Further characterization of agmatine binding to mitochondrial membranes: involvement of imidazoline I2 receptor.

Agmatine, a divalent diamine with two positive charges at physiological pH, is transported into the matrix of liver mitochondria by an energy-dependent mechanism, the driving force of which is the electrical membrane potential. Its binding to mitochondrial membranes is studied by applying a thermodynamic treatment of ligand-receptor interactions on the analyses of Scatchard and Hill. The presence of two mono-coordinated binding sites S(1) and S(2), with a negative influence of S(2) on S(1), has been demonstrated. The calculated binding energy is characteristic for weak interactions. S(1) exhibits a lower binding capacity and higher binding affinity both of about two orders of magnitude than S(2). Experiments with idazoxan, a ligand of the mitochondrial imidazoline receptor I(2), demonstrate that S(1) site is localized on this receptor while S(2) is localized on the transport system. S(1) would act as a sensor of exogenous agmatine concentration, thus modulating the transport of the amine by its binding to S(2)

Clinical Phenotypes and Comorbidity in European Sleep Apnoea Patients

Background Clinical presentation phenotypes of obstructive sleep apnoea (OSA) and their association with comorbidity as well as impact on adherence to continuous positive airway pressure (CPAP) treatment have not been established. Methods A prospective follow-up cohort of adult patients with OSA (apnoea-hypopnoea index (AHI) of 655/h) from 17 European countries and Israel (n = 6,555) was divided into four clinical presentation phenotypes based on daytime symptoms labelled as excessive daytime sleepiness ("EDS") and nocturnal sleep problems other than OSA (labelled as "insomnia"): 1) EDS (daytime+/nighttime-), 2) EDS/insomnia (daytime+/nighttime+), 3) non-EDS/noninsomnia (daytime-/nighttime-), 4) and insomnia (daytime-/nighttime+) phenotype. Results The EDS phenotype comprised 20.7%, the non-EDS/non-insomnia type 25.8%, the EDS/ insomnia type 23.7%, and the insomnia phenotype 29.8% of the entire cohort. Thus, clinical presentation phenotypes with insomnia symptoms were dominant with 53.5%, but only 5.6% had physician diagnosed insomnia. Cardiovascular comorbidity was less prevalent in the EDS and most common in the insomnia phenotype (48.9% vs. 56.8%, p<0.001) despite more severe OSA in the EDS group (AHI 35.0\ub125.5/h vs. 27.9\ub122.5/h, p<0.001, respectively). Psychiatric comorbidity was associated with insomnia like OSA phenotypes independent of age, gender and body mass index (HR 1.5 (1.188-1.905), p<0.001). The EDS phenotype tended to associate with higher CPAP usage (22.7 min/d, p = 0.069) when controlled for age, gender, BMI and sleep apnoea severity. Conclusions Phenotypes with insomnia symptoms comprised more than half of OSA patients and were more frequently linked with comorbidity than those with EDS, despite less severe OSA. CPAP usage was slightly higher in phenotypes with EDS

Pharmacological and Nonpharmacological Interventions to Arrest Neuroprogression in Psychiatric Disorders

The concept of neuroprogression describes the progressive course of the disorder and stresses the progressive, recurrent, and chronic course of the disease entity under consideration. It subsumes clinical manifestations of the disease process and may also entail morphological, biochemical, neurochemical, immunological, physiological, and genetic aspects that contribute to the progressive course of the disease in question. In an attempt to identify the appropriate agent or method that could arrest neuroprogression in psychiatric patients, we conducted an evaluation of the use of anti-inflammatory drugs under the perspective of current pharmacological and neurophysiological data. This evaluation included the use of nonsteroidal anti-inflammatory drugs (NSAIDs) as adjunctive treatment to conventional pharmacotherapy as well as the use of natural products exerting anti-inflammatory properties (i.e., ω-3 fatty acids) given as adjunctive or monotherapeutic treatments in less severe cases. The therapeutic significance of nonpharmacological methods, such as psychotherapy, physical exercise, and body-mind therapies, was also considered and will be discussed in this chapter. In conclusion, the role of psychotropic and select anti-inflammatory drugs in arresting neuroprogression is a very promising new frontier in psychiatric research and clinical practice. Modulators of a specific prostanoid synthase or receptor across the cyclooxygenase (COX)-2 downstream pathway along with new multitarget NSAIDs are expected to be tested by the pharmaceutical industry as potential agents to antagonize neuroprogression. Meanwhile, salicylates and selective COX-2 inhibitors could still be used in carefully selected subgroups of patients. Psychotherapy and nonpharmacological, stress-relieving methods should be considered as adjunctive tools to aid in arresting neuroprogression. © 2017 S. Karger AG, Basel

