Changes in expressions of proinflammatory cytokines IL-1β, TNF-α and IL-6 in the brain of senescence accelerated mouse (SAM) P8

The senescence-accelerated mouse (SAM) is known to be a murine model for accelerated aging. The SAMP8 strain shows age-related deterioration of learning and memory at an earlier age than control mice (SAMR1). In the present study, we investigated the changes in expressions of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the brain of SAMP8. In the hippocampus of 10 months old SAMP8, the expression of IL-1 mRNA was significantly elevated in comparison with that of SAMR1. In both strains of SAMs, increases in IL-1β protein in the brain were observed at 10 months of age compared with 2 and 5 months. The only differences found between the strain in protein levels were at 10 months and were elevations in IL-1β in the hippocampus and hypothalamus, and in TNF-α and IL-6 in the cerebral cortex and the hippocampus in SAMP8 as compared with SAMR1. However, lipopolysaccharide-induced increases in the expression of these cytokines in brain did not differ between SAMP8 and SAMR1. Increases in expression of proinflammatory cytokines in the brain may be involved in the age-related neural dysfunction and/or learning deficiency in SAMP8.     

Xanthine Oxidase Activation Modulates the Endothelial (Vascular) Dysfunction Related to HgCl<Subscript>2</Subscript> Exposure Plus Myocardial Infarction in Rats

Heavy metal exposure is associated with cardiovascular diseases such as myocardial infarction (MI). Vascular dysfunction is related to both the causes and the consequences of MI. We investigated whether chronic exposure to low doses of mercury chloride (HgCl₂) worsens MI-induced endothelial dysfunction 7 days after MI. Male Wistar rats were divided into four groups: Control (vehicle), HgCl₂ (4 weeks of exposure), surgically induced MI and combined HgCl₂-MI. Morphological and hemodynamic measurements were used to characterize the MI model 7 days after the insult. Vascular reactivity was evaluated in aortic rings. Chronic HgCl₂ exposure did not cause more heart injury than MI alone in terms of the morphological or hemodynamic parameters. Vascular reactivity increased in all groups, but the combination of HgCl₂-MI increased the vasorelaxation induced by ACh compared with the HgCl₂ and MI groups. Results showed reduced endothelial nitric oxide synthase (eNOS) protein expression in the MI group; increased iNOS activity in the HgCl₂-MI group, although without enough magnitude to reverse the reduction in NO bioavailability; and increased phenylephrine response in the HgCl₂-MI group due to an increase in ROS production, notably via xanthine oxidase (XO). Results suggest that the combination of 1 month pre-exposure of HgCl₂ before MI changed the endothelial generation of oxidative stress induced by mercury exposure from NADPH oxidase pathway to XO (xanthine oxidase)-dependent ROS production.     

Comprehensive long-term safety of adalimumab from 18 clinical trials in adult patients with moderate-to-severe plaque psoriasis

Adalimumab is a powerful drug used to treat psoriasis, that has been specially designed to mimic normal human molecules, and for this reason it is classed as a ‘biological’ drug. It reduces inflammation by inhibiting the activity of a chemical ‘cytokine’ in the body called ‘tumour necrosis factor alpha’ (TNF-alpha). The aim of this study, from the USA, was to assess long-term safety for patients with psoriasis receiving adalimumab. The authors looked at data from 3727 patients receiving the drug as part of 18 different clinical trials in which adverse events (AEs, meaning unwanted side effects while on the drug) were recorded. Overall, there were 16,536 AEs during 5429.7 patient years (304.6 AEs for every 100 patient years). Patient years (PYs) means the number of patients, multiplied by the amount of time they were included in the study. Most common AEs were nasopharyngitis (a common throat complaint), upper respiratory infection, and headache (23.7, 12.9, and 7.9 AEs per 100 PYs, respectively). Incidence rates for serious infections, tuberculosis, and opportunistic infections were 1.8, 0.3, and 0.02 AEs per 100 PYs, respectively. Incidence of malignancy (cancer) excluding non-melanoma skin cancer (NMSC) was 0.8 AEs per 100 PYs. Incidences of NMSC and melanoma were 0.6 and 0.2 AEs per 100 PYs, respectively. The authors conclude that AE rates remained stable in this analysis of patients with psoriasis receiving adalimumab; no new safety signals (such as increased AEs) were identified compared with earlier studies.     

