A pilot study on the feasibility of European harmonized human biomonitoring: Strategies towards a common approach, challenges and opportunities.

In 2004 the European Commission and Member States initiated activities towards a harmonized approach for Human Biomonitoring surveys throughout Europe. The main objective was to sustain environmental health policy by building a coherent and sustainable framework and by increasing the comparability of data across countries. A pilot study to test common guidelines for setting up surveys was considered a key step in this process. Through a bottom-up approach that included all stakeholders, a joint study protocol was elaborated. From September 2011 till February 2012, 17 European countries collected data from 1844 mother-child pairs in the frame of DEMOnstration of a study to COordinate and Perform Human Biomonitoring on a European Scale (DEMOCOPHES).(1) Mercury in hair and urinary cadmium and cotinine were selected as biomarkers of exposure covered by sufficient analytical experience. Phthalate metabolites and Bisphenol A in urine were added to take into account increasing public and political awareness for emerging types of contaminants and to test less advanced markers/markers covered by less analytical experience. Extensive efforts towards chemo-analytical comparability were included. The pilot study showed that common approaches can be found in a context of considerable differences with respect to experience and expertize, socio-cultural background, economic situation and national priorities. It also evidenced that comparable Human Biomonitoring results can be obtained in such context. A European network was built, exchanging information, expertize and experiences, and providing training on all aspects of a survey. A key challenge was finding the right balance between a rigid structure allowing maximal comparability and a flexible approach increasing feasibility and capacity building. Next steps in European harmonization in Human Biomonitoring surveys include the establishment of a joint process for prioritization of substances to cover and biomarkers to develop, linking biomonitoring surveys with health examination surveys and with research, and coping with the diverse implementations of EU regulations and international guidelines with respect to ethics and privacy.

Interpreting biomarker data from the COPHES/DEMOCOPHES twin projects: Using external exposure data to understand biomarker differences among countries.

In 2011 and 2012, the COPHES/DEMOCOPHES twin projects performed the first ever harmonized human biomonitoring survey in 17 European countries. In more than 1800 mother-child pairs, individual lifestyle data were collected and cadmium, cotinine and certain phthalate metabolites were measured in urine. Total mercury was determined in hair samples. While the main goal of the COPHES/DEMOCOPHES twin projects was to develop and test harmonized protocols and procedures, the goal of the current paper is to investigate whether the observed differences in biomarker values among the countries implementing DEMOCOPHES can be interpreted using information from external databases on environmental quality and lifestyle. In general, 13 countries having implemented DEMOCOPHES provided high-quality data from external sources that were relevant for interpretation purposes. However, some data were not available for reporting or were not in line with predefined specifications. Therefore, only part of the external information could be included in the statistical analyses. Nonetheless, there was a highly significant correlation between national levels of fish consumption and mercury in hair, the strength of antismoking legislation was significantly related to urinary cotinine levels, and we were able to show indications that also urinary cadmium levels were associated with environmental quality and food quality. These results again show the potential of biomonitoring data to provide added value for (the evaluation of) evidence-informed policy making.

Gender differences in cadmium and cotinine levels in prepubertal children.

Susceptibility to environmental stressors has been described for fetal and early childhood development. However, the possible susceptibility of the prepubertal period, characterized by the orchestration of the organism towards sexual maturation and adulthood has been poorly investigated and exposure data are scarce. In the current study levels of cadmium (Cd), cotinine and creatinine in urine were analyzed in a subsample 216 children from 12 European countries within the DEMOCOPHES project. The children were divided into six age-sex groups: boys (6-8 years, 9-10 years and 11 years old), and girls (6-7 years, 8-9 years, 10-11 years). The number of subjects per group was between 23 and 53. The cut off values were set at 0.1 µg/L for Cd, and 0.8 µg/L for cotinine defined according to the highest limit of quantification. The levels of Cd and cotinine were adjusted for creatinine level. In the total subsample group, the median level of Cd was 0.180 µg/L (range 0.10-0.69 µg/L), and for cotinine the median wet weight value was 1.50 µg/L (range 0.80-39.91 µg/L). There was no significant difference in creatinine and cotinine levels between genders and age groups. There was a significant correlation between levels of cadmium and creatinine in all children of both genders. This shows that even at such low levels the possible effect of cadmium on kidney function was present and measurable. An increase in Cd levels was evident with age. Cadmium levels were significantly different between 6-7 year old girls, 11 year old boys and 10-11 year old girls. As there was a balanced distribution in the number of subjects from countries included in the study, bias due to data clustering was not probable. The impact of low Cd levels on kidney function and gender differences in Cd levels needs further investigation.

