The systemic response to topical Aldara treatment is mediated through direct TLR7 stimulation as Imiquimod enters the circulation

Topical application of Aldara cream, containing the Toll-like receptor 7/8 agonist Imiquimod, is a widely used mouse model for investigating the pathogenesis of psoriasis. We have previously used this model to study the effects of peripheral inflammation on the brain, and reported a brain-specific response characterised by increased transcription, infiltration of immune cells and anhedonic-like behavior. Here, we perform a more robust characterisation of the systemic response to Aldara application and find a potent but transient response in the periphery, followed by a prolonged response in the brain. Mass spectrometry analysis of plasma and brain samples identified significant levels of Imiquimod in both compartments at molar concentrations likely to evoke a biological response. Indeed, the association of Imiquimod with the brain correlated with increased Iba1 and GFAP staining, indicative of microglia and astrocyte reactivity. These results highlight the potency of this model and raise the question of how useful it is for interpreting the systemic response in psoriasis-like skin inflammation. In addition, the potential impact on the brain should be considered with regards to human use and may explain why fatigue, headaches and nervousness have been reported as side effects following prolonged Aldara use

A 50 year old with a rapid neuropsychiatric deterioration and choreaform movements

A 50-year-old man presented acutely to the hospital with behavioural disturbance, choreiform movements and profound nihilistic delusions. He reported recent drug and alcohol abuse, and also apparent involvement in several recent criminal activities, for which he felt he should be punished. He arrived alone at the hospital after a concerned neighbour had called an ambulance. His initial level of agitation prevented formal cognitive testing. However, he was alert, verbally responsive and could obey commands. He was afebrile with normal observations and normal plasma glucose. Although his examination was challenging, the only abnormal neurological findings were bilateral choreiform upper limb movements

Peripheral inflammation is associated with remote global gene expression changes in the brain

Background: Although the central nervous system (CNS) was once considered an immunologically privileged site, in recent years it has become increasingly evident that cross talk between the immune system and the CNS does occur. As a result, patients with chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease or psoriasis, are often further burdened with neuropsychiatric symptoms, such as depression, anxiety and fatigue. Despite the recent advances in our understanding of neuroimmune communication pathways, the precise effect of peripheral immune activation on neural circuitry remains unclear. Utilizing transcriptomics in a well-characterized murine model of systemic inflammation, we have started to investigate the molecular mechanisms by which inflammation originating in the periphery can induce transcriptional modulation in the brain.<p></p> Methods: Several different systemic and tissue-specific models of peripheral toll-like-receptor-(TLR)-driven (lipopolysaccharide (LPS), lipoteichoic acid and Imiquimod) and sterile (tumour necrosis factor (TNF) and 12-O-tetradecanoylphorbol-13-acetate (TPA)) inflammation were induced in C57BL/6 mice. Whole brain transcriptional profiles were assessed and compared 48 hours after intraperitoneal injection of lipopolysaccharide or vehicle, using Affymetrix GeneChip microarrays. Target gene induction, identified by microarray analysis, was validated independently using qPCR. Expression of the same panel of target genes was then investigated in a number of sterile and other TLR-dependent models of peripheral inflammation.<p></p> Results: Microarray analysis of whole brains collected 48 hr after LPS challenge revealed increased transcription of a range of interferon-stimulated genes (ISGs) in the brain. In addition to acute LPS challenge, ISGs were induced in the brain following both chronic LPS-induced systemic inflammation and Imiquimod-induced skin inflammation. Unique to the brain, this transcriptional response is indicative of peripherally triggered, interferon-mediated CNS inflammation. Similar models of sterile inflammation and lipoteichoic-acid-induced systemic inflammation did not share the capacity to trigger ISG induction in the brain.<p></p> Conclusions: These data highlight ISG induction in the brain as being a consequence of a TLR-induced type I interferon response. As considerable evidence links type I interferons to psychiatric disorders, we hypothesize that interferon production in the brain could represent an important mechanism, linking peripheral TLR-induced inflammation with behavioural changes.<p></p&gt

Suicide and undetermined death in South East Scotland: a case-control study using the psychological autopsy method

