Polygenic interactions with environmental adversity in the aetiology of major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene-environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD. METHOD: The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them. RESULTS: PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10(-6)). SLEs and CT were also associated with MDD status (p = 2.19 × 10(-4) and p = 5.12 × 10(-20), respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples. CONCLUSIONS: CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene-environment interactions in complex traits.

Genetic predisposition to schizophrenia associated with increased use of cannabis.

Cannabis is the most commonly used illicit drug worldwide. With debate surrounding the legalization and control of use, investigating its health risks has become a pressing area of research. One established association is that between cannabis use and schizophrenia, a debilitating psychiatric disorder affecting ~1% of the population over their lifetime. Although considerable evidence implicates cannabis use as a component cause of schizophrenia, it remains unclear whether this is entirely due to cannabis directly raising risk of psychosis, or whether the same genes that increases psychosis risk may also increase risk of cannabis use. In a sample of 2082 healthy individuals, we show an association between an individual's burden of schizophrenia risk alleles and use of cannabis. This was significant both for comparing those who have ever versus never used cannabis (P=2.6 × 10(-4)), and for quantity of use within users (P=3.0 × 10(-3)). Although directly predicting only a small amount of the variance in cannabis use, these findings suggest that part of the association between schizophrenia and cannabis is due to a shared genetic aetiology. This form of gene-environment correlation is an important consideration when calculating the impact of environmental risk factors, including cannabis use.

Estimating the heritability of reporting stressful life events captured by common genetic variants.

BACKGROUND: Although usually thought of as external environmental stressors, a significant heritable component has been reported for measures of stressful life events (SLEs) in twin studies. Method We examined the variance in SLEs captured by common genetic variants from a genome-wide association study (GWAS) of 2578 individuals. Genome-wide complex trait analysis (GCTA) was used to estimate the phenotypic variance tagged by single nucleotide polymorphisms (SNPs). We also performed a GWAS on the number of SLEs, and looked at correlations between siblings. RESULTS: A significant proportion of variance in SLEs was captured by SNPs (30%, p = 0.04). When events were divided into those considered to be dependent or independent, an equal amount of variance was explained for both. This 'heritability' was in part confounded by personality measures of neuroticism and psychoticism. A GWAS for the total number of SLEs revealed one SNP that reached genome-wide significance (p = 4 × 10-8), although this association was not replicated in separate samples. Using available sibling data for 744 individuals, we also found a significant positive correlation of R 2 = 0.08 in SLEs (p = 0.03). CONCLUSIONS: These results provide independent validation from molecular data for the heritability of reporting environmental measures, and show that this heritability is in part due to both common variants and the confounding effect of personality.

Non-steroidal anti-inflammatory drugs and efficacy of antidepressants in major depressive disorder.

BACKGROUND: It has been proposed that non-steroidal anti-inflammatory drugs (NSAIDs) may interfere with the efficacy of antidepressants and contribute to treatment resistance in major depressive disorder (MDD). This effect requires replication and a test of whether it is specific to serotonin-reuptake inhibiting (SRI) antidepressants. METHOD: We tested the effect of concomitant medication with NSAIDs on the efficacy of escitalopram, a SRI antidepressant, and nortriptyline, a tricyclic antidepressant, among 811 subjects with MDD treated for up to 12 weeks in the GENDEP study. Effects of NSAIDs on improvement of depressive symptoms were tested in mixed-effect linear models. Effects on remission were tested in logistic regression. Age, sex, baseline severity and centre of recruitment were considered as potential confounding factors. RESULTS: Ten percent (n=78) of subjects were taking NSAIDs during the antidepressant treatment. Older subjects were significantly more likely to take NSAIDs. After controlling for age, sex, centre of recruitment and baseline severity, concomitant medication with NSAIDs did not significantly influence the efficacy of escitalopram [ß=0.035, 95% confidence interval (CI) -0.145 to 0.215, p=0.704] or nortriptyline (ß=0.075, 95% CI -0.131 to 0.281, p=0.476). Although slightly fewer subjects who took NSAIDs reached remission [odds ratio (OR) 0.80, 95% CI 0.49-1.31, p=0.383], this non-significant effect was reversed after controlling for age, sex, baseline severity and recruitment centre effects (OR 1.04, 95% CI 0.61-1.77, p=0.882). CONCLUSIONS: NSAIDs are unlikely to affect the efficacy of SRI or other antidepressants. Concurrent use of NSAIDs and antidepressants does not need to be avoided.

