SCIM: universal single-cell matching with unpaired feature sets.

MOTIVATION: Recent technological advances have led to an increase in the production and availability of single-cell data. The ability to integrate a set of multi-technology measurements would allow the identification of biologically or clinically meaningful observations through the unification of the perspectives afforded by each technology. In most cases, however, profiling technologies consume the used cells and thus pairwise correspondences between datasets are lost. Due to the sheer size single-cell datasets can acquire, scalable algorithms that are able to universally match single-cell measurements carried out in one cell to its corresponding sibling in another technology are needed. RESULTS: We propose Single-Cell data Integration via Matching (SCIM), a scalable approach to recover such correspondences in two or more technologies. SCIM assumes that cells share a common (low-dimensional) underlying structure and that the underlying cell distribution is approximately constant across technologies. It constructs a technology-invariant latent space using an autoencoder framework with an adversarial objective. Multi-modal datasets are integrated by pairing cells across technologies using a bipartite matching scheme that operates on the low-dimensional latent representations. We evaluate SCIM on a simulated cellular branching process and show that the cell-to-cell matches derived by SCIM reflect the same pseudotime on the simulated dataset. Moreover, we apply our method to two real-world scenarios, a melanoma tumor sample and a human bone marrow sample, where we pair cells from a scRNA dataset to their sibling cells in a CyTOF dataset achieving 90% and 78% cell-matching accuracy for each one of the samples, respectively. AVAILABILITY AND IMPLEMENTATION: https://github.com/ratschlab/scim. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A Stronger Effect of Body Mass Index and Waist Circumference on the Prevalence of Uncontrolled Hypertension among Caucasian Men than Women.

BACKGROUND: Gender-related differences in fat distribution may affect blood pressure (BP) control in hypertensive subjects. The aim of the study was to assess how body mass (BM), BMI, and waist circumference (WC) influence the effectiveness of antihypertension therapy in hypertensive men and women in daily clinical practice. PATIENTS AND METHODS: The observational study involved 12,289 adult hypertensive Caucasians (6,163 women) declaring regular use of antihypertensive drugs. BP control was scored based on the mean values of 2 attended office BP measurements. WC thresholds for visceral obesity were adopted from definitions of the International Diabetes Federation (≥94/80 cm for men/women) and National Cholesterol Education Program Adult Treatment Panel III (≥102/88 cm for men/women). Stepwise backward multivariable logistic regression was used to analyse correlates of the effectiveness of hypertension therapy. RESULTS: The predictive value of BMI ≥30 (for uncontrolled hypertension) was stronger than that of visceral obesity, regardless of the criteria used. In men, BP control rapidly deteriorated with BMI (odds ratio [OR] up to 8.58 [95% CI: 5.74-12.83]) and WC (OR up to 5.09 [3.84-6.74]), while in women, the association was more flattened (OR up to 3.63 [2.78-4.74] and 1.93 [1.59-2.35], respectively). However, the highest risk of uncontrolled BP occurred in women with BM ≥110 kg (OR = 10.47 [5.05-21.71]) and men with BM ≥125 kg (OR = 9.66 [5.86-15.94]). CONCLUSIONS: (1) Obesity and visceral obesity limit the effectiveness of antihypertension therapy more in men than in women. (2) This phenomenon should be taken into account in the prescription of adequate doses of antihypertensive drugs.

Lower utilization of home blood pressure monitoring in younger, poorly educated hypertensive males - real-life data.

