Health, pre-disease and critical transition to disease in the psycho-immune-neuroendocrine network: Are there distinct states in the progression from health to major depressive disorder?

The psycho-immune-neuroendocrine (PINE) network is a regulatory network of interrelated physiological pathways that have been implicated in major depressive disorder (MDD). A model of disease progression for MDD is presented where the stable, healthy state of the PINE network (PINE physiome) undergoes progressive pathophysiological changes to an unstable but reversible pre-disease state (PINE pre-diseasome) with chronic stress. The PINE network may then undergo critical transition to a stable, possibly irreversible disease state of MDD (PINE pathome). Critical transition to disease is heralded by early warning signs which are detectible by biomarkers specific to the PINE network and may be used as a screening test for MDD. Critical transition to MDD may be different for each individual, as it is reliant on diathesis, which comprises genetic predisposition, intrauterine and developmental factors. Finally, we propose the PINE pre-disease state may form a "universal pre-disease state" for several non-communicable diseases (NCDs), and critical transition of the PINE network may lead to one of several frequently associated disease states (influenced by diathesis), supporting the existence of a common Chronic Illness Risk Network (CIRN). This may provide insight into both the puzzle of multifinality and the growing clinical challenge of multimorbidity.

Conduction Mechanisms on High Retention Annealed MgO-based Resistive Switching Memory Devices.

We report on the conduction mechanisms of novel Ru/MgO/Cu and Ru/MgO/Ta resistive switching memory (RSM) devices. Current-voltage (I-V) measurements revealed Schottky emission (SE) as the dominant conduction mechanism in the high resistance state (HRS), which was validated by varying temperatures and transmission electron microscopy (TEM) results. Retention of more than 10 years at 85 °C was obtained for both Ru/MgO/Ta and Ru/MgO/Cu RSM devices. In addition, annealing processes greatly improved the consistency of HRS and LRS switching paths from cycle to cycle, exhibiting an average ON/OFF ratio of 102. Further TEM studies also highlighted the difference in crystallinity between different materials in Ru/MgO/Cu RSM devices, confirming Cu filament identification which was found to be 10 nm in width.

From feedback loop transitions to biomarkers in the psycho-immune-neuroendocrine network: Detecting the critical transition from health to major depression.

BACKGROUND: Biological pathways underlying major depressive disorder (MDD) can be viewed as systems biology networks. The psycho-immune-neuroendocrine (PINE) network comprises central nervous, immune, endocrine and autonomic systems, integrating biological mechanisms of MDD. Such networks exhibit recurrent motifs with specific functions, including positive and negative feedback loops, and are subject to critical transitions, influenced by feedback loop transitions (FLTs). AIMS: We aim to identify critical feedback loops and their FLTs, as well sentinel network nodes (SNNs), key network nodes that drive FLTs, within the PINE network. Examples of biomarkers are provided which may reflect early warning signs of impending critical transition to MDD. RESULTS: Disruption of homeostatic feedback loops reflects the physiological transition to MDD. Putative FLTs are identified within hypothalamic-pituitary-adrenal (HPA) and sympathetic-parasympathetic axes, the kynurenine pathway, gut function and dysbiosis. CONCLUSIONS: Progression from health to disease is driven by FLTs in the PINE network, which is likely to undergo changes characteristic of system instability. Biomarkers of system instability may effectively predict the critical transition to MDD.

Efficacy of a web-based cognitive rehabilitation intervention for adult cancer survivors: A pilot study.

The purpose of this study was to evaluate the efficacy of a web-based cognitive rehabilitation intervention in survivors of adult-onset cancer and a sample of non-cancer community dwelling adults. Fifty-one participants were recruited and allocated to a cancer intervention group, a non-cancer intervention group, or a non-cancer waitlist group. Intervention groups completed a 4-week online program and all participants were assessed at baseline, post-intervention and 3-month follow-up. The primary outcome measure was subjective cognitive functioning. Secondary outcome measures included objective cognitive functioning, distress, quality of life (QoL), illness perception and program satisfaction. Results from the study found significant improvements on self-report measures of cognitive functioning in both treatment groups, as well as improvements on objective measures assessing attention and executive functioning. No intervention effects were observed for distress, QoL or illness perception. High participant satisfaction was observed with 75% of participants in the cancer group reporting being either "satisfied" or "very satisfied" with the program compared to 87% in the non-cancer treatment group. Initial evaluation of the program suggests that the web-based cognitive rehabilitation intervention shows potential for improving subjective and objective cognitive functioning in cancer survivors and community dwelling adults.

