Liver and serum expression of matrix metalloproteinases in asymptomatic pediatric liver transplant recipients

We related hepatic gene and serum expression of matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) to liver histology in pediatric LT recipients. Liver biopsies and serum samples were obtained from 52 patients 10.6 years post‐LT and age‐matched controls for analyses of MMPs and TIMPs. Patients with fibrosis had significantly higher hepatic gene expression of MMP‐2, MMP‐9, MMP‐14, TIMP‐1, and TIMP‐2 than patients without. Expression of these genes correlated with graft Metavir fibrosis stage (r = 0.494–0.684, P ≤ 0.006 for all). Gene expression of MMP‐1, MMP‐3, MMP‐8, TIMP‐3, and TIMP‐4 was undetectable in both patients and controls. Portal inflammation and cytokeratin 7 correlated positively with gene expression of TIMP‐1. Gene expression of MMP‐2, MMP‐9, and TIMP‐2 correlated negatively with the time of low‐dose cortisone usage (r = ?0.448 to ?0.422, P < 0.05 for all). Serum concentrations of MMP‐8 and TIMP‐1 were significantly increased and MMP‐9 decreased among patients compared with controls, but no correlations to graft histology or gene expression were observed. Hepatic gene expression of certain MMPs and TIMPs is increased in stable pediatric LT recipients displaying graft fibrosis, but this did not reflect to their serum concentrations. Increased hepatic gene expression of TIMP‐1 correlated with graft fibrosis stage, inflammation, and chronic cholestasis.     

Angiographic 20-year follow-up of 61 consecutive patients with internal thoracic artery grafts.

OBJECTIVE: To assess the behavior of internal thoracic artery (ITA) grafts versus venous grafts in repeated angiograms up to 20 years. SUMMARY BACKGROUND DATA: Use of ITA grafts to bypass left anterior descending artery stenosis has been shown to be associated with improved survival in patients undergoing coronary artery bypass grafting. METHODS: Sixty-one consecutive patients who received one or two ITA grafts and who underwent surgery from Oct. 5, 1971, to Dec. 18, 1973, in Helsinki University Central Hospital, Finland, were included in this prospective follow-up series. Fifty-six of the patients (92%) also received at least one venous graft. The number of distal anastomoses was 157, of which 47.7% (75) were performed with ITA grafts. The median age of the patients was 47.7 years (range 30.0 to 63.1), and 85% (52) were men. RESULTS: After 20 years of follow-up, 18/20 (90%) of the survivors underwent angiography; the patency rate was 88.9% for ITA grafts and 47.8% for venous grafts. Cumulative graft patency at 20 years, using all the information obtained from repeated angiographic examinations and autopsies, was also calculated to eliminate selection bias. The cumulative 20-year patency rate was 81% for ITA-left anterior descending artery anastomoses, 53.8% for venous graft-right coronary artery anastomoses, and 48.5% for venous graft-left circumflex artery anastomoses. In paired comparisons between anastomoses, the patency time of the ITA-left anterior descending artery anastomoses was on average 2.8 years longer than the venous graft-left circumflex artery patency time and 2.6 years longer than the venous graft-right coronary artery. CONCLUSIONS: Internal thoracic artery grafts, especially in left anterior descending artery anastomoses, should be considered as a primary solution in coronary artery bypass grafting surgery in patients with >10 years of life expectancy; if venous grafting is preferred, further evidence is needed.     

Alterations in bone turnover and impaired development of bone mineral density in newly diagnosed children with cancer: a 1-year prospective study.

