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Influence of changes in levels of coagulation factors and anticoagulants on acquired activated protein C (APC) resistance were studied in 40 healthy women during normal pregnancy. Factor VIII (FVIII), von Willebrand factor antigen (VWF:Ag), free protein S (FPS) and protein C were determined at 5-13, 14-26 and 27-40 weeks gestation and more than 6 weeks postpartum. APC anticoagulant activity was determined by measuring the activated partial thromboplastin time before and after adding human APC, expressed as the APC-sensitivity ratio (APC-SR). During the second and third gestation trimesters a significant increase (P < 0.05) in FVIII and VWF:Ag levels and a decrease in FPS levels were seen compared with the first trimester. Postpartum FVIII and VWF:Ag levels significantly decreased and FPS levels increased compared with the third trimester. Protein C levels remained unchanged during pregnancy and postpartum. Between increased FVIII and lowered APC-SR a trend of inverse correlation (r = -0.329; P = 0.076) occurred in the second trimester. No correlation was found between APC-SR and FPS or VWF:Ag levels. A remarkable finding is the strong inverse relationship between APC-SR and protein C levels (r

Breast feeding (BF) provides many advantages to the offspring; however, at present there is an ongoing debate as to whether or not it prevents allergic diseases. The aim of the current study was to investigate the effect of duration of BF on eczema in the first year of life. A birth cohort of 1128 infants was followed prospectively from 5 months of pregnancy. Data were collected using questionnaires, a medical examination and blood tests for allergy at the age of 1 yr. Breast feeding was not statistically significant associated with eczema in the first year of life [adj ORs with 95% CIs: 0.8 (0.4-1.3), 0.8 (0.5-1.3) and 1.0 (0.6-1.5) for BF duration of 1-6 wk, 7-12 wk and > or = 13 wk, respectively]. Eczema was positively associated with atopy and educational level of the mother, use of antibiotics in pregnancy and passive smoking by the child during the first 12 months. Regular postnatal contact of the infants with dogs was inversely associated with eczema. Breast feeding was positively associated with eczema among children with non-atopic parents [adj ORs with 95% CIs: 2.1 (0.4-10.6), 2.2 (0.4-11.3) and 1.9 (0.4-8.5) for BF duration of 1-6 wk, 7-12 wk and > or = 13 wk, respectively], whereas an inverse association was found among children with atopic parents [adj ORs with 95% CIs: 0.6 (0.3-1.3), 0.7 (0.3-1.4) and 0.9 (0.5-1.7) for the same BF durations]. However, these associations were not statistically significant. Breast feeding has no significant effect on the prevalence of eczema in the first year of life. The effect of BF on eczema in children depends on parental atopy.

Purpose: Inflammatory breast cancer (IBC) is the most aggressive form of locally advanced breast cancer with high metastatic potential. In a previous study, we showed that IBC is a different form of breast cancer compared with non-IBC by cDNA microarray analysis. A list of 756 genes with significant expression differences between IBC and non-IBC was identified. In-depth functional analysis revealed the presence of a high number of nuclear factor-kappaB (NF-kappaB) target genes with elevated expression in IBC versus non-IBC. This led to the hypothesis that NF-kappaB contributes to the phenotype of IBC. The aim of the present study was to further investigate the role of NF-kappaB in IBC., Experimental Design: Immunohistochemistry and NF-kappaB DNA-binding experiments were done for all NF-kappaB subunits (RelA, RelB, cRel, NFkB1, and NFkB2) using IBC and non-IBC specimens. Transcriptionally active NF-kappaB dimers were identified by means of coexpression analysis. In addition, quantitative real-time reverse transcription-PCR for eight NF-kappaB target genes, selected upon a significant, 3-fold gene expression difference between IBC and non-IBC by cDNA microarray analysis, was done., Results: We found a significant overexpression for all of eight selected NF-kappaB target genes in IBC compared with non-IBC by quantitative real-time reverse transcription-PCR. In addition, we found a statistically elevated number of immunostained nuclei in IBC compared with non-IBC for RelB (P = 0.038) and NFkB1 (P < 0.001). Immunohistochemical data were further validated by NF-kappaB DNA-binding experiments. Significant correlations between immunohistochemical data and NF-kappaB DNA binding for RelA, RelB, NFkB1, and NFkB2 were found. Transcriptionally active NF-kappaB dimers, composed of specific combinations of NF-kappaB family members, were found in 19 of 44 IBC specimens compared with 2 of 45 non-IBC specimens (P < 0.001). In addition, we found evidence for an estrogen receptor (ER)-mediated inhibition of the NF-kappaB signaling pathway. NF-kappaB target genes were significantly elevated in ER- versus ER+ breast tumors. Also, the amount of immunostained nuclei for RelB (P = 0.025) and NFkB1 (P = 0.031) was higher in ER- breast tumors versus ER+ breast tumors., Conclusions: The NF-kappaB transcription factor pathway probably contributes to the phenotype of IBC and possibly offers new options for treatment of patients diagnosed with this aggressive form of breast cancer.

