Effect of KEPI (Ppp1r14c) deletion on morphine analgesia and tolerance in mice of different genetic backgrounds: when a knockout is near a relevant quantitative trait locus.

We previously identified KEPI as a morphine-regulated gene using subtractive hybridization and differential display PCR. Upon phosphorylation by protein kinase C, KEPI becomes a powerful inhibitor of protein phosphatase 1. To gain insights into KEPI functions, we created KEPI knockout (KO) mice on mixed 129S6xC57BL/6 genetic backgrounds.

The 'timely' development of Rexin-G: first targeted injectable gene vector (review).

In an age where we can i) know precisely where a misplaced automobile resides by its global positioning, ii) send mechanistic probes to Mars with pinpoint accuracy, iii) calculate exactly how many mutations are required to create (i.e., to transform) a cancer cell, and iv) determine how many fewer genes it takes to develop a human being than it does a rice plant, it is difficult to fathom the previously unanswered question: 'Whatever happened to the promise and potential of cancer gene therapy?' This review answers that question with a resounding clinical dénouement.

Dopamine signaling is required for depolarization-induced slow current in cerebellar Purkinje cells.

Brief strong depolarization of cerebellar Purkinje cells produces a slow inward cation current. This current, called depolarization-induced slow current (DISC), is triggered by Ca influx in the Purkinje cell and is attenuated by a blocker of vesicular fusion. Previous work in other brain regions, such as the substantia nigra and ventral tegmental area, has shown that dopamine can be released from dendrites to produce paracrine and autocrine signaling.

Phase I/II and phase II studies of targeted gene delivery in vivo: intravenous Rexin-G for chemotherapy-resistant sarcoma and osteosarcoma.

Rexin-G, a pathotropic nanoparticle bearing a cytocidal cyclin G1 construct was tested in a phase I/II study for chemotherapy-resistant sarcomas and a phase II study for chemotherapy-resistant osteosarcoma. Twenty sarcoma patients and 22 osteosarcoma patients received escalating doses of Rexin-G intravenously from 8 x 10(11) to 24 x 10(11) colony forming units (cfu)/cycle. Treatment was continued if there was View Article and Find Full Text PDF

Cocaine-conditioned locomotion in dopamine transporter, norepinephrine transporter and 5-HT transporter knockout mice.

The behavioral effects of cocaine are affected by gene knockout (KO) of the dopamine transporter (DAT), the serotonin transporter (SERT) and the norepinephrine transporter (NET). The relative involvement of each of these transporters varies depending on the particular behavioral response to cocaine considered, as well as on other factors such as genetic background of the subjects. Interestingly, the effects of these gene knockouts on cocaine-induced locomotion are quite different from those on reward assessed in the conditioned place preference paradigm.

[Psychopharmacological combination therapy in bipolar disorder].

In the course of time, the treatment regime of bipolar disorder has changed: in mild cases of manic and depressive episodes, monotherapeutic approaches are still commonly used. Besides the use of the common agents like lithium, valproatic acid and carbamazepine, other agents such as atypical antipsychotics (AAP) are used more frequently. For the therapy of manic episodes, most of the usual AAP are approved; some of them are or will be approved in the near future even for the continuation therapy and for depressive episodes.

Differential involvement of the norepinephrine, serotonin and dopamine reuptake transporter proteins in cocaine-induced taste aversion.

Despite the impact of cocaine's aversive effects on its abuse potential, the neurochemical basis of these aversive effects remains poorly understood. By blocking the reuptake of the monoamine neurotransmitters dopamine (DA), norepinephrine (NE) and serotonin (5-HT) into the presynaptic terminal, cocaine acts as a potent indirect agonist of each of these systems. The following studies attempted to assess the extent of monoaminergic mediation of cocaine's aversive effects using conditioned taste aversion (CTA) learning [Garcia, J.

Dramatically decreased cocaine self-administration in dopamine but not serotonin transporter knock-out mice.

There has been much interest in the relative importance of dopamine and serotonin transporters in the abuse-related-effects of cocaine. We tested the hypotheses that mice lacking the dopamine transporter (DAT(-/-)), the serotonin transporter (SERT(-/-)), or both (DAT(-/-)SERT(-/-)) exhibit decreased reinforcing effects of cocaine. We also assessed whether observed effects on self-administration are specific to cocaine or if operant behavior maintained by food or a direct dopamine agonist are similarly affected.

Sigma1 receptor antagonists determine the behavioral pattern of the methamphetamine-induced stereotypy in mice.

Objective: The effects of sigma receptor antagonists on methamphetamine (METH)-induced stereotypy have not been examined. We examined the effects of sigma antagonists on METH-induced stereotypy in mice.

Results: The administration of METH (10 mg/kg) to male ddY mice induced stereotyped behavior consisting of biting (90.

Targeting metastatic cancer from the inside: a new generation of targeted gene delivery vectors enables personalized cancer vaccination in situ.

The advent of pathotropic (disease-seeking) targeting technologies, combined with advanced gene delivery vectors, provides a unique opportunity for the systemic delivery of immunomodulatory cytokine genes to remote sites of cancer metastasis. When injected intravenously, such pathotropic nanoparticles seek out and accumulate selectively at sites of tumor invasion and neo-angiogenesis, resulting in enhanced gene delivery, and thus cytokine production, within the tumor nodules. Used in conjunction with a primary tumoricidal agent (e.

Animal models of depression in dopamine, serotonin, and norepinephrine transporter knockout mice: prominent effects of dopamine transporter deletions.

Antidepressant drugs produce therapeutic actions and many of their side effects via blockade of the plasma membrane transporters for serotonin (SERT/SLC6A2), norepinephrine (NET/SLC6A1), and dopamine (DAT/SLC6A3). Many antidepressants block several of these transporters; some are more selective. Mouse gene knockouts of these transporters provide interesting models for possible effects of chronic antidepressant treatments.

Comparison of outcomes in patients undergoing defibrillation threshold testing at the time of implantable cardioverter-defibrillator implantation versus no defibrillation threshold testing.

Background: Inability to perform defibrillation threshold (DFT) testing during implantable cardioverter defibrillator (ICD) implantation due to co-morbidities may influence long-term survival.

Methods: Retrospective review at The University of Michigan (1999-2004) identified 55 patients undergoing ICD implantation without DFT testing ("No-DFT group"). A randomly selected sample of patients (n = 57) undergoing standard DFT testing ("DFT group") was compared in terms of appropriate shocks, clinical shock efficacy and all-cause mortality.

Risk factors for well-differentiated thyroid carcinoma in patients with thyroid nodular disease.

Objectives: Evaluate current accepted risk factors for well-differentiated thyroid carcinoma, and develop a predictive model to determine one's risk of malignancy given a thyroid nodule.

Study Design: Retrospective analysis of 600 patients.

Subjects And Methods: Patients with benign thyroid nodular disease and with well-differentiated thyroid cancer were randomly selected.

Inducible nitric oxide synthase activity is increased in patients with rheumatoid arthritis and contributes to endothelial dysfunction.

Background: Recent in vitro studies suggest that inducible nitric oxide synthase (iNOS) activity mediates endothelial dysfunction. Rheumatoid arthritis (RA) is a chronic inflammatory condition and is associated with endothelial dysfunction and increased risk of cardiovascular disease. The aim of the study was to establish the contribution of iNOS to endothelial function.