Incident depression in patients diagnosed with multiple sclerosis: a multi-database study.

BACKGROUND AND PURPOSE: Data on rates of newly diagnosed depression after multiple sclerosis (MS) diagnosis are sparse. Here, incident, treated depression in MS patients after diagnosis compared with matched non-MS patients is described. METHODS: A matched cohort study was conducted in two separate electronic medical databases: the US Department of Defense (US-DOD) military healthcare system and the UK's Clinical Practice Research Datalink GOLD (UK-CPRD). The study population included all patients with a first recorded diagnosis of MS and matched non-MS patients. Patients with a history of treated depression were excluded. Incidence rates and incidence rate ratios with 95% confidence intervals for treated depression after MS diagnosis/matched date were estimated. RESULTS: Incidence rate ratios of treated depression amongst MS patients compared with non-MS patients were 3.20 (95% confidence interval 3.05-3.35) in the US-DOD and 1.90 (95% confidence interval 1.74-2.06) in the UK-CPRD. Incidence rate ratios were elevated across age and sex. Rates were higher in females than males but, compared to non-MS patients, males with MS had a higher relative risk than females with MS. CONCLUSIONS: Multiple sclerosis patients in the UK and the USA have a two- to three-fold increased risk of new, treated depression compared to matched non-MS patients.

Infections in patients diagnosed with multiple sclerosis: A multi-database study.

BACKGROUND: Recent data on the rates of infections among patients with multiple sclerosis (MS) are sparse. The objective of this study was to quantify incidence of infections in patients with MS compared with a matched sample of patients without MS (non-MS). METHODS: This study was conducted in two separate electronic medical databases: the United States Department of Defense (US-DOD) military health care system and the United Kingdom's Clinical Practice Research Datalink GOLD (UK-CPRD). We identified patients with a first recorded diagnosis of MS between 2001 and 2016 (UK-CPRD) or 2004 and 2017 (US-DOD) and matched non-MS patients. We identified infections recorded after the MS diagnosis date (or the matched date in non-MS patients) and calculated incidence rates (IRs) and incidence rate ratios (IRRs) with 95% confidence intervals (CIs) by infection site and type. RESULTS: Relative to non-MS patients, MS patients had higher rates of any infection (US-DOD IRR 1.76; 95% CI 1.72-1.80 and UK-CPRD IRR 1.25; 95% CI 1.21-1.29) and a two-fold higher rate of hospitalized infections (US-DOD IRR 2.43; 95% CI 2.23-2.63 and UK-CPRD IRR 2.00; 95% CI 1.84-2.17). IRs of any infection were higher in females compared with males in both MS and non-MS patients, while IRs of hospitalized infections were similar between sexes in both MS and non-MS patients. The IR of first urinary tract or kidney infection was nearly two-fold higher in MS compared with non-MS patients (US-DOD IRR 1.88; 95% CI 1.81-1.95 and UK-CPRD IRR 1.97; 95% CI 1.86-2.09) with higher rates in females compared with males. IRs for any opportunistic infection, candidiasis and any herpes virus were increased between 20 and 52% among MS patients compared with non-MS patients. IRs of meningitis, tuberculosis, hepatitis B and C were all low. CONCLUSION: MS patients have an increased risk of infection, notably infections of the renal tract, and a two-fold increased risk of hospitalized infections compared with non-MS patients.

The risk of treated anxiety and treated depression among patients with psoriasis and psoriatic arthritis treated with apremilast compared to biologics, DMARDs and corticosteroids: a cohort study in the United States MarketScan database.