Cognitive compromise following exercise in monozygotic twins discordant for chronic fatigue syndrome: fact or artifact?

This study examined the effects of exhaustive exercise on cognitive functioning among 21 monozygotic twin pairs discordant for chronic fatigue syndrome (CFS). The co-twin control design adjusts for genetic and family environmental factors not generally accounted for in more traditional research designs of neuropsychological function. Participants pedaled a cycle ergometer to exhaustion; maximum oxygen output capacity (VO2max) as well as perceived exertion were recorded. Neuropsychological tests of brief attention and concentration, speed of visual motor information processing, verbal learning and recognition memory, and word and category fluency were administered with alternate forms to participants pre- and postexercise. The preexercise neuropsychological test performance of CFS twins tended to be slightly below that of the healthy twin controls on all measures. However, twins with CFS did not demonstrate differential decrements in neuropsychological functioning after exercise relative to their healthy co-twins. Because exercise does not appear to diminish cognitive function, rehabilitative treatment approaches incorporating exercise are not contraindicated in CFS.

Monozygotic twins discordant for chronic fatigue syndrome: regional cerebral blood flow SPECT.

PURPOSE: To evaluate the relationship between regional cerebral blood flow (rCBF) and chronic fatigue syndrome (CFS) in monozygotic twins discordant for CFS. MATERIALS AND METHODS: The authors conducted a co-twin control study of 22 monozygotic twins in which one twin met criteria for CFS and the other was healthy. Twins underwent a structured psychiatric interview and resting technetium 99m-hexamethyl-propyleneamine oxime single photon emission computed tomography of the brain. They also rated their mental status before the procedure. Scans were interpreted independently by two physicians blinded to illness status and then at a blinded consensus reading. Imaging fusion software with automated three-dimensional matching of rCBF images was used to coregister and quantify results. Outcomes were the number and distribution of abnormalities at both reader consensus and automated quantification. Mean rCBF levels were compared by using random effects regression models to account for the effects of twin matching and potential confounding factors. RESULTS: The twins with and those without CFS were similar in mean number of visually detected abnormalities and in mean differences quantified by using image registration software. These results were unaltered with adjustments for fitness level, depression, and mood before imaging. CONCLUSION: The study results did not provide evidence of a distinctive pattern of resting rCBF abnormalities associated with CFS. The described method highlights the importance of selecting well-matched control subjects.

Gustatory function after third molar extraction.

OBJECTIVE: The purpose of this study was to determine the severity and time course of taste changes after extraction of all 4 third molars. STUDY DESIGN: Taste function in 17 patients was measured before third molar surgery and at 1 month and 6 months after surgery. Two tests were administered: a whole-mouth, above-threshold test in which subjects sipped, expectorated, and then rated the intensities and identified the taste qualities of various solutions, and a localized test in which subjects rated and identified solutions painted with cotton swabs on different oral sites. RESULTS: Intensity ratings for solutions in the whole-mouth test were reduced by approximately 14% for NaCl, citric acid, and quinine hydrochloride at 1 month after surgery and had not recovered by 6 months after surgery for citric acid (P<.02). The taste quality of NaCl was identified correctly less frequently after third molar extraction. Perceived taste intensity on discrete areas of the tongue was significantly reduced after surgery (P<.05). Patients with the most severely impacted molars gave the lowest taste intensity ratings to whole-mouth test solutions at 6 months after surgery (P<.02). In contrast, taste function in a group of subjects who received only local dental anesthesia was not affected. CONCLUSIONS: Gustatory deficits occur after third molar extraction, persist for as long as 6 months after surgery, and appear to be associated with depth of impaction.

