Vascular endothelial growth factor in thyroid cyst fluids

BACKGROUND: The pathogenesis of cystic thyroid nodules is incompletely understood. Based on the assumption that vascular endothelial growth factor (VEGF) may play an important role in the pathogenesis of thyroid cyst fluid, we investigated the VEGF concentration in cyst fluids of thyroid lesions. DESIGN: Cyst fluids from 24 patients (age 31-84 years) were obtained using ultrasound-guided fine-needle aspiration. The patients' cystic thyroid nodules were of different origins. METHODS: Thyroid and cyst volumes were determined using high-resolution ultrasonography. VEGF concentrations were determined using a solid-phase enzyme-linked immunosorbent assay (ELISA). RESULTS: Differing elevated VEGF concentrations were demonstrated in cyst fluids of thyroid nodules of varied origins. The VEGF concentration in cyst fluid of patients with adenomatous goiter was significantly higher (P < 0.05) than that in thyroid nodules with cystic degeneration. The highest level of VEGF was found in bloody cyst fluid when compared with levels in other cyst fluids (P < 0.05). Interestingly, there was significant correlation (P < 0.01) between thyroid volume and VEGF concentration in cyst fluid, but no significant correlation (P = 0.20) between cyst volume and VEGF concentration. CONCLUSION: Significantly increased VEGF concentrations were found in bloody cyst fluid and in cyst fluid of thyroid adenomatous goiter, compared with VEGF concentrations in degenerative thyroid cysts. Our results suggest that VEGF may play an important role in the pathogenesis of thyroid cyst fluid.     

Amino acid variations in hepatitis C virus p7 and sensitivity to antiviral combination therapy with amantadine in chronic hepatitis C

BACKGROUND: Formation of transmembrane ion channels by hepatitis C virus (HCV) p7 and abrogation of channel function by amantadine was demonstrated in vitro. The relevance of HCV p7 amino acid (aa) variations for response to antiviral therapy with amantadine is unknown. METHODS: HCV p7 was sequenced in 86 individuals who were infected with HCV genotype 1. Thirty-six of 86 patients received amantadine within an interferon-alpha (IFN-alpha)-based antiviral therapy. Helical wheel modelling for HCV p7 was performed. RESULTS: No significant correlation of overall aa variations within HCV p7 was observed with response to IFN-alpha-based therapy with amantadine in HCV genotype 1alpha/b infected patients. When analysis was restricted to non-conservative aa variations, a higher number of aa substitutions within complete HCV p7 and transmembrane helix 2 was associated with non-response in HCV-1b-infected patients receiving therapy with amantadine (P=0.015 and P=0.037, respectively), without amantadine (P=0.106 and P=0.118, respectively), and in the total cohort of HCV-1b-infected patients (P=0.00007 and P=0.011, respectively). Furthermore, substitution L20F was observed more often in non-responders than responders with HCV-1b infection and therapy with amantadine (P=0.099). By in silico modelling, aa 20 was located toward the p7 channel lumen. Substitution L20F may impair amantadine action by altering the shape of the ion channel pore. CONCLUSION: Substitution L20F within HCV p7 may be associated with non-response to combination therapy specifically with amantadine in HCV-1b-infected patients. Non-responders with HCV-1b infection showed higher numbers of non-conservative aa variations within HCV p7 than responders, irrespective of the application of amantadine.     

The central melanocortin system directly controls peripheral lipid metabolism

Disruptions of the melanocortin signaling system have been linked to obesity. We investigated a possible role of the central nervous melanocortin system (CNS-Mcr) in the control of adiposity through effects on nutrient partitioning and cellular lipid metabolism independent of nutrient intake. We report that pharmacological inhibition of melanocortin receptors (Mcr) in rats and genetic disruption of Mc4r in mice directly and potently promoted lipid uptake, triglyceride synthesis, and fat accumulation in white adipose tissue (WAT), while increased CNS-Mcr signaling triggered lipid mobilization. These effects were independent of food intake and preceded changes in adiposity. In addition, decreased CNS-Mcr signaling promoted increased insulin sensitivity and glucose uptake in WAT while decreasing glucose utilization in muscle and brown adipose tissue. Such CNS control of peripheral nutrient partitioning depended on sympathetic nervous system function and was enhanced by synergistic effects on liver triglyceride synthesis. Our findings offer an explanation for enhanced adiposity resulting from decreased melanocortin signaling, even in the absence of hyperphagia, and are consistent with feeding-independent changes in substrate utilization as reflected by respiratory quotient, which is increased with chronic Mcr blockade in rodents and in humans with loss-of-function mutations in MC4R. We also reveal molecular underpinnings for direct control of the CNS-Mcr over lipid metabolism. These results suggest ways to design more efficient pharmacological methods for controlling adiposity.     

