Vitamin D supplementation of 4000 IU daily and cardiac function in patients with advanced heart failure: The EVITA trial.

BACKGROUND: Data regarding the effects of vitamin D on cardiac function are inconclusive. METHODS: In a post-hoc analysis of the EVITA (Effect of vitamin D on mortality in heart failure) trial, we investigated whether a daily vitamin D3 supplement of 4000 IU for three years affects echocardiography parameters like left ventricular end-diastolic diameter (LVEDD), LV end-systolic diameter (LVESD), and LV ejection fraction (LVEF) in patients with advanced heart failure (HF) and 25­hydroxyvitamin D levels <75 nmol/L. Of 400 patients enrolled, 199 were assigned to vitamin D and 201 to placebo. We assessed time × treatment interaction effects using linear mixed models and analyzed in subgroups vitamin D effects at 12 and 36 months post-randomization using analysis of covariance with adjustments for baseline values. RESULTS: At baseline, values of LVEDD, LVESD, and LVEF were 67.5 ±â€¯10.5 mm, 58.9 ±â€¯12.0 mm, and 30.47 ±â€¯10.2%, respectively. There were no time × treatment interaction effects on LV echocardiographic parameters in the entire study cohort, neither at 12 months nor at 36 months post-randomization (P-values > 0.05). However, in the subgroup of patients aged ≥50 years, vitamin D treatment was associated with an increase in LVEF of 2.73% (95%CI: 0.14 to 5.31%) at 12 months post-randomization (n = 311). The increase was slightly attenuated to 2.60% (95%CI: -2.47 to 7.67%) at 36 months post-randomization (n = 242). CONCLUSION: Our data indicate that vitamin D supplementation does not significantly improve cardiac function in all patients with advanced HF. However, vitamin D probably improves LV function in HF patients aged ≥50 years.

Vitamin D supplementation and bone turnover in advanced heart failure: the EVITA trial.

Low vitamin D status is common in patients with heart failure and may influence bone health. A daily vitamin D dose of 4000 IU (moderately high dose) for 3 years had however no effect on parameters of bone metabolism, even in patients with very low vitamin D status. INTRODUCTION: Low vitamin D status is common in patients with heart failure (HF) and has been related to disturbed bone turnover. The present study investigated the effect of a daily vitamin D3 dose of 4000 IU on bone turnover markers (BTMs) in patients with advanced HF and 25-hydroxyvitamin D (25OHD) concentrations < 75 nmol/L. METHODS: In this pre-specified secondary analysis of a randomized controlled trial, we assessed in 158 male HF patients (vitamin D group: n = 80; placebo group: n = 78) between-group differences in calciotropic hormones (25OHD, 1,25-dihydroxyvitamin D [1,25(OH)2D], intact parathyroid hormone [iPTH]), and BTMs (cross-linked C-telopeptide of type I collagen, bone-specific alkaline phosphatase, undercarboxylated osteocalcin). Comparisons were performed at the end of a 3-year vitamin D supplementation period with adjustments for baseline values. RESULTS: Compared with placebo, vitamin D increased 25OHD on average by 54.3 nmol/L. At study termination, 25OHD and 1,25(OH)2D were significantly higher (P < 0.001 and P = 0.007, respectively), whereas iPTH tended to be lower in the vitamin D group than in the placebo group (P = 0.083). BTMs were initially within their reference ranges and did not differ significantly between groups at study termination, neither in the entire study cohort nor when data analysis was restricted to the subgroup of patients with initial 25OHD concentrations < 30 nmol/L (n = 54) or to patients with initial hyperparathyroidism (n = 65) (all P values > 0.05). CONCLUSIONS: A daily vitamin D3 dose of 4000 IU did not influence BTMs. Data indicate that vitamin D supplementation will not lower bone turnover in male patients with heart failure.

Randomized supplementation of 4000 IU vitamin D3 daily vs placebo on the prevalence of anemia in advanced heart failure: the EVITA trial.