Perioperative outcomes of major hepatic resections under low central venous pressure anesthesia: blood loss, blood transfusion, and the risk of postoperative renal dysfunction.

BACKGROUND: We have previously demonstrated that maintenance of a low central venous pressure (LCVP) combined with extrahepatic control of venous outflow reduced the overall blood loss during major hepatic resections. This study examined the overall outcomes and, in particular, renal morbidity associated with a large series of consecutive major liver resections performed with this approach. In addition, the rationale for the anesthetic management to maintain LCVP was carefully reviewed. STUDY DESIGN: All major hepatectomies performed between December 1991 and April 1997 were reviewed. The prospective Hepatobiliary Surgical Service database was merged with the Memorial Hospital Laboratory and Blood Bank databases to yield the nature of the operation, blood loss, blood product transfusions, outcomes, and levels of preoperative, postoperative, and discharge serum creatinine and blood urea nitrogen. RESULTS: A total of 496 LCVP-assisted major liver resections were performed, with no intraoperative deaths and an in-hospital mortality rate of 3.8%. The median blood loss was 645 mL. Sixty-seven percent of the patients did not require perioperative blood transfusion during surgery and the immediate 12 hours after surgery. The median number of blood transfusions was 2. Only 3% of the patients experienced a persistent and clinically significant increase in serum creatinine possibly attributable to the anesthetic technique. Renal failure directly attributable to the anesthetic technique did not occur. CONCLUSIONS: Major resection with LCVP allowed easy control of the hepatic veins before and during parenchymal transection. The anesthetic technique, designed to maintain LCVP during the critical stages of hepatic resection, not only helped to minimize blood loss and mortality but also preserved renal function.

Preoperative pulmonary evaluation of the thoracic surgical patient.

A test designed to separate those undergoing thoracic surgery without complications and those with complications must be both highly specific and sensitive. Clearly, the difference between patients at opposite ends of the population curves is easy to identify. Spirometry can be helpful for screening, although it is not a very discriminating test. If patients fall in the overlap region between the populations, however, it is impossible to discern the risks with any certainty using low-yield tests. A test with higher sensitivity, specificity, and predictive values is necessary to ascertain such marginal differences. With this kind of analysis at hand, preoperative testing can be divided into three predictive value groups. Calculating the predictive value of each preoperative test can provide a comparative measure of usefulness of discriminative power (Table 1). In this way, spirometry, blood gas analysis, and stair climbing tolerance are shown to be poor predictors of outcome. An intermediate predictive value can be achieved using diffusion capacity, exercise-induced decreases in O2 saturation, and exercise PVR. High predictive value can be accomplished with combination indexes (PPP, possibly PRQ), measurement of VO2 at 40 watts of exercise, or VO2max. Logic dictates a step-wise preoperative evaluation using prediction value analysis (Fig.4). A flow decision chart for the preoperative evaluation of patients for pulmonary resection begins with exercise oximetry, spirometry, and blood gas analysis as general screening tests to separate those patients at minimal or no risks for complications from those patients that require further evaluation. Functional indexes (PPP, PRQ) or exercise testing can aid further in the selection of those patients in whom a nonsurgical option should be considered. Flow decision chart for the preoperative evaluation of patients for pulmonary resection should continue to evolve as new information about outcome studies is gathered. Examination of outcome data will provide us with reduction of the size of the nonoperable population, so that we can deny only those patients who truly pose a prohibitive risk.

The effects of endobronchial cuff inflation on double-lumen endobronchial tube movement after lateral decubitus positioning.

