Clinically Relevant Interactions with Anti-Infectives on Intensive Care Units-A Multicenter Delphi Study.

Patients in intensive care units (ICUs) are at high risk of drug-drug interactions (DDIs) due to polypharmacy. Little is known about type and frequency of DDIs within German ICUs. Clinical pharmacists' interventions (PI) recorded in a national database (ADKA-DokuPIK) were filtered for ICU patients. Binary DDIs involving ≥1 anti-infective agent with >1 database entry were selected. A modified two-step Delphi process with a group of senior hospital pharmacists was employed to evaluate selected DDIs for clinical relevance by using a five-point scale and to develop guidance for clinical practice. In total, 16,173 PI were recorded, including 1836 (11%) DDIs in the ICU setting. Of the latter, 41% (756/1836) included ≥1 anti-infective agent, 32% (590/1836) were binary DDIs, and 25% (455/1836) were listed at least twice. This translates into 88 different DDIs, 74% (65/88) of which were rated as being clinically relevant by our expert panel. The majority of DDIs (76% [67/88]) included macrolides, antifungals, or fluoroquinolones. This percentage was even higher in DDIs being rated as clinically relevant by the experts (85% [55/65]). It is noted that an inter-professional discussion and approach is needed in the individual patient management of DDIs. The guidance developed might be a tool for decision support.

Modulating endothelial adhesion and migration impacts stem cell therapies efficacy.

BACKGROUND: Limited knowledge of stem cell therapies` mechanisms of action hampers their sustainable implementation into the clinic. Specifically, the interactions of transplanted stem cells with the host vasculature and its implications for their therapeutic efficacy are not elucidated. We tested whether adhesion receptors and chemokine receptors on stem cells can be functionally modulated, and consequently if such modulation may substantially affect therapeutically relevant stem cell interactions with the host endothelium. METHODS: We investigated the effects of cationic molecule polyethylenimine (PEI) treatment with or without nanoparticles on the functions of adhesion receptors and chemokine receptors of human bone marrow-derived Mesenchymal Stem Cells (MSC). Analyses included MSC functions in vitro, as well as homing and therapeutic efficacy in rodent models of central nervous system´s pathologies in vivo. FINDINGS: PEI treatment did not affect viability, immunomodulation or differentiation potential of MSC, but increased the CCR4 expression and functionally blocked their adhesion receptors, thus decreasing their adhesion capacity in vitro. Intravenously applied in a rat model of brain injury, the homing rate of PEI-MSC in the brain was highly increased with decreased numbers of adherent PEI-MSC in the lung vasculature. Moreover, in comparison to untreated MSC, PEI-MSC featured increased tumour directed migration in a mouse glioblastoma model, and superior therapeutic efficacy in a murine model of stroke. INTERPRETATION: Balanced stem cell adhesion and migration in different parts of the vasculature and tissues together with the local microenvironment impacts their therapeutic efficacy. FUNDING: Robert Bosch Stiftung, IZEPHA grant, EU grant 7 FP Health.

[Lyme-Arthritis--a case report]. / Lyme-Arthritis--ein Fallbeispiel.

Lyme disease is a serious infectious disease which, if untreated, does not recover and leads to further complications that might be severe. This exemplary case report describes a possible secondary Borrelia infection. It underlines that early antibiotic therapy in the correct dosage is essential. Furthermore, problems are discussed that might occur in context of the decision process concerning the best antibiotic substance and the optimal application route. Last but not least, possible problems associated with the discharge from hospital are discussed. In conclusion, early diagnosis together with an on-time optimal antibiotic therapy are fundamental in the clinical management of Lyme disease.

[Clostridium difficile infection - an update]. / Therapie der Clostridium-difficile- assoziierten Infektion - was gibt es Neues?