BACKGROUND: Low 25-hydroxyvitamin D (25OHD) levels (< 75 nmol/l) are inversely associated with anemia prevalence. Since anemia and low 25OHD levels are common in patients with heart failure (HF), we aimed to investigate whether vitamin D supplementation can reduce anemia prevalence in advanced HF. METHODS: EVITA (Effect of Vitamin D on Mortality in Heart Failure) is a randomized, placebo-controlled clinical trial in patients with initial 25OHD levels < 75 nmol/l. Participants received either 4000 IU vitamin D3 daily or a matching placebo for 36 months. A total of 172 patients (vitamin D group: n = 85; placebo group: n = 87) were investigated in this pre-specified secondary data analysis. Hemoglobin (Hb) and other hematological parameters were measured at baseline and study termination. Assessment of between-group differences in anemia prevalence and Hb concentrations was performed at study termination, while adjusting for baseline differences. RESULTS: In the vitamin D and placebo group, baseline proportions of patients with anemia (Hb < 12.0 g/dL in females and < 13.0 g/dL in males) were 17.2% and 10.6%, respectively (P = 0.19). At study termination, the proportion of patients with anemia in the vitamin D and placebo groups was 32.2% and 31.8%, respectively (P > 0.99). There was no between-group difference in change in the Hb concentrations (- 0.04 g/dL [95%CI:-0.53 to 0.45 g/dL]; P = 0.87). Results regarding anemia risk and Hb concentrations were similar in the subgroup of patients with chronic kidney disease (vitamin D group: n = 26; placebo group: n = 23). Moreover, results did not differ substantially when data analysis was restricted to patients with deficient baseline 25OHD levels. CONCLUSIONS: A daily vitamin D supplement of 4000 IU did not reduce anemia prevalence in patients with advanced HF. Data challenge the clinical relevance of vitamin D supplementation to increase Hb levels. TRIAL REGISTRATION: The study was registered at EudraCT (No. 2010-020793-42) and clinicaltrials.gov ( NCT01326650 ).

The most fulminant course of the Marburg variant of multiple sclerosis-autopsy findings.

Multiple sclerosis (MS) is usually a chronic and disabling inflammatory disease. Marburg's type of MS is characterized by rapid progression and severe disease course that leads to death within one year after the onset of clinical signs. We describe a fulminant clinical presentation of this malignant subtype of MS and discuss the neuropathological hallmarks as well as differential diagnoses of other fulminant demyelinating diseases. To the best of our knowledge, this is the most fulminant course of this MS variant reported in the literature.

Preclinical development of AMG 139, a human antibody specifically targeting IL-23.

BACKGROUND AND PURPOSE: AMG 139 is a human anti-IL-23 antibody currently in a phase II trial for treating Crohn's disease. To support its clinical development in humans, in vitro assays and in vivo studies were conducted in cynomolgus monkeys to determine the pharmacology, preclinical characteristics and safety of this monoclonal antibody. EXPERIMENTAL APPROACH: The in vitro pharmacology, pharmacokinetics (PK), pharmacodynamics and toxicology of AMG 139, after single or weekly i.v. or s.c. administration for up to 26 weeks, were evaluated in cynomolgus monkeys. KEY RESULTS: AMG 139 bound with high affinity to both human and cynomolgus monkey IL-23 and specifically neutralized the biological activity of IL-23 without binding or blocking IL-12. After a single dose, linear PK with s.c. bioavailability of 81% and mean half-life of 8.4-13 days were observed. After weekly s.c. dosing for 3 or 6 months, AMG 139 exposure increased approximately dose-proportionally from 30 to 300 mg·kg(-1) and mean accumulation between the first and last dose ranged from 2- to 3.5-fold. Peripheral blood immunophenotyping, T-cell-dependent antigen responses and bone formation markers were not different between AMG 139 and vehicle treatment. No adverse clinical signs, effects on body weight, vital signs, ophthalmic parameters, clinical pathology, ECG, organ weights or histopathology were observed in the monkeys with the highest dose of AMG 139 tested (300 mg·kg(-1) s.c. or i.v.). CONCLUSIONS AND IMPLICATIONS: The in vitro pharmacology, PK, immunogenicity and safety characteristics of AMG 139 in cynomolgus monkeys support its continued clinical development for the treatment of various inflammatory diseases.