OBJECT: This study was designed to measure changes in tracheal and bronchial lumen distances from mainstem and secondary carina with lateral positioning, and to assess whether inflation of the endobronchial cuff before lateral positioning would further secure a double-lumen endobronchial tube (DLT) and reduce movement. DESIGN: Prospective study. SETTING: University-affiliated cancer center. PARTICIPANTS: Fifty adult patients scheduled for elective thoracic surgical procedures requiring the placement of a left DLT. INTERVENTIONS: Patients were sequentially assigned to either the endobronchial cuff-inflated group or the deflated group during lateral positioning. After induction of general anesthesia, a left polyvinylchloride (PVC) DLT was placed and the position confirmed. In the supine position, the distance from the tip of the tracheal lumen to main carina was measured using a fiberoptic bronchoscope (FOB) passed through the tracheal lumen, and the distance from the bronchial lumen to secondary carina was measured with the FOB passed through the bronchial lumen. The patients were then positioned laterally and a second set of measurements taken. Overall movement was determined by increases and decreases in tracheal and bronchial distances obtained by substracting supine values from lateral values. MEASUREMENTS AND MAIN RESULTS: There was significant tracheal movement in 40 of 50 patients, with a mean of 0.92 +/- 1.0 cm. This was predominantly in the upward direction, as seen in 35 of 50 patients. There was significant bronchial movement in 37 of 50 patients, with a mean of 0.92 +/- 1.15 cm. Also, predominance in the upward direction was seen in 34 of 50 patients. CONCLUSIONS: DLTs move with lateral positioning, regardless of endobronchial cuff inflation. The movement is predominantly in the upward direction. Therefore, fiberoptic visualization in the supine position should be used only to confirm that the endobronchial lumen is placed on the appropriate side and the cuff is at least 1 cm inside the left mainstem bronchus. Final positioning should always be verified in the lateral position.

Focal hyperintensities in cerebral white matter on MR images of asymptomatic volunteers: correlation with social and medical histories.

OBJECTIVE: Previous attempts to explain the presence of focal hyperintensities in the cerebral white matter on MR images have focused on the patient's age and cardiovascular risk factors. The purpose of this study was to survey many variables in subjects' social, medical, and surgical histories to identify those factors associated with focal hyperintensities in asymptomatic persons. SUBJECTS AND METHODS: Asymptomatic volunteers were examined with MR imaging of the head and questioned concerning smoking history; chemical dependence; alcohol consumption; medical history (e.g., high blood pressure, kidney disease); surgical history (e.g., for appendix, gallbladder); medications (e.g., antihypertensives, analgesics); and other historical family and social variables. Vital signs were recorded. Focal hyperintensities were counted by observers who were not provided any information about the subjects other than that they were either volunteers or patients. Each of the variables in the history was tested for an association with the number of focal hyperintensities seen on MR images. RESULTS: A statistically significant positive association was found between both age and the use of antihypertensive medications and the number of focal hyperintensities. Associations were also found between the number of focal hyperintensities and diastolic and systolic blood pressures at the time of MR imaging, but these associations did not reach statistical significance. No other variables in the medical, surgical, or social histories were found to be significantly related to the number of focal hyperintensities. CONCLUSION: Age and the use of antihypertensive medications were the only significant risk factors identified in respect to focal hyperintensities of the cerebral white matter.

Propofol versus midazolam for monitored sedation: a comparison of intraoperative and recovery parameters.

