Medical treatments and risk factors for resection surgery in Crohn's disease: results from the Swiss IBD Cohort Study

Background: Surgery has been previously reported to be necessary in up to 80% of Crohn's disease (CD) patients, and up to 65% of patients needed reoperation after 10 years. Prevention of surgery is therefore a particularly important issue for these patients. Treatment options are controversial and data on them are scarce. This study reports medical treatments and main clinical risk factors in CD patients having undergone one or several surgeries. Risks for being free from surgery were also assessed. Methods: Retrospective cohort study, using data from patients included in the Swiss IBD cohort study from November 2006 to July 2011. History of resective surgeries, clinical characteristics and drug regimens were collected through detailed medical records. Univariate and multivariate analyses for clinical and therapeutic factors were performed. Cox regression was made to estimate free-of-surgery risks for different phenotypes and drugs. Results: Out of 1138 CD patients in the cohort, 721 (63.4%) were free of surgery at inclusion; 203 (17.8%) had 1 surgery and 214 (18.8%) >1 surgery. Main risk factors for surgery were disease duration 5-10 years (OR=2.92; p<0.001) and >10 years (OR=10.45; p<0.001), as well as stricturing (OR=8.33; p<0.001) or fistulizing disease (OR=7.34; p<0.001). Risk factors for repeated surgery was disease duration >10 years (OR=2.55; p=0.006) or fistulizing disease (OR=3.79; p<0.001). At inclusion, 107 patients (25.7%) had at least one anti-TNF alpha, 168 (40.3%) at least one immunosuppressive agent, and 41 (9.8%) at least 5-ASA or antibiotics. 64 (15.3%) were not exposed to any medical treatment. Kaplan-Meier curves showed that the risk of being free of surgery was 65% after 10 years, 42% after 20 years and 23% after 40 years. Surgical risks were four resp. five time higher for fistulizing and stricturing phenotypes (Hazard ratio (HR) =4.2; p<0.001; resp. HR=4.7; p<0.001) compared to inflammatory phenotype. Surgical risk was 4 times lower (HR=0.27; p=0.063) in CD patients under anti-TNF alpha compared to those under other or no drugs. Conclusion: The risk of having resective surgery was confirmed to be very high for CD in our cohort. Duration of disease, fistulizing and stricturing disease pattern enhance the risk of surgery. Anti-TNF alpha tends to lower this risk.

Ultrasound assessment of ocular vascular effects of repeated intravitreal injections of ranibizumab for wet age-related macular degeneration.

PURPOSE: Determine the effect of repeated intravitreal injections of ranibizumab (0.5 mg; 0.05 ml) on retrobulbar blood flow velocities (BFVs) using ultrasound imaging quantification in twenty patients with exudative age-related macular degeneration treated for 6 months. METHODS: Visual acuity (ETDRS), central macular thickness (OCT), peak-systolic, end-diastolic and mean-BFVs in central retinal (CRA), temporal posterior ciliary (TPCA) and ophthalmic (OA) arteries were measured before, 2 days, 3 weeks and 6 months after the first injection. Patients were examined monthly and received 1-5 additional injections depending on ophthalmologic examination results. RESULTS: Six months after the first injection, a significant increase in visual acuity 50.9 ± 25.9 versus 44.4 ± 21.7 (p < 0.01) and decrease in mean central macular thickness 267 ± 74 versus 377 ± 115 μm (p < 0.001) were observed compared to baseline. Although mean-BFVs decreased by 16%±3% in CRA and 20%±5% in TPCA (p < 0.001) 2 days after the first injection, no significant change was seen thereafter. Mean-BFVs in OA decreased by 19%±5% at week 3 (p < 0.001). However, the smallest number of injections (two injections) was associated with the longest time interval between the last injection and month 6 (20 weeks) and with the best return to baseline levels for mean-BFVs in CRA, suggesting that ranibizumab had reversible effects on native retinal vascular supply after its discontinuation. Moreover, a significant correlation between the number of injections and percentage of changes in mean-BFVs in CRA was observed at month 6 (R = 0.74, p < 0.001) unlike TPCA or OA. CONCLUSION: Ranibizumab could impair the native choroidal and retinal vascular networks, but its effect seems reversible after its discontinuation.

Workgroup report: incorporating in vitro alternative methods for developmental neurotoxicity into international hazard and risk assessment strategies.