Clostridium difficile infection represents a severe illness which very often results in emergency surgery, intensive care unit stay or death. Although standard treatment procedures are well known and seem to be sufficient at the first glance, there is need for improvement of therapy guidelines due to high rates of recurrences or treatment failures. This article suggests some adjustments so far without claiming to be a complete review of all new development in this area. On the one hand, the recent actualization of the European guideline has been taken as a basis of this report; on the other hand some new highly promising developments in the treatment of CDI are exemplarily reported. Possibly the development with the highest impact in literature is fecal transplantation (or better said microbiome instillation). However, standard therapies need some critical review as well: an upgrading of vancomycin to first-line therapy and with a higher daily dose (250 mg qid) might be beneficial for many patients. For severe CDI, there is a recommendation against the usage of metronidazole, since vancomycin represents a better alternative. The dosage ofvancomycin might be further increased: although some authors are precautious in this point, dosage of vancomycin 500 mg qid should be favored. Last but not least, the pipeline bears some good tools for treatment of recurrent and complicated CDI, first data are promising and we hope for more.

MDMA modulates spontaneous firing of subthalamic nucleus neurons in vitro.

3,4-Methylene-dioxy-N-methylamphetamine (MDMA, 'ecstasy') has a broad spectrum of molecular targets in the brain, among them receptors and transporters of the serotonergic (5-hydroxytryptamine, 5-HT) and noradrenergic systems. Its action on the serotonergic system modulates motor systems in rodents and humans. Although parts of the basal ganglia could be identified as mediators of the motor effects of MDMA, very little is known about the role of the subthalamic nucleus (STN). Therefore, this study investigated the modulation of spontaneous action potential activity of the STN by MDMA (2.5-20 µM) in vitro. MDMA had very heterogeneous effects, ranging from a complete but reversible inhibition to a more than twofold increase in firing at 5 µM. On average, MDMA excited STN neurons moderately, but lost its excitatory effect in the presence of the 5-HT(2A) antagonist MDL 11,939. 5-HT(1A) receptors did not appear to play a major role. Effects of MDMA on transporters for serotonin (SERT) and norepinephrine (NET) were investigated by coapplication of the reuptake inhibitors citalopram and desipramine, respectively. Similar to the effects of 5-HT(2A) receptor blockade, antagonism of SERT and NET bestowed an inhibitory effect on MDMA. From these results, we conclude that both the 5-HT and the noradrenergic system mediate MDMA-induced effects on STN neurons.

[Management of bleeding complications associated with NOAC]. / Management von NOAK-assoziierten Blutungen.

New oral anticoagulant drugs (NOAC) represent a promising alternative to the classical anticoagulant therapy with vitamin K antagonists like phenprocoumon or warfarin. Meanwhile, these substances are well implemented in the management of several indications with elevated thromboembolic risk, e.g. atrial fibrillation. Nevertheless, it is not easy to use these substances and even in the phase III studies side effects of significant bleeding occurred. Thus, patients should be closely monitored for signs of bleeding or anaemia. In the clinical setting, the therapists meet the challenge to primarily ensure a sufficient anticoagulation but to concomitantly avoid any occurrence of a serious bleeding complication. However, this optimum is not reached in many cases: Patients frequently present with relevant bleeding or a serious bleeding occurs in surgery. This article presents a short overview of possible actions to manage such a bleeding complication.

Chronic co-administration of the cannabinoid receptor agonist WIN55,212-2 during puberty or adulthood reverses 3,4 methylenedioxymetamphetamine (MDMA)-induced deficits in recognition memory but not in effort-based decision making.

Cannabis and 3,4 methylenedioxymetamphetamine (MDMA, "ecstasy") are the most frequently combined illegal drugs among young adults in western societies. This study examined the effects of chronic co-administration of the cannabinoid receptor agonist WIN55,212-2 (WIN) and MDMA on working memory and effort-based decision making in rats. Treatment consisted of MDMA (7.5 mg/kg), WIN (1.2 mg/kg), a combination of these substances (MDMA+WIN) or vehicle over a period of 25 days during puberty (PD40-65) or adulthood (PD80-105). Ten days after the last treatment, WIN reversed MDMA-induced working memory deficits in the object recognition test in animals treated during adulthood or puberty, but had no influence on impairment of adult rats in the effort-based T-maze task. No differences were observed between groups of pubertally treated rats in the decision making task. During a subsequent acute drug challenge MDMA and MDMA+WIN decreased high reward choices in both age groups, indicating MDMA-induced cost-aversive choice. Differential long-term interactions on the neuronal level in the hippocampus and MDMA-induced disturbances in cortico-limbic connections are suggested.