BACKGROUND: Anxiety and depression are common among psoriasis and psoriatic arthritis (PsA) patients, but rates may differ by treatment. OBJECTIVE: To quantify the risk of incident treated anxiety, depression and mixed anxiety + depression in users of apremilast compared with users of other treatments for psoriasis and PsA. METHODS: We conducted two separate cohort studies of psoriasis and PsA patients treated with apremilast, tumour necrosis factor inhibitor biologics, interleukin-17, -23 or -12/23 inhibitor biologics, conventional DMARDs or systemic corticosteroids in the United States MarketScan database. Cohort entry was date of first study drug after 21 March 2014. We identified cases who had a depression and/or anxiety diagnosis with a prescription for antidepressant/antianxiety medication within 30 days of the diagnosis code. We calculated incidence rates (IRs) and incidence rate ratios with 95% confidence intervals (CIs) for treated anxiety, treated depression and treated anxiety + depression per 1000 patient-years (PY) among patients. RESULTS: Among the psoriasis cohort, IRs for each outcome were similar between exposure categories and highest among users of systemic corticosteroids alone. IRs (95% CI) for apremilast alone were 9.2 (6.6-12.5), 4.6 (2.8-7.1) and 4.6 (2.8-7.1) per 1000 PY for treated anxiety, treated depression and treated anxiety + depression, respectively. In the PsA cohort, the rate of anxiety was highest among users of apremilast alone; rates of depression and anxiety + depression were similar for apremilast compared with other PsA treatments. IRs for each outcome were also high for users of corticosteroids in both the psoriasis and PsA cohorts. CONCLUSIONS: Among patients with psoriasis, users of apremilast had similar rates of anxiety and depression as users of other non-corticosteroid systemic psoriasis treatments. Among PsA patients, users of apremilast had similar rates of depression and anxiety + depression compared with users of other systemic non-corticosteroid PsA drugs; however, the rate of anxiety was slightly higher.

Inducing Hepatitis C Virus Resistance After Pig Liver Transplantation-A Proof of Concept of Liver Graft Modification Using Warm Ex Vivo Perfusion.

Normothermic ex vivo liver perfusion (NEVLP) offers the potential to optimize graft function prior to liver transplantation (LT). Hepatitis C virus (HCV) is dependent on the presence of miRNA(microRNA)-122. Miravirsen, a locked-nucleic acid oligonucleotide, sequesters miR-122 and inhibits HCV replication. The aim of this study was to assess the efficacy of delivering miravirsen during NEVLP to inhibit miR-122 function in a pig LT model. Pig livers were treated with miravirsen during NEVLP or cold storage (CS). Miravirsen absorption, miR-122 sequestration, and miR-122 target gene derepression were determined before and after LT. The effect of miravirsen treatment on HCV infection of hepatoma cells was also assessed. NEVLP improved miravirsen uptake versus CS. Significant miR-122 sequestration and miR-122 target gene derepression were seen with NEVLP but not with CS. In vitro data confirmed miravirsen suppression of HCV replication after established infection and prevented HCV infection with pretreatment of cells, analogous to the pretreatment of grafts in the transplant setting. In conclusion, miravirsen delivery during NEVLP is a potential strategy to prevent HCV reinfection after LT. This is the first large-animal study to provide "proof of concept" for using NEVLP to modify and optimize liver grafts for transplantation.

Effects of lifestyle factors on concentrations of salivary cortisol in healthy individuals.

OBJECTIVE: Salivary cortisol is widely used in occupational health research. However, many ordinary daily activities can influence the concentrations of cortisol and the interpretation of field studies. The aim of the present study was to evaluate the effect of lifestyle factors on salivary cortisol in everyday settings. MATERIAL AND METHODS: Healthy employees participated in one or more sub-studies on the effect of eating a vegetable salad versus protein-rich mid-day meal (n = 40), drinking coffee and smoking (n = 12), drinking alcohol (n = 32), awakening at different times (n = 29) and exercising (n = 21). Cortisol in saliva was measured by radioimmunoassay (RIA). RESULTS: When eating a mid-day meal, salivary cortisol was increased by 10 % (CI -1 % to 24 %) 1 h after eating compared to before eating in the case of both types of meal. Salivary cortisol increased by 80 % (CI 9 % to 199 %) after exercising compared to before exercise. The relative awakening response was approximately 100 % when using an alarm clock on both work-days and days off. However, the awakening response was 39 % (CI 10 % to 75 %) on a day off with spontaneous awakening. No effects of alcohol, coffee or smoking were observed. DISCUSSION: In field studies, the biological variation in salivary cortisol may be reduced by restricting physical exercise and in collecting pre-meal samples. However, the protein content of food and moderate consumption of alcohol had no effect on concentrations of cortisol. Differences in relative awakening responses on work-days and days off are related to time and mode of awakening.

Physiological restitution after night-call duty in anaesthesiologists: impact on metabolic factors.

