Patient-Clinician Brain Response During Clinical Encounter and Pain Treatment.

The patient-clinician relationship is known to significantly affect the pain experience, as empathy, mutual trust and therapeutic alliance can significantly modulate pain perception and influence clinical therapy outcomes. The aim of the present study was to use an EEG hyperscanning setup to identify brain and behavioral mechanisms supporting the patient-clinician relationship while this clinical dyad is engaged in a therapeutic interaction. Our previous study applied fMRI hyperscanning to investigate whether brain concordance is linked with analgesia experienced by a patient while undergoing treatment by the clinician. In this current hyperscanning project we investigated similar outcomes for the patient-clinician dyad exploiting the high temporal resolution of EEG and the possibility to acquire the signals while patients and clinicians were present in the same room and engaged in a face-to-face interaction under an experimentally-controlled therapeutic context. Advanced source localization methods allowed for integration of spatial and spectral information in order to assess brain correlates of therapeutic alliance and pain perception in different clinical interaction contexts. Preliminary results showed that both behavioral and brain responses across the patient-clinician dyad were significantly affected by the interaction style.Clinical Relevance- The context of a clinical intervention can significantly impact the treatment of chronic pain. Effective therapeutic alliance, based on empathy, mutual trust, and warmth can improve treatment adherence and clinical outcomes. A deeper scientific understanding of the brain and behavioral mechanisms underlying an optimal patient-clinician interaction may lead to improved quality of clinical care and physician training, as well as better understanding of the social aspects of the biopsychosocial model mediating analgesia in chronic pain patients.

Reactive hyperemia and baseline pulse amplitude among smelter workers exposed to fine and ultrafine particles.

OBJECTIVE: Ambient exposure to fine particles is associated with increased cardiovascular morbidity and mortality. Associations between occupational particulate matter (PM) exposure and cardiovascular disease have been studied less. The objective of this study was to examine associations between PM exposure and endothelial function among workers in Norwegian smelters. METHODS: We examined endothelial function with Endo-PAT equipment after a working day (WD) and on a day off (DO) in 59 furnace workers recruited from three metal smelters in Norway. The difference in baseline pulse amplitude (BPA) and reactive hyperemia index (RHI) between the 2 days was analysed in relation to individual exposure to PM < 250 nm (PM250) or the respirable aerosol fraction of particles, and adjusted for relevant covariates. RESULTS: The exposure to PM250 ranged from 0.004 to 5.7 mg/m3. The mean BPA was significantly higher on WD relative to DO (772 vs. 535, p = 0.001). This difference was associated with PM concentrations among participants ≥ 34 years, but not among the younger workers. Reactive hyperemia was significantly lower on workdays relative to days off (1.70 vs. 1.84, p = 0.05). This difference was observed only among participants above the age 34. No associations with PM exposure were observed. CONCLUSIONS: PM exposure was associated with higher BPA among participants older than 34 years. BPA reflects microvessel pulsatility. Our results may indicate an age-dependent cardiovascular susceptibility to PM exposure. Endothelial function measured by RHI was reduced on WD among participants 34 years and older, but we found no associations between PM exposure and RHI.

Slow brushing reduces heat pain in humans.

BACKGROUND: C-tactile (CT) afferents are unmyelinated low-threshold mechanoreceptors optimized for signalling affective, gentle touch. In three separate psychophysical experiments, we examined the contribution of CT afferents to pain modulation. METHODS: In total, 44 healthy volunteers experienced heat pain and CT optimal (slow brushing) and CT sub-optimal (fast brushing or vibration) stimuli. Three different experimental paradigms were used: Concurrent application of heat pain and tactile (slow brushing or vibration) stimulation; Slow brushing, applied for variable duration and intervals, preceding heat pain; Slow versus fast brushing preceding heat pain. RESULTS: Slow brushing was effective in reducing pain, whereas fast brushing or vibration was not. The reduction in pain was significant not only when the CT optimal touch was applied simultaneously with the painful stimulus but also when the two stimuli were separated in time. For subsequent stimulation, the pain reduction was more pronounced for a shorter time interval between brushing and pain. Likewise, the effect was more robust when pain was preceded by a longer duration of brush stimulation. Strong CT-related pain reduction was associated with low anxiety and high calmness scores obtained by a state anxiety questionnaire. CONCLUSIONS: Slow brushing - optimal for CT activation - is effective in reducing pain from cutaneous heating. The precise mechanisms for the pain relief are as yet unknown but possible mechanisms include inhibition of nociceptive projection neurons at the level of the dorsal horn as well as analgesia through cortical mechanisms. SIGNIFICANCE: Slow brushing stimuli - optimal for activation of C-tactile fibres - can reduce pain from cutaneous heating. No such effect was seen with fast brushing or vibration. These observations indicate the role of C-tactile fibres in pain modulation.

