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1.  Potential blood-based markers of celiac disease 
BMC Gastroenterology  2014;14(1):176.
Background
Blood-based diagnostics has the potential to simplify the process of diagnosing celiac disease (CD). Although high levels of autoantibodies against tissue transglutaminase (anti-TG2) are strongly indicative of active CD, several other scenarios involve a need for additional blood-based CD markers.
Methods
We investigated the levels of messenger RNA (mRNA) in whole blood (n = 49) and protein in plasma (n = 22) from cases with active CD (n = 20), with confirmed CD and normalized histology (n = 15), and without a CD diagnosis (n = 14). Group differences were analyzed using Kruskal-Wallis one-way analysis of variance by ranks. We also investigated correlations between levels of potential markers, histopathology according to the modified Marsh scale, and CD risk gradient based on HLA type, using Spearman rank correlation. The relation between HLA-DQ2 gene dose effect and the expression levels of selected blood-based markers was investigated using the Mann–Whitney U test. Finally, the diagnostic performance of anti-TG2, potential blood-based CD markers, and logistic regression models of combined markers was evaluated using receiver operating characteristic (ROC) curve analysis.
Results
CXCL11 protein levels and TNFRSF9 and TNFSF13B mRNA levels were identified as potential CD markers. These are all affected by or involved in the regulation of the NF-κB complex. CXCL11 protein levels and IL21 and IL15 mRNA levels were correlated with histopathology according to the modified Marsh scale, as were the established CD markers. HLA genotype risk and HLA-DQ2 gene dose effect did not show any significant relations with either the potential CD markers or the established CD markers. ROC curve analysis revealed a slight, non-significant increase in the area under the curve for the combined use of anti-TG2 and different constellations of potential blood-based CD markers compared to anti-TG2 alone.
Conclusions
The CD markers identified in this study further emphasize the significance of components related to NF-κB regulation in relation to CD. However, the relevance of CXCL11, TNFSF13B, TNFRSF9, and other NF-κB interacting proteins recognized by pathway analysis, needs to be further investigated in relation to diagnosis and monitoring of CD.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-230X-14-176) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-230X-14-176
PMCID: PMC4287385  PMID: 25298177
Celiac disease; Molecular diagnostics; Blood-based biological markers
2.  Caffeine Interaction with Glutamate Receptor Gene GRIN2A: Parkinson's Disease in Swedish Population 
PLoS ONE  2014;9(6):e99294.
A complex interplay between genetic and environmental factors is thought to be involved in the etiology of Parkinson's disease (PD). A recent genome-wide association and interaction study (GWAIS) identified GRIN2A, which encodes an NMDA-glutamate-receptor subunit involved in brain's excitatory neurotransmission, as a PD genetic modifier in inverse association with caffeine intake. Here in, we attempted to replicate the reported association of a single nucleotide polymorphism, GRIN2A_rs4998386, and its interaction with caffeine intake with PD in patient-control study in an ethnically homogenous population in southeastern Sweden, as consistent and independent genetic association studies are the gold standard for the validation of genome-wide association studies. All the subjects (193 sporadic PD patients and 377 controls) were genotyped, and the caffeine intake data was obtained by questionnaire. We observed an association between rs4998386 and PD with odds ratio (OR) of 0.61, 95% confidence intervals (CI) of 0.39–0.96, p = 0.03, under a model excluding rare TT allele. There was also a strong significance in joint effects of gene and caffeine on PD risk (TC heavy caffeine vs. CC light caffeine: OR = 0.38, 95%CI = [0.20–0.70], p = 0.002) and gene-caffeine interaction (OR = 0.998, 95%CI = [0.991–0.999], p<0.001). Overall, our results are in support of the findings of the GWAIS and provided additional evidence indicating PD protective effects of coffee drinking/caffeine intake as well as the interaction with glutamate receptor genotypes.
doi:10.1371/journal.pone.0099294
PMCID: PMC4051678  PMID: 24915238
3.  Social stimulation and corticolimbic reactivity in premenstrual dysphoric disorder: a preliminary study 
Background
Premenstrual dysphoric disorder (PMDD), characterized by luteal phase-induced negative affect and loss of impulse control, often results in compromised social interactions. Although amygdala activation is generally linked to negative affect, increased amygdala reactivity to aversive stimuli in the luteal phase has not been consistently reported in PMDD. We tested the hypothesis that amygdala hyper-reactivity in PMDD is symptom specific, rather than generalized, and linked to socially relevant stimuli. Blood oxygenation level dependent signal changes during exposure to negative images with social and non-social content were evaluated in the mid-follicular and late luteal phase of the menstrual cycle. Fourteen women with PMDD and 13 healthy controls participated.