Objectives: To investigate how physicians felt about HRT use in breast cancer survivors a half year after the WHI trial., Methods: In December 2002, a questionnaire was conducted in Flanders (Belgium). The survey contained a presentation of a 35-year-old breast cancer survivor who presented with climacteric symptoms after treatment with tamoxifen., Results: With a response rate of 33.65%, a majority of the physicians did not prescribe classical oral HRT (5.40%) in this patient. Physicians prefer to prescribe tibolone (30.68%) or other alternative treatment (50.00%). The main reason was the fear for increased recurrence of breast cancer. Furthermore the WHI oestrogen plus progestin trial and its attention in the media, a half year prior to the survey, influenced one-third of the physician's prescribing attitude., Conclusions: Two-thirds of the physicians did not change prescribing attitude after the WHI oestrogen plus progestin trial. HRT is a well proven effective treatment in breast cancer survivors with severe climacteric complaints, but a majority of physicians is not convinced of its safety in breast cancer survivors. Therefore, a majority of physicians do not find the need to prescribe HRT in breast cancer survivors.

In 2003, the United States Food and Drug Administration has approved the Hybrid Capture 2 assay for use with a Pap test to adjunctively screen women of 30 years and older for the presence of high-risk human papillomavirus (HR-HPV) infection. Although the predictive power of a negative test is strong, the number of false-positives may still be high. We investigated HPV prevalence in relation to age in a group of 2293 women, aged between 20 and 50, with normal cytology. Overall HR-HPV prevalence was 6.9% (95%CI=5.9-8.0%). Regression analysis using 5-year intervals showed that the HR-HPV prevalence did not significantly decline up to age 34, whereas it declined significantly after age 35. This would suggest that postponing HPV detection in primary screening from age 30 to 35 would result in a decrease of almost 50% of the number of women with normal cytology and a transient HPV infection. However, larger scale studies are required to confirm this finding.

Objective: Isolated lung perfusion (ILuP) is an experimental technique currently tested to increase the 5-year survival of 40% after surgical resection of pulmonary metastases from certain solid tumors. The standard technique of anterograde perfusion was compared with retrograde isolated lung perfusion in which the drug is introduced through the pulmonary veins while the effluent is collected from the pulmonary artery. Since the lung has a dual arterial circulation through the pulmonary artery and bronchial circulation, perfusion through the pulmonary veins can result in a more homogeneous distribution throughout the lung with subsequent higher melphalan concentration., Methods: We randomized 20 rats into two groups. Group one underwent anterograde isolated left lung perfusion while group two underwent retrograde isolated left lung perfusion. A dose of 2 mg/kg melphalan (MN) was administered to the lung at a flow of 0.5 mL/min during 30 min, followed by a 5-min washout with buffered hetastarch (BHE). The final melphalan lung concentration (FMLC) was determined in the hilum, at the apex, the mid-periphery and the base of the lung. Statistical analysis was done with an unpaired student's t-test., Results: Retrograde left ILuP resulted in a higher FMLC in the hilum (P<0.0001) and in the base of the lung (P=0.03), while anterograde ILuP induced a higher concentration at the apex of the lung (P=0.04). No difference was seen in the mid-peripheral area of the lung (P=0.92)., Conclusions: In this experimental study, retrograde perfusion seems to increase final melphalan lung concentration in hilar and basal regions of the lung compared to anterograde perfusion.