Misidentification of mental health symptoms in presence of organic diseases and delirium during psychiatric liaison consulting

Objective: To identify predictors of misidentification of organic mental disorders and delirium in patients undergoing psychiatric liaison consultation.

Methods: Data were collected at Santa Casa de São Paulo between July of 2009 and March of 2013. We included in our analysis all inpatients for whom the requesting service judged that a psychiatric consultation was required for a possible mental health condition. Outcomes of interest were the instances of misidentification where a condition was initially deemed to be of a psychiatric nature, whereas the final diagnosis by the liaison psychiatric team was of an organic disease or delirium. Our predictors were the clinical specialty of the requesting service, requester and patient characteristics. A series of generalised linear models were used to evaluate misidentification risks.

Results: A total of 947 subjects met our inclusion criteria, 14.6% having a final liaison diagnosis of organic mental disorder and 8.1% of delirium. Older patients were significantly associated with increased risk of misidentification for both organic conditions (OR 3.01 – 95% CI 2.01, 4.5) and delirium (OR 3.92 – 2.4, 6.39).

Conclusions: Educational interventions in general hospitals focused on preventing psychiatric misdiagnosis should target in-hospital services where patients tend to be older.     

Cardiovascular effects elicited by milonine, a new 8,14-dihydromorphinandienone alkaloid

Abstract: The mechanisms underlying the cardiovascular responses evoked by milonine (i.v.), an alkaloid, were investigated in rats. In normotensive rats, milonine injections produced hypotension and tachycardia, which were attenuated after N^w‐nitro‐l ‐arginine methyl esther (l ‐NAME; 20 mg/kg, i.v.). In phenylephrine (10 μM), pre‐contracted mesenteric artery rings, milonine (10^?10 M to 3 × 10^?4 M) caused a concentration‐dependent relaxation (EC₅₀ = 1.1 × 10^?6 M, E_max = 100 ± 0.0%) and this effect was rightward shifted after either removal of the vascular endothelium (EC₅₀ = 1.6 × 10^?5, p < 0.001), or after l ‐NAME 100 μM (EC₅₀ = 6.2 × 10^?5, p < 0.001), hydroxocobalamin 30 μM (EC₅₀ = 1.1 × 10^?4, p < 0.001) or ODQ 10 μM (EC₅₀ = 1.9 × 10^?4p < 0.001). In addition, in rabbit aortic endothelial cells, milonine increased NO₃^? levels. The relaxant effect induced by milonine was attenuated in the presence of KCl (20 mM), a modulator efflux K⁺ (EC₅₀ = 1.2 × 10^?5, p < 0.001), or different potassium channel blockers such as glibenclamide (10 μM) (EC₅₀ = 6.3 × 10^?5, p < 0.001), TEA (1 mM) (EC₅₀ = 2.3 × 10^?5 M, n = 6) or Charybdotoxin (0.2 μM) plus apamin (0.2 μM) (EC₅₀ = 3.9 × 10^?4 M, n = 7). In addition, pre‐contraction with high extracellular potassium concentration prevented milonine‐induced vasorelaxation (EC₅₀ = 1.0 × 10^?4, p < 0.001). Milonine also reduced CaCl₂‐induced contraction in Ca²⁺‐free solution containing KCl (60 mM). In conclusion, using combined functional and biochemical approaches, we demonstrated that the hypotensive and vasorelaxant effects produced by milonine are, at least in part, mediated by the endothelium, likely via nitric oxide release, activation of nitric oxide‐cGMP pathway and opening of K⁺ channels.