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1.  Stage managing bipolar disorder 
Bipolar disorders  2013;16(5):471-477.
Objectives
Clinical staging is widespread in medicine—it informs prognosis, clinical course and treatment, and assists individualized care. Staging places an individual on a probabilistic continuum of increasing potential disease severity, ranging from clinically at-risk or latency stage through first threshold episode of illness or recurrence and finally to late or end-stage disease. The aim of this paper was to examine and update the evidence regarding staging in bipolar disorder, and how this might inform targeted and individualized intervention approaches.
Methods
We provide a narrative review of the relevant information.
Results
In bipolar disorder, the validity of staging is informed by a range of findings that accompany illness progression, including neuroimaging data suggesting incremental volume loss, cognitive changes, and a declining likelihood of response to pharmacological and psychosocial treatments. Staging informs the adoption of a number of approaches, including the active promotion of both indicated prevention for at-risk individuals and early intervention strategies for newly diagnosed individuals, and the tailored implementation of treatments according to the stage of illness.
Conclusions
The nature of bipolar disorder implies the presence of an active process of neuroprogression that is considered at least partly mediated by inflammation, oxidative stress, apoptosis and changes in neurogenesis. It further supports the concept of neuroprotection, in that a diversity of agents have putative effects against these molecular targets. Clinically, staging suggests that the at-risk state or first episode is a period that requires particularly active and broad-based treatment, consistent with the hope that the temporal trajectory of the illness can be altered. Prompt treatment may be potentially neuroprotective and attenuate the neurostructural and neurocognitve changes that emerge with chronicity. Staging highlights the need for interventions at a service delivery level and implementing treatments at the earliest stage of illness possible.
doi:10.1111/bdi.12099
PMCID: PMC3864129  PMID: 23782499
bipolar disorder; clinical staging; depression; early intervention; mania; neuroprogression; treatment
2.  Caspase 3 inactivation protects against hepatic cell death and ameliorates fibrogenesis in a diet induced NASH model 
Digestive diseases and sciences  2014;59(6):1197-1206.
Background/Aims
Hepatocyte cell death is a key feature of nonalcoholic steohepatitis (NASH). As the contribution of specific caspases remains unclear, our aim was to ascertain the effect of caspase 3 suppression on liver injury and fibrogenesis.
Methods
C57BL/6 wild-type (WT), and caspase 3 knock out (Casp3−/−) mice were placed on a methionine- and choline-deficient (MCD) diet for 6 weeks to induce steatohepatitis and liver fibrosis. Thereafter, liver injury, liver fibrosis and hepatocellular apoptosis were quantified in liver sections. Additionally, expression of proteins associated with liver inflammation and fibrogenesis were analyzed.
Results
WT mice fed MCD diet showed marked activation of caspase 3 in hepatocytes, in conjunction with steatohepatitis and increased hepatic triglyceride levels, hepatocyte ballooning, inflammation and fibrosis. Casp3−/− fed the MCD diet showed similar serum ALT levels and NAFLD activity scores (NAS) compared to WT MCD-fed mice. However Casp3−/− mice on the MCD diet showed a marked reduction in expression of transcripts for pro-fibrogenic genes i which translated into reduced hepatic collagen deposition. These changes were associated with decreased levels of apoptosis, and a significant reduction in the expression of cytokines involved in inflammatory signaling. Casp3−/− mice on the MCD showed a reduction in expression of chemokine receptor 2 (CCR2) leading to ameliorated infiltration of inflammatory lymphocyte antigen 6 complex, locus C1 (Ly6c) positive monocytes.
Conclusion
These findings support a prominent role for hepatocyte caspase 3 activation in NASH related apoptosis, fibrogenesis and fibrosis which in part is mediated via CCR2 dependent infiltration of Ly6c positive monocytes.
doi:10.1007/s10620-014-3167-6
PMCID: PMC4512760  PMID: 24795036
nonalcoholic fatty liver disease; caspases; apoptosis; liver injury; liver fibrosis
3.  Excessive daytime sleepiness and falls among older men and women: cross-sectional examination of a population-based sample 
BMC Geriatrics  2015;15:74.
Background
Excessive daytime sleepiness (EDS) has been associated with an increased risk for falls among clinical samples of older adults. However, there is little detailed information among population-representative samples. The current study aimed to assess the relationship between EDS and falls among a cohort of population-based older adults.
Methods
This study assessed 367 women aged 60-93years (median 72, interquartile range 65-79) and 451 men aged 60-92years (median 73, interquartile range 66-80) who participated in the Geelong Osteoporosis Study between the years 2001 and 2008. Falls during the prior year were documented via self-report, and for men, falls risk score was obtained using an Elderly Fall Screening Test (EFST). Sleepiness was assessed using the Epworth Sleepiness Scale (ESS), and scores of ≥ 10 indicated EDS. Differences among those with and without EDS in regard to falls were tested using logistic regression models.
