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Adjuvant treatment for post-menopausal women with early breast cancer (BC) includes aromatase inhibitors (AI), known to decrease bone mineral density (BMD). In this study, we investigate whether denosumab is a valid second option for patients unable to receive standard adjuvant i.v. zoledronic acid (ZA). In total, 212 patients have been evaluated after they did not receive ZA. Of those 194 were included. After evaluation by an endocrinologist, all patients were offered ZA as their first choice and 15% accepted (

BACKGROUND: SGLT2 inhibitors are a promising treatment option in patients with heart failure and reduced ejection fraction. We aimed to investigate the effects of empagliflozin on estimated extracellular volume, estimated plasma volume, and measured glomerular filtration rate (GFR) in patients with heart failure and reduced ejection fraction.METHODS: Empire HF Renal was a prespecified substudy of the investigator-initiated, double-blind, randomised, placebo-controlled Empire HF trial. The study was done at Herlev and Gentofte University Hospital (Herlev, Denmark), with patients recruited from four Danish heart failure outpatient clinics. Patients with New York Heart Association class I-III symptoms, with a left ventricular ejection fraction of 40% or lower, and on guideline-directed heart failure therapy were randomly assigned (1:1) to receive either oral empagliflozin 10 mg or matched placebo once daily for 12 weeks. The allocation sequence was computer-generated. Patients and study investigators were masked to treatment allocation. The coprimary prespecified renal outcomes were the between-group difference in the changes in estimated extracellular volume, estimated plasma volume, and measured GFR from baseline to 12 weeks. All analyses were done in the intention-to-treat population (apart from safety analyses, which were done in patients who received at least one dose of study drug), with no interim analyses done during the trial. The Empire HF trial is registered with ClinicalTrials.gov, NCT03198585, and EudraCT, 2017-001341-27.FINDINGS: Between June 29, 2017, and July 15, 2019, we assessed 391 patients for eligibility, of whom 120 (31%) were randomly assigned to empagliflozin or placebo, including 105 (88%) without diabetes. In intention-to-treat analyses, 60 (100%) patients in the empagliflozin group and 59 (98%) patients in the placebo group were included for estimated extracellular volume and estimated plasma volume, and 59 (98%) patients in the empagliflozin group and 58 (97%) patients in the placebo group were included for measured GFR. Empagliflozin treatment resulted in reductions in estimated extracellular volume (adjusted mean difference -0·12 L, 95% CI -0·18 to -0·05; p=0·00056), estimated plasma volume (-7·3%, -10·3 to -4·3; pINTERPRETATION: In patients with heart failure and reduced ejection fraction, empagliflozin reduced estimated extracellular volume, estimated plasma volume, and measured GFR after 12 weeks. Fluid volume changes might be an important mechanism underlying the beneficial clinical effects of SGLT2 inhibitors.FUNDING: Research Council at Herlev and Gentofte University Hospital, Research and Innovation Foundation of the Department of Cardiology at Herlev and Gentofte University Hospital, Capital Region of Denmark, Danish Heart Foundation, and AP Møller Foundation for the Advancement of Medical Science.

Purpose Chemotherapy-induced peripheral neuropathy (CIPN) is a recognized adverse effect of standard (neo)adjuvant chemotherapy in breast cancer (BC) treatment. However, there is no consensus on a validated method for assessing CIPN. Heart rate variability (HRV) and vibration perception threshold (VPT) could be used as objective measures to describe CIPN. The aim of this pilot study was to investigate whether subjectively reported CIPN was associated with altered HRV and VPT in BC patients. Methods We performed a cross-sectional pilot study evaluating 30 BCE patients previously treated with chemotherapy, 26 BCE patients who did not receive chemotherapy, and 22 controls without breast cancer. Self-reported CIPN was registered for the BC patients. All participants were subjected to multi-frequency vibration analyses to determine VPT along with short ECG measurements to determine HRV measures. Results Self-reported CIPN was registered in 14 (46.6%) BC patients treated with chemotherapy. The VPT at 64 Hz (P = 0.022) and mean HR (P = 0.022) were significantly higher and the HRV measures SDNN (P = 0.023), RMSSD (P = 0.007), LF (P = 0.050) and HF (P = 0.045) were significantly lower in BC patients reporting CIPN compared to controls when adjusted for age. VPT at 64 Hz and 125 Hz were significantly higher in BC patients not reporting CIPN compared to controls when adjusted for age. Conclusion We found elevated VPT and mean HR along with decreased HRV parameters in 14 BCE patients reporting CIPN. These findings support the need for further investigation into whether HRV and vibration analysis could contribute to an objective assessment of CIPN.

Osteomalacia is a bone-demineralizing disease of adulthood, often caused by hypovitaminosis D. Current animal models of the disease mimic osteomalacia as a consequence of gastric bypass or toxic exposure to metals, but a relevant model of diet-induced osteomalacia is lacking. For that purpose, 7-month-old female Sprague Dawley rats were randomly assigned into 2 weight-stratified groups and maintained for 4 months on synthetic diets containing negligible or normal levels of vitamin D. The dietary regimen resulted in vitamin D deficiency as measured by 25-hydroxyvitamin D serum levels; however, hypovitaminosis D per se did not affect biomarkers of calcium metabolism and bone turnover, nor did it result in increased osteoid. Thus, vitamin D depletion through the diet was found to be insufficient to induce an osteomalacia-like phenotype in the adult rat. After 4 months, the phosphate content of the vitamin D–depleted diet had decreased to 0.16% (calcium:phosphorus ratio of 5.85), resulting in an osteomalacic-like condition (trabecular osteoid surface/bone surface constituted 33%; CI, 26-40). The diet change also affected both metabolic and bone turnover biomarkers, including significantly suppressing serum fibroblast growth factor 23. Furthermore, decreased dietary phosphate in a vitamin D–depleted diet led to microarchitectural changes of trabecular and cortical bone, lower bone mass density, lower bone mass content and decreased bone strength, all indicating reduced bone quality. Taken together, our results show that osteomalacia can be induced in the adult female rat by depleting vitamin D and lowering phosphate content in the diet.