Background: Efficacy studies of isolated lung perfusion (ILuP) with melphalan showed superior results compared to intravenous therapy. However, the influence of pharmacokinetic parameters on the final melphalan lung concentration (FMLC) is unknown. In this study, we studied the impact of three different perfusion parameters on the FMLC in different areas of the lung., Material and Methods: Fifty-four rats were randomized into nine groups. Each group underwent ILuP with variation of perfusion duration (15, 30, and 60 min), the flow (0.125, 0.25, and 0.5 ml/min), concentration (8.3, 16.7, 33.3, 66.7, and 133.3 microg/ml) and the resulting dose (maximum 4 mg/kg). Lung samples were taken from the hilum and at the periphery of the lung (apex, base). Additional samples were taken to evaluate wet-to-dry ratio (W/D-ratio). Multiple linear regression and Student's t test were used for analysis. Significance was defined as a P

Background: Fluoroquinolones are an important group of antibiotics widely used in adults, and, despite the absence of official approval, these drugs are also used in children. So far, resistance to fluoroquinolones in Streptococcus pyogenes is very rare., Methods: During a national surveillance programme in Belgium from 1999 to 2002, 2793 non-duplicate S. pyogenes recovered from tonsillopharyngitis patients were screened for fluoroquinolone resistance. Mutations in topoisomerase genes and the presence of any efflux pump activity were investigated to elucidate the fluoroquinolone resistance mechanisms. Clonality was assessed by pulsed-field gel electrophoresis (PFGE) and emm typing., Results: Non-susceptibility to fluoroquinolones, defined as ciprofloxacin MIC > or = 2 mg/L, was identified in 152 (5.4%) of 2793 S. pyogenes. Fifty-five (36%) fluoroquinolone non-susceptible isolates were investigated for known resistance mechanisms; all showed mutations in parC, and 29 (19%) isolates also in parE; antibiotic efflux was not noted. Two major PFGE types comprised 88% of fluoroquinolone non-susceptible S. pyogenes and belonged to serotypes emm6 and emm75. Overall, emm6 and emm75 constituted >90% of all fluoroquinolone non-susceptible isolates and showed a significant temporal and geographical shift within Belgian provinces. Although fluoroquinolone-susceptible S. pyogenes also showed fluctuations in the predominant S. pyogenes serotypes, emm6 or emm75 were under-represented in this population. Approx. 55% of the fluoroquinolone non-susceptible isolates were recovered from children ( < or =16 years)., Conclusions: We show here, for the first time, a multi-clonal spread of fluoroquinolone non-susceptible S. pyogenes exhibiting a known resistance mechanism. Non-susceptibility to fluoroquinolones in paediatric isolates is of concern.