Results
When compared with healthy controls, women with PMDD in the luteal phase had enhanced reactivity to social stimuli compared to non-social stimuli in the amygdala and insula, but attenuated reactivity in the anterior cingulate cortex. Functional couplings between emotion processing and controlling areas were significantly different, being positive in women with PMDD and negative in healthy controls. Changes in progesterone levels in women with PMDD correlated positively with altered amygdala reactivity.
Conclusions
Socially relevant aversive stimulation elicited enhanced activity in affective processing brain regions that were functionally coupled to compromised activity in cognitive control areas. Because increased reactivity correlated positively with alterations in ovarian steroid levels, data preliminary support the hypothesis that enhanced progesterone sensitivity in PMDD affects corticolimbic processing of social emotions.
doi:10.1186/2045-5380-4-3
PMCID: PMC4015856  PMID: 24572042
4.  Classifying social anxiety disorder using multivoxel pattern analyses of brain function and structure☆ 
Behavioural Brain Research  2014;259(100):330-335.
Highlights
•Social anxiety disorder (SAD) is a common and disabling psychiatric disorder.•Support vector machines (SVM) were trained to separate SAD from controls.•Neural face processing in the fear network separated SAD patients from controls.•Gray matter volume alterations over the whole brain separated SAD from controls.•SVM classifiers may be useful for identifying imaging biomarkers of SAD.
Functional neuroimaging of social anxiety disorder (SAD) support altered neural activation to threat-provoking stimuli focally in the fear network, while structural differences are distributed over the temporal and frontal cortices as well as limbic structures. Previous neuroimaging studies have investigated the brain at the voxel level using mass-univariate methods which do not enable detection of more complex patterns of activity and structural alterations that may separate SAD from healthy individuals. Support vector machine (SVM) is a supervised machine learning method that capitalizes on brain activation and structural patterns to classify individuals. The aim of this study was to investigate if it is possible to discriminate SAD patients (n = 14) from healthy controls (n = 12) using SVM based on (1) functional magnetic resonance imaging during fearful face processing and (2) regional gray matter volume. Whole brain and region of interest (fear network) SVM analyses were performed for both modalities. For functional scans, significant classifications were obtained both at whole brain level and when restricting the analysis to the fear network while gray matter SVM analyses correctly classified participants only when using the whole brain search volume. These results support that SAD is characterized by aberrant neural activation to affective stimuli in the fear network, while disorder-related alterations in regional gray matter volume are more diffusely distributed over the whole brain. SVM may thus be useful for identifying imaging biomarkers of SAD.
doi:10.1016/j.bbr.2013.11.003
PMCID: PMC3888925  PMID: 24239689
Support vector machine; Classification; Social anxiety disorder; Multivoxel pattern analysis; Biomarker
5.  Health-related quality of life scores after intensive care are almost equal to those of the normal population: a multicenter observational study 
Critical Care  2013;17(5):R236.
Introduction
Health-related quality of life (HRQoL) in patients treated in intensive care has been reported to be lower compared with age- and sex-adjusted control groups. Our aim was to test whether stratifying for coexisting conditions would reduce observed differences in HRQoL between patients treated in the ICU and a control group from the normal population. We also wanted to characterize the ICU patients with the lowest HRQoL within these strata.
Methods
We did a cross-sectional comparison of scores of the short-form health survey (SF-36) questionnaire in a multicenter study of patients treated in the ICU (n = 780) and those from a local public health survey (n = 6,093). Analyses were in both groups adjusted for age and sex, and data stratified for coexisting conditions. Within each stratum, patients with low scores (below -2 SD of the control group) were identified and characterized.
Results
After adjustment, there were minor and insignificant differences in mean SF-36 scores between patients and controls. Eight (n = 18) and 22% (n = 51) of the patients had low scores (-2 SD of the control group) in the physical and mental dimensions of SF-36, respectively. Patients with low scores were usually male, single, on sick leave before admission to critical care, and survived a shorter time after being in ICU.