Intra-operative washing of morcellised bone allograft with pulse lavage: how effective is it in reducing blood and marrow content?

The use of unprocessed bone carries a risk of transmission of blood borne diseases. Although models of infectivity are unproven, a theoretical risk of transmission of variant Creutzfeld-Jakob Disease, a human prion disease, exists as probable blood borne transmission has been reported in three cases. The aim of our study was to determine the effectiveness of standard operating theatre pulse lavage in removing protein, fat and double stranded Deoxyribonucleic acid (dsDNA) from morcellised bone allograft. Twelve donated femoral heads were divided into halves and milled into bone chips. One half of the bone chips were washed with pulse lavage, whereas, the other half acted as control. In order to determine the amount of protein, fat and dsDNA present in the washed and unwashed samples, a validated multistep washing protocol was used. Using the validated technique, simple intra-operative washing of morcellised unprocessed bone allograft removed a significant amount of the protein (70.5%, range: 39.5-85%), fat (95.2%, range: 87.8-98.8%) and DNA (68.4%, range: 31.4-93.1%) content. Intra-operative washing of morcellised bone allograft with pulse lavage may thereby reduce the theoretical risk of prion and other blood borne disease transmission. Combined with the known improved mechanical characteristics of washed allograft, we would recommend pulse lavage as a routine part of bone allograft preparation.

Targeting cellular memory to reprogram the epigenome, restore potential, and improve somatic cell nuclear transfer.

Successful cloning by somatic cell nuclear transfer (SCNT) is thought to require reprogramming of a somatic nucleus to a state of restored totipotentiality [Dean, W., Santos, F., Reik, W., 2003. Epigenetic programming in early mammalian development and following somatic cell nuclear transfer. Semin. Cell. Dev. Biol. 14, 93-100; Jouneau, A., Renard, J.P., 2003. Reprogramming in nuclear transfer. Curr. Opin. Genet. Dev. 13, 486-491; ]. Though SCNT-induced reprogramming is reminiscent of the reprogramming that occurs after fertilization, reprogramming a differentiated nucleus to an embryonic state is delayed and incomplete in comparison (for review, see ). This is likely due to the existence of an epigenetic-based cellular memory, or program, that serves to regulate global patterns of gene expression, and is the basis of a genome defense mechanism that silences viruses and transposons. The mechanisms of this memory include CpG methylation and modification of histones. Recent evidence by Feng et al. [Feng, Y.-Q., Desprat, R., Fu, H., Olivier, E., Lin, C.M., Lobell, A., Gowda, S.N., Aladjem, M.I., Bouhasira, E.E., 2006. DNA methylation supports intrinsic epigenetic memory in mammalian cells. PLOS Genet. 2, 0461-0470], using a transgenic experimental system, indicates that these marks may be acquired in more than one order and thus, silent heterochromatic structure can be initiated by either methylation of CpG dinucleotides or by histone modifications. In this system, however, CpG methylation appears to differ from histone modifications because it bestows a persistent epigenetic, or cellular, memory. In other words, CpG methylation can independently confer cellular memory, whereas histone modifications appear to be limited in this capacity. Therefore, in the context of genomic reprogramming induced by SCNT, efficient demethylation is likely a key (if not the only) rate-limiting step to improving the efficiency and outcomes of SCNT cloning. This review discusses the possibility of targeting cellular memory, and in particular inducing demethylation of a somatic nucleus prior to nuclear transfer, to enable reprogramming events typically carried out by oocyte factors and thereby improve developmental competence of SCNT-reconstructed embryos. Several recent published reviews of SCNT, cellular reprogramming and genomic demethylation served as valuable sources for the authors and are recommended as supplemental reading. These include the following: Bird, A., 2002. DNA methylation patterns and epigenetic memory. Gen. Dev. 16, 6-21; Grafi, G., 2004. How cells dedifferentiate: a lesson from plants. Dev. Biol. 268, 1-6; Latham, K.E., 2005. Early and delayed aspects of nuclear reprogramming during cloning. Biol. Cell 97, 119-132; Lyko, F., Brown, R., 2005. DNA methyltransferase inhibitors and the development of epigenetic cancer therapies. J.Natl. Cancer Inst. 97, 1498-1506; Morgan, H.D., Santos, F., Green, K., Dean, W., Reik, W., 2005. Epigenetic reprogramming in mammals. Hum. Mol. Gen. 14, R47-R58; Szyf, M., 2005. DNA methylation and demethylation as targets for anticancer therapy. Biochemistry 70, 533-549; Buszczak, M., Spradling, A.C., 2006. Searching chromatin for stem cell identity. Cell 125, 233-236; Gurdon, J.B., 2006. From nuclear transfer to nuclear reprogramming: the reversal of cell differentiation. Annu. Rev. Cell. Dev. Biol. 22, 1-22; Yoo, C.B., Jones, P.A., 2006. Epigenetic therapy of cancer: past, present and future. Nat. Rev. 5, 37-50.

