Epsom Hospital

We review the findings in major depression of a low plasma and particularly red cell folate, but also of low vitamin B12 status. Both low folate and low vitamin B12 status have been found in studies of depressive patients, and an association between depression and low levels of the two vitamins is found in studies of the general population. Low plasma or serum folate has also been found in patients with recurrent mood disorders treated by lithium. A link between depression and low folate has similarly been found in patients with alcoholism. It is interesting to note that Hong Kong and Taiwan populations with traditional Chinese diets (rich in folate), including patients with major depression, have high serum folate concentrations. However, these countries have very low life time rates of major depression. Low folate levels are furthermore linked to a poor response to antidepressants, and treatment with folic acid is shown to improve response to antidepressants. A recent study also suggests that high vitamin B12 status may be associated with better treatment outcome. Folate and vitamin B12 are major determinants of one-carbon metabolism, in which S-adenosylmethionine (SAM) is formed. SAM donates methyl groups that are crucial for neurological function. Increased plasma homocysteine is a functional marker of both folate and vitamin B12 deficiency. Increased homocysteine levels are found in depressive patients. In a large population study from Norway increased plasma homocysteine was associated with increased risk of depression but not anxiety. There is now substantial evidence of a common decrease in serum/red blood cell folate, serum vitamin B12 and an increase in plasma homocysteine in depression. Furthermore, the MTHFR C677T polymorphism that impairs the homocysteine metabolism is shown to be overrepresented among depressive patients, which strengthens the association. On the basis of current data, we suggest that oral doses of both folic acid (800 microg daily) and vitamin B12 (1 mg daily) should be tried to improve treatment outcome in depression.

OBJECTIVE: To identify pre-operative predictors of patient-reported outcomes of primary total knee replacement (TKR) surgery. METHODS: The Elective Orthopaedic Centre database is a large prospective cohort of 1991 patients receiving primary TKR in south-west London from 2005 to 2008. The primary outcome is the 6-month post-operative Oxford Knee Score (OKS). To classify whether patients had a clinically important outcome, we calculated a patient acceptable symptom state (PASS) for the 6-month OKS related to satisfaction with surgery. Potential predictor variables were pre-operative OKS, age, sex, BMI, deprivation, surgical side, diagnosis, operation type, American Society of Anesthesiologists grade and EQ5D anxiety/depression. Regression modelling was used to identify predictors of outcome. RESULTS: The strongest determinants of outcome include pre-operative pain/function-those with less severe pre-operative disease obtain the best outcomes; diagnosis in relation to pain outcome-patients with RA did better than those with OA; deprivation-those living in poorer areas had worse outcomes; and anxiety/depression-worse pre-operative anxiety/depression led to worse pain. Differences were observed between predictors of pain and functional outcomes. Diagnosis of RA and anxiety/depression were associated with pain, whereas age and gender were specifically associated with function. BMI was not a clinically important predictor of outcome. CONCLUSION: This study identified clinically important predictors of attained pain/function post-TKR. Predictors of pain were not necessarily the same as functional outcomes, which may be important in the context of a patient's expectations of surgery. Other predictive factors need to be identified to improve our ability to recognize patients at risk of poor TKR outcomes.

UNLABELLED: Restoration of femoral offset and acetabular inclination may have an effect on polyethylene (PE) wear in THA. We therefore assessed the effect of femoral offset and acetabular inclination (angle) on acetabular conventional (not highly cross-linked) PE wear in uncemented THA. We prospectively followed 43 uncemented THAs for a minimum of 49 months (mean, 64 months; range, 49-88 months). Radiographs were assessed for femoral offset, acetabular inclination, and conventional PE wear. The mean (+/- standard deviation) linear wear rate in all THAs was 0.14 mm/year (+/- 0.01 mm/year) and the mean volumetric wear rate was 53.1 mm(3)/year (+/- 5.5 mm(3)/year). In THAs with an acetabular angle less than 45 degrees , the mean wear was 0.12 mm/year (+/- 0.01 mm/year) compared with 0.18 mm/year (+/- 0.02 mm/year) in those with a reconstructed acetabular angle greater than 45 degrees . Reproduction of a reconstructed femoral offset to within 5 mm of the native femoral offset was associated with a reduction in conventional PE wear (0.12 mm/year versus 0.16 mm/year). Careful placement of the acetabular component to ensure an acetabular angle less than 45 degrees in the reconstructed hip allows for reduced conventional PE wear. LEVEL OF EVIDENCE: Level II, prospective study. See Guidelines for Authors for a complete description of levels of evidence.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