Effect of Oral Chenodeoxycholic Acid on Bile Acid Kinetics and Biliary Lipid Composition in Women with Cholelithiasis

Bile acid kinetics and biliary lipid composition were characterized in six women with gallstones before and after 6 mo of oral therapy with chenodeoxycholic acid, an agent that induces dissolution of cholesterol gallstones in man. Over a dosage range of 1-4 g/day, absorption varied from 0.8 to 2.3 g/day. The chenodeoxycholic acid pool expanded two-to sixfold, and bile became composed predominantly (> 90%) of chenodeoxycholic acid conjugated chiefly with glycine. Cholic acid and deoxycholic acid pools decreased markedly, so that the total bile acid pool expanded much less, about twofold on the average. Cholic acid synthesis decreased in five of the six patients, consistent with negative feedback inhibition of cholic acid synthesis by chenodeoxycholic acid. In four patients whose bile was above or close to saturation with cholesterol, the bile became unsaturated; in two patients, whose bile was unsaturated, it remained so. In five patients with radiolucent gallstones, chenodeoxycholic acid therapy was continued after completion of kinetic and composition measurements; the stones decreased in size or dissolved entirely during the subsequent 6 to 18 mo. Similar measurements of bile acid kinetics and biliary lipid composition were made before and after a 6-mo period without medication in a control group of six healthy women; no changes occurred.     

Bronchial allergy in cystic fibrosis

Thirty-one patients with cystic fibrosis (CF) were thoroughly evaluated for allergy. This included a clinical history, skin tests with twenty-three allergens and bronchial provocation with inhaled allergens and histamine. The bronchial response was measured by whole body plethysmography. Of the patients studied, 40% showed a bronchoconstrictor response to inhaled allergens, despite the fact that none had reported asthma in their clinical history. Strong skin test reactions (3+ and 4+) and weak reactions (2+) were associated with 65% and 4% of positive reactions of the airways respectively. Weak skin reactions with Aspergillus fumigatus, however, were associated with 43% of positive bronchial challenges. In addition to Aspergillus, the mould Alternaria tenuis was found to be an important allergen causing a bronchial response in CF patients. There was no correlation between the thresholds of bronchial sensitivity to allergen and histamine, suggesting that the pathogenetic mechanisms of CF and bronchial asthma are different.     

Effectiveness of Physical Therapy Combined With Epidural Steroid Injection for Individuals With Lumbar Spinal Stenosis: A Randomized Parallel-Group Trial

Objective

To examine the effectiveness of epidural steroid injection (ESI) and back education with and without physical therapy (PT) in individuals with lumbar spinal stenosis (LSS).

Spatial distribution of avoidable cancer deaths in Germany

Aim

To investigate the spatial distribution of avoidable cancer mortality (ACM) rates in Germany and to identify small areas with exceptionally high rates using districts (Landkreise/Kreise and kreisfreie St?dte) as a unit of analysis. Avoidable cancer mortality reflects deaths from cancer that should not occur in the presence of effective and timely health care.

Methods

Age-standardised, average ACM rates were calculated for the period from 2000 through 2004 for each of the 439 districts in Germany using unit-record mortality data. The spatial distribution of ACM was subsequently analysed using country maps, interval estimates and regression analysis. Data on mortality and age distribution were obtained from the German Federal Statistical Office (DESTATIS) and the Federal Office for Building and Regional Planning (INKAR).

Results

We found that in women under 70?years, the highest ACM rates were seen for cancer of the breast and for cancer of the trachea, bronchus and lung, whereas in men under 70?years, the highest ACM rates were seen for cancer of the trachea, bronchus and lung, and for cancer of the colon, rectosigmoid junction, rectum, anus and anal canal. The statistically lowest mean ACM rates could be found in the south of Germany for men and women. Although the mean ACM rates in men in former East Germany were significantly higher than elsewhere in the country, they were not substantially higher than those in the west and northwest. The mean ACM rates in women were even lower in the east than in the northwest and west.

Conclusion

The spatial distribution of ACM rates in women in Germany showed a north-south gradient rather than the east-west gradient that often appears or, for sociohistorical reasons, is even assumed in the German context. When applying measures of ACM, we suggest using districts with statistically lower ACM rates than the nationwide average as a benchmark for the maximum number of excess deaths that should be considered preventable, whether within the current German context or beyond.