Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of specific congenital anomalies: a European register-based study

Evidence of an association between early pregnancy exposure to selective serotonin reuptake inhibitors (SSRI) and congenital heart defects (CHD) has contributed to recommendations to weigh benefits and risks carefully. The objective of this study was to determine the specificity of association between first trimester exposure to SSRIs and specific CHD and other congenital anomalies (CA) associated with SSRI exposure in the literature (signals). A population-based case-malformed control study was conducted in 12 EUROCAT CA registries covering 2.1 million births 1995-2009 including livebirths, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. Babies/fetuses with specific CHD (n = 12,876) and non-CHD signal CA (n = 13,024), were compared with malformed controls whose diagnosed CA have not been associated with SSRI in the literature (n = 17,083). SSRI exposure in first trimester pregnancy was associated with CHD overall (OR adjusted for registry 1.41, 95% CI 1.07-1.86, fluoxetine adjOR 1.43 95% CI 0.85-2.40, paroxetine adjOR 1.53, 95% CI 0.91-2.58) and with severe CHD (adjOR 1.56, 95% CI 1.02-2.39), particularly Tetralogy of Fallot (adjOR 3.16, 95% CI 1.52-6.58) and Ebstein's anomaly (adjOR 8.23, 95% CI 2.92-23.16). Significant associations with SSRI exposure were also found for ano-rectal atresia/stenosis (adjOR 2.46, 95% CI 1.06-5.68), gastroschisis (adjOR 2.42, 95% CI 1.10-5.29), renal dysplasia (adjOR 3.01, 95% CI 1.61-5.61), and clubfoot (adjOR 2.41, 95% CI 1.59-3.65). These data support a teratogenic effect of SSRIs specific to certain anomalies, but cannot exclude confounding by indication or associated factors.

Bilingual Lexical Access in Reading : Analyzing the Effect of Semantic Context on Non-Selective Access in Bilingual Memory

Recent empirical studies about the neurological executive nature of reading in bilinguals differ in their evaluations of the degree of selective manifestation in lexical access as implicated by data from early and late reading measures in the eye-tracking paradigm. Currently two scenarios are plausible: (1) Lexical access in reading is fundamentally language non-selective and top-down effects from semantic context can influence the degree of selectivity in lexical access; (2) Cross-lingual lexical activation is actuated via bottom-up processes without being affected by top-down effects from sentence context. In an attempt to test these hypotheses empirically, this study analyzed reader-text events arising when cognate facilitation and semantic constraint interact in a 22 factorially designed experiment tracking the eye movements of 26 Swedish-English bilinguals reading in their L2. Stimulus conditions consisted of high- and low-constraint sentences embedded with either a cognate or a non-cognate control word. The results showed clear signs of cognate facilitation in both early and late reading measures and in either sentence conditions. This evidence in favour of the non-selective hypothesis indicates that the manifestation of non-selective lexical access in reading is not constrained by top-down effects from semantic context.

State-Selective Attachment of Helium to Molecular Ions in a New Cryogenic Ion Trap

Light is the main information about the interstellar medium accessible on Earth. Based on this information one can conclude on the composition of the region where the light originates from, as well as on its history. The requirement for this is that it is possible to identify the different absorption and emission features in the spectrum and assign them to certain molecules, atoms or ions. To enable the identification of the different species, precise spectroscopic investigations of the species in the laboratory are necessary. In this work a new spectroscopic method is presented, which can be used to record pure rotational spectra of mass selected, cold, stored molecular ions. It is based on the idea of state specific attachment of helium atoms to the stored molecular ions. The new technique has been made possible through the development and recent completion of two new 22-pole ion trap instruments in the work group of Laboratory Astrophysics at the University of Cologne. These new instruments have the advantage to reach temperatures as low as 4K compared to the 10K of the predecessor instrument. These low temperatures enable the ternary attachment of helium atoms to the stored molecular ions and by this make it possible to develop this new method for pure rotational spectroscopy. According to this, this work is divided into two parts. The first part deals with the new FELion experiment that was build and characterized in the first part of the thesis. FELion is a cryogenic 22-pole ion trap apparatus, allowing to generate, mass select, store and cool down, and analyze molecular ions. The different components of the instrument, e.g. the Storage Ion Source for generating the ions or the first quadrupole mass filter, are described and characterized in this part. Besides this also the newly developed control and data acquisitions system is introduced. With this instrument the measurements presented in the second part of the work were performed. The second part deals with the new action spectroscopic method of state-selective helium attachment to the stored molecular ions. For a deeper analysis of the new technique the systems of CD+ and helium and HCO+ and helium are investigated in detail. Analytical and numerical models of the process are presented and compared to experimental results. The results of these investigations point to a seemingly very general applicability of the new method to a wide class of molecular ions. In the final part of the thesis measurements of the rotational spectrum of l-C3H+ are presented. These measurements have to be high-lighted, since it was possible for the first time in the laboratory to unambiguously measure four low-lying rotational transitions of l-C3H+. These measurements (Brünken et al. ApJL 783, L4 (2014)) enabled the reliable identification of so far unidentified emision lines observed in several regions of the interstellar medium (Pety et al. Astron. Astrophys. 548, A68 (2012), McGuire et al. The Astrophysical Journal 774, 56 (2013) and McGuire et al. The Astrophysical Journal 783, 36 (2014)).

