Statistical evaluation of the influence of writing postures on on-line signatures. Study of the impact of time.

The aim of this study is to investigate the influence of unusual writing positions on a person's signature, in comparison to a standard writing position. Ten writers were asked to sign their signature six times, in each of four different writing positions, including the standard one. In order to take into consideration the effect of the day-to-day variation, this same process was repeated over 12 sessions, giving a total of 288 signatures per subject. The signatures were collected simultaneously in an off-line and on-line acquisition mode, using an interactive tablet and a ballpoint pen. Unidimensional variables (height to width ratio; time with or without in air displacement) and time-dependent variables (pressure; X and Y coordinates; altitude and azimuth angles) were extracted from each signature. For the unidimensional variables, the position effect was assessed through ANOVA and Dunnett contrast tests. Concerning the time-dependent variables, the signatures were compared by using dynamic time warping, and the position effect was evaluated through classification by linear discriminant analysis. Both of these variables provided similar results: no general tendency regarding the position factor could be highlighted. The influence of the position factor varies according to the subject as well as the variable studied. The impact of the session factor was shown to cover the impact that could be ascribed to the writing position factor. Indeed, the day-to-day variation has a greater effect than the position factor on the studied signature variables. The results of this study suggest guidelines for best practice in the area of signature comparisons and demonstrate the importance of a signature collection procedure covering an adequate number of sampling sessions, with a sufficient number of samples per session.

Characterization of the murine high Km glucose transporter GLUT2 gene and its transcriptional regulation by glucose in a differentiated insulin-secreting cell line.

In pancreatic beta-cells, the high Km glucose transporter GLUT2 catalyzes the first step in glucose-induced insulin secretion by glucose uptake. Expression of the transporter has been reported to be modulated by glucose either at the protein or mRNA levels. In this study we used the differentiated insulinoma cell line INS-1 which expresses high levels of GLUT2 and show that the expression of GLUT2 is regulated by glucose at the transcriptional level. By run-on transcription assays we showed that glucose induced GLUT2 gene transcription 3-4-fold in INS-1 cells which was paralleled by a 1.7-2.3-fold increase in cytoplasmic GLUT2 mRNA levels. To determine whether glucose regulatory sequences were present in the promoter region of GLUT2, we cloned and characterized a 1.4-kilobase region of mouse genomic DNA located 5' of the translation initiation site. By RNase protection assays and primer extension, we determined that multiple transcription initiation sites were present at positions -55, -64, and -115 from the first coding ATG and which were identified in liver, intestine, kidney, and beta-cells mRNAs. Plasmids were constructed with the mouse promoter region linked to the reporter gene chloramphenicol acetyltransferase (CAT), and transiently and stably transfected in the INS-1 cells. Glucose induced a concentration-dependent increase in CAT activity which reached a maximum of 3.6-fold at 20 mM glucose. Similar CAT constructs made of the human GLUT2 promoter region and the CAT gene displayed the same glucose-dependent increase in transcriptional activity when transfected into INS-1 cells. Comparison of the mouse and human promoter regions revealed sequence identity restricted to a few stretches of sequences which suggests that the glucose responsive element(s) may be conserved in these common sequences.

Benign pineal cysts in children with bilateral retinoblastoma: a new variant of trilateral retinoblastoma?

PURPOSE: Patients with hereditary retinoblastoma (Rb) develop in 4%-8% a malignant midline tumor called trilateral Rb (TRb). We report in this study on benign pineal cysts observed in patients investigated for TRb. PATIENTS AND METHODS: Between September 1990 and December 2001, 172 patients were screened for TRb. Ninty-five had bilateral, 77 unilateral disease. The median age at diagnosis of Rb was 7 months (range 1-26). Treatment included enucleation, local treatment with cryotherapy or photocoagulation, first-line chemotherapy (CT), thermo-chemotherapy (TCT), Ruthenium plaque, and, rarely, external beam radiation (EBR). RESULTS: TRb was found in 5/95 patients (5.3%) with bilateral disease. Interestingly, five other patients (5.3%) presented a pineal cyst on magnetic resonance imaging (MRI). No cysts were recorded in the 77 patients with unilateral disease. This difference was statistically significant (P < 0.05). The median age at diagnosis of the pineal cyst was 26 months (range 16-80), much younger than reported in literature for healthy children. Four of five patients with TRb died of the disease, while all the patients with pineal cysts remained stable and asymptomatic during a median follow-up of 41 months (range 37-54). CONCLUSIONS: This report describes benign cystic lesions of the pineal gland in patients with hereditary Rb, suggesting a benign variant of TRb. Underlying possible pathogenetic mechanisms are discussed.

