Vitamin K supplementation and bone mineral density in dialysis: results of the double-blind, randomized, placebo-controlled RenaKvit trial.

BACKGROUND: Vitamin K deficiency is highly prevalent in patients on dialysis and may contribute to their low bone mineral density (BMD) and increased risk of fracture. This study investigated the effect of menaquinone-7 (MK-7) supplementation on BMD in patients on chronic dialysis. METHODS: In a multicentre, double-blind, placebo-controlled intervention trial, 123 patients on chronic dialysis were randomised to a daily oral supplement of either MK-7 360 µg or placebo for 2 years. BMD of the distal radius (1/3, mid, ultradistal and total), femoral neck, lumbar spine (L1-L4) and whole body was assessed by dual-energy X-ray absorptiometry. Serum levels of vitamin K1 and MK-7 and plasma levels of total osteocalcin, dephosphorylated-uncarboxylated matrix Gla protein and protein induced by vitamin K absence II were measured to assess vitamin K status. RESULTS: After 2 years, an accelerated BMD loss of the 1/3 distal radius was found with MK-7 supplementation {mean difference of changes relative to placebo -0.023 g/cm2 [95% confidence interval (CI) -0.039 to -0.008]}, whereas the decrease in lumbar spine BMD seen in the placebo group was prevented [mean difference of changes between groups 0.050 g/cm2 (95% CI 0.015-0.085)]. No significant effects were observed at the remaining skeletal sites. Vitamin K status strongly improved in MK-7-supplemented participants. CONCLUSION: Compared with placebo, an accelerated BMD loss of the 1/3 distal radius was found after 2 years of MK-7 supplementation, whereas a decline in lumbar spine BMD was prevented. As such, MK-7 supplementation might modify BMD site-specifically in patients on dialysis. In aggregate, our findings do not support MK-7 supplementation to preserve bone in patients on dialysis.

Correlation between stage of prostate cancer and tyrosine and tryptophan in urine samples measured electrochemically.

Prostate cancer (PCa) is the second most common cancer in men and one of the leading causes of cancer-related deaths. Early detection is the key to successful treatment and provides the greatest chance to cure the patient. Currently, early detection involves screening for prostate-specific antigen levels in blood, which is not a tumor-specific biomarker. There is a critical need to develop clinically useful methods for screening for more reliable biomarkers. Here, we introduce an electrochemical biosensor that measures the concentrations of the amino acids tyrosine and tryptophan, and propose it as a possible diagnostic and prognostic tool for PCa. The limits of detection of tyrosine and tryptophan using the electrochemical sensors were 1.15 and 1.13 µmol/L in 1:10 urine: PBS, respectively. This study is the first to present electrochemical measurements of tyrosine and tryptophan directly in patient urine samples. We demonstrated an inverse correlation between the measured electrochemical signals and the severity of PCa. The most notable observation was a significant difference between controls and metastatic PCa patients (P ≤ 0.001). This observation was further validated using Liquid-Chromatography-Mass Spectrometry. Our data provides the basis for further research with electrochemical measurements of tyrosine and tryptophan as potential biomarkers for PCa.

Image-derived and physiological markers to predict adequate adenosine-induced hyperemic response in Rubidium-82 myocardial perfusion imaging.

AIMS: This study aimed to investigate the potential of different markers to identify adequate stressing in subjects with and without caffeine intake prior to Rubidium-82 myocardial imaging. METHODS AND RESULTS: This study comprised 40 healthy subjects who underwent four serial Rubidium-82 rest/adenosine stress MPI; two with 0mg caffeine consumption (baseline MPIs) and two with controlled consumption of caffeine (arm 1: 100 and 300mg, or arm 2: 200 and 400mg). We report the sensitivity and specificity of seven markers ability to predict adequate adenosine-induced hyperemic response: (1) the splenic response ratio (SRR); (2) splenic stress-to-rest intensity ratios (SIR); (3) changes in heart rate (ΔHR); (4) percentwise change in heart rate (Δ%HR); (5) changes in the rate pressure product (ΔRPP); (6) changes in the systolic blood pressure (ΔSBP); and (7) changes in the cardiovascular resistance (ΔCVR). Adequate stressing was determined as stress myocardial blood flow > 3ml/g/min and a corresponding myocardial flow reserve >68% of the individual maximum myocardial flow reserve obtained in the baseline MPIs. RESULTS: 129 MPI sessions (obtained in 39 subjects) were considered for this study. The following sensitivities were obtained: SSR = 72.7%, SIR = 63.6%, ΔHR = 45.5%, Δ%HR = 77.3%, ΔRPP = 54.5%, ΔSBP = 47.7%, and ΔCVR =40.9%, while the specificities were SSR = 80.9%, SIR = 85.0%, ΔHR = 90.4%, Δ%HR = 81.6%, ΔRPP=81.1%, ΔSBP = 86.4%, and ΔCVR =90.4%. CONCLUSION: The image-derived and physiological markers all provide acceptable sensitivities and specificities when patients follow the caffeine pausation before MPI. However, their use warrants great care when caffeine consumption cannot be ruled out.