Results
Among women, 50 (13.6 %) individuals reported EDS. Women with EDS were more likely to report a fall, and were more likely to report the fall occurring outside. EDS was similarly associated with an increased risk of a fall following adjustment for use of a walking aid, cases of nocturia and antidepressant medication use (adjusted OR = 2.54, 95 % CI 1.24-5.21). Multivariate modelling revealed antidepressant use (current) as an effect modifier (p < .001 for the interaction term). After stratifying the data by antidepressant medication use, the association between EDS and falls was sustained following adjustment for nocturia among antidepressant non-users (adjusted OR = 2.63, 95 % CI 1.31-5.30). Among men, 72 (16.0 %) individuals reported EDS. No differences were detected for men with and without EDS in regard to reported falls, and a trend towards significance was noted between EDS and a high falls risk as assessed by the EFST (p = 0.06), however, age explained this relationship (age adjusted OR = 2.20, 95 % CI 1.03-1.10).
Conclusions
For women, EDS is independently associated with at least one fall during the previous year, and this is more likely to occur whilst located outside. Amelioration of EDS may assist in improving functional outcomes among these individuals by reducing the risk for falls.
doi:10.1186/s12877-015-0068-2
PMCID: PMC4491238  PMID: 26141865
Excessive daytime sleepiness; Falls; Older adults; Epidemiology; Population; Elderly
4.  Impact of Cannabis Use on Long-Term Remission in Bipolar I and Schizoaffective Disorder 
Psychiatry Investigation  2015;12(3):349-355.
Objective
To investigate the impact of regular cannabis use on long-term remission of mood symptoms in bipolar spectrum disorders.
Methods
The 24-month prospective observational study included patients (n=239) with bipolar I disorder and schizoaffective disorder, bipolar type. Participants were classified as regular cannabis users (three times or more per week) or non-users. The primary outcome measure was the achievement of remission on the evaluations during the 24 months.
Results
Of the 234 participants for whom data was available, 25 (10.7%) were regular cannabis users, and the group comprised significantly more males than females. In the total population, cannabis use was significantly associated with decreased likelihood of remission during the 24-month follow-up period. Subgroup analyses showed that cannabis use was significantly associated with lower remission rates on the Hamilton Depression Rating Scale in females (n=139) and patients prescribed mood stabilizers alone (n=151), whereas in males (n=95) and patients prescribed olanzapine and/or a mood stabilizer (n=83), cannabis use was significantly associated with lower remission rates on the Young Mania Rating Scale. Remission rates were lowest in the concurrent cannabis and tobacco smoking group (n=22) followed by the tobacco smoking only group (n=97), and the non-smoker group (n=116). The post-hoc analysis revealed that all remission rates were significantly lower in the concurrent cannabis and the tobacco smoking group compared to the non-smoker group.
Conclusion
Cannabis use negatively affects the long-term clinical outcome in patients with bipolar spectrum disorders. A comprehensive assessment and integrated management of cannabis use are required to achieve better treatment outcomes for bipolar spectrum disorders.
doi:10.4306/pi.2015.12.3.349
PMCID: PMC4504917  PMID: 26207128
Cannabis; Bipolar disorder; Schizoaffective disorder; Observational study; Substance; Remission
5.  Mechanisms Underlying Neurocognitive Dysfunctions in Recurrent Major Depression 
Recent work shows that depression is intimately associated with changes in cognitive functioning, including memory, attention, verbal fluency, and other aspects of higher-order cognitive processing. Changes in cognitive functioning are more likely to occur when depressive episodes are recurrent and to abate to some degree during periods of remission. However, with accumulating frequency and duration of depressive episodes, cognitive deficits can become enduring, being evident even when mood improves. Such changes in cognitive functioning give depression links to mild cognitive impairment and thereby with neurodegenerative conditions, including Alzheimer’s disease, Parkinson’s disease, schizophrenia, and multiple sclerosis. Depression may then be conceptualized on a dimension of depression – mild cognitive impairment – dementia. The biological underpinnings of depression have substantial overlaps with those of neurodegenerative conditions, including reduced neurogenesis, increased apoptosis, reactive oxygen species, tryptophan catabolites, autoimmunity, and immune-inflammatory processes, as well as decreased antioxidant defenses. These evolving changes over the course of depressive episodes drive the association of depression with neurodegenerative conditions. As such, the changes in cognitive functioning in depression have important consequences for the treatment of depression and in reconceptualizing the role of depression in wider neuroprogressive conditions. Here we review the data on changes in cognitive functioning in recurrent major depression and their association with other central conditions.
