Pregnancy Outcome Following Maternal Exposure To Statins: A Multicenter Prospective Study

Introduction: Statin use for the treatment of hypercholesterolemia in women of childbearing age is increasingly common. However, published data on pregnancy outcome after exposure to statins are scarce and conflicting. This contribution addresses the safety of exposure to statins during pregnancy.Method: In a multi-center (n = 11) observational, prospective study we compared the outcomes of 249 women exposed during the 1st trimester of pregnancy to simvastatin (n = 124), atorvastatin (n = 67), pravastatin (n = 32), rosuvastatin (n = 18), fluvastatin (n = 7) or cerivastatin (n = 1) with a control group exposed to agents known to be non-teratogenic (n = 249). The data were collected by members of the European Network of Teratology Information Services (ENTIS) during individual risk counseling between 1990 and 2009. Standardized procedures for data collection were used in each center.Results: The difference in the rate of major birth defects between the statin-exposed group and the control group was not statistically significant (4.0% vs. 2.7% OR 1.5; 95% CI 0.5-4.5, P = 0.44). The crude rate of spontaneous abortions (12.8% vs. 7.1%, OR 1.9, 95% CI 1.0-3.6, P = 0.04) was higher in the exposed group. However, after adjustment to maternal age and gestational age at initial contact, the difference became statistically insignificant. The rate of elective pregnancy-termination (8.8% vs. 4.4%, P = 0.05) was higher and the rate of deliveries resulting in live births was significantly lower in the statin exposed group (77.9% vs. 88.4%, P = 0.002). Prematurity was more frequent in exposed pregnancies (16.1% vs. 8.5%; OR 2.1, 95% CI 1.1-3.8, P = 0.02). Nonetheless, gestational age at birth (median 39 weeks, IQR 37-40 vs. 39 weeks, IQR 38-40, P = 0.27) and birth weight (median 3280 g, IQR 2835-3590 vs. 3250 g, IQR 2880-3600, P = 0.95) did not differ between exposed and non-exposed pregnancies.Conclusion: This study did not detect a clear teratogenic effect of statins. Its statistical power however is not sufficient to reverse the recommendation of treatment discontinuation during pregnancy. At most, the results are reassuring in case of inadvertent exposure.

What do we know about gliotransmitter release from astrocytes?

Astrocytes participate in information processing by actively modulating synaptic properties via gliotransmitter release. Various mechanisms of astrocytic release have been reported, including release from storage organelles via exocytosis and release from the cytosol via plasma membrane ion channels and pumps. It is still not fully clear which mechanisms operate under which conditions, but some of them, being Ca(2+)-regulated, may be physiologically relevant. The properties of Ca(2+)-dependent transmitter release via exocytosis or via ion channels are different and expected to produce different extracellular transmitter concentrations over time and to have distinct functional consequences. The molecular aspects of these two release pathways are still under active investigation. Here, we discuss the existing morphological and functional evidence in support of either of them. Transgenic mouse models, specific antagonists and localization studies have provided insight into regulated exocytosis, albeit not in a systematic fashion. Even more remains to be uncovered about the details of channel-mediated release. Better functional tools and improved ultrastructural approaches are needed in order fully to define specific modalities and effects of astrocytic gliotransmitter release pathways.

On the transition of genetic differentiation from isolation to panmixia: What we can learn from GST and D.

Population genetic differentiation characterizes the repartition of alleles among populations. It is commonly thought that genetic differentiation measures, such as GST and D, should be near zero when allele frequencies are close to their expected value in panmictic populations, and close to one when they are close to their expected value in isolated populations. To analyse those properties, we first derive analytically a reference function f of known parameters that describes how important features of genetic differentiation (e.g. gene diversity, proportion of private alleles, frequency of the most common allele) are close to their expected panmictic and isolation value. We find that the behaviour of function f differs according to three distinct mutation regimes defined by the scaled mutation rate and the number of populations. Then, we compare GST and D to f, and demonstrate that their signal of differentiation strongly depends on the mutation regime. In particular, we show that D captures well the variations of genetic diversity when mutation is weak, otherwise it overestimates it when panmixia is not met. GST detects population differentiation when mutation is intermediate but has a low sensitivity to the variations of genetic diversity when mutation is weak. When mutation is strong the domain of sensitivity of both measures are altered. Finally, we also point out the importance of the number of populations on genetic differentiation measures, and provide recommendations for the use of GST and D.

ATP-competitive inhibitors of mTOR: new perspectives in the treatment of renal cell carcinoma.