BACKGROUND: Several studies have shown impaired mental well-being and performance in physicians work on call, but knowledge of the physiological effects is scarce. The aims of the present study were to investigate if there was a metabolic stress response in the restitutional phase after night-call duty, indicating potential negative health effects, and determine whether there were differences between physician specialities. METHODS: Anaesthesiologists (n = 19) were compared with paediatricians/ear, nose and throat (ENT) surgeons (n = 18). On an ordinary workday, 1 and 3 days after work on night call, blood samples were taken for analysis of glucose, thyroid-stimulating hormone (TSH), free thyroxine, testosterone, insulin growth factor-1 (IGF-1), high- and low-density lipoprotein cholesterol (HDL and LDL), triglycerids (TG) and insulin. Saliva cortisol was sampled on an ordinary working day, a day including 16-h night call, the third day following, and for anaesthesiologists also on a day off work. RESULTS: TSH differed significantly between days in both groups, with a 26% lower level 1 day after on-call duty (P < 0.001). A 48% cortisol rise in the morning preceding night duty was found for paediatricians/ENT surgeons (P < 0.01). CONCLUSION: The significant dip in TSH level 24 h after night-call duty indicates a metabolic effect of working on night call and should be studied further. However, the levels were within the normal range and the overall results do not imply any serious metabolic changes and only minor differences were seen between specialist groups.

Personality, mental distress, and subjective health complaints among persons with environmental annoyance.

The aim of this study was to assess possible early determinants of idiopathic environmental intolerance (IEI), contributing to an integrated model for the development of IEI. Questionnaires concerning personality traits, current mental distress, subjective health complaints, work load and satisfaction, and options for recovery, were given to 84 persons from the general population attributing annoyance to (i) chemicals/smells (smell-annoyed (SA) n= 29); (ii) electrical equipment (electrically annoyed (EA) n= 16); and (iii) both smells and electricity (generally annoyed (GA) n= 39), but otherwise healthy and in active work. Compared to referents (n= 54), the EA and GA groups showed strongly elevated scores on 5/6 scales within the trait anxiety/neuroticism personality dimension, while the SA group had a slight elevation on only one anxiety scale. Current mental distress and subjective health complaints scores were generally elevated in the EA and GA groups, but only partially in the SA group. Higher proportions of the EA, GA, and SA groups reported low satisfaction with their work situation, including more frequent fatigue after work and a higher, and often unfulfilled, need for recovery. The findings suggest that trait anxiety is prominent already at prodromal stages of IEI, possibly indicating that trait anxiety facilitates the acquisition of attribution of health complaints to environmental factors.

Chlorhexidine and preservation of sound tooth structure in older adults. A placebo-controlled trial.

The Trial to Enhance Elderly Teeth Health (TEETH) was designed to test the impact of regular rinsing with a 0.12% chlorhexidine (CHX) solution on tooth loss, and the causes of tooth loss (caries, periodontal disease and trauma) were also investigated. This paper reports on the effectiveness of a 0.12% CHX solution for controlling caries using a tooth surface (coronal and root) survival analysis. A total of 1,101 low income elders in Seattle (United States) and Vancouver (Canada), aged 60-75 years, were recruited for a double-blind clinical trial and assigned to either a CHX (n = 550) or a placebo (n = 551) mouth rinse. Subjects alternated between daily rinsing for 1 month, followed by weekly rinsing for 5 months. All sound coronal and root surfaces at baseline were followed annually for up to 5 years. At each follow-up examination, those tooth surfaces with caries, restored, or extracted were scored as 'carious'. The hazard ratio associated with CHX for a sound surface to become filled, decayed, or extracted was 0.87 for coronal surfaces (95% confidence interval: 0.71-1.14, p = 0.20) and 0.91 for root surfaces (95% confidence interval: 0.73-1.14, p = 0.41). These findings suggest that regular rinsing with CHX does not have a substantial effect on the preservation of sound tooth structure in older adults.

Clinical mass spectrometry in neuroscience. Proteomics and peptidomics.

In this review we discuss the merits and drawbacks with the use of proteomic and peptidomic strategies for identification of proteins and peptides in their multidimensional interactions in complex biological processes. The progress in proteomics and peptidomics during the last years offer us new challenges to study changes in the protein and peptide synthesis. These strategies also offer new tools to follow post-translational modifications and other disturbed chemical processes that may be indicative of pathophysiological alteration(s). Furthermore these techniques can contribute to improvements in the diagnosis and therapy of neurodegenerative diseases, such as Alzheimer's disease, and psychiatric diseases, as depression and post traumatic stress disorders. We also consider different practical aspects of the applications of mass spectrometry in clinical neuroscience, illustrated by example from our laboratories. The new proteomic and peptidomic strategies will further enable the progress for clinical neuroscience research.

