High incidence of (ultra)low oesophageal temperatures during cryoballoon pulmonary vein isolation for atrial fibrillation.

BACKGROUND: Low oesophageal temperatures (OTs) during cryoballoon pulmonary vein isolation (PVI) have been associated with complications. This study assessed the incidence of low OT in clinical practice during cryoballoon PVI and verified possible predictive values for low OT. METHODS: Consecutive patients who underwent PVI using the second-generation cryoballoon were retrospectively included. The distance from the oesophagus to the different pulmonary veins (PVs) (OP distance), body mass index (BMI), sex, age, balloon temperature and application time were studied as potential predictors of low OTs. Computed tomography was performed before the procedure to determine the OP distance. OT was measured using an oesophageal temperature probe. Applications were ended prematurely if the OT reached <16 °C. Low and ultralow OT were defined as OT <20 and <16 °C respectively. RESULTS: Two hundred and four patients were included. Low OT was observed in 54 patients (26%) and 27 patients (13%) reached ultralow OTs. OP distance was the only predictor of low OTs after multivariate analysis. A cut-off value of 19 mm showed 96.2% sensitivity and 37.8% specificity in predicting low OTs. No clinically relevant relation was found between low OTs and BMI, age, sex, balloon temperature or application duration. CONCLUSIONS: The incidence of low OT was 26% for cryoballoon PVI. OP distance was the only predictor of low OTs. Since an OP distance <19 mm was present in all patients in at least one PV, we recommend routine OT measurement during PVI cryoballoon therapy to prevent oesophagus-related complications.

Use of three-dimensional computed tomography overlay for real-time cryoballoon ablation in atrial fibrillation reduces radiation dose and contrast dye.

AIMS: Cryoballoon pulmonary vein (PV) isolation in patients with atrial fibrillation has proven to be effective in short-term and long-term follow-up. To visualise the PV anatomy, pre-ablation contrast pulmonary venography is commonly performed. Three-dimensional (3D) computed tomography (CT) overlay is a new technique creating a live 3D image of the left atrium by integrating a previously obtained CT scan during fluoroscopy. To evaluate the benefits of 3D CT overlay during cryoballoon ablation, we studied the use of 3D CT overlay versus contrast pulmonary venography in a randomised fashion in patients with paroxysmal atrial fibrillation undergoing cryoballoon PV isolation. METHODS AND RESULTS: Between October 2012 and June 2013, 30 patients accepted for PV isolation were randomised to cryoballoon PV isolation using either 3D CT overlay or contrast pulmonary venography. All patients underwent a pre-procedural cardiac CT for evaluation of the anatomy of the left atrium (LA) and the PVs. In the 3D CT overlay group, a 3D reconstruction of the LA and PVs was made. An overlay of the CT reconstruction was then projected over live fluoroscopy. Patients in the contrast pulmonary venography group received significantly more contrast agent (77.1 ± 21.2 cc vs 40.1 ± 17.6 cc, p < 0.001) and radiation (43.0 ± 21.9 Gy.cm2 vs 28.41 ± 11.7 Gy.cm2, p = 0.04) than subjects in the 3D CT overlay group. There was no difference in total procedure time, fluoroscopy time and the amount of cryoapplications between the two groups. CONCLUSION: The use of 3D CT overlay decreases radiation and contrast dye exposure and can assist in guiding cryoballoon-based PV isolation.

Optimisation of cardiac resynchronization therapy in clinical practice during exercise.

AIMS: Although cardiac resynchronisation therapy (CRT) is an established treatment to improve cardiac function, a significant amount of patients do not experience noticeable improvement in their cardiac function. Optimal timing of the delay between atrial and ventricular pacing pulses (AV delay) is of major importance for effective CRT treatment and this optimum may differ between resting and exercise conditions. In this study the feasibility of haemodynamic measurements by the non-invasive finger plethysmographic method (Nexfin) was used to optimise the AV delay during exercise. METHODS AND RESULTS: Thirty-one patients implanted with a CRT device in the last 4 years participated in the study. During rest and in exercise, stroke volume (SV) was measured using the Nexfin device for several AV delays. The optimal AV delay at rest and in exercise was determined using the least squares estimates (LSE) method. Optimisation created a clinically significant improvement in SV of 10 %. The relation between HR and the optimal AV delay was patient dependent. CONCLUSION: A potential increase in SV of 10 % can be achieved using Nexfin for optimisation of AV delay during exercise. A considerable number of patients showed benefit with lengthening of the AV delay during exercise.