Cellular origin and diagnostic significance of high-fluorescent cells in cerebrospinal fluid detected by the XE-5000 hematology analyzer.

INTRODUCTION: The Sysmex XE-5000 is a blood and body fluid analyzer able to differentiate cells into polymorphonuclear, mononuclear, and high-fluorescent cells (HFC). The identity of HFC in cerebrospinal fluid (CSF) has been uncertain; however, compatible with their high nucleic acid content, HFC could represent intrathecal tumor cells. Here, we studied the cellular origin and the diagnostic significance of HFC in CSF. METHODS: Results of CSF examinations with the XE-5000 were analyzed in 65 CSF samples with and 126 CSF samples without tumor cells, as defined by manual microscopy of CSF cytospin preparations. RESULTS: The XE-5000 detected HFC in 51 of 65 tumor cell-positive and in 33 of 126 tumor cell-negative CSF samples (sensitivity: 78.5%, specificity: 73.8%, positive likelihood ratio: 3.0, negative likelihood ratio: 0.29). The percentages of HFC and tumor cells in CSF samples correlated (r² = 0.41, P < 0.0001). Tumor cells escaped detection by the XE-5000 especially in CSF samples with a low percentage of tumor cells. CONCLUSION: While this study identifies tumor cells as the predominant correlate of HFC in CSF, it suggests that measuring HFC is not an appropriate diagnostic test for intrathecal tumor cells. However, if HFC are incidentally detected in CSF, further evaluation by CSF microscopy seems mandatory.

Comparison of immunosorbent assays for the quantification of biomarkers for Alzheimer's disease in human cerebrospinal fluid.

BACKGROUND: The clinical diagnosis of Alzheimer's disease in early stages may be substantiated by the quantification of the biomarkers Abeta42, Abeta40 and total-Tau (t-Tau) in cerebrospinal fluid (CSF). Different commercially available immunosorbent assays yield reliable results, yet the absolute values obtained may differ in between tests. METHODS: We used CSF samples from patients that reported to our memory clinic. Enzyme-linked immunosorbent assays obtained from Innogenetics were used for the quantification of Abeta42 and t-Tau, test kits from IBL International were used to determine Abeta42 and Abeta40 concentrations. The multiplex assay system obtained from Mesoscale Discovery (MSD) Systems was used for the quantification of all three biomarkers. RESULTS: For all biomarkers, the absolute values obtained with different test systems differ. However, the data sets highly correlate for all comparisons, with the MSD test system proving to be slightly more sensitive. Correlation coefficients (c) for the Abeta42 and Abeta40 quantifications lie between c = 0.80 and c = 0.87, and for the t-Tau quantifications we determined c = 0.99. CONCLUSION: We conclude that all assays evaluated give reliable results, yet absolute values obtained have to be assessed differently within the framework of diagnostic procedures, depending on the system used.

[Amyloidoses in neuropathology]. / Amyloidosen in der Neuropathologie.

Amyloidoses play an important role in neuropathology, both in autopsies and biopsy specimens. Cerebral amyloidoses are typically characterized by the deposition of beta-amyloid and mostly affect patients >60 years. The cardinal symptom of cerebral amyloid angiopathy (CAA) is spontaneous intracerebral hemorrhage, whereas the clinical presentation of Alzheimer's disease is dementia. Rare familial forms of amyloidoses may affect young patients and need thorough neuropathological assessment, similar to the relatively infrequent prion diseases. Amyloidoses within neuromuscular tissues mainly occur in the setting of systemic amyloid diseases. Detailed evaluation including thorough characterisation of amyloid is essential for ensuring the neuropathological diagnosis.

Cerebral oxygenation and systemic trauma related factors determining neurological outcome after brain injury.