Background: Home blood pressure monitoring (HBPM) became a standard in the management of hypertension. However, there are few data concerning the utilisation of blood pressure (BP) monitors in daily clinical practice.Aim: The aim of this analysis was to show: (1) how frequently hypertensive patients are equipped with BP monitors, (2) how often they perform regular HBPM and running BP diaries, (3) what are the correlates of utilisation of BP monitors, in a large real-life cohort of hypertensives examined for the efficacy of antihypertensive therapy. Patients and methods: The survey was conducted by 570 physicians among 14,200 hypertensive patients, of whom 12,289 (6163 women; mean age 63 ± 12 years) declared use of antihypertensive medicines. Each patient was asked whether at home is having and using regularly or occasionally BP monitor and running BP diary. BP control was assessed based on the mean of two attended office BP measurements.Results: Among patient equipped with BP monitors (87.2%), 73.4% were conducting HBPM regularly, while 26.6% occasionally, and 66.9% were running BP diaries. Controlled BP was achieved by 34.5% (32.9% men and 36.1% women; p < .001), more frequently by equipped with BP monitors (34.9 vs 31.7%, p < .001). Female sex, education, professional activity, active lifestyle, older age, hypertensive polytherapy, longer than 5-year therapy for hypertension, and coexistence of diabetes were factors increasing, while alcohol consumption, visceral obesity and heart failure decreasing the probability of being equipped with BP monitor and running BP diary. Regular HBPM were more frequently among women, physically active, older, diabetics, viscerally obese and patients with coronary artery disease.Conclusions: (1) The majority of hypertensive Poles are already equipped with BP monitors, (2) three-fourth patients perform regular HBPM and two-third run BP diaries, (3) there is still a need to promote utilisation of BP monitors among younger, poorly educated hypertensive males.

Transcriptional signatures of steroid hormones in the striatal neurons and astrocytes.

BACKGROUND: The mechanisms of steroids actions in the brain mainly involve the binding and nuclear translocation of specific cytoplasmic receptors. These receptors can act as transcription factors and regulate gene expression. However, steroid-dependent transcriptional regulation in different types of neural cells is not yet fully understood. The aim of this study was to evaluate and compare transcriptional alterations induced by various steroid receptor agonists in primary cultures of astrocytes and neurons from mouse brain. RESULTS: We utilized whole-genome microarrays (Illumina Mouse WG-6) and quantitative PCR analyses to measure mRNA abundance levels. To stimulate gene expression we treated neuronal and astroglial cultures with dexamethasone (100 nM), aldosterone (200 nM), progesterone (200 nM), 5α-dihydrotestosterone (200 nM) and ß-Estradiol (200 nM) for 4 h. Neurons were found to exhibit higher levels of expression of mineralocorticoid receptor, progesterone receptor and estrogen receptor 2 than astrocytes. However, higher mRNA level of glucocorticoid receptor mRNA was observed in astrocytes. We identified 956 genes regulated by steroids. In astrocytes we found 381 genes altered by dexamethasone and 19 altered by aldosterone. Functional classification of the regulated genes indicated their putative involvement in multiple aspects of cell metabolism (up-regulated Slc2a1, Pdk4 and Slc45a3) and the inflammatory response (down-regulated Ccl3, Il1b and Tnf). Progesterone, dihydrotestosterone and estradiol did not change gene expression in astrocytes. We found no significant changes in gene expression in neurons. CONCLUSIONS: The obtained results indicate that glial cells might be the primary targets of transcriptional action of steroids in the central nervous system. Substantial changes in gene expression driven by the glucocorticoid receptor imply an important role for the hypothalamic-pituitary-adrenal axis in the hormone-dependent regulation of brain physiology. This is an in vitro study. Hence, the model may not accurately reflect all the effects of steroids on gene expression in neurons in vivo.

N-Terminal Prohormone of Brain Natriuretic Peptide but not C-Terminal Pre-Pro Vasopressin (Copeptin) Level is Associated with the Response to Antihypertensive Therapy in Haemodialysis Patients.