Salivary Cortisol Awakening Response as a Predictor for Depression Severity in Adult Patients with a Major Depressive Episode Performing a Daily Exercise Program.

INTRODUCTION: The hypothalamic-pituitary-adrenal axis function in depression has been the subject of considerable interest, and its function has been tested with a variety of methods. We investigated associations between saliva cortisol at awakening and the 24-h urine cortisol output, both measured at study baseline, with endpoint depression scores. METHODS: Patients were admitted to a psychiatric inpatient ward with a major depressive episode and were started on fixed duloxetine treatment. They delivered saliva samples at awakening and 15, 30, and 60 min post-awakening and sampled urine for 24 h. Subsequently, they started a daily exercise program maintained for a 9-week period. Clinician-rated depression severity was blindly assessed with the Hamilton Depression Rating 6-item subscale (HAM-D6). The cortisol awakening response was quantified by the area under the curve with respect to the ground (AUCG) and with respect to the rise (AUCI) using saliva cortisol levels in the 1-h period after awakening. Analysis of expected associations between depression severity, AUCG, AUCI, exercise, and 24-h cortisol output was performed in a general linear model. RESULTS: In all, 35 participants delivered saliva or 24-h urine samples. The mean age was 49.0 years (SD = 11.0) with 48.6% females with a mean baseline HAM-D6 score of 12.2 (SD = 2.3). In a statistical model investigating the association between HAM-D6 at week 9 as a dependent variable and AUCI, concurrent HAM-D6, gender, smoking, and exercise volume as covariates, we found a significant effect of AUCI, concurrent HAM-D6, and exercise. The following statistics were found: AUCI (regression coefficient 0.008; F value = 9.1; p = 0.007), concurrent HAM-D6 (regression coefficient 0.70; F value = 8.0; p = 0.01), and exercise (regression coefficient -0.005; F value = 5.7; p = 0.03). The model had an R2 of 0.43. The association between HAM-D6 endpoint scores and the AUCI showed that higher AUCI values predicted higher HAM-D6 endpoint values. The association between HAM-D6 endpoint scores and the exercise level showed that a high exercise level was associated with lower HAM-D6 endpoint values. CONCLUSION: The results thus showed that high AUCI values predicted less improvement of depression and high exercise levels predicted more improvement of depression. These findings need to be confirmed in larger samples to test if more covariates can improve prediction of depression severity.

Paediatric reference range for overnight urinary cortisol corrected for creatinine.

OBJECTIVES: Systemic activity of inhaled corticosteroids (ICS) may be assessed via urinary cortisol measurement. Overnight urinary free cortisol corrected for creatinine (OUFCC) has been extensively reported in adult studies. However, a paediatric mass spectrometric (MS) reference range for OUFCC is not established. MS methods for OUFCC avoid cross-reactivity with other steroid hormones and are thus preferable to immunoassays. The aim of the present study was to define an MS OUFCC normative range in children. METHODS: This was a cross-sectional study of healthy pre-pubertal children from 5 to 11 years. Children collected urine from 10 pm or bedtime, whichever was earlier, until 8 am. Urinary free cortisol was measured via a liquid chromatography tandem mass spectrometry (LC-MS/MS) assay (Acquity UPLC with Xevo TQ-S Mass Spectrometer [Waters]) with in-house reagents. Urinary creatinine was measured using a commercial assay (Roche). RESULTS: Complete urine collections were obtained from 72 males and 70 females, mean age (SD) 8.6 (1.9) (range 5.0-11.8) years. The OUFCC 95% prediction interval was 1.7-19.8 nmol/mmol. Geometric mean OUFCC was 5.7; range 1.1-24.8 nmol/mmol. CONCLUSIONS: The obtained normative LC-MS/MS OUFCC reference data facilitate the use of mass spectrometry OUFCC assays in assessment of systemic activity of endogenous and exogenous corticosteroids in children.

