Association between rheumatoid arthritis and risk of radiotherapy toxicity: a systematic review.

Objective: There is sometimes concern over the use of radiotherapy for cancer in individuals with rheumatoid arthritis (RA), but little evidence to support its avoidance. Identifying any association between RA and risk of radiotherapy toxicity could impact current guidance. We aimed to review the evidence base.

A few thoughts on workplace safety.

In an industry known for its workplace hazards, such as the management and manipulation of animals that could bite, kick or cause considerable damage simply because of their size, combined with long working hours, lifting of heavy loads and the general mental stress, it is perhaps surprising that the veterinary industry is not also known for its safety culture and structures. One would expect that where such hazards and risks have been identified, there would be many and varied levels of education on risk and hazard management, a comprehensive set of tools with which to mitigate these risks as well as discussion and debriefing of significant adverse events to ensure they do not occur again. One would also assume that there would be a strong sense of safety culture in the workplace and that personnel would expect each other to ensure that the health and safety of themselves and their colleagues was a number one priority.

Single dose S-ketamine rescues transcriptional dysregulation of Mtor and Nrp2 in the prefrontal cortex of FSL rats 1 hour but not 14 days post dosing.

There is a pressing need to identify biological indicators of major depression to help guide proper diagnosis and optimize treatment. Animal models mimicking aspects of depression constitute essential tools for early-stage exploration of relevant pathways. In this study, we used the Flinders Sensitive and Resistant Line (FSL/FRL) to explore central and peripheral transcriptional changes in vascular endothelial growth factor (VEGF) pathway genes and their temporal regulation after a single dose of S-ketamine (15 mg/kg).

Reduced Brd1 expression leads to reversible depression-like behaviors and gene-expression changes in female mice.

The schizophrenia-associated gene, BRD1, encodes an epigenetic regulator in which chromatin interactome is enriched with genes implicated in mental health. Alterations in histone modifications and epigenetic regulation contribute to brain transcriptomic changes in affective disorders and preclinical data supports a role for BRD1 in psychopathology. However, the implication of BRD1 on affective pathology remains poorly understood.

Maternal stress and placental function; ex vivo placental perfusion studying cortisol, cortisone, tryptophan and serotonin.

Background: Exposure to maternal stress during pregnancy can have adverse effects on the fetus, which has potential long-term effects on offspring´s development and health. We investigated the kinetics and metabolism of the hormones and amino acids: cortisol, cortisone, tryptophan and serotonin in the term placenta in an ex vivo human placental perfusion model. The placentas used in the experiments were donated from families participating in the Maternal Stress and Placental Function project with a known maternal stress background.

Latent toxoplasmosis aggravates anxiety- and depressive-like behaviour and suggest a role of gene-environment interactions in the behavioural response to the parasite.

Toxoplasma gondii (TOX) is an intracellular parasite which infects warm-blooded animals including humans. An increasing number of clinical studies now hypothesize that latent toxoplasmosis may be a risk factor for the development of psychiatric disease. For depression, the results have been varied and we speculate that genetic background is important for the response to latent toxoplasmosis.

Hemisphere-dependent endocannabinoid system activity in prefrontal cortex and hippocampus of the Flinders Sensitive Line rodent model of depression.

Altered endocannabinoid (eCB) signalling is suggested as an important contributor to the pathophysiology of depression. To further elucidate this, we conducted a study using a genetic rat model of depression, the Flinders Sensitive Line (FSL), and their controls, the Flinders Resistant Line (FRL) rats. Plasma, right and left prefrontal cortex, and hippocampus were isolated from FSL and FRL rats.

A Preclinical Study of Casein Glycomacropeptide as a Dietary Intervention for Acute Mania.

Background: Casein glycomacropeptide is a peptide that lacks phenylalanine, tyrosine, and tryptophan. This profile may enable it to deplete phenylalanine, tyrosine, and tryptophan, and subsequently the synthesis of dopamine and serotonin in the brain. Dopamine- and serotonin-depleting amino acid mixtures have shown promise as acute antimanic treatments.

-Ketamine Mediates Its Acute and Sustained Antidepressant-Like Activity through a 5-HT Receptor Dependent Mechanism in a Genetic Rat Model of Depression.

The mechanisms responsible for the unique antidepressant properties of ketamine have only been partly resolved. Recent preclinical reports implicate the neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] in the antidepressant-like response of ketamine, and modulation of 5-HT receptors has been hypothesized to attain an important role. To evaluate the role of endogenous stimulation of 5-HT heteroreceptors in the antidepressant-like activity of -ketamine.

ZL006, a small molecule inhibitor of PSD-95/nNOS interaction, does not induce antidepressant-like effects in two genetically predisposed rat models of depression and control animals.