The Repellent DEET Potentiates Carbamate Effects via Insect Muscarinic Receptor Interactions: An Alternative Strategy to Control Insect Vector-Borne Diseases.

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Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury.

Electrical neuromodulation of lumbar segments improves motor control after spinal cord injury in animal models and humans. However, the physiological principles underlying the effect of this intervention remain poorly understood, which has limited the therapeutic approach to continuous stimulation applied to restricted spinal cord locations. Here we developed stimulation protocols that reproduce the natural dynamics of motoneuron activation during locomotion. For this, we computed the spatiotemporal activation pattern of muscle synergies during locomotion in healthy rats. Computer simulations identified optimal electrode locations to target each synergy through the recruitment of proprioceptive feedback circuits. This framework steered the design of spatially selective spinal implants and real-time control software that modulate extensor and flexor synergies with precise temporal resolution. Spatiotemporal neuromodulation therapies improved gait quality, weight-bearing capacity, endurance and skilled locomotion in several rodent models of spinal cord injury. These new concepts are directly translatable to strategies to improve motor control in humans.

Tear Secretion Induced by Selective Stimulation of Corneal and Conjunctival Sensory Nerve Fibers

Purpose. To measure the increase in tear secretion evoked by selective stimulation of the different populations of sensory receptors of the cornea and conjunctiva by using moderate and intense mechanical, chemical, and cold stimuli. Methods. Six healthy subjects participated in the study. Tear secretion was measured in both eyes by the Schirmer’s test conducted under control conditions and after stimulation of the center of the cornea and the temporal conjunctiva with a gas esthesiometer. Mechanical stimulation consisted in three pulses of 3 seconds’ duration of warmed air (at 34°C on the eye surface) applied at moderate (170 mL/min) and high (260 mL/min) flow rates. Cold thermal stimulation was made with cooled air that produced a corneal temperature drop of −1°C or −4.5°C. Chemical (acidic) stimulation was performed with a jet of gas containing a mixture of 80% CO2 in air. Results. The basal volume of tear secretion increased significantly (P < 0.05, paired t-test) after stimulation of the cornea with high-flow mechanical stimuli (260 mL/min), intense cooling pulses (−4.5°C), and chemical stimulation (80% CO2). The same stimuli were ineffective when applied to the conjunctiva. Moderate mechanical (170 mL/min) and cold (−1°C) stimulation of the cornea or the conjunctiva did not change significantly the volume of tear secretion. Conclusions. Reflex tear secretion caused by corneal stimulation seems to be chiefly due to activation of corneal polymodal nociceptors, whereas selective excitation of corneal mechanonociceptors or cold receptors appears to be less effective in evoking an augmented lacrimal secretion. Conjunctival receptors stimulated at equivalent levels do not evoke an increased tear secretion.

Selective and Specific Activation of Rab5 during Endocytosis of Receptor Tyrosine Kinases