Psycho-oncology assessment in Chinese populations: a systematic review of quality of life and psychosocial measures.

This systematic review describes psychosocial and quality of life (QOL) measures used in psycho-oncology research with cancer patients and caregivers in China. Medline and PsycINFO databases were searched (1980-2014). Studies reviewed met the following criteria: English language; peer-reviewed; sampled Chinese cancer patients/caregivers; developed, validated or assessed psychometric properties of psychosocial or QOL outcome measures; and reported validation data. The review examined characteristics of measures and participants, translation and cultural adaptation processes and psychometric properties of the measures. Ninety five studies met review criteria. Common characteristics of studies reviewed were they: assessed primarily QOL measures, sampled patients with breast, colorectal, or head and neck cancer, and validated existing measures (>80%) originating in North America or Europe. Few studies reported difficulties translating measures. Regarding psychometric properties of the measures >50% of studies reported subscale reliabilities <α = 0.70, <50% reported test-retest reliability, and <30% reported divergent validity. Few reported sensitivity, specificity or responsiveness. Improved accuracy and transparency of reporting for translation, cultural adaptation and psychometric testing of psychosocial measures is needed. Developing support structures for translating and validating psychosocial measures would enable this and ensure Chinese psycho-oncology clinical practice and research keeps pace with international focus on patient reported outcome measures and data management.

Neural stem cells harvested from live brains by antibody-conjugated magnetic nanoparticles.

It stems from the magnetism: The extraction of stem/progenitor cells from the brain of live animals is possible using antibodies conjugated to magnetic nanoparticles (Ab-MNPs). The Ab-MNPs are introduced to a rat's brain with a superfine micro-syringe. The stem cells attach to the Ab-MNPs and are magnetically isolated and removed. They can develop into neurospheres and differentiate into different types of cells outside the subject body. The rat remains alive and healthy.

BDNF and TNF-α polymorphisms in memory.

Here, we investigate the genetic basis of human memory in healthy individuals and the potential role of two polymorphisms, previously implicated in memory function. We have explored aspects of retrospective and prospective memory including semantic, short term, working and long-term memory in conjunction with brain derived neurotrophic factor (BDNF) and tumor necrosis factor-alpha (TNF-α). The memory scores for healthy individuals in the population were obtained for each memory type and the population was genotyped via restriction fragment length polymorphism for the BDNF rs6265 (Val66Met) SNP and via pyrosequencing for the TNF-α rs113325588 SNP. Using univariate ANOVA, a significant association of the BDNF polymorphism with visual and spatial memory retention and a significant association of the TNF-α polymorphism was observed with spatial memory retention. In addition, a significant interactive effect between BDNF and TNF-α polymorphisms was observed in spatial memory retention. In practice visual memory involves spatial information and the two memory systems work together, however our data demonstrate that individuals with the Val/Val BDNF genotype have poorer visual memory but higher spatial memory retention, indicating a level of interaction between TNF-α and BDNF in spatial memory retention. This is the first study to use genetic analysis to determine the interaction between BDNF and TNF-α in relation to memory in normal adults and provides important information regarding the effect of genetic determinants and gene interactions on human memory.

A systematic review of psycho-oncology research in Chinese populations: emerging trends.

The burden of cancer in China is increasing with future psycho-oncological interventions crucial. A systematic review of psycho-oncology research in China was undertaken to assess quantity, design and target trends over time. Medline, PsycINFO, CINAHL, ProQuest, Web of Science (1999-November Week 4, 2012) were searched. Inclusion criteria were: included cancer patients and/or partners or caregivers from resident Chinese populations (either at least 80% of participants are from China, Hong Kong or Taiwan); assessed psychological adjustment relating to cancer and published in English after 1 January 1999 and prior to 30 November 2012. In all, 208 articles met inclusion criteria. Of these: 52 were cross-sectional descriptive quantitative; 30 were cross-sectional descriptive qualitative; 27 were prospective descriptive quantitative; 2 were prospective descriptive qualitative; 18 assessed interventions; 79 presented instrument validation. Publications increased eightfold from 1999 to 2012. Most studies included patients (n = 195) with 11 articles focusing on caregivers and two on patient-caregiver dyads. The most common cancer studied was breast cancer. The psycho-oncology research effort in China is dramatically increasing. A focus on culturally relevant approaches to underpin the evaluation of empirically derived interventions is warranted; as is direction of efforts to other cancers such as lung and prostate.

