Up-regulation of trypsin and mesenchymal MMP-8 during development of hyperoxic lung injury in the rat

Acute lung injury is marked by damage to alveolar-capillary barrier. High pulmonary levels of matrix-degrading serine proteinase trypsin and matrix metalloproteinases (MMP)-2, -8, and -9 have been shown in preterm infants with respiratory distress syndrome (RDS). We studied expression of trypsin and MMP-2, -8, and -9 in rats exposed to >95% oxygen for 24, 48, or 60 h. As demonstrated by zymography and Western immunoblotting, levels of trypsin and MMP-2, -8, and -9 in bronchoalveolar lavage fluid (BALF) sharply increased after 48 h of hyperoxia relative to normoxia controls. This coincided with increase in alveolar-capillary permeability, as indicated by increased protein concentration in BALF. Both neutrophil-derived 80-kD and mesenchymal cell-derived 60-kD MMP-8 isoforms were detected in BALF. Of them, mesenchymal-type MMP-8 predominated. In immunohistochemistry, alveolar epithelium showed strong trypsin expression at 48 and 60 h of hyperoxia, whereas it was predominantly negative in controls. MMP-8 was mostly expressed in macrophages. Marked up-regulation of trypsin and MMP-8 early during hyperoxic lung injury suggests that these enzymes play a role in the pathogenesis of acute lung injury and may therefore be potential targets for therapy of lung injury.     

Inhibin/activin betaB-subunit expression in pheochromocytomas favors benign diagnosis

Malignancy of pheochromocytomas is difficult to estimate on the basis of histopathological features. Good prognostic markers are not available. In our search for new markers to differentiate malignant pheochromocytomas from benign ones we tested the value of inhibin/activin subunit expression. Inhibins are heterodimeric glycoproteins consisting of an alpha-subunit and either a betaA- or a betaB-subunit. Activins are composed of beta-subunits only. Immunohistochemically inhibin/activin betaB-subunit was strongly positive in the normal adrenal medulla, but the cortex was negative. A striking difference was found in inhibin/activin betaB expression between benign and malignant pheochromocytomas. The majority of benign adrenal tumors (27 of 30) showed strong or moderate immunoreactivity, whereas all seven malignant tumors were negative or only weakly positive for inhibin/activin betaB-subunit. The percentage of positively staining cells varied greatly in extraadrenal pheochromocytomas and in those benign tumors that showed over 5 mitoses/10 high power fields, necrosis, or capsular or vascular invasion, here called borderline tumors. Inhibin/activin betaB messenger ribonucleic acid was also found in pheochromocytomas. However, no significant differences in messenger ribonucleic acid levels were found in various types of tumors. Weak immunohistochemical positivity for inhibin/activin betaA-subunit was detected in the adrenal cortex, but the medulla and most of the pheochromocytomas were negative. Our data show that inhibin/activin betaB-subunit is expressed in normal adrenal medullary cells. Strong staining is found in most benign adrenal pheochromocytomas, whereas malignant tumors are almost negative. This suggests that loss of inhibin/activin betaB-subunit expression in pheochromocytomas may be used as an indicator of malignant potential.     

Pediatric oncology nurses’ perceptions of prognosis-related communication

Background

Disclosure of prognosis-related information is an essential aspect of communication with pediatric patients with cancer and their families. The nurse is believed to play an important role in this process, but nurse perceptions and experiences have not been well-described.