Anogenital distance in children born of mothers with polycystic ovary syndrome: the Odense Child Cohort.

STUDY QUESTION: Are higher testosterone levels during pregnancy in women with polycystic ovary syndrome (PCOS) associated with longer offspring anogenital distance (AGD)? SUMMARY ANSWER: AGD was similar in 3-month-old children born of mothers with PCOS compared to controls. WHAT IS KNOWN ALREADY: AGD is considered a marker of prenatal androgenization. STUDY DESIGN, SIZE, DURATION: Maternal testosterone levels were measured by mass spectrometry at Gestational Week 28 in 1127 women. Maternal diagnosis of PCOS before pregnancy was defined according to Rotterdam criteria. Offspring measures included AGD from anus to posterior fourchette (AGDaf) and clitoris (AGDac) in girls and to scrotum (AGDas) and penis (AGDap) and penile width in boys and body composition (weight and BMI SD scores) at age 3 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was part of the prospective study, Odense Child Cohort (OCC), and included mothers with PCOS (n = 139) and controls (n = 1422). The control population included women with regular menstrual cycles (<35 days) before conception and no signs of androgen excess (hirsutism and/or acne). MAIN RESULTS AND THE ROLE OF CHANCE: AGD measures were comparable in offspring of women with PCOS compared to controls (all P > 0.2) despite significantly higher maternal levels of total testosterone (mean: 2.4 versus 2.0 nmol/l) and free testosterone (mean: 0.005 versus 0.004 nmol/l) in women with PCOS versus controls (both P < 0.001). In women with PCOS, maternal testosterone was an independent positive predictor of offspring AGDas and AGDap in boys. Maternal testosterone levels did not predict AGD in girls born of mothers with PCOS or in boys or girls born of women in the control group. LIMITATIONS, REASONS FOR CAUTION: The diagnosis of PCOS was based on retrospective information and questionnaires during pregnancy. Women participating in OCC were more ethnically homogenous, leaner, more educated and less likely to smoke compared to the background population. Our study findings, therefore, need to be reproduced in prospective study cohorts with PCOS, in more obese study populations and in women of other ethnicities. WIDER IMPLICATIONS OF THE FINDINGS: Our finding of the same AGD in girls born of mothers with PCOS compared to controls expands previous results of studies reporting longer AGD in adult women with PCOS. Our results suggest that longer AGD in adult women with PCOS could be the result of increased testosterone levels in puberty, perhaps in combination with weight gain. STUDY FUNDING/COMPETING INTEREST(S): Financial grants for the study were provided by the Danish Foundation for Scientific Innovation and Technology (09-067180), Ronald McDonald Children Foundation, Odense University Hospital, the Region of Southern Denmark, the Municipality of Odense, the Mental Health Service of the Region of Southern Denmark, The Danish Council for Strategic Research, Program Commission on Health, Food and Welfare (2101-08-0058), Odense Patient data Explorative Network, Novo Nordisk Foundation (grant no. NNF15OC00017734), the Danish Council for Independent Research and the Foundation for research collaboration between Rigshospitalet and Odense University Hospital and the Health Foundation (Helsefonden). There is no conflict of interest of any author that could be perceived as prejudicing the impartiality of the research reported.

Does stress affect food preferences? - a randomized controlled trial investigating the effect of examination stress on measures of food preferences and obesogenic behavior.

