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Premenstrual dysphoric disorder (PMDD) is a common mood disorder, characterized by distressing affective, behavioral, and somatic symptoms in the late luteal phase of the menstrual cycle. The authors investigated continuous treatment with a selective progesterone receptor modulator, ulipristal acetate (UPA), as a potential treatment for PMDD.The authors conducted an investigator-initiated, multicenter, double-blind, randomized, parallel-group clinical trial in which women with PMDD (N=95) were treated with either 5 mg/day of UPA or placebo during three 28-day treatment cycles. The primary outcome was the change in premenstrual total score on the Daily Record of Severity of Problems (DRSP) from baseline to end of treatment. DRSP scores were captured by daily ratings using a smartphone application and were analyzed with linear mixed models for repeated measures.The mean improvement in DRSP score after 3 months was 41% (SD=18) in the UPA group, compared with 22% (SD=27) in the placebo group (mean difference -18%; 95% CI=-29, -8). Treatment effects were also noted for the DRSP depressive symptom subscale (42% [SD=22] compared with 22% [SD=32]) and the DRSP anger/irritability subscale (47% [SD=21] compared with 23% [SD=35]), but not for the DRSP physical symptom subscale. Remission based on DRSP score was attained by 20 women in the UPA group (50.0%) and eight women in the placebo group (21.1%) (a statistically significant difference).If these results are replicated, UPA could be a useful treatment for PMDD, particularly for the psychological symptoms associated with the disorder.

Background: Evidence on a possible association between newer hormonal contraceptives (HC) and risk of breast cancer remains inconclusive, especially as concerns progestogen-only methods. Methods: In this nationwide prospective cohort study, all Swedish women aged 15-34 at study start on January 1st 2005, or who turned 15 years during the study period, were followed until December 31st 2017. Using information from seven National Registers, we assessed the risk ratio of developing breast cancer and breast cancer in situ in relation to different HC using Poisson regression. We adjusted the analyses for several known confounders of breast cancer. Findings: This cohort included 1.5 million women providing more than 14 million person-years. During the study period, 3842 women were diagnosed with breast cancer. Compared with never users of any HC, we found no increased risk of developing breast cancer among current users of any combined HC, IRR 1.03 (0.91-1.16), whereas current users of progestogen-only methods had an increased risk of developing breast cancer, IRR 1.32 (1.20-1.45). Across all types of HC, the risk of developing breast cancer appeared to be highest the first five years of use (combined HC IRR 1.39 (1.14-1.69); progestogen-only methods IRR 1.74 (1.44-2.10). The risk disappeared ten years after the women stopped using HC. The absolute risk of breast cancer per 100,000 women-years was 22.4 for never users, 10.9 for current users of combined HC, and 29.8 for current users of progestogen-only methods. Interpretation: Current use of progestogen-only methods is associated with a small increased risk of developing breast cancer, whereas we could only detect an increased risk among users of combined HC during the first five years of use. This may partly be explained by a selective prescription of progestogen-only methods to women with risk factors for breast cancer, like smoking or obesity. As the absolute risk of breast cancer was small, the many health benefits associated with HC must also be taken into account in contraceptive counselling.

BackgroundWomen are advised to primarily use non-oral contraceptive alternatives after Roux-en-Y gastric bypass since it is not known if the surgery affects the pharmacokinetics of oral contraceptives.MethodsThis is a multi-center, open label, phase 2 pharmacokinetic study performed at the University Hospital of Linköping and the Clinical Trials Center, Department of Obstetrics and Gynecology, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden. Fifteen women aged 18–40 years who had previously undergone Roux-en-Y gastric bypass surgery and reached a BMI 0–24h) was the main outcome measure.ResultsThere were no significant differences in the studied pharmacokinetic parameters, AUC0–24h, total AUC, peak serum concentration (Cmax), time to peak serum concentrations (Tmax), apparent oral clearances of levonorgestrel (CLoral), or terminal half-lives (t½) between the groups.ConclusionThis is to our knowledge the first study to evaluate the pharmacokinetics of oral levonorgestrel in women with a BMI Clinical Trial NumberEudraCT 2014–004677-17.

Introduction The use of glucose point-of-care testing (POCT) devices for the diagnosis of diabetes mellitus (DM) is an ongoing controversy. In patient management, glucose concentrations are determined by POCT and core laboratory glucose methods, and the values are commonly compared even though the samples collected are different, namely, capillary whole blood and venous plasma. In individual patients it is difficult to distinguish between factors that can influence the results, such as sample type and measuring procedure. In this study, glucose concentrations obtained using POCT and core laboratory instruments were assessed to duplicate typical scenarios experienced in healthcare. Corresponding diagnosis rates of impaired glucose tolerance (IGT) and DM based on fixed, method-independent cutoffs were compared. Methods Glucose concentration was measured by the 2-h oral glucose tolerance test (OGTT) in samples collected from an inpatient cohort and a cohort from the general population. Two POCT methods, namely, a handheld unit-use glucometer and a small bench-top analyzer with batch reagents, and two core laboratory procedures were used to measure glucose concentrations. The sample types were whole blood and plasma samples collected from venous and capillary blood. The glycated hemoglobin level in whole blood was also determined. Results A total of 231 subjects were included in the study. The 2-h OGTT glucose concentrations in the capillary whole blood samples showed a positive bias of 0.8 mmol/L compared to those obtained using core laboratory plasma glucose methods, leading to increased rates of diabetes diagnosis. This bias decreased to 0.2 mmol/L when venous blood was used in the tests. A change in the method used by the core laboratory introduced a negative bias of 0.5 mmol/L and, consequently, a lower diagnosis rates. Discussion and Conclusion Venous blood samples measured at the point-of-care are the most suitable sample type for the measurement of the glucose concentration in the 2-h OGTT. The investigated unit-use POCT method is suitable for the diagnosis of IGT and DM when venous blood samples are collected. Importantly, changes in measurement procedures can introduce a bias and affect diagnosis rates, thereby emphasizing the need for further harmonization of glucose methods. Plain Language Summary A plain language summary is available for this article. Electronic supplementary material The online version of this article (10.1007/s13300-018-0495-0) contains supplementary material, which is available to authorized users., Plain Language Summary In clinical practice, a physician may be confronted with blood glucose concentrations determined using different devices. It is difficult for the treating physician to assess the effect of factors that can impact the glucose measurement, such as sample type and measuring procedure, for a given glucose concentration result. The aim of this study was to duplicate typical scenarios in the healthcare setting in terms of differences in glucose concentrations in capillary and venous samples obtained using a handheld point-of-care testing device, one benchtop device, and two core laboratory instruments. The diagnosis rates of impaired glucose tolerance and diabetes mellitus were compared to demonstrate the effects of the glucose concentrations measured using these different devices in terms of clinical response. We performed an oral glucose tolerance test and obtained the blood glucose concentration immediately before and 2 h after an oral glucose load. The results were compared and presented using difference and scatter plots. A total of 231 subjects were included in the study. Glucose concentrations in capillary whole blood samples showed a positive bias compared to those determined using core laboratory methods, leading to increased rates of diabetes diagnosis. This bias decreased when venous whole blood samples were used. A change in the method used in the core laboratory introduced a negative bias and, consequently, lower diagnosis rates. Changing laboratory devices can introduce a bias that is sufficiently large as to affect the diagnosis of diabetes since the latter is based on method-independent cutoffs. From these findings we conclude that both of the point-of-care devices investigated are suitable for the diagnosis of diabetes when venous samples are used. Our findings also emphasize the need for further harmonization of the glucose testing method. Electronic supplementary material The online version of this article (10.1007/s13300-018-0495-0) contains supplementary material, which is available to authorized users.