Despite the indisputable link between smoking and the increased risk for lung cancer, the inclusion of this factor in prognostic survival analysis has been scarce. Important clinical questions regarding the smoking status are the basis of this study and are as follow: what is the prognostic benefit of having been a non-smoker or having stopped smoking prior to developing lung cancer and what is the prognostic benefit of smoking cessation at the time of diagnosis of lung cancer? Cigarette smoking status of 311 patients operated for non-small cell lung cancer (NSCLC) by a single surgeon was determined based on two independent questionnaires taken prospectively prior to lung operation. Of all patients analysed, 169 (54.3%) were current smokers, 25 (8.0%) were non-smokers, 82 (26.4%) were former smokers and 35 (11.3%) were recent quitters. A Cox multiple regression model was used to test the prognostic value of smoking status on survival together with other relevant clinicopathological factors. For overall survival, older age (P = 0.011), presence of lymph node metastases (P < 0.001) and current smoking (P = 0.001) were independent predictors of poor prognosis, while non-smokers (relative risk = 0.447, 95% confidence interval = 0.206-0.970, P = 0.042), former smokers (relative risk = 0.543, 95% confidence interval = 0.350-0.843, P = 0.006) and recent quitters (relative risk = 0.340, 95% confidence interval = 0.164-0.705, P = 0.004) had a significant better prognosis compared to current smokers (referent group). Similar results were obtained for disease-free survival. These results indicate that smoking cessation is beneficial for lung cancer patients at any time point prior to lung operation and current smoking at the time of operation is associated with poor prognosis.

About 50% of patients with breast cancer have no involvement of axillary lymph nodes at diagnosis and can be considered cured after primary locoregional treatment. However, about 20-30% will experience distant relapse. The group of patients at risk is not well characterised: recurrence is probably due to the establishment of micrometastases before treatment. Given the early steps of metastasis in which tumour cells interact with endothelial cells of blood vessels, and, given the independent prognostic value in breast cancer of both the quantification of tumour vascularisation and the detection of micrometastases in the bone marrow, the aim of this study was to determine the relationship between vascularisation, measured by Chalkley morphometry, and the bone marrow content of cytokeratin-19 (CK-19) mRNA, quantified by real-time reverse transcriptase polymerase chain reaction, in a series of 68 patients with localised untreated breast cancer. The blood concentration of factors involved in angiogenesis (interleukin-6 and vascular endothelial growth factor) and of factors involved in coagulation (D-dimer, fibrinogen, platelets) was also measured. When bone marrow CK-19 relative gene expression (RGE) was categorised according to the cut-off value of 0.77 (95th centile of control patients), 53% of the patients had an elevated CK-19 RGE. Patients with bone marrow micrometastases, on the basis of an elevated CK-19 RGE, had a mean Chalkley count of 7.5 +/- 1.7 (median 7, standard error [SE] 0.30) compared with a mean Chalkley count of 6.5 +/- 1.7 in other patients (median 6, SE 0.3) (Mann-Whitney U-test; P = 0.04). Multiple regression analysis revealed that Chalkley count, not lymph node status, independently predicted CK-19 RGE status (P = 0.04; odds ratio 1.38; 95% confidence interval 1.009-1.882). Blood parameters reflecting angiogenesis and coagulation were positively correlated with Chalkley count and/or CK-19 RGE. Our data are in support of an association between elevated relative microvessel area of the primary tumour and the presence of bone marrow micrometastases in breast cancer patients with operable disease, and corroborate the paracrine and endocrine role of interleukin-6 and the involvement of coagulation in breast cancer growth and metastasis.

The purpose of our study was to assess prospectively the value of MRI in characterization of soft tissue tumors (STT) and soft tissue tumor-like lesions in a multi-institutional setting by a group of experts. The material consisted of 548 untreated and proven STT or tumor-like lesions originating from a multi-institutional database of STT in which 930 consecutive patients with STT examined by MRI were registered between 1 January 2001 and 28 April 2003. Based on MRI findings, a suitably ordered differential diagnosis was made in consensus by two radiologists (J.L.M.A.G and A.M.D.S). MRI diagnoses were compared with histology results (455 cases, 83%) and/or 6-month follow-up (93 cases, 17%) as reference standards. The correlation between the MRI and histological diagnosis and between the radiological and histological phenotype were statistically determined. One hundred twenty-three patients presented with a malignant STT; 425 patients presented with a benign one. Concerning differentiation between malignant and benign lesions (dignity), a sensitivity of 93%, specificity of 82%, negative predictive value (NPV) of 98% and positive predictive value (PPV) of 60% with accuracy of 85% were obtained. Concerning phenotype characterization, if only the first MRI diagnosis was taken into account, a sensitivity of 67%, specificity of 98%, NPV of 98%, PPV of 70% and accuracy of 96% were obtained. For benign lesions, sensitivity of 75%, specificity of 98%, NPV of 98%, PPV of 76% and accuracy of 97% were obtained. The phenotype's definition of malignant STT had a sensitivity of 37%, a specificity of 96%, NPV of 96%, PPV of 40% and an accuracy of 92%. A correct diagnosis compared with histological assessment was proposed in 227(50%) of the 455 histologically confirmed cases. Despite non-quantified MR parameter evaluation, the results of our prospective study were better than those reported in previous studies and demonstrated the need for a centralized approach to such rare pathology.