Lay summary: Human and animal studies have shown that chronic stress interfers with both homeostatic and hedonic appetite control. Here, we investigated the effect of chronic stress on food preferences and eating behavior in real life settings. In random order, fifty healthy students participated in two test periods of 4-5 days; a stressful period (one week prior to an examination) and a nonstressful period (four weeks after an examination). Food preferences were assessed by counting money spent on highly rewarding foods bought with gift certificates, and changes in eating behavior was further assessed by the Three Factor Eating Questionnaire. Cohen's Perceived Stress Scale, the Recovery-Stress Questionnaire, heart rate variability and Cortisol awakening response were used to evaluate the level of stress. Data on glycemic control, blood pressure, physical activity and sleep were also collected. Forty-four subjects had complete data on the primary outcome. Self-perceived stress was higher and recovery lower in the exam period (p ≤ .001). Subjects were less cognitively restrained (p = .037), less moderately-to-vigorously and lightly physically active (p ≤ .037) and were more sedentary (p = .009) in the examination period. However, no difference was found in money spent on high reward foods, disinhibition or hunger between the examination and control condition. Furthermore, no differences in the physiological markers of stress, glycemic measures and sleep were found. Data does not convincingly support the hypothesis that perceived stress increases the preference for highly palatable foods or leads to adverse effects on different markers of health. However, the stressor might have been to mild to induce obesogenic behaviors.

The half-life of 25(OH)D after UVB exposure depends on gender and vitamin D receptor polymorphism but mainly on the start level.

The 25-hydroxy vitamin D (25(OH)D) production caused by UVB exposure is usually underestimated as the concurrent degradation of 25(OH)D is not considered. Therefore, the decrease in 25(OH)D was investigated during a 7-week period in winter when ambient UVB is negligible. Twenty-two healthy Danish individuals (113 samples) participated and had a mean and steady maximal 25(OH)D start level of 132 nmol l-1 (range of 68-216 nmol l-1) due to long-term UVB treatment prior to this study. In this group with high 25(OH)D start levels, the decrease in 25(OH)D was best described by an exponential model. This suggests a quantitatively larger elimination of 25(OH)D at high 25(OH)D start levels. A linear model (logarithm of 25(OH)D) including personal start levels as intercepts and a slope influenced by gender and the vitamin D receptor gene polymorphism rs2228570 explained 87.8% of the observed variation. The mean half-life was 89 days with a difference in half-life of 120 days between a male with rs2228570 genotype GG (59 days) and a female with rs2228570 genotype AA/AG (179 days). Thus, these two parameters explained a large part of the observed inter-individual variation of 25(OH)D. Furthermore, the decrease was analysed in two groups with medium and low 25(OH)D start levels resulting in longer half-lives of 149 days and 199 days, respectively. The longer half-lives at lower 25(OH)D levels may be caused by storage mobilisation, changed catabolism or increased intestinal absorption.

Evaluation of cefuroxime concentration in the intrathecal and extrathecal compartments of the lumbar spine-an experimental study in pigs.

BACKGROUND AND PURPOSE: Optimal antibiotic prophylaxis is crucial to prevent postoperative infection in spinal surgery. Sufficient time above the minimal inhibitory concentration (fT > MIC) for relevant bacteria in target tissues is required for cefuroxime. We assessed cefuroxime concentrations and fT > MIC of 4 µg·ml-1 for Staphylococcus aureus in the intrathecal (spinal cord and cerebrospinal fluid, CSF) and extrathecal (epidural space) compartments of the lumbar spine. EXPERIMENTAL APPROACH: Eight female pigs were anaesthetized and laminectomized at L3-L4. Microdialysis catheters were placed for sampling in the spinal cord, CSF, and epidural space. A single dose of 1500 mg cefuroxime was administered intravenously over 10 min. Microdialysates and plasma were obtained continuously during 8 h. Cefuroxime concentrations were determined by ultra-high-performance liquid chromatography. KEY RESULTS: Mean fT > MIC (4 µg·ml-1 ) was 58 min in the spinal cord, 0 min in the CSF, 115 min in the epidural space, and 123 min in plasma. Tissue penetration was 32% in the spinal cord, 7% in the CSF, and 63% in the epidural space. CONCLUSION AND IMPLICATIONS: fT > MIC (4 µg·ml-1 ) and tissue penetration for cefuroxime were lower in the intrathecal compartments (spinal cord and CSF) than in the extrathecal compartment (epidural space) and plasma, suggesting a significant effect of the blood-brain barrier. In terms of fT > MIC, a single dose of 1500 mg cefuroxime seems inadequate to prevent intrathecal infections related to spinal surgery for bacteria presenting with a MIC target of 4 µg· ml-1 or above.

