A comparison of patient characteristics and 30-day mortality outcomes after transcatheter aortic valve implantation and surgical aortic valve replacement for the treatment of aortic stenosis: a two-centre study

AIMS: It is unclear whether transcatheter aortic valve implantation (TAVI) addresses an unmet clinical need for those currently rejected for surgical aortic valve replacement (SAVR) and whether there is a subgroup of high-risk patients benefiting more from TAVI compared to SAVR. In this two-centre, prospective cohort study, we compared baseline characteristics and 30-day mortality between TAVI and SAVR in consecutive patients undergoing invasive treatment for aortic stenosis. METHODS AND RESULTS: We pre-specified different adjustment methods to examine the effect of TAVI as compared with SAVR on overall 30-day mortality: crude univariable logistic regression analysis, multivariable analysis adjusted for baseline characteristics, analysis adjusted for propensity scores, propensity score matched analysis, and weighted analysis using the inverse probability of treatment (IPT) as weights. A total of 1,122 patients were included in the study: 114 undergoing TAVI and 1,008 patients undergoing SAVR. The crude mortality rate was greater in the TAVI group (9.6% vs. 2.3%) yielding an odds ratio [OR] of 4.57 (95%-CI 2.17-9.65). Compared to patients undergoing SAVR, patients with TAVI were older, more likely to be in NYHA class III and IV, and had a considerably higher logistic EuroSCORE and more comorbid conditions. Adjusted OR depended on the method used to control for confounding and ranged from 0.60 (0.11-3.36) to 7.57 (0.91-63.0). We examined the distribution of propensity scores and found scores to overlap sufficiently only in a narrow range. In patients with sufficient overlap of propensity scores, adjusted OR ranged from 0.35 (0.04-2.72) to 3.17 (0.31 to 31.9). In patients with insufficient overlap, we consistently found increased odds of death associated with TAVI compared with SAVR irrespective of the method used to control confounding, with adjusted OR ranging from 5.88 (0.67-51.8) to 25.7 (0.88-750). Approximately one third of patients undergoing TAVI were found to be potentially eligible for a randomised comparison of TAVI versus SAVR. CONCLUSIONS: Both measured and unmeasured confounding limit the conclusions that can be drawn from observational comparisons of TAVI versus SAVR. Our study indicates that TAVI could be associated with either substantial benefits or harms. Randomised comparisons of TAVI versus SAVR are warranted.

Eczematous skin reaction to atopy patch testing with cockroach in patients with atopic dermatitis

BACKGROUND: Aeroallergens from house dust mite (HDM) may be an important trigger in a subgroup of patients with atopic dermatitis (AD). HDM and cockroach (CR) contain cross-reactive allergens, such as tropomyosin. OBJECTIVE: To investigate the diagnostic value of patch testing with an aeroallergen and the role of CR allergen and HDM allergen in persons with AD. METHODS: We performed skin prick tests (SPT) with a panel of common aeroallergens and total serum immunoglobulin (Ig)E and specific IgE tests for CR and HDM on 23 patients with AD and 9 nonatopic control participants. Atopy patch tests (APT) were performed with CR and HDM extracts on clinically uninvolved skin on the back, and evaluated after 48 and 72 hours. RESULTS: A positive APT reaction to CR was found in 10/23 (43%) patients with AD. No positive reactions were observed in the nonatopic control participants. Positive APT reactions for CR showed no significant correlation with SPT or specific IgE levels for this allergen. Twelve of the 23 (52%) patients with AD were also sensitized to HDM. There was no significant correlation between positive results for SPT, APT, and specific IgE to CR and HDM. CONCLUSION: We demonstrate that CR allergens can induce positive patch test reactions in patients with AD. The absence of a significant correlation to SPT and specific IgE antibodies suggests that T-cell- and IgE-sensitization may be mediated by different allergens. There was no significant relationship between CR and HDM sensitivity, thus indicating no major cross-reactivity.

