Premature processing of mouse mammary tumor virus Gag polyprotein impairs intracellular capsid assembly

Mouse mammary tumor virus (MMTV) is the prototypical member of the Betaretrovirus genus, but the processes of its morphogenesis are poorly characterized. In this report, we describe an unusual intracellular processing of MMTV Gag polyprotein in human 293T cells transiently expressing MMTV from heterologous promoter. The same specific cleavage products of the viral protease were seen for the wild type as well as for nonmyristylated mutant of MMTV Gag polyprotein completely defective in the particle release. Inactivation of the viral protease resulted in more stable Gag polyprotein and in accumulation of intracytoplasmic particles for nonmyristylated Gag. The intracellular processing of nonmyristylated MMTV Gag indicates that protease activation in betaretrovirus can occur independently of budding.     

Evaluation of matrix metalloproteinase 7 in plasma and pancreatic juice as a biomarker for pancreatic cancer.

Differentiating between periampullary carcinoma and chronic pancreatitis with an inflammatory mass is difficult. Consequently, 6% to 9% of pancreatic resections for suspected carcinoma are done inappropriately for chronic pancreatitis. Here, we test if matrix metalloproteinase 7 (MMP-7), a secreted protease frequently expressed in pancreatic carcinoma, can be measured in plasma, pancreatic, and duodenal juice, and if it can distinguish between periampullary carcinoma and chronic pancreatitis. Ninety-four patients who underwent pancreatic surgery for a (peri)pancreatic neoplasm (n = 63) or chronic pancreatitis (n = 31) were analyzed. Median plasma MMP-7 levels were significantly higher in carcinoma (1.95 ng/mL; interquartile range, 0.81-3.22 ng/mL) compared with chronic pancreatitis and benign disease (0.83 ng/mL; interquartile range, 0.25-1.21 ng/mL; P < 0.01). MMP-7 levels in pancreatic juice were higher, although not significantly, in carcinoma (62 ng/mg protein; interquartile range, 18-241 ng/mg protein) compared with chronic pancreatitis and benign disease (23 ng/mg protein; interquartile range, 8.5-99 ng/mg protein; P = 0.17). MMP-7 levels in duodenal juice were universally low. At an arbitrary cutoff of 1.5 ng/mL in plasma, positive and negative predictive values were 83% and 57%, respectively, values comparable to those of today's most common pancreatic tumor marker, carbohydrate antigen 19-9 (CA19-9; 83% and 53%, respectively). Positive and negative likelihood ratios for plasma MMP-7 were 3.35 and 0.52, respectively. The area under the receiver operating characteristic curve for MMP-7 was 0.73 (95% confidence interval, 0.63-0.84) and for CA19-9, 0.75 (95% confidence interval, 0.64-0.85). Combined MMP-7 and CA19-9 assessment gave a positive predictive value of 100%. Thus, plasma MMP-7 levels discriminated between patients with carcinoma and those with chronic pancreatitis or benign disease. The diagnostic accuracy of plasma MMP-7 alone is not sufficient to determine treatment strategy in patients with a periampullary mass, but combined evaluation of plasma MMP-7 with CA19-9 and other markers may be clinically useful.     

Histamine-induced cytokine production and ICAM-1 expression in human conjunctival fibroblasts

PURPOSE: Conjunctival fibroblasts stimulated with histamine (H) may be directly involved in the inflammatory and remodeling processes of chronic allergic conjunctival diseases. METHODS: Proinflammatory cytokine and growth factor production, and the expression of intercellular adhesion molecule-1 (ICAM-1) were studied in conjunctival fibroblast cultures challenged with different concentrations of H (from 10(-9) M to 10(-) (4) M). Interleukin (IL)-1, IL-4, IL-6, IL-8, tumor necrosis factor-alfa (TNF-alpha), fibroblast growth factor (FGF), epidermal growth factor (EGF) and transforming growth factor-beta (TGFbeta-1) were measured in supernatants. ICAM-1 expression was evaluated by a fluorescence activated cell sorter (FACS). Inhibitory effects of the H-1 antagonists (antiH): emedastine, levocabastine, and azelastine, and of the antiH-2, cimetidine, on H-stimulated fibroblasts were evaluated by measuring both cytokines in supernatants and the cellular expression of ICAM-1. RESULTS: Histamine increased the production of IL-1, IL-6 and IL-8, and ICAM-1 expression. TNF-alpha, IL-4 and growth factor production were not modified by histamine. The antiH-1, emedastine, significantly reduced H-induced production of IL-1, IL-6 and IL-8, while azelastine reduced only IL-1. Levocabastine and cimetidine were less effective. The histamine-induced increase in ICAM-1 expression was inhibited by emedastine but not by azelastine and levocabastine. CONCLUSIONS: Histamine has pro-inflammatory effects on conjunctival fibroblasts, inducing the production of cytokines and the expression of ICAM-1. Emedastine significantly reduced cytokine and ICAM-1 expression from H-stimulated fibroblasts. Conjunctival fibroblasts may contribute to the maintenance of inflammation in chronic allergic diseases.     