Is behavioral sensitization to 3,4-methylenedioxymethamphetamine (MDMA) mediated in part by cholinergic receptors?

Behavioral sensitization to the repeated administration of a psychostimulant presumably plays a key role in the pathogenesis of addiction and schizophrenia. Among other psychostimulants, 3,4-methylenedioxymethamphetamine (MDMA) is known to produce behavioral sensitization, too, but its mechanism of action is still not fully understood. Along with the strong release of catecholamines and serotonin, MDMA exerts actions at additional transmitter systems, including acetylcholine (ACh). To identify the cholinergic involvement in the development and expression of MDMA-induced sensitization, rats were treated daily with MDMA (5.0 mg/kg), MDMA plus the muscarinic antagonist atropine (4.28 mg/kg), or MDMA plus the nicotinic antagonist mecamylamine (1.0 mg/kg) for 13 consecutive days. The results show that atropine co-treatment was able to block the development of behavioral sensitization to MDMA, measured as horizontal activity and rearing, whereas mecamylamine did not. Pharmacological challenge with MDMA alone increased the locomotion in all substance pretreated groups with the MDMA plus atropine group showing the lowest values. The second challenge with MDMA plus atropine showed a decrease in locomotor behavior in the MDMA- and an increase in the MDMA plus atropine pretreated groups, resulting in similar levels of activity for both groups. A control experiment revealed no change in horizontal activity and rearing when only the cholinergic antagonists (atropine; mecamylamine) were administered. This is the first study that shows a substantial role of muscarinic receptors for the development of behavioral sensitization to MDMA.

Short- and long-term unilateral 6-hydroxydopamine lesions in rats show different changes in characteristics of spontaneous firing of substantia nigra pars reticulata neurons.

The unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle induces hemiparkinsonism in rats and is a well established animal model of Parkinson's disease. In this study, we assessed the spontaneous activity of substantia nigra pars reticulata (SNr) neurons in unilateral 6-OHDA- or sham-treated rats. Extracellular single cell recordings revealed a bilaterally decreased firing rate in short-term 6-OHDA-lesioned rats (8-10 weeks post lesion) while no rate differences were evident in long-term lesioned animals (5-8 months post lesion) in vivo under chloral hydrate anaesthesia. However, firing pattern of the SNr neurons (indicated by interspike interval (ISI) histogram parameters: coefficient of variation, skewness and kurtosis) was significantly altered only after long-term lesion: 53.8 % of the recorded cells in the ipsilateral 6-OHDA-lesioned SNr fired in a bursting pattern (compared to 5.9-16.7 % in contralateral SNr or sham controls). Additionally, behavioural effects of the lesion were assessed 4 weeks post lesion by the forelimb adjusting stepping test. A decreased number of adjusting steps with the contralateral forepaw, as well as an increased performance with the ipsilateral paw was found for the 6-OHDA-lesioned rats as compared to sham controls. Furthermore, stepping values were negatively correlated with the ISI parameters after long-term lesion, while there were no correlations with the short-term groups. Firing rate was not correlated regardless of the time frame. In conclusion, long-term changes in firing pattern may represent a neuronal correlate of the 6-OHDA-induced hemiparkinsonism and may be useful for the interpretation of 6-OHDA-induced motor deficits and compensatory mechanisms as well.

Imaging DA release in a rat model of L-DOPA-induced dyskinesias: a longitudinal in vivo PET investigation of the antidyskinetic effect of MDMA.