Higher Maternal Cortisol Associated With Lower Blood Pressure in Offspring From 3 Months to 5 Years of Age in the Odense Child Cohort.

BACKGROUND: Synthetic glucocorticoid exposure in late pregnancy may be associated with higher blood pressure in offspring. We hypothesized that endogenous cortisol in pregnancy relates to offspring blood pressure (OBP). OBJECTIVE: To investigate associations between maternal cortisol status in third trimester pregnancy and OBP. METHODS: We included 1317 mother-child pairs from Odense Child Cohort, an observational prospective cohort. Serum (s-) cortisol and 24-hour urine (u-) cortisol and cortisone were assessed in gestational week 28. Offspring systolic blood pressure and diastolic blood pressure were measured at age 3, 18 months, and 3 and 5 years. Associations between maternal cortisol and OBP were examined by mixed effects linear models. RESULTS: All significant associations between maternal cortisol and OBP were negative. In boys in pooled analyses, 1 nmol/L increase in maternal s-cortisol was associated with average decrease in systolic blood pressure (ß=-0.003 mmHg [95% CI, -0.005 to -0.0003]) and diastolic blood pressure (ß=-0.002 mmHg [95% CI, -0.004 to -0.0004]) after adjusting for confounders. At 3 months of age, higher maternal s-cortisol was significantly associated with lower systolic blood pressure (ß=-0.01 mmHg [95% CI, -0.01 to -0.004]) and diastolic blood pressure (ß=-0.010 mmHg [95% CI, -0.012 to -0.011]) in boys after adjusting for confounders, which remained significant after adjusting for potential intermediate factors. CONCLUSIONS: We found temporal sex dimorphic negative associations between maternal s-cortisol levels and OBP, with significant findings in boys. We conclude that physiological maternal cortisol is not a risk factor for higher blood pressure in offspring up to 5 years of age.

Low-dose naltrexone for treatment of pain in patients with fibromyalgia: a randomized, double-blind, placebo-controlled, crossover study.

Introduction: Fibromyalgia (FM) is a chronic fluctuating, nociplastic pain condition. Naltrexone is a µ-opioid-receptor antagonist; preliminary studies have indicated a pain-relieving effect of low-dose naltrexone (LDN) in patients with FM. The impetus for studying LDN is the assumption of analgesic efficacy and thus reduction of adverse effects seen from conventional pharmacotherapy. Objectives: First, to examine if LDN is associated with analgesic efficacy compared with control in the treatment of patients with FM. Second, to ascertain the analgesic efficacy of LDN in an experimental pain model in patients with FM evaluating the competence of the descending inhibitory pathways compared with controls. Third, to examine the pharmacokinetics of LDN. Methods: The study used a randomized, double-blind, placebo-controlled, crossover design and had a 3-phase setup. The first phase included baseline assessment and a treatment period (days -3 to 21), the second phase a washout period (days 22-32), and the third phase a baseline assessment followed by a treatment period (days 33-56). Treatment was with either LDN 4.5 mg or an inactive placebo given orally once daily. The primary outcomes were Fibromyalgia Impact Questionnaire revised (FIQR) scores and summed pain intensity ratings (SPIR). Results: Fifty-eight patients with FM were randomized. The median difference (IQR) for FIQR scores between LDN and placebo treatment was -1.65 (18.55; effect size = 0.15; P = 0.3). The median difference for SPIR scores was -0.33 (6.33; effect size = 0.13; P = 0.4). Conclusion: Outcome data did not indicate any clinically relevant analgesic efficacy of the LDN treatment in patients with FM.

Increase in serum 25-hydroxyvitamin-D3 in humans after solar exposure under natural conditions compared to artificial UVB exposure of hands and face.