A novel FIP1L1-PDGFRA mutant destabilizing the inactive conformation of the kinase domain in chronic eosinophilic leukemia/hypereosinophilic syndrome

BACKGROUND: The Fip1-like-1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) gene fusion is a common cause of chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome (HES), and patients suffering from this particular subgroup of CEL/HES respond to low-dose imatinib therapy. However, some patients may develop imatinib resistance because of an acquired T674I mutation, which is believed to prevent drug binding through steric hindrance. METHODS: In an imatinib resistant FIP1L1-PDGFRA positive patient, we analyzed the molecular structure of the fusion gene and analyzed the effect of several kinase inhibitors on FIP1L1-PDGFRA-mediated proliferative responses in vitro. RESULTS: Sequencing of the FIP1L1-PDGFRA fusion gene revealed the occurrence of a S601P mutation, which is located within the nucleotide binding loop. In agreement with the clinical observations, imatinib did not inhibit the proliferation of S601P mutant FIP1L1-PDGFRA-transduced Ba/F3 cells. Moreover, sorafenib, which has been described to inhibit T674I mutant FIP1L1-PDGFRA, failed to block S601P mutant FIP1L1-PDGFRA. Structural modeling revealed that the newly identified S601P mutated form of PDGFRA destabilizes the inactive conformation of the kinase domain that is necessary to bind imatinib as well as sorafenib. CONCLUSIONS: We identified a novel mutation in FIP1L1-PDGFRA resulting in both imatinib and sorafenib resistance. The identification of novel drug-resistant FIP1L1-PDGFRA variants may help to develop the next generation of target-directed compounds for CEL/HES and other leukemias.

Effect of natural seasonal pollen exposure and repeated nasal allergen provocations on elevation of exhaled nitric oxide

BACKGROUND: Exhaled nitric oxide (FENO) is a marker for allergic airway inflammation. We wondered whether in patients with intermittent allergic rhinitis only (i) natural pollen exposure and (ii) artificial pollen exposure by repeated nasal allergen provocations may lead to an elevation of FENO. METHODS: In two prospective studies, we compared the FENO of nonatopic controls with the FENO of nonasthmatic individuals with mild intermittent rhinitis to tree and/or grass pollen. Study I: 13 atopic individuals and seven controls had measurements of FENO, blood eosinophils and eosinophilic cationic protein (ECP) before, during and after pollen season. Study II: 16 atopic individuals and 12 controls had nasal allergen provocations on four following days out of pollen season, with daily measurements of FENO before, 2 and 6 h after provocation, and determination of blood eosinophils, ECP and FEV1 at baseline, on days 5 and 10-12. RESULTS: Natural pollen exposure (study I) caused a significant elevation of FENO in allergic individuals. Nasal allergen provocations (study II) did not elicit a statistically significant rise neither of FENO nor of blood eosinophils between baseline and day 5. However, a subgroup of four individuals with a rise of blood eosinophils during nasal allergen provocations showed also a rise of FENO. CONCLUSIONS: We suppose that in allergic rhinitis a concomitant reaction of the bronchial system is dependent on a strong local inflammation leading to a generalized immune stimulation.

Altered hypertrophic chondrocyte kinetics in GDF-5 deficient murine tibial growth plates

The growth/differentiation factors (GDFs) are a subgroup of the bone morphogenetic proteins best known for their role in joint formation and chondrogenesis. Mice deficient in one of these signaling proteins, GDF-5, exhibit numerous skeletal abnormalities, including shortened limb bones. The primary aim of this study was determine whether GDF-5 deficiency would alter the growth rate in growth plates from the long bones in mice and, if so, how this is achieved. Stereologic and cell kinetic parameters in proximal tibial growth plates from 5-week-old female GDF-5 -/- mice and control littermates were examined. GDF-5 deficiency resulted in a statistically significant reduction in growth rate (-14%, p=0.03). The effect of genotype on growth rate was associated with an altered hypertrophic phase duration, with hypertrophic cells from GDF-5 deficient mice exhibiting a significantly longer phase duration compared to control littermates (+25%, p=0.006). These data suggest that one way in which GDF-5 might modulate the rate of endochondral bone growth could be by affecting the duration of the hypertrophic phase in growth plate chondrocytes.