Motivational structure and alcohol use of university students across four nations

OBJECTIVE: The ability of motivational structure and other variables to predict alcohol consumption was assessed in university students (N = 370; 244 women) in the Czech Republic, The Netherlands, Norway and the United States. METHOD: Motivational structure was assessed with the Motivational Structure Questionnaire (MSQ), which inquires about respondents' individual personal concerns in various areas of life and dimensions of their goal strivings related to the resolution of concerns. Alcohol-related problems were measured with the Short Michigan Alcoholism Screening Test. RESULTS: Factor analysis of MSQ indices yielded a two-factor solution, one factor of which reflects an adaptive motivational structure marked by elements necessary for attaining psychologically satisfying resolutions of personal concerns. The other factor reflects a more maladaptive motivational structure marked by feelings of indifference about the achievement of personal goals. As hypothesized, MSQ Factor I was a significant inverse predictor of the amount of alcohol that students drank, but only among those who experienced alcohol-related problems. CONCLUSIONS: The similarity in results across culturally varied samples suggests the robustness of the relationships for understanding the motivational bases for alcohol use.     

Temperature related mortality and ambulance service interventions during the heat waves of 2003 in Ticino (Switzerland)

Objectives  

This study investigates a potential increase in mortality and in the demand for ambulance emergency services among the elderly in particular, in Ticino in the summer of 2003.     

Adolescence as possible critical temporal window for blood pressure short term monitoring in boys and girls

Adolescence is a critical temporal window for the development of obesity in adult age. We studied this period for short-term monitoring of blood pressure in both genders. Weight, height, body mass index (BMI), systolic and diastolic blood pressure (SBP, DBP) were recorded in 937 adolescents, 474 boys and 463 girls aged 12 years, and again 2 years later in the same subjects. Boys with BP values ≥95th percentile at both ages (no.=8) showed at 12 years weight (kg 61.4) height (cm 159.5) and BMI (23.5), and also at 14 years (77.0, 172.4, 25.6) values consistently higher than boys with high BP values at either ages taken singularly (no.=32 + 32) (mean 49.2, 154.4, 21.5, respectively, at 12 years, and 62.1, 167.0, 22.2 at 14 years). These 64 boys, had values higher than boys with BP always below the 95th percentile (no.=402) (45.5, 151.4, 19.7 at 12 years, and 56.9, 164.6, 20.9 at 14 years). This was confirmed for weight and BMI in girls. Stepwise logistic regression revealed that weight at 12 years and high BP values at 12 years were predictive independent risk factors for hypertension at 14 years. Odds ratio indicated that increment of body weight unit (1 kg) at 12 years predicted an average increase of 4 of risk for high BP values at 14 years, while high BP values at 12 years was predictive for a 2.19 times risk for high BP values at 14 years. Body weight, BMI and BP at 12 years of age may give useful indications for the prevision (and possible prevention) of hypertension and overweight at 14 years of age.     

Long-term serial echocardiographic examination of late anthracycline cardiotoxicity and its prevention by dexrazoxane in paediatric patients

The authors conducted an 8-year prospective non-randomised study to determine whether dexrazoxane (ICRF-187) would reduce late anthracycline-induced cardiotoxicity in patients treated in childhood for haematological malignancy. The authors examined prospectively 75 patients (40 male/35 female) aged 2–17 years (median 6.5 years) at the time of diagnosis. The cardioprotection was given to 53 patients (26 male/17 female) and the standard protocol was used in 22 patients (14 male/8 female). The prospective echocardiographic evaluation was done before and after the chemotherapy and every year during the follow-up period. Dynamic stress echocardiography (DSE) was assessed in the final year. The clinical cardiotoxicity was not diagnosed. Higher cumulative doses of anthracycline were given in the dexrazoxane group (234±58 mg/m², median 240 mg/m² versus 203±86 mg/m², median 210 mg/m², P <0.04) and a significantly higher percentage of patients received cumulative doses >240 mg/m² of anthracycline ( P <0.05). During the follow-up period, the fractional shortening (FS) declined in the no-dexrazoxane group only in the 8th year and was significantly lower compared to the dexrazoxane group ( P <0.05). The pathological decrease in FS was present in 24% of patients; 41% in the no-dexrazoxane and 17% in the dexrazoxane groups, respectively ( P <0.05). DSE demonstrated lower rest EF and cardiac index (CI) in the no-dexrazoxane group ( P <0.05); however, neither the response of EF and CI to the stress echocardiography nor the exercise tolerance significantly differed between sub-groups. A higher number of patients in the dexrazoxane group had very good exercise tolerance (ET) >3 Watts/kg ( P <0.05) and a lower number responded with a decreased ET <2 Watts/kg ( P <0.05) compared to the no-dexrazoxane group. Conclusion:Dexrazoxane seems to reduce the risk of late subclinical cardiotoxicity. Dexrazoxane-treated patients revealed better exercise tolerance; however the haemodynamic response to the stress was no different in both sub-groups.