal, insulin sensitivity, weight gain, and fat accumulation and may be a novel therapeutic target in the treatment of type 2 diabetes, obesity, and other insulin-resistant conditions.     

The effect of single-level, total disc arthroplasty on sagittal balance parameters: a prospective study

A prospective radiographic study of the influence of total disc replacement on spinal sagittal balance. The goal of this study was to prospectively determine the effect of a single-level, total disc replacement on the sagittal balance of the spine, especially on sacral tilt (ST), pelvic tilt (PT), and lumbar lordosis. It has been shown that lumbar fusion may deleteriously alter the sagittal balance of the spine, including a decrease in the ST and lumbar lordosis. Clinically, postfusion pain has been shown to be significantly related to a decreased ST, increased PT, and decreased lumbar lordosis, independent of other factors such as pseudoarthrosis. To our knowledge, the influence of total disc replacement on spinal sagittal balance has not yet been reported in the literature. This is a prospective study of 35 patients who received a single level disc replacement using the Maverick Total Disc Arthroplasty system (Medtronic Sofamor Danek, Memphis, Tennessee) by a single surgeon at one institution from March 2002 to September 2003. The preoperative and postoperative radiographic evaluation included standing anteroposterior and lateral full spine films that included the femoral heads. The parameters studied were ST, PT, global and segmental lordosis, and global kyphosis. The average age of the 35 patients studied was 44.3 years (range 35–57). There were 18 females and 17 males. The disc arthroplasty was performed at the L4–L5 level in 19 patients and at the L5–S1 level in 16 patients. The average follow-up was 14 months (range 6–22 months). The preoperative values of global lordosis, ST, and PT were 51.5°, 37.8°, 16.9° and, at last follow-up, they were 51.4°, 37.4°, and 17.5°, respectively. These changes were not significantly different. When the groups were separated according to the level operated, there was still no statistical difference with regard to the overall lordosis, ST, PT or kyphosis from pre- to postoperative period or when the two groups were compared with each other. The level above the prosthesis has always significantly less lordosis. In the present study with use of a motion-preserving Maverick prosthesis, it appears that the patient is able to maintain the preoperative sagittal balance. The prosthesis has enough freedom of motion to allow the patient to maintain the natural sagittal and spinopelvic balance needed to prevent potential undue stress on the muscles and the sacroiliac joint. Although the number of patients is small, this is the first study to our knowledge that evaluates the sagittal balance after motion-preserving total disc arthroplasty.     

The natural history of renal disease in Australian Aborigines. Part 1. Changes in albuminuria and glomerular filtration rate over time.

BACKGROUND: The purpose of this study was to describe changes over time in albuminuria and glomerular filtration rate (GFR) in a cohort of Australian Aborigines from a community with high rates of renal disease and renal failure. METHODS: Participants were 486 adult community members (20+ years at first exam) who were screened for renal disease and related factors on at least two occasions (mean 2.7 occasions), at least a year apart, between 1990 and 1997. Renal function was assessed by the albumin:creatinine ratio (ACR; g/mol) on a random urine specimen and by the GFR estimated from the Cockcroft-Gault formula. Evolution over time was expressed as the average annual changes in these parameters. RESULTS: On baseline examination, 70% of participants had albuminuria (ACR 1.1+ g/mol) There was a significant net increase in ACR and a fall in GFR in the cohort over time. Among individuals, however, changes were strongly correlated with ACR levels at baseline. There was no loss of GFR in persons with normal renal parameters at baseline and a rapid loss of GFR in those with substantial levels of albuminuria at baseline. Other factors significantly correlated with progression of ACR included age, baseline body mass index and systolic blood pressure, the presence of diabetes (or levels of fasting glucose), and elevated levels of serum gamma glutamyl transferase. Factors significantly associated with loss of GFR included body mass index, diabetes, systolic and diastolic blood pressures, microscopic hematuria, and marginally high cholesterol levels. CONCLUSION: Albuminuria progresses and GFR is lost over time in individuals in this community, at rates that are strongly dependent on levels of pre-existing albuminuria. Much loss of GFR and all renal failure should be avoided by preventing the development of albuminuria and minimizing its progression. This depends on improving the weight, blood pressure, and metabolic profile of the entire community and reducing infections. Modification of the course in people with established disease depends on vigorous control of blood pressure and the metabolic profile and the specific use of angiotensin-converting enzyme inhibitors.     

Fecal sterols and bacterial β‐glucuronidase activity: A preliminary metabolic epidemiology study of healthy volunteers from Umea,Sweden, and metropolitan New York

The dietary pattern, fecal bile acid and neutral sterol concentrations, and the bacterial β‐glucuronidase activity of 2 population groups with a varied risk for colon cancer development (i.e., a high‐risk population in the metropolitan New York area and an intermediate‐risk population in Umea, Sweden) were investigated. The average daily intake of dietary protein was the same in the 2 groups, but the fat intake was higher in Umea than in New York. The daily total fiber intake was also higher in Umea, as was the daily total stool output. The concentration of fecal secondary bile acids and β‐glucuronidase activity was lower in Umea than in New York, but the total daily excretion of these constituents was the same in both groups. The data suggest that one of the factors contributing to the lower risk of colon cancer in Umea, despite the high dietary fat intake, is the high intake of dietary whole grain and cereal fiber, which leads to an increase in stool bulk, thus diluting and/or binding promoters.     