Concomitant cisplatin and hyperfractionated radiotherapy in locally advanced head and neck cancer: 10-year follow-up of a randomized phase III trial (SAKK 10/94).

Purpose: To compare the long-term outcome of treatment with concomitant cisplatin and hyperfractionated radiotherapy versus treatment with hyperfractionated radiotherapy alone in patients with locally advanced head and neck cancer.Methods and Materials: From July 1994 to July 2000, a total of 224 patients with squamous cell carcinoma of the head and neck were randomized to receive either hyperfractionated radiotherapy alone (median total dose, 74.4 Gy; 1.2 Gy twice daily; 5 days per week) or the same radiotherapy combined with two cycles of cisplatin (20 mg/m(2) for 5 consecutive days during weeks 1 and 5). The primary endpoint was the time to any treatment failure; secondary endpoints were locoregional failure, metastatic failure, overall survival, and late toxicity assessed according to Radiation Therapy Oncology Group criteria.Results: Median follow-up was 9.5 years (range, 0.1-15.4 years). Median time to any treatment failure was not significantly different between treatment arms (hazard ratio [HR], 1.2 [95% confidence interval [CM 0.9-1.7; p = 0.17]). Rates of locoregional failure-free survival (HR, 1.5 [95% CI, 1.1-2.1;p = 0.021), distant metastasis-free survival (HR, 1.6 [95% CI, 1.1-2.5; p = 0.021), and cancer-specific survival (HR, 1.6 [95% CI, 1.0-2.5;p = 0.03]) were significantly improved in the combined-treatment arm, with no difference in major late toxicity between treatment arms. However, overall survival was not significantly different (HR, 1.3 [95% CI, 0.9-1.8; p = 0.11]).Conclusions: After long-term follow-up, combined-treatment with cisplatin and hyperfractionated radiotherapy maintained improved rates of locoregional control, distant metastasis-free survival, and cancer-specific survival compared to that of hyperfractionated radiotherapy alone, with no difference in major late toxicity. (C) 2012 Elsevier Inc.

Involvement of nuclear factor-kappaB in macrophage migration inhibitory factor gene transcription up-regulation induced by interleukin- 1 beta in ectopic endometrial cells.

OBJECTIVE: To investigate the involvement of the nuclear factor (NF)-kappaB in the interleukin (IL)-1 beta-mediated macrophage migration inhibitory factor (MIF) gene activation. DESIGN: Prospective study. SETTING: Human reproduction research laboratory. PATIENT(S): Nine women with endometriotic lesions. INTERVENTION(S): Endometriotic lesions were obtained during laparoscopic surgery. MAIN OUTCOME MEASURE(S): The MIF protein secretion was analyzed by ELISA, MIF mRNA expression by quantitative real-time polymerase chain reaction (PCR), NF-kappaB translocation into the nucleus by electrophoresis mobility shift assay, I kappaB phosphorylation and degradation by Western blot, and human MIF promoter activity by transient cell transfection. RESULT(S): This study showed a significant dose-dependent increase of MIF protein secretion and mRNA expression, the NF-kappaB translocation into the nucleus, I kappaB phosphorylation, I kappaB degradation, and human MIF promoter activity in endometriotic stromal cells in response to IL-1 beta. Curcumin (NF-kappaB inhibitor) significantly inhibited all these IL-1 beta-mediated effects. Analysis of the activity of deletion constructs of the human MIF promoter and a computer search localized two putative regulatory elements corresponding to NF-kappaB binding sites at positions -2538/-2528 bp and -1389/-1380 bp. CONCLUSION(S): This study suggests the involvement of the nuclear transcription factor NF-kappaB in MIF gene activation in ectopic endometrial cells in response to IL-1 beta and identifies a possible pathway of endometriosis-associated inflammation and ectopic cell growth.

The origin of black colouration in onyx agate from Mali

Natural onyx agate from Mali was investigated in an integrated mineralogical and chemical study to reveal the origin of the unusual black colouration. Detailed studies by polarizing microscopy, scanning electron microscopy and micro-Raman spectroscopy showed that the colour of the dark bands is related to the incorporation of small particles of carbon (low-crystalline graphite) up to 200 nm in size into the cryptocrystalline silica matrix. The dark bands have carbon contents of 1.88 wt.%. The location of the graphite particles is closely related to the primary structural banding in the chalcedony. Cathodoluminescence data shows that the banding is interrupted by small fissures containing secondary hydrothermal quartz. The carbon isotope composition (delta C-13 value of -31.1+/-0.2 parts per thousand) of the carbonaceous material points to an organic precursor. Both the direct hydrothermal formation of graphite from methane under elevated temperature and the graphitization of organic precursors by secondary hydrothermal or metamorphic overprint are possible explanations for the colour of the dark bands. The graphitization of organic precursors results in an intense electron spin resonance line at g(eff) = 2.0026.