In the context of Parkinson's disease, motor symptoms result from the degeneration of nigrostriatal neurons. Dopamine (DA) replacement using l-3,4-dihydroxyphenylalanine (L-DOPA) has been the treatment of choice in the early stages of the disease. However, with disease progression, patients suffer from motor complications, which have been suggested to arise from DA released from serotonergic terminals according to the false neurotransmitter hypothesis. The synthetic amphetamine derivative (±) 3,4-methylenedioxymethamphetamine (MDMA) has been shown to significantly inhibit dyskinesia in humans and in animal models of PD. In this study, we examined the effect of MDMA on L-DOPA-induced DA release by using [(11)C]raclopride kinetic modeling to assess alterations in DA neurotransmission in a rat model of L-DOPA-induced dyskinesia (LID) in a longitudinal in vivo PET study. Rats were submitted to 6-OHDA lesions, and the lesions were confirmed to be sufficiently severe based on the performance during stepping tests and [(11)C]methylphenidate PET scans. The rats underwent two [(11)C]raclopride PET sessions before (baseline) and after two weeks of chronic L-DOPA treatment (priming). L-DOPA priming led to strong abnormal involuntary movements (AIMs). In group 1, L-DOPA priming reduced L-DOPA-induced DA release in the lesioned striatum with no effect on the healthy side, while the concomitant administration of L-DOPA and MDMA (group 2) increased the DA levels in the lesioned and healthy striatum. In addition, behavioral analysis, which was performed two weeks after the second PET session, confirmed the antidyskinetic effect of MDMA. Our data show that L-DOPA-induced DA release is attenuated in the Parkinsonian striatum after chronic L-DOPA pretreatment and that the antidyskinetic mechanism of MDMA does not depend primarily on dopaminergic neurotransmission.

6-Hydroxydopamine leads to T2 hyperintensity, decreased claudin-3 immunoreactivity and altered aquaporin 4 expression in the striatum.

The neurotoxin 6-hydroxydopamine (6-OHDA) is frequently used in animal models to mimic Parkinson's disease. Imaging studies describe hyperintense signalling in regions close to the site of the 6-OHDA injection in T2-weighted (T2w) magnetic resonance imaging (MRI). The nature of this hyperintense signal remains elusive and still is matter of discussion. Here we demonstrate hyperintense signalling in T2w MRI and decreased apparent diffusion coefficient (ADC) values following intraventricular injection of 6-OHDA. Moreover, we show decreased GFAP immunoreactivity in brain regions corresponding to the region revealing the hyperintense signalling, probably indicating a loss of astrocytes due to a toxic effect of 6-OHDA. In the striatum, where no hyperintense signalling in MRI was observed following intraventricular 6-OHDA injection, immunohistochemical and molecular analyses revealed an altered expression of the water channel aquaporin 4 and the emergence of vasogenic edema, indicated by an increased perivascular space. Moreover, a significant decrease of claudin-3 immunoreactivity was observed, implying alterations in the blood brain barrier. These findings indicate that intraventricular injection of 6-OHDA results (1) in effects close to the ventricles that can be detected as hyperintense signalling in T2w MRI accompanied by reduced ADC values and (2) in effects on brain regions not adjacent to the ventricles, where a disturbance of water homeostasis occurs. We clearly demonstrate that 6-OHDA leads to brain edema that in turn may affect the overall results of experiments (e.g. behavioral alterations). Therefore, when using 6-OHDA in Parkinson's models effects that are not mediated by degeneration of catecholaminergic neurons have to be considered.

In vivo quantification of dopamine transporters in mice with unilateral 6-OHDA lesions using [11C]methylphenidate and PET.

