Various experiences and preferences of Dutch parents in prenatal counseling in extreme prematurity

Objective

To investigate experienced and preferred prenatal counseling among parents of extremely premature babies.

Urokinase and the intestinal mucosa: evidence for a role in epithelial cell turnover

Background—The functions of urokinase inintestinal epithelia are unknown.
Aims—To determine the relation of urokinaseexpressed by intestinal epithelial cells to their position in thecrypt-villus/surface axis and of mucosal urokinase activity toepithelial proliferative kinetics in the distal colon.
Methods—Urokinase expression was examinedimmunohistochemically in human intestinal mucosa. Urokinase activitywas measured colorimetrically in epithelial cells isolated sequentiallyfrom the crypt-villus axis of the rat small intestine. In separate experiments, urokinase activity and epithelial kinetics (measured stathmokinetically) were measured in homogenates of distal colonic mucosa of 14 groups of eight rats fed diets known to alter epithelial turnover.
Results—From the crypt base, an ascendinggradient of expression and activity of urokinase was associated withthe epithelial cells. Median mucosal urokinase activities in each ofthe dietary groups of rats correlated positively with autologous mediannumber of metaphase arrests per crypt (r=0.68; p<0.005)and per 100 crypt cells (r=0.75; p<0.001), but not withcrypt column height.
Conclusions—Localisation of an enzyme capable ofleading to digestion of cell substratum in the region where cells areloosely attached to their basement membrane, and the association of its activity with indexes of cell turnover, suggest a role for urokinase infacilitating epithelial cell loss in the intestine.

Keywords:urokinase; intestinal epithelium; colon; epithelialproliferation

     

Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia

Analysis of the chronic lymphocytic leukemia (CLL) coding genome has recently disclosed that the NOTCH1 proto-oncogene is recurrently mutated at CLL presentation. Here, we assessed the prognostic role of NOTCH1 mutations in CLL. Two series of newly diagnosed CLL were used as training (n = 309) and validation (n = 230) cohorts. NOTCH1 mutations occurred in 11.0% and 11.3% CLL of the training and validation series, respectively. In the training series, NOTCH1 mutations led to a 3.77-fold increase in the hazard of death and to shorter overall survival (OS; P < .001). Multivariate analysis selected NOTCH1 mutations as an independent predictor of OS after controlling for confounding clinical and biologic variables. The independent prognostic value of NOTCH1 mutations was externally confirmed in the validation series. The poor prognosis conferred by NOTCH1 mutations was attributable, at least in part, to shorter treatment-free survival and higher risk of Richter transformation. Although NOTCH1 mutated patients were devoid of TP53 disruption in more than 90% cases in both training and validation series, the OS predicted by NOTCH1 mutations was similar to that of TP53 mutated/deleted CLL. NOTCH1 mutations are an independent predictor of CLL OS, tend to be mutually exclusive with TP53 abnormalities, and identify cases with a dismal prognosis.     

Standardised pre-competitive screening of athletes in some European and African countries: the SMILE study

Most of the available data on the cardiovascular screening of athletes come from Italy, with fewer records being available outside of Italy and for non-Caucasian populations. The goals of the SMILE project (Sport Medicine Intervention to save Lives through ECG) are to evaluate the usefulness of 12-lead ECGs for the detection of cardiac diseases in athletes from three European countries and one African country and to estimate how many second-level examinations are needed subsequent to the initial screening in order to classify athletes with abnormal characteristics. A digital network consisting of Sport Centres and second and third opinion centres was set up in Greece, Germany, France and Algeria. Standard digital data input was carried out through the application of 12-lead ECGs, Bethesda questionnaires and physical examinations. Two hundred ninety-three of the 6,634 consecutive athletes required further evaluation, mostly (88.4 %) as a consequence of abnormal ECGs. After careful evaluation, 237 were determined to be healthy or apparently healthy, while 56 athletes were found to have cardiac disorders and were thus disqualified from active participation in sports. There was a large difference in the prevalence of diseases detected in Europe as compared with Algeria (0.23 and 4.01 %, respectively). Our data confirmed the noteworthy value of 12-lead resting ECGs as compared with other first-level evaluations, especially in athletes with asymptomatic cardiac diseases. Its value seems to have been even higher in Algeria than in the European countries. The establishment of a digital network of Sport Centres for second/third opinions in conjunction with the use of standard digital data input seems to be a valuable means for increasing the effectiveness of screening.     

Secretion of urokinase and plasminogen activator inhibitor-1 by normal colonic epithelium in vitro.

Urokinase is a neutral protease whose major site of action is the external surface of the plasma membrane of cells and whose major function seems to be modulation of cell adhesion, such as that which occurs during cell migration. This study aimed to determine whether colonic epithelium is involved with the urokinase system. The contents of urokinase and one of its specific inhibitors, plasminogen activator inhibitor-1, were measured in culture supernatant and cell homogenates of isolated human colonic crypt cells. The amounts of both factors increased in supernatants over 24 hours, and approximately twice the amount was found in supernatants than in autologous cell homogenates. The secretion of both factors was similar in serum free and serum containing media. Northern blot analysis showed that messenger ribonucleic acid specific for urokinase and plasminogen activator inhibitor-1 was present in colonic crypt cells and that expression over 18 hours of culture was increased 12 fold for urokinase type plasminogen activator and two to fourfold for the inhibitor compared with values found in autologous freshly isolated cells. Urokinase activity was detected in crypt cell homogenates and supernatants indicating that it was present in excess of its inhibitors. Control experiments indicated that the epithelial cells themselves were responsible for the observations and excluded artefactual effects of the isolation procedure. In conclusion, isolated human colonic epithelial cells secrete urokinase and at least one of its specific inhibitors. Further investigation of the role of urokinase in the physiology and pathophysiology of colonic epithelium is indicated.     