Essentials Age-adjusted D-dimer cut-offs decrease the false positives in the elderly. Four D-dimer assays were compared in venous thromboembolism outpatients in an emergency ward. Age-adjusted cut-off resulted in improved specificity with maintained sensitivity for all assays. There was a substantial decrease in false positive results, especially in the older population. SUMMARY Background The study compares different D-dimer assays and age-adjusted cut-offs in outpatients with suspected venous thromboembolism (VTE). The plasma concentration of this sensitive biomarker is increased by activated coagulation, but also by several conditions that are linked to an increased risk of VTE. One such condition is old age, which poses a common clinical problem where many prefer not to analyze D-dimer in elderly patients. Age-adjusted cut-offs have been validated for both deep venous thrombosis (DVT) and pulmonary embolism, aiming to increase specificity without notably decreasing sensitivity. Objectives We evaluated four common D-dimer assays in parallel, with and without applying age-adjusted cut offs for VTE. Patients/methods The prospective single-center study was conducted in 940 outpatients attending the emergency department with clinically suspected pulmonary embolism or DVT. Four automated D-dimer assays were compared (Siemens INNOVANCE® , Roche Tina-quant, Medirox MRX and STA® -Liatest® D-Di PLUS). Results All assays performed with areas under the ROC curve (AUC) > 0.9 and maintained their sensitivities after implementation of age-adjusted cut-offs. Specificities increased by 6-7% and number needed to test decreased by < 0.3. The rate of false positive results decreased by 6% overall and by 10-20% for patients ≥ 70. Conclusions Age-adjusted cut-offs resulted in maintained high sensitivity and a modest improvement in specificity and number needed to test for all evaluated D-dimer assays. There was a significant reduction in false positive results, which reflects avoidable unnecessary imaging without any compromise of clinical safety. This suggests a potential to benefit the management of VTE in elderly patients, both clinically and economically.

Introduction The diagnosis of diabetes mellitus is based on suitable cut-off values of specific biomarkers, such as the concentration of glucose in plasma. The German Diabetes Association has very recently published a clinical practice guideline on the definition, classification and diagnosis of diabetes mellitus that recommends measurements of plasma glucose concentration have an imprecision defined as a minimal difference (MD) of at a fasting plasma glucose concentration of 7.0 mmol/L. To obtain reliable values for the MD, we investigated long-term and short-term measurement uncertainty. Methods The imprecision was determined by two approaches: (1) a long-term dataset with imprecision based on the Guideline of the German Medical Association on Quality Assurance in Medical Laboratory Examinations (Rili-BAEK), in a medical laboratory operating 24/7, using internal quality control (IQC) data for four concentrations during a 10-year period; and (2) a detailed short-term dataset with imprecision assessed by hourly measurements of control materials. These datasets were used to calculate the MD cut-off (MDcut-off) as: \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ {\text{MD}}_{\text{cut-off}} = k \times {\text{SD}} $$\end{document}MDcut-off=k×SD = 2 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \times {\text{SD}} $$\end{document}×SD, where SD is the standard deviation and k = 2 represents a confidence level of 95%. Results The MDcut-off of ≤ 0.7 mmol/L at a fasting plasma glucose concentration of 7.0 mmol/L (MDcut-off 7.0) for the long-term and the short-term approaches were 0.44 and 0.40 mmol/L, respectively. The MDcut-off 7.0 from both approaches was therefore below the recommended value of 0.7 mmol/L. It was noted that the variability in performance within and between instruments can be covered by reporting the long-term MDcut-off 7.0 across all connected instruments. In this study, stable results for the MDcut-off 7.0 were obtained after 1 year. Conclusion Imprecision as measured by IQC data is remarkably stable over many years of operation. Current imprecision assessment usually focuses on only single instruments, whereas clinicians perceive the measurement as the result of the combined analytical performance of all instruments used for a certain assay. In the clinical setting, the MD may be a more useful measure of imprecision, and we suggest deriving the MDcut-off combined from all instruments and control cycles that are used in the patient care setting for a given analyte. Electronic supplementary material The online version of this article (10.1007/s13300-019-00740-w) contains supplementary material, which is available to authorized users.