We examined the relationship between clinical and radiological findings, cerebral oxygenation patterns during intensive care management, presence of systemic trauma related injuries and severity of illness in 50 patients (age: 32.3 +/- 12 years, GCS: 8 +/- 4) who were rescued from the accident scene within a 30 min period after trauma. Presence of systemic injuries was quantified using the Injury Severity Score (ISS) and severity of illness was scored using the Acute Physiology and Chronic Health Evaluation (APACHE II). Cerebral oxygenation parameters included continuous monitoring of jugular bulb oxygen saturation (SjvO(2)) for 12 840 h, and 2323 periodical blood sampling for measurement of arteriovenous differences in oxygen content (AVDO(2)), arteriovenous difference of lactate (AVDL) and lactate oxygen index (LOI). Fifteen patients (30%) presented with anisocoria or non-reacting pupils. Diffuse lesions on computed tomography (CT) were found in 34% of the patients and in 66% a mass lesion was removed. The mean ISS was 28 +/- 15.3 and 34 patients (68%) had an APACHE II score between 20 and 29 (mean 24 +/- 15). No statistically significant association between age (P = 0.45), gender (P = 0.83), initial Glasgow Coma Score (GCS) (P = 0.43), episodes of cerebral perfusion pressure (CPP) < 70 mm Hg (P = 0.8), ISS (P = 0.28), pupillary abnormalities (P = 0.57), initial CT findings (P = 0.74), APACHE II scores (P = 0. 36) and outcome could be demonstrated. The number of SjvO(2)desaturations (< 60%) was the only statistically significant factor associated with outcome (P = 0.05). The percentage of patients with poor neurological outcomes (GOS 1-3) was 38% in patients with no or one desaturation episode, and 57.6% in those with multiple desaturations. In conclusion, in patients who are resuscitated early and quickly transferred to the hospital, the number of SjvO(2)desaturations during intensive care management might be associated with outcome more strongly than other clinical and radiological features.

Correlation between jugular bulb oxygen saturation and partial pressure of brain tissue oxygen during CO2 and O2 reactivity tests in severely head-injured patients.

PURPOSE: To correlate the jugular bulb oxygen saturation (SjvO2) and brain tissue oxygen pressure (PbtO2) during carbon dioxide (CO2) and oxygen (O2) reactivity tests in severely head-injured patients. METHODS AND RESULTS: In nine patients (7 men, 2 women, age: 26 +/- 6.5 years, GCS of 6.5 +/- 2.9), a polarographic microcatheter (Clark-type) was inserted into nonlesioned white matter (frontal lobe). PbtO2 and SjvO2 were monitored simultaneously and cerebral vasoreactivity to CO2 and O2 was tested on days three, five and seven after injury. Simultaneous measurements of vasoreactivity by transcranial Doppler (TCD) were undertaken. A total of twenty-one CO2 and O2 reactivity tests were performed. Critical values of PbtO2 (< 15 mm Hg) during induced hyperventilation could be observed four times in two patients. High PbtO2 values up to 80 mm Hg were observed during hyperoxygenation (FiO2 100%). CO2 vasoreactivity by means of PbtO2 was absent in four tests in which measurements by TCD showed intact responses. A stronger correlation between SjvO2 and PbtO2 during the O2 reactivity tests was observed (r = 0.6, p < 0.001), in comparison to values obtained during the CO2 reactivity tests (r = 0.33, p < 0.001). In addition, there was no statistically significant correlation (r = 0.22, p = 0.26) between CO2 reactivity values measured by TCD (4.5 +/- 5.7%) and PbtO2 (3 +/- 2.8%). CONCLUSIONS: Correlation between SjvO2 and PbtO2 during CO2 reactivity test is low, even if significant differences between normo- and hyperventilation values are present. In comparison to SjvO2, monitoring of PbtO2 might more accurately detect possible focal ischaemic events during rapidly induced hyperventilation in severely head-injured patients. The CO2 vasoreactivity by means of changes in Vm MCA seems to be higher in comparison to changes of PbtO2. These observations lead to the hypothesis that vasoreactivity measured by TCD overestimates the cerebrovascular response to CO2.