Origin and Loss of Nested LRRTM/alpha-Catenin Genes during Vertebrate Evolution

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Different Requirements for GFR alpha 2-Signaling in Three Populations of Cutaneous Sensory Neurons

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Cycling injuries and alcohol

Background: Most of the cycling accidents that occur in Finland do not end up in the official traffic accident statistics. Thus, there is minimal information on these accidents and their consequences, particularly in cases in which alcohol was involved. The focus of the present study is on cycling accidents and injuries involving alcohol in particular. Methods: Data on patients visiting the emergency department at North Kymi Hospital because of a cycling accident was prospectively collected for two years, from June 1, 2004 to May 31, 2006. Blood alcohol concentration (BAC) was measured on admission with a breath analyser. The severity of the cycling injuries was classified according to the Abbreviated Injury Scale (AIS). Results: A total of 217 cycling accidents occurred. One third of the injured cyclists were involved with alcohol at the time of visiting the hospital. Of these, 85% were males. A blood alcohol concentration of Conclusions: Cyclists involved with alcohol were, in most cases, heavily intoxicated and were not wearing a bicycle helmet. Head injuries were more common among these cyclists than among sober cyclists. As cycling continues to increase, it is important to monitor cycling accidents, improve the accident statistics and heighten awareness of the risks of head injuries when cycling under the influence of alcohol. (c) 2018 Elsevier Ltd. All rights reserved.Peer reviewe

Neurturin Evokes MAPK-Dependent Upregulation of Egr4 and KCC2 in Developing Neurons

The K-Cl cotransporter KCC2 plays a crucial role in the functional development of GABAA-mediated responses rendering GABA hyperpolarizing in adult neurons. We have previously shown that BDNF upregulates KCC2 in immature neurons through the transcription factor Egr4. The effect of BDNF on Egr4 and KCC2 was shown to be dependent on the activation of ERK1/2. Here we demonstrate that the trophic factor neurturin can also trigger Egr4 expression and upregulate KCC2 in an ERK1/2-dependent manner. These results show that Egr4 is an important component in the mechanism for trophic factor-mediated upregulation of KCC2 in immature neurons involving the activation of specific intracellular pathways common to BDNF and Neurturin

Role of the K+-Cl- Cotransporter KCC2a Isoform in Mammalian Respiration at Birth

In central respiratory circuitry, synaptic excitation is responsible for synchronizing neuronal activity in the different respiratory rhythm phases, whereas chloride-mediated inhibition is important for shaping the respiratory pattern itself. The potassium chloride cotransporter KCC2, which serves to maintain low intraneuronal Cl- concentration and thus render chloride-mediated synaptic signaling inhibitory, exists in two isoforms, KCC2a and KCC2b. KCC2 is essential for functional breathing motor control at birth, but the specific contribution of the KCC2a isoform remains unknown. Here, to address this issue, we investigated the respiratory phenotype of mice deficient for KCC2a. In vivo plethysmographic recordings revealed that KCC2a-deficient pups at P0 transiently express an abnormally low breathing rate and a high occurrence of apneas. Immunostainings confirmed that KCC2a is normally expressed in the brainstem neuronal groups involved in breathing (pre-Botzinger complex, parafacial respiratory group, hypoglossus nucleus) and is absent in these regions in the KCC2a(-/-) mutant. However, in variously reduced in vitro medullary preparations, spontaneous rhythmic respiratory activity is similar to that expressed in wild-type preparations, as is hypoglossal motor output, and no respiratory pauses are detected, suggesting that the rhythm-generating networks are not intrinsically affected in mutants at P0. In contrast, inhibitory neuromodulatory influences exerted by the pons on respiratory rhythmogenesis are stronger in the mutant, thereby explaining the breathing anomalies observed in vivo. Thus, our results indicate that the KCC2a isoform is important for establishing proper breathing behavior at the time of birth, but by acting at sites that are extrinsic to the central respiratory networks themselves.Peer reviewe

Implications of the N-terminal heterogeneity for the neuronal K-Cl cotransporter KCC2 function

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Decreased mortality risk due to first acute coronary syndrome in women with postmenopausal hormone therapy use