Understanding the neurochemical basis for cognitive function is one of the major goals of neuroscience, with a potential impact on the diagnosis, prevention and treatment of a range of psychiatric and neurological disorders. In this review, the focus will be on a biochemical pathway that remains under-recognized in its implications for brain function, even though it can be responsible for moderating the activity of two neurotransmitters fundamentally involved in cognition - glutamate and acetylcholine. Since this pathway - the kynurenine pathway of tryptophan metabolism - is induced by immunological activation and stress, it also stands in a unique position to mediate the effects of environmental factors on cognition and behaviour. Targeting the pathway for new drug development could, therefore, be of value not only for the treatment of existing psychiatric conditions, but also for preventing the development of cognitive disorders in response to environmental pressures.

These guidelines have been prepared by the British Society of Gastroenterology. They represent a

These volumes present the results of a study undertaken for the Commission of the European Communities. The aim was to review available data concerning the movement of radionuclides through the environment and to recommend values of parameters for use in environmental transport models. The elements reviewed all have radioactive isotopes which could contribute significantly to the radiological impact of chronic releases of radioactivity from nuclear installations within the countries of the European Community, i.e. the major activation and fission products. In dividing these elements between volumes an effort has been made to take account of the method of production of their major radioisotopes, together with their chemical similarities and environmental interactions. This volume contains the major fission products, namely rubidium, strontium, zirconium, niobium, ruthenium, caesium, cerium and the lanthanides. The main areas which are covered include the deposition of radionuclides on plants and soils, transport in soils, uptake and translocation in plants via the roots and foliage, metabolism in domestic animals and radionuclide transfers through the main physical and biotic components of the aquatic environment. In reviewing these subject areas, account has been taken not only of the literature relating to specific radionuclides, but also of the literature relating to the stable element of which they are radioisotopes.

The generation of reactive oxygen species (free radicals) is an important factor in the development and maintenance of rheumatoid arthritis in humans and animal models. One source of free radicals is nitric oxide produced within the synoviocytes and chondrocytes and giving rise to the highly toxic radical peroxynitrite. Several cytokines, including tumour necrosis factor-α (TNFα) are involved in the formation of free radicals, partly by increasing the activity of nitric oxide synthase. Indeed, nitric oxide may mediate some of the deleterious effects of cytokines on bone resorption. Aspirin, tetracyclines, steroids and methotrexate can suppress nitric oxide synthase. Dietary antioxidants include ascorbate and the tocopherols and beneficial effects of high doses have been reported especially in osteoarthritis. There is also evidence for beneficial effects of β-carotene and selenium, the latter being a component of the antioxidant enzyme glutathione peroxidase. The polyunsaturated fatty acids (PUFA) include the n -3 compounds, some of which are precursors of eicosanoid synthesis, and the n -6 group which can increase formation of the pro-inflammatory cytokines TNFα and interleukin-6, and of reactive oxygen species. Some prostaglandins, however, suppress cytokine formation, so that n -3 PUFA often oppose the inflammatory effects of some n -6-PUFA. γ-linolenic acid (GLA) is a precursor of prostaglandin E 1 , a fact which may account for its reported ability to ameliorate arthritic symptoms. Fish oil supplements, rich in n -3 PUFA such as eicosapentaenoic acid have been claimed as beneficial in rheumatoid arthritis, possibly by suppression of the immune system and its cytokine repertoire. Some other oils of marine origin (e.g. from the green-lipped mussel) and a range of vegetable oils (e.g. olive oil and evening primrose oil) have indirect anti-inflammatory actions, probably mediated via prostaglandin E 1 . Overall, there is a growing scientific rationale for the use of dietary supplements as adjuncts in the treatment of inflammatory disorders such as rheumatoid arthritis and osteoarthritis.