This is the report of the first workshop on Incorporating In Vitro Alternative Methods for Developmental Neurotoxicity (DNT) Testing into International Hazard and Risk Assessment Strategies, held in Ispra, Italy, on 19-21 April 2005. The workshop was hosted by the European Centre for the Validation of Alternative Methods (ECVAM) and jointly organized by ECVAM, the European Chemical Industry Council, and the Johns Hopkins University Center for Alternatives to Animal Testing. The primary aim of the workshop was to identify and catalog potential methods that could be used to assess how data from in vitro alternative methods could help to predict and identify DNT hazards. Working groups focused on two different aspects: a) details on the science available in the field of DNT, including discussions on the models available to capture the critical DNT mechanisms and processes, and b) policy and strategy aspects to assess the integration of alternative methods in a regulatory framework. This report summarizes these discussions and details the recommendations and priorities for future work.

Repeated surgical excision for an unusual variant of nephroblastoma: case report and review of the literature.

Bilateral fetal rhabdomyomatous nephroblastoma is a rare variant of Wilms' Tumor. The authors report the evolution over 48 months of a 10-month-old baby with bilateral nephroblastoma for which a left nephrectomy was initially performed. A right kidney tumor was enucleated preserving the kidney. The transformation of the primary tumor into a completely differentiated cystic nephroblastoma or nephromalike tumor and the appearance of a metachronous lesion was seen. This report emphasizes the role of nephron-sparing surgery in bilateral Wilms' Tumor when a benign transformation occurs under chemotherapy.

Risk of cardiovascular events and blood pressure control in hypertensive HIV-infected patients: Swiss HIV Cohort Study (SHCS).

BACKGROUND: Prevalence of hypertension in HIV infection is high, and information on blood pressure control in HIV-infected individuals is insufficient. We modeled blood pressure over time and the risk of cardiovascular events in hypertensive HIV-infected individuals. METHODS: All patients from the Swiss HIV Cohort Study with confirmed hypertension (systolic or diastolic blood pressure above 139 or 89 mm Hg on 2 consecutive visits and presence of at least 1 additional cardiovascular risk factor) between April 1, 2000 and March 31, 2011 were included. Patients with previous cardiovascular events, already on antihypertensive drugs, and pregnant women were excluded. Change in blood pressure over time was modeled using linear mixed models with repeated measurement. RESULTS: Hypertension was diagnosed in 2595 of 10,361 eligible patients. Of those, 869 initiated antihypertensive treatment. For patients treated for hypertension, we found a mean (95% confidence interval) decrease in systolic and diastolic blood pressure of -0.82 (-1.06 to -0.58) mm Hg and -0.89 (-1.05 to -0.73) mm Hg/yr, respectively. Factors associated with a decline in systolic blood pressure were baseline blood pressure, presence of chronic kidney disease, cardiovascular events, and the typical risk factors for cardiovascular disease. In patients with hypertension, increase in systolic blood pressure [(hazard ratio 1.18 (1.06 to 1.32) per 10 mm Hg increase], total cholesterol, smoking, age, and cumulative exposure to protease inhibitor-based and triple nucleoside regimens were associated with cardiovascular events. CONCLUSIONS: Insufficient control of hypertension was associated with increased risk of cardiovascular events indicating the need for improved management of hypertension in HIV-infected individuals.

Repeated exposure to Ochratoxin A generates a neuroinflammatory response, characterized by neurodegenerative M1 microglial phenotype.

Neurotoxic effects of the environmentally abundant mycotoxin Ochratoxin A (OTA) were studied in histotypic 3D rat brain cell cultures, comprising all brain cell types. Cultures were exposed to nanomolar OTA concentrations and samples were collected 48h after a single exposure, or after 10 days of repeated administration. OTA-induced changes in gene- and protein expression, as well as alterations in cell morphology were assessed. Forty-eight-hour OTA exposure resulted in a disruption of the neuronal cytoskeleton and reduced expression of several oligodendrocyte-specific markers indicative of demyelination. Astrocyte disturbances were revealed by a decrease in two astrocytic proteins involved in regulation of inflammatory responses, metallothioneins I and II. Repeated OTA administration induced a neuroinflammatory response, as visualized by an increase of isolectin B4 labelled cells, increased expression of pro-inflammatory cytokines, and detection of macrophagic ED1/CD68 positive cells, as well as an upregulation of neurodegenerative M1 microglial phenotype markers. Partial recovery from OTA-induced deleterious effects on oligodendrocytes and astrocytes was achieved by co-treatment with sonic hedgehog (SHH). In addition, metallothionein I and II co-treatment partially restored OTA-induced effects on oligodendrocytes after 48h, and modulated microglial reactivity after 10 days. These results suggest that OTA-exposure affects Shh-signalling, which in turn may influence both oligodendrocytes and astrocytes. Furthermore, the primarily astrocytic proteins MTI/MTII may affect microglial activation. Thus the neuroinflammatory response appears to be downstream of OTA-induced effects on demyelination, axonal instabilities and astrocytes disturbances. In conclusion, repeated OTA-exposure induced a secondary neuroinflammatory response characterized by neurodegenerative M1 microglial activation and pro-inflammatory response that could exacerbate the neurodegenerative process.