Background It is well known that breast cancer (BC) patients often suffer from chemotherapy-induced peripheral neuropathy (CIPN). However, it is not always recognized that they have higher risk of falling, dizziness and other signs of dysfunctional autonomous nervous system. We performed a systematic review of the literature on vibration perception threshold (VPT) and heart rate variability (HRV) as methods to objectively assess (CIPN) in BC-patients. Could VPT and HRV describe coexisting sensory and autonomic nerve damage? Materials and Methods PubMed was searched in September 2019. The included studies had to address HRV and/or VPT in BC-patients who received chemotherapy. Results Seven studies assessed VPT and six studies assessed HRV in BC-patients. Studies showed lowered perception of vibrations after chemotherapy reflected in higher VPT and no changes in HRV after taxane-based chemotherapy. No studies evaluated VPT and HRV at the same time. Conclusion The results were limited by short follow-up, small sample sizes, and different chemotherapy regimens which makes generalizability problematic. A standard assessment method of CIPN is still missing and further research is needed to evaluate if VPT and HRV could contribute to an objective assessment of CIPN. With higher survival rates for BC-patients autonomous and sensory nerve damage will be an increasing task. However, our literature review showed that no one have focused on the combination of autonomous and sensory affection measured by the simple methods VPT and HRV. Therefore, we encourage the development of international guidelines for the objective measure of nerve damage in BC-patients.

Psychotic symptoms have been linked to salience abnormalities in the brain reward system, perhaps caused by a dysfunction of the dopamine neurotransmission in striatal regions. Blocking dopamine D2 receptors dampens psychotic symptoms and normalises reward disturbances, but a direct relationship between D2 receptor blockade, normalisation of reward processing and symptom improvement has not yet been demonstrated. The current study examined the association between blockade of D2 receptors in the caudate nucleus, alterations in reward processing and the psychopathology in a longitudinal study of antipsychotic-naïve first-episode schizophrenia patients.Twenty-two antipsychotic-naïve first-episode schizophrenia patients (10 males, mean age 23.3) and 23 healthy controls (12 males, mean age 23.5) were examined with single-photon emission computed tomography using 123I-labelled iodobenzamide. Reward disturbances were measured with functional magnetic resonance imaging (fMRI) using a modified version of the monetary-incentive-delay task. Patients were assessed before and after 6 weeks of treatment with amisulpride.In line with previous results, patients had a lower fMRI response at baseline (0.2 ± 0.5 v. 0.7 ± 0.6; p = 0.008), but not at follow-up (0.5 ± 0.6 v. 0.6 ± 0.7), and a change in the fMRI signal correlated with improvement in Positive and Negative Syndrome Scale positive symptoms (ρ = -0.435, p = 0.049). In patients responding to treatment, a correlation between improvement in the fMRI signal and receptor occupancy was found (ρ = 0.588; p = 0.035).The results indicate that salience abnormalities play a role in the reward system in schizophrenia. In patients responding to a treatment-induced blockade of dopamine D2 receptors, the psychotic symptoms may be ameliorated by normalising salience abnormalities in the reward system.

Background and aim: Atherosclerosis evolves or accelerates when arteries are exposed to ionizing radiation, both early and late after exposure. Radioiodine therapy of benign thyroid disease exposes the carotid arteries to 4–50 Gy, and may thereby increase the risk of atherosclerosis. Increased risk of cerebrovascular events has been reported after radioiodine therapy. This study aimed to examine whether atherosclerosis develops early or late after radioiodine therapy of benign thyroid disease. Method: Patients treated for benign thyroid disorders (nontoxic goiter, adenoma, and hyperthyroidism) were examined with ultrasound for the main outcome, carotid intima media thickness (CIMT), and for plaque presence (plaque presence only in late damage). Signs of early damage from radioiodine were studied in 39 radioiodine-treated patients, who were examined before treatment and at 1, 3, 6, and 12 months after treatment. Late changes were studied in a cross-sectional case-control design, with radioiodine-treated patients as cases (n = 193) and patients treated with surgery as controls (n = 95). Data were analyzed with repeated measurement for longitudinal data, and with multivariate regression for cross-sectional data. Results were adjusted for age, sex, cholesterol, smoking status, known atherosclerotic disease, and body mass index. Results: No changes in CIMT were found in the patients followed prospectively for one year after treatment with radioactive iodine for benign thyroid disease (p = 0.58). In the study on late effects, there was no difference in CIMT (p = 0.25) or presence of plaques (p = 0.70) between those treated with radioactive iodine and those treated with surgery (9.8 and 5.6 years since treatment, respectively). Furthermore, the level of thyrotropin (TSH) did not influence these atherosclerosis markers. Conclusion: No early changes in CIMT were detected in patients treated with radioactive iodine for benign thyroid disease. No signs of late effects of radioactive iodine on CIMT or plaque presence were found after 10 years of follow-up. The radiation to the carotid arteries by radioactive iodine therapy for benign thyroid disease may therefore have no or low effect on atherosclerotic burden of the carotid arteries in general.