A comparison of the shrinkage of commercial bone cements when mixed under vacuum.

The outcome of a cemented hip arthroplasty is partly dependent on the type of cement which is used. The production of an interface gap between the stem and the cement mantle as a result of shrinkage of the cement, may be a factor involved. Palacos R, Palacos LV (both with gentamicin), CMW 1, CMW 2, CMW Endurance (CMWE) and Simplex were prepared under vacuum and allowed to cure overnight in similar cylinders. The next day this volume was determined by the displacement of water. Shrinkage varied between 3.82% and 7.08% with CMWE having the lowest and Palacos LV the highest. This could be a factor to consider when choosing a cement for a shape-closed stem.

Incidence of infection with the use of non-irradiated morcellised allograft bone washed at the time of revision arthroplasty of the hip.

Implantation of allograft bone is an integral part of revision surgery of the hip. One major concern with its use is the risk of transmission of infective agents. There are a number of methods of processing allograft bone in order to reduce this risk. One method requires washing the tissue using pulsed irrigation immediately before implantation. We report the incidence of deep bacterial infection in 138 patients (144 revision hip arthroplasties) who had undergone implantation of allograft bone. The bone used was fresh-frozen, non-irradiated and pulse-washed with normal saline before implantation. The deep infection rate at a minimum follow-up of one year was 0.7%. This method of processing appears to be associated with a very low risk of allograft-related bacterial infection.

The effect of iron supplementation on the level of haemoglobin after lower limb arthroplasty.

We randomised 120 patients who were undergoing either primary total hip or knee arthroplasty to receive either ferrous sulphate or a placebo for three weeks after surgery. The level of haemoglobin and absolute reticulocyte count were measured at one and five days, and three and six weeks after operation. Ninety-nine patients (ferrous sulphate 50, placebo 49) completed the study. The two groups differed only in the treatment administered. Recovery of level of haemoglobin was similar at five days and three weeks and returned to 85% of the pre-operative level, irrespective of the treatment group. A small, albeit greater recovery in the level of haemoglobin was identified at six weeks in the ferrous sulphate group in both men (ferrous sulphate 5%, placebo 1.5%) and women (ferrous sulphate 6%, placebo 3%). The clinical significance of this is questionable and may be outweighed by the high incidence of reported side effects of oral iron and the cost of the medication. Administration of iron supplements after elective total hip or total knee arthroplasty does not appear to be worthwhile.

Heritability estimates of the Big Five personality traits based on common genetic variants.