BACKGROUND/AIMS: Volume overload, frequently clinically asymptomatic is considered as a causative factor limiting the effectiveness of antihypertensive therapy in haemodialysis (HD) patients. Therefore, the aim of this study was to assess plasma levels of N-terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP) and a C-terminal portion of the precursor of vasopressin (CT-proAVP, copeptin), surrogate markers of volume overload in HD patients in relation to the number of antihypertensive drugs used in the hypertension treatment. METHODS: One hundred and fifty adult HD patients (92 males) were enrolled into this study. Clinical data concerning blood pressure (BP) measurements prior haemodialysis session and pharmacotherapy were collected from all patients. In addition to routine laboratory parameters, plasma levels of NT-proBNP and CT-proAVP were measured, and daily sodium and water consumption were estimated with a portion-size food frequency questionnaire. RESULTS: Among 145 (96.7%) hypertensive HD patients, 131 were receiving antihypertensive medication. Despite antihypertensive therapy, 31.0% had inadequate BP control. Plasma concentration of NT-proBNP was associated with systolic (R=0.19; p=0.02) but not diastolic BP values and with the number of received antihypertensive drugs (R=0.21; p=0.01). The highest NT-proBNP values were observed in patients receiving 3 or more antihypertensive drugs. In contrast, no significant correlation was found between plasma CT-proAVP concentrations and BP values as well as and the number of antihypertensive drugs. Receiver operator curve analysis showed that NT-proBNP values over 13,184 pg/mL predicted the use of at least 3 antihypertensive drugs in maximal doses in the therapy of hypertension, similar analyses performed for CT-proAVP showed much less specificity. CONCLUSIONS: 1. Increased levels of NT-proBNP seems to be a better biomarker of multidrug antihypertensive therapy requirement than CT-proAVP. 2. Whether estimation of NT-proBNP in these patients will be also better biomarker than copeptin in the prediction of cardiovascular complications related to hypertension needs further investigations.

Behavioral and transcriptional patterns of protracted opioid self-administration in mice.

Chronic exposure to opioids induces adaptations in brain function that lead to the formation of the behavioral and physiological symptoms of drug dependence and addiction. Animal models commonly used to test these symptoms typically last less than two weeks, which is presumably too short to observe the alterations in the brain that accompany drug addiction. Here, we analyzed the phenotypic and molecular effects of nearly lifelong morphine or saccharin intake in C57BL/6J mice. We used multiple paradigms to evaluate the symptoms of compulsive drug intake: a progressive ratio schedule, intermittent access and a schedule involving a risk of punishment were programmed into an automated IntelliCage system. Gene expression profiles were evaluated in the striatum using whole-genome microarrays and further validated using quantitative polymerase chain reaction in the striatum and the prefrontal cortex. Mice voluntary self-administering morphine showed addiction-related behavioral pattern that included: higher motivation to work for a drug reward, increased reward seeking and increased craving. The analysis of molecular changes revealed a tolerance effect in the transcriptional response to morphine injection (20 mg/kg, ip), as well as some long-lasting alterations in gene expression profiles between the analyzed groups of animals. Interestingly, among the morphine-drinking animals, certain transcriptional profiles were found to be associated with alterations in behavior. In conclusion, our model represents a novel approach for investigating the behavioral and molecular mechanisms underlying opioid addiction. Prolonged morphine intake caused adaptive processes in the brain that manifested as altered behavior and transcriptional sensitivity to opioids.

Seqinspector: position-based navigation through the ChIP-seq data landscape to identify gene expression regulators.

BACKGROUND: The regulation of gene expression in eukaryotic cells is a complex process that involves epigenetic modifications and the interaction of DNA with multiple transcription factors. This process can be studied with unprecedented sensitivity using a combination of chromatin immunoprecipitation and next-generation DNA sequencing (ChIP-seq). Available ChIP-seq data can be further utilized to interpret new gene expression profiling experiments. RESULTS: Here, we describe seqinspector, a tool that accepts any set of genomic coordinates from ChIP-seq or RNA-seq studies to identify shared transcriptional regulators. The presented web resource includes a large collection of publicly available ChIP-seq and RNA-seq experiments (>1300 tracks) performed on transcription factors, histone modifications, RNA polymerases, enhancers and insulators in humans and mice. Over-representation is calculated based on the coverage computed directly from indexed files storing ChIP-seq data (bigwig). Therefore, seqinspector is not limited to pre-computed sets of gene promoters. CONCLUSION: The tool can be used to identify common gene expression regulators for sets of co-expressed transcripts (including miRNAs, lncRNAs or any novel unannotated RNAs) or for sets of ChIP-seq peaks to identify putative protein-protein interactions or transcriptional co-factors. The tool is available at http://seqinspector.cremag.org.