Pulmonary vascular endothelial growth factor-C in development and lung injury in preterm infants

RATIONALE: In mice, vascular endothelial growth factor-C (VEGF-C) plays an important role in development of the lymphatic system and in pathogenesis of pulmonary inflammation. Its role in development of the lymphatic system in human lung and in lung injury in newborns remains unclear. OBJECTIVES: We studied the role of VEGF-C in developing human lung, and in acute and chronic lung injury in preterm infants. METHODS: Included in the immunohistochemistry study were 10 fetuses, 15 control neonates without primary lung disease, 15 preterm infants with respiratory distress syndrome, and 8 infants with bronchopulmonary dysplasia. Tracheal aspirate fluid samples of intubated very-low-birth-weight infants during Postnatal Weeks 1-5 were analyzed with ELISA. RESULTS: Bronchiolar staining for VEGF-C was observed in all 48 samples. Alveolar epithelial staining was seen in most fetuses (8/10). In addition, staining was observed in alveolar macrophages in bronchopulmonary dysplasia (4/8), and late respiratory distress syndrome (2/7). VEGF receptor-3 (VEGFR-3) staining was observed in lymphatic endothelium adjacent to vascular endothelium. VEGF-C was expressed consistently in tracheal aspirate fluid, being highest during the first 2 postnatal days. Antenatal administration of glucocorticoids was associated with higher VEGF-C in tracheal aspirate fluid. CONCLUSIONS: The pattern of pulmonary VEGF-C and VEGFR-3 protein expression and consistent VEGF-C protein appearance in tracheal aspirate fluid in human preterm infants indicate a role for VEGF-C in the physiologic development of the lymphatic system of the lung.     

Genotypic heterogeneity and phenotypic mimicry among unrelated patients referred for catecholaminergic polymorphic ventricular tachycardia genetic testing

BACKGROUND: Mutations in the RyR2-encoded cardiac ryanodine receptor/calcium release channel and in CASQ2-encoded calsequestrin cause catecholaminergic polymorphic ventricular tachycardia (CPVT1 and CPVT2, respectively). OBJECTIVES: The purpose of this study was to evaluate the extent of genotypic and phenotypic heterogeneity among referrals for CPVT genetic testing. METHODS: Using denaturing high-performance liquid chromatography and DNA sequencing, mutational analysis of 23 RyR2 exons previously implicated in CPVT1, comprehensive analysis of all translated exons in CASQ2 (CPVT2), KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), KCNE2 (LQT6), and KCNJ2 (Andersen-Tawil syndrome [ATS1], also annotated LQT7), and analysis of 10 ANK2 exons implicated in LQT4 were performed on genomic DNA from 11 unrelated patients (8 females) referred to Mayo Clinic's Sudden Death Genomics Laboratory explicitly for CPVT genetic testing. RESULTS: Overall, putative disease causing mutations were identified in 8 patients (72%). Only 4 patients (3 males) hosted CPVT1-associated RyR2 mutations: P164S, V186M, S3938R, and T4196A. Interestingly, 4 females instead possessed either ATS1- or LQT5-associated mutations. Mutations were absent in >400 reference alleles. CONCLUSION: Putative CPVT1-causing mutations in RyR2 were seen in <40% of unrelated patients referred with a diagnosis of CPVT and preferentially in males. Phenotypic mimicry is evident with the identification of ATS1- and LQT5-associated mutations in females displaying a normal QT interval and exercise-induced bidirectional VT, suggesting that observed exercise-induced polymorphic VT in patients may reflect disorders other than CPVT. Clinical consideration for either Andersen-Tawil syndrome or long QT syndrome and appropriate genetic testing may be warranted for individuals with RyR2 mutation-negative CPVT, particularly females.     

Tick-borne encephalitis (TBE) in Skåne, southern Sweden: A new TBE endemic region?

No case of tick-borne encephalitis (TBE) has previously, to our knowledge, been reported from the region of north-eastern Sk?ne in southern Sweden. However, since the y 2001 we have identified 6 cases of TBE in this region occurring in a limited geographical area covering about 100 km2. Sera from 393 patients living in the vicinity of those TBE cases were analysed for the presence of TBE virus-specific IgG by use of ELISA. TBE virus IgG titres >126 VIEU (Vienna Units) were detected in 28 (7.1%) of the patients' sera. However, in only 3 of the ELISA TBE virus IgG positive sera were neutralizing antibodies against TBE virus demonstrated. Those 3 sera all had IgG titres of >380 VIEU. The TBE seroprevalence rate in this non-randomized population sample in north-eastern Sk?ne was calculated at 0.8%.     