Results of peripheral arterial bypass using polytetrafluoroethylene grafts have remained poor in comparison with those using saphenous vein grafts, particularly for anastomoses to tibial and peroneal vessels. A simple modification to the conventional operative technique, involving the incorporation of a vein patch into the distal anastomosis, has enabled considerable improvement. Five-year patency rates of 71 per cent for popliteal and 54 per cent for infrapopliteal grafts have been achieved in a series of 256 patients operated on between 1982 and 1989.

1. There are differences between the excitotoxic actions of quinolinic acid and N-methyl-D-aspartate (NMDA) which suggest that quinolinic acid may act by mechanisms additional to the activation of NMDA receptors. The present study was designed to examine the effect of a potent antioxidant, melatonin, and the potential neuroprotectant, deprenyl, as inhibitors of quinolinic acid-induced brain damage. Injections were made into the hippocampus of anaesthetized rats, which were allowed to recover before the brains were taken for histology and the counting of surviving neurones. 2. Quinolinic acid (120 nmols) induced damage to the pyramidal cell layer, which was prevented by the co-administration of melatonin (5 nmols locally plus 2x20 mg kg(-1) i.p.). This protective effect was not prevented by the melatonin receptor blocker luzindole. Neuronal damage produced by NMDA (120 nmols) was not prevented by melatonin. 3. Quinolinic acid increased the formation of lipid peroxidation products from hippocampal tissue and this effect was prevented by melatonin. 4. Deprenyl also prevented quinolinic acid-induced damage at a dose of 50 nmols but not 10 nmols plus 2x1.0 mg kg(-1) i.p. The non-selective monoamine oxidase inhibitor nialamide (10 and 50 nmols plus 2x25 mg kg(-1)) did not afford protection. 5. The results suggest that quinolinic acid-induced neuronal damage can be prevented by a receptor-independent action of melatonin and deprenyl, agents which can act as a potent free radical scavenger and can increase the activity of endogenous antioxidant enzymes respectively. This suggests that free radical formation contributes significantly to quinolinic acid-induced damage in vivo.

OBJECTIVE: To develop definitions of bloodstream infections in the newborn that would enable clinicians to identify infection early, so patients can be enrolled in clinical trials. The definitions should be useful for surveillance and epidemiologic purposes. METHOD: Search of EMBASE, MEDLINE, and Cochrane Library using age and English language limited key words sepsis, septicemia, and shock. Extensive study of textbook of neonatology and discussions with experts in the field. RESULTS: The search identified >2,000 references. The most appropriate were selected and reviewed. Definitions of bloodstream infection were developed after consultation with an international faculty. CONCLUSION: Current definitions of neonatal infection (and associated categories) used by neonatal clinicians and researchers have been either adapted/modified from definitions developed for adults or generated by individuals to suit their local needs or the needs of a particular study. It is clear that definitions generated for adults are not applicable to children or to newborn infants. In addition, developing and using unique definitions to suit individual or local needs make comparisons of outcome data and result of studies very difficult. This article proposes a set of definitions that are based as much as possible on current evidence. These definitions may be applicable widely for daily management of an infant with an infection and for research and epidemiologic studies.

Leptin acts on the brain to inhibit feeding, increase thermogenesis, and decrease body weight. Neuropeptide Y (NPY)-ergic neurons of the hypothalamic arcuate nucleus (ARC) that project to the paraventricular nuclei (PVN) and dorsomedial nuclei (DMH) are postulated to control energy balance by stimulating feeding and inhibiting thermogenesis, especially under conditions of energy deficit. We investigated whether leptin's short-term effects on energy balance are mediated by inhibition of the NPY neurons. Recombinant murine leptin (11 microg) injected into the lateral ventricle of fasted adult Wistar rats inhibited food intake by 20-25% between 2 and 6 h after administration, compared with saline-treated controls (P < 0.05). Uncoupling protein mRNA levels in brown adipose tissue (BAT) rose by 70% (P < 0.01). Leptin treatment significantly reduced NPY concentrations by 20-50% (P < 0.05) in the ARC, PVN, and DMH and significantly decreased hypothalamic NPY mRNA levels (0.61 +/- 0.02 vs. 0.78 +/- 0.03 arbitrary units; P < 0.01). A second study examined changes in leptin during 5 days' intracerebroventricular NPY administration (10 microg/day), which induced sustained hyperphagia and excessive weight gain. In NPY-treated rats, leptin mRNA levels in epididymal fat were comparable to those in saline-treated controls (0.94 +/- 0.17 vs. 1.0 +/- 0.28 arbitrary units; P > 0.1), but plasma leptin levels were significantly higher (4.88 +/- 0.66 vs. 2.85 +/- 0.20 ng/ml; P < 0.01). Leptin therefore acts centrally to decrease NPY synthesis and NPY levels in the ARC-PVN projection; reduced NPY release in the PVN may mediate leptin's hypophagic and thermogenic actions. Conversely, NPY-induced obesity results in raised circulating leptin concentrations. Leptin and the NPY-ergic ARC-PVN neurons may interact in a homeostatic loop to regulate body fat mass and energy balance.