Noncardiac chest pain: systematic review of the literature on prognosis

Edwin Meresh, John Piletz, Angelos Halaris Department of Psychiatry and Behavioral Neurosciences, Loyola University Medical Center, Stritch School of Medicine, Maywood, IL, USA Background: Noncardiac chest pain (NCCP) is defined as persistent angina-like chest pain with no evidence of cardiac disease. There is some controversy about the long-term morbidity and mortality outcomes of NCCP patients. Many studies have found no significant differences in death rates in chest pain patients without coronary artery disease compared to the general population. However, studies that include longer follow-up periods and a better characterization of the NCCP population reveal a twofold elevation in the relative risk of adverse cardiac events over 5&ndash;26 years. This review sought to identify studies in relation to cardiovascular and psychological prognosis of NCCP patients.Methods: PubMed database and reference lists from relevant publications were reviewed. Inclusion criteria were systematic reviews, prospective studies, and retrospective surveys from 1970 to 2011. Search terms were as follows: chest pain, noncardiac chest pain, nonspecific chest pain, unexplained chest pain, prognosis of noncardiac chest pain, prognosis of angina with normal angiography, and angina with normal coronary arteries.Results: Studies supporting worse outcome (cardiac morbidity and mortality; n=16) included 173,875 patients with mean age 57 and mean length of follow-up 7.5 years. Studies supporting good outcome (n=25) included 244,998 patients with age 50 and length of follow-up 5 years. Articles supporting poor psychological outcome (n=9) included 3,987 patients and length of follow-up 2 years.Conclusion: There are mixed data on long-term morbidity, cardiovascular adverse events, and mortality of NCCP patients. Some studies provide supporting evidence for poor outcome, while others provide evidence for positive outcome. However, many patients with NCCP have prolonged psychosocial comorbidity. The heterogeneity of NCCP and study populations limited definitive conclusions. However, many patients with NCCP have psychiatric morbidity and poor quality of life. Several questions remain about NCPP with respect to the psychopathology and pathophysiology of this condition. Whether NCCP patients have good or bad outcome requires careful risk stratification. Keywords: chest pain, noncardiac chest pain, anxiety, angina with normal coronary arteries, microvascular angina, prognosi

Modulation of the inflammatory response exerts beneficial effects on anger in treatment-resistant bipolar depression

Background: : Anger can worsen a person's emotions and increase the severity of an individual's mood state, notably depression. The State-Trait Anger Expression Inventory (STAXI) assessment tool is useful for assessing the experience, expression, and control of anger in normal individuals, and in evaluating anger experienced by patients with a variety of psychological and medical disorders. Since its creation, STAXI has been utilized in various studies involving substance abuse and major depressive disorder; however, anger has never been studied systematically in bipolar depression. Scientific evidence supports the hypothesis that immune system activation, reflected in its inflammatory response, contributes to the pathophysiology and phenomenology of bipolar disorder. However, there is limited research showing how the treatment of bipolar disorder is enhanced with an anti-inflammatory agent and how it affects anger, which prompted this investigation. The current clinical study tested the hypothesis that co-administration of a specific anti-inflammatory agent, Celecoxib, along with Escitalopram, a selective serotonin reuptake inhibitor, would be beneficial in patients with treatment resistant bipolar depression. In comparison to patients receiving Escitalopram monotherapy, it was hypothesized that the combination therapy would lead to an augmented response in alleviating bipolar depression. In addition, the combination therapy would result in a greater percentage of responders and remitters. It also was hypothesized that the combination therapy would reduce anger symptoms as assessed by STAXI from beginning to end of treatment. Method: : In this double-blind, two-arm, placebo-controlled study, 65 consenting patients diagnosed with treatment resistant bipolar depression were randomized to receive either Escitalopram (10 mg twice/day) + Celecoxib (200 mg twice/day), or Escitalopram + placebo (twice/day). There were 47 completers: 27 in the Celecoxib, and 20 in the Placebo arm. The 17-item Hamilton Depression Rating Scale was used to assess response to treatment, with a 50% reduction from baseline indicating treatment response and a score < 7 indicating remission. The Beck Depression Index also was used as a self-report measure of depression. Levels of state and trait anger were assessed using the 57-item STAXI scale. Measures of depression, anger and perceived stress were collected at baseline and at week 8 of treatment. Results: : A multiple regression analysis of baseline data indicated that the Hamilton depression score was significantly related to the feelings subscale of the state STAXI. However, the baseline Beck score was found to be predicted by perceived stress. To test treatment effects, an analysis of covariance revealed that the week 8 Hamilton depression score was significantly lower for patients receiving the combination therapy, controlling for baseline differences. The week 8 Beck score also was lower for those in the combination therapy group, but was not statistically significant. In comparison to the monotherapy group, those receiving the combination therapy showed a statistically higher proportion of responders and remitters. Significant differences in state or trait anger subscales were found only responders to the CBX add-on arm at week 8. Limitations: : Limitations of the study include small sample size and short period of treatment. Conclusion: : An analysis of baseline data suggest that depression is associated with state feelings of anger and perceived stress. In comparison to receiving Escitalopram alone, the combination therapy was more effective in lowering Hamilton depression scores and was associated with greater proportions of responders and remitters. Anti-inflammatory combination therapy reduced state and trait anger by the end of treatment