Conclusions
After adjusting for age, sex, and coexisting conditions, mean HRQoL scores were almost equal in patients and controls. Up to 22% (n = 51) of the patients had, however, a poor quality of life as compared with the controls (-2 SD). This group, which more often consisted of single men, individuals who were on sick leave before admission to the ICU, had an increased mortality after ICU. This group should be a target for future support.
doi:10.1186/cc13059
PMCID: PMC4056627  PMID: 24119915
6.  A prospective longitudinal multicentre study of health related quality of life in ICU survivors with COPD 
Critical Care  2013;17(5):R211.
Introduction
Mortality amongst COPD patients treated on the ICU is high. Health-related quality of life (HRQL) after intensive care is a relevant concern for COPD patients, their families and providers of health care. Still, there are few HRQL studies after intensive care of this patient group. Our hypothesis was that HRQL of COPD patients treated on the ICU declines rapidly with time.
Methods
Fifty-one COPD patients (COPD-ICU group) with an ICU stay longer than 24 hours received a questionnaire at 6, 12 and 24 months after discharge from ICU. HRQL was measured using two generic instruments: the EuroQoL instrument (EQ-5D and EQ-VAS) and the Short Form 36 Health Survey (SF-36). The results were compared to HRQL of two reference groups from the general population; an age- and sex-adjusted reference population (Non-COPD reference) and a reference group with COPD (COPD reference).
Results
HRQL of the COPD-ICU group at 6 months after discharge from ICU was lower compared to the COPD reference group: Median EQ-5D was 0.66 vs. 0.73, P = 0.08 and median EQ-VAS was 50 vs.55, P < 0.05. There were no significant differences in the SF-36 dimensions between the COPD-ICU and COPD-reference groups, although the difference in physical functioning (PF) approached statistical significance (P = 0.059). Patients in the COPD-ICU group who were lost to follow-up after 6 months had low HRQL scores at 6 months. Scores for patients who died were generally lower compared to patients who failed to respond to the questionnaire. The PF and social functioning (SF) scores in those who died were significantly lower compared to patients with a complete follow up. HRQL of patients in the COPD-ICU group that survived a complete 24 months follow up was low but stable with no statistically significant decline from 6 to 24 months after ICU discharge. Their HRQL at 24 months was not significantly different from HRQL in the COPD reference group.
Conclusions
HRQL in COPD survivors after intensive care was low but did not decline from 6 to 24 months after discharge from ICU. Furthermore, HRQL at 24 months was similar to patients with COPD who had not received ICU treatment.
doi:10.1186/cc13019
PMCID: PMC4056744  PMID: 24063309
7.  Amygdala Subregions Tied to SSRI and Placebo Response in Patients with Social Anxiety Disorder 
Neuropsychopharmacology  2012;37(10):2222-2232.
The amygdala is a key structure in the pathophysiology of anxiety disorders, and a putative target for anxiolytic treatments. Selective serotonin reuptake inhibitors (SSRIs) and placebo seem to induce anxiolytic effects by attenuating amygdala responsiveness. However, conflicting amygdala findings have also been reported. Moreover, the neural profile of responders and nonresponders is insufficiently characterized and it remains unknown whether SSRIs and placebo engage common or distinct amygdala subregions or different modulatory cortical areas. We examined similarities and differences in the neural response to SSRIs and placebo in patients with social anxiety disorder (SAD). Positron emission tomography (PET) with oxygen-15-labeled water was used to assess regional cerebral blood flow (rCBF) in 72 patients with SAD during an anxiogenic public speaking task, before and after 6–8 weeks of treatment under double-blind conditions. Response rate was determined by the Clinical Global Impression-Improvement scale. Conjunction analysis revealed a common rCBF-attenuation from pre- to post-treatment in responders to SSRIs and placebo in the left basomedial/basolateral and right ventrolateral amygdala. This rCBF pattern correlated with behavioral measures of reduced anxiety and differentiated responders from nonresponders. However, nonanxiolytic treatment effects were also observed in the amygdala. All subgroups, including nonresponders, showed deactivation of the left lateral part of the amygdala. No rCBF differences were found between SSRI responders and placebo responders. This study provides new insights into the brain dynamics underlying anxiety relief by demonstrating common amygdala targets for pharmacologically and psychologically induced anxiety reduction, and by showing that the amygdala is functionally heterogeneous in anxiolysis.