Molecular profile of dissociative drug ketamine in relation to its rapid antidepressant action.

BACKGROUND: The NMDA receptor antagonist ketamine was found to act as a fast-acting antidepressant. The effects of single treatment were reported to persist for days to weeks, even in otherwise treatment-refractory cases. Identification of the mechanisms underlying ketamine's antidepressant action may permit development of novel drugs, with similar clinical properties but lacking psychotomimetic, sedative and other side effects. METHODS: We applied whole-genome microarray profiling to analyze detailed time-course (1, 2, 4 and 8 h) of transcriptome alterations in the striatum and hippocampus following acute administration of ketamine, memantine and phencyclidine in C57BL/6 J mice. The transcriptional effects of ketamine were further analyzed using next-generation sequencing and quantitative PCR. Gene expression alterations induced by the NMDA antagonists were compared to the molecular profiles of psychotropic drugs: antidepressants, antipsychotics, anxiolytics, psychostimulants and opioids. RESULTS: We identified 52 transcripts (e.g. Dusp1, Per1 and Fkbp5) with altered expression (FDR < 1 %) in response to treatment with NMDA receptor antagonists. Functional links that connect expression of the regulated genes to the MAPK, IL-6 and insulin signaling pathways were indicated. Moreover, ketamine-regulated expression of specific gene isoforms was detected (e.g. Tsc22d3, Sgk1 and Hif3a). The comparison with other psychotropic drugs revealed that the molecular effects of ketamine are most similar to memantine and phencyclidine. Clustering based on expression profiles placed the NMDA antagonists among fluoxetine, tianeptine, as well as opioids and ethanol. CONCLUSIONS: The identified patterns of gene expression alteration in the brain provided novel molecular classification of ketamine. The transcriptional profile of ketamine reflects its multi-target pharmacological nature. The results reveal similarities between the effects of ketamine and monoaminergic antidepressants that may explain the mechanisms of its rapid antidepressant action.

[Renalase and its role in the development of hypertension in patients with chronic renal failure]. / Renalaza i jej udzial w rozwoju nadcisnienia tetniczego u chorych z przewlekla niewydolnoscia nerek.

Renalase is a newly-discovered enzyme--amine oxidase containing flavin adenine dinucleotide that determines its activity. Kidneys are the main source of renalase, however, the enzyme has also been detected in the myocardium, skeletal muscles, small intestine, peripheral nerves, adrenal cortex and adipose tissue. This enzyme metabolizes circulating catecholamines, particularly epinephrine and L-3,4-dihydroxyphenylalanine (a dopamine precursor). For this reason, it is considered that renalase may play a significant role in the regulation of blood pressure. There are some factors enhancing the release of renalase: rising catecholamines levels in the circulation and increase in blood pressure. Experimental and clinical studies revealed renalase deficiency in chronic kidney disease (CKD) and hypertension. In contrast, the results of assays based on currently available ELISA kits demonstrate an increase in renalase concentration in patients with CKD. On the basis of currently available studies it is difficult to determine how important are changes in the expression and secretion of renalase in the pathogenesis of hypertension in CKD patients. Stimulation of catecholamines degradation, perhaps using recombinant renalase or its analogues, is a new concept in the treatment of hypertension in CKD.

Bronchial asthma control after argon plasma coagulation turbinectomy in patients with chronic rhinitis.

Bronchial asthma is frequently accompanied by chronic rhinitis. It has been observed that effective treatment of rhinitis may reduce asthma symptoms. The aim of the study was the evaluation of the control of bronchial asthma symptoms in patients with chronic rhinitis after argon plasma coagulation turbinectomy (APCt). The effect of APCt was assessed in 47 adults with drug-resistant chronic rhinitis and bronchial asthma 3-month post-procedure. Changes of asthma symptoms were scored using Asthma Control Test (ACT). Subjective improvement of nasal congestion 3 months after APCt was observed in 87% and of rhinorrhoea in 75% patients. Rhinomanometry showed 219 ± 19 cm³/s increase of flow and 0.75 ± 0.06 Pa/cm³/s reduction of resistance. The prevalence of patients with insufficient bronchial asthma control decreased from 79 to 4%. The decrease was associated with diminished frequency of eosinophils >20% in nasal cytology from 83% pre-procedure to 28% in the follow-up. The percentage of eosinophils >20% in cytology before APCt increased the chance for asthma control improvement by 22.8 times. Reduction in symptoms of drug-resistant rhinitis after APCt is followed by significant improvement of asthma control. The most beneficial therapeutic effects of APCt are noted in patients with a high rate of eosinophils in nasal cytology.