Primary hyperaldosteronism (PA), known as Mb Conn, is one of the most common forms of secondary hypertension in middle-aged adults. High plasma aldosterone has been associated with severe organ damage. The unilateral aldosterone-producing adenoma (lateralized disease) is a subtype of PA, which can be fully or partly cured by adrenalectomy.Retrospective review of data from 50 patients who underwent adrenal venous sampling (AVS) was performed. Medical records, plasma renin and aldosteron, confirmatory tests and medical imaging (predominantly Computed Tomography and Magnetic Resonance Imaging) were available. Patients with lateralized disease (n = 39) underwent adrenalectomy and additional clinical data at least one year after surgery was recorded.Age and gender were widely and equally distributed (median age = 51, age span = 28-73). Patients with lateralized disease had higher blood pressure (BP) and lower serum potassium compared to patients with bilateral hyperplasia. No difference regarding age and gender distribution was detected. Despite lateralized disease diagnosed from AVS, the medical images were normal in 10 patients (28%). Follow-up of 30 patients who underwent adrenalectomy showed that six patients were cured, 17 had better BP control, five patients had no effect and one patient had higher BP but decreased number of antihypertensive drugs.PA is of equal prevalence in men and women, young and old individuals. The agreement between imaging modalities and AVS is limited, and the final diagnosis must rely on AVS. Patients prone for surgery had better BP control after adrenalectomy.

One of best validated findings in schizophrenia research is the association between blockade of dopamine D2 receptors and the effects of antipsychotics on positive psychotic symptoms. The aim of the present study was to examine correlations between baseline striatal D(2/3) receptor binding potential (BP(p)) values and treatment outcome in a cohort of antipsychotic-naïve first-episode schizophrenia patients. Additionally, we wished to investigate associations between striatal dopamine D(2/3) receptor blockade and alterations of negative symptoms as well as functioning and subjective well-being. Twenty-eight antipsychotic-naïve schizophrenia patients and 26 controls were included in the study. Single-photon emission computed tomography (SPECT) with [(123)I]iodobenzamide ([(123)I]-IBZM) was used to examine striatal D(2/3) receptor BP(p). Patients were examined before and after 6 weeks of treatment with the D(2/3) receptor antagonist amisulpride. There was a significant negative correlation between striatal D(2/3) receptor BP(p) at baseline and improvement of positive symptoms in the total group of patients. Comparing patients responding to treatment to nonresponders further showed significantly lower baseline BP(p) in the responders. At follow-up, the patients demonstrated a negative correlation between the blockade and functioning, whereas no associations between blockade and negative symptoms or subjective well-being were observed. The results show an association between striatal BP(p) of dopamine D(2/3) receptors in antipsychotic-naïve first-episode patients with schizophrenia and treatment response. Patients with a low BP(p) have a better treatment response than patients with a high BP(p). The results further suggest that functioning may decline at high levels of dopamine receptor blockade.

Very few studies have investigated the determinants of circulating 25-hydroxyvitamin D (25[OH]D) in young adults (18-25 years old) using a set of variables that include lifestyle, sociodemographic, and anthropometric data. Our aim was to investigate the association between these variables and vitamin D status in a sample of untreated young adults.A total of 738 young adults were enrolled in a (June cross-sectional study 2012 to May 2014) and were recruited from educational institutions in the Copenhagen area. For multivariate logistic regression subjects was categorized based on 25[OH]D in serum into; vitamin D sufficiency (S-25[OH]D 50 nmol/L), vitamin D insufficiency (25 nmol/L ≤ S-25[OH]D ≤ 50 nmol/L), vitamin D deficiency (S-25[OH]D 25 nmol/L). Information on lifestyle factors and education was obtained by self-reported questionnaires.700 subjects with a valid measurement of S-25[OH]D and a completed questionnaire was analysed. 238 had vitamin D insufficiency, 135 had vitamin D deficiency of which 13 had severe vitamin D deficiency (S-25[OH]D 12.5 nmol/L). The relative risk (RR) for vitamin D deficiency was highest for men 2.09 (1.52, 2.87); obese subjects 2.00 (1.27, 3.15); smokers 1.33 (1.02, 1.73); subjects who exercised 0-½ hours a week 1.88 (1.21, 2.94); and subjects who consumed fast food once a week 1.59 (1.05, 2.43). The relative risk was significantly lower for subjects who were studying for a Bachelor's degree (0.40 (0.23, 0.68). For vitamin D insufficiency, the highest RR was again for men 1.31 (1.06, 1.61); obese subjects 1.57 (1.17, 2.11); and subjects who exercised 0-½ hours a week 1.51 (1.11, 2.06).In this study of young adults, vitamin D deficiency was highly prevalent. Modifiable factors such as smoking, maintenance of normal BMI, and physical activity are all potential targets for interventional trials to determine the causal order; such knowledge would be useful in improving S-25[OH]D in young adults. The small group with severe vitamin D deficiency warrants increased attention.