Cyclic Vomiting Syndrome is characterized by altered functional brain connectivity of the insular cortex: A cross-comparison with migraine and healthy adults.

Cyclic Vomiting Syndrome (CVS) has been linked to episodic migraine, yet little is known about the precise brain-based mechanisms underpinning CVS, and whether these associated conditions share similar pathophysiology. We investigated the functional integrity of salience (SLN) and sensorimotor (SMN) intrinsic connectivity networks in CVS, migraine and healthy controls using brain functional Magnetic Resonance Imaging. CVS, relative to both migraine and controls, showed increased SLN connectivity to middle/posterior insula, a key brain region for nausea and viscerosensory processing. In contrast, this same region showed diminished SMN connectivity in both CVS and migraine. These results highlight both unique and potentially shared pathophysiology between these conditions, and suggest a potential target for therapeutics in future studies.

The impact of iron status and smoking on blood divalent metal concentrations in Norwegian women in the HUNT2 Study.

Low iron (Fe) stores may result in increased absorption of divalent metals, in particular cadmium (Cd). We have previously shown that in non-smoking women participating in the Norwegian HUNT2 cohort study this also included other divalent metals, e.g. manganese (Mn) and cobalt (Co). The diet is the main source of metals in non-smoking individuals, whereas in smoking individuals tobacco smoke contributes significant amounts of Cd and lead (Pb). The aim of the present study was to investigate the impact of smoking on the relationship between low iron status and divalent metals. Blood concentrations of the divalent metals Cd, Mn, Co, Pb, copper (Cu) and zinc (Zn), determined using an Element 2 sector field mass spectrometer (ICP-MS), were investigated in smoking women of fertile age (range 21-55 years) (n=267) from the HUNT2 cohort. Among these, 82 were iron-deplete (serum ferritin<12µg/L) and 28 had iron deficiency anaemia (serum ferritin<12µg/L & Hb<120g/L). 150 (56%) women smoked 10 or more cigarettes daily, 101 (38%) had smoked for more than 20 years, and 107 (40%) had smoked for 11-20 years. Results from the smoking population were compared with results from our previous study in non-smoking women (n=448) of which 132 were previous smokers, all from the same cohort. Increasing concentrations of Cd in blood were observed for previous smokers, low-to-moderate smokers and high intensity smokers in all subgroups compared to never smokers, and according to age groups, education level, BMI and serum ferritin. Smokers had higher Pb concentrations than non-smokers in all subgroups, but less pronounced than for Cd. Smoking was not associated with Mn and Co concentrations in blood. In multiple regression models, low ferritin was associated with increased blood concentrations of Cd, Pb, Mn and Co. Ferritin was strongly associated with Cd at low smoking intensity, but was not a significant factor in heavy smokers, where intensity and duration of smoking emerged as main determinants. Ferritin associations with Co and Pb varied with tertiles of blood Cd. Ferritin emerged as the main determinant of blood Co and Mn, while for blood Pb, age and smoking intensity had higher impact. Cu and Zn remained within reference values and no significant associations with ferritin were found. Strong positive associations between blood concentrations of Pb, Mn, Cd and Co were observed, also when controlled for their common association with ferritin. Apart from these associations, the models showed no significant interactions between the divalent metals studied. Mild anaemia (110

Particle size distribution of workplace aerosols in manganese alloy smelters applying a personal sampling strategy.