Background: Ibuprofen is used for treatment and prevention of patent ductus arteriosus in low-birthweight infants. Its effects on regional circulations differ from those of indometacin. Because prophylactic indometacin reduces the frequency of severe intraventricular haemorrhage and patent ductus arteriosus, we aimed to study the efficacy of early ibuprofen in reducing these outcomes in a double-blind, multicentre trial., Methods: Within 6 h after birth, 415 low-birthweight infants (gestational age <31 weeks) were randomly allocated ibuprofen-lysine (10 mg/kg then two doses of 5 mg/kg after 24 h and 48 h) or placebo intravenously. The primary outcome was occurrence of severe intraventricular haemorrhage; secondary outcomes were occurrence of patent ductus arteriosus and possible adverse effects of ibuprofen. Analysis was by intention to treat., Findings: 17 (8%) of 205 infants assigned ibuprofen and 18 (9%) of 210 assigned placebo developed severe intraventricular haemorrhage (relative risk 0.97 [95% CI 0.51-1.82]). In 172 (84%) infants of the ibuprofen group, the ductus was closed on day 3 compared with 126 (60%) of the placebo group (relative risk 1.40 [1.23-1.59]). No important differences in other outcomes or side-effects were noted; however, urine production was significantly lower on day 1 and concentration of creatinine in serum was significantly higher on day 3 after ibuprofen., Interpretation: Ibuprofen prophylaxis in preterm infants does not reduce the frequency of intraventricular haemorrhage, but does decrease occurrence of patent ductus arteriosus.

The neuropeptide hormone somatostatin reduces fibrosis and Schistosoma-caused clinical morbidity in the rodent model. In our study we aimed to delineate an association between fibrosis and the inability to generate critical levels of endogenous somatostatin in S. mansoni infected subjects. In June 2001, 85 subjects from the district dispensary at Richard Toll in the Medical Region of Saint-Louis, Senegal, were selected. Fifty-seven subjects were infected with S. mansoni of whom 32 were suffering from severe morbidity (SM). Twenty-eight subjects showed an inactive disease status with no evident infection at the actual time of study. All subjects were classified according to age, sex, occupation, height, weight, and parasite eggs per gram. All 85 participated in a water contact and morbidity questionnaire, underwent a clinical examination and donated 5ml of peripheral blood for detecting plasma levels of somatostatin. Ultrasonography detected fibrosis grade in all the subjects. To address whether inherent somatostatin levels determined clinically evident disease severity (epg, hepatomegaly, splenomegaly, hematemesis, ascites), the mean somatostatin values of the inactive disease status group and severe morbidity group were compared. Low somatostatin levels were depicted in subjects with severe morbidity symptoms associated with schistosomiasis as compared to exposed but inactive disease status subjects residing in the same region. Logistic regression analysis indicated that with decreasing somatostatin values the probability of severe morbidity increased with age being a confounding factor. To address whether inherent somatostatin levels determined fibrosis and if this association was significant, plasma somatostatin levels of non-fibrotics (ultrasonographic grading A), and fibrotics (ultrasonographic grading B-E) were compared. In all age groups as well as in adults alone, mean somatostatin levels were higher in the non-fibrotic group as compared to the fibrotics group, the difference being significant. The group B comprised of borderline fibrotic cases, therefore a separate analysis was done between groups A (non-fibrotics) and groups C, D (confirmed fibrotics). Mean somatostatin values were higher in the non-fibrotic group as compared to the fibrotics group, the difference being borderline significant. In schistosomiasis patients, circulating levels of somatostatin by binding to hepatic stellate cells (HSC) may modulate fibrosis. This phenomenon is regulated by age whereas gender and prior treatment have no effect on this association. Host specific somatostatin levels may create a 'preset environment' status that can determine progression to severe fibrosis., (Copyright 2004 Elsevier B.V.)