Patients with bipolar disorders share similar but attenuated prospective memory impairments with patients with schizophrenia.

BACKGROUND: Prospective memory (PM) refers to the ability to remember to carry out an intended action in the future. PM is consistently found to be impaired in individuals with schizophrenia. Bipolar disorder and schizophrenia may represent conditions along a continuum, and share similar neurocognitive and genetic architecture. This study aimed to compare the nature and extent of PM impairment in individuals with schizophrenia and bipolar disorder. METHOD: Participants were 38 out-patients with schizophrenia and 40 out-patients with bipolar disorder in an early psychosis intervention programme, and 37 healthy controls. Time-, event- and activity-based PMs were assessed using a dual-task laboratory paradigm. Self-reported PM performance was gauged using the Prospective and Retrospective Memory Questionnaire. Analysis of covariance (ANCOVA), with intelligence quotient (IQ) and education included as covariates, was used to examine group difference on various types of PM. Repeated measures of ANCOVA were used to examine the group × PM type interaction effect. Correspondence between laboratory and self-reported PM measures was examined using correlational analysis. RESULTS: The group × PM type interaction effect was not significant, but the main effect of group was significant. Patients with schizophrenia and patients with bipolar disorder both performed more poorly than healthy participants in PM. The two clinical groups did not significantly differ in PM. Laboratory and self-reported PM measures did not correlate significantly with each other. CONCLUSIONS: Patients with bipolar disorder shared a similar PM impairment with those with schizophrenia. Findings of this study extended the similarity in neurocognitive impairments between the two psychiatric disorders to PM.

Role of the apolipoprotein E and catechol-O-methyltransferase genes in prospective and retrospective memory traits.

Human memory is a complex neurocognitive process. By combining psychological and molecular genetics expertise, we examined the APOE ε4 allele, a known risk factor for Alzheimer's disease, and the COMT Val 158 polymorphism, previously implicated in schizophrenia, for association with lowered memory functioning in healthy adults. To assess memory type we used a range of memory tests of both retrospective and prospective memory. Genotypes were determined using RFLP analysis and compared with mean memory scores using univariate ANOVAs. Despite a modest sample size (n=197), our study found a significant effect of the APOE ε4 polymorphism in prospective memory. Supporting our hypothesis, a significant difference was demonstrated between genotype groups for means of the Comprehensive Assessment of Prospective Memory total score (p=0.036; ε4 alleles=1.99; all other alleles=1.86). In addition, we demonstrate a significant interactive effect between the APOE ε4 and COMT polymorphisms in semantic memory. This is the first study to investigate both APOE and COMT genotypes in relation to memory in non-pathological adults and provides important information regarding the effect of genetic determinants on human memory.

Cool and hot executive functions in medication-naive attention deficit hyperactivity disorder children.

BACKGROUND: This study aimed to compare 'cool' [working memory (WM) and response inhibition] and 'hot' (delay aversion) executive functions (EFs) in children with and without attention deficit hyperactivity disorder (ADHD). METHOD: A total of 100 ADHD children (45 with family history of ADHD and 55 with no family history) and 100 healthy controls, all medication free, were tested on tasks related to the 'hot' (i.e. two choice-delay tasks) and 'cool' domains of EF (i.e. Digits backward, Corsi Block Task backward, Go/No-Go Task, Stop-Signal Task, and the Stroop). RESULTS: Compared with the controls, children with ADHD were found to perform significantly worse on one or more measures of response inhibition, WM, and delay aversion after controlling for co-morbidities and estimated IQ. In addition, comparisons between ADHD children with family history of ADHD and those with no family history found significant differences on measures of response inhibition and WM but not delay aversion. These results are largely supported by results of two logistic regressions. CONCLUSIONS: ADHD was found to be associated with deficits on both cool and hot EFs. There is also evidence to suggest that cool EFs impairment is related to a family history of ADHD. Findings of this study have helped to elucidate the nature and extent of EF deficits in children with ADHD.