Periodontitis and perceived risk for periodontitis in elders with evidence of depression.

BACKGROUND: Depression and periodontitis are common conditions in older adults. There is some evidence that these two conditions may be related. AIMS: To study a population of dentate elders and assess the prevalence of depression, self-assessment of risk for periodontitis and tooth loss, in relation to periodontal disease status. MATERIAL AND METHODS: Data were obtained from 701 older subjects (mean age 67.2 years (SD+/-4.6), of whom 59.5% were women. Self-reports of a diagnosis of depression, scores of the Geriatric Depression Scale (GDS), and self-assessment of risk for future tooth loss and periodontitis were compared with a diagnosis of periodontitis based on probing depth, and bone loss assessed from panoramic radiographs. Other systemic diseases and smoking habits were also determined and studied in relation to depression. RESULTS: A history of depression was reported by 20% of the subjects. GDS scores >/=8 were reported by 9.8% of the elders. Periodontitis was identified in 48.5% of the subjects. Depression was associated with heart attack (p<0.05), stroke (p<0.01), high blood pressure (p<0.02), all combined cardiovascular diseases (p<0.001), chronic pain (p<0.01), osteoarthritis (p<0.001), and osteoporosis (p< 0.001) but not with periodontitis (p=0.73). Subjects with depression had a higher self-reported risk score for future tooth loss (p<0.02). No group difference emerged for self-perceived risk for periodontitis. Logistic regression analysis demonstrated that a past history of tooth loss (p<0.001), self-perceived risk for periodontitis (p<0.02), the number of years with a smoking habit (p<0.02), and male gender (p<0.02) were associated with a diagnosis of periodontitis but neither measure of depression could be included in an explanatory model for periodontitis. CONCLUSIONS: Evidence of depression (self-report or by GDS) is not associated with risk for periodontitis in older subjects but is associated with tooth loss and chronic conditions associated with pain.

Assessment of periodontal conditions and systemic disease in older subjects.

BACKGROUND: An increased risk for periodontitis has been associated both with type-1 or insulin dependent diabetes (IDDM) and with type-2 or non-insulin dependent diabetes (NIDDM). AIMS: 1) To describe and analyze periodontal conditions in older low-income ethnic diverse subjects with or without a diagnosis of diabetes. 2) To assess to what extent diabetes mellitus is associated with periodontal status, and 3) how periodontitis ranks as a coexisting disease among other diseases in subjects with diabetes mellitus. MATERIAL AND METHODS: Radiographic signs of alveolar bone loss were studied in 1101 older subjects 60-75 years old (mean age 67.6, SD+/-4.7). The number of periodontal sites and the proportions of teeth with probing depth (PD) > or =5 mm, clinical attachment levels (CAL) > or =4 mm were studied in a subset of 701 of the subjects. RESULTS: IDDM was reported by 2.9% and NIDDM by 9.2% of the subjects. The number of remaining teeth did not differ by diabetic status. The number of sites with PD > or =5 mm and the proportion of PD with > or =5 mm was significantly smaller in the non-diabetic group (chi2=46.8, p<0.01, and chi2=171.1, p<0.001, respectively). Statistical analysis failed to demonstrate group differences for the number and proportions of sites with CAL > or =4 mm and for radiographic findings of alveolar bone loss. Combining all periodontal parameters revealed that the Mantel-Haenszel common odds of having IDDM/NIDDM and periodontitis was 1.8 : 1 (95% CI: 1.1-3.1, p<0.03). The common odds ratio estimate of an association between heart disease and diabetes was 3.6 : 1 (95% CI: 2.1-2.6, p<0.001). CONCLUSIONS: Probing depth differences between IDDM/NIDDM vs. non-diabetic subjects may reflect the presences of pseudo-pockets and not progressive periodontitis in many subjects with diabetes mellitus. Periodontitis is not a predominant coexisting disease in older subjects with diabetes mellitus.