The two-sided role of the vaginal microbiome in Chlamydia trachomatis and Mycoplasma genitalium pathogenesis.

Sexually transmitted infections (STI) can have major consequences for the reproductive health of women. Mycoplasma genitalium is a STI that is not as well studied but causes pelvic inflammatory disease (PID) among other complications. Another well-known STI is Chlamydia trachomatis, notorious for its capability to cause infertility. Both C. trachomatis and M. genitalium share some of the same clinical aspects. Parts of the pathogenesis of C. trachomatis and M. genitalium infections are unclear but potential factors are the microbiome and other STIs. The healthy vaginal microbiome is dominated by Lactobacillus spp; these bacteria protect the host against invading bacteria like C. trachomatis and M. genitalium by producing antibacterial compounds and providing a mechanical barrier. A dysbiosis of the vaginal microbiome is characterized by a non-Lactobacillus spp. dominated microbiome, also known as bacterial vaginosis (BV). BV and BV associated bacteria play a role in the pathogenesis of STIs such as C. trachomatis and M. genitalium. The different species of BV associated bacteria have distinct characteristics that could play a role in C. trachomatis and M. genitalium infections. Host factors should also be considered when analysing the interaction of C. trachomatis and M. genitalium and the microbiome. One important factor is the hormonal homeostasis. Oral hormonal contraception influences the vaginal milieu and could influence the infection process of STIs. Overall, this review attempts to give an overview of the pathogenesisof C. trachomatis and M. genitalium infections and the relationship between M. genitalium, C. trachomatis, and the vaginal microbiome.

Identification of APC2, a homologue of the adenomatous polyposis coli tumour suppressor.

The adenomatous polyposis coli (APC) tumour-suppressor protein controls the Wnt signalling pathway by forming a complex with glycogen synthase kinase 3beta (GSK-3beta), axin/conductin and betacatenin. Complex formation induces the rapid degradation of betacatenin. In colon carcinoma cells, loss of APC leads to the accumulation of betacatenin in the nucleus, where it binds to and activates the Tcf-4 transcription factor (reviewed in [1] [2]). Here, we report the identification and genomic structure of APC homologues. Mammalian APC2, which closely resembles APC in overall domain structure, was functionally analyzed and shown to contain two SAMP domains, both of which are required for binding to conductin. Like APC, APC2 regulates the formation of active betacatenin-Tcf complexes, as demonstrated using transient transcriptional activation assays in APC -/- colon carcinoma cells. Human APC2 maps to chromosome 19p13.3. APC and APC2 may therefore have comparable functions in development and cancer.

Two members of the Tcf family implicated in Wnt/beta-catenin signaling during embryogenesis in the mouse.

Tcf transcription factors interact with beta-catenin and Armadillo to mediate Wnt/Wingless signaling. We now report the characterization of genes encoding two murine members of the Tcf family, mTcf-3 and mTcf-4. mTcf-3 mRNA is ubiquitously present in embryonic day 6.5 (E6.5) mouse embryos but gradually disappears over the next 3 to 4 days. mTcf-4 expression occurs first at E10.5 and is restricted to di- and mesencephalon and the intestinal epithelium during embryogenesis. The mTcf-3 and mTcf-4 proteins bind a canonical Tcf DNA motif and can complex with the transcriptional coactivator beta-catenin. Overexpression of Wnt-1 in a mammary epithelial cell line leads to the formation of a nuclear complex between beta-catenin and Tcf proteins and to Tcf reporter gene transcription. These data demonstrate a direct link between Wnt stimulation and beta-catenin/Tcf transcriptional activation and imply a role for mTcf-3 and -4 in early Wnt-driven developmental decisions in the mouse embryo.

Differential expression of the Groucho-related genes 4 and 5 during early development of Xenopus laevis.

Recently, we demonstrated that the Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors (Roose et al., 1998. Nature 395, 608-612). A long form of the Groucho-related genes, XGrg-4, was shown to repress axis formation in the Xenopus embryo, whereas a short form, XGrg-5, acted as a potentiator. In this study, the temporal and spatial expression of XGrg-4 and XGrg-5 is described in Xenopus laevis embryos. Both genes are maternally expressed. In the gastrula, transcripts of both genes are present in the animal as well as the vegetal region. At later stages, XGrg-4 and XGrg-5 show specific patterns of expression in the central nervous system (CNS), cranial ganglia, eyes, otic vesicles, stomodeal-hypophyseal anlage, cement gland, head mesenchyme, branchial arches, neural crest and derivatives, somites, pronephros, pronephric duct, heart and tailbud. Differences in the expression of XGrg-4 and XGrg-5 were found in the CNS, cranial ganglia, olfactory placodes, stomodeal-pharyngeal anlage, cement gland, head mesenchyme and ectoderm.

