The molecular factors involved in the development of Post-Traumatic Stress Disorder (PTSD) remain poorly understood. Previous transcriptomic studies investigating the mechanisms of PTSD apply ...targeted approaches to identify individual genes under a cross-sectional framework lack a holistic view of the behaviours and properties of these genes at the system-level. Here we sought to apply an unsupervised gene-network based approach to a prospective experimental design using whole-transcriptome RNA-Seq gene expression from peripheral blood leukocytes of U.S. Marines (N=188), obtained both pre- and post-deployment to conflict zones. We identified discrete groups of co-regulated genes (i.e., co-expression modules) and tested them for association to PTSD. We identified one module at both pre- and post-deployment containing putative causal signatures for PTSD development displaying an over-expression of genes enriched for functions of innate-immune response and interferon signalling (Type-I and Type-II). Importantly, these results were replicated in a second non-overlapping independent dataset of U.S. Marines (N=96), further outlining the role of innate immune and interferon signalling genes within co-expression modules to explain at least part of the causal pathophysiology for PTSD development. A second module, consequential of trauma exposure, contained PTSD resiliency signatures and an over-expression of genes involved in hemostasis and wound responsiveness suggesting that chronic levels of stress impair proper wound healing during/after exposure to the battlefield while highlighting the role of the hemostatic system as a clinical indicator of chronic-based stress. These findings provide novel insights for early preventative measures and advanced PTSD detection, which may lead to interventions that delay or perhaps abrogate the development of PTSD.
Sub-cortical volumetric differences were associated with attention-deficit/hyperactivity disorder (ADHD) in a recent multi-site, mega-analysis of 1713 ADHD persons and 1529 controls. As there was a ...wide range of effect sizes among the sub-cortical volumes, it is possible that selective neuronal vulnerability has a role in these volumetric losses. To address this possibility, we used data from Allen Brain Atlas to investigate variability in gene expression profiles between subcortical regions of typically developing brains. We tested the hypothesis that the expression of genes in a set of curated ADHD candidate genes and five a priori selected, biological pathways would be associated with the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) findings. Across the subcortical regions studied by ENIGMA, gene expression profiles for three pathways were significantly correlated with ADHD-associated volumetric reductions: apoptosis, oxidative stress and autophagy. These correlations were strong and significant for children with ADHD, but not for adults. Although preliminary, these data suggest that variability of structural brain anomalies in ADHD can be explained, in part, by the differential vulnerability of these regions to mechanisms mediating apoptosis, oxidative stress and autophagy.
This study describes the Osseointegration Group of Australia's Accelerated Protocol two-stage strategy (OGAAP-1) for the osseointegrated reconstruction of amputated limbs.
We report clinical outcomes ...in 50 unilateral trans-femoral amputees with a mean age of 49.4 years (24 to 73), with a minimum one-year follow-up. Outcome measures included the Questionnaire for persons with a Trans-Femoral Amputation, the health assessment questionnaire Short-Form-36 Health Survey, the Amputation Mobility Predictor scores presented as K-levels, 6 Minute Walk Test and timed up and go tests. Adverse events included soft-tissue problems, infection, fractures and failure of the implant.
Our results demonstrated statistically significant improvements in all five outcome measures. A total of 27 patients experienced adverse events but at the conclusion of the study, all 50 were walking on osseointegrated prostheses.
These results demonstrate that osseointegrated prostheses are a suitable alternative to socket-fit devices for amputees experiencing socket-related discomfort and that our strategy offers more rapid progress to walking than other similar protocols. Cite this article: Bone Joint J 2016;98-B:952-60.
The D2 subtype of dopamine receptor has been widely implicated in the pathogenesis of schizophrenia. Early evidence supporting an association between the Cys311Ser polymorphism of the D2 receptor ...gene (DRD2) and schizophrenia was subsequently refuted and, eventually, dismissed. From all 24 published case-control studies, we calculated a pooled estimate of this association. The pooled odds ratio was 1.3 for the Cys allele, which was highly significant (P=0.007). The odds ratio derived from each study was unrelated to the ethnicity or gender composition of the sample, or the age of the control group. There was no evidence of publication bias or excessive influence attributable to any given study. Although more family-based studies are needed to confirm this relation, our results provide strong evidence that DRD2 influences susceptibility to schizophrenia.
Schizophrenia's (SZ's) heritability and familial transmission have been known for several decades; however, despite the clear evidence for a genetic component, it has been very difficult to pinpoint ...specific causative genes. Even so genetic studies have taught us a lot, even in the pregenomic era, about the molecular underpinnings and disease-relevant pathways. Recurring themes emerged revealing the involvement of neurodevelopmental processes, glutamate regulation, and immune system differential activation in SZ etiology. The recent emergence of epigenetic studies aimed at shedding light on the biological mechanisms underlying SZ has provided another layer of information in the investigation of gene and environment interactions. However, this epigenetic insight also brings forth another layer of complexity to the (epi)genomic landscape such as interactions between genetic variants, epigenetic marks-including cross-talk between DNA methylation and histone modification processes-, gene expression regulation, and environmental influences. In this review, we seek to synthesize perspectives, including limitations and obstacles yet to overcome, from genetic and epigenetic literature on SZ through a qualitative review of risk factors and prevailing hypotheses. Encouraged by the findings of both genetic and epigenetic studies to date, as well as the continued development of new technologies to collect and interpret large-scale studies, we are left with a positive outlook for the future of elucidating the molecular genetic mechanisms underlying SZ and other complex neuropsychiatric disorders.