Although the relation between cervical cancer and the human papillomavirus (HPV) has been established beyond doubt, the introduction of HPV detection in cervical cancer screening is halted, primarily by the high rate of false positivity in relation to morbidity, since the majority of women infected with HPV will not develop lesions. To counteract overconsumption of cervical cancer screening in elderly women, we wanted to test the hypothesis that women of 50 years or older who are HPV-negative and have a cytologically normal smear might be encouraged to refrain from further screening. As a first step, the prevalence of high-risk HPV in a population of 1,936 women of 50 years and older was investigated. After an initial decline, a slightly higher prevalence can be seen with increasing age. There is a decrease in the prevalence of multiple infections with age, paralleled by an increase in single infections, especially of HPV type 16 in the eldest-age group. However, neither the decrease in multiple infections nor the increase in single infections is statistically significant. The data obtained in this study show that, even in the presence of a slight increase in the HPV prevalence in elderly women, approximately 94% of the elderly women can be withdrawn from the cervical cancer screening. However, a follow-up study will be necessary to determine the frequency of (re)infection as well as the course of an HPV infection in elderly women., (Copyright 2003 Wiley-Liss, Inc.)

This paper evaluates the performance of an algorithm developed for opportunistic, selective screening of women for chlamydial infection in general practice in Antwerp, Belgium. Its performance was examined in 2 independent sets of patients: A) a cohort of 326 women participating in a pilot screening study, and B) a sample of 25 Chlamydia positive women, identified from the records of a laboratory of clinical microbiology. For group A, positive and negative predictive values were calculated and the accuracy of the algorithm was assessed. For group B, we examined the proportion of patients complying with the algorithm. In group A, the screening algorithm would have detected 73% of the cases in 35.6% of the population. The positive and negative predictive values were 7.7% and 98.4%, respectively. In group B, 84% of patients complied with the algorithm. The screening algorithm worked reasonably well in 2 datasets from a similar population studied 2 y later, but needs further validation.

Background: Herpes simplex virus (HSV) is occasionally detected in the lower respiratory tract of patients in intensive care, but its clinical importance in such situations remains unclear. We did a prospective cohort study to define the prevalence, origin, risk factors, and clinical relevance of HSV in the respiratory tract of patients undergoing critical care., Methods: We tested 764 patients admitted to intensive care for the presence of HSV in the respiratory tract, and assessed statistical relations between this virus and clinical variables., Findings: HSV was detected by oropharyngeal swab in the upper respiratory tract of 169 (22%) of 764 patients, within 10 days of admission for 150 (89%) of these individuals. The virus was isolated in 58 (16%) of 361 patients whose lower respiratory tract was sampled. The presence of HSV in the throat was a risk factor for development of HSV infections in the lower respiratory tract (p<0.001). HSV was isolated most frequently in patients with severe disease. HSV in the throat was associated with acute respiratory distress syndrome (p<0.001) and with increased length of stay in intensive care (p<0.001)., Interpretation: Our data suggest that HSV reactivation or infection of the upper respiratory tract is frequent among patients in intensive care, and is a risk factor for development of lower respiratory tract infection with this virus, possibly by means of aspiration.