Prospective population-based study of RSV-related intermediate care and intensive care unit admissions in Switzerland over a 4-year period (2001-2005)

OBJECTIVES: Respiratory syncytial virus (RSV) infections are a leading cause of hospital admissions in small children. A substantial proportion of these patients require medical and nursing care, which can only be provided in intermediate (IMC) or intensive care units (ICU). This article reports on all children aged < 3 years who required admission to IMC and/or ICU between October 1, 2001 and September 30, 2005 in Switzerland. PATIENTS AND METHODS: We prospectively collected data on all children aged < 3 years who were admitted to an IMC or ICU for an RSV-related illness. Using a detailed questionnaire, we collected information on risk factors, therapy requirements, length of stay in the IMC/ICU and hospital, and outcome. RESULTS: Of the 577 cases reported during the study period, 90 were excluded because the patients did not fulfill the inclusion criteria; data were incomplete in another 25 cases (5%). Therefore, a total of 462 verified cases were eligible for analysis. At the time of hospital admission, only 31 patients (11%) were older than 12 months. Since RSV infection was not the main reason for IMC/ICU admission in 52% of these patients, we chose to exclude this subgroup from further analyses. Among the 431 infants aged < 12 months, the majority (77%) were former near term or full term (NT/FT) infants with a gestational age > or = 35 weeks without additional risk factors who were hospitalized at a median age of 1.5 months. Gestational age (GA) < 32 weeks, moderate to severe bronchopulmonary dysplasia (BPD), and congenital heart disease (CHD) were all associated with a significant risk increase for IMC/ICU admission (relative risk 14, 56, and 10, for GA < or = 32 weeks, BPD, and CHD, respectively). Compared with NT/FT infants, high-risk infants were hospitalized at an older age (except for infants with CHD), required more invasive and longer respiratory support, and had longer stays in the IMC/ICU and hospital. CONCLUSIONS: In Switzerland, RSV infections lead to the IMC/ICU admission of approximately 1%-2% of each annual birth cohort. Although prematurity, BPD, and CHD are significant risk factors, non-pharmacological preventive strategies should not be restricted to these high-risk patients but also target young NT/FT infants since they constitute 77% of infants requiring IMC/ICU admission.

The prognostic value of cytology and fluorescence in situ hybridization in the follow-up of nonmuscle-invasive bladder cancer after intravesical Bacillus Calmette-Guérin therapy

Molecular markers reliably predicting failure or success of Bacillus Calmette-Guérin (BCG) in the treatment of nonmuscle-invasive urothelial bladder cancer (NMIBC) are lacking. The aim of our study was to evaluate the value of cytology and chromosomal aberrations detected by fluorescence in situ hybridization (FISH) in predicting failure to BCG therapy. Sixty-eight patients with NMIBC were prospectively recruited. Bladder washings collected before and after BCG instillation were analyzed by conventional cytology and by multitarget FISH assay (UroVysion, Abbott/Vysis, Des Plaines, IL) for aberrations of chromosomes 3, 7, 17 and 9p21. Persistent and recurrent bladder cancers were defined as positive events during follow-up. Twenty-six of 68 (38%) NMIBC failed to BCG. Both positive post-BCG cytology and positive post-BCG FISH were significantly associated with failure of BCG (hazard ratio (HR)= 5.1 and HR= 5.6, respectively; p < 0.001 each) when compared to those with negative results. In the subgroup of nondefinitive cytology (all except those with unequivocally positive cytology), FISH was superior to cytology as a marker of relapse (HR= 6.2 and 1.4, respectively). Cytology and FISH in post-BCG bladder washings are highly interrelated and a positive result predicts failure to BCG therapy in patients with NMIBC equally well. FISH is most useful in the diagnostically less certain cytology categories but does not provide additional information in clearly malignant cytology.