Assessment of periodontal conditions and systemic disease in older subjects. I. Focus on osteoporosis.

BACKGROUND: Osteoporosis (OPOR) is a common chronic disease, especially in older women. Patients are often unaware of the condition until they experience bone fractures. Studies have suggested that OPOR and periodontitis are associated diseases and exaggerated by cytokine activity. Panoramic radiography (PMX) allows studies of mandibular cortical index (MCI), which is potentially diagnostic for OPOR. AIMS: i). To study the prevalence of self-reported history of OPOR in an older, ethnically diverse population, ii). to assess the agreement between PMX/MCI findings and self-reported OPOR, and iii). to assess the likelihood of having both a self-reported history of OPOR and a diagnosis of periodontitis. MATERIALS AND METHODS: PMX and medical history were obtained from 1084 subjects aged 60-75 (mean age 67.6, SD +/- 4.7). Of the films, 90.3% were useful for analysis. PMXs were studied using MCI. The PMXs were used to grade subjects as not having periodontitis or with one of three grades of periodontitis severity. RESULTS: A positive MCI was found in 38.9% of the subjects, in contrast to 8.2% self-reported OPOR. The intraclass correlation between MCI and self-reported OPOR was 0.20 (P < 0.01). The likelihood of an association between OPOR and MCI was 2.6 (95%CI: 1.6, 4.1, P < 0.001). Subjects with self-reported OPOR and a positive MCI had worse periodontal conditions (P < 0.01). The Mantel-Haentzel odds ratio for OPOR and periodontitis was 1.8 (95%CI: 1.2, 2.5, P < 0.001). CONCLUSIONS: The prevalence of positive MCI was high and consistent with epidemiological studies, but only partly consistent with a self-reported history of osteoporosis with a higher prevalence of positive MCI in Chinese women. Horizontal alveolar bone loss is associated with both positive self-reported OPOR and MCI.

Assessment of periodontal conditions and systemic disease in older subjects. II. Focus on cardiovascular diseases.

BACKGROUND: Panoramic radiographs (PMX)s may provide information about systemic health conditions. AIMS: i). To study clinical periodontal conditions and collect self-reported health status in a cohort of 1084 older subjects; ii). to study signs of alveolar bone loss and carotid calcification from panoramic radiographs obtained from these subjects; and iii). to study associations between study parameters. MATERIAL AND METHODS: PMXs from 1064 adults aged 60-75 (mean age 67.6, SD +/- 4.7) were studied. Signs of alveolar bone loss, vertical defects, and molar furcation radiolucencies defined periodontal status. Medical health histories were obtained via self-reports. Signs of carotid calcification were identified from panoramic radiographs. RESULTS: The PMX allowed assessment of 53% of the films (Seattle 64.5% and Vancouver 48.4%). A self-reported history of a stroke was reported by 8.1% of men in Seattle and 2.9% of men in Vancouver (P < 0.01). Heart attacks were reported by 12% of men in Seattle and 7.2% in Vancouver (N.S.). PMX evidence of periodontitis was found in 48.5% of the subjects, with carotid calcification in 18.6%. The intraclass correlation score for PMX findings of carotid calcification and stroke was 0.24 (95% CI: 0.10-0.35, P < 0.001). The odds ratio for PMX carotid calcification and periodontitis was 2.1 (95% CI: 1.3-3.2, P < 0.001), and for PMX carotid calcification and stroke 4.2 (95% CI: 1.9-9.1, P < 0.001). The associations disappeared when smoking was accounted for. A history of a heart attack was associated with stroke, gender, age, and PMX scores of alveolar bone loss. CONCLUSIONS: PMXs may provide valuable information about both oral conditions and signs of carotid calcification, data that are consistent with self-reported health conditions. Alveolar bone loss as assessed from PMXs is associated with cardiovascular diseases.

Association of early onset periodontitis microbiota with aspartate aminotransferase activity in gingival crevicular fluid.