Vitamin D studies are often performed under controlled laboratory conditions and the findings may be difficult to translate to natural conditions. We aimed to determine and compare the doses of natural solar ultraviolet radiation (UVR) with doses of artificial UVB radiation of hands and face needed to increase serum 25-hydroxyvitamin-D(3) (25(OH)D). Furthermore, we aimed to investigate the natural course of 25(OH)D due to solar exposure from April to September. 46 Caucasian volunteers were included. 17 volunteers received solar UVR (Group 1) in their natural Danish environment. Individual daily solar UVR doses in standard erythema doses (SEDs) were determined with personal wristwatch UV-dosimeters. 29 volunteers (Group 2) received artificial UVB doses of 6 SEDs (N = 14) and 3 SEDs (N = 15) on hands and face during late-winter/early-spring when outdoor UVB is negligible. 25(OH)D-levels were determined around every second week during study periods. Solar-UVR doses and sun-exposure diaries with information of sun-exposed areas were available from 8 volunteers and used for comparison with artificial UVB doses. However no significant solar-induced Δ25(OH)D was observed when sun-exposed areas were limited to hands and face. Instead the earliest period (week 17-19) with significant Δ25(OH)D, occurring after a mean of 2 days of sun-exposing more than hands and face, was used to estimate an approximate UVR dose required to increase 25(OH)D. This estimate resulted in a dose of 4.1 solar SEDs required to increase 25(OH)D by 1 nmol l(-1). The artificial dose of 6 SEDs of only hands and face significantly increased 25(OH)D and resulted in a dose of 0.52 SEDs required to increase 25(OH)D significantly by 1 nmol l(-1). Artificial UVB was thus at least 8 times more efficient in increasing 25(OH)D than solar UVR at a UV-exposed area consisting of approximately hands and face. Solar UVR exposure of larger areas may lead to enhanced efficacy but was not relevant for this comparison. Significant solar-induced Δ25(OH)D was present earliest at April 8, maximal by early August and decreased by late August.

Cefuroxime concentrations in the anterior and posterior column of the lumbar spine - an experimental porcine study.

BACKGROUND CONTEXT: Surgical site infection following spine surgery is associated with increased morbidity and mortality. Perioperative antibiotic prophylaxis is a key factor in lowering the risk of acquiring an infection. Previous studies have assessed perioperative cefuroxime concentrations in the anterior column of the cervical spine with an anterior surgical approach. However, the majority of surgeries are performed in the posterior column and many surgeries involve the lumbar spine. PURPOSE: The objective of this study was to compare the perioperative tissue concentrations of cefuroxime in the anterior and posterior column during lumbar spine surgery with a posterior surgical approach. STUDY DESIGN: In vivo experimental pharmacokinetic study of cefuroxime concentrations in an acute preclinical porcine model. METHODS: The lumbar vertebral column was exposed from L1 to L5 in 8 female pigs. Microdialysis catheters were placed for sampling in the anterior column (vertebral body) and posterior column (posterior arch) within the same vertebra (L5). Cefuroxime (1.5 g) was administered intravenously. Microdialysates and plasma samples were continuously obtained over 8 hours. Cefuroxime concentrations were quantified by Ultra High Performance Liquid Chromatography Tandem Mass Spectrometry. The primary endpoint was the time above the cefuroxime clinical breakpoint minimal inhibitory concentration (T>MIC) for Staphylococcus aureus of 4 µg/mL. The secondary endpoint was tissue penetration (AUCtissue/AUCplasma). RESULTS: Mean T>MIC 4 µg/mL (95% confidence interval) was 123 min (105-141) in plasma, 97 min (79-115) in the anterior column and 93 min (75-111) in the posterior column. Tissue penetration (95% confidence interval) was incomplete for both the anterior column 0.48 (0.40-0.56) and posterior column 0.40 (0.33-0.48). CONCLUSIONS: T>MIC was comparable between the anterior and posterior column. Mean cefuroxime concentrations decreased below the clinical breakpoint minimal inhibitory concentration for S. aureus of 4 µg/mL after 123 minutes (plasma), 97 minutes (anterior column) and 93 minutes (posterior column). This is shorter than the duration of most lumbar spine surgeries, and therefore alternative dosing regimens should be considered in posterior open lumbar spine surgeries lasting more than 1.5 hours. CLINICAL SIGNIFICANCE: Open lumbar spine surgery often involves extensive soft tissue dissection, stripping and retraction of the paraspinal muscles which may impair the local blood flow exposing the lumbar vertebra to postoperative infections. A single intravenous administration of 1.5 g cefuroxime only provided sufficient prophylactic target tissue concentrations in the vertebra of the lumbar spine for up to 1.5 hours.