The Tumor Profiler Study: integrated, multi-omic, functional tumor profiling for clinical decision support.

The application and integration of molecular profiling technologies create novel opportunities for personalized medicine. Here, we introduce the Tumor Profiler Study, an observational trial combining a prospective diagnostic approach to assess the relevance of in-depth tumor profiling to support clinical decision-making with an exploratory approach to improve the biological understanding of the disease.

Relationship between plasma levels of sclerostin, calcium-phosphate disturbances, established markers of bone turnover, and inflammation in haemodialysis patients.

PURPOSE: Data concerning the relation between increased levels of circulating sclerostin (a physiological inhibitor of bone formation) and bone turnover in patients with chronic renal failure (CRF) are limited. Therefore, the aim of this study was to evaluate associations between plasma sclerostin levels and calcium-phosphate disturbances, markers of bone turnover as well as inflammation in haemodialysis (HD) patients. METHODS: In plasma samples obtained in 150 stable HD patients (92 men) aged 40-70 years, levels of sclerostin, fibroblast growth factor (cFGF23), osteocalcin, the N-terminal propeptide of type I procollagen, C-terminal telopeptide of the alpha chain of type I collagen (ß-CTx), and inflammatory markers (IL-6 and TNF-α) in addition to routine parameters (calcium, phosphorus, parathyroid hormone-iPTH, 25-OH-D, alkaline phosphatase) were measured. RESULTS: Plasma sclerostin concentrations were significantly higher in HD men than women (2.61 vs. 1.88 ng/mL, p < 0.01). Patients with sclerostin levels above median were characterized by lower iPTH and IL-6, but higher cFGF23 and TNF-α (significantly only in men) concentrations. Plasma sclerostin concentration positively correlated with serum 25-OH-D (τ = 0.204), phosphorus (τ = 0.1482), and TNF-α (τ = 0.183) and inversely with iPTH (τ = - 0.255), alkaline phosphatase (τ = - 0.203), IL-6 (τ =- 0.201), and ß-CTx (τ = - 0.099) levels. In multivariate regression analysis, variability of sclerostin levels was explained by sex and 25-OH-D and phosphorus levels. CONCLUSIONS: Increased circulating sclerostin levels seem to reflect slower bone turnover in HD patients. Low levels of sclerostin are associated with vitamin D deficiency and good phosphates alignment.

Calcaneal CT is a useful tool for identifying Achilles tendon disorders: a pilot study.

BACKGROUND: In various Achilles tendon disorders, little attention is paid to the bone environment at the tendon insertion sites. The aim of the present study was to assess the calcaneal bone structure in Achilles tendon disorders using computed tomography (CT). METHODS: This study included 31 male patients diagnosed with various Achilles disorders, including episodes of tendon rupture (TR), conservatively treated tendinopathy (TP), and critical-stage Achilles TP treated with endoscopic surgery (TS). CT scans of both feet were conducted to assess the calcaneal bone structure in the TP and TS groups, which comprised 23 patients. Bone measurements were calculated, including the bone volume-to-total volume ratio (BV/TV), cross-sectional area (CSA), product moment of area (Ipm), and polar section modulus (Zpol). RESULTS: The results demonstrated increased BV/TV, CSA, Ipm, and Zpol values in patients who underwent tendinoscopy and in patients with insertional TP. CONCLUSIONS: CT images are useful for evaluating calcaneal trabecular structural alterations in patients with Achilles pathology and correlate with the TP type.

Caudal Fossa Ratio in Normal Dogs and Eurasier Dogs with VLDLR-Associated Genetic Cerebellar Hypoplasia.

