High motivation for exercise is associated with altered chromatin regulators of monoamine receptor gene expression in the striatum of selectively bred mice.

Although exercise is critical for health, many lack the motivation to exercise, and it is unclear how motivation might be increased. To uncover the molecular underpinnings of increased motivation for exercise, we analyzed the transcriptome of the striatum in four mouse lines selectively bred for high voluntary wheel running and four non-selected control lines. The striatum was dissected and RNA was extracted and sequenced from four individuals of each line. We found multiple genes and gene systems with strong relationships to both selection and running history over the previous 6 days. Among these genes were Htr1b, a serotonin receptor subunit and Slc38a2, a marker for both glutamatergic and γ-aminobutyric acid (GABA)-ergic signaling. System analysis of the raw results found enrichment of transcriptional regulation and kinase genes. Further, we identified a splice variant affecting the Wnt-related Golgi signaling gene Tmed5. Using coexpression network analysis, we found a cluster of interrelated coexpression modules with relationships to running behavior. From these modules, we built a network correlated with running that predicts a mechanistic relationship between transcriptional regulation by nucleosome structure and Htr1b expression. The Library of Integrated Network-Based Cellular Signatures identified the protein kinase C δ inhibitor, rottlerin, the tyrosine kinase inhibitor, Linifanib and the delta-opioid receptor antagonist 7-benzylidenenaltrexone as potential compounds for increasing the motivation to run. Taken together, our findings support a neurobiological framework of exercise motivation where chromatin state leads to differences in dopamine signaling through modulation of both the primary neurotransmitters glutamate and GABA, and by neuromodulators such as serotonin.

Evaluation of a C57BL/6J × 129S1/SvImJ Hybrid Nestin-Thymidine Kinase Transgenic Mouse Model for Studying the Functional Significance of Exercise-Induced Adult Hippocampal Neurogenesis.

New neurons are continuously generated in the adult hippocampus but their function remains a mystery. The nestin thymidine kinase (nestin-TK) transgenic method has been used for selective and conditional reduction of neurogenesis for the purpose of testing the functional significance of new neurons in learning, memory and motor performance. Here we explored the nestin-TK model on a hybrid genetic background (to increase heterozygosity, and "hybrid vigor"). Transgenic C57BL/6J (B6) were crossed with 129S1/SvImJ (129) producing hybrid offspring (F1) with the B6 half of the genome carrying a herpes simplex virus thymidine kinase (TK) transgene regulated by a modified nestin promoter. In the presence of exogenously administered valganciclovir, new neurons expressing TK undergo apoptosis. Female B6 nestin-TK mice (n = 80) were evaluated for neurogenesis reduction as a positive control. Male and female F1 nestin-TK mice (n = 223) were used to determine the impact of neurogenesis reduction on the Morris water maze (MWM) and rotarod. All mice received BrdU injections to label dividing cells and either valganciclovir or control chow, with or without a running wheel for 30 days. Both the F1 and B6 background displayed approximately 50% reduction in neurogenesis, a difference that did not impair learning and memory on the MWM or rotarod performance. Running enhanced neurogenesis and performance on the rotarod but not MWM suggesting the F1 background may not be suitable for studying pro-cognitive effects of exercise on MWM. Greater reduction of neurogenesis may be required to observe behavioral impacts. Alternatively, new neurons may not play a critical role in learning, or compensatory mechanisms in pre-existing neurons could have masked the deficits. Further work using these and other models for selectively reducing neurogenesis are needed to establish the functional significance of adult hippocampal neurogenesis in behavior.

Chronic D-amphetamine administered from childhood to adulthood dose-dependently increases the survival of new neurons in the hippocampus of male C57BL/6J mice.

Adderall is widely prescribed for attention deficit hyperactivity disorder (ADHD) though long term neurological effects of the main ingredient d-amphetamine are not well understood. The purpose of this study was to examine effects of clinically prescribed doses of d-amphetamine and one abuse dose administered from childhood to adulthood on adult hippocampal neurogenesis and activation of the granule layer of the dentate gyrus. Beginning in early adolescence (age 28 days) to adulthood (age 71), male C57BL/6J mice were administered twice daily i.p. injections of vehicle, 0.25, 0.5 or 2mg/kg d-amphetamine. Locomotor activity was measured in home cages by video tracking. At age 53-56, mice received bromodeoxyuridine (BrdU) injections to label dividing cells. Immunohistochemical detection of BrdU, neuronal nuclear protein (NeuN), doublecortin (DCX) and Ki67 was used to measure neurogenesis and cell proliferation at age 71. ΔFosB was measured as an indicator of repeated neuronal activation. An additional cohort of mice was treated similarly except euthanized at age 58 to measure activation of granule neurons from d-amphetamine (by detection of c-Fos) and cell proliferation (Ki67) at a time when the fate of BrdU cells would have been determined in the first cohort. d-Amphetamine dose-dependently increased survival and differentiation of BrdU cells into neurons and increased number of DCX cells without affecting the number of Ki67 cells. Low doses of d-amphetamine decreased c-Fos and ΔFosB in the granule layer. Only the high dose induced substantial locomotor stimulation and sensitization. Results suggest both therapeutic and abuse doses of d-amphetamine increase the number of new neurons in the hippocampus when administered from adolescence to adulthood by increasing survival and differentiation of cells into neurons not by increasing progenitor cell proliferation. Mechanisms for amphetamine-induced neurogenesis are unknown but appear activity independent. Results suggest part of the beneficial effects of therapeutic doses of d-amphetamine for ADHD could be via increased hippocampal neurogenesis.