Use of hormonal contraceptives (HC) may influence total plasma concentrations of vitamin D metabolites. A likely cause is an increased synthesis of vitamin D binding protein (VDBP). Discrepant results are reported on whether the use of HC affects free concentrations of vitamin D metabolites. Aim: In a cross-sectional study, plasma concentrations of vitamin D metabolites, VDBP, and the calculated free vitamin D index in users and non-users of HC were compared and markers of calcium and bone metabolism investigated. Results: 75 Caucasian women aged 25–35 years were included during winter season. Compared with non-users (n = 23), users of HC (n = 52) had significantly higher plasma concentrations of 25-hydroxyvitamin D (25OHD) (median 84 interquartile range: [67–111] vs. 70 [47–83] nmol/L, p = 0.01), 1,25-dihydroxyvitamin D (1,25(OH)2D) (198 [163–241] vs. 158 [123–183] pmol/L, p = 0.01) and VDBP (358 [260–432] vs. 271 [179–302] µg/mL, p < 0.001). However, the calculated free indices (FI-25OHD and FI-1,25(OH)2D) were not significantly different between groups (p > 0.10). There were no significant differences in indices of calcium homeostasis (plasma concentrations of calcium, parathyroid hormone, and calcitonin, p > 0.21) or bone metabolism (plasma bone specific alkaline phosphatase, osteocalcin, and urinary NTX/creatinine ratio) between groups. In conclusion: Use of HC is associated with 13%–25% higher concentrations of total vitamin D metabolites and VDBP. This however is not reflected in indices of calcium or bone metabolism. Use of HC should be considered in the interpretation of plasma concentrations vitamin D metabolites. View Full-Text

Fermented milk (FM) with putative antihypertensive effect in humans could be an easy applicable lifestyle intervention against hypertension. The mode of action is supposed to be through active milk peptides, shown to possess in vitro ACE-inhibitory effect. Blood pressure (BP) reductions upto 23 mm Hg have been reported in spontaneously hypertensive rats fed FM. Results from human studies of the antihypertensive effect are inconsistent. However, many studies suffer from methodological weaknesses, as insufficient blinding and the use of office BP measurements. We conducted a randomised, double-blind placebo-controlled study of the antihypertensive effect of Lactobacillus helveticus FM in 94 prehypertensive and borderline hypertensive subjects. The participants were randomised into three treatment groups with a daily intake of 150 ml of FM, 300 ml of FM or placebo (chemically acidified milk). The primary outcome was repeated 24-h ambulatory BP measurements. There were no statistically significant differences in the outcome between the groups (systolic BP (SBP), P=0.9; diastolic BP (DBP), P=0.2). However, the group receiving 300 ml FM had reduced BP across the 8-week period in several readings, which could be compatible with a minor antihypertensive effect. Heart rate and lipids remained unchanged between groups. Hence, our study does not support earlier studies measuring office BP-measurements, reporting antihypertensive effect of FM. Based on straight performed 24-h ambulatory BP measurements, milk fermented with Lactobacillus helveticus does not posses significant antihypertensive effect.

It is important to find a reliable and bedside method, which can estimate the cerebral blood flow (CBF) of patients in clinical settings. Estimation of CBF by calculating a blood flow index (BFI) using continuous wave near-infrared spectroscopy (CW-NIRS) and indocyanine green (ICG) as an i.v. tracer has been proposed to be a feasible and promising method. To validate if the BFI method can detect relative changes in CBF we compared data with the established method (133)Xenon single photon emission computer tomography ((133)Xe-SPECT).Ten healthy subjects were investigated before and after a bolus of acetazolamide. NIRS data were obtained using a multi source detector separation configuration in order to assess a corrected BFI (BFI(corr)) value, which attempts to eliminate contamination of skin blood flow.Data obtained showed no significant correlation between CBF changes measured by (133)Xe-SPECT and BFI(corr) (0.133, P = 0.732). After acetazolamide, a 49% increase in CBF was detected using the (133)Xe-SPECT method, whereas no changes in any ICG variables were observed after acetazolamide.The study shows that it is not possible to obtain reliable BFI data, which reflect changes in CBF after acetazolamide infusion, using the CW-NIRS and ICG method.

Recently introduced iterative reconstruction algorithms with resolution recovery (RR) and noise-reduction technology seem promising for reducing scan time or radiation dose without loss of image quality. However, the relative effects of reduced acquisition time and reconstruction software have not previously been reported. The aim of the present study was to investigate the influence of reduced acquisition time and reconstruction software on quantitative and qualitative myocardial perfusion single photon emission computed tomography (SPECT) parameters using full time (FT) and half time (HT) protocols and Evolution for Cardiac Software. We studied 45 consecutive, non-selected patients referred for a clinically indicated routine 2-day stress/rest 99mTc-Sestamibi myocardial perfusion SPECT. All patients underwent an FT and an HT scan. Both FT and HT scans were processed according to our standard procedure with both ordered-subset expectation maximization (OSEM) + filtered back projection (FBP) reconstructions and a second reconstruction of HT scans was performed with the RR software producing three datasets for each patient for visual analysis (FT-OSEM, HT-OSEM, and HT-RR) and for quantitative analysis (FT-FBP, HT-FBP, and HT-RR). The datasets were analyzed using commercially available QGS/QPS software and read by two observers evaluating image quality and clinical interpretation. Image quality was assessed on a 10-cm visual analog scale score. HT imaging was associated with loss of image quality that was compensated for by RR reconstruction. HT imaging was also associated with increasing perfusion defect extents, an effect more pronounced using RR than FBP reconstruction. Compared to standard FT-FBP, HT-RR significantly reduced left ventricular volumes whereas HT-FBP increased end-systolic volume. HT imaging had no effect on measured left ventricular ejections fraction or measures of reversibility. Image interpretation found a higher level of concordance between FT-OSEM and HT-RR than between FT-OSEM and HT-OSEM without any observable systematic effects. Use of RR reconstruction algorithms compensates for loss of image quality associated with reduced scan time. Both HT acquisition and RR reconstruction algorithm had significant effects on motion and perfusion parameters obtained with standard software, but these effects were relatively small and probably of limited clinical importance. Although no systematic effects on image interpretation were observed, the influence on diagnostic accuracy remains to be determined.