Expression of vesicular glutamate transporters in peripheral vestibular structures and vestibular nuclear complex of rat.

Glutamate transmission from vestibular end organs to central vestibular nuclear complex (VNC) plays important role in transferring sensory information about head position and movements. Three isoforms of vesicular glutamate transporters (VGLUTs) have been considered so far the most specific markers for glutamatergic neurons/cells. In this study, VGLUT1 and VGLUT2 were immunohistochemically localized to axon terminals in VNC and somata of vestibular primary afferents in association with their central and peripheral axon endings, and VGLUT1 and VGLUT3 were co-localized to hair cells of otolith maculae and cristae ampullaris. VGLUT1 and VGLUT2 defined three subsets of Scarpa's neurons (vestibular ganglionic neurons): those co-expressing VGLUT1 and VGLUT2 or expressing only VGLUT2, and those expressing neither. In addition, many neurons located in all vestibular subnuclei were observed to contain hybridized signals for VGLUT2 mRNA and a few VNC neurons, mostly scattered in medial vestibular nucleus (MVe), displayed VGLUT1 mRNA labelling. Following unilateral ganglionectomy, asymmetries of VGLUT1-immunoreactivity (ir) and VGLUT2-ir occurred between two VNCs, indicating that the VNC terminals containing VGLUT1 and/or VGLUT2 are partly of peripheral origin. The present data indicate that the constituent cells/neurons along the vestibular pathway selectively apply VGLUT isoforms to transport glutamate into synaptic vesicles for glutamate transmission.

Time course of cortically induced fos expression in auditory thalamus and midbrain after bilateral cochlear ablation.

Expression of c-fos in the medial geniculate body (MGB) and the inferior colliculus (IC) in response to bicuculline-induced corticofugal activation was examined in rats at different time points after bilateral cochlear ablation (4 h-30 days). Corticofugal activation was crucial in eliciting Fos expression in the MGB after cochlear ablation. The pars ovoidea (OV) of the medial geniculate body ventral division (MGv) showed dense Fos expression 4 h after cochlear ablation; the expression declined to very low levels at 24 h and thereafter. In turn, strong Fos expression was found in the pars lateralis (LV) of the MGv 24 h after cochlear ablation and dropped dramatically at 14 days. The dorsal division of the MGB (MGd) showed high Fos expression 7 days after cochlear ablation, which persisted for a period of time. Using multi-electrode recordings, neuronal activity of different MGB subnuclei was found to correlate well with Fos expressions. The temporal changes in cortically activated Fos expression in different MGB subnuclei after bilateral cochlear ablation indicate differential denervation hypersensitivities of these MGB neurons and likely point to differential dependence of these nuclei on both auditory ascending and corticofugal descending inputs. After bilateral cochlear ablation, significant increases in Fos-positive neurons were detected unilaterally in all IC subnuclei, ipsilateral to the bicuculline injection.

The proNGF-p75NTR-sortilin signalling complex as new target for the therapeutic treatment of Parkinson's disease.

Growing evidence has shown that the p75 neurotrophin receptor (p75NTR) may play important roles in controlling neuronal survival or cell apoptosis within the central nervous system in development, and in pathological or neural injury. Recent studies have further revealed that p75NTR acts as a "molecular signal switch" that determines cell death or survival by three processes. First, pro-nerve growth factor (proNGF) triggers cell apoptosis by its high affinity binding to p75NTR, while NGF induces neuronal survival with low-affinity binding. Second, p75NTR mediates cell death by combining with co-receptor sortilin, whereas it promotes neuronal survival through combination with proNGF. Third, release of the intracellular domain chopper or cleavaged "short p75NTR" can independently initiate neuronal apoptosis. We have identified the cell self-destructive proNGF-p75NTR-sortilin signalling apparatus assembled in ventral tier dopamine neurons of the substantia nigra pars compacta, suggesting that p75NTR signalling might be involved in selective cell death mechanisms of substantia nigra neurons or disease progression of Parkinson's disease (PD). In addition, experimental manipulation of p75NTR benefited cell survival of cholinergic or motor neurons and improved disease progression of the neurodegenerative diseases Alzheimer's disease and Amyotrophic lateral sclerosis. The proNGF-p75NTR-sortilin signalling complex may thus provide new target for neuroprotection of substantia nigra neurons and the therapeutic treatment of PD.

