Multi-site pre-therapeutic biopsies demonstrate genetic heterogeneity in patients with newly diagnosed diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, both regarding clinical presentation, response to treatment and outcome. Recently, subclassification of DLBCL based on mutational profile has been suggested, and next generation sequencing (NGS) analysis may be relevant as part of the diagnostic workflow. This will, however, often be based on analysis of one tumor biopsy.

Routine CT evaluation of central vascular ligation in patients undergoing complete mesocolic excision for sigmoid colon cancer.

Aim: Objective and reproducible quality measures of complete mesocolic excision (CME) for colon cancer are not currently available. This study aimed to measure the inferior mesenteric stump length following CME for sigmoid colon cancer and explore surgical, pathological and oncological outcomes in patients with a stump length of <10 mm vs. ≥10 mm.

Revealing a compulsive phenotype in cholinergic M mice depends on the inter-trial interval initiation settings in a five choice serial reaction time task.

Background: Muscarinic acetylcholine receptor 4 (M) modulates dopaminergic neurotransmission and is a target for novel treatments of schizophrenia, cognitive deficits, and addiction. Impulsive and compulsive behaviors are key traits of addiction, yet the importance of M receptor signaling to these traits is poorly understood. We investigated impulsive action and compulsivity by measuring premature and perseverative responses in the five choice serial reaction time task (5CSRTT).

G protein-coupled receptor signaling in VTA dopaminergic neurons bidirectionally regulates the acute locomotor response to amphetamine but does not affect behavioral sensitization.

Amphetamine (AMPH) acts as a substrate of the dopamine transporter (DAT) and causes a dramatic increase in extracellular dopamine (DA). Upon entering DA neurons, AMPH promotes DA efflux via DAT through a mechanism implicating depletion of DA from vesicular stores, activation of kinase pathways and transporter phosphorylation. Despite the role of intracellular signaling for AMPH action, it remains elusive how the response to AMPH is affected in vivo by metabotropic regulation via G protein coupled receptor signaling pathways.

PICK1-Deficient Mice Exhibit Impaired Response to Cocaine and Dysregulated Dopamine Homeostasis.

Protein interacting with C-kinase 1 (PICK1) is a widely expressed scaffold protein known to interact via its PSD-95/discs-large/ZO-1 (PDZ)-domain with several membrane proteins including the dopamine (DA) transporter (DAT), the primary target for cocaine's reinforcing actions. Here, we establish the importance of PICK1 for behavioral effects observed after both acute and repeated administration of cocaine. In PICK1 knock-out (KO) mice, the acute locomotor response to a single injection of cocaine was markedly attenuated.

Ketogenic Diet Suppresses Alcohol Withdrawal Syndrome in Rats.

Background: Alcohol use disorder is underdiagnosed and undertreated, and up to 50% of alcohol-abstinent patients diagnosed with alcohol dependence relapse within the first year of treatment. Current treatments for the maintenance of alcohol abstinence in patients with alcohol use disorder have limited efficacy, and there is an urgent need for novel treatment strategies. Decreased cerebral glucose metabolism and increased brain uptake of acetate were recently reported in heavy drinkers, relative to controls.

Physiological roles of CNS muscarinic receptors gained from knockout mice.

Because the five muscarinic acetylcholine receptor subtypes have overlapping distributions in many CNS tissues, and because ligands with a high degree of selectivity for a given subtype long remained elusive, it has been difficult to determine the physiological functions of each receptor. Genetically engineered knockout mice, in which one or more muscarinic acetylcholine receptor subtype has been inactivated, have been instrumental in identifying muscarinic receptor functions in the CNS, at the neuronal, circuit, and behavioral level. These studies revealed important functions of muscarinic receptors modulating neuronal activity and neurotransmitter release in many brain regions, shaping neuronal plasticity, and affecting functions ranging from motor and sensory function to cognitive processes.

The glucagon-like peptide 1 receptor agonist Exendin-4 decreases relapse-like drinking in socially housed mice.

Glucagon-like peptide-1 (GLP-1) is a gut peptide that regulates food intake and glucose metabolism. GLP-1 is also produced and released in the brain, and GLP-1 receptors are expressed in brain regions important for alcohol and drug reward, and for the development of addiction. GLP-1 receptor agonists can decrease alcohol intake acutely in rodents.

Subjective perception of cocaine reward in mice assessed by a single exposure place preference (sePP) paradigm.

Background: The potential of abused drugs to induce addiction and compulsive drug-related behavior is associated with their ability to alter dopamine signaling. Dopamine plays a key role in reward signaling and it has been of great interest to investigate how various drugs of abuse alter reward-related behavior.

Comparison With Existing Methods: In rodents, the rewarding effects of drugs have often been assessed in self-administration or place preference paradigms; both involving repeated drug exposure and weeks of training and testing.

Muscarinic receptor M positive allosteric modulators attenuate central effects of cocaine.

Background: Cocaine addiction is a chronic brain disease affecting neurotransmission. Muscarinic cholinergic receptors modulate dopaminergic signaling in the reward system, and muscarinic receptor stimulation can block direct reinforcing effects of cocaine. Here, we tested the hypothesis that specific muscarinic M receptor stimulation can attenuate the discriminative stimulus effects and conditioned rewarding effects of cocaine, measures believed to predict the ability of cocaine and cocaine-associated cues to elicit relapse to drug taking.

Frequency and Effect of Access-Related Vascular Injury and Subsequent Vascular Intervention After Transcatheter Aortic Valve Replacement.

Vascular access and closure remain a challenge in transcatheter aortic valve replacement (TAVR). This single-center study aimed to report the incidence, predictive factors, and clinical outcomes of access-related vascular injury and subsequent vascular intervention. During a 30-month period, 365 patients underwent TAVR and 333 patients (94%) were treated by true percutaneous transfemoral approach.