In the present study, longitudinal changes in bone mineral density, bone turnover, and bone hormonal metabolism were evaluated in newly diagnosed children with cancer. Lumbar spine (L2-L4) and femoral neck bone mineral densities (grams per cm2) were measured by dual energy x-ray absorptiometry in 28 children (age, 2.9-16.0 yr; median, 8.0 yr; 10 acute lymphoblastic leukemias, 18 solid tumors) at diagnosis and after a 1-yr follow-up. Apparent volumetric density (grams per cm3) was calculated to minimize the effect of bone size on BMD. Serum levels of osteocalcin (OC), type I collagen carboxyl-terminal propeptide (PICP), and type I collagen carboxyl-terminal telopeptide were measured serially during the study. Serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, insulin-like growth factor I (IGF-I), and IGF-binding protein-3 were analyzed at diagnosis and at 1-yr follow-up. A significant decrease in femoral bone mineral density and apparent volumetric density was observed during the year after diagnosis [(mean (SD), -10.1% (8.8%) and -11.3% (8.1%) respectively; P < 0.01], whereas age- and sex-matched controls showed annual increments of +5.4% (7.7%; P < 0.01) and +0.7% (5.7%; P = NS) respectively. The markers of bone formation (PICP and OC) were significantly decreased at diagnosis. By the end of the follow-up, PICP and OC were normalized, whereas the marker of bone resorption (type I collagen carboxyl-terminal telopeptide) was significantly increased. Reduced levels of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and IGF-binding protein-3 were observed during the study. To conclude, increased bone resorption and impaired development of femoral bone density were observed in children with cancer during chemotherapy. Deficient accumulation of bone mass may lead to impaired development of peak bone mass and predispose children with cancer to increased risk of osteoporosis and diminished skeletal resistance to fractures later in life.     

Reduced bone density at completion of chemotherapy for a malignancy

Environmental factors very early in life may be important for later development of insulin dependent diabetes. Because several of these factors, such as infections, vary with season, we predicted a difference in birth pattern compared with the general population among children who develop diabetes. In a population based study we analysed all 1248 children from seven paediatric departments in the south east part of Sweden to evaluate whether there is such a relation. There was a significant difference in birth pattern in patients with diabetes compared with the general population. Children who developed diabetes at the age of 10-15 years accounted for most of this difference. Boys had a more pronounced difference in birth pattern than girls. Children diagnosed with diabetes during years of high incidence, as well as children with an infection before diagnosis of diabetes, showed a significantly different birth pattern compared with the background population. These results indicate that there is a difference in birth pattern in children who develop diabetes compared with the background population. This supports the theory that environmental factors early in life play a role in the development of diabetes many years later.     

Disturbance in bone turnover in children with a malignancy at completion of chemotherapy.

BACKGROUND: Osteoporosis and pathological fractures have been observed in children with a malignancy. The mechanisms of osteopenia in childhood malignancies have not been well established. The purpose of the present study was to evaluate changes in bone turnover and in bone hormonal metabolism in children with a malignancy at completion of their chemotherapy. PROCEDURE: Serum levels of human intact osteocalcin, type I collagen carboxyterminal propeptide (PICP), type I collagen carboxyterminal telopeptide (ICTP), 25-hydroxyvitamin D [25-(OH)-D], 1,25-dihydroxyvitamin D [1, 25-(OH)(2)-D], intact parathyroid hormone, insulin-like growth factor I (IGF-I), IGF binding protein 3 (IGFBP-3), alkaline phosphatase, calcium, and phosphate were analyzed in 22 children with acute lymphoblastic leukemia and in 26 children with other malignancies. Results were expressed as Z-scores [mean (95% confidence intervals)] relative to healthy Caucasian-children. RESULTS: The marker of collagen degradation (ICTP) was significantly increased [1.43 (1.10-1.76), P < 0.0001] compared to reference values, whereas the markers of bone formation (PICP, osteocalcin) were not changed [0.07 (-0.55 to 0.49), 0.35 (-0.05 to 0.74), respectively, NS]. Serum 25-(OH)-D, 1,25-(OH)(2)-D, and calcium were significantly reduced [-0.65 (-0.87 to -0.42), -0.68 (-0.92 to -0. 42), -1.42 (-1.80 to -1.04), P < 0.0001, respectively]. CONCLUSIONS: Disturbance in bone turnover with low serum 25-(OH)-D, 1, 25-(OH)(2)-D, and calcium was observed in children with a malignancy at completion of their chemotherapy. A controlled study determining the possible benefits of vitamin D and calcium supplementation on bone turnover could be considered in these patients.     

Drug utilisation pattern and off-label use of medicines in Estonian neonatal units

Objectives  

To characterise neonatal hospital drug use and to compare the availability of drug information between Estonian Summaries of Product Characteristics (SPCs) and other sources.