Clinical significance of the RT-PCR positive sentinel node in melanoma.

BACKGROUND: The clinical relevance of RT-PCR positivity for melanoma markers in the sentinel node remains controversial. Our purpose was to determine whether patients with a histologically negative but RT-PCR positive node were at an increased risk for recurrence than their RT-PCR negative counterparts. METHODS: Thirty-nine adult patients underwent sentinel node biopsies for melanoma between 1998 and 2000. Each sentinel node was bivalved. Half was serially sectioned and examined by routine hematoxylin and eosin (H&E) and immunohistochemistry (IHC; S100, HMB-45, melanA, and tyrosinase). The other half was analyzed by a nested RT-PCR assay for tyrosinase. RESULTS: Patients were followed for recurrence with a mean follow-up of 71.1 months. The odds ratio of recurrence for RT-PCR positive versus RT-PCR negative patients was 1.39 (0.34, 5.62; p = 0.73). Within the histology negative subgroups, the risk of recurrence in the RT-PCR positive group (26.7%) was not significantly different from the risk of recurrence in the RT-PCR negative group (22.2%) (p = 0.33 chi-squared). RT-PCR of the sentinel node was not a predictor for recurrence on multivariate analysis (p = 0.65). CONCLUSION: Sentinel node RT-PCR positivity did not risk stratify histologically negative melanoma patients beyond routine pathologic examination in this series.

Tyrosine kinase receptor immunoreactivity in trigeminal mesencephalic and motor neurons following transection of masseteric nerve of the rat.

Neurotrophins are known to promote survival after neural injury. To determine the relative importance of tyrosine kinase receptors on the survival of axotomized trigeminal nuclear neurons, we examined the temporal expression profile of tyrosine kinase A, tyrosine kinase B and tyrosine kinase C receptors in the mesencephalic trigeminal nucleus and the motor trigeminal nucleus following transection of the masseteric nerve in rats. Axotomized neurons in these nuclei were retrogradely identified with FluoroGold. We found increase in tyrosine kinase A-immunoreactive mesencephalic trigeminal nucleus neurons in the second week after axotomy but no change in the number of tyrosine kinase A-immunoreactive motor trigeminal nucleus neurons. There was no change in the number of tyrosine kinase B-immunoreactive mesencephalic trigeminal nucleus neurons but the significant increase of tyrosine kinase B-immunoreactive motor trigeminal nucleus neurons throughout the period of observation (3 weeks) peaked at approximately 1 week after axotomy. There was no alteration in the number of tyrosine kinase C-immunoreactive mesencephalic trigeminal nucleus neurons but significant increase in tyrosine kinase C-immunoreactive motor trigeminal nucleus neurons observable by 4 days post-axotomy was followed by decline to levels lower than the control in 2 weeks. Temporal changes in the expression of individual tyrosine kinase receptors in mesencephalic trigeminal nucleus and motor trigeminal nucleus neurons following transection of the masseteric nerve suggest differential contribution of tyrosine kinase-specific neurotrophins to the survival of these neurons after axotomy.

Differential expression of NMDA and AMPA/KA receptor subunits in the inferior olive of postnatal rats.