Decompressive hemicraniectomy in subarachnoid haemorrhage: the influence of infarction, haemorrhage and brain swelling

OBJECTIVE: To analyse decompressive hemicraniectomy (DHC) in patients with aneurysmal subarachnoid haemorrhage (SAH) with regard to infarction, haemorrhage or brain swelling. METHODS: DHC was performed in 43 of 787 patients with SAH. Patients were stratified according to (1) primary brain swelling without and (2) with additional intracerebral haematoma, (3) secondary brain swelling without rebleeding or infarcts and (4) with infarcts or (5) with rebleeding. Outcome was assessed according to the modified Rankin scale at 6 months RESULTS: Overall, 36 of 43 patients (83.7%) with DHC and 241 of 744 patients (32.4%) without DHC have been of a poor grade on admission (World Federation of Neurological Societies grading 4-5; p<0.0001). Favourable outcome was achieved in 11 of 43 (25.6%) patients with DHC. There was no difference in favourable outcome after primary (25%) versus secondary (26.1%) DHC (p = 1.0). Subgroup analysis (brain swelling vs bleeding vs infarcts) revealed no difference in the rate of favourable outcome. In a multivariate analysis, acute hydrocephalus (p = 0.02) and clinical herniation (p = 0.03) were significantly associated with unfavourable outcome. CONCLUSIONS: We conclude that primary and secondary hemicraniectomy may be warranted, irrespective of the underlying aetiology-infarction, haemorrhage or brain swelling. The time from onset of intractable ICP to DHC seems to be crucial, rather than the time from SAH to DHC.

Decompressive craniectomy in subarachnoid hemorrhage

OBJECT: The aim of this study was to analyze decompressive craniectomy (DC) in the setting of subarachnoid hemorrhage (SAH) with bleeding, infarction, or brain swelling as the underlying pathology in a large cohort of consecutive patients. METHODS: Decompressive craniectomy was performed in 79 of 939 patients with SAH. Patients were stratified according to the indication for DC: 1) primary brain swelling without or 2) with additional intracerebral hematoma, 3) secondary brain swelling without rebleeding or infarcts, and 4) secondary brain swelling with infarcts or 5) with rebleeding. Outcome was assessed according to the modified Rankin Scale (mRS) at 6 months (mRS Score 0-3 favorable vs 4-6 unfavorable). RESULTS: Overall, 61 (77.2%) of 79 patients who did and 292 (34%) of the 860 patients who did not undergo DC had a poor clinical grade on admission (World Federation of Neurosurgical Societies Grade IV-V, p < 0.0001). A favorable outcome was attained in 21 (26.6%) of 79 patients who had undergone DC. In a comparison of favorable outcomes in patients with primary (28.0%) or secondary DC (25.5%), no difference could be found (p = 0.8). Subgroup analysis with respect to the underlying indication for DC (brain swelling vs bleeding vs infarction) revealed no difference in the rate of favorable outcomes. On multivariate analysis, acute hydrocephalus (p = 0.009) and clinical signs of herniation (p = 0.02) were significantly associated with an unfavorable outcome. CONCLUSIONS: Based on the data in this study the authors concluded that primary as well as secondary craniectomy might be warranted, regardless of the underlying etiology (hemorrhage, infarction, or brain swelling) and admission clinical grade of the patient. The time from the onset of intractable intracranial pressure to DC seems to be crucial for a favorable outcome, even when a DC is performed late in the disease course after SAH.