Effects of prior repeated-sprints with different recovery duration on oxygen uptake kinetics during subsequent heavy-exercise.

Introduction: Prior repeated-sprints (6) has become an interesting method to resolve the debate surrounding the principal factors that limits the oxygen uptake (V'O2) kinetics at the onset of exercise [i.e., muscle O2 delivery (5) or metabolic inertia (3)]. The aim of this study was to compare the effects of two repeated-sprints sets of 6x6s separated by different recovery duration between the sprints on V'O2 and muscular de-oxygenation [HHb] kinetics during a subsequent heavy-intensity exercise. Methods: 10 male subjects performed a 6-min constant-load cycling test (T50) at intensity corresponding to half of the difference between V'O2max and the ventilatory threshold. Then, they performed two repeated-sprints sets of 6x6s all-out separated by different recovery duration between the sprints (S1:30s and S2:3min) followed, after 7-min-recovery, by the T50 (S1T50 and S2T50, respectively). V'O2, [HHb] of the vastus lateralis (VL) and surface electromyography activity [i.e., root-mean-square (RMS) and the median frequency of the power density spectrum (MDF)] from VL and vastus medialis (VM) were recorded throughout T50. Models using a bi-exponential function for the overall T50 and a mono-exponential for the first 90s of T50 were used to define V'O2 and [HHb] kinetics respectively. Results: V'O2 mean value was higher in S1 (2.9±0.3l.min-1) than in S2 (1.2±0.3l.min-1); (p<0.001). The peripheral blood flow was increased after sprints as attested by a higher basal heart rate (HRbaseline) (S1T50: +22%; S2T50: +17%; p≤0.008). Time delay [HHb] was shorter for S1T50 and S2T50 than for T50 (-22% for both; p≤0.007) whereas the mean response time of V'O2 was accelerated only after S1 (S1T50: 32.3±2.5s; S2T50: 34.4±2.6s; T50: 35.7±5.4s; p=0.031). There were no significant differences in RMS between the three conditions (p>0.05). MDF of VM was higher during the first 3-min in S1T50 than in T50 (+6%; p≤0.05). Conclusion: The study show that V'O2 kinetics was speeded by prior repeated-sprints with a short (30s) but not a long (3min) inter-sprints-recovery even though the [HHb] kinetics was accelerated and the peripheral blood flow was enhanced after both sprints. S1, inducing a greater PCr depletion (1) and change in the pattern of the fibres recruitment (increase in MDF) compared with S2, may decrease metabolic inertia (2), stimulate the oxidative phosphorylation activation (4) and accelerate V'O2 kinetics at the beginning of the subsequent high-intensity exercise.

Repeated sprinting on natural grass impairs vertical stiffness but does not alter plantar loading in soccer players.

This study aimed to determine changes in spring-mass model (SMM) characteristics, plantar pressures, and muscle activity induced by the repetition of sprints in soccer-specific conditions; i.e., on natural grass with soccer shoes. Thirteen soccer players performed 6 × 20 m sprints interspersed with 20 s of passive recovery. Plantar pressure distribution was recorded via an insole pressure recorder device divided into nine areas for analysis. Stride temporal parameters allowed to estimate SMM characteristics. Surface electromyographic activity was monitored for vastus lateralis, rectus femoris, and biceps femoris muscles. Sprint time, contact time, and total stride duration lengthened from the first to the last repetition (+6.7, +12.9, and +9.3%; all P < 0.05), while flight time, swing time, and stride length remained constant. Stride frequency decrease across repetitions approached significance (-6.8%; P = 0.07). No main effect of the sprint number or any significant interaction between sprint number and foot region was found for maximal force, mean force, peak pressure and mean pressure (all P > 0.05). Center of mass vertical displacement increased (P < 0.01) with time, together with unchanged (both P > 0.05) peak vertical force and leg compression. Vertical stiffness decreased (-15.9%; P < 0.05) across trials, whereas leg stiffness changes were not significant (-5.9%; P > 0.05). Changes in root mean square activity of the three tested muscles over sprint repetitions were not significant. Although repeated sprinting on natural grass with players wearing soccer boots impairs their leg-spring behavior (vertical stiffness), there is no substantial concomitant alterations in muscle activation levels or plantar pressure patterns.