We have employed immunohistochemistry to determine the expression patterns of receptor subunits of N-methyl-d-aspartate (NMDA-NR1 and NR2A/B) and alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid/kainic acid (AMPA/KA-GluR1, GluR2, GluR2/3, GluR4, and GluR5/6/7) in the inferior olive of postnatal rats up to adulthood. Immunoreactivity for distinct receptor subunits was predominantly localized in the soma and dendrites of neurons. Semi-quantification showed that the overall immunoreactivity in the inferior olive of adults was intense for GluR1, moderate for NR1 and NR2A/B, and low for GluR2, GluR2/3, GluR4, and GluR5/6/7. At P7, GluR1 was restricted to the dorsomedial cell column, subnucleus beta, principal nucleus and ventrolateral protrusion while the other subunits were found in all subnuclei of the inferior olive. The immunoreactivities for all glutamate receptor subunits ranged from low to moderate. As the rats matured, the immunoreactivity of GluR4 decreased after the second postnatal week, while those of the other subunits showed a general trend of increase, reaching adult level during the third postnatal week. Double immunofluorescence revealed that all NR1-containing neurons exhibited NR2A/B immunoreactivity, indicating that native NMDA receptors comprise of hetero-oligomeric combinations of NR1 and NR2A/B. Furthermore, co-localization of NMDA and AMPA/KA receptor subunits was demonstrated in individual neurons of the inferior olive. All NR1-containing neurons exhibited GluR1 immunoreactivity, and all NR2A/B-containing neurons showed GluR5/6/7 immunoreactivity. Our data suggest that NMDA and AMPA/KA receptors are involved in glutamate-mediated neurotransmission, contributing to synaptic plasticity and reorganization of circuitry in the inferior olive during postnatal development.

Expression of Trk receptors in otolith-related neurons in the vestibular nucleus of rats.

The expression of the three Trk receptors (TrkA, TrkB, and TrkC) in otolith-related neurons within the vestibular nuclei of adult Sprague-Dawley rats was examined immunohistochemically. Conscious animals were subjected to sinusoidal linear acceleration along either the anterior-posterior (AP) or interaural (IA) axis on the horizontal plane. Neuronal activation was defined by Fos expression in cell nuclei. Control animals, viz labyrinthectomized rats subjected to stimulation and normal rats that remained stationary, showed only a few sporadically scattered Fos-labeled neurons. Among experimental rats, the number of Fos-labeled neurons and their distribution pattern in each vestibular subnucleus in animals stimulated along the antero-posterior axis were similar to those along the interaural axis. No apparent topography was observed among neurons activated along these two directions. Only about one-third of the Trk-immunoreactive neurons in the vestibular nucleus expressed Fos. Double-labeled Fos/TrkA, Fos/TrkB and Fos/TrkC neurons constituted 85-98% of the total number of Fos-labeled neurons in vestibular nuclear complex and its subgroups x and y. Our findings suggest that Trk receptors and their cognate neurotrophins in central otolith neurons may contribute to the modulation of gravity-related spatial information during horizontal head movements.

Chondroitinase ABC enhances axonal regrowth through Schwann cell-seeded guidance channels after spinal cord injury.

Grafting of Schwann cell-seeded channels into hemisected adult rat thoracic spinal cords has been tested as a strategy to bridge the injured cord. Despite success in guiding axonal growth into the graft, regeneration across the distal graft-host interface into the host spinal cord was limited. We hypothesized that chondroitin sulfate (CS) glycoforms deposited at the gliotic front of the interface constitute a molecular barrier to axonal growth into the host cord. Because CS glycoforms deposited by purified astrocytes in vitro were removable by digestion with chondroitinase ABC, we attempted to achieve likewise by infusion of the enzyme to the host side of the interface. By 1 month post-treatment, significant numbers of regenerating axons crossed an interface that was subdued in macrophage/microglia reaction and decreased in CS-immunopositivity. The axons extended as far into the caudal cord as 5 mm, in contrast to nil in vehicle-infused controls. Fascicular organizations of axon-Schwann cell units within the regenerated tissue cable were better-preserved in enzyme-treated cords than in vehicle-infused controls. We conclude that CS glycoforms deposited during gliosis at the distal graft-host interface could be cleared by the in vivo action of chondroitinase ABC to improve prospects of axonal regeneration into the host spinal cord.

Receptors of glutamate and neurotrophin in vestibular neuronal functions.

The last decade has witnessed advances in understanding the roles of receptors of neurotrophin and glutamate in the vestibular system. In the first section of this review, the biological actions of neurotrophins and their receptors in the peripheral and central vestibular systems are summarized. Emphasis will be placed on the roles of neurotrophins in developmental plasticity and in the maintenance of vestibular function in the adult animal. This is reviewed in relation to the developmental expression pattern of neurotrophins and their receptors within the vestibular nuclei. The second part is focused on the functional role of different glutamate receptors on central vestibular neurons. The developmental expression pattern of glutamate receptor subunits within the vestibular nuclei is reviewed in relation to the potential role of glutamate receptors in regulating the development of vestibular function.