Circulating Fibronectin Controls Tumor Growth

Fibronectin is ubiquitously expressed in the extracellular matrix, and experimental evidence has shown that it modulates blood vessel formation. The relative contribution of local and circulating fibronectin to blood vessel formation in vivo remains unknown despite evidence for unexpected roles of circulating fibronectin in various diseases. Using transgenic mouse models, we established that circulating fibronectin facilitates the growth of bone metastases by enhancing blood vessel formation and maturation. This effect is more relevant than that of fibronectin produced by endothelial cells and pericytes, which only exert a small additive effect on vessel maturation. Circulating fibronectin enhances its local production in tumors through a positive feedback loop and increases the amount of vascular endothelial growth factor (VEGF) retained in the matrix. Both fibronectin and VEGF then cooperate to stimulate blood vessel formation. Fibronectin content in the tumor correlates with the number of blood vessels and tumor growth in the mouse models. Consistent with these results, examination of three separate arrays from patients with breast and prostate cancers revealed that a high staining intensity for fibronectin in tumors is associated with increased mortality. These results establish that circulating fibronectin modulates blood vessel formation and tumor growth by modifying the amount of and the response to VEGF. Furthermore, determination of the fibronectin content can serve as a prognostic biomarker for breast and prostate cancers and possibly other cancers.     

Localisation and distribution of hyaluronan in normal bone marrow matrix: a novel method to evaluate impending fibrosis?

Bone marrow trephine biopsies from 30 healthy volunteers, 10 men and 20 women aged 18-60 yr were obtained for identification and localisation of hyaluronan (HYA). Fixation, decalcification and embedding were performed by two different methods, with identical results in both. For comparison bone marrow trephine biopsies from three patients with different haematological diseases and known fibrosis were studied. All bone marrow specimens were also stained for reticulin grading. HYA was found in the bone marrow specimens from healthy individuals in a pattern that was concordant with the reticulin staining, the common way of visualising bone marrow fibrosis. In bone marrow from the patients with known fibrosis the HYA and reticulin staining were both more intense and abundant. Interestingly, HYA was also found intracellularly in eosinophilic cells in normal bone marrow. HYA is a polysaccharide unique both in structural and biological properties, and in excess it may predict bone marrow fibrosis.     

The effect of ethanol and alcoholic beverages on gastric emptying of solid meals in humans

AIMS: The systematic study of the effect of pure ethanol, alcoholic beverages, and their non-alcoholic components on gastric emptying of solid meals in humans. METHODS: 16 fasting healthy male subjects received once weekly 300 ml of the following solutions in random order: 4 and 10% (v/v) ethanol, beer, red wine, 5.5 and 11.4% (w/v) glucose, and water. The test solutions were given either together with a low caloric (270 kcal, n = 8) or a high caloric (740 kcal, n = 8) solid meal. Ultrasonography of the antrum was used to determine gastric emptying. RESULTS: Gastric half emptying time (t(1/2) ) of the high caloric solid meal with water was 131.3 +/- 7 min. The ingestion of 4 and 10% (v/v) ethanol (158.8 +/- 9.3 and 165.6 +/- 6.2 min, respectively), beer (163.1 +/- 11 min), and red wine (186.3 +/- 8.4 min) resulted in a significantly longer t(1/2) than water. The lag phases after 4 and 10% (v/v) ethanol, beer, and red wine were not significantly different from that of water (48.1 +/- 6.5 min). Compared with water, the ingestion of 5.5 and 11.4% (w/v) glucose resulted in a significantly longer t(1/2) (153.8 +/- 5 and 168.1 +/- 14.4 min, respectively) by increasing the duration of the lag phase. The high caloric meals resulted in a 2-fold prolongation of t(1/2) when compared with the low caloric meals. The effect of the solutions on the gastric emptying times, however, was similar for both test meals. CONCLUSIONS: (i) Ethanol in low concentrations of 4 and 10% (v/v) prolongs gastric emptying of solid meals; this inhibitory effect is not dose-dependent. (ii) Alcoholic beverages (beer and red wine) also result in a prolongation of gastric emptying. The inhibitory effect of red wine, but not of beer, is more pronounced than that of the corresponding ethanol concentration and amount. (iii) The inhibitory effect of ethanol and alcoholic beverages is mainly induced by a prolongation of the gastric emptying phase (without affecting the lag phase), whereas 5.5 and 11.4% (w/v) glucose prolong the lag phase in a dose-dependent manner. (iv) The inhibitory effect of ethanol, beer, and red wine on gastric emptying does not depend on the caloric content of the meal.     

