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.     

Long-term risk of IDDM in first-degree relatives of patients with IDDM

Summary Due to a short observation period previous studies may have underestimated prevalence and recurrence risk of IDDM in relatives of IDDM patients. To obtain a more exact life-time risk estimate we identified 310 probands, representative of Danish IDDM patients, characterized by current age more than 50 years, age at onset 40 years or less and diabetes duration of more than 30 years. Family data were obtained from 291 probands. Mean observation times (age) (± SD) for siblings (n = 553) and offspring (n=359) were 59.4 ± 16.1 years and 33.8 ± 8.8 years, respectively. Of the probands 73 (25.1%) had at least one first-degree relative with IDDM. Seventeen percent had at least one affected sibling. An increase from 10.4% to 22.4% of having first-degree relatives with IDDM among probands with age at onset below 20 years was observed during the period from proband at age 21 years up to 1 September 1992. Among affected siblings 48% of the second cases were affected more than 10 years after the first affected sibling. Using the life-table method cumulative recurrence risks from time of birth were calculated for siblings up to age 30 years of 6.4% and up to age 60 years of 9.6%. For offspring the risk up to age 34 years was 6.3%. In addition, we present a life-table method evaluating the cumulative recurrence risk from time of onset in the proband, as this is the most relevant when giving genetic counselling. In conclusion, the long-term risks of IDDM in siblings and offspring are high compared to that shown in previous reports.Abbreviations IDDM insulin-dependent diabetes mellitus - SE standard error     

Pitfalls in the diagnosis of intestinal tuberculosis: a case report

An 18-year-old long-term Norwegian resident of Somali origin was submitted to hospital with bloody diarrhoea, fever, weight loss and abdominal pain. On initial colonoscopy, colitis with segmental appearance was seen. Apart from a single polymerase chain reaction (PCR) from gastric aspirate staining, PCR and culture for acid-fast bacilli revealed negative results from the multiple samples taken including sputum, gastric fluid, stool, urine and intestinal mucosa. On physical examination and CT scan, there was no evidence of ascites, lymph node enlargement or pathologic pulmonary findings. Although the diagnosis was uncertain, tuberculostatic therapy was initiated. As the conformational testing of the PCR and the microbiological work-up remained negative and the patient's condition did not improve, tuberculostatic treatment was stopped and Crohn's disease was stated as the most likely diagnosis. Although the patient improved clinically under therapy with prednisolone, newly appearing fistulas deriving from the ascending colon were noted on follow-up. Thus tuberculostatic treatment was restarted. However, signs of an acute abdomen appeared and laparotomy was performed, thereby revealing a peritoneal spread of nodules. Resection of the ileum and ascending colon was performed. Diagnosis of intestinal tuberculosis with peritoneal spread was made by histology from resected bowel specimens showing caseating granulomas and a positive PCR result. The patient's condition improved after resection of the highly inflamed bowel segments and tuberculostatic therapy. Our case report shows the difficulty of proving intestinal tuberculosis by microbiological testing, macroscopic features on colonoscopy, histology, imaging such as CT scan and by empirical therapy. Therefore, in cases of colonic inflammation, where intestinal tuberculosis is an important differential diagnosis, a more aggressive diagnostic approach such as explorative laparoscopy should be considered.