doi:10.12659/MSM.893176
PMCID: PMC4459569  PMID: 26017336
Cognition; Depression; Inflammation; Neurogenesis; Oxidants
6.  Cognitive impairment in first-episode mania: a systematic review of the evidence in the acute and remission phases of the illness 
There is evidence of cognitive impairment that persists in the remission phase of bipolar disorder; however, the extent of the deficits that occur from the first onset of the disorder remains unclear. This is the first systematic review on cognitive functioning in the early stages of bipolar I disorder. The aim of the study was to identify the patterns and degree of cognitive impairment that exists from first-episode mania. Three electronic databases (MEDLINE, PsycINFO and PubMed) were systematically searched for studies published from January 1980 to June 2014. Eligible studies were separated into two groups: acute and remission. The Newcastle-Ottawa quality assessment scale was utilised to measure the quality of the included studies. A total of seven studies (three acute and four remission), including 230 first-episode mania and 345 healthy control participants, were eligible for the review. The studies in the acute phase only examined aspects of executive functioning, with impairments identified in cognitive flexibility, though not in response inhibition and verbal fluency relative to healthy controls. The most consistent finding during the remission phase was a deficit in working memory, whereas in the other domains, the findings were equivocal. Non-verbal memory and verbal fluency were not impacted in remission from first-episode mania. In conclusion, deficits are present in some but not all areas of cognitive functioning during the early stages of bipolar I disorder. Further research is warranted to understand the longitudinal trajectory of change from first-episode mania.
Electronic supplementary material
The online version of this article (doi:10.1186/s40345-015-0024-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s40345-015-0024-2
PMCID: PMC4408302  PMID: 25914866
Mania; Cognition; Bipolar disorder; Depression; First episode; Early intervention
8.  Oxidant/antioxidant imbalance is an inherent feature of depression 
BMC Psychiatry  2015;15:71.
Background
50% to 60% of the people who have recovered from the first episode of depression experience a relapse. The immune system of the people suffering from depression is in a permanent state of pathological pro-inflammatory readiness. There are some reports that depressive episodes cause sensitization of immune-inflammatory pathways and that staing of depression (e.g. number of depressive episodes) is correlated with immune-inflammatory markers.
The main objective of the study was to delineate whether recurrent major depression (rDD) is characterized by alterations in selected immune-inflammatory biomarkers as compared with first episode of depression (ED-I), i.e. expression of mRNA and enzymatic activity of manganese superoxide dismutase (MnSOD, SOD-2), myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS, NOS-2), and cyclooxygenase-2 (COX-2).
Methods
The study was carried out in a group of 131 patients: ED-I group – 42 patients, rDD group – 89 patients. Depression severity was assessed with the 17-item Hamilton Depression Rating Scale (HDRS). The number of depression episodes and the disease duration periods were recorded in each patient. For the patients, HDRS was administered at admission during the symptomatic phase, which would generally be either before or shortly after modification of the previous antidepressant drug regimen. Reassessment of the mental condition was conducted after 8 weeks of the pharmacological treatment also with the use of the HDRS scale.
Results
No significant statistical differences were found between the analysed groups as regards the intensity of depressive disorders. No differences in the expression of MnSOD, MPO, COX-2 and i-NOS genes on the level of both mRNA and protein were observed between both groups. No significant interrelation was noticed between the number of depression episodes experienced and the expression of selected genes on the mRNA level and protein level.
Conclusions
There is no significant difference in MnSOD, MPO, COX-2 and i-NOS between patients with recurrent depressive disorders and those in a first episode of depression. These findings suggest that these enzymes are trait markers of depression and are not related to staging of depression.
doi:10.1186/s12888-015-0454-5
PMCID: PMC4392866  PMID: 25880127
Depression episode; rDD; MnSOD; MPO; COX-2; i-NOS
9.  Psychiatric disorders, psychotropic medication use and falls among women: an observational study 
BMC Psychiatry  2015;15:75.
Background
Psychotropic agents known to cause sedation are associated with an increased risk of falls, but the role of psychiatric illness as an independent risk factor for falls is not clear. Thus, this study aimed to investigate the association between psychiatric disorders, psychotropic medication use and falls risk.
Methods
This study examined data collected from 1062 women aged 20-93 yr (median 50 yr) participating in the Geelong Osteoporosis Study, a large, ongoing, population-based study. Depressive and anxiety disorders for the preceding 12-month period were ascertained by clinical interview. Current medication use and falls history were self-reported. Participants were classified as fallers if they had fallen to the ground at least twice during the same 12-month period. Anthropometry, demographic, medical and lifestyle factors were determined. Logistic regression was used to test the associations, after adjusting for potential confounders.
Results
Fifty-six women (5.3%) were classified as fallers. Those meeting criteria for depression within the past 12 months had a 2.4-fold increased odds of falling (unadjusted OR = 2.4, 95% CI 1.2-4.5). Adjustment for age and mobility strengthened the relationship (adjusted OR = 2.7, 95% CI 1.4-5.2) between depression and falling, with results remaining unchanged following further adjustment for psychotropic medication use (adjusted OR = 2.7, 95% CI 1.3-5.6). In contrast, past (prior to 12-month) depression were not associated with falls. No association was observed between anxiety and falls risk. Falling was associated with psychotropic medication use (unadjusted OR = 2.8, 95% CI 1.5-5.2), as well as antidepressant (unadjusted OR = 2.4, 95% CI 1.2-4.8) and benzodiazepine use (unadjusted OR = 3.4, 95% CI 1.6-7.3); associations remained unchanged following adjustment for potential confounders.