Objectives: The role of postmenopausal hormone therapy (HT) in the incidence of acute coronary syndrome (ACS) has been studied extensively, but less is known of the impact of HT on the mortality risk due to an ACS. Study design and main outcome measures: We extracted from a population-based ACS register, FINAMI, 7258 postmenopausal women with the first ACS. These data were combined with HT use data from the National Drug Reimbursement Register; 625 patients (9%) had used various HT regimens. The death risks due to ACS before admission to hospital, 2-28, or 29-365 days after the incident ACS were compared between HT users and non-users with logistic regression analyses. Results: In all follow-up time points, the ACS death risks in HT ever-users were smaller compared to non-users. Of women with FIT ever use, 42% died within one year as compared with 52% of non-users (OR 0.62, p = 5 year FIT use (OR 0.54, p <0.001) died as compared to 43% of the non-users. Age 60 years at the HT initiation was accompanied with similar reductions in ACS mortality risk. Conclusions: Postmenopausal HT use is accompanied with reduced mortality risk after primary ACS. (C) 2016 Elsevier Ireland Ltd. All rights reserved.Peer reviewe

BDNF-induced TrkB activation down-regulates the K+–Cl− cotransporter KCC2 and impairs neuronal Cl− extrusion

Pathophysiological activity and various kinds of traumatic insults are known to have deleterious long-term effects on neuronal Cl− regulation, which can lead to a suppression of fast postsynaptic GABAergic responses. Brain-derived neurotrophic factor (BDNF) increases neuronal excitability through a conjunction of mechanisms that include regulation of the efficacy of GABAergic transmission. Here, we show that exposure of rat hippocampal slice cultures and acute slices to exogenous BDNF or neurotrophin-4 produces a TrkB-mediated fall in the neuron-specific K+–Cl− cotransporter KCC2 mRNA and protein, as well as a consequent impairment in neuronal Cl− extrusion capacity. After kindling-induced seizures in vivo, the expression of KCC2 is down-regulated in the mouse hippocampus with a spatiotemporal profile complementary to the up-regulation of TrkB and BDNF. The present data demonstrate a novel mechanism whereby BDNF/TrkB signaling suppresses chloride-dependent fast GABAergic inhibition, which most likely contributes to the well-known role of TrkB-activated signaling cascades in the induction and establishment of epileptic activity

Risk factors for major adverse cardiovascular events after the first acute coronary syndrome

Aims To evaluate risk factors for major adverse cardiac event (MACE) after the first acute coronary syndrome (ACS) and to examine the prevalence of risk factors in post-ACS patients. Methods We used Finnish population-based myocardial infarction register, FINAMI, data from years 1993-2011 to identify survivors of first ACS (n = 12686), who were then followed up for recurrent events and all-cause mortality for three years. Finnish FINRISK risk factor surveys were used to determine the prevalence of risk factors (smoking, hyperlipidaemia, diabetes and blood pressure) in post-ACS patients (n = 199). Results Of the first ACS survivors, 48.4% had MACE within three years of their primary event, 17.0% were fatal. Diabetes (p = 4.4 x 10(-7)), heart failure (HF) during the first ACS attack hospitalization (p = 6.8 x 10(-15)), higher Charlson index (p = 1.56 x 10(-19)) and older age (p = .026) were associated with elevated risk for MACE in the three-year follow-up, and revascularization (p = .0036) was associated with reduced risk. Risk factor analyses showed that 23% of ACS survivors continued smoking and cholesterol levels were still high (>5mmol/l) in 24% although 86% of the patients were taking lipid lowering medication. Conclusion Diabetes, higher Charlson index and HF are the most important risk factors of MACE after the first ACS. Cardiovascular risk factor levels were still high among survivors of first ACS.Peer reviewe

Retarded Growth and Deficits in the Enteric and Parasympathetic Nervous System in Mice Lacking GFRα2, a Functional Neurturin Receptor

AbstractGlial cell line–derived neurotrophic factor (GDNF) and a related protein, neurturin (NTN), require a GPI-linked coreceptor, either GFRα1 or GFRα2, for signaling via the transmembrane Ret tyrosine kinase. We show that mice lacking functional GFRα2 coreceptor (Gfra2−/−) are viable and fertile but have dry eyes and grow poorly after weaning, presumably due to malnutrition. While the sympathetic innervation appeared normal, the parasympathetic cholinergic innervation was almost absent in the lacrimal and salivary glands and severely reduced in the small bowel. Neurite outgrowth and trophic effects of NTN at low concentrations were lacking in Gfra2−/− trigeminal neurons in vitro, whereas responses to GDNF were similar between the genotypes. Thus, GFRα2 is a physiological NTN receptor, essential for the development of specific postganglionic parasympathetic neurons