UNLABELLED: Quantification of the binding of [11C]methylphenidate to the dopamine transporter (DAT) using positron emission tomography (PET) is often used to evaluate the integrity of dopaminergic neurons in the striatal regions of the brain. Over the past decade, many genetically engineered mouse models of human disease have been developed and have become particularly useful for the study of disease onset and progression over time. Quantitative imaging of small structures such as the mouse brain is especially challenging. Thus, the aims of this study were (1) to evaluate the accuracy of quantifying DAT binding using in vivo PET and (2) to examine the impact of different methodologies. METHODS: Eight mice were scanned with [11C]methylphenidate under true or transient equilibrium conditions using a bolus and constant infusion protocol or a bolus injection protocol to evaluate the accuracy of the Logan graphical approach for [11C]methylphenidate imaging in mice. Displacement with unlabeled methylphenidate (0.1, 3 and 10 mg/kg) was used to verify specific binding. In a second experiment, 30 mice were lesioned by injection of 6-hydroxydopamine (6-OHDA) at doses of 0, 2 or 4 µg (n=10) into the right striatum to assess the dose-dependent correlation between the PET signal and dopaminergic degeneration. In addition, we performed test-retest experiments and used ex vivo autoradiography (AR) to validate the effect of partial volume on the accuracy of the [11C]methylphenidate PET quantification in the mouse striatum. RESULTS: The binding potentials (BPND) calculated from the Logan graphical analysis under transient equilibrium conditions (1.03±0.1) were in excellent agreement with those calculated at true equilibrium (1.07±0.1). Displacement of specific binding with 0.1, 3 and 10mg/kg methylphenidate resulted in 38%, 77% and 81% transporter occupancy in the striatum. Intra-striatal injections of 6-OHDA caused a dose-dependent decrease in the specific binding of [11C]methylphenidate to the DAT in the striatum. The BPND was reduced by 49% and 61% after injection with 2 and 4 µg of 6-OHDA, respectively. The test-retest reproducibility was 6% in the healthy striatum and 27% in the lesioned striatum. In addition, only a small (15%) difference was found between the [11C]methylphenidate DVR-1 values determined by PET and AR on the healthy side, and no differences were observed on the lesioned side. CONCLUSION: The present work demonstrates for the first time that [11C]methylphenidate PET is useful for the quantification of striatal dopamine transporters at the dopaminergic nerve terminals in the mouse striatum; therefore, this marker may be used as a biomarker in genetically engineered mouse models of neurodegenerative disorders. However, only changes resulting in greater than 10% differences in BPND values can reliably be detected in vivo.

Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease.

Safe and effective cell delivery remains one of the main challenges in cell-based therapy of neurodegenerative disorders. Graft survival, sufficient enrichment of therapeutic cells in the brain, and avoidance of their distribution throughout the peripheral organs are greatly influenced by the method of delivery. Here we demonstrate for the first time noninvasive intranasal (IN) delivery of mesenchymal stem cells (MSCs) to the brains of unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. IN application (INA) of MSCs resulted in the appearance of cells in the olfactory bulb, cortex, hippocampus, striatum, cerebellum, brainstem, and spinal cord. Out of 1 × 106 MSCs applied intranasally, 24% survived for at least 4.5 months in the brains of 6-OHDA rats as assessed by quantification of enhanced green fluorescent protein (EGFP) DNA. Quantification of proliferating cell nuclear antigen-positive EGFP-MSCs showed that 3% of applied MSCs were proliferative 4.5 months after application. INA of MSCs increased the tyrosine hydroxylase level in the lesioned ipsilateral striatum and substantia nigra, and completely eliminated the 6-OHDA-induced increase in terminal deoxynucleotidyl transferase (TdT)-mediated 2'-deoxyuridine, 5'-triphosphate (dUTP)-biotin nick end labeling (TUNEL) staining of these areas. INA of EGFP-labeled MSCs prevented any decrease in the dopamine level in the lesioned hemisphere, whereas the lesioned side of the control animals revealed significantly lower levels of dopamine 4.5 months after 6-OHDA treatment. Behavioral analyses revealed significant and substantial improvement of motor function of the Parkinsonian forepaw to up to 68% of the normal value 40-110 days after INA of 1 × 106 cells. MSC-INA decreased the concentrations of inflammatory cytokines-interleukin-1ß (IL-1ß), IL-2, -6, -12, tumor necrosis factor (TNF), interferon-γ (IFN-γ, and granulocyte-macrophage colony-stimulating factor (GM-CSF)-in the lesioned side to their levels in the intact hemisphere. IN administration provides a highly promising noninvasive alternative to the traumatic surgical procedure of transplantation and allows targeted delivery of cells to the brain with the option of chronic application.