N-methyl-D-aspartate receptor (NMDA-R) antagonists and nitric oxide inhibitors have shown promising efficacy in depression but commonly induce adverse events. To circumvent these, a more indirect disruption of the nitric oxide synthase/postsynaptic density protein 95 kDa complex at the NMDA-R has been proposed. This disruption can be achieved using small molecule inhibitors such as ZL006, which has attracted attention as ischemic stroke therapy in rodents and has been proposed as a potential novel treatment for depression.

A dual inhibitor of FAAH and TRPV1 channels shows dose-dependent effect on depression-like behaviour in rats.

Objective: The cannabinoid receptor 1 (CB1) and transient receptor potential cation channel subfamily V member 1 (TRPV1) are proposed to mediate opposite behavioural responses. Their common denominator is the endocannabinoid ligand anandamide (AEA), which is believed to mediate antidepressant-like effect via CB1-R stimulation and depressive-like effect via TRPV1 activation. This is supposed to explain the bell-shaped dose-response curve for anandamide in preclinical models.

Differential interaction with the serotonin system by S-ketamine, vortioxetine, and fluoxetine in a genetic rat model of depression.

Rationale: The mechanisms mediating ketamine's antidepressant effect have only been partly resolved. Recent preclinical reports implicate serotonin (5-hydroxytryptamine; 5-HT) in the antidepressant-like action of ketamine. Vortioxetine is a multimodal-acting antidepressant that is hypothesized to exert its therapeutic activity through 5-HT reuptake inhibition and modulation of several 5-HT receptors.

Interferon-alpha treatment induces depression-like behaviour accompanied by elevated hippocampal quinolinic acid levels in rats.

Immunotherapy with the cytokine interferon-alpha (IFN-α) can induce symptoms of depression, and it is likely that the tryptophan-kynurenine pathway may be involved in this regard. In this study we investigated the effects of IFN-α on depression-like behaviour and central metabolites of the tryptophan-kynurenine pathway in rats. Secondly, we explored the modulating effects of an antidepressant (imipramine) and anti-inflammatory drug (celecoxib) on IFN-α-induced behavioural and pathophysiological changes in the brain.

Chronic lipopolysaccharide infusion fails to induce depressive-like behaviour in adult male rats.

Background: Chronic inflammation is implicated in numerous diseases, including major depression and type 2 diabetes mellitus (T2DM). Since depression and T2DM often co-exist, inflammatory pathways are suggested as a possible link. Hence, the establishment of an immune-mediated animal model would shed light on mechanisms possibly linking depression and metabolic alterations.

Chronic desipramine prevents acute stress-induced reorganization of medial prefrontal cortex architecture by blocking glutamate vesicle accumulation and excitatory synapse increase.

Background: Although a clear negative influence of chronic exposure to stressful experiences has been repeatedly demonstrated, the outcome of acute stress on key brain regions has only just started to be elucidated. Although it has been proposed that acute stress may produce enhancement of brain plasticity and that antidepressants may prevent such changes, we still lack ultrastructural evidence that acute stress-induced changes in neurotransmitter physiology are coupled with structural synaptic modifications.

Methods: Rats were pretreated chronically (14 days) with desipramine (10mg/kg) and then subjected to acute foot-shock stress.

Nitric oxide involvement in the antidepressant-like effect of ketamine in the Flinders sensitive line rat model of depression.

Objective: We investigated whether the nitric oxide (NO) precursor, L-arginine, can prevent the antidepressant-like action of the fast-acting antidepressant, ketamine, in a genetic rat model of depression, and/or induce changes in the glutamate (Glu)/N-methyl-D-aspartate receptor (NMDAR)/NO/cyclic guanosine monophosphate (cGMP) signalling pathway. Hereby it was evaluated whether the NO signalling system is involved in the antidepressant mechanism of ketamine.

Methods: Flinders sensitive line (FSL) rats received single i.

Ketamine regulates the presynaptic release machinery in the hippocampus.

In the search for new drug targets, that may help point the way to develop fast-acting treatments for mood disorders, we have explored molecular pathways regulated by ketamine, an NMDA receptor antagonist, which has consistently shown antidepressant response within a few hours of administration. Using Sprague-Dawley rats we investigated the effects of ketamine on the presynaptic release machinery responsible for neurotransmitter release at 1, 2 and 4 h as well as 7 days after administration of a single subanesthetic dose of ketamine (15 mg/kg). A large reduction in the accumulation of SNARE complexes was observed in hippocampal synaptic membranes after 1, 2 and 4 h of ketamine administration.

Chronic treatment with the phosphodiesterase type 5 inhibitors sildenafil and tadalafil display anxiolytic effects in Flinders Sensitive Line rats.