Effects of low-dose cisplatin on 89Sr therapy for painful bone metastases from prostate cancer: a randomized clinical trial.

This study evaluated the effects of low-dose cisplatin plus 89Sr versus 89Sr alone in the treatment of painful bone metastases from prostate cancer, addressing both pain palliation and cytostatic effects. METHODS: Seventy patients with metastatic hormone-refractory prostate cancer were randomized into 2 groups: One group (arm A) received 148 MBq 89Sr plus 50 mg/m(2) cisplatin, and the other group (arm B) received 148 MBq 89Sr plus placebo. After treatment, the patients were followed up until death to evaluate the outcome variables: grade and duration of pain palliation, onset of new painful sites, changes in bone disease, global survival, serum prostate-specific antigen and alkaline phosphatase changes, and hematologic toxicity. RESULTS: Overall pain relief occurred in 91% of patients in arm A and 63% of patients in arm B (P < 0.01), with a median duration of 120 d in arm A and 60 d in arm B (P = 0.002). New painful sites on previously asymptomatic bone metastases appeared in 14% of patients in arm A and in 30% of patients in arm B (P = 0.18). The median survival without new painful sites was 4 mo in arm A and 2 mo in arm B (P = 0.04). Bone disease progression was observed in 27% of patients in arm A and in 64% of patients in arm B (P = 0.01). Median global survival after therapy was 9 mo in arm A and 6 mo in arm B (P = 0.30). Transient and moderate hematologic toxicity, as determined by World Health Organization criteria, was apparent in both arms without significant differences. CONCLUSION: The addition of a low dose of cisplatin enhances the effect of a standard dose of 89Sr without significant side effects, producing a significant improvement in pain palliation and a cytostatic effect on bone disease.     

Anti-cancer activity of plant-produced HPV16 E7 vaccine

The E7 oncoprotein from Human Papilloma Virus (HPV) is an attractive candidate for anti-cancer vaccine development. In this study, we engineered HPV16 E7 coding sequence (wild type or mutagenized sequence, E7GGG) as fusions to beta-1,3-1,4-glucanase (LicKM) of Clostridium thermocellum and produced in Nicotiana benthamiana plants using a transient expression system. Target antigens were purified and evaluated in mice for their potential as prophylactic and therapeutic vaccine candidates. Both fusion proteins induced E7-specific IgG and cytotoxic T-cell responses and protected mice against challenge with E7-expressing tumor cells. Furthermore, when administered after challenge, these plant-produced antigens prevented tumor development.     

Uptake of cervical cancer screening in The Netherlands is mainly influenced by women's beliefs about the screening and by the inviting organization

BACKGROUND: This study aims to examine the impact of women's characteristics (demographics, risk behaviour, and beliefs) on the uptake of cervical cancer screening, taking practice characteristics (demographic and organizational) into account. METHODS: Routinely collected data of screening status were sampled from electronic medical records of 32 Dutch general practices. Additionally, a questionnaire was sent to a sample of 2224 listed women-1204 screened, 1020 unscreened. We used a step-by-step, logistic, multilevel approach to examine determinants of the screening uptake. RESULTS: Analyses of data for 1392 women (968 screened and 424 unscreened) showed that women's beliefs about cervical screening and attendance are the best predictors of screening uptake, even when demographic and organizational aspects are taken into account. Women aged 40-50 years who felt high personal moral obligation, who had only one sexual partner ever, and who were invited and reminded by their own general practice had the greatest likelihood of screening uptake. A non-response study was performed; the non-responders to the questionnaire (mainly unscreened) thought they had less risk of cervical cancer, were less motivated, less often intended to get future screening, and were more convinced that cervical cancer cannot be cured. CONCLUSION: To improve the uptake rate, we should focus on the personal moral obligation of eligible women, beliefs about the risks of cervical cancer, and available cures. Invitations and reminders within general practices enhance the uptake rate.     

Identification of a New Plasma α(1,3)Fucosyltransferase (FUT6) Allele Requires an Extended Genotyping Strategy

Screening the FUT6 gene of 40 Swedish individuals, originally selected for genotyping of FUT3, revealed an unexpected high frequency of mutations. Four were originally typed as homozygous for the enzyme lethal mutation G739A by TaqαI restriction pattern, but only one lacked plasma α(1,3)fucosyltransferase activity. Cloning and sequencing of FUT6 from 2 of them revealed a new allele, without the G739A mutation, but with two new point mutations C738T and G977A. Segregation of this allele was confirmed in Swedish and Indonesian families. Since G739A and C738T mutations are only one nucleotide apart and induce the same modification of TaqαI cleavage, a new screening strategy for FUT6 was adopted. The homozygous inactivating G739A mutation was for the first time identified in Caucasian and Polynesian individuals, both lacking plasma enzyme activity. The mutation C370T was present in 25 of the 40 Swedish individuals and the inactivating mutation C945A was not found at all. These findings stress the dangers of transferring restriction enzyme genotype strategies from one population to another and of inferring phenotypes from genotypes without phenotyping and/or performing confirmatory cloning and sequencing.