A rat model of bone cancer pain Medhurst, S.J; Walker, K; Bowes, M ...
Pain (Amsterdam),
03/2002, Letnik:
96, Številka:
1
Journal Article
Recenzirano
This study describes the first known model of bone cancer pain in the rat. Sprague–Dawley rats receiving intra-tibial injections of syngeneic MRMT-1 rat mammary gland carcinoma cells developed ...behavioural signs indicative of pain, including: mechanical allodynia, difference of weight bearing between hind paws and mechanical hyperalgesia. The development of the bone tumour and structural damage to the bone was monitored by radiological analysis, quantitative measurement of mineral content and histology.
Intra-tibial injections of 3×10
3 or 3×10
4 syngeneic MRMT-1 cells produced a rapidly expanding tumour within the boundaries of the tibia, causing severe remodelling of the bone. Radiographs showed extensive damage to the cortical bone and the trabeculae by day 10–14 after inoculation of 3×10
3 MRMT-1 cells, and by day 20, the damage was threatening the integrity of the tibial bone. While both mineral content and mineral density decreased significantly in the cancerous bone, osteoclast numbers in the peritumoural compact bone remained unchanged. However, tartarate-resistant acid phosphatase staining revealed a large number of polykariotic cells, resembling those of osteoclasts within the tumour. No tumour growth was observed after the injection of heat-killed MRMT-1 cells.
Intra-tibial injections of 3×10
3 or 3×10
4 MRMT-1 cells, heat-killed cells or vehicle did not show changes in body weight and core temperature over 19–20 days. The general activity of animals after injection with live or heat-killed MRMT-1 cells was higher than that of the control group, however, the activity of the MRMT-1 treated group declined during the progress of the disease.
Rats receiving intra-tibial injections of MRMT-1 cells displayed the gradual development of mechanical allodynia and mechanical hyperalgesia/reduced weight bearing on the affected limb, beginning on day 12–14 or 10–12 following injection of 3×10
3 or 3×10
4 cells, respectively. These symptoms were not observed in rats receiving heat-killed cells or vehicle.
Behavioural data suggest a reasonable time window for evaluation of anti-nociceptive agents between day 14 and 20 after cancer cell inoculation in this model.
Acute treatment with morphine (1–3
mg/kg, subcutanously (s.c.)) produced a dose-dependent reduction in the response frequency of hind paw withdrawal to von Frey filament stimulation 17 or 19 days following intra-tibial injections of 3×10
3 MRMT-1 cells. A significant reduction in the difference in hind limb weight bearing was also observed. Acute treatment with celebrex (10–30
mg/kg, s.c.) did not affect mechanical allodynia or difference in weight bearing in rats 20 days following treatment with 3×10
3 MRMT-1 cells.
Although the pathophysiology of cancer pain is largely unknown, significant enhancement of glial fibrillary acidic protein (GFAP) staining in the corresponding segments of the ipsilateral spinal cord highlights the possible involvement of astrocytes.
In summary, the induction of bone cancer in the rat by the syngeneic MRMT-1 mammary tumour cell line provides a valid pre-clinical model for pain associated with bone metastases. Significant mechanical hyperalgesia and allodynia develops in association with the progression of the tumour in the bone marrow cavity, while the general condition of the animal remains satisfactory. While acute treatment with morphine has some analgesic effect on hind limb sparing the selective COX-2 inhibitor, celebrex, has no influence on the pain-related behavioural changes in this model.
Abstract Background The Harvard Adolescent Family High Risk (FHR) Study examined multiple domains of function in young relatives of individuals diagnosed with schizophrenia to identify precursors of ...the illness. One such area is motor performance, which is deviant in people with schizophrenia and in children at risk for schizophrenia, usually offspring. The present study assessed accuracy of motor performance and degree of lateralization in FHR adolescents and young adults. Methods Subjects were 33 non-psychotic, first-degree relatives of individuals diagnosed with schizophrenia, and 30 non-psychotic comparison subjects (NpC), ranging in age from 13 to 25 who were compared using a line-drawing task. Results FHR individuals exhibited less precise and coordinated line drawing but greater degree of lateralization than controls. Performance on the linedrawing task was correlated with degree of genetic loading, a possible predictor of higher risk for schizophrenia in the pedigree. Conclusions The observation of increased motor deviance and increased lateralization in FHR can be utilized in identification and initiation of the treatment in those at high risk in order to prevent or delay the full manifestation of this devastating condition. The use of a rigorously quantified measure is likely to add to the sensitivity of measuring motor performance, especially when impairments may be subtle.
The rs1076560 polymorphism of DRD2 (encoding dopamine receptor D2) is associated with alternative splicing and cognitive functioning; however, a mechanistic relationship to schizophrenia has not been ...shown. Here, we demonstrate that rs1076560(T) imparts a small but reliable risk for schizophrenia in a sample of 616 affected families and five independent replication samples totaling 4017 affected and 4704 unaffected individuals (odds ratio=1.1; P=0.004). rs1076560(T) was associated with impaired verbal fluency and comprehension in schizophrenia but improved performance among healthy comparison subjects. rs1076560(T) also associated with lower D2 short isoform expression in postmortem brain. rs1076560(T) disrupted a binding site for the splicing factor ZRANB2, diminished binding affinity between DRD2 pre-mRNA and ZRANB2 and abolished the ability of ZRANB2 to modulate short:long isoform-expression ratios of DRD2 minigenes in cell culture. Collectively, this work implicates rs1076560(T) as one possible risk factor for schizophrenia in the Han Chinese population, and suggests molecular mechanisms by which it may exert such influence.
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