There is a need for real-time non-invasive, continuous monitoring of cerebral blood flow (CBF) during surgery, in intensive care units and clinical research. We investigated a new non-invasive hybrid technology employing ultrasound tagged near infrared spectroscopy (UT-NIRS) that may estimate changes in CBF using a cerebral blood flow index (CFI). Changes over time for UT-NIRS CFI and 133Xenon single photon emission computer tomography (133Xe-SPECT) CBF data were assessed in 10 healthy volunteers after an intravenous bolus of acetazolamide. UT-NIRS CFI was measured continuously and SPECT CBF was measured at baseline, 15 and 60 min after acetazolamide. We found significant changes over time in CFI by UT-NIRS and CBF by SPECT after acetazolamide (P ≤ 0.001). Post hoc tests showed a significant increase in CFI (P = 0.011) and SPECT CBF (P < 0.001) at 15 min after acetazolamide injection. There was a significant correlation between CFI and SPECT CBF values (r = 0.67 and P ≤ 0.033) at 15 min, but not at 60 min (P ≥ 0.777). UT-NIRS detected an increase in CFI following an acetazolamide bolus, which correlated with CBF measured with 133Xe-SPECT. This study demonstrates that UT-NIRS technology may be a promising new technique for non-invasive and real-time bedside CBF monitoring.

The objective of the study was to monitor collagen metabolism after thrombolytic therapy. Sequential measurements of serum aminoterminal type-III procollagen propeptide (S-PIIINP) and carboxyterminal type-I procollagen propeptide (S-PICP) were made in 62 patients suspected of acute myocardial infarction and receiving thrombolytic therapy. Regardless of whether acute myocardial infarction was confirmed or not, S-PIIINP increased (94-120%) 4 h after streptokinase therapy (por = 0.02), and decreased during the next 20 h with median values at 24 h still above the baseline (p0.02). With confirmed acute myocardial infarction, S-PIIINP increased from 24 h towards a plateau reached at day 2-3 (p0.01), with values still elevated at 6 months. No similar biphasic pattern was found for S-PICP, but patients with acute myocardial infarction had S-PICP above baseline at 1, 2, and 6 months (p0.05). A less pronounced S-PIIINP increase was noted with tissue-plasminogen activator than with streptokinase. Thrombolytic therapy induces collagen breakdown regardless of whether acute myocardial infarction is confirmed or not. With confirmed acute myocardial infarction collagen metabolism is altered for at least 6 months. Furthermore, fibrin-specific and nonspecific thrombolytic agents appear to affect collagen metabolism differently.

Pregnancy and lactation cause major changes in calcium homeostasis and bone metabolism. This population-based cohort study presents the physiological changes in biochemical indices of calcium homeostasis and bone metabolism during pregnancy and lactationWe describe physiological changes in calcium homeostasis, calcitropic hormones and bone metabolism during pregnancy and lactation.We studied 153 women planning pregnancy (n=92 conceived) and 52 non-pregnant, age-matched female controls. Samples were collected prior to pregnancy, once each trimester and 2, 16 and 36 weeks postpartum. The controls were followed in parallel.P-estradiol (E2), prolactin and 1,25-dihydroxyvitamin D (1,25(OH)2D) increased (p0.001) during pregnancy, whereas plasma levels of parathyroid hormone (P-PTH) and calcitonin decreased (p0.01). Insulin-like growth factor I (IGF-I) was suppressed (p0.05) in early pregnancy but peaked in the third trimester. Postpartum, E2 was low (p0.05); prolactin decreased according to lactation status (p0.05). 1,25(OH)2D was normal and IGF-I was again reduced (p0.05). P-PTH and calcitonin increased postpartum. From early pregnancy, markers of bone resorption and formation rose and fall, respectively (p0.001). From the third trimester, bone formation markers increased in association with IGF-I changes (p0.01). Postpartum increases in bone turnover markers were associated with lactation status (p0.001). During lactation, plasma phosphate was increased, whereas calcium levels tended to be decreased which may stimulate PTH levels during and after prolonged lactation.The increased calcium requirements in early pregnancy are not completely offset by increased intestinal calcium absorption caused by high 1,25(OH)2D since changes in bone markers indicated a negative bone balance. The rise in bone formation in late pregnancy may be initiated by a spike in IGF-I levels. The high bone turnover in lactating women may be related to high prolactin and PTH levels, low E2 levels and perhaps increased parathyroid hormone-related protein levels.