Tumour markers CA 19-9 and CA 50 in digestive tract malignancies.

CA 19-9 and CA 50 are tumour marker tests measuring the same carbohydrate structure, sialosyl-fucosyl-lactotetraose--that is, the sialylated Lewis blood group antigen. In addition, the C50 antibody reacts with sialosyl-lactotetraose, which may be expressed in small amounts in some carcinomas. In this study we compared these tests in sera from patients with benign and malignant digestive tract diseases. The sensitivity of the markers for different cancers was also compared at several specificity levels with patients with benign diseases as reference groups. Both markers showed a high sensitivity for pancreatic cancer (77% for CA 19-9; 69% for CA 50) and biliary cancer (88%). The figures in colorectal cancer were almost as high as those reported for CEA; 16-21% elevated values in Dukes A and B tumours and 44-47% in Dukes C and D tumours. The sensitivity for gastric cancer was 48% for both markers. CA 50 had a higher sensitivity for liver cancer (55%) than CA 19-9 (9%), but the proportion of elevated values in benign liver diseases was also higher (33% versus 15%, respectively). Overall, there was good correlation between the CA 19-9 and CA 50 levels, and the difference in sensitivity and specificity was marginal. In clinical practice the greatest value of CA 19-9 and CA 50 is in the diagnosis of pancreatic cancer.     

Economic Burden of NSAID-induced Gastropathy in Sweden

Background: Gastrointestinal side effects carry a significant cost related to the use of NSAID medications. Methods: The economic burden of NSAID-induced gastric side effects is estimated using the cost-of-illness methodology. Costs are calculated using both a prevalence (top-down) approach and an incidence (bottom-up) approach. Results: Using the top-down approach, the total cost in 1998 of NSAIDinduced ulcers was MSEK 329-586, direct costs accounting for 76%-83%. The bottom-up approach gives an estimate of MSEK 320, of which MSEK 290 was direct cost. About one-quarter of total costs for ulcer disease can be attributed to the use of NSAIDs. Conclusions: Gastrointestinal side effects carry a significant cost from the use of NSAIDs, costs that are as important as the price of NSAIDs. This should be considered when choice of drug and prophylaxis is being made.     

Inflammatory response in patients with malignant obstructive jaundice

Objective. Surgery in patients with malignant obstructive jaundice is associated with increased risks for postoperative septic complications. The aim of this study was to investigate the inflammatory and the local cellular immune response in patients accepted for surgery because of tumours in the hepatic-pancreatic-biliary (HPB) tract. Material and methods. Patients with obstructive jaundice (group HPB⁺) were compared with those without (HPB^?). Patients undergoing surgery for benign abdominal disorders served as controls. Obstructive jaundice was present in 18 out of 33 HPB patients. Preoperatively, blood was analysed for bacteria, endotoxins and cytokines (TNF-α, IL-6 and IL-10). At operation, mesenteric lymph nodes (MLNs) were excised for bacterial cultures using standard microbiological techniques, and immunohistochemistry, using antibodies CD4 and CD8 (mainly staining T lymphocytes), CD68 (macrophages), and anti-caspase-3 (to determine the rate of apoptosis). Results. Bacterial translocation was not demonstrated in any of the patients. Increased preoperative concentrations of endotoxins were found in group HPB⁺. The number of macrophages and the rate of apoptosis in MLNs were increased in jaundiced patients, while the number of T lymphocytes was decreased. Conclusions. Malignant obstructive jaundice causes increased blood concentrations of endotoxins and cytokines, an increased number of macrophages in MLNs, a higher rate of apoptosis in MLNs, but a decreased number of T lymphocytes in MLNs. The lymphocyte depletion is probably due to the increased rate of apoptosis, and might reduce the ability of jaundiced patients to eradicate infection.