Conclusion
The likelihood of falls was increased among those with depression within the past 12 months, independent of psychotropic medication use and other recognised confounders, suggesting an independent effect of depression on falls risk. Psychotropic drug use was also confirmed as an independent risk factor for falls, but anxiety disorders were not. Further research into the underlying mechanisms is warranted.
doi:10.1186/s12888-015-0439-4
PMCID: PMC4394398  PMID: 25884941
Depression; Anxiety; Falls; Psychotropic medication; Antidepressants; Benzodiazepine
10.  Microparticles Release by Adipocytes Act as “Find-Me” Signals to Promote Macrophage Migration 
PLoS ONE  2015;10(4):e0123110.
Macrophage infiltration of adipose tissue during weight gain is a central event leading to the metabolic complications of obesity. However, what are the mechanisms attracting professional phagocytes to obese adipose tissue remains poorly understood. Here, we demonstrate that adipocyte-derived microparticles (MPs) are critical “find-me” signals for recruitment of monocytes and macrophages. Supernatants from stressed adipocytes stimulated the attraction of monocyte cells and primary macrophages. The activation of caspase 3 was required for release of these signals. Adipocytes exposed to saturated fatty acids showed marked release of MPs into the supernatant while common genetic mouse models of obesity demonstrate high levels of circulating adipocyte-derived MPs. The release of MPs was highly regulated and dependent on caspase 3 and Rho-associated kinase. Further analysis identified these MPs as a central chemoattractant in vitro and in vivo. In addition, intravenously transplanting circulating MPs from the ob/ob mice lead to activation of monocytes in circulation and adipose tissue of the wild type mice. These data identify adipocyte-derived MPs as novel “find me” signals that contributes to macrophage infiltration associated with obesity.
doi:10.1371/journal.pone.0123110
PMCID: PMC4388837  PMID: 25849214
11.  Beta-Lactam Antibiotics as A Possible Novel Therapy for Managing Epilepsy and Autism, A Case Report and Review of Literature  
Autism is a disorder of unknown etiology. There are few FDA approved medications for treating autism. Co-occurring autism and epilepsy is common, and glutamate antagonists improve some symptoms of autism. Ceftriaxone, a beta-lactam antibiotic, increases the expression of the glutamate transporter 1 which decreases extracellular glutamate levels. It is hypothesized that modulating astrocyte glutamate transporter expression by ceftriaxone or cefixime might improve some symptoms of autism. This case report of a child with autism and epilepsy suggests a decrease in seizures after taking cefixime
PMCID: PMC4322506  PMID: 25767546
Cefixime; Antibiotic; Glutamate; Transporter; Therapy; Inflammation
12.  The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders 
BMC Medicine  2015;13:68.
Background
Mitochondrial dysfunction and defects in oxidative metabolism are a characteristic feature of many chronic illnesses not currently classified as mitochondrial diseases. Examples of such illnesses include bipolar disorder, multiple sclerosis, Parkinson’s disease, schizophrenia, depression, autism, and chronic fatigue syndrome.
Discussion
While the majority of patients with multiple sclerosis appear to have widespread mitochondrial dysfunction and impaired ATP production, the findings in patients diagnosed with Parkinson’s disease, autism, depression, bipolar disorder schizophrenia and chronic fatigue syndrome are less consistent, likely reflecting the fact that these diagnoses do not represent a disease with a unitary pathogenesis and pathophysiology. However, investigations have revealed the presence of chronic oxidative stress to be an almost invariant finding in study cohorts of patients afforded each diagnosis. This state is characterized by elevated reactive oxygen and nitrogen species and/or reduced levels of glutathione, and goes hand in hand with chronic systemic inflammation with elevated levels of pro-inflammatory cytokines.
Summary
This paper details mechanisms by which elevated levels of reactive oxygen and nitrogen species together with elevated pro-inflammatory cytokines could conspire to pave a major road to the development of mitochondrial dysfunction and impaired oxidative metabolism seen in many patients diagnosed with these disorders.
doi:10.1186/s12916-015-0310-y
PMCID: PMC4382850  PMID: 25889215
Autism; Bipolar disorder; Schizophrenia; Chronic fatigue syndrome; Cytokines; Depression; Immune dysfunction; Inflammatory; Mitochondrial dysfunction; Multiple sclerosis; Nitric oxide; Oxidative stress; Parkinson’s disease; Peroxynitrite; Psychiatry; Neurology
13.  N-Acetyl Cysteine in the Treatment of Obsessive Compulsive and Related Disorders: A Systematic Review 
Objective
Obsessive compulsive and related disorders are a collection of debilitating psychiatric disorders in which the role of glutamate dysfunction in the underpinning neurobiology is becoming well established. N-acetyl cysteine (NAC) is a glutamate modulator with promising therapeutic effect. This paper presents a systematic review of clinical trials and case reports exploring the use of NAC for these disorders. A further objective was to detail the methodology of current clinical trials being conducted in the area.