Aim: To investigate the ability of lactobacilli to persist in the genital area (vagina and labia) of women after the topical application of an ointment containing Lactobacillus gasseri LN40, L. fermentum LN99 and L. rhamnosus LN113. Secondary objectives were to study the presence of Escherichia coli and other contaminants, as well as subjective symptoms in the genital tract. Methods: Eighteen healthy postmenopausal women were randomized to use either the study product or placebo for 10 days. Gynecological examinations, labial and vaginal samplings for bacterial cultivation were performed at baseline (visit 1), after treatment (visit 2), and at a 10-day follow-up (visit 3). LN strains were identified by specific cultivation methods. Subjective symptoms were evaluated by a self-administered questionnaire. Results: The presence of LN99 was shown in 7 out of 8 women in the investigational group at visit 2 (p < 0.001 compared to placebo) and in 5 out of 8 at visit 3 (p < 0.05), whereas the presence of LN113 was shown in 2 out of 8 at visit 2 and in 1 out of 8 at visit 3. Subjective symptoms were significantly reduced (p < 0.01) at visits 2 and 3 for both products. Conclusion: Topical application of a probiotic ointment is feasible to achieve persistence of lactobacilli for at least 10 days.

Background: The IFCC Task Force on Clinical Applications of Cardiac Biomarkers suggests comparing several contemporary sensitive troponin assays in the same, sufficiently large reference population. Methods: Three contemporary sensitive assays were used to measure troponin I concentration in samples from a uniquely large healthy population (2404 individuals) and in a sub-group with tighter inclusion criteria of 908 individuals. The 99th percentiles were calculated using quantile regression which takes the entire population into account. Results: The 99th percentile for the ARCHITECT STAT Troponin I assay was 21 ng/L, 31 ng/L for the ADVIA Centaur Troponin I-Ultra assay and 28 ng/L for the Dimension Vista cTnI assay. Significantly higher values were found in males than in women only in the Dimension Vista cTnI assay and in the subgroup for the ARCHITECT STAT Troponin I assay. Conclusions: Quantile regression provides a tool to accurately estimate the 99th percentile and establish a continuous function of the relation between the 99th percentile and the age and gender. There was no age dependency demonstrated. A gender difference was found in one assay but inconclusive in another and not demonstrated in a third.

Objective To determine risks associated with prescribing mirabegron, the first-in-class β3-adrenoreceptor agonist, to non-selected female patients with overactive bladder. Study design Routine female patients seeking treatment for overactive bladder (n = 221) in a urology/gynecology outpatient clinic. Data on adverse events, cardiovascular outcomes, condition specific symptoms and drug discontinuation was collected at two months follow-up (FU). Non-parametric statistics was used as appropriate. Odds ratios (ORs) with 95% confidence intervals (CIs) for outcome association analyses using logistic regression. Results 16 patients (7.2%) discontinued treatment because of side effects. There were no significant associations between cardiovascular adverse events and pre-existing cardiovascular disease (OR 0.3, 95% CI 0.3–2.6), or pre-existing ECG abnormalities (OR 2.3, 95% CI 0.3–16.3). At FU ECGs there were no de novo cases of tachyarrhythmias and no significant difference in mean QTc between baseline (403 ms, SD 21.7) and the 2 months follow-up ECG (403 ms, SD 20.3) (p = 0.75). There was a significant decrease in the mean systolic blood pressure (p = 0.03) but no significant change in mean diastolic pressure (p = 0.8) or heart rates (p = 0.2) from baseline to FU. Overactive bladder specific symptoms and quality of life improved significantly (p Conclusions Mirabegron treatment is associated with a satisfactory cardiovascular safety profile, as well as, significant symptomatic improvement also in a heterogeneous population of non-selected women with overactive bladder presenting in everyday clinical practice.

The von Willebrand factor (VWF) is elevated in patients with diabetes mellitus and degraded by a metalloprotease, ADAMTS13. We hypothesized that this elevation is due to a decreased function of ADAMTS13. Thus, we investigated ADAMTS13 in patients with diabetes mellitus without and with peripheral artery occlusive disease (PAOD). When treating the latter group with dalteparin, VWF is reported to increase significantly, and we therefore measured ADAMTS13 also in these patients. VWF antigen and ADAMTS13 antigen and activity concentrations were measured in patients with diabetes mellitus but without PAOD (diabetes mellitus; n = 23) and with diabetes mellitus and PAOD (diabetes mellitus + PAOD; n = 65) before and after treatment with dalteparin or placebo. In the diabetes mellitus group, concentration of VWF antigen was significantly higher, whereas that of ADAMTS13 activity was significantly lower than in the healthy controls. In the diabetes mellitus along with PAOD group, VWF antigen was significantly higher, but ADAMTS13 antigen or activity did not differ significantly from those of healthy controls. The ADAMTS13 activity/antigen ratio was lower than in controls only in the diabetes mellitus patient group. VWF antigen increased significantly during dalteraprin treatment, whereas ADAMTS13 activity and antigen remained unchanged. Only patients with diabetes mellitus had significantly lower concentrations of ADAMTS13 activity in plasma than controls, although the diabetes mellitus along with PAOD had a more pronounced VWF antigen elevation than diabetes mellitus patients, illustrating a possible link between ADAMTS13 and microangiopathy in diabetes mellitus patients. The increase in VWF antigen concentration during treatment with dalteparin does not seem to be due to changes in ADAMTS13.

The diagnostic performance of six methods for bacteriuria testing has been studied in 781 urine specimens obtained in primary health care, using conventional culture as reference method. The cut-off limits for classification of test results into positive and negative have been optimized with respect to diagnostic performance in primary health care. With optimized tests the following diagnostic efficiencies were obtained: 1) Bacterial ATP, 0.94; 2) Bacterial count in sediment, 0.93; 3) Nitrite test, 0,92; 4) Dipslide test, 0,92; 5) White cell count in sediment; 0,87; 6) Granulocyte esterase test; 0.83. The diagnostic performance was also studied for all combinations of two tests. The highest diagnostic efficiency (0.96) was obtained by combining the ATP and dipslide tests. High diagnostic efficiencies can be obtained by a rapid primary test, using other tests for follow-up testing of specimens with intermediate or uninterpretable primary results. The most promising results were obtained by using ATP as the primary test, with follow-up testing of specimens with 3–25 nmol/l of ATP (12 per cent of the specimens). Follow-up testing by conventional culture resulted in overall diagnostic efficiency of 0.98. By performing the nitrite test on specimens with intermediary ATP-results, 81 per cent of the patients with UTI can be classified without culture. Only patients with intermediary ATP and negative nitrite results (10 per cent of the total number) will have to wait for final diagnosis based on conventional culture. Some alternative strategies to combine available methods are discussed in detail. Major advantages of the ATP test are that the test can be performed while the patients are waiting; it provides a numerical and objective result, and, in contrast to culture, it is not influenced by adhesion of bacteria to somatic cells.