Air samples were collected by personal sampling with five stage Sioutas cascade impactors and respirable cyclones in parallel among tappers and crane operators in two manganese (Mn) alloy smelters in Norway to investigate PM fractions. The mass concentrations of PM collected by using the impactors and the respirable cyclones were critically evaluated by comparing the results of the parallel measurements. The geometric mean (GM) mass concentrations of the respirable fraction and the <10 µm PM fraction were 0.18 and 0.39 mg m(-3), respectively. Particle size distributions were determined using the impactor data in the range from 0 to 10 µm and by stationary measurements by using a scanning mobility particle sizer in the range from 10 to 487 nm. On average 50% of the particulate mass in the Mn alloy smelters was in the range from 2.5 to 10 µm, while the rest was distributed between the lower stages of the impactors. On average 15% of the particulate mass was found in the <0.25 µm PM fraction. The comparisons of the different PM fraction mass concentrations related to different work tasks or different workplaces, showed in many cases statistically significant differences, however, the particle size distribution of PM in the fraction <10 µm d(ae) was independent of the plant, furnace or work task.

Essential and toxic element concentrations in blood and urine and their associations with diet: results from a Norwegian population study including high-consumers of seafood and game.

The first aim of the study was to evaluate calculated dietary intake and concentrations measured in blood or urine of essential and toxic elements in relation to nutritional and toxicological reference values. The second aim was to identify patterns of the element concentrations in blood and urine and to identify possible dietary determinants of the concentrations of these elements. Adults with a known high consumption of environmental contaminants (n=111), and a random sample of controls (n=76) answered a validated food frequency questionnaire (FFQ). Complete data on biological measures were available for 179 individuals. Blood and urine samples were analyzed for selenium, iodine, arsenic, mercury, cadmium and lead. Principal component analysis was used to identify underlying patterns of correlated blood and urine concentrations. The calculated intakes of selenium, iodine, inorganic arsenic and mercury were within guideline levels. For cadmium 24% of the high consumer group and 8% of the control group had intakes above the tolerable weekly intake. Concentrations of lead in blood exceeded the bench-mark dose lower confidence limits for some participants. However, overall, the examined exposures did not give rise to nutritional or toxicological concerns. Game consumption was associated with lead in blood (B(ln) 0.021; 95%CI:0.010, 0.031) and wine consumption. Seafood consumption was associated with urinary cadmium in non-smokers (B(ln) 0.009; 95%CI:0.003, 0.015). A novel finding was a distinct pattern of positively associated biological markers, comprising iodine, selenium, arsenic and mercury (eigenvalue 3.8), reflecting seafood intake (B 0.007; 95%CI:0.004, 0.010). The study clearly demonstrates the significance of seafood as a source of both essential nutrients and toxic elements simultaneously and shows that exposure to various essential and toxic elements can be intertwined.

Dietary mercury exposure in a population with a wide range of fish consumption--self-capture of fish and regional differences are important determinants of mercury in blood.

Human, low level, chronic exposure to mercury (Hg) from fish is of concern because of potential neurodevelopmental and cardiovascular toxicity. The purpose of the study was to 1) measure total mercury (THg) in blood and estimate dietary exposure in a population group with a wide range of seafood consumption, 2) assess the intake and blood concentration in relation to tolerable intake values, 3) characterise dietary sources, and 4) to investigate the relationship between dietary THg with THg in blood (BTHg), including factors that can explain the variance in BTHg concentrations. The participants (n=184) filled in an extensive food frequency questionnaire which was combined with a database on THg concentrations in Norwegian food, and donated blood and urine. Median consumption of seafood was 65 g/day (range 4 to 341 g/day). The calculated mean dietary THg exposure was 0.35 (median 0.30) µg/kg body weight/week. Seafood contributed on average 95% to the exposure. The JECFA Provisional Tolerable Weekly Intake (PTWI) of 1.6 µg MeHg/kg bw/week was not exceeded by any of the participants. BTHg ranged from 0.6 to 30 µg/L, with a mean of 5.3 (median 4.0 µg/L). There was a strong relationship between total seafood consumption and BTHg concentrations (r=0.58 95%CI: 0.48, 0.67) and between estimated THg dietary exposure and BTHg (r=0.46 95%CI: 0.35, 0.57). Fish consumption, sex, catching >50% of their seafood themselves, and living in coastal municipalities were significant factors in linear regression models with lnBTHg. Including urinary Hg in the regression model increased the explained variance from 54% to 65%. In a toxicokinetic model, the calculated dietary intake appeared to moderately underestimate the measured BTHg among the participants with the highest BTHg. Only two of the participants had BTHg slightly above a value equivalent to the JECFA PTWI, but none of them were women in fertile age.