Effect of 6-hydroxydopamine (6-OHDA) on proliferation of glial cells in the rat cortex and striatum: evidence for de-differentiation of resident astrocytes.

Reactive astrogliosis is the universal response to any brain insult. It is characterized by cellular hypertrophy, up-regulation of the astrocyte marker glial fibrillary acidic protein (GFAP), and proliferation. The source of these proliferating cells is under intense debate. Progenitor cells derived from the subventricular zone (SVZ), cells positive for chondroitin sulfate proteoglycan (NG2(+)), and de-differentiated astrocytes have been proposed as the origin of proliferating cells following injury. We have analyzed the effect of intraventricular-applied 6-hydroxydopamine (6-OHDA) on the proliferation and morphology of astrocytes in rat cortex and striatum by means of immunohistochemistry and confocal laser microscopy. At 4 days post-lesion, GFAP expression increased markedly. A subpopulation of the GFAP(+) cells co-expressed Ki-67, indicating that these cells were proliferating. To investigate whether these cells (1) arose from migrating SVZ progenitor cells, (2) derived from NG2(+) progenitor cells, or (3) de-differentiated from resident astrocytes, we studied the expression of the migration marker doublecortin (Dcx), the oligodendrocyte progenitor marker NG2, and the progenitor markers Nestin and Pax6. The proliferating Ki-67(+) cells co-expressed Nestin and Pax6, whereas no co-expression of Ki-67 with NG2 or the migration marker Dcx was observed. Thus, resident astrocytes de-differentiate, in response to the intraventricular application of 6-OHDA, to a phenotype resembling radial glia cells, which represent transient astrocyte precursors during development. An understanding of the mechanisms of the de-differentiation of mature astrocytes might be useful for designing new approaches to cell therapy in neurodegenerative diseases such as Parkinson's disease.

Atypical development of behavioural sensitization to 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') in adolescent rats and its expression in adulthood: role of the MDMA chirality.

Despite the great popularity of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) as a drug of abuse, not much is known about the detailed mechanisms of the acute and subchronic effects of the drug. There is especially a lack of information about the distinct behavioural effects of its optical isomers (enantiomers) R- and S-MDMA compared with the racemic RS-MDMA. For this purpose, adolescent rats were repetitively treated during two treatment stages (stage 1: days 1-10; stage 2: days 15, 17, 19) with RS-MDMA (5 or 10 mg/kg) or each of the respective enantiomers (5 mg/kg). The repeated treatment started on postnatal day (PND) 32 and locomotor activity was measured on each day by means of a photobeam-equipped activity box system. RS-MDMA or S-MDMA administration led acutely to massive hyperlocomotion and subchronically, to the development of behavioural sensitization after a short habituation period. R-MDMA was free of hyperactivating effects and even decreased locomotor behaviour upon repeated treatment. Nevertheless, co-administration of R-MDMA increased the hyperactivity of S-MDMA and made the S-MDMA induced behavioural sensitization state-dependent. The animals pre-treated with R-MDMA showed a sensitized response in adulthood when tested with RS-MDMA. Our results indicated that even in the absence of substantial neurotoxicity, both MDMA enantiomers can lead to long-term changes in brain circuitry and concomitant behavioural changes when repeatedly administered in adolescence. The sensitization development was most pronounced in the animals treated with S- and RS-MDMA; the animals with R-MDMA did not develop sensitization under repeated treatment but expressed a sensitized response when challenged with RS-MDMA.

5,7-dihydroxytryptamine injections into the prefrontal cortex and nucleus accumbens differently affect prepulse inhibition and baseline startle magnitude in rats.