The clinical manifestations in chronic alcoholics may sometimes mimic those of hyperthyroidism. However, diagnostic aids are somewhat contradictory in many cases. Ten chronic alcoholics with symptoms from the sympathoadrenal system were investigated. A significant increase (p less than 0.01) of T3 at 120 min after TRH stimulation was found despite a blunted TSH response (increment less than 3 mU/l) in some cases. This increase in T3 indicates a preserved thyroid function in chronic alcoholics despite generally low basal T3 levels. It is concluded that T3 determinations at 120 min in connection with TRH test may be an essential parameter in evaluating euthyroid function in chronic alcoholics.

One disadvantage of the TRH test is that an absent or blunted TSH response is seen not only in hyperthyroid patients but also in some normal subjects. The aim of the present study was to elucidate whether the discriminatory power between eu- and hyperthyroidism could be increased by determining the T3 and T4 levels before and after the TRH administration. The study population consists of 30 patients referred for evaluation of suspected hyperthyroidism. The results show that all but one of the patients (n=20) who had T3 levels within the normal reference limits increased these levels after TRH administration, whether their TSH response was normal or blunted. One patient's T3 levels decreased after TRH. All the patients (n=10) who had T3 levels within the hyperthyroid range showed a decrease after TRH. The decrease was significantly correlated (r=0.90) to the magnitude of the increase. No consistent T4 and no change in reverse-T3 response was obtained. The addition of T3, T4 or reverse-T3 determinations in connection with the TRH test does not seem to increase the discriminatory power of the test.

During studies on the mechanism underlying the low serum T3 levels in euthyroid patients with various acute and chronic non-thyroidal illnesses, it became evident that body temperature may be one parameter associated with changes in serum T3 levels. Forty-nine hospitalized, euthyroid patients with hyperpyrexia caused by various non-thyroidal illnesses were studied. The levels of serum T3 were found to decrease gradually with increasing body temperature. T3 was already below the normal level +/- 2 S.D. at a body temperature of around 38 degrees C. Such low T3 levels as were seen at temperatures of above 40 degrees C are observed in thyroid patients only during severe hypothyroidism. The levels of T4 and TSH remained unchanged and within the normal range regardless of body temperature. The levels of reverse-T3 in the sera analyzed were found to be unchanged in some cases, while in others they paralleled body temperature. It is concluded that the body temperature must be taken into consideration when studying the serum levels of T3.

Ethanol-induced hypoglycemia after 44 hours of complete fasting was allowed to last for four hours. S-T3 decreased significantly (p less than 0.05), by 16.5%, S-rT3 remained unchanged and S-cortisol increased significantly (p less than 0.01). No correlation was found between S-T3 and S-cortisol. An association was found between S-T3 and blood glucose (p less than 0.05). An acute low S-T3 was achieved by depressing the peripheral availability and utilization of glucose. No association to a simultaneous increase in S-cortisol was found. An increase in S-rT3 failed to appear, probably also due to glucopenia.

The use of MDRD-eGFR to diagnose Chronic Kidney Disease (CKD) is based on the assumption that the algorithm will minimize the influence of age, gender and ethnicity that is observed in S-Creatinine concentration and thus allow a single cut-off at which further diagnostic and therapeutic actions should be considered. This hypothesis is tested in a retrospective analysis of outpatients (N=93,404) and hospitalised (N=35,572) patients in UK and Sweden, respectively. An algorithm based on the same model as the MDRD-eGFR algorithm was derived from simultaneously measured S-Creatinine concentrations and Iohexol GFR in a subset of 565 patients. The combined uncertainty of using this algorithm was estimated to about 15 % which is about three times that of the S-Creatinine concentration results. The diagnostic performance of S-Creatinine concentration was evaluated using the Iohexol clearance as the reference procedure. It was shown that the diagnostic capacity of MDRD-eGFR, as it stands, has no added value compared to S-Creatinine. The gender and age differences of the S-Creatinine concentrations in the dataset persist after applying the MDRD-eGFR algorithm. Thus, a general use of the MDRD-eGFR does not seem justified. Furthermore the claim that the eGFR is adjusted for body area is misleading; the algorithm does not include any body size marker. It is thus a dangerous marker for guiding drug administration.

Introduction Ionized calcium (iCa) concentration is often used in critical care and measured using blood gas analyzers at the point of care. Controlling and adjusting regional citrate anticoagulation (RCA) for continuous renal replacement therapy (CRRT) involves measuring the iCa concentration in two samples: systemic with physiological iCa concentrations and post filter samples with very low iCa concentrations. However, modern blood gas analyzers are optimized for physiological iCa concentrations which might make them less suitable for measuring low iCa in blood with a high concentration of citrate. We present results of iCa measurements from six different blood gas analyzers and the impact on clinical decisions based on the recommendations of the dialysis’ device manufacturer. Method The iCa concentrations of systemic and post filter samples were measured using six distinct, frequently used blood gas analyzers. We obtained iCa results of 74 systemic and 84 post filter samples from patients undergoing RCA for CRRT at the University Medicine of Greifswald. Results The systemic samples showed concordant results on all analyzers with median iCa concentrations ranging from 1.07 to 1.16 mmol/L. The medians of iCa concentrations for post filter samples ranged from 0.21 to 0.50 mmol/L. Results of >70 % of the post filter samples would lead to major differences in decisions regarding citrate flow depending on the instrument used. Conclusion Measurements of iCa in post filter samples may give misleading information in monitoring the RCA. Recommendations of the dialysis manufacturer need to be revised. Meanwhile, little weight should be given to post filter iCa. Reference methods for low iCa in whole blood containing citrate should be established.