doi:10.1038/npp.2012.72
PMCID: PMC3422487  PMID: 22617357
amygdala; SSRIs; placebo; SAD; subregions; PET; mood; anxiety; stress disorders; imaging; clinical or preclinical; biological psychiatry; serotonin; amygdala; SAD; SSRIs; subregions; placebo
8.  Urinary 2,5-hexanedione excretion in cryptogenic polyneuropathy compared to the general Swedish population 
Background
2,5-hexanedione (2,5-HD) is the main neurotoxic metabolite of methyl-n-butyl ketone (MBK) and n-hexane, and known to cause polyneuropathy. The aim of our study was to compare the urinary levels of 2,5-HD between cases with cryptogenic polyneuropathy and the general Swedish population, and to elucidate the role of certain external factors.
Methods
Morning urine samples were collected from 114 cases with cryptogenic polyneuropathy (77 men and 37 women) and 227 referents (110 men and 117 women) randomly selected from the population registry. None had any current occupational exposure to n-hexane or MBK. The urine samples were analysed by a gas chromatographic method based on acidic hydrolysis.
Results
Cases had statistically higher urinary levels of 2,5-HD (0.48 mg/L) than the general population (0.41 mg/L) and men higher excretion than women (0.48 mg/L and 0.38 mg/L, respectively). There was no difference in 2,5-HD levels between current smokers and non-smokers. Occupational exposure to xylene, alcohol consumption and ever exposed to general anaesthesia were associated with lower excretion in men while for occupational exposure to nitrous oxide in women higher excretion was seen. Higher excretion of 2,5 HD was inversely related to increasing age.
Conclusions
Significantly higher levels of urinary 2,5-HD were seen in men and cryptogenic polyneuropathy cases seemingly unexposed to n-hexane. Hypothetically, this might be due to either differences in metabolic patterns or some concealed exposure. The difference in means between cases and the general population is small and can therefore not allow any firm conclusions of the causality, however.
doi:10.1186/1745-6673-8-21
PMCID: PMC3733657  PMID: 23898939
Polyneuropathy; Cryptogenic; Urine; 2,5-hexanedione; General population; Sweden; Occupational exposure
9.  Learned Cardiac Control with Heart Rate Biofeedback Transfers to Emotional Reactions 
PLoS ONE  2013;8(7):e70004.
Emotions involve subjective feelings, action tendencies and physiological reactions. Earlier findings suggest that biofeedback might provide a way to regulate the physiological components of emotions. The present study investigates if learned heart rate regulation with biofeedback transfers to emotional situations without biofeedback. First, participants learned to decrease heart rate using biofeedback. Then, inter-individual differences in the acquired skill predicted how well they could decrease heart rate reactivity when later exposed to negative arousing pictures without biofeedback. These findings suggest that (i) short lasting biofeedback training improves heart rate regulation and (ii) the learned ability transfers to emotion challenging situations without biofeedback. Thus, heart rate biofeedback training may enable regulation of bodily aspects of emotion also when feedback is not available.
doi:10.1371/journal.pone.0070004
PMCID: PMC3720933  PMID: 23894574
10.  NOTCH1 mutations influence survival in chronic lymphocytic leukemia patients 
BMC Cancer  2013;13:274.
Background
NOTCH1 PEST domain mutations in chronic lymphocytic leukemia have recently been shown to be of prognostic relevance. Both NOTCH1 and NOTCH2 are constitutively activated in B-cell CLL but not expressed in normal B cells and may be involved in survival and resistance to apoptosis in CLL. We screened for mutations in different parts of both NOTCH1 and NOTCH2 genes and related the changes to survival and other known risk factors.
Methods
In a cohort of 209 CLL patients, we used single strand conformation analysis to determine which of the samples carrying the NOTCH mutations and direct dideoxy sequencing was used to determine the exact nucleotide changes. Kaplan-Meier curves and log rank test were used to determine overall survival for NOTCH1 mutated cases and Cox regression analysis was used to calculate hazardous ratios.
Results
In the present study, we found NOTCH1 PEST domain mutations in 6.7% of the cases. A shorter overall survival was found in patients with NOTCH1 mutations compared to wildtype (p = 0.049). Further, we also examined the extracellular and the heterodimerisation domains of the NOTCH1 gene and the PEST domain and heterodimerisation domain of the NOTCH2 gene, but no mutations were found in these regions. NOTCH1 mutations were most commonly observed in patients with unmutated IGHV gene (10/14), and associated with a more aggressive disease course. In addition, NOTCH1 mutations were almost mutually exclusive with TP53 mutations. In the combined group of NOTCH1 (6.7%) or TP53 (6.2%) mutations, a significant difference in overall survival compared to the wildtype NOTCH1 and TP53 was found (p = 0.002).