Cerebellar and hindbrain malformations, such as cerebellar hypoplasia (CH), vermis hypoplasia, and Dandy-Walker malformation, occur in dogs as well as in humans. Neuroimaging is essential for a precise description of these malformations and defining translational animal models. Neuroimaging is increasingly performed in puppies, but there is a lack of data on developmental changes in the caudal fossa, which can impair assessment of caudal fossa size in this age group. The purpose of this study was to validate caudal fossa ratio (CFR) in dogs and to explore CFR in Eurasier dogs with genetic CH. CFR was calculated from midsagittal brain images of 130 dogs as caudal fossa area/total cranial cavity area. In addition, the volume of the caudal fossa was measured in 64 randomly selected dogs from this group. Repeated measurements were used to investigate inter- and intra-rater variability and influence of imaging modality. Furthermore, the influence of age, weight, and breed was explored. The CFR was a reliable parameter with negligible influence from the examiners, imaging modality, and weight of the dog. The midsagittal area of the caudal fossa and the volume of the caudal fossa correlated closely with each other. In this study, we observed a smaller CFR in puppies. The CFR in adult dogs lies within 0.255 and 0.330, while CFR is smaller in puppies up to 4 months of age. Besides age, there was also an effect of breed, which should be explored in larger data sets. Measurements of CFR in Eurasier dogs with genetic CH caused by a mutation in the very-low-density-lipoprotein-receptor gene revealed the presence of two variants, one with an enlarged caudal fossa and one with a normal to small caudal fossa. This observation indicates that there is phenotypic heterogeneity and interaction between the developing cerebellum and the surrounding mesenchyme in this animal model.

Relationship between plasma levels of zonulin, bacterial lipopolysaccharides, D-lactate and markers of inflammation in haemodialysis patients.

BACKGROUND: Increased permeability of the intestinal wall and intestinal dysbiosis may contribute to chronic systemic inflammation, one of the causes of accelerated atherosclerosis and cardiovascular morbidity and mortality burden in patients with chronic kidney disease. The aim of this study was to evaluate the association between markers of intestinal permeability and inflammation in haemodialysis (HD) patients. METHODS: Plasma concentration of zonulin, haptoglobin, TNFα, IL6, D-lactates and bacterial lipopolysaccharides (LPS) was assessed in blood samples obtained after overnight fast before midweek morning HD session in 150 stable, prevalent HD patients. Daily intake of energy and macronutrients was assessed on the basis of a food frequency questionnaire. RESULTS: Serum hsCRP level was increased in over 70% of patients. Plasma levels of zonulin [11.6 (10.9-12.3) vs 6.8 (5.8-7.8) ng/mL], IL6 [6.2 (1.0-10.3) vs 1.3 (1.0-2.0) pg/mL] and TNFα [5.9 (2.9-11.8) vs 1.6 (1.3-1.8) pg/mL], but not LPS and D-lactates were significantly higher in HD than in healthy controls. D-lactates and LPS levels were weakly associated with IL6 (R = 0.175; p = 0.03, and R = 0.241; p = 0.003). There was a borderline correlation between plasma zonulin and serum hsCRP (R = 0.159; p = 0.07), but not with IL6, LPS and D-lactates. In multiple regression, both serum CRP and plasma IL6 variability were explained by LPS (ß = 0.143; p = 0.08 and ß = 0.171; p = 0.04, respectively), only. CONCLUSION: The weak association between plasma D-lactate, LPS and IL6 levels indicates that intestinal flora overgrowth or increased intestinal permeability contributes very slightly to the chronic inflammation development in HD patients.

Endogenous opioids regulate glucocorticoid-dependent stress-coping strategies in mice.