According to twin studies, the Big Five personality traits have substantial heritable components explaining 40-60% of the variance, but identification of associated genetic variants has remained elusive. Consequently, knowledge regarding the molecular genetic architecture of personality and to what extent it is shared across the different personality traits is limited. Using genomic-relatedness-matrix residual maximum likelihood analysis (GREML), we here estimated the heritability of the Big Five personality factors (extraversion, agreeableness, conscientiousness, neuroticism and openness for experience) in a sample of 5011 European adults from 527,469 single-nucleotide polymorphisms across the genome. We tested for the heritability of each personality trait, as well as for the genetic overlap between the personality factors. We found significant and substantial heritability estimates for neuroticism (15%, s.e. = 0.08, P = 0.04) and openness (21%, s.e. = 0.08, P < 0.01), but not for extraversion, agreeableness and conscientiousness. The bivariate analyses showed that the variance explained by common variants entirely overlapped between neuroticism and openness (rG = 1.00, P < 0.001), despite low phenotypic correlation (r = - 0.09, P < 0.001), suggesting that the remaining unique heritability may be determined by rare or structural variants. As far as we are aware of, this is the first study estimating the shared and unique heritability of all Big Five personality traits using the GREML approach. Findings should be considered exploratory and suggest that detectable heritability estimates based on common variants is shared between neuroticism and openness to experiences.

Changes in gene expression associated with the bone anabolic effects of basic fibroblast growth factor in aged ovariectomized rats.

Basic fibroblast growth factor (bFGF) stimulates bone formation in vitro and in vivo. The purpose of this study was to determine changes in gene expression for bone matrix proteins, growth factors, and cytokines associated with the stimulatory effects of bFGF on bone formation in aged ovariectomized (ovx) rats. At 3 months of age, female Sprague-Dawley rats were sham-operated (sham) or ovariectomized (ovx), then maintained untreated for 1 year. At 15 months of age, baseline (BSL) sham and ovx rats were killed. All other rats received daily intravenous injections of bFGF (200 microg/kg) or vehicle (veh) for 14 days. Lumbar vertebrae were processed for quantitative bone histomorphometry or molecular analyses. Ovariectomy decreased vertebral cancellous bone volume by approximately 33% and increased most indices of bone turnover. Treatment of aged ovx rats with bFGF for only 14 days significantly increased cancellous bone volume compared with vehicle treatment of ovx rats, but this variable remained lower than in sham + veh rats. Osteoid volume, osteoblast surface, and osteoid surface were markedly increased, and osteoclast surface was significantly decreased in ovx + bFGF rats compared with sham + veh and ovx + veh rats. Northern analyses revealed that mRNA levels for osteocalcin and type I collagen, relative to 18S RNA, were significantly higher in ovx + bFGF rats than in ovx + veh rats by a factor of >10. RNase protection assays revealed that insulin-like growth factor (IGF-I) mRNA levels, relative to L32 housekeeping gene, were also significantly higher, by nearly a factor of 3, in ovx + bFGF rats than in ovx + veh rats. Treatment of ovx rats with bFGF did not appear to affect message levels for transforming growth factor-beta (TGF-beta), interleukin-6 (IL-6), and interferon-gamma (IFN-gamma). These in vivo results suggest that bFGF treatment upregulates gene expression for IGF-I, which may mediate, at least in part, the increased gene expression for bone matrix proteins and the bone anabolic effects of bFGF in aged ovx rats.

The androgenic anabolic steroid nandrolone decanoate prevents osteopenia and inhibits bone turnover in ovariectomized cynomolgus monkeys.

We examined the effects of nandrolone decanoate (25 mg im every 3 weeks) on bone mass, serum biomarkers, and bone histomorphometric endpoints in 52 female cynomolgus macaques randomized into four treatment groups: (1) sham-ovariectomized (sham); (2) ovariectomized + placebo for 2 years (ovx); (3) ovx + nandrolone decanoate for 2 years (Nan); and (4) ovx + nandrolone decanoate beginning 1 year after ovx (dNan). Serum alkaline phosphatase (ALP), osteocalcin, and tartrate-resistant acid phosphatase (TRAP) were assayed every 3 months, and X-ray densitometry of the lumbar spine was done every 6 months. Fluorochrome-labeled iliac biopsies collected at baseline and 1 year, and lumbar vertebrae and midshaft femur collected at 2 years, were evaluated histomorphometrically. Body weight increased over 50% with administration of nandrolone. After 2 years, ovx animals had lower spinal BMC and BMD than all other groups. Ovx animals also had higher bone turnover rates than all other groups, as indicated by higher levels of the serum and urine biomarkers, and by at least twofold higher label-based bone formation rates in the femur diaphysis and in both cancellous and cortical bone of the ilium and vertebral bodies. Nandrolone-treated animals had similar serum estradiol levels as the sham animals, presumably due to conversion of endogenous or exogenous androgens. The effects of nandrolone on bone in this experiment are consistent with estradiol action and may be attributable to the increased serum estradiol. Despite >50% higher body weight, nandrolone-treated, ovariectomized animals did not have higher bone mass than sham animals.

