Sanguinarine and chelerythrine: assessment of safety on pigs in ninety days feeding experiment.

Sanguinaria canadesis, Chelidonium majus and Macleya cordata have been used for centuries as alternative medicines. Currently the extracts from these medicinal plants are components of veterinary and human phytopreparations, and of oral-hygiene agents. Sanguinarine and chelerythrine (SA/CHE) are biologically active components of these extracts. They display distinct antibacterial and anti-inflammatory properties, but, on the other hand, they have been reported as having adverse effects - genotoxicity and hepatotoxicity. This paper is aimed at evaluation of the effects of daily administration of the extract from Macleya cordata (2 mg and 100 mg in 1 kg feed, sanguinarine:chelerythrine 3:1) in the diet on the health status of swine. After 90-day administration, alkaloids were retained to a different extent in tissues. The highest SA/CHE retention was detected in the gingiva (0.55 microg/g) and liver (0.15 microg/g), no SA/CHE were detected in muscles. Plasma SA levels attained 0.11 microg/ml. Treated animals did not display any results of hematological, biochemical or histological assay different from controls. A (32)P-postlabeling assay proved that no DNA-adducts with SA/CHE were detected in pig livers. We did not observe any symptom linked to epidemic dropsy syndrome often attributed to sanguinarine. In conclusion, an average daily oral dose of alkaloids up to 5 mg per 1 kg animal body weight proved to be safe.     

Mosaicism for GJB1 mutation causes milder Charcot-Marie-Tooth X1 phenotype in a heterozygous man than in a manifesting heterozygous woman

Charcot-Marie-Tooth (CMT) disease is a heterogeneous disorder of the peripheral nervous system that collectively affects approximately 1 in 2,500 individuals, thus making it the most common inherited neurologic disorder. X-linked inheritance may account for 10–20 % of CMT neuropathy. We report a Czech family with a 30-year-old woman affected by CMT since the age of 10 years, originally as an isolated case. Nerve conduction study (NCS) showed demyelinating neuropathy, and DNA testing revealed a novel heterozygous gap junction beta-1 protein (GJB1) mutation c.784_786delTA. The same mutation, but surprisingly in heterozygous state, was subsequently found in her subjectively healthy father and later also in one of her sisters but not in her two other sisters. NCS showed intermediate type of motor and sensory neuropathy in these two females manifesting heterozygotes and normal results in the other healthy sisters and one brother, all without the c.784_786delTA mutation. The father has a phenotype milder than his daughter and has only subclinical signs of CMT. The index female patient had normal karyotype 46, XX, and normal FISH for centromeric X chromosome. We concluded that the proband’s father is a heterozygote due to the somatic mosaicism for the GJB1 mutation in his leukocytes (detected by DNA sequencing) and also in his germ cells as confirmed by the unexpectedly different genotypes in his four daughters. Quantitative analysis revealed a mutated signal in 25:75 allele proportion of mutated to healthy allele in the mosaic father. This study has important consequences for genetic counseling and prognosis in CMTX1 families.     

World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders,Part 1: Update 2013 on the acute and continuation treatment of unipolar depressive disorders

Abstract

Objectives. This 2013 update of the practice guidelines for the biological treatment of unipolar depressive disorders was developed by an international Task Force of the World Federation of Societies of Biological Psychiatry (WFSBP). The goal has been to systematically review all available evidence pertaining to the treatment of unipolar depressive disorders, and to produce a series of practice recommendations that are clinically and scientifically meaningful based on the available evidence. The guidelines are intended for use by all physicians seeing and treating patients with these conditions. Methods. The 2013 update was conducted by a systematic update literature search and appraisal. All recommendations were approved by the Guidelines Task Force. Results. This first part of the guidelines (Part 1) covers disease definition, classification, epidemiology, and course of unipolar depressive disorders, as well as the management of the acute and continuation phase treatment. It is primarily concerned with the biological treatment (including antidepressants, other psychopharmacological medications, electroconvulsive therapy, light therapy, adjunctive and novel therapeutic strategies) of adults. Conclusions. To date, there is a variety of evidence-based antidepressant treatment options available. Nevertheless there is still a substantial proportion of patients not achieving full remission. In addition, somatic and psychiatric comorbidities and other special circumstances need to be more thoroughly investigated. Therefore, further high-quality informative randomized controlled trials are urgently needed.     