Conclusions
Both NOTCH1 and TP53 mutations seem to be independent predictive markers for worse outcome in CLL-patients and this study emphasizes the contention that NOTCH1 mutations is a novel risk marker.
doi:10.1186/1471-2407-13-274
PMCID: PMC3679784  PMID: 23734977
Chronic lymphocytic leukemia; NOTCH1 mutations; TP53 mutations; Prognostic markers
11.  The Q705K Polymorphism in NLRP3 Is a Gain-of-Function Alteration Leading to Excessive Interleukin-1β and IL-18 Production 
PLoS ONE  2012;7(4):e34977.
Background
The Q705K polymorphism in NLRP3 has been implicated in several chronic inflammatory diseases. In this study we determine the functional role of this commonly occurring polymorphism using an in-vitro system.
Principal Findings
NLRP3-WT and NLRP3-Q705K were retrovirally transduced into the human monocytic cell line THP-1, followed by the assessment of IL-1β and IL-18 levels in the cell culture supernatant. THP-1 cells expressing the above NLRP3 variants were sorted based upon Green Fluorescent Protein (GFP) expression. Cytokine response to alum (one of the most widely used adjuvants in vaccines) in the cells stably expressing NLRP3-WT and NLRP3-Q705K were determined. IL-1β and IL-18 levels were found to be elevated in THP-1 cells transduced with NLRP3-Q705K compared to the NLRP3-WT. Upon exposure to alum, THP-1 cells stably expressing NLRP3-Q705K displayed an increased release of IL-1β, IL-18 and TNF-α, in a caspase-1 and IL-1 receptor-dependent manner.
Conclusions
Collectively, these findings show that the Q705K polymorphism in NLRP3 is a gain-of-function alteration leading to an overactive NLRP3 inflammasome. The option of IL-1β blockade may be considered in patients with chronic inflammatory disorders that are unresponsive to conventional treatments.
doi:10.1371/journal.pone.0034977
PMCID: PMC3328489  PMID: 22529966
12.  Time trends in STEMI—improved treatment and outcome but still a gender gap: a prospective observational cohort study from the SWEDEHEART register 
BMJ Open  2012;2(2):e000726.
Objective
In ST elevation myocardial infarction women received less evidence-based medicine and had worse outcome during the fibrinolytic era. With the shift to primary percutaneous coronary intervention (pPCI) as preferred reperfusion strategy, the authors aimed to investigate whether these gender differences has diminished.
Design, setting and participants
Cohort study including consecutive ST elevation myocardial infarction patients registered 1998–2000 (n=15 697) and 2004–2006 (n=14 380) in the Register of Information and Knowledge about Swedish Heart Intensive care Admissions.
Outcome measures
1. Use of evidence-based medicine such as reperfusion therapy (pPCI or fibrinolysis) and evidence-based drugs at discharge. 2. Inhospital and 1-year mortality.
Results
Of those who got reperfusion therapy, pPCI was the choice in 9% in the early period compared with 68% in the late period. In the early period, reperfusion therapy was given to 63% of women versus 71% of men, p<0.001. Corresponding figures in the late period were 64% vs 75%, p<0.001. After multivariable adjustments, the ORs (women vs men) were 0.86 (95% CI 0.78 to 0.94) in the early and 0.80 (95% CI 0.73 to 0.89) in the late period. As regards evidence-based secondary preventive drugs at discharge in hospital survivors (platelet inhibitors, statins, ACE inhibitors/angiotensin receptor blockers and β-blockers), there were small gender differences in the early period. In the late period, women had 14%–25% less chance of receiving these drugs, OR 0.75 (95% CI 0.68 to 0.81) through 0.86 (95% CI 0.73 to 1.00). In both periods, multivariable-adjusted inhospital mortality was higher in women, OR 1.18 (95% CI 1.02 to 1.36) and 1.21 (1.00 to 1.46). One-year mortality was gender equal, HR 0.95 (95% CI 0.87 to 1.05) and 0.96 (0.86 to 1.08), after adding evidence-based medicine to the multivariable adjustments.