STUDY OBJECTIVE: To compare intraoperative and recovery parameters in patients who received either propofol infusion (PI), propofol bolus (PB), or midazolam bolus (MZ) for sedation. DESIGN: Randomized clinical study. SETTING: Medical/surgical patients in a specialized hospital. PATIENTS: Ninety patients, aged 18 to 85 years, scheduled for central venous access for chemotherapy and/or total parenteral nutrition. INTERVENTIONS: In 30 patients, sedation was induced with MZ 0.02 mg/kg intravenously (i.v.), repeated every 2 to 3 minutes to achieve a sedation level of 3 (eyes closed, responds to verbal stimulus) (SL3). Maintenance was with MZ 0.005 mg/kg i.v. repeated as necessary to maintain SL3. In both propofol groups (30 patients each), induction of sedation was with a bolus of propofol 0.75 to 1.0 mg/kg i.v. Maintenance in the PB group was with propofol 0.25 mg/kg IV, repeated as necessary to maintain SL3. Maintenance in the PI group was with propofol 2 to 4 mg/kg/hr or 33 to 66 micrograms/kg/min to maintain SL3. MEASUREMENTS AND MAIN RESULTS: Blood pressure, heart rate, respiratory rate, oxygen saturation, and sedation level were monitored each minute for 5 minutes and then at 5-minute intervals during the procedure. A right atrial blood sample was taken for pH and partial pressure of carbon dioxide at maximum sedation. Adequate sedation was achieved in all three groups. The time to reach SL3 was significantly shorter in the PB group than in the PI and MZ groups (p < 0.05 and p < 0.01, respectively). Cardiovascular and respiratory parameters were remarkably stable. Immediate recovery, as judged by spontaneous eye opening, response to commands, and ability to state date of birth, was significantly shorter in both the PB and PI groups than in the MZ group (p < 0.0001). Intermediate recovery, as measured by sedation score at recovery entry, Aldrete score, and time to standing, was slower in the MZ group (p < 0.05 for the MZ group vs. the PB and PI groups for sedation score and Aldrete score; p < 0.05 for the MZ group vs. the PI group in time to standing). Psychomotor recovery, judged by digit symbol substitution tests, was significantly faster in the PB and PI groups (p < 0.05 vs. the MZ group). Amnesia, measured by picture recall, was significantly greater in the MZ group than in the PI and PB groups (p < 0.05). Mood changes were measured on a visual analog scale. All groups showed improvement. Nausea, headache, dizziness, blurred vision, appetite, tension, pain, depression, drowsiness, and ability to concentrate were evaluated in the preoperative and postoperative periods. The frequency did not differ significantly between groups due to confounding factors such as postoperative chemotherapy and premedicant drugs. CONCLUSION: The PI, PB, and MZ groups all gave excellent sedation for patients undergoing surgical procedures with local anesthesia. Amnesia was greatest with midazolam, and recovery was more rapid with propofol.

Self-reported dietary changes with respect to American Cancer Society nutrition guidelines (1982-1986).

A follow-up study was conducted by the Illinois Division of the American Cancer Society (ACS) in conjunction with the ongoing National Cancer Prevention Study II (CPSII) to determine whether self-report dietary changes are occurring in accordance with the ACS nutrition guidelines and to identify demographic subgroups that may be targeted for future prevention and education programs. A total of 42,300 CPSII respondents completed a 1986 questionnaire and were matched to 1982 baseline data. Dietary items were recorded as "on the average, how many days per week do you eat the following foods?" Individuals with known chronic conditions, body mass index outside a moderate range, and fewer than four completed food items were excluded. The remaining study population (n = 18,062) included men and women who were apparently healthy and primarily over the age of 50. The distribution of foods reported in 1982 and changes in foods consumed (1982-1986) among selected food groups varied modestly by sex, age, and educational level. Modest changes in the direction of decreasing intake of high-fat foods and increasing intake of high-fiber foods and cruciferous vegetables were reported. Dietary changes consistent with the ACS nutrition guidelines appear to have taken place in this population, particularly for the use of fried foods in males and intake of high-fiber foods and cruciferous vegetables in females.

High-signal foci on MR images of the brain: observer variability in their quantification.