Weight-based cefuroxime dosing provides comparable orthopedic target tissue concentrations between weight groups - a microdialysis porcine study.

Antibiotic prophylaxis is a key element in prevention of surgical site infections. For the majority of orthopedic procedures, antibiotic administration follows fixed dosing regimens irrespective of weight. However, this may result in insufficient antibiotic target tissue concentrations and higher risk of surgical site infections in obese individuals. The aim of this study was to investigate the effect of weight-based cefuroxime dosing on plasma and target tissue concentrations. Eighteen female pigs were allocated into three groups differentiated by weight: 53-57 kg, 73-77 kg, and 93-97 kg. Microdialysis catheters were placed for continuous sampling in bone, muscle, and subcutaneous tissue during an 8h sampling interval. Blood samples were collected as reference. Cefuroxime was administered intravenously as a bolus according to weight (20 mg/kg). The primary endpoint was the time above the cefuroxime minimal inhibitory concentration for Staphylococcus aureus (T > MIC (4 µg/mL)). Comparable target tissue T > MICs (4 µg/mL) were found between weight groups. Mean T > MIC ranged between 116-137 min for plasma, 118-154 min for bone, 109-146 min for the skeletal muscle, and 117-165 min for subcutaneous tissue across the groups. Weight-based cefuroxime (20 mg/kg) dosing approach provides comparable perioperative plasma and target tissue T > MIC (4 µg/mL) in animals between 50-100 kg body weight, and thus a comparable prophylaxis of surgical site infections.

Sex Differences and Caffeine Impact in Adenosine-Induced Hyperemia.

Caffeine consumption before adenosine stress myocardial perfusion imaging (MPI) is known to affect the hemodynamic response and, thus, reduce the stress myocardial blood flow (MBF) and myocardial flow reserve (MFR) assessments. However, it is not clear if any sex-specific differences in the hemodynamic response after caffeine consumption exist. This study aimed to evaluate if such differences exist and, if so, their impact on MBF and MFR assessments. Methods: This study comprised 40 healthy volunteers (19 women). All volunteers underwent 4 serial rest/stress MPI sessions using 82Rb; 2 sessions were acquired without controlled caffeine consumption, and 2 sessions after oral ingestion of either 100 and 300 mg of caffeine or 200 and 400 mg of caffeine. For the caffeine imaging sessions, caffeine was ingested orally 1 h before the MPI scan. Results: Increase in plasma caffeine concentration (PCC) (mg/L) after consumption of caffeine was larger in women (MPI session without caffeine vs. MPI session with caffeine: women = 0.3 ± 0.2 vs. 5.4 ± 5.1, men = 0.1 ± 0.2 vs. 2.7 ± 2.6, both P < 0.001). Caffeine consumption led to reduced stress MBF and MFR assessments for men whereas no changes were reported for women (women [PCC < 1 mg/L vs. PCC ≥ 1 mg/L]: stress MBF = 3.3 ± 0.6 vs. 3.0 ± 0.8 mL/g/min, P = 0.07; MFR = 3.7 ± 0.6 vs. 3.5 ± 1.0, P = 0.35; men [PCC < 1 mg/L vs. PCC ≥ 1 mg/L]: stress MBF = 2.7 ± 0.7 vs. 2.1 ± 1.0 mL/g/min, P = 0.005; MFR = 3.8 ± 1.0 vs. 3.1 ± 1.4, P = 0.018). Significant differences in the stress MBF were observed for the 2 sexes (both P ≤ 0.001), whereas similar MFR was reported (both P ≥ 0.12). Conclusion: Associations between increases in PCC and reductions in stress MBF and MFR were observed for men, whereas women did not have the same hemodynamic response. Stress MBF was affected at lower PCCs in men than women.

Abdominal tissue concentrations and penetration of carboplatin in a HIPEC procedure ‒ assessment in a novel porcine model.