Mental disorders are major risk factors for suicide. Not all those who suffer from them kill themselves. Additional information is required to differentiate higher from lesser risk patients.Cases and controls did not differ in any significant way with respect to severity of mental disorder. The main factors independently associated with undetermined death or suicide were:- a history of deliberate self harm (adjusted OR 4.1) physical ill health ( adjusted OR 7.8) treatment of whatever kind by mental health services (adjusted OR 0.01). Other antecedents associated with increased risk (criminal record, involvement with police, financial problems and failure to vote) and those associated with decreased risk (contact with a doctor and in- patient care) did not exert effects after controlling for confounding.Controls were receiving more care of whatever kind. Treatment of mental disorder comorbid with physical illness and a a history of deliberate self harm may be especially important. Factors which separate those with mental disorder at high risk from those at lesser risk relate to care levels provided, which may be a function of engagement by and with health services. The role of mental health professionals is beneficial in suicide prevention. The focusing of that role toward engaging alienated or "difficult" patients should be addressed

Anatomical Constraints on Attention: Hemifield Independence Is a Signature of Multifocal Spatial Selection

Previous studies have shown independent attentional selection of targets in the left and right visual hemifields during attentional tracking (Alvarez & Cavanagh, 2005) but not during a visual search (Luck, Hillyard, Mangun, & Gazzaniga, 1989). Here we tested whether multifocal spatial attention is the critical process that operates independently in the two hemifields. It is explicitly required in tracking (attend to a subset of object locations, suppress the others) but not in the standard visual search task (where all items are potential targets). We used a modified visual search task in which observers searched for a target within a subset of display items, where the subset was selected based on location (Experiments 1 and 3A) or based on a salient feature difference (Experiments 2 and 3B). The results show hemifield independence in this subset visual search task with location-based selection but not with feature-based selection; this effect cannot be explained by general difficulty (Experiment 4). Combined, these findings suggest that hemifield independence is a signature of multifocal spatial attention and highlight the need for cognitive and neural theories of attention to account for anatomical constraints on selection mechanisms.Psycholog

Relationship between blood pressure values, depressive symptoms and cardiovascular outcomes in patients with cardiometabolic disease

We studied joint effect of blood pressure-BP and depression on risk of major adverse cardiovascular outcome in patients with existing cardiometabolic disease. A cohort of 35537 patients with coronary heart disease, diabetes or stroke underwent depression screening and BP was recorded concurrently. We used Cox’s proportional hazards to calculate risk of major adverse cardiovascular event-MACE (myocardial infarction/heart failure/stroke or cardiovascular death) over 4 years associated with baseline BP and depression. 11% (3939) had experienced MACE within 4 years. Patients with very high systolic BP-SBP (160-240) hazard ratio-HR 1.28 and with depression (HR 1.22) at baseline had significantly higher adjusted risk. Depression had significant interaction with SBP in risk prediction (p=0.03). Patients with combination of SBP and depression at baseline had 83% higher adjusted risk of MACE, as compared to patients with reference SBP and without depression. Patients with cardiometabolic disease and comorbid depression may benefit from closer monitoring of SBP

Maternal serum screening (MSS) in Newfoundland and Labrador: knowledge, opinion and practice

Objective: To investigate maternal serum screening (MSS) in Newfoundland and Labrador. -- Design: Cross-sectional anonymous physician and post-partum women surveys conducted between September and December 2003. Aggregate laboratory data for 2003 were also assessed. -- Population: Physicians practicing antenatal care in Newfoundland and Labrador in the previous 12 months (n = 490). Women (n = 300) who had recently given birth. -- Results: The response rates for the physician and patient surveys were 60.4% (n = 293) and 66.7% (n = 200) respectively. Most physicians (88.8%) reported that they offer maternal serum screening to their patients. These physicians were divided among those who offered MSS to all women (63.5%) and those who offered MSS to selective groups of women (36.5%). Physicians who were younger, female and educated in Canada were more likely to offer MSS than physicians who were older, male and educated outside of Canada. Obstetricians were more likely to offer MSS and to offer the screening test to all women than family physicians. The majority of both physician groups reported that they would prefer a first trimester screening test. -- The majority (62.9%) of patients surveyed reported discussing MSS with their physician. Less than half (46.2%) of these women chose to undergo the prenatal screen. Women who underwent MSS were significantly older than women who did not undergo the screening test. Twenty seven percent of patients surveyed underwent MSS. -- Data obtained from the Provincial MSS Program indicated that 22% of women undergo MSS. The overall false positive rate 1 associated with MSS in Newfoundland and Labrador was 13.1%. -- Conclusion: MSS is not being used as a population based screening test. It is being offered to and used by selected groups of women. Further education and promotion of this prenatal screening test are necessary

Relationship of depression screening in cardiometabolic disease with vascular events and mortality: findings from a large primary care cohort with 4 years follow-up