OBJECTIVES: The objective of this study was to determine the relationship between the activity of the enzyme aspartate aminotransferase (AST) in gingival crevicular fluid (GCF) using the colorimetric PerioGard (PTM) test and the subgingival microflora in early onset periodontitis lesions. MATERIAL AND METHODS: The study population consisted of 25 otherwise healthy individuals exhibiting early onset periodontitis (EOP). In each patient four experimental sites were identified comprising one deep periodontal pocket (PD >5 mm) randomly chosen in each quadrant. Bacterial samples were obtained from the experimental sites, consecutively cultured anaerobically and in 10% CO(2) using selective and nonselective media. Isolates were characterized to species level by conventional biochemical tests and various identification kits. Clinical measurements as well as AST activity, assessed either as positive or negative using the PTM, were recorded at the same sites. RESULTS: Sixty-two sites exhibited AST positive and 38 AST negative activity. Analysis of bacterial counts using the ANOVA (Mann Whitney U-test) showed that Streptococcus intermedius, Peptostreptococcus micros, Campylobacter concisus, Bacteroides forsythus, Camplobacter gracilis, Campylobacter rectus and Selenomonas sputigena were significantly higher in sites with AST-positive activity. The odds ratio of having high prevalence of S. intermedius, P. micros, C. concisus, B. forsythus, C. gracilis, C. rectus and S. sputigena in the presence of a positive AST site was very high (range: 3.5-17.0). Streptococcus sanguis, Actinomyces naeslundii, Gemella morbillorum, Capnocytophaga gingivalis, Veillonella parvula, Fusobacterium varium, Eubacterium lentum and Prevotella oralis were detected in significantly higher proportions in sites with AST negative activity and manifested a negative odds ratio in the presence of AST positive sites. The logistic regression analysis revealed that smoking and bleeding upon probing showed a significant association with AST activity, while plaque and suppuration were not found to be significant predictors of AST activity. The co-infection of Porphyromonas gingivalis, B. forsythus and P. micros, or P. gingivalis, B. forsythus and C. rectus were found to be significantly associated with the AST activity (p<0.001). AST positive sites revealed significantly higher occurrence of co-infections by P. gingivalis, B. forsythus, S. sputigena or by P. gingivalis, B. forsythus, S. intermedius than AST negative sites (p<0.001). P. gingivalis, B. forsythus, A. naeslundii co-infection was found significantly higher in the AST negative sites (p<0.001). CONCLUSIONS: The present study found a high level of agreement between the presence of putative periodontal pathogens and positive AST scores at periodontal sites that clinically were considered to be potentially disease active. Prospective studies should be performed to confirm the findings.

Atomic resolution structure of Escherichia coli dUTPase determined ab initio.

Cryocooled crystals of a mercury complex of Escherichia coli dUTPase diffract to atomic resolution. Data to 1.05 A resolution were collected from a derivative crystal and the structure model was derived from a Fourier map with phases calculated from the coordinates of the Hg atom (one site per subunit of the trimeric enzyme) using the program ARP/wARP. After refinement with anisotropic temperature factors a highly accurate model of the bacterial dUTPase was obtained. Data to 1.45 A from a native crystal were also collected and the 100 K structures were compared. Inspection of the refined models reveals that a large part of the dUTPase remains rather mobile upon freezing, with 14% of the main chain being totally disordered and with numerous side chains containing disordered atoms in multiple discrete conformations. A large number of those residues surround the active-site cavity. Two glycerol molecules (the cryosolvent) occupy the deoxyribose-binding site. Comparison between the native enzyme and the mercury complex shows that the active site is not adversely affected by the binding of mercury. An unexpected effect seems to be a stabilization of the crystal lattice by means of long-range interactions, making derivatization a potentially useful tool for further studies of inhibitor-substrate-analogue complexes of this protein at very high resolution.

Crystallization and preliminary crystallographic analysis of deoxyuridine 5'-triphosphate nucleotidohydrolase from Bacillus subtilis.

Single crystals of purified homotrimeric deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase) from Bacillus subtilis have been grown under several different conditions using vapour diffusion. X-ray diffraction data have been collected using synchrotron radiation from three crystal forms of the unliganded enzyme and from enzyme cocrystallized with a substrate analogue and inhibitor, dUDP, and a metal ion, Sr(2+). The three crystal forms of unliganded enzyme belong to hexagonal (P6(3)), orthorhombic (P2(1)2(1)2) and cubic (P2(1)3) space groups and data have been recorded to 1.75, 1.90 and 2.50 A spacing, respectively. Crystals grown in the presence of dUDP and Sr(2+) belong to the orthorhombic space group P2(1)2(1)2(1) and data were measured to 1.90 A spacing. Solution of the hexagonal crystal form by molecular replacement using the dUTPase from feline immunodeficiency virus as a search model is in progress.