Identification of Inflamed Atherosclerotic Lesions In Vivo Using PET-CT

Inflammation plays a major pathogenetic role in the development of atherosclerotic plaques and related thromboembolic events. The identification of vulnerable plaques is of the utmost importance, as this may allow the implementation of more effective preventive and therapeutic interventions. Fluorodeoxyglucose positron emission tomography (FDG-PET) has been shown to be useful for tracing inflammation within plaques. However, its relationship to immunohistochemical findings in different territories of the peripheral circulation was not completely elucidated. We aimed to determine whether plaque inflammation could be measured by PET in combination with computer tomography (CT) using FDG and what is the relationship between FDG uptake and immunohistochemical findings in the removed atherosclerotic lesions of the femoral and carotid arteries. The study included 31 patients, 21 patients with high-grade stenosis of the internal carotid artery (ICA) and 10 patients with occlusion of the common femoral artery (CFA), all of whom underwent endarterectomy. Before endarterectomy in all patients, FDG-PET/CT imaging was performed. FDG uptake was measured as the maximum blood—normalized standardized uptake value, known as the target to background ratio (TBR max). TBR max amounted to 1.72?±?0.8, and in patients with ICA, stenosis was not significantly different from patients with CFA occlusion. Immunohistochemical and morphometric analyses of the plaques obtained at endarterectomy showed that the density of T lymphocytes and macrophages (number of cells per square millimeter) was significantly higher in subjects with stenosis of the ICA than in subjects with occlusion of the femoral arteries: lymphocytes, 1.26?±?0.21 vs. 0.77?±?0.29; p?=?0.02 and macrophages, 1.01?±?0.18 vs. 0.69?±?0.23; p?=?0.003. In the whole group of patients, the density of inflammatory cells significantly correlated with FDG uptake represented by PET-TBR max: T lymphocytes, r?=?0.60; p?<?0.01 and macrophages, r?=?0.65; p?<?0.01. The results of our study show that FDG uptake is related to the accumulation of inflammatory cells in atherosclerotic lesions. This finding suggests that FDG uptake reflects the severity of atherosclerotic vessel wall inflammation, and in stenotic lesions, it could be an indicator of their vulnerability. However, data from large outcome studies is needed to estimate the usefulness of this technique in identifying the most dangerous atherosclerotic lesions and vulnerable patients.     

Mutation analysis of RyR2 gene in patients after arrhythmic storm

IntroductionMutations of RyR2 gene encoding calcium channel of sarcoplazmatic reticulum are the cause of congenital catecholaminergic polymorphic ventricular tachycardia. The aim of this study was to test the hypothesis that RyR2 variants can increase occurrence of malignant arrhythmias in patients with structural heart diseases.MethodsThe investigated group consisted of 36 patients with structural heart diseases with ICD implanted who suffered arrhythmic storm. In the control group there were 141 patients with coronary artery disease who were hospitalized at our department owing to an acute coronary event and they were alive at least 3 years after the index event. Thus, they could be considered as a group with a low risk of sudden cardiac death. In all of them mutation analysis of RyR2 gene was performed.ResultsWe detected 16 different sequence changes of RyR2 gene in both groups. None of the found nucleotide polymorphisms led to amino acid changes, were located close to splice sites or had any similarity to known splicing enhancer motifs. The occurrence of these variants was not different in both groups.ConclusionsThe prevalence of RyR2 gene variants was not different in cases versus controls suggesting a limited role of this gene in the arrhythmogenesis in structural heart disease patients.     