Aims: Benefits of routine depression screening for cardiometabolic disease patients remain unclear. We examined the association between depression screening and all-cause mortality and vascular events in cardiometabolic disease patients. Methods and results: 125 143 patients with cardiometabolic diseases (coronary heart disease, diabetes or previous stroke) in the UK participated in primary care chronic disease management in 2008/09, which included depression screening using the Hospital Anxiety and Depression Score. 10 670 receiving depression treatment exempted, 35 537 screened, while 78 936 not screened. We studied all-cause mortality and vascular events at 4 years, by electronic data linkage of 124 414 patients (99.4%) on primary care registers to hospital discharge and mortality records and used Cox proportional hazards on matched data using propensity score. Mean age for the screened and not screened population was 69 years (standard deviation—SD 11.9) and 67 years (SD 14.3), respectively; 58% (20 658) of the screened population were men and 65.3% (22 726) were socioeconomically deprived, compared with 54.2% (42 727) and 67.4% (51 686), respectively, in the not screened population. The screened population had lower all-cause mortality (Hazard Ratio—HR 0.89) and vascular events (HR 0.85) in the matched data of N = 21 893 patients each in the screened and the unscreened groups. Conclusion: Depression screening was associated with a reduction in all-cause mortality and vascular events in patients with cardiometabolic diseases. The uptake of screening was poor for unknown reasons. Reverse causality and confounding by disease severity and quality of care are important possible limitations. Further research to determine reproducibility and explore underlying mechanisms is merited

Sustained exposure to systemic endotoxin triggers chemokine induction in the brain followed by a rapid influx of leukocytes

Background: Recent years have seen an explosion of research pertaining to biological psychiatry, yet despite subsequent advances in our understanding of neuroimmune communication pathways, how the brain senses and responds to peripheral inflammation remains poorly understood. A better understanding of these pathways may be important for generating novel therapeutics to treat many patients with chronic inflammatory diseases who also suffer from neuropsychiatric comorbidities. Here we have systematically assessed the leukocyte infiltrate to the brain following systemic endotoxin exposure to better understand this novel route of neuroimmune communication. Methods: Mice were injected intraperitoneally with LPS daily for 2, 5 or 7 consecutive days. We systematically interrogated the subsequent induction of chemokine transcription in the brain using TaqMan low-density arrays. A combination of flow cytometry and immunohistochemistry was then used to characterise the accompanying leukocyte infiltrate Result: Repeated LPS challenges resulted in prolonged activation of brain-resident microglia, coupled with an increased local transcription of numerous chemokines. After 2 days of administering LPS, there was a marked increase in the expression of the neutrophil chemoattractants CXCL1 and CXCL2; the monocyte chemoattractants CCL2, CCL5, CCL7 and CCL8; and the lymphocyte chemoattractants CXCL9, CXCL10 and CXCL16. In a number of cases, this response was sustained for several days. Chemokine induction was associated with a transient recruitment of neutrophils and monocytes to the brain, coupled with a sustained accumulation of macrophages, CD8+ T cells, NK cells and NKT cells. Strikingly, neutrophils, monocytes and T cells appeared to extravasate from the vasculature and/or CSF to infiltrate the brain parenchyma. Conclusions: Prolonged exposure to a peripheral inflammatory stimulus triggers the recruitment of myeloid cells and lymphocytes to the brain. By altering the inflammatory or metabolic milieu of the brain, this novel method of immune-to-brain communication may have profound implications for patients with chronic inflammatory diseases, potentially leading to neuropsychiatric comorbidities

Risk assessment and predicting outcomes in patients with depressive symptoms: a review of potential role of peripheral blood based biomarkers

Depression is one of the major global health challenges and a leading contributor of health related disability and costs. Depression is a heterogeneous disorder and current methods for assessing its severity in clinical practice rely on symptom count, however this approach is unreliable and inconsistent. The clinical evaluation of depressive symptoms is particularly challenging in primary care, where the majority of patients with depression are managed, due to the presence of co-morbidities. Current methods for risk assessment of depression do not accurately predict treatment response or clinical outcomes. Several biological pathways have been implicated in the pathophysiology of depression; however, accurate and predictive biomarkers remain elusive. We conducted a systematic review of the published evidence supporting the use of peripheral biomarkers to predict outcomes in depression, using Medline and Embase. Peripheral biomarkers in depression were found to be statistically significant predictors of mental health outcomes such as treatment response, poor outcome and symptom remission; and physical health outcomes such as increased incidence of cardiovascular events and deaths, and all-cause mortality. However, the available evidence has multiple methodological limitations which must be overcome to make any real clinical progress. Despite extensive research on the relationship of depression with peripheral biomarkers, its translational application in practice remains uncertain. In future, peripheral biomarkers identified with novel techniques and combining multiple biomarkers may have a potential role in depression risk assessment but further research is needed in this area