Assessment of risk for coronary heart disease (CHD) indicates that apolipoprotein B and apolipoprotein A-I and their ratio are efficient predictors, possibly superior to hitherto used indicators, i.e. S-Cholesterol, S-Triglycerides, S-HDL cholesterol and S-LDL cholesterol. We used the ratio S-Apolipoprotein B/S-Apolipoprotein A-I as the gold standard to compare the diagnostic performance of the other properties based on consecutive routine measurements in patients attending primary health-care or a university hospital. The different cut-offs of the S-Apolipoprotein B/S-Apolipoprotein A-I ratio that were investigated created a prevalence of risk factors that might require intervention in the study group between 10 and 77%. The gender difference prompts for a partitioning related to the gender, whereas the changes related to age were small and were disregarded. The diagnostic sensitivity and specificity were demonstrated in ROC diagrams for the studied properties.

Objectives To characterize dynamics of changes of serum levels of TGF-β1 and TNF-α in rats with cardiac fibrosis (CF) occurring during chronic renal failure (CRF), and to reveal the character pf correlations of these factors with amounts of cardiac collagen. Design and Methods. CRF was induced by unilateral nephrectomy and by electrocoagulation of 25% of the cortex of remnant kidney. Post-operative checkpoints were 2, 4, and 6 months. Serum TGF-β1 and TNF-α levels were measured by ELISA. Results. CF became pronounced only at 6 months of CRF, while serum TGF-β1 concentrations reached maximum at 4 months, i.e., at the checkpoint preceding the development of CF. Multiple regression showed cardiac collagen to correlate with both serum TGF-β1 levels and time from the onset of CRF. Sensitivity and specificity of TGF-β1 as serum marker of CF were 86% and 75%.

Contracting human skeletal muscle is a major contributor to the exercise-induced increase of plasma interleukin-6 (IL-6). Although antioxidants have been shown to attenuate the exercise-induced increase of plasma IL-6, it is unknown whether antioxidants inhibit transcription, translation or translocation of IL-6 within contracting human skeletal muscle. Using a single-blind placebo-controlled design with randomization, young healthy men received an oral supplementation with either a combination of ascorbic acid (500 mg day(-1)) and RRR-alpha-tocopherol (400 i.u. day(-1)) (Treatment, n= 7), or placebo (Control, n= 7). After 28 days of supplementation, the subjects performed 3 h of dynamic two-legged knee-extensor exercise at 50% of their individual maximal power output. Muscle biopsies from vastus lateralis were obtained at rest (0 h), immediately post exercise (3 h) and after 3 h of recovery (6 h). Leg blood flow was measured using Doppler ultrasonography. Plasma IL-6 concentration was measured in blood sampled from the femoral artery and vein. The net release of IL-6 was calculated using Fick's principle. Plasma vitamin C and E concentrations were elevated in Treatment compared to Control. Plasma 8-iso-prostaglandin F(2alpha), a marker of lipid peroxidation, increased in response to exercise in Control, but not in Treatment. In both Control and Treatment, skeletal muscle IL-6 mRNA and protein levels increased between 0 and 3 h. In contrast, the net release of IL-6 from the leg, which increased during exercise with a peak at 3.5 h in Control, was completely blunted during exercise in Treatment. The arterial plasma IL-6 concentration from 3 to 4 h, when the arterial IL-6 levels peaked in both groups, was approximately 50% lower in the Treatment group compared to Control (Treatment versus Control: 7.9 pg ml(-1), 95% confidence interval (CI) 6.0-10.7 pg ml(-1), versus 19.7 pg ml(-1), CI 13.8-29.4 pg ml(-1), at 3.5 h, P < 0.05 between groups). Moreover, plasma interleukin-1 receptor antagonist (IL-1ra), C-reactive protein and cortisol levels all increased after the exercise in Control, but not in Treatment. In conclusion, our results show that supplementation with vitamins C and E attenuated the systemic IL-6 response to exercise primarily via inhibition of the IL-6 protein release from the contracting skeletal muscle per se.

The aim of the study was to elucidate if endogenous cortisol, as previously suggested, could be involved in the mechanism behind the reduced serum T3 levels seen in euthyroid patients with various non-thyroidal illnesses. The correlation between the serum levels of T3 and cortisol was investigated in 41 hospitalized patients with non-thyroidal illness during hyperpyrexia. The results showed a correlation coefficient of -0.94, indicating a close reciprocal association between the two hormones. Cortisol may thus be one factor associated with the decreased T3 levels seen in euthyroid patients with non-thyroidal illness. The results also indicate a close parallelism between the total and free T3 levels during hyperpyrexia.

Introduction and methods In order to study coagulation and fibrinolysis in acute coronary syndrome (ACS) we used a recently developed assay, called OH-index, which provides simultaneous measurements of fibrin formation and fibrinolysis (fibrin degradation) in the patients´ plasma. We also investigated thrombin generation using the calibrated automated thrombogram (CAT), and assessed thrombin generation in vivo by measuring F1 + 2 plasma concentrations. In addition, to better characterize the patients we also assessed markers of inflammation and endothelial function. Eighty-seven ACS patients were sampled at admission, within 24 hours during treatment with low molecular weight heparin (LMH), and 6 months later; 65 healthy controls were also sampled. Results As assessed by OH-index fibrin formation was slightly depressed at admission, profoundly depressed during LMH treatment and comparable to controls at 6 months, whereas fibrin degradation was elevated, particularly during LMH treatment. F1 + 2 levels decreased during LMH treatment but did not deviate significantly from controls at admission or in convalescence. CAT data showed that peak thrombin was higher at admission and after 6 months compared to controls, whereas the endogenous thrombin potential only tended to be elevated. Both variables were strongly reduced during LMH treatment. Patients had elevated levels of markers of inflammation and endothelial function as expected. Conclusion ACS-patients have an increased capacity to generate thrombin and an enhanced capacity to degrade fibrin in the acute phase. Increased thrombin generation persists also 6 months after the event.