Targeting mTOR (mammalian target of rapamycin) is an effective approach in the treatment of advanced RCC (renal cell carcinoma). Rapamycin-like drugs (rapalogues) have shown clinical activities and have been approved for the treatment of RCC. Recently, with the development of ATP-competitive inhibitors of mTOR, therapies targeting mTOR have entered a new era. Here, we discuss the biological relevance of blocking mTOR in RCC and review the mechanisms of action of rapalogues in RCC. We also advance some perspectives on the use of ATP-competitive inhibitors of mTOR in RCC.

Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study.

We sought to provide a contemporary picture of the presentation, etiology, and outcome of infective endocarditis (IE) in a large patient cohort from multiple locations worldwide. Prospective cohort study of 2781 adults with definite IE who were admitted to 58 hospitals in 25 countries from June 1, 2000, through September 1, 2005. The median age of the cohort was 57.9 (interquartile range, 43.2-71.8) years, and 72.1% had native valve IE. Most patients (77.0%) presented early in the disease (<30 days) with few of the classic clinical hallmarks of IE. Recent health care exposure was found in one-quarter of patients. Staphylococcus aureus was the most common pathogen (31.2%). The mitral (41.1%) and aortic (37.6%) valves were infected most commonly. The following complications were common: stroke (16.9%), embolization other than stroke (22.6%), heart failure (32.3%), and intracardiac abscess (14.4%). Surgical therapy was common (48.2%), and in-hospital mortality remained high (17.7%). Prosthetic valve involvement (odds ratio, 1.47; 95% confidence interval, 1.13-1.90), increasing age (1.30; 1.17-1.46 per 10-year interval), pulmonary edema (1.79; 1.39-2.30), S aureus infection (1.54; 1.14-2.08), coagulase-negative staphylococcal infection (1.50; 1.07-2.10), mitral valve vegetation (1.34; 1.06-1.68), and paravalvular complications (2.25; 1.64-3.09) were associated with an increased risk of in-hospital death, whereas viridans streptococcal infection (0.52; 0.33-0.81) and surgery (0.61; 0.44-0.83) were associated with a decreased risk. In the early 21st century, IE is more often an acute disease, characterized by a high rate of S aureus infection. Mortality remains relatively high.

Plasma Level of Mmp-9 as Predictive Factor for Response and Progression Free Survival in Patients Treated with Bevacizumab (Bev) and Pegylated Liposomal Doxorubicin (Pld): Sakk 24/06