Methods
PubMed, Web of Science and Cochrane Library Database were searched for human clinical trials or case reports investigating NAC in the treatment of obsessive compulsive disorder (OCD) or obsessive compulsive related disorders. Researchers with known involvement in NAC studies were contacted for any unpublished data.
Results
Four clinical trials and five case reports/series were identified. Study durations were commonly 12-weeks, using 2,400–3,000 mg/day of NAC. Overall, NAC demonstrates activity in reducing the severity of symptoms, with a good tolerability profile and minimal adverse effects. Currently there are three ongoing randomized controlled trials using NAC for OCD (two adults and one pediatric), and one for excoriation.
Conclusion
Encouraging results have been demonstrated from the few pilot studies that have been conducted. These results are detailed, in addition to a discussion of future potential research.
doi:10.9758/cpn.2015.13.1.12
PMCID: PMC4423164  PMID: 25912534
Obsessive-compulsive disorder; Trichotillomania, acetylcysteine; Glutamate; Review, systematic
14.  Effects of Persisting Emotional Impact from Child Abuse and Norepinephrine Transporter Genetic Variation on Antidepressant Efficacy in Major Depression: A Pilot Study 
Objective
Previous studies suggest child abuse and serotonergic polymorphism influence depression susceptibility and anti-depressant efficacy. Polymorphisms of the norepinephrine transporter (NET) may also be involved. Research in the area is possibly clouded by under reporting of abuse in researcher trials.
Methods
Adults (n=51) with major depressive disorder has 8 weeks treatment with escitalopram or venlafaxine. Abuse history was obtained, the ongoing emotional impact of which was measured with the 15-item impact of event scale (IES-15). The 17-item Hamilton Depression Rating Scale (HDRS) was applied serially. Two NET polymorphisms (rs2242446 and rs5569) were assayed, blinded to HDRS ratings and abuse history.
Results
No subjects reporting abuse with high impact in adulthood (IES-15 ≥26, n=12) remitted; whereas 77% reporting low impact (IES-15 <26; n=26) remitted (p<0.001). Subjects reporting high impact abuse (n=12) had a 50-fold (95% confidence interval=4.85–514.6) greater odds of carrying rs2242446-TT genotype, but the small sample size leaves this finding vulnerable to type I error.
Conclusion
The level of persisting impact of child abuse appears relevant to antidepressant efficacy, with susceptibility to such possibly being influence by NET rs2242446 polymorphism. Larger studies may be merited to expand on this pilot level finding given potential for biomarker utility.
doi:10.9758/cpn.2015.13.1.53
PMCID: PMC4423165  PMID: 25912538
Abuse; Child; Antidepressants; Norepinephrine transporter; Remission
15.  Tobacco Use in Bipolar Disorder 
Tobacco use in mental health in general and bipolar disorder in particular remains disproportionally common, despite declining smoking rates in the community. Furthermore, interactions between tobacco use and mental health have been shown, indicating the outcomes for those with mental health disorders are impacted by tobacco use. Factors need to be explored and addressed to improve outcomes for those with these disorders and target specific interventions for people with psychiatric illness to cease tobacco smoking. In the context of bipolar disorder, this review explores; the effects of tobacco smoking on symptoms, quality of life, suicidal behaviour, the biological interactions between tobacco use and bipolar disorder, the interactions between tobacco smoking and psychiatric medications, rates and factors surrounding tobacco smoking cessation in bipolar disorder and suggests potential directions for research and clinical translation. The importance of this review is to bring together the current understanding of tobacco use in bipolar disorder to highlight the need for specific intervention.
doi:10.9758/cpn.2015.13.1.1
PMCID: PMC4423166  PMID: 25912533
Bipolar disorder; Smoking; Smoking cessation; Quality of life; Psychotropic drugs
16.  A brief review of exercise, bipolar disorder, and mechanistic pathways 
Despite evidence that exercise has been found to be effective in the treatment of depression, it is unclear whether these data can be extrapolated to bipolar disorder. Available evidence for bipolar disorder is scant, with no existing randomized controlled trials having tested the impact of exercise on depressive, manic or hypomanic symptomatology. Although exercise is often recommended in bipolar disorder, this is based on extrapolation from the unipolar literature, theory and clinical expertise and not empirical evidence. In addition, there are currently no available empirical data on program variables, with practical implications on frequency, intensity and type of exercise derived from unipolar depression studies. The aim of the current paper is to explore the relationship between exercise and bipolar disorder and potential mechanistic pathways. Given the high rate of medical co-morbidities experienced by people with bipolar disorder, it is possible that exercise is a potentially useful and important intervention with regard to general health benefits; however, further research is required to elucidate the impact of exercise on mood symptomology.
doi:10.3389/fpsyg.2015.00147
PMCID: PMC4349127  PMID: 25788889
bipolar disorder; exercise; mechanistic pathways; depression; hypomania; neurogenesis
17.  Prevention of Schizophrenia—Will a Broader Prevention Agenda Support This Aim? 
Schizophrenia Bulletin  2014;40(2):237-239.
doi:10.1093/schbul/sbt202
PMCID: PMC3932093  PMID: 24391020
18.  Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses 
BMC Medicine  2015;13:28.