F8 and F9 mutations in US haemophilia patients: correlation with history of inhibitor and race/ethnicity.

Both genetic and treatment-related risk factors contribute to the development of inhibitors in haemophilia. An inhibitor surveillance system piloted at 12 US sites has the goal of assessing risk factors through prospective data collection. This report examines the relationship of genotype and race/ethnicity to history of inhibitor in a large cohort of US haemophilia patients. Mutation analysis was performed on 676 haemophilia A (HA) and 153 haemophilia B (HB) patients by sequencing, Multiplex Ligation-dependent Probe Amplification, and PCR for inversions in F8 introns 22 (inv22) and 1 (inv1). Two HB patients with deletions had history of inhibitor. In severe HA, frequency of history of inhibitor was: large deletion 57.1%, splice site 35.7%, inv22 26.8%, nonsense 24.5%, frameshift 12.9%, inv1 11.1% and missense 9.5%. In HA, 19.6% of 321 White non-Hispanics (Whites), 37.1% of 35 Black non-Hispanics (Blacks) and 46.9% of 32 Hispanics had history of inhibitor (P = 0.0003). Mutation types and novel mutation rates were similar across ethnicities. When F8 haplotypes were constructed, Whites and Hispanics showed only H1 and H2. Within H1, history of inhibitor was 12.4% in Whites, 40.0% in Blacks (P = 0.009) and 32.4% in Hispanics (P = 0.002). Inhibitor frequency is confirmed to vary by mutation type and race in a large US population. White patients with history of inhibitor did not exhibit rare F8 haplotypes. F8 gene analysis did not reveal a cause for the higher inhibitor frequencies in Black and Hispanic patients.

Physicochemical characterisation of different welding aerosols.

Physicochemical properties important in exposure characterisation of four different welding aerosols were investigated. Particle number size distributions were determined by scanning mobility particle sizer (SMPS), mass size distributions by separation and weighing the individual size fractions of an 11-stage cascade impactor. The size distribution of the primary particles of agglomerates, chemical composition and morphology of the particles were examined by TEM. There were significant differences in the particle number size distributions of the different welding aerosols according to the SMPS determinations. The particle mass size distributions determined gravimetrically were, however, not really different. The dominant range with respect to mass was between 0.1 and 1 µm, regardless of the welding technique. Most of the primary particles in all different welding aerosols had diameters between 5 and 40 nm. All types of primary particles had a tendency to form chainlike agglomerates. A clear size dependence of the particle chemical composition was encountered in the case of manual metal arc welding aerosol. Small particles with diameters below 50 nm were mostly metal oxides in contrast to larger particles which also contained more volatile elements (e.g. potassium, fluorine, sodium, sulphur).

[Evaluating biomarkers of exposure to electric welding aerosol].

Biologic monitoring data in electric welders revealed reliable correlation between manganese concentration in the whole blood and manganese concentrations in the workplace air. The chronic manganese intoxication patients showed reliable lower levels of urinary iron, cobalt and manganese vs. those values in the reference group.

Hygroscopic properties of the workroom aerosol in aluminium smelter potrooms: a case for transport of HF and SO2 into the lower airways.

The hygroscopic behaviour of individual aerosol particles from workplaces in a primary aluminium smelter was investigated by environmental scanning electron microscopy. At a high relative humidity, comparable with the human respiratory tract, most particles encountered in the Søderberg and Prebake potrooms either undergo partial deliquescence (leading to a water droplet with an insoluble core) or form thin water films at the surface. As gaseous HF and SO(2) are highly soluble in water, the aerosol particles may act as carrier for these two gases into the alveolar region of the lower respiratory tract. Based on a one-dimensional mass balance model, it is estimated that under peak exposure conditions (particle surface area concentration of 10(-4) cm(2) cm(-3)) approximately 10% of the initial gaseous HF may be transferred to the particle phase. For SO(2), this fraction is much lower (approximately 1%). These results indicate that at least HF may penetrate deeper into the lung in the presence of soluble particles or particles that form surface water films compared to HF alone.

[Peculiarities of nervous system functional state in electric welders exposed to manganese compounds].