Objectives: Peritoneal dissemination from intraabdominal cancers is associated with poor prognosis and rapid disease progression. Hyperthermic intraperitoneal chemotherapy (HIPEC) is an antineoplastic treatment, which has improved survival and recurrence-free survival, but little is known about the acquired chemotherapy concentrations in local tissues. The aim of this study was to assess concentrations of carboplatin during and after HIPEC treatment dynamically and simultaneously in various abdominal organ tissues by means of microdialysis in a novel porcine model. Methods: Eight pigs underwent imitation cytoreductive surgery followed by HIPEC (90 min) using a carboplatin dosage of 800 mg/m2. Microdialysis catheters were placed for sampling of drug concentrations in various solid tissues: peritoneum, liver, bladder wall, mesentery and in different depths of one mm and four mm in the hepatoduodenal ligament and rectum. During and after HIPEC, dialysates and blood samples were collected over 8 h. Results: No statistically significant differences in mean AUC0-last (range: 2,657-5,176 min·µg/mL), mean Cmax (range: 10.6-26.0 µg/mL) and mean Tmax (range: 105-206 min) were found between the compartments. In plasma there was a tendency towards lower measures. No difference between compartments was found for tissue penetration. At the last samples obtained (450 min) the mean carboplatin concentrations were 4.9-9.9 µg/mL across the investigated solid tissues. Conclusions: Equal carboplatin distribution in abdominal organ tissues, detectable concentrations for at least 6 h after HIPEC completion, and a carboplatin penetration depth of minimum four mm were found. The present study proposes a new HIPEC porcine model for future research.

Vitamin D production depends on ultraviolet-B dose but not on dose rate: a randomized controlled trial.

Ultraviolet-B (UV-B) radiation increases serum vitamin D level expressed as 25-hydroxyvitamin D(3) (25(OH)D), but the dose-response relationship and the importance of dose rate is unclear. Of 172 fair-skinned persons screened for 25(OH)D, 55 with insufficient baseline 25(OH)D≤50 nm (mean 31.2 nm) were selected and randomized to one of 11 groups of five participants. Each group was exposed to one of four different UV-B doses: 0.375, 0.75, 1.5 or 3.0 standard erythema dose (SED) for 1, 5, 10 or 20 min. All participants had four UV-B sessions with 2- to 3-day interval with 24% of their skin exposed. Skin pigmentation and 25(OH)D were measured before and after the irradiations. The increase in 25(OH)D after UV-B exposure (adjusted for baseline 25(OH)D) was positively correlated with the UV-B dose (P=0.001; R(2) =0.176) but not to dose rate (1-20 min). 25(OH)D increased in response to four UV-B treatments of 3 SED with 24.8 nm on average and 14.2 nm after four UV-B treatments of just 0.375 SED. In conclusion, the increase in 25(OH)D after UV-B exposure depends on the dose but not on the dose rate (1-20 min). Further, a significant increase in 25(OH)D was achieved with a very low UV-B dose.

Serum metal ion levels in adolescent idiopathic scoliosis (AIS) patients 25 years after treated with Harrington rod instrumentation or bracing.

INTRODUCTION: Surgical instrumentation in children with adolescent idiopathic scoliosis (AIS) is performed early in life and the implants are left in situ for the rest of the patient's life. Concern has been raised regarding persistent elevated levels of serum metal ions, but only a few studies on the topic have been published. The aim of this study was to compare the levels of serum metal ions in patients with AIS treated with either Harrington rod instrumentation or bracing. MATERIALS AND METHODS: AIS patients treated with Boston brace (BB) or posterior spinal fusion with Harrington rod instrumentation (HR) from 1983 to 1990 were requested to return to clinic. One hundred fifty-nine (73%) of 219 patients were available for follow-up of whom 115 agreed to have a blood draw. RESULTS: The proportion of patients who agreed to have a blood draw were similar in the BB (48 of 100, 48%) and HR (67 of 115, 60%, p = 0.085) groups. None of the surgical patients had their implants removed; mean age at follow-up (BB: 43.2 years vs HR: 43.5 years, p = 0.566) and mean length of follow-up (BB: 26.5 years vs HR: 24.5 years). Mean chromium serum levels were similar between the BB (2.7 nmol/L) and the HR (2.9 nmol/L, p = 0.827). Mean Cobalt serum levels were also similar between the BB (2.6 nmol/L) and the HR (2.8 nmol/L, p = 0.200). CONCLUSION: Serum metal ions were similar in AIS patients treated with bracing or Harrington rod instrumentation 25 years after initiation of treatment.