Age and gender-related reference values for serum dl-alpha-tocopherol and all-trans-retinol levels in Saudi population

We established a reference range for dl-alpha-tocopherol and all-trans-retinol in a Saudi population previously selected for a cross-sectional study evaluating selenium and vitamin status. Concentrations of dl-alpha-tocopherol and all-trans-retinol were 0.999 +/- 0.31 mg/dL (n=994, range 0.11-3.42 mg/dL) and 49.14 +/- 24.15 micro/dL (n=1000, range 11.20-400.85 microg/dL), respectively. The levels of dl-alpha-tocopherol and all-trans-retinol in serum were determined by high-pressure liquid chromatography (HPLC) equipped with a UV detector. We took the influence of age and gender into account. Both had significant effect on the levels of all-trans-retinol in serum, except in the case of dl-alpha-tocopherol, where no gender related effect was found. We used the 5th and 95th percentiles as reference limits. Based on these criteria, it was found that these reference limits differed between genders for all-trans-retinol. Our lower and upper limits for dl-alpha-tocopherol classified by three age groups were very close to the normal range of 0.5-1.6 mg/dL, as found in previous studies. The 5th percentile of all-trans-retinol in both males and females, stratified by age, was close to a level of <20 microg/dL, which could be regarded as a mild vitamin A deficiency according to WHO criteria. But the value corresponding to the 95th percentile was higher than the upper limit of vitamin A's normal range of 70 microg/dL, suggesting a potentially harmful high dietary intake of vitamin A. The reference intervals elaborated here may help in the assessment of the vitamin status and in detecting subjects at risk of developing pathologies associated with either excess intake or deficiency.     

Antibacterial resistance and their genetic location in MRSA isolated in Kuwait hospitals, 1994-2004

Background  

Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a major cause of serious infections in hospitals and in the community worldwide. In this study, MRSA isolated from patients in Kuwait hospitals were analyzed for resistance trends and the genetic location of their resistance determinants.     

Isoform of Fibronectin Mediates Bone Loss in Patients With Primary Biliary Cirrhosis by Suppressing Bone Formation

Osteoporosis is a major cause of morbidity and decreased quality of life in patients with chronic cholestatic liver disease. It is established that this osteoporosis results from decreased bone formation, but the mechanisms for the interaction between liver and bone remain elusive. The aim of this study was to test the hypothesis that an increase in the production of cellular fibronectins during liver disease may result in decreased osteoblast‐mediated mineralization and thus explain the decrease in bone formation. We performed a prospective cross‐sectional study in patients with primary biliary cirrhosis and matched controls, followed by experiments on human and mouse osteoblasts in culture and injections in mice in vivo. In patients with primary biliary cirrhosis, the oncofetal domain of fibronectin correlated significantly with the decrease in osteocalcin, a marker of bone formation (r = ?0.57, p < 0.05). In vitro, amniotic fluid fibronectin (aFN) containing mainly the oncofetal domain and EIIIA domain resulted in decreased osteoblast‐mediated mineralization in human osteoblasts (69% decrease at 100 μg/ml; p < 0.01) and mouse osteoblasts (71% decrease; p < 0.05). Removing the EIIIA domain from aFN similarly suppressed mineralization by osteoblasts (78% decrease; p < 0.05). Injection of labeled aFN in mice showed that it infiltrates the bone, and its administration over 10 days resulted in decreased trabecular BMD (17% drop; p < 0.05), mineralizing surface (30% drop; p < 0.005), and number of osteoblasts (45% drop; p < 0.05). Increased production of a fibronectin isoform containing the oncofetal domain and its release in the circulation in patients with primary biliary cirrhosis is at least partially responsible for the decrease in bone formation seen in these patients. This establishes that a molecule that has thus far been viewed as an extracellular matrix protein exerts hormone‐like actions.