The limited oral absorption in rodents of the antiherpesvirus agent 9-(4-hydroxy-3-hydroxymethylbut-l-yl)guanine (BRL 39123 [penciclovir; British approved name]) prompted a search for oral prodrugs. The 6-deoxy derivative of penciclovir (BRL 42359) and the corresponding diacetyl and dipropionyl 6-deoxy derivatives (BRL 42810 [famciclovir; British approved name] and BRL 43599) were tested as oral prodrugs. The in vivo absorption (dose, 0.2 mmol/kg) and the conversion to the active compound, penciclovir, were determined in rats. Compared with the sodium salt of penciclovir given intravenously, the bioavailabilities of penciclovir from orally administered penciclovir, BRL 42359, famciclovir, and BRL 43599 were 1.5, 9, 41, and 27%, respectively. These prodrugs and 6-deoxyacyclovir were tested for stability in rat duodenal contents and for metabolism in rat intestinal wall homogenate, liver homogenate, and blood and in the corresponding human fluids and tissues. Famciclovir was much more stable than BRL 43599 in human duodenal contents (half-lives, greater than 2 h and 7 min, respectively) yet was efficiently converted to penciclovir by the tissue homogenates. The major metabolic pathway was by deacetylation followed by oxidation at the 6 position. The rate of oxidation was comparable to that of 6-deoxyacyclovir, which is known to be converted efficiently to acyclovir in humans. Famciclovir was selected for further evaluation and progression to studies in humans. These subsequent studies confirmed that, after oral dosing with famciclovir, more than half the dose was absorbed and rapidly converted to penciclovir.

Secure fixation of displaced proximal fractures of the humerus is a challenging problem. A total of 32 patients with acutely displaced three- or four-part proximal fractures of the humerus were treated by open reduction and internal fixation using the proximal humeral internal locking system (PHILOS) plate. There were 23 women and nine men with a mean age of 59.9 years (18 to 87). Data were collected prospectively and the outcomes were assessed using the Constant score. The mean follow-up was for 11 months (3 to 24). In 31 patients (97%) the fracture united clinically and radiologically at a mean of 10 weeks (8 to 24). The mean Constant score at final review was 66.5 (30 to 92). There was no significant difference in outcome when comparing patients aged more than 60 years (18 patients) with those aged less than 60 years (14 patients) (t-test, p = 0.8443). There was one case each of nonunion, malunion and a broken screw in the elderly population. This plate provides an alternative method of fixation for fractures of the proximal humerus. It provides a stable fixation in young patients with good-quality bone sufficient to permit early mobilisation. Failure of the screws to maintain fixation in the elderly remains a problem.