The amino-terminal propeptide of type III procollagen (PIIINP, M(r) 42,000) is a promising marker for the formation of type III collagen of granulation tissue in experimental and clinical studies. The disposal kinetics of circulating PIIINP is, however, almost unknown. In conscious pigs with a thoracic duct-venous shunt, 125I-labeled PIIINP was injected intravenously. The initial distribution volume was 2.2 liters, which was 1.7 times the plasma volume (P < 0.01). The disappearance curve was three-phased, with an initial steep decline (t1/2 58 min), followed by two slower phases (t1/2 239 min and 289 h). Consecutive gel filtrations showed that the initial slope of the plasma disappearance curve corresponded to the plasma clearance of the intact PIIINP. The initial plasma clearance was 26.5 ml plasma/min, whereas the urinary clearance was 8.7 ml plasma/min (P < 0.01). The other components of the plasma disappearance curve originated from the formation and disappearance of a high and a low molecular weight (MW) fraction as part of the degradation of PIIINP. The high MW fraction (approximately M(r) 90,000) was similar to a previously described, but not further characterized, PIIINP immunoreactive component. The existence of the low MW fraction (approximately M(r) 20,000) has not been reported before. The lymphatic recirculation of intact PIIINP was rapid, and the lymph-serum ratio was almost constant within 1 h of injection. We conclude that the t1/2 of circulating PIIINP is 58 min, that PIIINP escapes the circulation very quickly, and that the degradation of PIIINP includes at least two intermediary steps.

Dual energy X-ray absorptiometry (DEXA) is the most accurate method and thus the method of choice for diagnosing osteoporosis. Due to the limited access to DEXA-scanners, screening of patients with low energy fractures (LEF) for osteoporosis is not routinely performed in Denmark. Pre-screening with a simple, less expensive device might be able to exclude patients with normal bone mineral density (BMD) from further DEXA-scans. We aimed to determine the frequency of osteoporosis in patients with LEF, and evaluate the diagnostic impact of a radiographic absorptiometry (RA) scanner in the casualty department of a major Danish county hospital. In a 5-month period, 136 adult patients with LEF were invited for BMD measurements. In 74 (54%) patients DEXA-scans (spine and femoral neck) and phalangeal RA-scans were performed. A total of 86% of the patients were female and 39% were suffering from osteoporosis (T-scoresor = -2.5) according to the DEXA results. RA-BMD and T-scores differed significantly between the two groups, with and without osteoporosis (p0.001). Comparing T-scores from RA with the lowest T-scores from DEXA, a highly significant correlation was found for women (R = 0.7, p0.001). Using a RA cut-off value (T-score-1) for women ensuring 100% sensitivity for identifying women with osteoporosis, the positive predictive value was 46%. Up to 19% of DEXA-scans could be avoided in this setting. In our population the simple RA-BMD-method was cost-effective as a pre-screening tool for osteoporosis in women. However, the final diagnosis still relies on results from DEXA-scans.

Summary Objective: Milk fermented by lactic acid bacteria is suggested to have antihypertensive effect in humans. In vitro and animal studies have established an angiotensin-converting enzyme (ACE) inhibitor effect of peptides in fermented milk. However, other modes of action must be considered, because until today no human studies have confirmed an ACE inhibition in relation to the intake of fermented milk. Materials and methods: We undertook a double-blinded randomized placebo-controlled study including 94 borderline-hypertensive persons to study the effect on human physiology of Lactobacillus helveticus fermented milk. The subjects were randomized into three groups: Cardi04-300 ml, Cardi04-150 ml or placebo. All components of the renin–angiotensin–aldosterone system were measured several times. Sympathetic activity was estimated by plasma noradrenaline and cardiovascular response to head-up tilt at baseline and after 8 weeks of intervention. Results: No ACE inhibition of the fermented milk was demonstrated, as none of the components of the renin–angiotensin–aldosteron system changed. Plasma noradrenaline response to tilt test after intervention stayed unchanged between groups (P = 0·38), but declined in the group Cardi04-300 from 2·01 ± 0·93 nmol l−1 at baseline to 1·49 ± 0·74 nmol l−1 after 8 weeks (P = 0·002). There was no change in 24-h ambulatory blood pressure or heart rate between groups. Conclusions: Despite a known ACE inhibitory effect in vitro and in animals, milk fermented with Lb. helveticus did not inhibit ACE in humans. Our results suggest that the intake of fermented milk decreases sympathetic activity, although not to an extent mediating reductions of blood pressure and heart rate in borderline-hypertensive subjects.

A noninvasive method allowing measurements of the propeptides of collagen type III (PIIINP) and type I (PICP) in ulcer washings was developed. The response to topical human growth hormone was examined. Fourteen patients with venous ulcers were treated sequentially with human growth hormone (0.1, 0.25, and 1 IU/cm2/day), each dose for 1 week, followed by 1 week washout. On alternate days, three and two times during treatment and washout periods, respectively, the ulcers were washed and incubated for 30 minutes with sterile water. No changes in healing rates in relation to growth hormone application were observed. In contrast, PIIINP increased significantly to 168% (154% to 184%) (mean, 95% confidence interval) and 195% (179% to 218%) 5 and 9 days, respectively, after start of treatment, (p < 0.01). Propeptides of collagen type I reached a significant increase, to 196% (172% to 232%), in the fourth week, (p < 0.01). The areas under the curves of PICP and PIIINP correlated significantly with the healing rates (r = 0.57, p = 0.04; and r = 0.64, p = 0.01, respectively). The authors conclude that propeptide measurements may be useful markers of healing in clinical studies.