Background
The genesis of severe fatigue and disability in people following acute pathogen invasion involves the activation of Toll-like receptors followed by the upregulation of proinflammatory cytokines and the activation of microglia and astrocytes. Many patients suffering from neuroinflammatory and autoimmune diseases, such as multiple sclerosis, Parkinson’s disease and systemic lupus erythematosus, also commonly suffer from severe disabling fatigue. Such patients also present with chronic peripheral immune activation and systemic inflammation in the guise of elevated proinflammtory cytokines, oxidative stress and activated Toll-like receptors. This is also true of many patients presenting with severe, apparently idiopathic, fatigue accompanied by profound levels of physical and cognitive disability often afforded the non-specific diagnosis of chronic fatigue syndrome.
Discussion
Multiple lines of evidence demonstrate a positive association between the degree of peripheral immune activation, inflammation and oxidative stress, gray matter atrophy, glucose hypometabolism and cerebral hypoperfusion in illness, such as multiple sclerosis, Parkinson’s disease and chronic fatigue syndrome. Most, if not all, of these abnormalities can be explained by a reduction in the numbers and function of astrocytes secondary to peripheral immune activation and inflammation. This is also true of the widespread mitochondrial dysfunction seen in otherwise normal tissue in neuroinflammatory, neurodegenerative and autoimmune diseases and in many patients with disabling, apparently idiopathic, fatigue. Given the strong association between peripheral immune activation and neuroinflammation with the genesis of fatigue the latter group of patients should be examined using FLAIR magnetic resonance imaging (MRI) and tested for the presence of peripheral immune activation.
Summary
It is concluded that peripheral inflammation and immune activation, together with the subsequent activation of glial cells and mitochondrial damage, likely account for the severe levels of intractable fatigue and disability seen in many patients with neuroimmune and autoimmune diseases.This would also appear to be the case for many patients afforded a diagnosis of Chronic Fatigue Syndrome.
doi:10.1186/s12916-014-0259-2
PMCID: PMC4320458  PMID: 25856766
Immune; Inflammation; Oxidative stress; Toll-like receptor; Fatigue; Mitochondria; Multiple sclerosis; Chronic fatigue syndrome; Parkinson’s disease
19.  A shared framework for the common mental disorders and Non-Communicable Disease: key considerations for disease prevention and control 
BMC Psychiatry  2015;15:15.
Background
Historically, the focus of Non Communicable Disease (NCD) prevention and control has been cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), cancer and chronic respiratory diseases. Collectively, these account for more deaths than any other NCDs. Despite recent calls to include the common mental disorders (CMDs) of depression and anxiety under the NCD umbrella, prevention and control of these CMDs remain largely separate and independent.
Discussion
In order to address this gap, we apply a framework recently proposed by the Centers for Disease Control with three overarching objectives: (1) to obtain better scientific information through surveillance, epidemiology, and prevention research; (2) to disseminate this information to appropriate audiences through communication and education; and (3) to translate this information into action through programs, policies, and systems. We conclude that a shared framework of this type is warranted, but also identify opportunities within each objective to advance this agenda and consider the potential benefits of this approach that may exist beyond the health care system.
doi:10.1186/s12888-015-0394-0
PMCID: PMC4342822  PMID: 25652365
Non-Communicable Disease; Common mental disorders; Prevention; Depression; Anxiety; Cardiovascular disease; Type 2 diabetes mellitus; Co-morbidity
20.  The impact of maternal smoking during pregnancy on depressive and anxiety behaviors in children: the Norwegian Mother and Child Cohort Study 
BMC Medicine  2015;13:24.
Background
Maternal smoking during pregnancy (MSDP) is associated with multiple adverse childhood outcomes including externalizing behaviors. However, the association between MSDP and internalizing (anxiety and depressive) behaviors in offspring has received less investigation. We aimed to assess the association between MSDP and childhood internalizing (anxiety and depressive) behaviors in a very large, well-characterized cohort study.
Methods
We assessed the association between MSDP and internalizing behaviors in offspring utilizing information drawn from 90,040 mother-child pairs enrolled in the Norwegian Mother and Child Cohort Study. Mothers reported smoking information, including status and frequency of smoking, twice during pregnancy. Mothers also reported their child’s internalizing behaviors at 18 months, 36 months, and 5 years. Associations between MSDP and childhood internalizing behaviors, including dose-response and timing of smoking in pregnancy, were assessed at each time point.
Results
MSDP was associated with increased internalizing behaviors when offspring were aged 18 months (B = 0.11, P <0.001) and 36 months (B = 0.06, P <0.01), adjusting for numerous potential confounders. Higher rates of smoking (e.g., >20 cigarettes per day) were associated with higher levels of internalizing behaviors. Maternal smoking during early pregnancy appeared to be the critical period for exposure.