Foci of high signal in the cerebral white matter are common incidental findings on MR images of the brain of control subjects or patients with a variety of diseases. Although the number of foci has been reported to correlate with age and several risk factors, the degree of observer variability in quantifying foci has not been reported. We used kappa statistics to determine radiologists' agreement in counting high-signal-intensity foci on MR images obtained in healthy volunteers and in patients with hypertension. Before interpreting the images, one pair of radiologists studied 30 routine MR images and reached consensus on differentiating high-signal foci from other foci of high intensity caused by normal structures (e.g., deep gyri or Virchow-Robin spaces). These two observers than independently determined the number of foci in the study group. Using their own criteria, other radiologists independently counted the foci. Agreement between observers was determined with the kappa statistic. The results showed fair agreement between the radiologists who first reached a consensus in counting foci of hyperintensity and poor agreement between the other observers. We conclude that in order to compare the frequency of foci of hyperintensity in different groups of patients, observer variability must be controlled. Studies without proper control subjects may lead to incorrect conclusions regarding the correlation of focal hyperintensities and various risk factors.

Quantitative MR in the diagnosis of multiple sclerosis.

In patients with multiple sclerosis (MS), the apparently uninvolved cerebral white matter between demyelinated plaques may have biochemical abnormalities. To what degree the changes in the white matter contribute to symptomatology in MS is unknown. In 39 patients with multiple sclerosis, and in 39 age-matched nondiseased volunteers, T1 and T2 were calculated from spin-echo images in four regions of apparently uninvolved white matter. In three of four white matter areas, the average T1 and T2 were significantly longer in the patients than in the controls. The T1 correlated with the disability, measured by the Kurtzke Extended Disability Status Scale, although the correlation was marginally significant. The results suggest that in patients with MS, white matter disease that is not visualized in MR as distinct foci of abnormal signal intensity may contribute to disease burden and disability.

T1 and T2 in the cerebrum: correlation with age, gender, and demographic factors.

The authors measured the T1 and T2 of cerebral tissue in 164 volunteers aged 5-90 years and correlated T1 and T2 with age, gender, and various demographic variables. A weak correlation with statistical significance was found between age and T1 and T2 in white and gray matter structures. The T1 and T2 in the telencephalon increased by about 0.1% per year. No correlation of T1 or T2 with any other demographic, life-style, or medical factors was found.

Multiple sclerosis: specificity of MR for diagnosis.

The specificity of magnetic resonance (MR) imaging in the diagnosis of multiple sclerosis (MS) has not been measured systematically. Conventional MR head images with sagittal localizer and axial multiple-echo sequences with long repetition times were obtained in 92 patients with clinically verified MS (Schumacher criteria), 100 healthy volunteers, 60 subjects with hypertension, and eight patients with dementia. Two readers, without the aid of any clinical or demographic information, classified each of the 260 studies as MS or not MS. The readers classified the studies again after being supplied with the subjects' ages and sex. True-negative and true-positive diagnoses of MS were tabulated. The specificity of the MR diagnosis of MS (true-negative results in proportion to all non-MS studies) was 95%-99% with all the control groups included. There is a small risk of misinterpreting incidental periventricular white matter foci as plaques of MS in MR studies.

Intervertebral disk: normal age-related changes in MR signal intensity.

The effect of age on the signal intensity of normal lumbar intervertebral disks was studied. Twenty-seven cadavers ranging in age from newborn to 79 years were studied with use of a 1.5-T magnetic resonance (MR) imager within 48 hours of death. The signal intensity in the central area of the disk was measured on a sagittal image obtained with a long repetition time (TR) and a long echo time (TE) and correlated to the age. A significant correlation between the decrease in signal intensity and age was found, although signal intensity changed less than 6% in 80 years. The decrease in signal intensity is concomitant with decreases in water and glycosaminoglycans and increases in collagen in the disk.

T1 and T2 measurements on a 1.5-T commercial MR imager.

In order for relaxation times to be used in clinical diagnosis, the precision of the measurement must be determined. The authors measured T1, T2, and proton density in a phantom and in human volunteers to determine the reproducibility of the method. The coefficient of variance of T1 measurements in the phantom during a 15-month period with two software upgrades was 5%. Variance of T2 measurements with any given software was 4% or less, and overall in the 15-month period, with two software changes, the T2 reproducibility was between 6% and 9%. The reproducibility is sufficiently high that precise clinical measurements of T1, T2, and proton density are feasible.