Fructose overconsumption causes dyslipidemia and ectopic lipid deposition in healthy subjects with and without a family history of type 2 diabetes

BACKGROUND: Both nutritional and genetic factors are involved in the pathogenesis of nonalcoholic fatty liver disease and insulin resistance. OBJECTIVE: The aim was to assess the effects of fructose, a potent stimulator of hepatic de novo lipogenesis, on intrahepatocellular lipids (IHCLs) and insulin sensitivity in healthy offspring of patients with type 2 diabetes (OffT2D)--a subgroup of individuals prone to metabolic disorders. DESIGN: Sixteen male OffT2D and 8 control subjects were studied in a crossover design after either a 7-d isocaloric diet or a hypercaloric high-fructose diet (3.5 g x kg FFM(-1) x d(-1), +35% energy intake). Hepatic and whole-body insulin sensitivity were assessed with a 2-step hyperinsulinemic euglycemic clamp (0.3 and 1.0 mU x kg(-1) x min(-1)), together with 6,6-[2H2]glucose. IHCLs and intramyocellular lipids (IMCLs) were measured by 1H-magnetic resonance spectroscopy. RESULTS: The OffT2D group had significantly (P < 0.05) higher IHCLs (+94%), total triacylglycerols (+35%), and lower whole-body insulin sensitivity (-27%) than did the control group. The high-fructose diet significantly increased IHCLs (control: +76%; OffT2D: +79%), IMCLs (control: +47%; OffT2D: +24%), VLDL-triacylglycerols (control: +51%; OffT2D: +110%), and fasting hepatic glucose output (control: +4%; OffT2D: +5%). Furthermore, the effects of fructose on VLDL-triacylglycerols were higher in the OffT2D group (group x diet interaction: P < 0.05). CONCLUSIONS: A 7-d high-fructose diet increased ectopic lipid deposition in liver and muscle and fasting VLDL-triacylglycerols and decreased hepatic insulin sensitivity. Fructose-induced alterations in VLDL-triacylglycerols appeared to be of greater magnitude in the OffT2D group, which suggests that these individuals may be more prone to developing dyslipidemia when challenged by high fructose intakes. This trial was registered at clinicaltrials.gov as NCT00523562.

Vascular risk factors and morphometric data in cervical artery dissection: a case-control study

BACKGROUND: Limited knowledge exists on vascular risk factors, body height and weight in patients with spontaneous cervical artery dissection (sCAD). PATIENTS AND METHODS: In this case-control study, major vascular risk factors, body weight, body height and body mass index (BMI) of 239 patients obtained from a prospective hospital-based sCAD registry were compared with 516 age- and sex-matched healthy controls undergoing systematic health examinations in the Clinical and Preventive Investigations Center, Paris. Gender-specific analyses were performed. RESULTS: The mean body height was higher in sCAD patients than in controls (171.3 cm (SD 8.6) vs 167.7 cm (8.9); p<0.0001) and sCAD patients had a significantly lower mean body weight (67.5 (12.2) kg vs 69.3 (14.6) kg; p<0.001) and mean BMI (22.9 (3.3) kg/m2 vs 24.5 (4.2) kg/m2; p<0.0001) than controls. The overall frequency of hypertension, diabetes, current smoking, past smoking and hypercholesterolaemia did not differ significantly between sCAD patients and controls. The mean total plasma cholesterol level was identical in both groups (5.5 mmol/l, SD 1.1). Gender specific subgroup analyses showed similar results for men and women. CONCLUSION: Patients with sCAD had a higher body height and a lower body weight and BMI than controls, while major vascular risk factors were similar in sCAD patients and controls.

High-risk clinical stage I nonseminomatous germ cell tumors: the case for chemotherapy

Testis cancer is the most frequent solid malignancy in young men. The majority of patients present with clinical stage I disease and about 50% of them are nonseminomatous germ cell tumors. In this initial stage of disease there is a subgroup of patients at high risk with a likelihood of more than 50% for relapse. Treatment options for these patients include: retroperitoneal lymph node dissection (RPLND), albeit 6-10% of patients will relapse outside the field of RPLND, active surveillance with even higher relapse rates and adjuvant chemotherapy. As most of these patients have the chance to become long-term survivors, avoidance of long-term side effects is of utmost importance. This review provides information on the potential of chemotherapy to achieve a higher chance of cure for patients with high-risk clinical stage I disease than its therapeutic alternatives and addresses toxicity and dose dependency.