Conclusions
We found evidence supporting a potential role for MSDP in increasing internalizing (anxiety and depressive) behaviors in offspring. We also found evidence supportive of a possible causal relationship, including dose-dependency and support for a predominant role of early pregnancy exposure. Further investigation utilizing genetically informed designs are warranted to assess this association.
doi:10.1186/s12916-014-0257-4
PMCID: PMC4314755  PMID: 25644294
Anxiety; Depression; Cigarette smoking; Pregnancy; Obstetrics; Psychiatry
21.  Stearoyl-CoA desaturase plays an important role in proliferation and chemoresistance in human hepatocellular carcinoma 
The Journal of surgical research  2013;186(1):29-38.
Background
Hepatocellular carcinoma (HCC) is often diagnosed at an advanced stage, when it is not amenable for aggressive therapies such as surgical resection or liver transplantation. Current therapeutic options achieve clinical responses in only a small percentage of cases. As a consequence, effective approaches for prevention and treatment are greatly needed. Altered lipid metabolism has been recently linked to HCC pathogenesis. The aims of this study were to define the cellular and molecular mechanisms linking stearoyl-CoA desaturase (SCD), the rate-limiting enzyme and an essential regulator of lipid homeostasis in liver cells, to carcinogenesis in HCC.
Material and methods
HCC and normal liver specimens were collected. Human HCC cell lines: HepG2, Hep3B, and PLC/PLF/5 were used for immunoblot, cell viability, proliferation, and apoptosis assays. Small interfering RNAs were used for genetic inhibition, and 10, 12 conjugated linoleic acid was used for pharmacologic SCD inhibition.
Results
SCD was strongly expressed in surgically resected HCC (n = 64) and various human HCC cell lines (HepG2, Hep3B, and PLC/PLF/5). The levels of SCD negatively correlated with degree of tumor differentiation (P < 0.01). Treatment of these HCC cell lines with a panel of chemotherapeutic drugs resulted in a time-dependent, phosphatidylinositol 3 kinase- and c-Jun N-terminal kinases1/2–mediated upregulation of SCD expression, which paralleled the degree of resistance to drug-induced apoptosis. Specific genetic or pharmacologic SCD suppression resulted in inhibition of cell proliferation (P < 0.001) and significantly increased sensitivity to chemotherapy-induced apoptosis.
Conclusions
Our data suggest that increased SCD expression plays an important role in HCC development and resistance to chemotherapy-induced apoptosis, and this is in part mediated by phosphatidylinositol 3 kinase/c-Jun N-terminal kinases activation. Specific targeted interruption of this pathway in HCC could be a desirable approach in designing novel therapeutic strategies.
doi:10.1016/j.jss.2013.07.001
PMCID: PMC3923502  PMID: 24135379
Lipid metabolism; Apoptosis; Stearoyl-CoA desaturase; Carcinogenesis; Chemotherapy
22.  Construct validity of the Experiences of Therapy Questionnaire (ETQ) 
BMC Psychiatry  2014;14:369.
Background
The Experiences of Therapy Questionnaire (ETQ) is a reliable measure of adverse effects associated with psychotherapy. The measure has not been subject to validity analyses. This study sought to examine the validity of the ETQ by comparison against a measure of therapist satisfaction.
Methods
Participants were recruited from the Black Dog Institute’s website and completed all measures online, at two time points (two weeks apart). Correlational analyses compared scale scores on the ETQ with related constructs of the Therapist Satisfaction Scale (TSS). To exclude any impact of current depression on ratings, we examined correlations between salient ETQ and TSS scales after controlling for depression severity.
Results
Forty-six participants completed all the measures at both time points. Hypothesised associations between the ETQ and TSS scales were supported, irrespective of current depression severity.
Conclusions
The validity of the ETQ is supported; however limitations of the study are noted, including generalizability due to sample characteristics.
doi:10.1186/s12888-014-0369-6
PMCID: PMC4299478  PMID: 25551579
Therapy; Psychotherapy; Measure; Validity; Side-effects; Psychology; Questionnaire
23.  OxNASH Score Correlates with Histologic Features and Severity of Nonalcoholic Fatty Liver Disease 
Digestive diseases and sciences  2014;59(7):1617-1624.
Background and Aims
Oxidative stress is a core abnormality responsible for disease progression in nonalcoholic fatty liver disease (NAFLD). By employing a highly sensitive liquid chromatography-tandem mass spectrometry (LC/MS/MS) approach we recently were able to define the circulating profile of bioactive lipid peroxidation products characteristic of patients with nonalcoholic steatohepatitis (NASH) and developed the OxNASH score for NASH diagnosis. The aims of this study were to assess the utility of OxNASH as a predictor of NASH and study the association between OxNASH and specific histological features of NAFLD.
Methods
Our cohort consisted of 122 patients undergoing liver biopsy for clinical suspicion of NAFLD. The NAFLD activity score (NAS) calculated for each patient. Levels of fatty acid oxidation products were quantified using stable isotope dilution LC/MS/MS and OxNASH was calculated.