Augmented epithelial multidrug resistance-associated protein 4 expression in peritoneal endometriosis: regulation by lipoxin A(4).

OBJECTIVE: To compare the expression of the prostaglandin (PG) E(2) transporter multidrug resistance-associated protein 4 (MRP4) in eutopic and ectopic endometrial tissue from endometriosis patients with that of control subjects and to examine whether MRP4 is regulated by the antiinflammatory lipid lipoxin A(4) (LXA(4)) in endometriotic epithelial cells. DESIGN: Molecular analysis in human samples and a cell line. SETTING: Two university hospitals and a private clinic. PATIENT(S): A total of 59 endometriosis patients and 32 age- and body mass index-matched control subjects undergoing laparoscopy or hysterectomy. INTERVENTION(S): Normal, eutopic, and ectopic endometrial biopsies as well as peritoneal fluid were obtained during surgery performed during the proliferative phase of the menstrual cycle. 12Z endometriotic epithelial cells were used for in vitro mechanistic studies. MAIN OUTCOME MEASURE(S): Tissue MRP4 mRNA levels were quantified by quantitative reverse-transcription polymerase chain reaction (qRT-PCR), and localization was analyzed with the use of immunohistochemistry. Cellular MRP4 mRNA and protein were quantified by qRT-PCR and Western blot, respectively. PGE(2) was measured in peritoneal fluid and cell supernatants using an enzyme immunoassay (EIA). RESULT(S): MRP4 was expressed in eutopic and ectopic endometrium, where it was overexpressed in peritoneal lesions and localized in the cytoplasm of glandular epithelial cells. LXA(4) attenuated MRP4 mRNA and protein levels in endometriotic epithelial cells in a dose-dependent manner, while not affecting the expression of enzymes involved in PGE(2) metabolism. Investigations employing receptor antagonists and small interfering RNA revealed that this occurred through estrogen receptor α. Accordingly, LXA(4) treatment inhibited extracellular PGE(2) release. CONCLUSION(S): We report for the first time that MRP4 is expressed in human endometrium, elevated in peritoneal endometriosis, and modulated by LXA(4) in endometriotic epithelial cells.

Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98.

PURPOSE: We report the long-term results of a randomized clinical trial comparing induction therapy with once per week for 4 weeks single-agent rituximab alone versus induction followed by 4 cycles of maintenance therapy every 2 months in patients with follicular lymphoma. PATIENTS AND METHODS: Patients (prior chemotherapy 138; chemotherapy-naive 64) received single-agent rituximab and if nonprogressive, were randomly assigned to no further treatment (observation) or four additional doses of rituximab given at 2-month intervals (prolonged exposure). RESULTS: At a median follow-up of 9.5 years and with all living patients having been observed for at least 5 years, the median event-free survival (EFS) was 13 months for the observation and 24 months for the prolonged exposure arm (P < .001). In the observation arm, patients without events at 8 years were 5%, while in the prolonged exposure arm they were 27%. Of previously untreated patients receiving prolonged treatment after responding to rituximab induction, at 8 years 45% were still without event. The only favorable prognostic factor for EFS in a multivariate Cox regression was the prolonged rituximab schedule (hazard ratio, 0.59; 95% CI, 0.39 to 0.88; P = .009), whereas being chemotherapy naive, presenting with stage lower than IV, and showing a VV phenotype at position 158 of the Fc-gamma RIIIA receptor were not of independent prognostic value. No long-term toxicity potentially due to rituximab was observed. CONCLUSION: An important proportion of patients experienced long-term remission after prolonged exposure to rituximab, particularly if they had no prior treatment and responded to rituximab induction.

Appropriateness and long-term discontinuation rate of biological therapies in ulcerative colitis.