Preserved dopaminergic homeostasis and dopamine-related behaviour in hemizygous TH-Cre mice.

Cre-driver mouse lines have been extensively used as genetic tools to target and manipulate genetically defined neuronal populations by expression of Cre recombinase under selected gene promoters. This approach has greatly advanced neuroscience but interpretations are hampered by the fact that most Cre-driver lines have not been thoroughly characterized. Thus, a phenotypic characterization is of major importance to reveal potential aberrant phenotypes prior to implementation and usage to selectively inactivate or induce transgene expression.

Major femoral vascular access complications after coronary diagnostic and interventional procedures: A Danish register study.

Background: Vascular access complications after coronary angiography (CAG) and percutaneous coronary intervention (PCI) are known to increase morbidity, prolong hospitalization and raise hospital costs. Therefore, risk factor identification and improvement of safety strategies for vascular management are important. We aimed to assess the incidence of major vascular complications related to femoral access, and to identify potential risk factors.

Enhanced self-administration of alcohol in muscarinic acetylcholine M4 receptor knockout mice.

Modulation of cholinergic neurotransmission via nicotinic acetylcholine receptors is known to alter alcohol-drinking behavior. It is not known if muscarinic acetylcholine receptor subtypes have similar effects. The muscarinic M4 receptor is highly expressed in the brain reinforcement system and involved in regulation of cholinergic and dopaminergic transmission.

Selective activation of M4 muscarinic acetylcholine receptors reverses MK-801-induced behavioral impairments and enhances associative learning in rodents.

Positive allosteric modulators (PAMs) of the M4 muscarinic acetylcholine receptor (mAChR) represent a novel approach for the treatment of psychotic symptoms associated with schizophrenia and other neuropsychiatric disorders. We recently reported that the selective M4 PAM VU0152100 produced an antipsychotic drug-like profile in rodents after amphetamine challenge. Previous studies suggest that enhanced cholinergic activity may also improve cognitive function and reverse deficits observed with reduced signaling through the N-methyl-d-aspartate subtype of the glutamate receptor (NMDAR) in the central nervous system.

An allosteric enhancer of M₄ muscarinic acetylcholine receptor function inhibits behavioral and neurochemical effects of cocaine.

Rationale: The mesostriatal dopamine system plays a key role in mediating the reinforcing effects of psychostimulant drugs like cocaine. The muscarinic M₄ acetylcholine receptor subtype is centrally involved in the regulation of dopamine release in striatal areas. Consequently, striatal M₄ receptors could be a novel target for modulating psychostimulant effects of cocaine.

Impact of tumour necrosis factor inhibitor treatment on radiographic progression in rheumatoid arthritis patients in clinical practice: results from the nationwide Danish DANBIO registry.

Objectives: To compare radiographic progression during treatment with disease-modifying antirheumatic drugs (DMARD) and subsequent treatment with tumour necrosis factor α inhibitors (TNF-I) in rheumatoid arthritis (RA) patients in clinical practice.

Methods: Conventional radiographs (x-rays) of hands and wrists were obtained ∼2 years before start (prebaseline), at baseline and ∼2 years after start (follow-up) of TNF-I. Clinical data were obtained from the DANBIO registry and the patient files.

Muscarinic Acetylcholine Receptor Subtypes as Potential Drug Targets for the Treatment of Schizophrenia, Drug Abuse and Parkinson's Disease.

The neurotransmitter dopamine plays important roles in modulating cognitive, affective, and motor functions. Dysregulation of dopaminergic neurotransmission is thought to be involved in the pathophysiology of several psychiatric and neurological disorders, including schizophrenia, Parkinson's disease and drug abuse. Dopaminergic systems are regulated by cholinergic, especially muscarinic, input.

Neuropeptide Y Y5 receptor antagonism attenuates cocaine-induced effects in mice.

Rationale: Several studies suggest a role for neuropeptide Y (NPY) in addiction to drugs of abuse, including cocaine. However, the NPY receptors mediating addiction-related effects remain to be determined.

Objectives: To explore the potential role of Y5 NPY receptors in cocaine-induced behavioural effects.

Increased cocaine self-administration in M4 muscarinic acetylcholine receptor knockout mice.

Rationale: The reinforcing effects of cocaine are mediated by the mesolimbic dopamine system. Behavioral and neurochemical studies have shown that the cholinergic muscarinic M(4) receptor subtype plays an important role in regulation of dopaminergic neurotransmission.

Objectives: Here we investigated for the first time the involvement of M(4) receptors in the reinforcing effects of cocaine using chronic intravenous cocaine self-administration in extensively backcrossed M(4) receptor knockout (M(4) (-/-)) mice.

Antipsychotic-induced catalepsy is attenuated in mice lacking the M4 muscarinic acetylcholine receptor.

A delicate balance exists between the central dopaminergic and cholinergic neurotransmitter systems with respect to motor function. An imbalance can result in motor dysfunction as observed in Parkinson's disease patients and in patients treated with antipsychotic compounds. Cholinergic receptor antagonists can alleviate extrapyramidal symptoms in Parkinson's disease and motor side effects induced by antipsychotics.

A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors.

Acetylcholine (ACh) regulates many key functions of the CNS by activating cell surface receptors referred to as muscarinic ACh receptors (M(1)-M(5) mAChRs). Like other mAChR subtypes, the M(4) mAChR is widely expressed in different regions of the forebrain. Interestingly, M(4) mAChRs are coexpressed with D(1) dopamine receptors in a specific subset of striatal projection neurons.