What patients and relatives expect from an intensivist--the Swiss side of a European survey

BACKGROUND: Until recently, patients' and families' expectations of specialists in intensive care medicine were largely unknown. This paper reports the results from the Swiss subgroup of a recently performed European multicentre study addressing this question. METHODS: Purposeful sample of adult ICUs in Switzerland. A questionnaire was distributed to ICU patients and relatives. It included 21 statements in the domains "medical knowledge", "communication with patients", "communication with relatives". Statements were rated for importance on a four-point Likert scale. RESULTS: All addressed ICUs participated; there were two from the French and eight from the German speaking part of Switzerland. 197 questionnaires were returned (46%). Overall, the majority of characteristics were rated as important. As in the other participating countries, patients and relatives ranked, "medical knowledge" as most essential, followed by, "communication with patients" and, "communication with relatives". This remained unchanged when analysed for German or French language, female or male, age >65 years. Female responders rated "communication" as more important than male responders. For French speaking participants "treating patients as individuals" was the most important statement. CONCLUSIONS: In accordance to respondents from other countries, Swiss patients and their families with experience of intensive care rate medical knowledge as most essential for specialists in intensive care medicine. However, communication with patients and with relatives is considered important, too. Accordingly, developing and ensuring medical knowledge and skills, as well as competence in communication must remain top priorities for the institutions responsible for training ICU physicians.

Trajectory of posttraumatic stress disorder caused by myocardial infarction: a two-year follow-up study

OBJECTIVE: A substantial proportion of patients develop posttraumatic stress disorder (PTSD) following myocardial infarction (MI). Previous research on the trajectory over time of PTSD in post-MI patients is scant and refers to self-rated posttraumatic symptoms. The aim of this study was to investigate the longitudinal course of an interviewer-rated diagnosis of PTSD and PTSD symptom severity following MI. METHODS: Study participants were 40 patients (78% men, mean age 54 +/- 8 years) who were diagnosed with PTSD using the Clinician-administered PTSD Scale (CAPS) after an average of 5 +/- 4 months (range 2-16 months) following an index MI. After a mean follow-up of 26 +/- 6 months (range 12-36 months), 24 patients underwent a second diagnostic interview. RESULTS: Two-thirds of patients (n = 16) still qualified for a diagnosis of PTSD at follow-up. In all 24 patients, total PTSD symptoms (p = 0.001), re-experiencing symptoms (p < 0.001), avoidance symptoms (p = 0.015), and, with borderline significance, hyperarousal symptoms (p < 0.06) had all decreased over time. However, in the subgroup of the 16 patients who had retained PTSD diagnostic status at follow-up, symptoms of avoidance (p = 0.23) and of hyperarousal (p = 0.48) showed no longitudinal decline. Longer duration of follow-up was associated with a greater decrease in avoidance symptoms (p = 0.029) and, with borderline significance, in re-experiencing symptoms (p < 0.07) across all patients. CONCLUSION: Although PTSD symptomatology waned over time and in relation to longer follow-up, two-thirds of patients still qualified for a diagnosis of PTSD 2 years after the initial diagnosis. In post-MI patients, clinical PTSD is a considerably persistent condition.

L'évolution du système consonantique des langues cangin

The Cangin languages are classified as an own subgroup of the Atlantic languages. Evidence for their common origin can be given by the comparative method. By means of the systematic grammatical comparison of different languages this method aims at the reconstruction of a hypothetic proto-language and allows to draw hypothesises on their diachronic linguistic development. This paper concentrates on the evolution of the consonant system of the Cangin languages.