BACKGROUND: Anti-TNFα agents are commonly used for ulcerative colitis (UC) therapy in the event of non-response to conventional strategies or as colon-salvaging therapy. The objectives were to assess the appropriateness of biological therapies for UC patients and to study treatment discontinuation over time, according to appropriateness of treatment, as a measure of outcome. METHODS: We selected adult ulcerative colitis patients from the Swiss IBD cohort who had been treated with anti-TNFα agents. Appropriateness of the first-line anti-TNFα treatment was assessed using detailed criteria developed during the European Panel on the Appropriateness of Therapy for UC. Treatment discontinuation as an outcome was assessed for categories of appropriateness. RESULTS: Appropriateness of the first-line biological treatment was determined in 186 UC patients. For 64% of them, this treatment was considered appropriate. During follow-up, 37% of all patients discontinued biological treatment, 17% specifically because of failure. Time-to-failure of treatment was significantly different among patients on an appropriate biological treatment compared to those for whom the treatment was considered not appropriate (p=0.0007). Discontinuation rate after 2years was 26% compared to 54% between those two groups. Patients on inappropriate biological treatment were more likely to have severe disease, concomitant steroids and/or immunomodulators. They were also consistently more likely to suffer a failure of efficacy and to stop therapy during follow-up. CONCLUSION: Appropriateness of first-line anti-TNFα therapy results in a greater likelihood of continuing with the therapy. In situations where biological treatment is uncertain or inappropriate, physicians should consider other options instead of prescribing anti-TNFα agents.

Loss to follow-up of HIV-infected women after delivery : The Swiss HIV Cohort Study and the Swiss Mother and Child HIV Cohort Study

INTRODUCTION: HIV-infected pregnant women are very likely to engage in HIV medical care to prevent transmission of HIV to their newborn. After delivery, however, childcare and competing commitments might lead to disengagement from HIV care. The aim of this study was to quantify loss to follow-up (LTFU) from HIV care after delivery and to identify risk factors for LTFU. METHODS: We used data on 719 pregnancies within the Swiss HIV Cohort Study from 1996 to 2012 and with information on follow-up visits available. Two LTFU events were defined: no clinical visit for >180 days and no visit for >360 days in the year after delivery. Logistic regression analysis was used to identify risk factors for a LTFU event after delivery. RESULTS: Median maternal age at delivery was 32 years (IQR 28-36), 357 (49%) women were black, 280 (39%) white, 56 (8%) Asian and 4% other ethnicities. One hundred and seven (15%) women reported any history of IDU. The majority (524, 73%) of women received their HIV diagnosis before pregnancy, most of those (413, 79%) had lived with diagnosed HIV longer than three years and two-thirds (342, 65%) were already on antiretroviral therapy (ART) at time of conception. Of the 181 women diagnosed during pregnancy by a screening test, 80 (44%) were diagnosed in the first trimester, 67 (37%) in the second and 34 (19%) in the third trimester. Of 357 (69%) women who had been seen in HIV medical care during three months before conception, 93% achieved an undetectable HIV viral load (VL) at delivery. Of 62 (12%) women with the last medical visit more than six months before conception, only 72% achieved an undetectable VL (p=0.001). Overall, 247 (34%) women were LTFU over 180 days in the year after delivery and 86 (12%) women were LTFU over 360 days with 43 (50%) of those women returning. Being LTFU for 180 days was significantly associated with history of intravenous drug use (aOR 1.73, 95% CI 1.09-2.77, p=0.021) and not achieving an undetectable VL at delivery (aOR 1.79, 95% CI 1.03-3.11, p=0.040) after adjusting for maternal age, ethnicity, time of HIV diagnosis and being on ART at conception. CONCLUSIONS: Women with a history of IDU and women with a detectable VL at delivery were more likely to be LTFU after delivery. This is of concern regarding their own health, as well as risk for sexual partners and subsequent pregnancies. Further strategies should be developed to enhance retention in medical care beyond pregnancy.

24 Hours in the Life of HIV-1 in a T Cell Line.

HIV-1 infects CD4+ T cells and completes its replication cycle in approximately 24 hours. We employed repeated measurements in a standardized cell system and rigorous mathematical modeling to characterize the emergence of the viral replication intermediates and their impact on the cellular transcriptional response with high temporal resolution. We observed 7,991 (73%) of the 10,958 expressed genes to be modulated in concordance with key steps of viral replication. Fifty-two percent of the overall variability in the host transcriptome was explained by linear regression on the viral life cycle. This profound perturbation of cellular physiology was investigated in the light of several regulatory mechanisms, including transcription factors, miRNAs, host-pathogen interaction, and proviral integration. Key features were validated in primary CD4+ T cells, and with viral constructs using alternative entry strategies. We propose a model of early massive cellular shutdown and progressive upregulation of the cellular machinery to complete the viral life cycle.

Success and Failure for Children Born with Facial Clefts in Africa: A 15-Year Follow-up.