Conclusion
In spite of an intense gender debate, focus on guideline adherence and the change in reperfusion strategy, the last decade gender differences in use of reperfusion therapy and evidence-based therapy at discharge did not decline during the study period, rather the opposite. Moreover, higher mortality in women persisted.
Article summary
Article focus
With (1) the focus on treatment guidelines, (2) the attention on gender differences in management and outcome and (3) the change in reperfusion strategy in STEMI in the last decade, we hypothesised
that gender differences in adherence to treatment guidelines would have diminished and
that gender differences in outcome would have decreased.
Key messages
Management improved and mortality decreased in STEMI patients in the late compared with the early period.
The gender treatment gap did not decrease between the two time periods.
The gender outcome gap did not decrease between the two time periods.
Strengths and limitations of this study
The study included a huge amount of STEMI patients, with enough numbers to assure adequate statistical analyses. Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies register is a unique Swedish National Quality register, with quality control and audit measures, covering all hospitals in Sweden treating STEMI patients and has standardised criteria for defining MI. Mortality data are complete as the vital status of all Swedish citizens is registered in the Cause of Death Register. One limitation is the non-randomised observational nature. Thus, multivariate analyses were used in order to reduce the bias inherent in this type of studies. Adjustments might be influenced by the lack of registration on some possible confounding factors in the database, for example, non-cardiac comorbidities and contraindications for specific treatments.
doi:10.1136/bmjopen-2011-000726
PMCID: PMC3323814  PMID: 22457480
13.  Learning in a simple biological system: a pilot study of classical conditioning of human macrophages in vitro 
Recent advances in cell biology and gene regulation suggest mechanisms whereby associative learning could be performed by single cells. Therefore, we explored a model of classical conditioning in human macrophages in vitro. In macrophage cultures, bacterial lipopolysaccharide (LPS; unconditioned stimulus) was paired once with streptomycin (conditioned stimulus). Secretion of interleukin-6 (IL-6) was used as response measure. At evocation, conditioning was not observed. Levels of IL-6 were higher only in those cultures that had been exposed to LPS in the learning phase (p's < .05), regardless whether they received the conditioned stimulus or not at evocation.
However, habituation was evident, with a 62% loss of the IL-6 response after three LPS presentations (p < .001). If further experiments confirm that simple learning can occur in immune cells, this may have bearings not only on immune regulation, but also on the brain response to molecular signals detected in the periphery. Importantly, whether capacities for simple learning in single cells extend beyond habituation, and how this would be demonstrated, remain open questions.
doi:10.1186/1744-9081-7-47
PMCID: PMC3247862  PMID: 22098673
associative learning; conditioning; habituation; in vitro; monocyte; macrophage; lipopolysaccharide; streptomycin; interleukin-6
14.  Polymorphisms of GSTT1, GSTM1, and EPHX genotypes in patients with cryptogenic polyneuropathy: a case–control study 
Brain and Behavior  2011;1(2):135-141.
The aim of this study was to analyze whether polymorphisms for the null alleles of Glutathione S-Transferase Mu-1 (GSTM1), Glutathione S-Transferase Theta-1 (GSTT1), and a low-activity genetic variation of epoxide hydrolase exon three (EPHX*3) affect the risk of developing polyneuropathy. The enzymes of these genes are important in the metabolism of toxic compounds. Seventy-nine patients with cryptogenic polyneuropathy (equivalent to chronic idiopathic axonal neuropathy) and 398 controls were tested for the genetic polymorphism. Medical records were reviewed to collect data regarding clinical findings at diagnosis, and exposure data was collected via questionnaires. The odds ratios (ORs) for the null forms of GSTM1 and GSTT1 and the normal activity YY form of EPHX*3 were close to one except GSTT1, which reached 1.86. The highest risk of polyneuropathy was found in smokers with GSTT1 null, who had a 3.7 times increased risk. Interactions between genes were analyzed and confirmed the increased OR for GSTT1, which was strongest if the patients had the low-activity HH form of EPHX*3 (OR 2.37). Our hypothesis is that the GSTT1 null polymorphism may be related to an impaired metabolism of toxic substances that could lead to nerve damage in the peripheral nervous system.
doi:10.1002/brb3.26
PMCID: PMC3236538  PMID: 22399093
Chronic idiopathic axonal neuropathy; Glutathione S-Transferase; epoxide hydrolase; smoking; solvents
15.  Comparing ambient, air-convection, and fluid-convection heating techniques in treating hypothermic burn patients, a clinical RCT 
Background
Hypothermia in burns is common and increases morbidity and mortality. Several methods are available to reach and maintain normal core body temperature, but have not yet been evaluated in critical care for burned patients. Our unit's ordinary technique for controlling body temperature (Bair Hugger®+ radiator ceiling + bed warmer + Hotline®) has many drawbacks e.g.; slow and the working environment is hampered.