Coping skills are essential in determining the outcomes of aversive life events. Our research was aimed to elucidate the molecular underpinnings of different coping styles in two inbred mouse strains, C57BL/6J and SWR/J. We compared the influence of a preceding stressor (0.5h of restraint) on behavioral and gene expression profiles between these two strains. The C57BL/6J strain exhibited increased conditioned fear and high immobility (passive coping). Oppositely, the SWR/J mice demonstrated low freezing and immobility, low post-restraint anxiety and considerable struggling during the forced swim test (active coping). Gene profiling in the amygdala revealed transcriptional patterns that were related to the differential stress reactivity, such as the activation of glucocorticoid-dependent genes specifically in the C57BL/6J mice. Post-restraint blood sampling for corticosterone levels confirmed the association of hypothalamic-pituitary-adrenal (HPA) activation with a passive coping style. Pharmacological tools were used to modulate the stress-coping strategies. The blockade of opioid receptors (ORs) before the aversive event caused transcriptional and neuroendocrine changes in the SWR/J mice that were characteristic of the passive coping strategy. We found that treatment with a glucocorticoid receptor (GR) agonist (dexamethasone (DEX), 4mg/kg) impaired the consolidation of fear memory in the C57BL/6J mice and that this effect was reversed by OR blockade (naltrexone (NTX), 2mg/kg). In parallel, a glucocorticoid receptor antagonist (mifepristone (MIF), 20mg/kg) reversed the effect of morphine (20mg/kg) on conditioned fear in the C57BL/6J mice. Our results suggest that in mice, stress-coping strategies are determined by opioid-dependent mechanisms that modulate activity of the HPA axis.

Regulation of alternative gene transcription in the striatum in response to antidepressant drugs.

The mechanisms that control the selection of transcription initiation and termination sites in response to pharmacological stimulation of neuronal cells are poorly understood. We used next-generation sequencing and bioinformatics to construct a genome-wide inventory of protein-coding and non-coding transcripts altered by antidepressant treatment. We analyzed available ChIP-seq data to identify mechanisms that control drug-inducible expression of alternative gene variants in the brain. We identified 153 transcripts of various biotypes regulated in the mouse striatum in response to tranylcypromine or mianserin (at a 0.1% FDR threshold). Five drug-responsive gene patterns are enriched in protein-coding variants (77%), regulated by different sets of transcriptional factors (including SRF/CREB1 and GR/CTCF) and expressed in separate cellular compartments of the brain. We found that alterations mediated by proximal promoters in neurons are more specific in the selection of regulated transcriptional isoforms compared with enhancer-dependent alterations in glia. The change in transcriptional programs, from housekeeping to inducible, provides cells with the resource of functionally distinct proteins. We conclude that the regulation of drug-induced brain plasticity may occur at the level of transcripts rather than genes. The expression of specific isoforms in response to antidepressants may constitute a trigger that initiates the long-lasting effects of these drugs.

Plasma concentrations of tumor necrosis factor alpha may predict the outcome of patients with acute renal failure.

BACKGROUND/AIMS: Elevated plasma tumor necrosis factor-alpha (TNFalpha) concentration is frequently found in patients with chronic renal failure on hemodialysis (HD) and correlates with their mortality. The present study aimed to analyze the relationship between plasma TNFalpha concentrations and survival of patients with nonseptic acute renal failure (ARF). METHODS: Twenty-seven patients with ARF and 27 HD patients were examined. In ARF the patients' plasma TNFalpha concentrations were assessed 3 times: before the first HD session (phase I), 5 days later at the anuric/oliguric phase (phase II), and at the polyuric phase at discharge of the patients from the hospital (phase III). In 17 ARF patients kidney function recovered and 10 patients died in phase I. RESULTS: In ARF patients plasma TNFalpha concentration was markedly higher [70 pg/ml (37-275)] than reference values (<5 pg/ml) but significantly lower than in HD patients [216 pg/ml (18-350)]. Moreover, also plasma TNFalpha levels at the polyuric phase remained elevated. An initial plasma TNFalpha concentration in ARF patients lower than 70 pg/ml predicted the beneficial outcome with a sensitivity of 64.7% and a specificity of 70.0%. CONCLUSIONS: (1) Plasma TNFalpha concentration may predict the outcome in patients with ARF. (2) Plasma TNFalpha concentration remained elevated at the polyuric phase in ARF despite a marked improvement of excretory kidney function.