BACKGROUND: This study reviews the 15 year program of our Department of Pediatric Surgery for the treatment and follow-up of children born with a cleft in Benin and Togo. METHODS: We analyzed files of children born in Africa with a cleft. They were referred to us through a nongovernmental organization (NGO) between 1993 and 2008 and assessed in Africa by local pediatricians before and after surgery. Operations were performed by our team. RESULTS: Two hundred files were reviewed: 60 cases of unilateral cleft lip, seven of bilateral cleft lip, 44 of unilateral cleft lip palate (UCLP), 29 of bilateral cleft lip palate (BCLP), 53 of cleft palate (CP), three of bilateral oro-ocular cleft, one of unilateral and two of median clefts (Binder), and one of commissural cleft. Sixty-nine (35 %) of these cases were not operated in Africa: 25 (12.5 %) had not shown up, 28 (15 %) were considered unfit for surgery (Down's syndrome, HIV-positive, malnutrition, cardiac malformation), and 16 (7.5 %) were transferred to Switzerland. Palatal fistula occurred in 20 % of UCLP, 30 % of BCLP, and 16 % of CP. Evaluation of speech after palate surgery gave less than 50 % of socially acceptable speech. CONCLUSIONS: Our partnership with a NGO and a local team makes it possible to treat and subsequently follow children born with a cleft in West Africa. Surgery is performed under good conditions. If aesthetic results are a success, functional results after palate surgery need further improvement to promote integration in school and social life.

Clinical characteristics and outcome of patients admitted to a medico- surgical ICU requiring non invasive ventilation (NIV) for hypercapnic respiratory failure

Introduction Because it decreases intubation rate and mortality, NIV has become first-line treatment in case of hypercapnic acute respiratory failure (HARF). Whether this approach is equally successful for all categories of HARF patients is however debated. We assessed if any clinical characteristics of HARF patients were associated with NIV intensity, success, and outcome, in order to identify prognostic factors. Methods Retrospective analysis of the clinical database (clinical information system and MDSi) of patients consecutively admitted to our medico-surgical ICU, presenting with HARF (defined as PaCO2 > 50 mmHg), and receiving NIV between May 2008 and December 2010. Demographic data, medical diagnoses (including documented chronic lung disease), reason for ICU hospitalization, recent surgical interventions, SAPS II and McCabe scores were extracted from the database. Total duration of NIV and the need for tracheal intubation during the 5 days following the first hypercapnia documentation, as well as ICU, hospital and one year mortality were recorded. Results are reported as median [IQR]. Comparisons were carried out with Chi2 or Kruskal-Wallis tests, p<0.05 (*). Results Two hundred and twenty patients were included. NIV successful patients received 16 [9-31] hours of NIV for up to 5 days. Fifty patients (22.7%) were intubated 11 [2-34] hours after HARF occurence, after having receiving 10 [5-21] hours of NIV. Intubation was correlated with increased ICU (18% vs. 6%, p<0.05) and hospital (42% vs. 31%, p>0.05) mortality. SAPS II score was related to increasing ICU (51 [29-74] vs. 23 [12-41]%, p<0.05), hospital (37% [20-59] vs 20% [12-37], p<0.05) and one year mortality (35% vs 20%, p<0.05). Surgical patients were less frequent among hospital fatalities (28.8% vs. 46.3%, p<0.05, RR 0.8 [0-6-0.9]). Nineteen patients (8.6%) died in the ICU, 73 (33.2%) during their hospital stay and 108 (49.1%) were dead one year after HARF. Conclusion The practice to start NIV in all suitable patients suffering from HARF is appropriate. NIV can safely and appropriately be used in patients suffering from HARF from an origin different from COPD exacerbation. Beside usual predictors of severity such as severity score (SAPS II) appear to be associated with increased mortality. Although ICU mortality was low in our patients, hospital and one year mortality were substantial. Surgical patients, although undergoing a similar ICU course, had a better hospital and one year outcome.

Identification of estrogen-responsive DNA sequences by transient expression experiments in a human breast cancer cell line.

The expression of a hybrid gene formed by the promoter region of the Xenopus laevis vitellogenin gene B1 and the CAT coding region is regulated by estrogen when the gene is transfected into hormone-responsive MCF-7 cells. Furthermore, the 5' flanking region of the gene B1 alone can confer inducibility to heterologous promoters, although to a varying extent depending on the promoter used. Deletion mapping of he vitellogenin hormone-responsive sequences revealed that a 13 bp element 5'-AGTCACTGTGACC-3' at position -334 is essential for estrogen inducibility. We have shown previously that this 13 bp element is present upstream of several liver-specific estrogen-inducible genes.