The aim of this study was to compare our ordinary heating technique with newly-developed methods: the Allon™2001 Thermowrap (a temperature regulating water-mattress), and Warmcloud (a temperature regulating air-mattress).
Methods
Ten consecutive burned patients (> 20% total burned surface area and a core temperature < 36.0°C) were included in this prospective, randomised, comparative study. Patients were randomly exposed to 3 heating methods. Each treatment/measuring-cycle lasted for 6 hours. Each heating method was assessed for 2 hours according to a randomised timetable. Core temperature was measured using an indwelling (bladder) thermistor. Paired t-tests were used to assess the significance of differences between the treatments within the patients. ANOVA was used to assess the differences in temperature from the first to the last measurement among all treatments. Three-way ANOVA with the Tukey HSD post hoc test and a repeated measures ANOVA was used in the same manner, but included information about patients and treatment/measuring-cycles to control for potential confounding. Data are presented as mean (SD) and (range). Probabilities of less than 0.05 were accepted as significant.
Results
The mean increase, 1.4 (SD 0.6°C; range 0.6-2.6°C) in core temperature/treatment/measuring-cycle highly significantly favoured the Allon™2001 Thermowrap in contrast to the conventional method 0.2 (0.6)°C (range -1.2 to 1.5°C) and the Warmcloud 0.3 (0.4)°C (range -0.4 to 0.9°C). The procedures for using the Allon™2001 Thermowrap were experienced to be more comfortable and straightforward than the conventional method or the Warmcloud.
Conclusions
The Allon™2001 Thermowrap was more effective than the Warmcloud or the conventional method in controlling patients' temperatures.
doi:10.1186/1750-1164-5-4
PMCID: PMC3141603  PMID: 21736717
16.  Elevated [11C]-D-Deprenyl Uptake in Chronic Whiplash Associated Disorder Suggests Persistent Musculoskeletal Inflammation 
PLoS ONE  2011;6(4):e19182.
There are few diagnostic tools for chronic musculoskeletal pain as structural imaging methods seldom reveal pathological alterations. This is especially true for Whiplash Associated Disorder, for which physical signs of persistent injuries to the neck have yet to be established. Here, we sought to visualize inflammatory processes in the neck region by means Positron Emission Tomography using the tracer 11C-D-deprenyl, a potential marker for inflammation. Twenty-two patients with enduring pain after a rear impact car accident (Whiplash Associated Disorder grade II) and 14 healthy controls were investigated. Patients displayed significantly elevated tracer uptake in the neck, particularly in regions around the spineous process of the second cervical vertebra. This suggests that whiplash patients have signs of local persistent peripheral tissue inflammation, which may potentially serve as a diagnostic biomarker. The present investigation demonstrates that painful processes in the periphery can be objectively visualized and quantified with PET and that 11C-D-deprenyl is a promising tracer for these purposes.
doi:10.1371/journal.pone.0019182
PMCID: PMC3079741  PMID: 21541010
17.  Neuroticism-related personality traits are related to symptom severity in patients with premenstrual dysphoric disorder and to the serotonin transporter gene-linked polymorphism 5-HTTPLPR 
Archives of Women's Mental Health  2010;13(5):417-423.