OBJECTIVES: The aims of this study were to examine the impact of peripheral joint OA across five large European countries and how people with OA use pharmacotherapies. METHODS: People with self-reported peripheral joint OA were selected from the 2011 five European countries (5EU) National Health and Wellness Survey (NHWS), which included 57 512 respondents from France, Germany, Italy, Spain and the UK. Information was recorded on symptoms, health status, health care utilization, work productivity and medication usage. All variables were analysed descriptively for the total population and individual countries. RESULTS: A total of 3750 respondents met the inclusion criteria: 1635 (43.6%) UK, 961 (25.6%) France, 570 (15.2%) Germany, 316 (8.4%) Spain and 268 (7.1%) Italy. The majority were ages 55-74 years and most were overweight or obese. Health status [12-item Short Form version 2 (SF12v2)] was similar across all countries, with a mean (s.d.) of 40.53 (10.99); 21.5% self-reported experiencing depression. Most had visited a health care provider in the previous 6 months (n = 3537; 94.3%). One third were employed: 7% reported absenteeism and 24% presenteeism. The use of prescription medication for OA was reported by 46.9% of patients, over-the-counter (OTC) medication by 26.5%, and both by 9.4%. Medication use increased with pain severity. NSAIDs were the most commonly used medication. Opioid use varied from 1.8% in Italy to 54.5% in France. Fifty per cent reported full adherence (4-point Morisky Medication Adherence Scale), but only 30% reported satisfaction with their OA medication. Most used medication for half the days of the month. CONCLUSION: Despite some wide variations in pharmacotherapy for OA treatment, the impact of OA on health status and work productivity is substantial and looks largely similar across major European countries.

We audited the relationship between obesity and the age at which hip and knee replacement was undertaken at our centre. The database was analysed for age, the Oxford hip or knee score and the body mass index (BMI) at the time of surgery. In total, 1369 patients were studied, 1025 treated by hip replacement and 344 by knee replacement. The patients were divided into five groups based on their BMI (normal, overweight, moderately obese, severely obese and morbidly obese). The difference in the mean Oxford score at surgery was not statistically significant between the groups (p > 0.05). For those undergoing hip replacement, the mean age of the morbidly obese patients was ten years less than that of those with a normal BMI. For those treated by knee replacement, the difference was 13 years. The age at surgery fell significantly for those with a BMI > 35 kg/m(2) for both hip and knee replacement (p > 0.05). This association was stronger for patients treated by knee than by hip replacement.

Sodium pseudomonate was shown to be a powerful competitive inhibitor of Escherichia coli B isoleucyl-tRNA synthetase (Ile-tRNA synthetase). The antibiotic competitively inhibits (Ki 6 nM; cf. Km 6.3 microM), with respect top isoleucine, the formation of the enzyme . Ile approximately AMP complex as measured by the pyrophosphate-exchange reaction, and has no effect on the transfer of [14C]isoleucine from the enzyme . [14C]Ile approximately AMP complex to tRNAIle. The inhibitory constant for the pyrophosphate-exchange reaction was of the same order as that determined for the inhibition of the overall aminoacylation reaction (Ki 2.5 nM; cf. Km 11.1 microM). Sodium [9'-3H]pseudomonate forms a stable complex with Ile-tRNA synthetase. Gel-filtration and gel-electrophoresis studies showed that the antibiotic is only fully released from the complex by 5 M-urea treatment or boiling in 0.1% sodium dodecyl sulphate. The molar binding ratio of sodium [9'-3H]pseudomonate to Ile-tRNA synthetase was found to be 0.85:1 by equilibrium dialysis. Aminoacylation of yeast tRNAIle by rat liver Ile-tRNA synthetase was also competitively inhibited with respect to isoleucine, Ki 20 microM (cf. Km 5.4 microM). The Km values for the rat liver and E. coli B enzymes were of the same order, but the Ki for the rat liver enzyme was 8000 times the Ki for the E. coli B enzyme. This presumably explains the low toxicity of the antibiotic in mammals.

Tranexamic acid is a fibrinolytic inhibitor which reduces blood loss in total knee replacement. We examined the effect on blood loss of a standardised intravenous bolus dose of 1 g of tranexamic acid, given at the induction of anaesthesia in patients undergoing total hip replacement and tested the potential prothrombotic effect by undertaking routine venography. In all, 36 patients received 1 g of tranexamic acid, and 37 no tranexamic acid. Blood loss was measured directly per-operatively and indirectly post-operatively. Tranexamic acid reduced the early post-operative blood loss and total blood loss (p = 0.03 and p = 0.008, respectively) but not the intraoperative blood loss. The tranexamic acid group required fewer transfusions (p = 0.03) and had no increased incidence of deep-vein thrombosis. The reduction in early post-operative blood loss was more marked in women (p = 0.05), in whom this effect was dose-related (r = -0.793). Our study showed that the administration of a standardised pre-operative bolus of 1 g of tranexamic acid was cost-effective in reducing the blood loss and transfusion requirements after total hip replacement, especially in women.