Background: There is currently no identified marker predicting benefit from Bev in patients with breast cancer (pts). We monitored prospectively 6 angiogenesis-related factors in the blood of advanced stage pts treated with a combination of Bev and PLD in a phase II trial of the Swiss Group for Clinical Cancer Research, SAKK.Methods: Pts received PLD (20 mg/m2) and Bev (10 mg/kg) every 2 weeks for a maximum of 12 administrations, followed by Bev monotherapy until progression or severe toxicity. Blood samples were collected at baseline, during treatment and at treatment discontinuation. Enzyme-linked immunosorbent assays (Quantikine, R&DSystems and Reliatech) were used to measure vascular endothelial growth factor (VEGF), placental growth factor (PlGF), matrix metalloproteinase 9 (MMP-9) and soluble VEGF receptors -1, -2 and -3. The natural log-transformed (ln) data for each factor was analyzed by analysis of variance (ANOVA) model to investigate differences between the mean values of the subgroups of interest (where a = 0.05), based on the best tumor response by RECIST.Results: 132 samples were collected in 41 pts. The mean of baseline ln MMP-9 levels was significantly lower in pts with tumor progression than those with tumor response (p=0.0202, log fold change=0.8786) or disease control (p=0.0035, log fold change=0.8427). Higher MMP-9 level was a significant predictor of superior progression free survival (PFS): p=0.0417, hazard ratio=0.574, 95% CI=0.336-0.979. In a multivariate cox proportional hazards model, containing performance status, disease free interval, number of tumor sites, visceral involvement and prior adjuvant chemotherapy, using stepwise regression baseline MMP-9 was still a statistically 117P Table 1. SOLTI-0701* AC01B07* NU07B1* SOR+CAP N=20 PL+CAP N=33 SOR+ GEM/CAP N=23 PL+ GEM/CAP N=27 SOR+PAC N=48 PL+PAC N=46 Baseline characteristics Age, median (range), y 49 (32-72) 53 (30-78 54 (32-69) 57 (31-82) 50 (27-80) 52 (23-74) AJCC stage, n (%) IIIB/IIIC 3 (15) 6 (18) 0 (0) 3 (11) 8 (17) 9 (20) IV 17 (85) 27 (82) 23 (100) 24 (89) 40 (83) 37 (80) Metastatic site, n (%) Non-visceral 3 (15) 6 (18) 7 (30) 6 (22) 9 (19) 17 (37) Visceral 17 (85) 27 (82) 16 (70) 21 (78) 39 (81) 29 (63) Prior metastatic chemo, n (%) 8 (40) 15 (45) 21 (91) 25 (93) - - Efficacy PFS, median, mo 4.3 2.5 3.1 2.6 5.6 5.5 HR (95% CI)_ 0.60 (0.31, 1.14) 0.57 (0.30, 1.09) 0.86 (0.50, 1.45) 1-sided P value_ 0.055 0.044 0.281 Overall survival, median, mo 17.5 16.1 Pending 14.7 18.2 HR (95% CI)_ 0.98 (0.50, 1.89) 1.11 (0.64, 1.94) 1-sided P value_ 0.476 0.352 Safety N=20 N=33 N=22 N=27 N=46 N=46 Tx-emergent Grade 3/4, n (%) 15 (75) 16 (48) 20 (91) 17 (63) 36 (78) 16 (35) Grade 3§ hand-foot skin reaction/ syndrome 8 (40) 5 (15) 8 (36) 0 (0) 14 (30) 2 (4) *Efficacy results based on intent-to-treat population and safety results based on safety population (pts who received study drug[s]); _Cox regression within each subgroup; _log-rank test within each subgroup; §maximum toxicity grade for hand-foot skin reaction/syndrome; AJCC, American Joint Committee on Cancer mittedabstractsª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com Downloaded from annonc.oxfordjournals.org at Bibliotheque Cantonale et Universitaire on June 6, 2011 significant factor (p=0.0266). The results of the other measured factors were presented elsewhere.Conclusions: Higher levels of MMP-9 could predict tumor response and superior PFSin pts treated with a combination of Bev and PLD. These exploratory results justify further investigations of MMP-9 in pts treated with Bev combinations in order to assess its role as a prognostic and predictive factor.Disclosure: K. Zaman: Participation in advisory board of Roche; partial sponsoring ofthe study by Roche (the main sponsor was the Swiss Federation against Cancer (Oncosuisse)). B. Thu¨rlimann: stock of Roche; Research grants from Roche. R. vonMoos: Participant of Advisory Board and Speaker honoraria

Comment évaluer le risque oncologique d'un patient souffrant de dermatomyosite [Can we predict the risk of malignancy associated with dermatomyositis?]

Dermatomyositis (DM) and polymyositis (PM) are idiopathic inflammatory muscle diseases which remain a therapeutic challenge. The association between DM and malignancy is relatively well established while this relationship is weaker with PM. The clinical management and research for an occult malignancy as well as the follow-up of patients with DM or PM is a matter of debate. Herein we report a case of DM who, despite an extensive clinical, radiological and biological work-up developed an occult ovarian cancer 12 months after the initial diagnosis. This case report was used as support to review the actual expert recommendations for the search of an occult malignancy in presence of DM or PM.

Clinical and biological determinants of kidney outcomes in a population-based cohort study

BACKGROUND/AIMS: Prospective studies on factors associated with adverse kidney outcomes in European general populations are scant. Also, few studies consider the potential confounding effect of baseline kidney function. METHODS: We used baseline (2003-2006) and 5-year follow-up data of adults from the general population to evaluate the effect of baseline kidney function and proteinuria on the association of clinical, biological (e.g. uric acid, homocysteine, cytokines), and socioeconomic factors with change in kidney function, rapid decline in kidney function, and incidence of chronic kidney disease (CKD). Estimated glomerular filtration rate (eGFR) and urinary albuminuria-to-creatinine ratio (UACR) were collected. Kidney outcomes were modeled using multivariable regressions. RESULTS: A total of 4,441 subjects were included in the analysis. Among participants without CKD at baseline, 11.4% presented rapid decline in eGFR and/or incident CKD. After adjustment for baseline eGFR and log UACR, only age (Odds Ratio; 1.25 [95%CI 1.18-1.33]), diabetes (OR 1.48 [1.03-2.13]), education (OR middle vs. high 1.51 [1.08-2.11]) and log ultrasensitive CRP (OR 1.16 [1.05-1.22]) were associated with rapid decline in eGFR or incident CKD. Baseline log UACR (OR 1.18 [1.06-1.32]) but not eGFR was associated with rapid decline in eGFR and/or incident CKD. CONCLUSION: In addition to age and diabetes, education and CRP levels are associated with adverse kidney outcomes independently of baseline kidney function.