Results
The mean age was 49.3 (± 11.6) years and the mean BMI was 31.5 (± 4.8) kg/m2. The majority of patients were Caucasian (82%) and 48% were female. OxNASH correlated with NAS and its individual histologic features (steatosis, inflammation, and ballooning. P <0.05) with the strongest association being with inflammation [rho (95% CI) = 0.40 (0.23–0.57), p < 0.001]. Furthermore, there was a correlation between the stage of fibrosis and OxNASH (p = 0.001). These associations remained statistically significant after adjusting for multiple confounders.
Conclusions
In adult patients with NAFLD, OxNASH correlates with histologic features of NASH and appears to be a promising noninvasive marker.
doi:10.1007/s10620-014-3031-8
PMCID: PMC4279921  PMID: 24464211
Nonalcoholic steatohepatitis; oxidative stress; lipid peroxidation; noninvasive
24.  The effects of escitalopram on myocardial apoptosis and the expression of Bax and Bcl-2 during myocardial ischemia/reperfusion in a model of rats with depression 
BMC Psychiatry  2014;14:349.
Background
Major depressive disorder (MDD) is an independent risk factor for coronary heart disease (CHD), and influences the occurrence and prognosis of cardiovascular events. Although there is evidence that antidepressants may be cardioprotective after acute myocardial infarction (AMI) comorbid with MDD, the operative pathophysiological mechanisms remain unclear. Our aim was therefore to explore the molecular mechanisms of escitalopram on myocardial apoptosis and the expression of Bax and Bcl-2 in a rat model of depression during myocardial ischemia/reperfusion (I/R).
Methods
Rats were divided randomly into 3 groups (n = 8): D group (depression), DI/R group (depression with myocardial I/R) and escitalopram + DI/R group. The rats in all three groups underwent the same chronic mild stress and separation for 21 days, at the same time, in the escitalopram + DI/R group, rats were administered escitalopram by gavage (10 mg/kg/day). Ligation of the rat’s left anterior descending branch was done in the myocardial I/R model. Following which behavioral tests were done. The size of the myocardial infarction was detected using 1.5% TTC dye. The Tunel method was used to detect apoptotic myocardial cells, and both the Rt-PCR method and immunohistochemical techniques were used to detect the expression of Bcl–2 and Bax.
Results
Compared with the D and DI/R groups, rats in Escitalopram + DI/R group showed significantly increased movements and sucrose consumption (P < .01). Compared with the DI/R group, the myocardial infarct size in the escitalopram + DI/R group was significantly decreased (P < .01). Compared with the D group, there were significantly increased apoptotic myocardial cells in the DI/R and escitalopram + DI/R groups (P < .01); however compared with the DI/R group, apoptotic myocardial cell numbers in the escitalopram + DI/R group were significantly decreased (P < .01). Compared with the DI/R group, there was a down-regulated Bax:Bcl-2 ratio in the escitalopram + DI/R group (P < .01).
Conclusions
These results suggest that in patients with AMI comorbid with MDD, there is an increase in pro-apoptotic pathways that is reversed by escitalopram. This suggests that clinically escitalopram may have a direct cardioprotective after acute myocardial infarction.
doi:10.1186/s12888-014-0349-x
PMCID: PMC4259089  PMID: 25471226
Escitalopram; Depression; Myocardial infarction; Bax; Bcl-2
25.  Statin use and risk of depression: a Swedish national cohort study 
BMC Psychiatry  2014;14:348.
Background
Statin medications, used to prevent heart disease by reducing cholesterol, also reduce inflammation and protect against oxidative damage. As inflammation and oxidative stress occur in depression, there is interest in their potential to reduce depression risk. We investigated whether use of statin medications was associated with a change in the risk of developing depression in a very large Swedish national cohort (n = 4,607,990).
Methods
National register data for adults ≥40yr was analyzed to obtain information about depression diagnoses and prescriptions of statin medications between 2006 and 2008. Associations were tested using logistic regression.
Results
Use of any statin was shown to reduce the odds of depression by 8% compared to individuals not using statin medications (OR = 0.92, 95% CI, 0.89-0.96; p < 0.001). Simvastatin had a protective effect (OR = 0.93, 95% CI, 0.89-0.97; p = 0.001), whereas atorvastatin was associated with increased risk of depression (OR = 1.11, 95% CI, 1.01-1.22; p = 0.032). There was a stepwise decrease in odds ratio with increasing age (OR ≥ 40 years = 0.95, OR ≥ 50 years = 0.91, OR ≥ 60 years = 0.85, OR ≥ 70 years = 0.81).
Conclusions
The use of any statin was associated with a reduction in risk of depression in individuals over the age of 40. Clarification of the strength of these protective effects, the clinical relevance of these effects and determination of which statins are most effective is needed.
doi:10.1186/s12888-014-0348-y
PMCID: PMC4266881  PMID: 25471121
Statins; Atorvastatin; Simvastatin; Depression; Aetiology; Inflammation; Oxidative stress

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