Peculiarities of nervous system functional state in electric welders exposed to manganese compounds. To evaluate nervous system functional state in electric welders exposed to manganese compounds, the authors conducted transverse study with matched pairs. The electric welders' tests for response rate, diadochokinesis and grasping power were not reliable. No changes were found in tremor characteristics and posture steadiness. Bradykinesia appeared to prevail in welders.

Determination of airborne trialkyl and triaryl organophosphates originating from hydraulic fluids by gas chromatography-mass spectrometry. Development of methodology for combined aerosol and vapor sampling.

Methodology for personal occupational exposure assessment of airborne trialkyl and triaryl organophosphates originating from hydraulic fluids by active combined aerosol and vapor sampling at 1.5L/min is presented. Determination of the organophosphates was performed by gas chromatography-mass spectrometry. Combinations of adsorbents (Anasorb 747, Anasorb CSC, Chromosorb 106, XAD-2 and silica gel) with an upstream cassette with glass fiber or PTFE filters and different desorption/extraction solvents (CS(2), CS(2)-dimethylformamide (50:1, v/v), toluene, dichloromethane, methyl-t-butyl ether and methanol) have been evaluated for optimized combined vapor and aerosol air sampling of the organophosphates tri-isobutyl, tri-n-butyl, triphenyl, tri-o-cresyl, tri-m-cresyl and tri-p-cresyl phosphates. The combination of Chromosorb 106 and 37 mm filter cassette with glass fiber filter and dichloromethane as desorption/extraction solvent was the best combination for mixed phase air sampling of the organophosphates originating from hydraulic fluids. The triaryl phosphates were recovered solely from the filter, while the trialkyl phosphates were recovered from both the filter and the adsorbent. The total sampling efficiency on the combined sampler was in the range 92-101% for the studied organophosphates based on spiking experiments followed by pulling air through the sampler. Recoveries after 28 days storage were 98-102% and 99-101% when stored at 5 and -20 degrees C, respectively. The methodology was further evaluated in an exposure chamber with generated oil aerosol atmospheres with both synthetic and mineral base oils with added organophosphates in various concentrations, yielding total sampling efficiencies in close comparison to the spiking experiments. The applicability of the method was demonstrated by exposure measurements in a mechanical workshop where system suitability tests are performed on different aircraft components in a test bench, displaying tricresyl phosphate air concentrations of 0.024 and 0.28 mg/m(3), as well as during aircraft maintenance displaying tri-n-butyl phosphate air concentrations of 0.061 and 0.072 mg/m(3).

Cross shift changes in lung function among bar and restaurant workers before and after implementation of a smoking ban.

OBJECTIVE: To study possible cross shift effects of environmental tobacco smoke (ETS) on pulmonary function among bar and restaurant employees before and after the implementation of a smoking ban in Norway. METHODS: The study included 93 subjects employed in 13 different establishments in Oslo. They were examined at the beginning and end of a workshift both while ETS exposure was present and when smoking was banned. The mean exposure level of nicotine and total dust before the ban was 28 microg/m3 (range 3-65) and 275 microg/m3 (range 81-506), respectively. Following the smoking ban, the mean level of nicotine and total dust was 0.6 mug/m3 and 77 microg/m3, respectively. Assessment of lung function included dynamic lung volumes and flows. RESULTS: The cross shift reduction in forced vital capacity (FVC) among 69 subjects participating in both examinations changed from 81 ml (SD 136) during exposure to ETS to 52 ml (SD 156) (p = 0.24) following the smoking ban. The reduction in forced expired volume in one second (FEV1) during a workshift, was borderline significantly reduced when comparing the situation before and after the intervention, by 89 ml (SD = 132) compared to 46 ml (SD = 152) (p = 0.09), respectively. The reduction in forced mid-expiratory flow rate (FEF25-75%) changed significantly from 199 ml/s (SD = 372) to 64 ml/s (SD = 307) (p = 0.01). Among 26 non-smokers and 11 asthmatics, the reduction in FEV1 and FEF25-75% was significantly larger during ETS exposure compared to after the smoking ban. There was an association between the dust concentration and decrease in FEF25-75% before the ban among non-smokers (p = 0.048). CONCLUSIONS: This first study of cross shift changes before and after the implementation of a smoking ban in restaurants and bars shows a larger cross shift decrease in lung function before compared with after the implementation of the ban.