Arginine vasopressin in the cytoplasm and nuclear fraction of lymphocytes from healthy donors and patients with depression or schizophrenia.

We investigated whether cytoplasmic or nuclear extracts of human peripheral blood lymphocytes contain AVP in samples from healthy controls and patients diagnosed as depressed or schizophrenic. Both the cytoplasmic and nuclear extracts contained AVP as determined by radioimmunoassay. AVP and other peptides were detected in the purified samples by matrix-assisted laser desorption/ionization time of flight mass spectrometry. It is the first time that AVP has been characterized in human lymphocytes of patients with depression or schizophrenia. This finding demonstrates the presence of another important component within the potential regulatory loop between immune and neuro-endocrine tissues.

Homotrimeric dUTPases; structural solutions for specific recognition and hydrolysis of dUTP.

Prevention of incorporation of dUTP into DNA is essential for maintenance of the genetic information. Prompt and specific removal of dUTP from the nucleotide pool, as expedited by the ubiquitous enzyme dUTPase, is therefore required for full viability in most biological systems. Conserved structural features perpetuate specificity in choice of substrate, which is crucial as hydrolysis of the structurally closely related nucleotides dTTP, dCTP and UTP would debilitate DNA and RNA synthesis. The most common family of dUTPases is the homotrimeric variety where X-ray structures are available for one bacterial, one mammalian and two retroviral dUTPases. These four enzymes have similar overall structural layouts, but the interactions that stabilise the trimer vary markedly, ranging from exclusively hydrophobic to water-mediated interactions. Trimeric dUTPases contain five conserved sequence motifs, positioned at the subunit interfaces where they contribute to the formation of the active sites. Each of the three identical active sites per trimer is built of residues contributed by all three subunits. One subunit provides residues involved in base and sugar recognition, where a beta-hairpin acts to maintain exquisite selectivity, while a second subunit contributes residues for phosphate interactions. The third subunit supplies a glycine-rich consensus motif located in the flexible C-terminal part of the subunit, known from crystallographic studies to cover the active site in the presence of substrate and certain substrate analogues. All dUTPases studied require the presence of a divalent metal ion, preferably Mg(2+), for optimal activity. The putative position of the essential metal ion has been identified in the structure of one retroviral dUTPase. Structure-function studies are essential if the properties of dUTPases are to be understood fully in relation to their biological role. In this review the structural arrangement of the homotrimeric dUTPases is discussed in the context of active site geometry, achievement of specificity and subunit interactions.

Influence of personality traits on neuropsychological test performance in toxic encephalopathy cases and healthy referent subjects.

The relationship between personality traits and cognitive performance was studied in two groups: men with symptoms and neuropsychological test results compatible with toxic encephalopathy (TE) and demographically similar healthy men (N=57 per group). Personality traits were assessed with the Karolinska Scales of Personality (KSP). The neuropsychological examination included 13 tests covering various functional domains. The TE group displayed elevated scores on all three KSP anxiety scales as well as an elevated impulsiveness score. Furthermore, the TE group had a lower score on the socialization scale than did the referent group. Different relationships between personality dispositions and cognitive functioning emerged in the two groups. Within the referent group the highest correlations were observed between KSP anxiety and socialization scale scores and reaction times measures. This pattern did not appear in the TE group; instead, divergent and a few weak relationships emerged. These relationships involved correlations between the KSP monotony avoidance score and some motor speed scores. By dividing the referent group into low anxiety and high anxiety subgroups on the basis of the multi-component anxiety scale score, it was shown that the test scores in the high anxiety subgroup mostly were indistinguishable from the scores in the TE group. In contrast, the low anxiety group had higher test scores than the TE group in 8 of the 13 tests. In conclusion, the expected relationship between anxiety and cognitive vigilance is absent in TE cases. This indicates that the neuropsychological performance decrement in TE cases is not primarily related to elevated mental distress, but is probably dominated by the effects of organic brain impairment. Thus, in TE cases low neuropsychological test scores should not be regarded as a consequence of emotional symptoms. Furthermore, personality traits may be considered as potential confounders even if traditional matching by demographic criteria has been successfully implemented.