The Rab family of proteins are low molecular weight GTPases that have the ability to switch between GTP- (active) and GDP- (inactive) bound form, and in that sense act as molecular switches. Through distinct localization on various vesicles and organelles and by cycling through GTP/GDP bound forms, Rabs are able to recruit and activate numerous effector proteins, both spatially and temporally, and hence behave as key regulators of trafficking in both endocytic and biosynhtetic pathways. The Rab5 protein has been shown to regulate transport from plasma membrane to the early endosome as well as activate signaling pathways from the early endosome. This dissertation focused on understanding Rab5 activation via endocytosis of receptor tyrosine kinases (RTKs). First, tyrosine kinase activity of RTKs was linked to endosome fusion by demonstrating that tyrosine kinase inhibitors block endosome fusion and activation of Rab5, and a constitutively active form of Rab5 is able to rescue endosome fusion. However, depending on how much ligand is available at the cell surface, the receptor-ligand complexes can be internalized via a number of distinct pathways. Similarly, Rab5 was activated in a ligand-dependent concentration dependent manner via clathrin- and caveolin-mediated pathways, as well as a pathway independent of both. However, overexpression Rabex-5, a nucleotide exchange factor for Rab5, is able to rescue activation even when all of the pathways of EGF-receptor internalization were blocked. Next, the three naturally occurring splice variants of Rabex-5 selectively activated Rab5. Lastly, Rabex-5 inhibits differentiation of 3T3-L1 and PC12 cells through 1) degradation of signaling endosome via Rab5-dependent fusion with the early endosome, 2) and inhibition of signaling cascade via ubiquitination of Ras through the ZnF domain at the N-terminus of Rabex-5. In conclusion, these data shed light on complexity of the endosomal trafficking system where tyrosine kinase activity of the receptor is able to affect endosome fusion; how different endocytic pathways affect activation of one of the key regulators of early endocytic events; and how selective activation of Rab5 via Rabex-5 can control adipogenesis and neurogenesis.

New weapons to fight old enemies: novel strategies for the (bio)control of bacterial biofilms in the food industry

Biofilms are microbial communities characterized by their adhesion to solid surfaces and the production of a matrix of exopolymeric substances, consisting of polysaccharides, proteins, DNA and lipids, which surround the microorganisms lending structural integrity and a unique biochemical profile to the biofilm. Biofilm formation enhances the ability of the producer/s to persist in a given environment. Pathogenic and spoilage bacterial species capable of forming biofilms are a significant problem for the healthcare and food industries, as their biofilm-forming ability protects them from common cleaning processes and allows them to remain in the environment post-sanitation. In the food industry, persistent bacteria colonize the inside of mixing tanks, vats and tubing, compromising food safety and quality. Strategies to overcome bacterial persistence through inhibition of biofilm formation or removal of mature biofilms are therefore necessary. Current biofilm control strategies employed in the food industry (cleaning and disinfection, material selection and surface preconditioning, plasma treatment, ultrasonication, etc.), although effective to a certain point, fall short of biofilm control. Efforts have been explored, mainly with a view to their application in pharmaceutical and healthcare settings, which focus on targeting molecular determinants regulating biofilm formation. Their application to the food industry would greatly aid efforts to eradicate undesirable bacteria from food processing environments and, ultimately, from food products. These approaches, in contrast to bactericidal approaches, exert less selective pressure which in turn would reduce the likelihood of resistance development. A particularly interesting strategy targets quorum sensing systems, which regulate gene expression in response to fluctuations in cell-population density governing essential cellular processes including biofilm formation. This review article discusses the problems associated with bacterial biofilms in the food industry and summarizes the recent strategies explored to inhibit biofilm formation, with special focus on those targeting quorum sensing.

Development of a continuous process for α-thio-β-chloroacrylamide synthesis with enhanced control of a cascade transformation

A continuous process strategy has been developed for the preparation of α-thio-β chloroacrylamides, a class of highly versatile synthetic intermediates. Flow platforms to generate the α-chloroamide and α-thioamide precursors were successfully adopted, progressing from the previously employed batch chemistry, and in both instances afford a readily scalable methodology. The implementation of the key α-thio-β-chloroacrylamide casade as a continuous flow reaction on a multi-gram scale is described, while the tuneable nature of the cascade, facilitated by continuous processing, is highlighted by selective generation of established intermediates and byproducts.

A second order control-volume finite-element least-squares strategy for simulating diffusion in strongly anisotropic media

An unstructured mesh �nite volume discretisation method for simulating di�usion in anisotropic media in two-dimensional space is discussed. This technique is considered as an extension of the fully implicit hybrid control-volume �nite-element method and it retains the local continuity of the ux at the control volume faces. A least squares function recon- struction technique together with a new ux decomposition strategy is used to obtain an accurate ux approximation at the control volume face, ensuring that the overall accuracy of the spatial discretisation maintains second order. This paper highlights that the new technique coincides with the traditional shape function technique when the correction term is neglected and that it signi�cantly increases the accuracy of the previous linear scheme on coarse meshes when applied to media that exhibit very strong to extreme anisotropy ratios. It is concluded that the method can be used on both regular and irregular meshes, and appears independent of the mesh quality.