Differential expression of the HMG box transcription factors XTcf-3 and XLef-1 during early xenopus development.

The recent discovery that the HMG box transcription factor XTCF-3 is involved in early axis specification in Xenopus laevis (Molenaar, M., van de Wetering, M., Oosterwegel, M., Peterson-Maduro, J. Godsave, S., Korinek, V., Roose, J., Destree, O., Clevers, H., 1996. XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell 86, 391-399) led us to search for other members of the TCF/LEF family in this species. A newly identified HMG box factor was cloned with highest homology to human LEF-1, called XLEF-1. Unlike XTcf-3, XLef-1 is not expressed maternally, but its transcripts become detectable directly after the mid blastula transition (MBT). At later stages, both genes are expressed in the central nervous system (CNS), eyes, otic vesicles, head mesenchyme, neural crest and derivatives, branchial arches, developing heart, tailbud and limb buds. The expression pattern of Lef-1 during later stages of development is evolutionarily conserved.

In vivo analysis of Frat1 deficiency suggests compensatory activity of Frat3.

The Frat1 gene was first identified as a proto-oncogene involved in progression of mouse T cell lymphomas. More recently, FRAT/GBP (GSK-3beta Binding Protein) family members have been recognized as critical components of the Wnt signal transduction pathway. In an attempt to gain more insight into the function of Frat1, we have generated Frat1-deficient mice in which most of the coding domain was replaced by a promoterless beta-galactosidase reporter gene. While the pattern of LacZ expression in Frat1(lacZ)/+ mice indicated Frat1 to be expressed in various neural and epithelial tissues, homozygous Frat1(lacZ) mice were apparently normal, healthy and fertile. Tissues of homozygous Frat1(lacZ) mice showed expression of a second mouse Frat gene, designated Frat3. The Frat1 and Frat3 proteins are structurally and functionally very similar, since both Frat1 and Frat3 are capable of inducing a secondary axis in Xenopus embryos. The overlapping expression patterns of Frat1 and Frat3 during murine embryogenesis suggest that the apparent dispensability of Frat1 for proper development may be due to the presence of a second mouse gene encoding a functional Frat protein.

A tight control over Wnt action.

Here, we review the WNT pathway and its regulation at different levels. We focus on the transcriptional regulation of WNT target genes, in light of the recently identified negative regulators, i.e. relatives of groucho and CBP.

[Use of alternative treatments by patients with multiple sclerosis]. / Gebruik van alternatieve behandelwijzen door patiënten met multipele sclerose.

OBJECTIVE: Survey on the use of alternative treatments by patients with multiple sclerosis (MS). SETTING: Vrije Universiteit Amsterdam. DESIGN: Descriptive. METHOD: A structured telephone interview was conducted with 100 MS patients randomly selected from the membership list of the Dutch Multiple Sclerosis Society. RESULTS: At the time of the survey 26% of the 88 respondents reported current use of alternative treatments. An additional 42% reported use of alternative treatments in the past, but had ceased to take them. The currently most frequently used treatment was homeopathy followed by vitamin treatments, paranormal treatments and phytotherapy. The treatments most used in the past were paranormal treatments, homeopathic remedies and enzyme therapy. Recommendations by friends and relatives were strong incentives to start alternative treatment. Patients ceased using these treatments when the treatments proved ineffective. In general, the current users of alternative treatments had a favourable impression of their alternative therapist. CONCLUSION: When compared with patients with other chronic diseases, the use of alternative treatments by MS patients is high.

[Acute transit symptoms caused by spontaneous rupture of the esophagus]. / Acute passageklachten veroorzaakt door een spontane intramurale ruptuur van de oesofagus.

A 44-year-old woman was admitted to our hospital with acute severe chest pain and dysphagia, without an assignable cause. Radiological investigation of the oesophagus with water soluble contrast revealed an intramural rupture. Conservative management led to complete recovery within eight days. Spontaneous intramural rupture of the oesophagus is a very uncommon disease requiring adequate differentiation from other more serious diseases in order to apply correct therapy.

Piercing the left lung with a pacemaker lead, an uncommon complication.

Although percutaneous insertion of pacemaker leads is a simple and safe method, it remains a procedure with a relatively high complication rate. We describe an uncommon and avoidable complication of this technique: piercing the lung with a pacemaker lead in an obese patient after direct puncture of the subclavian vein.