Determination by bioluminescence of the bacterial adenosine triphosphate (ATP) level in urine was evaluated as a method for detection of bacteriuria in 1126 women with symptoms of UTI and 530 attending for follow-up. Conventional urine culture was used as reference method. The criterion for bacteriuria was growth of greater than or equal to 10(5) cfu/ml, giving a prevalence of 0.60. ATP levels of less than 10 nmol/l and greater than 50 mmol/l indicated abacteriuria and bacteruiria, respectively, whereas intermediate concentrations required culture if the nitrite test was negative. With this diagnostic strategy the sensitivity and specificity was 0.96 and 0.90 at the first visit and 0.90 and 0.98 at follow-up. With some methodological improvement the ATP test could be useful in medium-sized and small laboratories.

A number of biochemical markers were monitored in 38 male alcoholic patients at admittance and one week later. In patients with a drinking period of greater than 3 weeks the median fasting B-glucose decreased significantly as well as S-fructosamine concentrations. The ability of S-fructosamine to identify patients with a diabetic glucose tolerance test, expressed in terms of sensitivity and specificity, was 12 and 47%, respectively; that of HbA1c was still lower.

Uncertainty has arisen as to whether vitamin supplements are needed by dialysis patients, in particular those treated by means of hemofiltration or hemodiafiltration using highly permeable (high-flux) filters. We therefore measured the concentrations of vitamin C, cobalamin (vitamin B12) and folic acid in conventional (low-flux) dialysis patients and in those receiving on-line treatment (hemofiltration or hemodiafiltration).Plasma (P-)ascorbate, serum (S-)cobalamin and S-folate concentrations were measured before and after a treatment session in 15 patients treated with low-flux hemodialysis and in 14 treated with on-line hemofiltration or hemodiafiltration. The patients' vitamin supplementations were also recorded.P-ascorbate concentrations were lowered by 51% and 53% in the hemodialysis and on-line groups, respectively after treatment and this reduction was significant (p0.001). Concentrations below the reference values were found in 12/14 patients not receiving vitamin C supplementation. S-cobalamin did not decrease in the hemodialysis or on-line groups. S-folates did not change significantly in the hemodialysis or filtration groups. Patients without folacin supplementation had low values.P-ascorbate was reduced by both dialysis and filtration treatments. Neither S-cobalamin nor S-folate were reduced by dialysis or filtration treatments.

Background Fibrinogen and C-reactive protein (CRP) concentrations are predictors of outcome in the atherosclerotic patient. It is important in risk stratification that these quantities are measured reproducibly in routine and research. Method In the present study, we compare measurements of fibrinogen and high-sensitivity CRP in EDTA and citrate plasma samples (n=150) using nephelometric immunoassays. Fibrinogen was also measured in citrate plasma using a clotting method. Results In approximately one-third of the samples, the fibrinogen concentration measured by immunoassay was higher in citrate plasma than in EDTA plasma, in spite of the dilution by citrate. The immunoassay results of fibrinogen concentration measurements in EDTA and citrate plasma differed significantly and also differed from those of functionally measured fibrinogen concentrations. A difference was found between the concentration of CRP in EDTA plasma and citrated plasma which also did not correspond to the dilution. Conclusions Reproducibility of results is essential in risk stratification by fibrinogen or high-sensitivity CRP concentrations and small differences close to the decision limits may have a decisive impact. Immunological measurements are liable to confounding effects that may be difficult to foresee, qualitatively and quantitatively. Great care should be observed when measuring the concentration of calcium containing analytes in anticoagulated samples. Fibrinogen concentrations should preferably be measured functionally in citrate plasma.

Glycated albumin was prepared by incubation of serum from rabbits with randomly labelled 14C-glucose. The isolated glycated albumin fraction was re-infused to the same animal. 14C-labelled glucose was given to alloxan-treated rabbits. The disappearance of the radioactivity showed a rapid initial phase and a slow elimination phase, which could be acceptably described by first-order kinetics. The estimated half-life of glycated albumin was about 6 days, which is about 70% of that generally stated for albumin in the rabbit. If these findings were transferred to human conditions, the half-life of fructosamine would be in the range of 13-14 days.

Manipulation of the blood's oxygen carrying capacity (CaO(2)) through reinfusion of red blood cells, injections of recombinant erythropoietin or by other means results in an increased maximal oxygen uptake and concomitantly enhanced endurance performance. Therefore, there is a need to establish a system--"A Blood Pass"--through which such illegal and unethical methods can be detected. Venous blood samples were taken under standardized conditions from 47 male and female Swedish national and international elite endurance athletes four times during the athletic year of the individual sport (beginning and end of the preparation period and at the beginning and during peak performance in the competition period). In these samples, different hematological values were determined. ON(hes) and OFF(hre) values were calculated according to the formula of Gore et al. A questionnaire regarding training at altitude, alcohol use and other important factors for hematological status was answered by the athletes. There were some individual variations comparing hematological values obtained at different times of the athletic year or at the same time in the athletic year but in different years. However, the median values of all individual hematological, ON(hes) and OFF(hre), values taken at the beginning and the end of the preparation or at the beginning and the end of the competition period, respectively, as well as median values for the preparation and competition periods in the respective sport, were all within the 95% confidence limit (CI) of each comparison. It must be mentioned that there was no gender difference in this respect. This study shows that even if there are some individual variations in different hematological values between different sampling times in the athletic year, median values of important hematological factors are stable over time. It must be emphasized that for each blood sample, the 95% CI in each athlete will be increasingly narrower. The conclusion is that there is a physiological basis for establishing an individual-based "Blood Pass" system, mainly for athletes competing at the international level. On indications of manipulations of hemoglobin concentration and red cell mass by deviations from established "Blood Pass" data, more specific methods can be applied.

TAFI was measured as relative activity concentration (Pefakit) and antigen concentration (Haemochrom and Asserachrom) both acutely and during convalescence in patients suffering from acute coronary syndrome, and in a group of healthy controls. There was a rather weak but significant correlation between the activity and antigen concentrations. The results obtained by the Haemochrom method, assumed to measure the concentrations of all forms of TAFI, were lower than those by the Asserachrom method although the latter is assumed to only measure the pro-TAFI concentration. Both immunoassays gave lower results than the functional method (Pefakit). The patients in the convalescence phase showed a higher activity concentration than the healthy controls. The Asserachrom showed a higher concentration in the acute and convalescence phases of the patients compared to the controls, whereas the Haemochrom did not show any such difference. This could be related to different species of the TAFI molecule and thus different reactivity to the antibodies. Therefore the optimal choice of assay for determination of TAFI in different clinical studies is of importance. The Pefakit and Asserachrom seem to be appropriate candidates.