Body dissatisfaction on top of depressive mood among adolescent with severe dysmenorrhea

Purpose: Dysmenorrhea is the leading cause of recurrent short-term school absenteeism among adolescent girls. Yet, studies of menstrual symptoms in the light of adolescent psychological background seldom appear in the recent literature. This study aims to determine whether adolescent girls with severe dysmenorrhea (SD) have different body perception on top of poorer psychological health. Methods: We analyzed data from the Swiss Multicentre Adolescent Survey on Health (SMASH 2002) among a nationally representative sample of adolescents (n = 7548; 3340 females) aged 16 to 20 years attending post-mandatory education. Dysmenorrhea was defined as presence of abdominal or back pain during menstruation on the last 12 months. The severity of dysmenorrhea was defined according to the impact on daily activity and was assessed by 3 questions on the way menstruations interfere with daily life: 1) "You feel well and have normal activities", 2)"you must stay at home" and 3) "you feel restricted in your school or professional activities". Studied variables were: depressive symptoms, suicidal attempt, sexual abuse, health perception in general, body satisfaction, desire to modify body shape, and disordered eating behavior (DEB) with restrictive or bulimic tendency. Controlling variables included socio-economic status (SES) as measured by both parent's level of education, gynecological age (age-age at menarche), academic track (student/apprentice) and age. Results: 12.4% (95% CI: 11.0-14) declared severe dysmenorrhea, 74.2% (95% CI: 71.8-76.5) mild to moderate dysmenorrhea and 13,4% (95% CI: 11.5-15.5) had no dysmenorrhea. Compared to their peers, controlling for confounding variables, subjects with SD were more numerous to report depressive symptoms (AOR: 1.73; 95% CI: 1.39-2.15), to feel in poor health (AOR: 1.44; 95% CI: 1.14-1.81). Moreover, the proportion of those reporting dissatisfaction with their body appearance was higher (AOR: 1.48; 95% CI: 1.00-2.18). Conclusion: Patients with SD not only show a different profile than their peers in terms of their mental health and health perception, but also a distinct relation to their body. Therefore clinicians should pay particular attention to patients with SD and offer them a global evaluation keeping in mind what can be associated with SD.

Treatment of advanced soft-tissue sarcomas using a combined strategy of high-dose ifosfamide, high-dose doxorubicin and salvage therapies.

Having determined in a phase I study the maximum tolerated dose of high-dose ifosfamide combined with high-dose doxorubicin, we now report the long-term results of a phase II trial in advanced soft-tissue sarcomas. Forty-six patients with locally advanced or metastatic soft-tissue sarcomas were included, with age <60 years and all except one in good performance status (0 or 1). The chemotherapy treatment consisted of ifosfamide 10 g m(-2) (continuous infusion for 5 days), doxorubicin 30 mg m(-2) day(-1) x 3 (total dose 90 mg m(-2)), mesna and granulocyte-colony stimulating factor. Cycles were repeated every 21 days. A median of 4 (1-6) cycles per patient was administered. Twenty-two patients responded to therapy, including three complete responders and 19 partial responders for an overall response rate of 48% (95% CI: 33-63%). The response rate was not different between localised and metastatic diseases or between histological types, but was higher in grade 3 tumours. Median overall survival was 19 months. Salvage therapies (surgery and/or radiotherapy) were performed in 43% of patients and found to be the most significant predictor for favourable survival (exploratory multivariate analysis). Haematological toxicity was severe, including grade > or =3 neutropenia in 59%, thrombopenia in 39% and anaemia in 27% of cycles. Three patients experienced grade 3 neurotoxicity and one patient died of septic shock. This high-dose regimen is toxic but nonetheless feasible in multicentre settings in non elderly patients with good performance status. A high response rate was obtained. Prolonged survival was mainly a function of salvage therapies.

Effects of anxiety on visuospatial pattern discrimination and decision-making processes: what can we learn from brain dynamics ?