The prefrontal cortex and the nucleus accumbens are two brain sites which are known to be involved in the modulation of the acoustic startle response. In particular, the release of monoaminergic transmitters within these brain sites plays an important role in prepulse inhibition of the startle response which serves as an operational measure of sensorimotor gating. Like for dopamine, it is well established that serotonin transmission plays an important role in prepulse inhibition. However, there are only few studies investigating the effects of local manipulation of serotonin transmission on prepulse inhibition. The aim of the present study was to test whether prepulse inhibition or the startle response itself was affected by serotonergic depletion of either the prefrontal cortex or the nucleus accumbens. Serotonergic depletion was induced by local injections of 5,7-dihydroxytryptamine and verified by ex vivo analysis of transmitter levels by high pressure liquid chromatography. In our behavioural tests, we found that 5,7-dihydroxytryptamine into the prefrontal cortex decreased prepulse inhibition, whereas injections into the nucleus accumbens facilitated prepulse inhibition. The time course of these behavioural effects, as well as the transmitter level changes within the different brain sites was very different. Most interestingly, 5,7-dihydroxytryptamine injections into the nucleus accumbens affect serotonin and dopamine levels in both, nucleus accumbens and prefrontal cortex. Taken together, the present study supports an important role of serotonin in the modulation of prepulse inhibition and baseline startle magnitude. However, the observed changes cannot be attributed to a specific brain site since our data clearly show that local 5,7-dihydroxytryptamine injections also affect transmitter levels in brain sites away from the injection site.

Intranasal delivery of cells to the brain.

The safety and efficacy of cell-based therapies for neurodegenerative diseases depends on the mode of cell administration. We hypothesized that intranasally administered cells could bypass the blood-brain barrier by migrating from the nasal mucosa through the cribriform plate along the olfactory neural pathway into the brain and cerebrospinal fluid (CSF). This would minimize or eliminate the distribution of cellular grafts to peripheral organs and will help to dispense with neurosurgical cell implantation. Here we demonstrate transnasal delivery of cells to the brain following intranasal application of fluorescently labeled rat mesenchymal stem cells (MSC) or human glioma cells to naive mice and rats. After cells crossed the cribriform plate, two migration routes were identified: (1) migration into the olfactory bulb and to other parts of the brain; (2) entry into the CSF with movement along the surface of the cortex followed by entrance into the brain parenchyma. The delivery of cells was enhanced by hyaluronidase treatment applied intranasally 30 min prior to the application of cells. Intranasal delivery provides a new non-invasive method for cell delivery to the CNS.

A neurocomputational account of catalepsy sensitization induced by D2 receptor blockade in rats: context dependency, extinction, and renewal.

RATIONALE: Repeated haloperidol treatment in rodents results in a day-to-day intensification of catalepsy (i.e., sensitization). Prior experiments suggest that this sensitization is context-dependent and resistant to extinction training. OBJECTIVES: The aim of this study was to provide a neurobiological mechanistic explanation for these findings. MATERIALS AND METHODS: We use a neurocomputational model of the basal ganglia and simulate two alternative models based on the reward prediction error and novelty hypotheses of dopamine function. We also conducted a behavioral rat experiment to adjudicate between these models. Twenty male Sprague-Dawley rats were challenged with 0.25 mg/kg haloperidol across multiple days and were subsequently tested in either a familiar or novel context. RESULTS: Simulation results show that catalepsy sensitization, and its context dependency, can be explained by "NoGo" learning via simulated D2 receptor antagonism in striatopallidal neurons, leading to increasingly slowed response latencies. The model further exhibits a non-extinguishable component of catalepsy sensitization due to latent NoGo representations that are prevented from being expressed, and therefore from being unlearned, during extinction. In the rat experiment, context dependency effects were not dependent on the novelty of the context, ruling out the novelty model's account of context dependency. CONCLUSIONS: Simulations lend insight into potential complex mechanisms leading to context-dependent catalepsy sensitization, extinction, and renewal.