Fluorescent multiplex polymerase chain reaction analysis of four genes associated with inpaired fibrinolysis and myocardial infarction.

Multiplex polymerase chain reaction (PCR) allows for the simultaneous amplification of several genes, thereby optimizing the use of reagents and decreasing personnel time. Multiplex PCR was used to amplify four genes in one PCR reaction, demonstrating the advantage of multiplex PCR for our study since it allowed us to amplify four separate genes using only 1 microl DNA, thus maximizing the use of study DNA. As compared with conventional multiplex PCR analysis with ethidium bromide, incorporating fluorescence-labeled primers into multiplex PCR reactions facilitated accurate, simultaneous analysis of many DNA fragments within one base discrimination. We have used this fluorescence methodology to analyze polymorphisms associated with either impaired fibrinolysis or myocardial infarction. These include the angiotensin converting enzyme insertion/deletion (I/D) polymorphism in intron 16 of the DCP1 gene, the Alu I/D polymorphism of the tissue plasminogen activator-25 locus in intron 8, the plasminogen activator inhibitor 4G/5G repeat polymorphism, and the variable number tandem repeat of the endothelial cell nitric oxide synthase gene, all characterized by an insertion, deletion, or repeat. The amplified products were diluted 1 : 60 and analyzed on the ABI PRISM 310 Genetic Analyzer using GeneScan software. With this method, we were able to amplify four genes using 75% less reagents and personnel time, thus demonstrating the benefit of multiplex PCR and fluorescence technology.

Neuropsychological effects of low mercury vapor exposure in chloralkali workers.

Neuropsychological effects were examined in 47 mercury vapor exposed male chloralkali workers with current low concentrations of urinary mercury (mean U-Hg 5.9 nmol/mmol creatinine (Cr)). Their average duration of exposure was 13.3 years, and the calculated mean concentration of U-Hg was 9.0 nmol Hg/mmol Cr per year (exposure intensity) during their time of exposure. They were compared with 47 age-matched male referents in a cross-sectional study. The two groups were not statistically significantly different with respect to neuropsychological test performance or number of self-reported subjective symptoms. The test results of the Static Steadiness Test, which assesses tremor, were not associated with exposure to mercury vapor. However current smokers had more hand tremor than non-smokers. Statistically significant associations were found between indices of current exposure (the concentration of inorganic mercury in whole blood) and the results of the WAIS Digit Symbol Test and the Benton Visual Retention Test (number of correct responses). This could indicate a small effect of current exposure on visuomotor/psychomotor speed and attention, and immediate visual memory. Whether the association found between the historical exposure intensity and the Digit Symbol Test results may represent long-term consequences of exposure cannot be determined in this study.

Factor V Leiden and factor V R2 allele: high-throughput analysis and association with venous thromboembolism.

Thrombophilia is a multigenic disease in which the combination of genetic polymorphisms increases the risk of deep vein thrombosis (DVT). The rapid identification of these genetic combinations requires high-throughput analysis of single nucleotide polymorphisms (SNPs). The TaqMan fluorogenic 5'-->*3' nuclease assay (PE/Applied Biosystems, Foster City, CA) with custom-designed primers, probes and controls has provided a highly efficient platform for high throughput. This assay was used to rapidly detect two SNPs, FV Leiden (G1691A) and FV A4070G (R2 allele), in a study of 6295 subjects. With one thermal cycler, we completed sample set-up, PCR and analysis on 84 samples in 3 h with an additional 12 wells containing 4 "no template controls" (NTC), 4 "allele-1 controls", and 4 "allele-2 controls" in a 96-well plate. When additional thermal cyclers were used and more assays were set up while the initial sets of reactions were in the PCR machines, the output could correspondingly be increased. The TaqMan assay was extremely accurate, avoided contamination by using uracil-N-glycolase (UNG) in a single, closed tube, and offered the possibility for additional automation with robotic equipment to implement the PCR. This TaqMan assay facilitates high throughput to screen large populations quickly and economically while utilizing a simple protocol that requires minimal expenditure of personnel time. Our results demonstrated a prevalence of the R2 allele of 11.9% in U.S. Caucasians, 5.6% in African-Americans, 13.4% in Asian or Pacific Islanders and 11.3% in Hispanics. No association between venous thromboembolism and the R2 allele was noted, and furthermore no interaction with FV Leiden was observed.