Increased levels of reactive oxygen and nitrogen species, as seen in response to exercise, challenge the cellular integrity. Important protective adaptive changes include induction of heat shock proteins (HSPs). We hypothesized that supplementation with antioxidant vitamins C (ascorbic acid) and E (tocopherol) would attenuate the exercise-induced increase of HSP72 in the skeletal muscle and in the circulation. Using randomization, we allocated 21 young men into three groups receiving one of the following oral supplementations: RRR-α-tocopherol 400 IU/day + ascorbic acid (AA) 500 mg/day (CEα), RRR-α-tocopherol 290 IU/day + RRR-γ-tocopherol 130 IU/day + AA 500 mg/day (CEαγ), or placebo (Control). After 28 days of supplementation, the subjects performed 3 h of knee extensor exercise at 50% of the maximal power output. HSP72 mRNA and protein content was determined in muscle biopsies obtained from vastus lateralis at rest (0 h), postexercise (3 h), and after a 3-h recovery (6 h). In addition, blood was sampled for measurements of HSP72, α-tocopherol, γ-tocopherol, AA, and 8-iso-prostaglandin-F2α(8-PGF2α). Postsupplementation, the groups differed with respect to plasma vitamin levels. The marker of lipid peroxidation, 8-iso-PGF2α, increased from 0 h to 3 h in all groups, however, markedly less ( P < 0.05) in CEα. In Control, skeletal muscle HSP72 mRNA content increased 2.5-fold ( P < 0.05) and serum HSP72 protein increased 4-fold ( P < 0.05) in response to exercise, whereas a significant increase of skeletal muscle HSP72 protein content was not observed ( P = 0.07). In CEα, skeletal muscle HSP72 mRNA, HSP72 protein, and serum HSP72 were not different from Control in response to exercise. In contrast, the effect of exercise on skeletal muscle HSP72 mRNA and protein, as well as circulating HSP72, was completely blunted in CEαγ. The results indicate that γ-tocopherol comprises a potent inhibitor of the exercise-induced increase of HSP72 in skeletal muscle as well as in the circulation.

A thin and soft multifunctional catheter was evaluated for the simultaneous real time monitoring of left ventricular volume and pressure with special consideration to side effects such as interference with normal cardiac electrophysiology. In four pigs, pressure and volume were simultaneously recorded by using the thin single segment pressure and conductance catheter. Measurements were done under varied cardiac conditions: at baseline, during preload reduction and afterload increase. Volumes were calibrated with intracardiac ultrasound measurements. During preload reduction the pressure and volume decreased as expected. A cautious afterload increase resulted in a corresponding pressure and volume increase, the maximum of the pressure curve changed from early to late. Both SV and EDV increased. The very few arrhythmias were mainly caused by surgical interference. The present study demonstrates that our thin single segment conductance catheter for the simultaneous measurement of LV volume and pressure has a performance that warrants further development with the goal of making the method available for human use. In particular, the catheter did not cause any arrhythmias.

In view of reports of health problems induced by low frequency (50-60 Hz) electromagnetic fields (EMF), we carried out a study in 18 healthy subjects, comparing sleep with and without exposure to a 50 Hz/1 mu Tesla electrical field. We found that the EMF condition was associated with reduced: total sleep time (TST), sleep efficiency, stages 3 + 4 slow wave sleep (SWS), and slow wave activity (SWA). Circulating melatonin, growth hormone, prolactin, testosterone or cortisol were not affected. The results suggest that commonly occurring low frequency electromagnetic fields may interfere with sleep.

Vitamin C deficiency in guinea pigs leads to cholesterol supersaturation of bile and formation of cholesterol gallstones. It has been suggested that there may also exist an association between vitamin C and cholesterol gallstones in man, but such a relationship has not been studied in gallstone patients. In order to study the possible effects of vitamin C on gallstone disease in humans, plasma lipid levels, hepatic cholesterol metabolism, biliary lipid composition, cholesterol saturation and nucleation time of gallbladder bile were analysed in 16 consecutive gallstone patients, who were planned for laparoscopic cholecystectomy and were treated with vitamin C (500 mg, four times a day) for 2 weeks before surgery. The plasma concentration of vitamin C increased by 42% in the treatment group. The concentrations of plasma lipids did not differ before and after vitamin C treatment; nor did the plasma levels of lathosterol and 7 alpha-hydroxy-4-cholesten-3-one, reflecting cholesterol and bile acid synthesis respectively. The relative concentrations of cholesterol, bile acids and cholesterol concentration of bile did not differ significantly between the two groups, but the relative concentration of phospholipids was slightly higher in the treated group. The bile acid composition was changed; the percentage of cholic acid being lower and those of deoxycholic acid, ursodeoxycholic acid and lithocholic acid higher in the vitamin C-treated patients compared with the untreated group. The nucleation time was significantly longer in the treatment group (7 days) compared with the untreated group (2 days). Our findings indicate that vitamin C supplementation may also influence the conditions for cholesterol gallstone formation in humans.

Cold cardioplegic arrest causes reperfusion injury to both endothelium and myocardium. We investigated release of troponin-T (TnT), tissue plasminogen activator activity (t-PA) and histamine (HA) from the heart before and after 2h of cold crystalloid cardioplegia in eight Swedish landrace pigs. Coronary sinus blood flow was measured in an external shunt between the coronary sinus and the right atrium. TnT, t-PA and HA were measured concomitantly in arterial and coronary sinus plasma, and the cardiac release was calculated. Cardiac release of TnT increased from 18 (15-25) micrograms/min (median (central 90% percentile)) before cold cardioplegia to maximum 281 (132-510) micrograms/min 30 min after aortic declamping (p0.02 vs initial value). t-PA rose from -4 (-52-34) to maximum 249 (75-691) IU/min 2 min after declamping (p0.01) and thereafter returned to baseline levels. The net cardiac release of HA was 72 (-80-1321) nmol/min before cardioplegia, rising to 234 (-188-524) after 2 min of reperfusion (p0.02) and returning to baseline after 30 minutes. We conclude that the porcine heart releases t-PA, Tn-T and HA during postcardioplegic reperfusion. The differing kinetics of their release may indicate different affection of the myocardium and the endothelium. Tn-T, t-PA and HA are potential markers of myocardial and endothelial injury in the porcine heart.