To investigate the lymphatic transport of the aminoterminal propeptide of type III procollagen (PIIINP) we established a thoracic duct-venous shunt in 6 pigs. Porcine PIIINP was purified, characterised, and compared with human PIIINP to ensure the suitability of the radioimmunoassay of human PIIINP for measurements in pigs. SDS-PAGE and radioimmunoinhibition assays show human and porcine PIIINP to be similar, thus indicating that the assay of human PIIINP is also reliable for determinations on pig serum and lymph. Intact PIIINP, as identified by gel filtration, accounted for 60% and 40% of the total PIIINP immunoreactivity in lymph and serum, respectively. The higher amount of total immunoreactivity and proportion of intact PIIINP in lymph compared with serum support the hypothesis that intact PIIINP is transported from peripheral tissue into the circulation by lymph. Two days after the shunt was established, the lymph was collected quantitatively hour-by-hour for 24 h. The flow was higher during the light periods than in the dark (p less than 0.01). The PIIINP concentration varied inversely with the flow, being higher in the dark hours (p less than 0.03). However, the total collected amount of PIIINP in lymph did not differ during the light and dark periods. Serum PIIINP remained unchanged over the 24 h. The lymphatic clearance of total PIIINP immunoreactive components was 6.2 ml serum/min and the lymphatic clearance of intact PIIINP was 9.1 ml serum/min, equal to 7 and 10 times the plasma volume/24 h, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Udgivelsesdato: 2008-Apr-8 OBJECTIVE: To investigate possible effects of insulin-sensitizing treatment on cortisol metabolism in insulin-resistant patients with polycystic ovary syndrome (PCOS). DESIGN: Randomized placebo-controlled study. SETTING: Academic tertiary care medical center. PATIENT(S): Thirty insulin-resistant PCOS patients. INTERVENTION(S): Sixteen weeks of pioglitazone (30 mg/day) or placebo treatment. MAIN OUTCOME MEASURE(S): Twenty-four-hour 20 min integrated blood sampling for measurement of cortisol and 24 h urinary excretion of steroid metabolites. Relative 5alpha-reductase activity was evaluated by allotetrahydrocortisol (alloTHF)/THF and androsterone/etiocholanolone (A/E) ratios. Delta values denoted changes during the treatment period (16 weeks - basal). Pyridostigmine growth hormone (GH) stimulation tests were performed, and testosterone (T), dihydrotestosterone (DHT), DHEA, DHEAS, adiponectin, and insulin-like growth factor I (IGF-I) were measured before and after intervention. RESULT(S): Insulin sensitivity, GH, adiponectin, and IGF-I significantly increased during pioglitazone treatment, whereas alloTHF/THF levels significantly decreased. Delta alloTHF/THF levels inversely correlated with Delta adiponectin levels. Delta A/E ratio inversely correlated with Delta IGF-I and Delta peak GH during GH stimulation tests. No significant changes were measured in T, DHT, DHEA, DHEAS, 24 h mean cortisol, or urinary excretion of steroid metabolites. CONCLUSION(S): Pioglitazone decreased relative 5alpha-reductase activity, whereas no significant changes were measured in cortisol levels or urinary cortisol excretion.

The effect of increasing doses of growth hormone on collagen synthesis in GH-treated GH-deficient patients was determined in a short-term study. The synthesis of type I and III collagen was estimated by measurements of the carboxyterminal propeptide of type I procollagen and the aminoterminal propeptide of type III procollagen. Type I collagen is mainly found in bone and type III collagen in loose connective tissue. We observed a GH dose dependency of both procollagen propeptides. Serum type I procollagen propeptide was significantly higher following GH doses of 4 and 6 IU/day for 14 days compared with 2 IU/day (normal replacement dose) (p=0.04). Withdrawal of GH therapy for 14 days resulted in wider variation, but not significantly different from the levels at 2, 4 and 6 IU/day. A dose dependency was found regarding type III procollagen propeptide, showing significantly higher serum concentrations at a GH dose of 4 IU/day compared with 2 IU/day (p=0.001), and of 6 IU/day compared with 4 IU/day (p=0.001). Withdrawal of GH therapy resulted in significantly lower type III procollagen propeptide concentrations compared with those at a GH dose of 4 and 6 IU/day (p=0.03). Serum type III procollagen propeptide increased twice as much as type I procollagen propeptide, by 47 vs 25%, at a GH dose of 6 IU/day compared with 2 IU/day. The differences between the effects on type I and type III collagen may reflect differences in secretion or turn-over rate of collagen in bone and loose connective tissue. Serum type I and type III procollagen propeptides may prove useful as monitors of GH therapy, especially regarding the GH dose levels in the individual patients.

Seventy-nine osteoporotic (prior forearm or vertebral fracture), but otherwise healthy, postmenopausal women (aged 55 to 75 years) were allocated to two double-blind trials: (1) 39 women received either nandrolone decanoate (anabolic steroid) 50 mg as an intramuscular depot injection or a placebo injection every 3 weeks for 1 year; and (2) 40 women received either 2 mg 17 beta-estradiol plus 1 mg norethisterone acetate or placebo tablets daily for 1 year. Sixty-seven (85%) completed the 1 year of treatment. Serum concentration of type I procollagen carboxy-terminal propeptide (PICP) was measured before and at 3, 6, 9, and 12 months of therapy. In addition, 32 of the women had an iliac bone biopsy taken after double tetracycline labeling. Initial serum PICP correlated significantly with histomorphometrically measured rate of bone formation (r = .4; P less than .05) and plasma bone Gla protein (r = .6; P less than .001), but not with histomorphometrically measured bone resorption or biochemical estimates of bone resorption (fasting urinary hydroxyproline and calcium). Estrogen-progestogen therapy significantly decreased (P less than .001) serum PICP by about 30%, whereas anabolic steroid therapy hardly affected it. We conclude that serum PICP may be used as a noninvasive measurement of bone formation on a group basis. Whereas bone formation is clearly decreased during estrogen-progestogen therapy, it is not affected by long-term therapy with anabolic steroids.