BACKGROUND: Research indicates schizophrenia is a cause of burden for patients and caregivers. This study examined health-related quality of life (HRQoL) and comorbidities experienced by informal schizophrenia caregivers compared with non-caregivers and caregivers of adults with other conditions (e.g., Alzheimer's disease, cancer, and stroke). METHODS: Data were obtained from the 5EU (France, Germany, Italy, Spain, UK) National Health and Wellness Survey, an online questionnaire that is representative of the total 5EU adult (18+ years) population. Respondents provided information on HRQoL (SF-36v2: mental and physical component summary (MCS, PCS) and SF-6D (health utility) scores), items from the Caregiver Reaction Assessment (strongly disagree to strongly agree) and comorbidities (sleep difficulties, insomnia, pain, headaches, heartburn, anxiety, depression) experienced in the past 12 months. Schizophrenia caregivers (n = 398) were matched to non-caregivers (n = 158,989) and caregivers of other conditions (n = 14,341) on baseline characteristics via propensity scores. Chi-square tests and ANOVAs were used to determine significant differences across groups. RESULTS: The average age of schizophrenia caregivers was 45.3 years (SD = 15.8), and 59.6% were female. After matching, schizophrenia caregivers reported lower MCS (40.3 vs. 45.9), PCS (46.8 vs. 49.0), and health utilities (0.64 vs. 0.71) compared with non-caregivers (all p < 0.001). Schizophrenia caregivers were more likely to experience sleep difficulties (42.7% vs. 28.5%), insomnia (32.4% vs. 18.5%), pain (39.7% vs. 30.4%), headaches (48.0% vs. 42.0%), heartburn (31.7% vs. 22.9%), anxiety (37.9% vs. 23.6%), and depression (29.4% vs. 19.4%) than non-caregivers. Comparing schizophrenia caregivers and other caregivers, schizophrenia caregivers reported lower MCS (40.3 vs. 42.7, p < 0.001), and health utilities (0.64 vs. 0.67, p < 0.001). Schizophrenia caregivers were more likely to experience sleep difficulties, insomnia, pain, and anxiety than other caregivers. Almost 60% of schizophrenia caregivers agree/strongly agree that caring for the patient is important to them, but only 31.9% agree/strongly agree that they have the financial resources to provide adequate care. CONCLUSIONS: Schizophrenia caregivers reported worse HRQoL than non-caregivers and caregivers of other conditions. Providing care for an adult relative with schizophrenia is important to caregivers, but caregivers need more resources to provide adequate care. Providing informal schizophrenia caregivers with support services to help better manage patients may improve their health status.

We obtained information from the Elective Orthopaedic Centre on 1523 patients with baseline and six-month Oxford hip scores (OHS) after undergoing primary hip replacement (THR) and 1784 patients with Oxford knee scores (OKS) for primary knee replacement (TKR) who completed a six-month satisfaction questionnaire. Receiver operating characteristic curves identified an absolute change in OHS of 14 points or more as the point that discriminates best between patients' satisfaction levels and an 11-point change for the OKS. Satisfaction is highest (97.6%) in patients with an absolute change in OHS of 14 points or more, compared with lower levels of satisfaction (81.8%) below this threshold. Similarly, an 11-point absolute change in OKS was associated with 95.4% satisfaction compared with 76.5% below this threshold. For the six-month OHS a score of 35 points or more distinguished patients with the highest satisfaction level, and for the six-month OKS 30 points or more identified the highest level of satisfaction. The thresholds varied according to patients' pre-operative score, where those with severe pre-operative pain/function required a lower six-month score to achieve the highest levels of satisfaction. Our data suggest that the choice of a six-month follow-up to assess patient-reported outcomes of THR/TKR is acceptable. The thresholds help to differentiate between patients with different levels of satisfaction, but external validation will be required prior to general implementation in clinical practice.