Revision osteoarticular allograft transplantation in weight-bearing joints. A clinical review.

The early results of revision osteoarticular allografts in weight-bearing joints are reported. Sixteen consecutive patients underwent surgery over a six-year period between 1982 and 1988. At the time of review eight patients (50%) had surviving second allografts with an average follow-up time of 48 months (range 12 to 87). Five patients were graded excellent according to the Mankin scale, one good and two fair. Eight patients (50%) required further surgery, but only two patients came to amputation.

Relations among measures of body composition, age, and sex in the common marmoset monkey (Callithrix jacchus).

Few studies of body composition have been done in New World primates. In the study reported here, four methods of assessing body composition (body weight, anthropometry, labeled-water dilution, and total body electroconductivity) were compared in 20 marmosets, aged 0.96 to 7.97 years. Males and females did not differ in any measure (P > 0.05). Body weight ranged from 272 to 466 g, and body fat estimates varied from 1.6 to 19.5%. Strong positive correlations were observed between total body water and total body electroconductivity (R2 = 0.77), body weight and fat-free mass (males R2 = 0.95; females R2 = 0.91), and body weight and fat mass (males R2 = 0.86; females R2 = 0.85; P < 0.01). Male and female slopes were equivalent (P > 0.05) for the regressions of fat and fat-free mass against body weight. Positive correlations also were observed between girth measures and fat-free mass (R2 = 0.48 to 0.78) and fat mass (R2 = 0.60 to 0.74; P < 0.01). A good second- order polynomial relationship was observed between age and fat-free mass for the combined sample (R2 = 0.64). Results indicated that: subjects were lean; there was no sexual dimorphism relative to measures; body weight provided a reliable estimate of fat and fat-free mass; and within-subject body weight changes reflected a similar relationship between body weight and fat-free mass as did that across subjects.

Revision hip arthroplasty activity in a single UK health region: an audit of 1265 cases.

Revision hip arthroplasty is an operation which is steadily increasing in number and can often be technically challenging. We have utilised a regional hip register (the Trent Regional Arthroplasty Study) to analyse the epidemiology of revision hip arthroplasties in a single UK health region. The study shows that of the large number (1265) of procedures performed over a 7-year period (1991-1997), the majority were performed by general orthopaedic surgeons, with 91 different surgeons performing the operation and only two surgeons performing more than 20 procedures per year. Of more than 100 prosthetic combinations used for the procedure, the Charnley prosthesis was the most common (38.3% of acetabular revisions and 37.5% of femoral revisions). The same component was also the most commonly explanted (43%). There was an even geographical spread across the region with revision hip arthroplasty being performed in all hospitals with an orthopaedic in-patient facility. Prospective audit of this large and varied cohort is necessary to determine differences in outcome (if any) between 'specialist' hip surgeons and general orthopaedic surgeons.

Iliopsoas tendon reformation after psoas tendon release.

Internal snapping hip syndrome, or psoas tendonitis, is a recognised cause of nonarthritic hip pain. The majority of patients are treated conservatively; however, occasionally patients require surgical intervention. The two surgical options for iliopsoas tendinopathy are step lengthening of the iliopsoas tendon or releasing the tendon at the lesser trochanter. Although unusual, refractory snapping usually occurs soon after tenotomy. We report a case of a 47-year-old active female with internal snapping and pain following an open psoas tenotomy. Postoperatively she was symptom free for 13 years. An MRI arthrogram revealed reformation of a pseudo iliopsoas tendon reinserting into the lesser trochanter. The pain and snapping resolved after repeat iliopsoas tendon release. Reformation of tendons is an uncommon sequela of tenotomies. However the lack of long-term studies makes it difficult to calculate prevalence rates. Tendon reformation should be included in the differential diagnosis of failed tenotomy procedures after a period of symptom relief.