Effect of butylated hydroxytoluene and butylated hydroxyanisole on the mutagenicity of 3,2´‐dimethyl‐4‐aminobiphenyl

This study was undertaken to investigate the possible antimutagenic effects of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) on 3,2´‐dimethyl‐4‐aminobiphenyl (DMAB)‐induced mutagenicity, using the Ames Salmonella/mammalian microsome system. The addition of 100–250 μg of BHT or 25–500 μg of BHA/plate was found to inhibit DMAB‐induced mutagenicity in Salmonella strains TA 98 and TA 100. In TA 100, the mutagenicity was further inhibited with the addition of S9 prepared from the livers of rats fed a 0.6% BHT diet as compared to S9 from the animals fed a diet containing no BHT.     

Dietary fiber and cancer: A supplement for intervention studies

Dietary fiber is one of several variables being considered in the study of the relationship between diet and cancer. Intervention trials in which dietary fiber is increased are the most direct way of assessing the possible role of fiber in this disease. Two dietary snack products have been developed for use in a fiber intervention study: the high‐fiber snack (HFS), which supplies 23 g of dietary fiber per day (mostly from wheat bran) and the low‐fiber product (LFS), which provides 3.5 g. Over a 12‐week period, 28 volunteers consumed the HFS for 6 weeks and the LFS for 6 weeks. Compliance, as assessed by reports, through recovery of a riboflavin marker in the urine and fecal fiber analysis, was good. The only adverse effects reported were mild abdominal discomfort and gas. Serum ferritin and calcium decreased in some subjects, indicating a need to supplement the products with these essential minerals. Consumption of the snacks did not affect total energy intake or the intake of the nutrients monitored.     

Estimation of the effect of neutropenia on rates of clinical bacteraemia in HIV-infected patients.

A retrospective cohort study was conducted to quantitate the relationship between neutropenia and rates of clinical bacteraemia among adults with HIV infection receiving medical care at one institution between 1991-5. The primary exposure, absolute neutrophil count (ANC), was summarized as mean ANC within a given week, using a five-level stratification (reference > 1000/microl). ANC stratum-specific rates of bacteraemia were calculated, by organism type. Linear trend tests were performed to assess dose-response relationship between neutropenia and rates of bacteraemia. The cohort included 1645 patients contributing 26,785 patients-weeks and 191 episodes of bacteraemia. The unadjusted effect of neutropenia was most evident for bacteraemia due to E. coli (RR 3.4), Klebsiella pneumoniae (RR 16.7), and P. aeruginosa (RR 10.4). For bacteraemia due to any of these three organisms (47 episodes), with reference ANC > 1000/microl, relative rates were: 751-1000/microl, 1.12; 501-750/microl, 2.11; 251-500/microl, 13.58; 0-250/microl, 21.89.     

Apparent dietary intake in remote Aboriginal communities

Abstract: Apparent per capita food and nutrient intake in six remote Australian Aboriginal communities using the ‘store-turnover’ method is described. The method is based on the analysis of community-store food invoices. The face validity of the method supports the notion that, under the unique circumstances of remote Aboriginal communities, the turnover of foodstuffs from the community store is a useful measure of apparent dietary intake for the community as a whole. In all Aboriginal communities studied, the apparent intake of energy, sugars and fat was excessive, while the apparent intake of dietary fibre and several nutrients, including folic acid, was low. White sugar, flour, bread and meat provided in excess of 50 per cent of the apparent total energy intake. Of the apparent high fat intake, fatty meats contributed nearly 40 per cent in northern coastal communities and over 60 per cent in central desert communities. Sixty per cent of the apparent high intake of sugars was derived from sugar per se in both regions. Compared with national Australian apparent consumption data, intakes of sugar, white flour and sweetened carbonated beverages were much higher in Aboriginal communities, and intakes of wholemeal bread, fruit and vegetables were much lower. Results of the store-turnover method have important implications for community-based nutrition intervention programs.     

Primary hepatocellular carcinoma in Aboriginal Australians

Abstract: We identified incident cases of primary hepatocellular carcinoma (PHC) in the Northern Territory from 1980 to 1989: there were 18 Aboriginal and six non-Aboriginal cases, yielding incidence rates of 5.2 per 100 000 (Aboriginal) and 0.5 per 100 000 (non-Aboriginal) with a relative risk of 10.4 (95 per cent confidence interval (CI) 4.0 to 26.6). The carcinoma was more frequent in males (2.3 per 100 000) than in females (0.7 per 100 000), with a relative risk of 3.4 (CI 1.3 to 9.3). Incidence increased with age; the trend was statistically significant in Aborigines (X²₁, = 4.7, P < 0.05) but not in non-Aborigines (X²₁ = 3.4, P > 0.05). Hepatitis B virus (HBV) serology was available for 11 Aboriginal and four non-Aboriginal cases; seven of the Aboriginal cases and two of the non-Aboriginal cases were positive for hepatitis B surface antigen (HBsAg). The prevalence of HBsAg in Aboriginal patients with the carcinoma (63.6 per cent) was much higher than that (13.1 per cent) in Aborigines surveyed from communities in the Northern Territory (X²₁ = 21.7, P < 0.001). Our results show that the age-specific incidence of PHC in Aborigines in the Northern Territory (30.9 for ages 40 and over) is comparable to that in high-incidence countries such as China (36.9 for ages 40 and over), and that hepatitis B is of major aetiological importance in the Aboriginal population. This underlines the importance of universal immunisation for prevention of HBV infection and for long-term prevention of PHC.