Skeletal and hepatic changes induced by chronic vitamin A supplementation in cats.

The first aim of this study was to determine whether vitamin D supplementation influenced the effects of high vitamin A intake on new bone formation in adult cats. The second aim was to determine whether high vitamin A intake in cats caused liver pathology and, if so, whether the current upper limit for the dietary intake of vitamin A for healthy adult cats would be safe. Twenty-four healthy adult cats were divided into four groups that received a control diet supplemented with peanut oil (control), or peanut oil containing a 100-fold increase in vitamin A (HA), or a 100-fold increase in vitamin A and a fivefold increase in vitamin D (HAMD), or a 100-fold increase in vitamin A and a 65-fold increase in vitamin D (HAHD) over a period of 18 months. Cats did not show abnormal locomotion or clinical signs of liver failure after 18 months of supplementation but did show subtle skeletal changes and liver pathology, suggesting that the current National Research Council (2006) safe upper limit for vitamin A for cats is too high. The addition of vitamin D did not seem to influence bone pathology. While moderately elevated dietary vitamin D levels (HAMD) seemed to protect cats against the liver pathology caused by the consumption of large amounts of vitamin A, higher dietary levels of vitamin D (HAHD) did not seem to be protective.

Poromechanics of compressible charged porous media using the theory of mixtures.

Osmotic, electrostatic, and/or hydrational swellings are essential mechanisms in the deformation behavior of porous media, such as biological tissues, synthetic hydrogels, and clay-rich rocks. Present theories are restricted to incompressible constituents. This assumption typically fails for bone, in which electrokinetic effects are closely coupled to deformation. An electrochemomechanical formulation of quasistatic finite deformation of compressible charged porous media is derived from the theory of mixtures. The model consists of a compressible charged porous solid saturated with a compressible ionic solution. Four constituents following different kinematic paths are identified: a charged solid and three streaming constituents carrying either a positive, negative, or no electrical charge, which are the cations, anions, and fluid, respectively. The finite deformation model is reduced to infinitesimal theory. In the limiting case without ionic effects, the presented model is consistent with Blot's theory. Viscous drag compression is computed under closed circuit and open circuit conditions. Viscous drag compression is shown to be independent of the storage modulus. A compressible version of the electrochemomechanical theory is formulated. Using material parameter values for bone, the theory predicts a substantial influence of density changes on a viscous drag compression simulation. In the context of quasistatic deformations, conflicts between poromechanics and mixture theory are only semantic in nature.

XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos.

XTcf-3 is a maternally expressed Xenopus homolog of the mammalian HMG box factors Tcf-1 and Lef-1. The N-terminus of XTcf-3 binds to beta-catenin. Microinjection of XTcf-3 mRNA in embryos results in nuclear translocation of beta-catenin. The beta-catenin-XTcf-3 complex activates transcription in a transient reporter gene assay, while XTcf-3 by itself is silent. N-terminal deletion of XTcf-3 (delta N) abrogates the interaction with beta-catenin, as well as the consequent transcription activation. This dominant-negative delta N mutant suppresses the induction of axis duplication by microinjected beta-catenin. It also suppresses endogenous axis specification upon injection into the dorsal blastomeres of a 4-cell-stage embryo. We propose that signaling by beta-catenin involves complex formation with XTcf-3, followed by nuclear translocation and activation of specific XTcf-3 target genes.

The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors.

Tcf/Lef transcription factors mediate signalling from Wingless/Wnt proteins by recruiting Armadillo/beta-catenin as a transcriptional co-activator. However, studies of Drosophila, Xenopus and Caenorhabditis elegans have indicated that Tcf factors may also be transcriptional repressors. Here we show that Tcf factors physically interact with members of the Groucho family of transcriptional repressors. In transient transfection assays, the Xenopus Groucho homologue XGrg-4 inhibited activation of transcription of synthetic Tcf reporter genes. In contrast, the naturally truncated Groucho-family member XGrg-5 enhanced transcriptional activation. Injection of XGrg-4 into Xenopus embryos repressed transcription of Siamois and Xnr-3, endogenous targets of beta-catenin-Tcf. Dorsal injection of XGrg-4 had a ventralizing effect on Xenopus embryos. Secondary-axis formation induced by a dominant-positive Armadillo-Tcf fusion protein was inhibited by XGrg-4 and enhanced by XGrg-5. These data indicate that expression of Tcf target genes is regulated by a balance between Armadillo and Groucho.