Hypertension and ischemic heart disease

Hypertension is one of the major risk factors for ischemic heart disease and appropriate control of blood pressure is the cornerstone of both primary and secondary ischemic heart disease prevention. Effective blood pressure (BP) control is recommended in primary prevention, i.e., maintaining blood pressure <140/90 mmHg, while in secondary prevention values <130/85 mmHg used to be recommended. Treatment of hypertension in patients with ischemic heart disease is based on ACE inhibitors and/or AII antagonists (trials HOPE, EUROPA, and PEACE) in combination with beta blockers or with verapamil if beta blockers are not tolerated.According to epidemiologic data, cardiovascular mortality increases with blood pressure, starting as low as from the 110/70 mmHg level. Czech, European, and American guidelines from the early 21st century recommend that blood pressure in patients with ischemic heart disease (IHD) be maintained below 130/80 mmHg. Data from the INVEST a ACCORD trials led, however, to reappraisal of these strict recommendations and the blood pressure values currently recommended in secondary prevention correspond to high-normal blood pressure, i.e., 130–139 mmHg/80–89 mmHg.INVEST is the largest clinical trial that focused on hypertonic patients with IHD. Its results showed that verapamil is an appropriate alternative to beta blockers and that while lowering of blood pressure below 140/90 mmHg is necessary, its further decrease below 130/80 mmHg is not associated with any additional benefit.Trials with beta blockers demonstrated that lowering of heart rate (HR) improves the patients' prognosis. This hypothesis was definitely verified by trials BEAUTIFUL a SHIFT. The recommended heart rate for patients in secondary prevention is 50–70 bpm.     

Spectrum of mutations in gastrointestinal stromal tumor patients – a population‐based study from Slovakia

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of gastrointestinal tract and are characterized by presence of mutations in tyrosine kinases cKIT (KIT) and PDGFRα (PDGFRA). Mutations identified are highly heterogeneous, but some mutations are associated with specific clinical features of the tumor. Samples from 278 GIST patients collected during the period 2004–2011 were screened for mutations in exons 9, 11, 13, and 17 of KIT and 12, 14 and 18 of PDGFRA. Results of mutation screening were summarized and tested for possible association with clinical parameters of tumors. Mutations were identified in 83.81% of patients. Most frequent mutations were found in KIT exon 11 reaching frequency of 62.95%. Other exons contributed to the mutation pool with frequencies 8.27%, 7.55%, 2.52%, 1.44%, 1.08%, and 0.00%, in decreasing order KIT exon 9, PDGRFA exons 18 and 12, KIT exon 13, PDGFRA exon 14, and KIT exon 17. General linear model analysis showed no effect of any individual analyzed mutation on the phenotypic variables, but we confirmed association between mutations KIT exon 9 p. 503‐504_dup2, and PDGFRA exon 18 p. D842V and intestinal and gastric localization of tumors.     

Dopaminergic mediation in the brain aging and neurodegenerative diseases:a role of senescent cells

正Aging is well known to be the main risk factor for the neurodegenerative pathologies,in particular,Parkinson’s disease(PD)and Alzheimer’s disease(AD).In aging and in the diseases,similar changes in various hallmarks of neurodegeneration(lipofuscin accumulation,autophagia weakening,and disturbances in functions of mitochondria     

Age and activation determines the anticonvulsant effect of ifenprodil in rats

Ifenprodil, an antagonist of NMDA receptors containing the NR2B subunit, was expected to exhibit anticonvulsant action in rat pups up to the third postnatal week because of predominance of NR2B subunit at early development. Cortical epileptic afterdischarges (ADs) were used to study possible effects on threshold current intensities and duration of ADs in 12-, 15-, 18-, and 25-day-old rats. A series of 18 stimulation series with stepwise increasing current intensities (from 0.2 to 15 mA) was applied with 10-min intervals. The first experiment studied rats pretreated with ifenprodil (20 or 40 mg/kg), the second experiment studied an effect of ifenprodil on already present ADs—the dose of 20 mg/kg was administered after stimulation with the 3.5-mA current intensity. Pretreatment with ifenprodil resulted in an anticonvulsant effect in 15-day-old rats only, on the contrary, proconvulsant action was found in 18- and 25-day-old animals (decrease of thresholds especially for transition into the second, limbic type of ADs and increase in duration of ADs). Anticonvulsant effect was found in 12-, 15-, and 18-day-old rats in the second experiment—ADs were shortened. In contrast, no effect was observed in 25-day-old animals. An anticonvulsant action of ifenprodil is not only age-dependent but also activation-dependent.