Relationships between anthropometric measures and athletic performance, with special reference to repeated-sprint ability, in the Qatar national soccer team.

The aim of this study was to determine potential relationships between anthropometric parameters and athletic performance with special consideration to repeated-sprint ability (RSA). Sixteen players of the senior male Qatar national soccer team performed a series of anthropometric and physical tests including countermovement jumps without (CMJ) and with free arms (CMJwA), straight-line 20 m sprint, RSA (6 × 35 m with 10 s recovery) and incremental field test. Significant (P < 0.05) relationships occurred between muscle-to-bone ratio and both CMJs height (r ranging from 0.56 to 0.69) as well as with all RSA-related variables (r < -0.53 for sprinting times and r = 0.54 for maximal sprinting speed) with the exception of the sprint decrement score (Sdec). The sum of six skinfolds and adipose mass index were largely correlated with Sdec (r = 0.68, P < 0.01 and r = 0.55, P < 0.05, respectively) but not with total time (TT, r = 0.44 and 0.33, P > 0.05, respectively) or any standard athletic tests. Multiple regression analyses indicated that muscular cross-sectional area for mid-thigh, adipose index, straight-line 20 m time, maximal sprinting speed and CMJwA are the strongest predictors of Sdec (r(2) = 0.89) and TT (r(2) = 0.95) during our RSA test. In the Qatar national soccer team, players' power-related qualities and RSA are associated with a high muscular profile and a low adiposity. This supports the relevance of explosive power for the soccer players and the larger importance of neuromuscular qualities determining the RSA.

The Vi element. A transposon-like repeated DNA sequence interspersed in the vitellogenin locus of Xenopus laevis.

A repeated DNA element in Xenopus laevis is described that is present in about 7500 copies dispersed throughout the genome. It was first identified in the 5' flanking region of one vitellogenin gene and was therefore named the Vi element. Seven copies are present within the vitellogenin gene region, three of them within introns of the genes A1, A2 and B2, and the other four copies in the gene flanking regions. Four of these copies have been sequenced. The Vi element is bounded by a well-conserved 13 base-pair inverted repeat; in addition, it is flanked by a three base-pair direct repeat that appears to be site-specific. The length of these four copies varies from 112 to 469 base-pairs; however, sequence homology between the different copies is very high. Their structural characteristics suggest that length heterogeneity may have arisen by either unequal recombinations, deletions or tandem duplications. Altogether, the characteristics and properties of the Vi element indicate that it might represent a mobile genetic element. One of the four copies sequenced is inserted close (position -535) to the transcription initiation site of the vitellogenin gene B2 in a region otherwise showing considerable homology with the closely related gene B1. Nevertheless, the presence of the Vi element does not seem to influence significantly the estrogen-controlled expression of gene B2. In addition, three alleles of this gene created by length polymorphism in intron 3 and in the Vi element inserted near the transcription initiation site are described.

Stability of repeated student evaluations of teaching in the second preclinical year of a medical curriculum

RESUME L'étude de la médecine à la Faculté de l'Université de Lausanne est un cursus de six ans. Depuis la réforme générale du curriculum en octobre 1995, le programme de la deuxième année consacrée à l'étude de l'être humain sain a été transformé. L'enseignement intégré par système ou organe a été introduit en remplaçant l'enseignement par discipline. Parallèlement, un système d'évaluation de l'enseignement par les étudiants a été proposé. Il a été amélioré au fil des années et depuis l'année académique 1998-99, l'évaluation est devenue systémique et régulière. Notre étude présente et compare les résultats des évaluations de l'enseignement et des enseignants de neuf cours intégrés dispensés en deuxième année durant deux années académiques (1998-99 et 1999-2000). Une forte corrélation entre les résultats des deux années consécutives ainsi qu'une importante disparité des estimations à l'intérieure de chacune de deux années ont été observées. Ceci démontre un engagement sérieux des étudiants dans le processus d'évaluation, révèle la pertinence de leur analyse et leur bonne capacité de discernement. L'analyse de nos résultats montre que les évaluations effectuées par les étudiants peuvent constituer une source fiable d'informations et contribuer à l'amélioration du processus d'enseignement.