There are conflicting results from behavioural studies regarding whether the activation or inhibition of the cGMP-nitric oxide (NO) pathway induces anxiolytic-like behaviour. Sildenafil, an inhibitor of cGMP-selective phosphodiesterase-5, increases anxiety acutely, but previous evidence suggests that its chronic administration may be anxiolytic, and could involve a cholinergic interaction. We used the Flinders Sensitive Line (FSL) rat, a genetic model of depression that presents with increased anxiety- and depression-like behaviour, to investigate the action of chronic treatment with the PDE5 inhibitors sildenafil or tadalafil, with/without atropine on social interaction behaviour, a correlate for anxiety.

Isolation-induced behavioural changes in a genetic animal model of depression.

Depression is a heterogeneous disorder displaying a range of symptoms including feelings of despair and social withdrawal. Social isolation may complicate the progression of depression and have effects on both behaviour and physiology. The aim of this study was to investigate the effects of social isolation on behavioural and metabolic parameters in a genetic rat model of depression, the Flinders Sensitive and Resistant Line (FSL/FRL) rats.

Pharmacological effects of Lu AA21004: a novel multimodal compound for the treatment of major depressive disorder.

1-[2-(2,4-Dimethylphenyl-sulfanyl)-phenyl]-piperazine (Lu AA21004) is a human (h) serotonin (5-HT)(3A) receptor antagonist (K(i) = 3.7 nM), h5-HT(7) receptor antagonist (K(i) = 19 nM), h5-HT(1B) receptor partial agonist (K(i) = 33 nM), h5-HT(1A) receptor agonist (K(i) = 15 nM), and a human 5-HT transporter (SERT) inhibitor (K(i) = 1.6 nM) (J Med Chem 54:3206-3221, 2011).

Neuropeptide S alters anxiety, but not depression-like behaviour in Flinders Sensitive Line rats: a genetic animal model of depression.

Neuropeptide S (NPS) and its receptor (NPSR) have been implicated in the mediation of anxiolytic-like behaviour in rodents. However, little knowledge is available regarding the NPS system in depression-related behaviours, and whether NPS also exerts anxiolytic effects in an animal model of psychopathology. Therefore, the aim of this work was to characterize the effects of NPS on depression- and anxiety-related parameters, using male and female rats in a well-validated animal model of depression: the Flinders Sensitive Line (FSL), their controls, the Flinders Resistant Line (FRL), and Sprague-Dawley (SD) rats.

An inhibitor of cAMP-dependent protein kinase induces behavioural and neurological antidepressant-like effects in rats.

Although it is well established that cyclic adenosine monophosphate (cAMP) signalling via cAMP-dependent protein kinase (PKA)within neurons plays an important role in depression and antidepressant treatment, the importance of several newly discovered targets that function independently from PKA, such as exchange protein activated by cAMP (Epac), remains unexplored in this regard. In this study we used a cAMP analogue that inhibits PKA but not Epac (Rp-8-Br-cAMP), to explore the modifying actions of these two targets on immobility in the forced swim test (FST) and cerebellar cAMP response element binding protein (CREB) phosphorylation in rats. In addition, we assessed central cAMP and cGMP levels and investigated the involvement of cGMP-dependent protein kinase (PKG) on any observed effects by using a selective PKG inhibitor (Rp-8-Br-PET-cGMPS).

Antidepressant-like properties of phosphodiesterase type 5 inhibitors and cholinergic dependency in a genetic rat model of depression.

We explored the antidepressant-like properties of two phosphodiesterase type 5 (PDE5) inhibitors in a genetic animal model of depression, namely Flinders sensitive line rats. We investigated the dose-dependency of the antidepressant-like action of sildenafil, and its interaction with the cholinergic system and behavioural correlates of monoaminergic neurotransmission, in the forced swim test. Antidepressant-like properties of tadalafil (a structurally distinct PDE5 inhibitor) were also evaluated.

Investigating the role of protein kinase-G in the antidepressant-like response of sildenafil in combination with muscarinic acetylcholine receptor antagonism.

The cGMP/PK-G pathway plays a crucial role in neuroprotection and neurotrophin support, and is possibly involved in antidepressant action. Recently we reported on a novel antidepressant-like response following simultaneous administration of sildenafil (phosphodiesterase 5 (PDE5) inhibitor, thereby increasing cGMP levels), and atropine (muscarinic acetylcholine receptor antagonist) in the rat forced swim test (FST). However, it is unclear whether the antidepressant-like activity of sildenafil+atropine is mediated via the activation of PK-G, an important down-stream effector for cGMP, and whether this may target known pathways in antidepressant action.

Penetrating abdominal wounds--a prospective trial of conservative treatment based on physical signs.

Between 1980-1987 605 patients with penetrating abdominal wounds were admitted to Victoria Hospital; 105 had gunshot wounds of whom 103 had laparotomies with positive findings. It is concluded that virtually all patients with gunshot wounds of the abdomen require laparotomy. The remaining 500 patients presented with stab wounds of the abdomen and were admitted to the surgical wards; of these 357 had physical signs necessitating immediate laparotomy while the remainder were observed.