Neuroticism has been linked to a functional polymorphism in the serotonin transporter gene (5-HTTLPR), with short-allele carriers being overrepresented among high-scorers on neuroticism. Studies evaluating neuroticism-related personality traits in relation to the 5-HTTLPR polymorphism among patients with premenstrual dysphoric disorder (PMDD) and are lacking. The primary aim of this study was to evaluate the relationship between PMDD and neuroticism-related personality traits, and secondly, to relate the personality trait scores of PMDD patients to experienced symptom severity and to the 5-HTTLPR short allele. Thirty PMDD patients and 55 asymptomatic healthy controls were included in the study. The Swedish Universities Scale of Personality was used to evaluate personality traits. Genotype analyses were available in 27 PMDD patients and 18 healthy controls. Women with PMDD displayed higher levels of neuroticism-related personality traits (psychic trait anxiety, somatic trait anxiety, embitterment, stress susceptibility and mistrust) than healthy controls, and these effects were most prominent in women with more severe luteal phase symptoms. Furthermore, PMDD patients with at least one copy of the short allele of the 5-HTTLPR polymorphism scored higher on psychic trait anxiety and lack of assertiveness than PMDD patients who were homozygous for the long allele. PMDD patients who suffer from more severe luteal phase symptoms also display increased scores of neuroticism-related personality traits in comparison with healthy controls. Within the group of PMDD patients, differences in certain personality trait scores are associated with the short allele of the 5-HTTLPR polymorphism.
doi:10.1007/s00737-010-0164-4
PMCID: PMC2941046  PMID: 20440524
Personality; Neuroticism; Premenstrual dysphoric disorder; Swedish universities scale of personality; 5-HTTPLPR
18.  The Genetic Covariation between Fear Conditioning and Self-Report Fears 
Biological psychiatry  2007;63(6):587-593.
Background
Fear conditioning is a traditional model for the acquisition of phobias, while behavioral therapies utilize processes underlying extinction to treat phobic and other anxiety disorders. Furthermore, fear conditioning has been proposed as an endophenotype for genetic studies of anxiety disorders. While prior studies have demonstrated that fear conditioning and self-report fears are heritable, no studies have determined whether they share a common genetic basis.
Methods
We obtained fear conditioning data from 173 twin pairs from the Swedish Twin Registry who also provided self-report ratings of 16 common fears. Using multivariate structural equation modeling, we analyzed factor-derived scores for the subjective fear ratings together with the electrophysiologic skin conductance responses during habituation, acquisition, and extinction to determine the extent of their genetic covariation.
Results
Phenotypic correlations between experimental and self-report fear measures were modest and, and counter-intuitively, negative; that is, subjects who reported themselves as more fearful had smaller electrophysiologic responses. Best-fit models estimated a significant (negative) genetic correlation between them, although genetic factors underlying fear conditioning accounted for only 9% of individual differences in self-report fears.
Conclusions
Experimentally-derived fear conditioning measures share only a small portion of the genetic factors underlying individual differences in subjective fears, cautioning against relying too heavily on the former as an endophenotype for genetic studies of phobic disorders.
doi:10.1016/j.biopsych.2007.06.009
PMCID: PMC2268873  PMID: 17698042
twin study; psychophysiology; fears; phobias; endophenotype; fear conditioning
19.  Genotype over-diagnosis in amygdala responsiveness: affective processing in social anxiety disorder 
Background
Although the amygdala is thought to be a crucial brain region for negative affect, neuroimaging studies do not always show enhanced amygdala response to aversive stimuli in patients with anxiety disorders. Serotonin (5-HT)–related genotypes may contribute to interindividual variability in amygdala responsiveness. The short (s) allele of the 5-HT transporter linked polymorphic region (5-HTTLPR) and the T variant of the G-703T polymorphism in the tryptophan hydroxylase-2 (TPH2) gene have previously been associated with amygdala hyperresponsivity to negative faces in healthy controls. We investigated the influence of these polymorphisms on amygdala responsiveness to angry faces in patients with social anxiety disorder (SAD) compared with healthy controls.
Methods
We used positron emission tomography with oxygen 15-labelled water to assess regional cerebral blood flow in 34 patients with SAD and 18 controls who viewed photographs of angry and neutral faces presented in counterbalanced order. We genotyped all participants with respect to the 5-HTTLPR and TPH2 polymorphisms.
Results
Patients with SAD and controls had increased left amygdala activation in response to angry compared with neutral faces. Genotype but not diagnosis explained a significant portion of the variance in amygdala responsiveness, the response being more pronounced in carriers of s and/or T alleles.
Limitations
Our analyses were limited owing to the small sample and the fact that we were unable to match participants on genotype before enrolment. In addition, other imaging techniques not used in our study may have revealed additional effects of emotional stimuli.
Conclusion
Amygdala responsiveness to angry faces was more strongly related to serotonergic polymorphisms than to diagnosis of SAD. Emotion activation studies comparing amygdala excitability in patient and control groups could benefit from taking variation in 5-HT–related genes into account.
PMCID: PMC2612081  PMID: 19125211

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