Detection and discrimination of visuospatial input involve at least extracting, selecting and encoding relevant information and decision-making processes allowing selecting a response. These two operations are altered, respectively, by attentional mechanisms that change discrimination capacities, and by beliefs concerning the likelihood of uncertain events. Information processing is tuned by the attentional level that acts like a filter on perception, while decision-making processes are weighed by subjective probability of risk. In addition, it has been shown that anxiety could affect the detection of unexpected events through the modification of the level of arousal. Consequently, purpose of this study concerns whether and how decision-making and brain dynamics are affected by anxiety. To investigate these questions, the performance of women with either a high (12) or a low (12) STAI-T (State-Trait Anxiety Inventory, Spielberger, 1983) was examined in a decision-making visuospatial task where subjects have to recognize a target visual pattern from non-target patterns. The target pattern was a schematic image of furniture arranged in such a way as to give the impression of a living room. Non-target patterns were created by either the compression or the dilatation of the distances between objects. Target and non-target patterns were always presented in the same configuration. Preliminary behavioral results show no group difference in reaction time. In addition, visuo-spatial abilities were analyzed trough the signal detection theory for quantifying perceptual decisions in the presence of uncertainty (Green and Swets, 1966). This theory treats detection of a stimulus as a decision-making process determined by the nature of the stimulus and cognitive factors. Astonishingly, no difference in d' (corresponding to the distance between means of the distributions) and c (corresponds to the likelihood ratio) indexes was observed. Comparison of Event-related potentials (ERP) reveals that brain dynamics differ according to anxiety. It shows differences in component latencies, particularly a delay in anxious subjects over posterior electrode sites. However, these differences are compensated during later components by shorter latencies in anxious subjects compared to non-anxious one. These inverted effects seem indicate that the absence of difference in reaction time rely on a compensation of attentional level that tunes cortical activation in anxious subjects, but they have to hammer away to maintain performance.

Medical aspects of helicopter rescue missions involving winching of a physician

Introduction: Whereas the use of helicopters as a rapid means toreach victims and to bring them to a secure place is well-recognized,very few data are available about the value of winching physicians toprovide medical care for the victims directly on-site. We sought to studythe medical aspects of alpine helicopter rescue operations involving thewinching of an emergency physician to the victim.Methods: We retrospectively reviewed the medical reports of a singlehelicopter-based emergency medical service. Data from 1 January 2003to 31 December 2008 were analyzed. Cases with emergency callindicating that the victim was deceased were excluded. Data includedthe category (trauma or illnesses), and severity (NACA score) of theinjuries, along with the main medical procedures performed on site.Results: 9879 rescue missions were conducted between 1 January2003 and 31 December 2008. The 921 (9.3%) missions involvingwinching of the emergency physician were analysed. 840 (91%)patients suffered from trauma-related injuries. The cases of the 81 (9%)people presenting with medical emergencies were, when compared tothe trauma victims, significantly more severe according to the NACAindex (p <0.001). Overall, 246 (27%) patients had a severe injury orillness, namely, a potential or overt vital threat (NACA score between4-6, table 1). A total of 478 (52%) patients required administration ofmajor analgesics: fentanyl (443 patients; 48%), ketamine (42 patients;5%) or morphine (7 patients; 1%). The mean dose of fentanyl was 188micrograms (range 25-750, SD 127). Major medical interventions wereperformed 72 times on 39 (4%) patients (table 2).Conclusions: The severity of the patients' injuries or illnesses alongwith the high proportion of medical procedures performed directlyon-site validate emergency physician winching for advanced life supportprocedures and analgesia.

The worldwide expansion of the Argentine ant

Aim The aim of this study was to determine the number of successful establishments of the invasive Argentine ant outside native range and to see whether introduced supercolonies have resulted from single or multiple introductions. We also compared the genetic diversity of native versus introduced supercolonies to assess the size of the propagules (i.e. the number of founding individuals) at the origin of the introduced supercolonies. Location Global. Methods We used mitochondrial DNA (mtDNA) markers and microsatellite loci to study 39 supercolonies of the Argentine ant Linepithema humile covering both the native (n = 25) and introduced range (n = 14). Results Data from three mitochondrial genes and 13 nuclear microsatellites suggest that the introduced supercolonies studied originated from at least seven founding events out of the native area in Argentina (primary introductions). The distribution of mtDNA haplotypes also suggests that supercolonies in the introduced range each derive from a single source supercolony and that one of these source supercolonies has been particularly successful, being the basis of many introduced populations spread across the world. Comparison of the genetic diversity of supercolonies based on the five most diverse loci also revealed that native and introduced supercolonies have greatly overlapping ranges of diversity, although the genetic diversity is on average less in introduced than in native supercolonies. Main conclusions Both primary introductions (from the native range) and secondary introductions (from sites with established invasive supercolonies) were important in the global expansion of the Argentine ant. In combination with the similar social organization of colonies in the native and introduced range, this indicates that invasiveness did not evolve recently as a unique and historically contingent event (e.g. reduction of genetic diversity) in this species. Rather, native L. humile supercolonies have characteristics that make them pre-adapted to invade new - and in particular disturbed - habitats when given the opportunity. These results have important implications with regard to possible strategies to be used to control invasive ants.