In 16 patients with acute myocardial infarction and in 15 controls, procollagen type III aminoterminal peptide in serum (PIIINP) was measured consecutively. Serum PIIINP was increased on the second to third postinfarction day (p less than 0.01) and remained elevated for more than 4 months. Peak values were observed on the third to seventh postinfarction day. The individual peak changes were correlated to infarction size calculated from serum CK-MB and serum lactate dehydrogenase (p = 0.60, p = 0.02). The changes in distribution of PIIINP-related antigens in serum after gel chromatography were similar to changes observed during wound healing in humans. PIIINP is cleaved off procollagen type III during the biosynthesis of type III collagen, which characterizes the early stages of repair and inflammation. Our findings suggest that serum PIIINP reflects the repair processes and scar formation following acute myocardial infarction. The serum PIIINP alterations in acute myocardial infarction differ essentially from the changes in myocardial enzymes reflecting myocardial injury. Serum PIIINP may therefore provide new and clinically relevant information on the healing of myocardial infarction.

Triptans are effective and well tolerated in acute migraine management but their exact mechanism of action is still debated. Triptans might exert their antimigraine effect by reducing the levels of circulating calcitonin gene-related peptide (CGRP). To examine this question, we examined whether sumatriptan modulate the baseline CGRP levels in vivo, under conditions without trigeminovascular system activation. We sampled blood from the internal and external jugular, the cubital veins, and the radial artery before and after administration of subcutaneous sumatriptan in 16 healthy volunteers. Repeated-measure ANOVA showed no interaction between catheter and time of sampling and thus no significant difference in CGRP between the four catheters (P = 0.75). CGRP did not change over time in the four compartments (P > 0.05). The relative changes in CGRP between baseline and maximal sumatriptan concentration did not differ between the four vascular compartments (P = 0.49). It was found that Sumatriptan did not change the levels of circulating CGRP in the intra or extracerebral circulation in healthy volunteers. This speaks against a direct CGRP-reducing effect of sumatriptan in vivo in humans when the trigemino vascular system is not activated.

Purpose Young men and women accrue the majority of their bone mass in their teens and twenties, where their bone mass peaks (PBM), yet little is known about the roles of physical exercise, vitamin D levels and bone mineral density (BMD) near PBM. Methods To comparatively examine the effect of physical exercise and two vitamin D levels (insufficient s-25[OH]D 80 nmol/L) on the BMD measured at the femoral neck, total hip (bilaterally) and the lumbar spine (L2–L4) in male and female participants approaching PBM. Results The insufficient s-25[OH]D group, median age 21.6 (19.8–22.8) years, and BMI 24.2 ± 5.0 kg/m2 had BMD 0.10 (0.03, 0.17) g/cm2 (p = 0.008) lower at all DXA-scan sites compared to the sufficient s-25[OH]D group, median age 19.5 (19.0–22.3) years, and BMI of 22.6 ± 1.8 kg/m2. Exercise was positively associated with the BMD at all DXA-scan sites (ptrend = 0.0001) and with equal benefit; there was no interaction between exercise and the DXA-scan site (p = 0.09). The male participants did not have a systematically higher BMD than the female participants for all scan sites; only for hips total and femoral neck bilaterally, while it was equal at the lumbar spine. Conclusion The BMD in young healthy adults is associated with physical exercise, independent of sex and s-25[OH]D status. A sufficient s-25[OH]D status was systematically associated with a higher BMD for all levels of exercise. For both sexes and vitamin D levels exercise was equally positively associated with BMD.

The effect of anabolic steroid therapy and estrogen-progestogen substitution therapy on serum concentration of procollagen type III aminoterminal peptide (PIIINP), a measure of collagen synthesis, in postmenopausal women was studied in two double-blind studies: (1) 39 women allocated to treatment with either 50 mg nandrolone decanoate as an intramuscular depot or placebo injections every third week for 1 year, and (2) 40 women allocated to receive either 2 mg 17 beta-estradiol plus 1 mg norethisterone acetate daily or placebo tablets for 1 year. Serum PIIINP was measured every 3 months during the study. Anabolic steroid therapy resulted in a more than 50% increase (P less than .001) in serum PIIINP at 3 months, which thereafter decayed but remained significantly increased throughout the study period. Serum PIIINP showed the same pattern during estrogen-progestogen therapy, but to a lesser degree. We conclude that anabolic steroids stimulate type III collagen synthesis in postmenopausal women, while estrogen-progestogen therapy may have such an effect, but only to a lesser degree.

There is considerable evidence suggesting, that older antiepileptic drugs (AEDs) and some of the newer ones decrease bone mineral density (BMD). However, there is only limited and conflicting data concerning the effect of levetiracetam on BMD. In this cross-sectional study we analysed data from 168 adult consecutive outpatients treated with AEDs for more than 2 years, and who underwent measurement of the BMD. We compared the incidence of decreased BMD among the patients treated with 6 different AEDs: carbamazepine (CBZ), oxcarbazepine (OXC), valproic acid (VPA), lamotrigine (LTG), topiramate (TPM) and levetiracetam (LEV). Among the patients on monotherapy, reduced BMD was present significantly most often in patients treated with LEV and those treated with OXC. In the group of patients on polytherapy there was no significant difference in the incidence of low BMD among patients treated with various AEDs. Our data suggest that patients on long-term treatment with LEV have a higher risk for affection of bone density.