Objectives. To obtain a simple standard regimen, suitable for general practice, and based upon the addition of antithyroid drug plus thyroxine for attaining euthyroidism in patients with Graves' disease. Design. Prospective, randomized trial of patients with Graves' disease followed for 3 months after the initiation of therapy with an antithyroid drug and combined with the later addition of triiodothyronine to keep the patient euthyroid. The patients were randomized, according to birth date, between methimazole and propylthiouracil. Three dose schemes were tested for each antithyroid drug. Setting. The study was performed at the thyroid outpatient units of two general hospitals, with the patients having been referred from primary care. Subjects. Ninety-four patients with Graves' disease who were suitable for treatment with antithyroid drugs. Interventions. The patients were allocated into six groups. Three groups received methimazole (10 mg every 6th, 8th or 12th h) and three received propylthiouracil (100 mg every 6th, 8th or 12th h). Twenty micrograms of triiodothyronine was added when the patients were euthyroid to avoid hypothyroidism. Main outcome measures. The lowest serum free thyroxine level within 3 months of the initiation of the antithyroid treatment. Results. Fourteen per cent of the patients on methimazole 10 mg every 12th h and 29% on propylthiouracil 100 mg every 12th h did not achieve euthyroidism within the 3-month observation period. All but one patient on methimazole 10 mg every 8th h or propylthiouracil 100 mg every 8th h reduced the free serum thyroxine levels to the normal or hypothyroid range within the observation period. All of the patients on methimazole 10 mg every 6th h and 56% on propylthiouracil 100 mg every 6th h reduced the serum T4 values into the hypothyroid range within the period. Conclusion. A standard regimen, based upon the addition of methimazole 10 mg every 8th or 6th h or propylthiouracil 100 mg every 8th or 6th h and followed by the addition of thyroxine or triiodothyronine when euthyroid to avoid hypothyroidism, seems to be suitable for attaining euthyroidism within 3 months in patients with Graves' disease. A dose scheme based on methimazole 10 mg every 12th h or propylthiouracil 100 mg every 12th h were found to be unsuitable due to an unacceptably high incidence of failure to attain euthyroidism or hypothyroidism within 3 months.

The aim of this study was to investigate whether urinary excretion of other compounds than ketone bodies are also increased in starved, selenium (Se)-deficient rats. Two groups of male rats were fed an Se-deficient diet with 0.009 mg Se/kg, ("Se-deficient" and "Se-repleted") and one group was fed the same diet with 0.23 mg Se/kg as control for eleven weeks. The urinary excretion of ketone bodies was highly enhanced in Se deficiency, with a 7-fold increase in 3-hydroxybutyrate and an 18-fold increase in acetoacetate. Despite this, the plasma concentration of ketone bodies and the glomerular filtration rate were unaffected in the Se-deficient rats. Starvation resulted in a significant decrease in the urinary content of potassium, magnesium and calcium, in both dietary groups of rats and of urea in the Se-adequate group. No Se-dependent difference was noted for the urinary excretion of these compounds or of sodium, phosphate, creatinine and uric acid in any of the groups. This was unexpected in view of certain previous results and indicates that disturbances in the renal handling of compounds are progressive in Se deficiency, with increased excretion of ketone bodies being an early event while more severe deficiency is required to impair the renal handling of electrolytes and other compounds studied.

Lactate dehydrogenase (LDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations and platelet counts were measured in 26 normal pregnant women and 51 preeclamptic women. In the normal-pregnancy group, no significant changes were found in the results of these tests. In the preeclampsia group, ALT and AST concentrations were not significantly higher than those in normal pregnancy, but the LDH concentrations increased and the platelet counts decreased significantly through the pregnancy. The increases in LDH did not correlate with changes in ALT or AST. Preeclamptic women with small-for-gestational-age (SGA) infants had significantly higher LDH concentrations than those in the appropriate-for-gestational-age (AGA) group, but ALT and AST concentrations did not increase significantly. As reasons for the LDH increase in our subjects, liver damage was excluded and more active glycolysis in addition to severe cell damage due to chronic anoxemia were inferred. It is suggested that an increase in LDH is predictive of SGA infants in preeclamptic pregnancy, especially in those with normal liver function.

A total of 207 patients (diagnoses revised according to DSM-III-R) attended our outpatient clinic and were treated with lithium for 1-30 years. They were subjected to conventional renal, thyroid and parathyroid function tests. With increasing treatment duration, the renal tests showed only moderate deviations from expected reference values. No patient developed renal insufficiency. Oversubstitution (thyrotropin < or = 0.1 mU/l) was suspected in 25% of the patients on thyroxine. Cross-sectionally unrecognized hypothyroidism was found in 6% of the patients. Elevated ionized serum calcium was found in 25% and elevated serum intact parathyroid hormone in 23% of the patients.

In the present study a new technique for measuring the erythrocyte sedimentation rate (ESR) is clinically evaluated. This technique extends the measuring range above that of the traditional ESR by calculating the sedimentation (S) at 60 minutes from data collected between 18 and 24 minutes. Measurement of ESR, S and C-reactive protein (CRP) was performed prospectively three times a week in 25 patients developing 30 fever episodes following chemotherapy for a hematological malignancy. A good correlation was obtained between S and ESR values up to 90 mm (r = 0.98; p0.0001). The use of S may allow the clinician to follow an infectious or inflammatory process more accurately than with ESR. During neutropenia a rise in S preceded fever in all episodes were two samples were obtained before start of fever (n = 13). Changes in CRP and S values showed the same pattern in 11 episodes, in 12 CRP preceded S and in 7 episodes there was no correlation between the results. CRP, opposed to S, discriminated between bacteremias and blood culture negative episodes (p0.05) in samples obtained during the first 72 hours after start of fever. In patients with fever during neutropenia determination of S does not offer any clear advantage to CRP.