[Morbus Weil - a case study and principles]. / Morbus Weil - kazuistika a princípy.

We present a case of a 66 years old man without significant medical history who was admitted to a geriatric department of a local hospital for a critical clinical state with severe icterus (billirubin 368 µmol/l), acute renal failure (urea 48 mmol/l, creatinine 714 µmol/l) and severe thrombocytopaenia. When the patients son completed his personal history on the 4th day of hospitalization reporting that the patient had worked in a pub flooded during local floods, we also considered leptospirosis as a potential cause of his current state. Parenteral penicillin antibiotics (amoxicillin + clavulanate) were prescribed and comprehensive infusion rehydration, corrective and haemostyptic treatments were continued. Despite transient worsening of thrombocytopaenia to 8 × 103/µl, we did not observe any severe bleeding, thrombocytopaenia gradually improved and thrombocyte levels were in the reference range from the 7th day of hospitalization. Acute renal failure (ARF) did not involve oliguria and an intensive conservative treatment provided gradual improvement of the clinical status as well as laboratory parameters with creatinine levels at discharge of 121.3 µmol/l. Heamodialysis was not used. Billirubin levels also gradually declined to 25 µmol/l at discharge. Leptospiral antibodies in the urine and serum were suggestive of leptospirosis. The diagnosis was confirmed with follow up investigations 13 days after discharge. The condition was caused by Leptospira icterohaemorrhagiae. The patients condition was complicated with deterioration of pre-existing hearing impairment. We also expect a contribution of leptospirosis to its anamnesis. Antibiotic treatment continued for 16 day, 7 of which with parenteral administration. Haemodynamically stable, normotensive, afebrile, self-sufficient patient was discharged on 37th day of hospitalization to primary care.

[A case of a flapping infected thrombus in the internal jugular vein, septic pneumonias and heparin-induced thrombocytopaenia]. / Prípad vlajúceho infikovaného trombu v. jugularis interna, septických pneumónií a heparínom indukovanej trombocytopénie.

We present a case of a 54 years old female patient after anterior wall left ventricular myocardial infarction in 2005 who underwent coronary artery bypass graft (CABG) surgery requiring cannulation of the right internal jugular vein (IJV). She was admitted to a Department of Pulmonary Diseases with left bronchopneumonia (BPN) following 7 day treatment, with hemoptysis, dyspnoea and fevers. Duplex ultrasound (DUS) was used to diagnose flapping thrombus in the right IJV, severe thrombocytopenia and, in addition, progressing multiple infiltrates on X-ray a few days later. We empirically adjusted the treatment initiated in primary care and observed deterioration of the severe thrombocytopenia during treatment with low molecular weight heparine. We diagnosed heparin-induced thrombocytopenia (HIT) and, even though this indication was not included in our drug formulary, we initiated treatment with Arixtra (fondaparinux) 2.5 mg s.c. daily. Intensive conservative treatment was associated with significant clinical and laboratory improvement of the condition, significant regression of the IJV thrombus as well as the finding on X-ray. The final effective antibiotic treatment lasted 20 (amoxicillin + clavulanate) and 10 (clindamycin) days, respectively. Treatment with Arixtra (fondaparinux) continued in primary care and lasted a total of 65 days until normal thrombocyte levels were achieved, with gradual transition to oral anticoagulation treatment. The patient was discharged to primary care on the 23rd day of hospitalization when she was stabilized, a febrile and her cardiopulmonary functions were compensated. We did not identify any case of treatment of jugular thrombosis and concurrent HIT with fondaparin anywhere in the international literature.

Valproic acid inhibits proliferation and induces apoptosis in acute myeloid leukemia cells expressing P-gp and MRP1.

The multidrug resistance (MDR) phenotype, induced by the overexpression of several ABC transporters or by antiapoptotic mechanisms, has been identified as the major cause of drug resistance in the treatment of patients with acute myeloid leukemia (AML). In this study, we have shown that valproic acid (VPA) (a histone deacetylase inhibitor) can inhibit the proliferation of both P-glycoprotein (P-gp)- and MDR-associated protein 1 (MRP1)-positive and -negative cells. VPA also induced apoptosis of P-gp-positive cells. VPA induced apoptosis in K562 cells led to decrease in Flip (FLICE/caspase-8 inhibitory protein) expression with Flip cleavage, which could not be observed in HL60 cells. In HL60/MRP cell line, which proved to be resistant to apoptosis by VPA, we observed an abnormal expression of apoptotic regulatory proteins, overexpression of Bcl-2 and absence of Bax. Also, the Bcl-2 antagonist HA14-1 rapidly restored apoptosis in this cell line. Cotreatment with cytosine arabinoside induced very strong apoptosis in both K562/DOX and HL60/DNR cell lines. VPA also induced apoptosis in AML patient cells expressing P-gp and/or MRP1. Our findings show VPA as an interesting drug that should be tested in clinical trials for overcoming the MDR phenotype in AML patients.