Neurofilaments as a plasma biomarker for ICU-acquired weakness: an observational pilot study

Introduction

Early diagnosis of intensive care unit – acquired weakness (ICU-AW) using the current reference standard, that is, assessment of muscle strength, is often hampered due to impaired consciousness. Biological markers could solve this problem but have been scarcely investigated. We hypothesized that plasma levels of neurofilaments are elevated in ICU-AW and can diagnose ICU-AW before muscle strength assessment is possible.

Methods

For this prospective observational cohort study, neurofilament levels were measured using ELISA (NfH^SMI35 antibody) in daily plasma samples (index test). When patients were awake and attentive, ICU-AW was diagnosed using the Medical Research Council scale (reference standard). Differences and discriminative power (using the area under the receiver operating characteristic curve; AUC) of highest and cumulative (calculated using the area under the neurofilament curve) neurofilament levels were investigated in relation to the moment of muscle strength assessment for each patient.

Results

Both the index test and reference standard were available for 77 ICU patients. A total of 18 patients (23%) fulfilled the clinical criteria for ICU-AW. Peak neurofilament levels were higher in patients with ICU-AW and had good discriminative power (AUC: 0.85; 95% CI: 0.72 to 0.97). However, neurofilament levels did not peak before muscle strength assessment was possible. Highest or cumulative neurofilament levels measured before muscle strength assessment could not diagnose ICU-AW (AUC 0.59; 95% CI 0.37 to 0.80 and AUC 0.57; 95% CI 0.32 to 0.81, respectively).

Conclusions

Plasma neurofilament levels are raised in ICU-AW and may serve as a biological marker for ICU-AW. However, our study suggests that an early diagnosis of ICU-AW, before muscle strength assessment, is not possible using neurofilament levels in plasma.

Electronic supplementary material

The online version of this article (doi:10.1186/cc13699) contains supplementary material, which is available to authorized users.     

Targeted Antigen Delivery to DEC-205+ Dendritic Cells for Tolerogenic Vaccination

Dendritic cells (DCs) and Foxp3-expressing CD4⁺ regulatory T (Treg) cells play non-redundant roles in the maintenance of peripheral tolerance to self-antigens, thereby preventing fatal autoimmunity. A common hallmark of intra- and extra-thymic Treg cell lineage commitment is the induction of Foxp3 expression as a consequence of appropriate T cell receptor engagement with MHC class II:agonist ligand. It has now become increasingly clear that agonist ligand presentation by immature DCs in the steady state induces T cell tolerance by both recessive and dominant mechanisms, rather than promoting productive T helper cell responses. In this context, the ability of steady-state DCs to promote the extrathymic conversion of initially naïve CD4⁺Foxp3^- T cells into Foxp3⁺ Treg cells is of particular interest as it provides novel perspectives to enhance antigen-specific Treg cell function in clinical settings of unwanted immunity, such as β-cell autoimmunity.     

Synthesis of DNA and Poly(Adenosine Diphosphate Ribose) in Normal and Chronic Lymphocytic Leukemia Lymphocytes

Peripheral blood lymphocytes were isolated from 9 patients with chronic lymphocytic leukemia (CLL) and 12 normal control donors. The cells were assayed for synthesis of DNA and poly-(adenosine diphosphate ribose) (poly[ADPR]) immediately after isolation and on successive days following their treatment with phytohemagglutinin (PHA). Two different techniques were used to measure DNA synthesis. In the standard technique, DNA synthesis was measured by incubating intact cells with [³H]deoxythymidine. In the new technique, the lymphocytes were first rendered permeable to nucleotides, then DNA synthesis was measured by incubating them with [³H]deoxythymidine triphosphate in the presence of deoxyATP, deoxyGTP, deoxyCTP, ATP, and Mg⁺⁺. Both assays showed the anticipated rise in DNA synthesis after PHA stimulation of normal cells. PHA-stimulated lymphocytes from patients with CLL demonstrated low levels of DNA synthesis in both assay systems.     

Acute cerebral infarction and extra pontine myelinolysis in children with new onset type 1 diabetes mellitus

Neurological complications of diabetic ketoacidosis (DKA) are still associated with significant mortality and morbidity. We report on two children who suffered from acute cerebral infarction (CI) and extra pontine myelinolysis (EPM) at onset of type 1 diabetes. Initially, clinical management had not been performed according to generally accepted guidelines. Putative risk factors that may have predisposed for the development of acute cerebrovascular complications are discussed. Not only cerebral edema (CE) but also other severe neurological complications such as CI should be suspected when neurological deterioration occurs during DKA. We conclude that not only an exceeded rehydration therapy but also a rapidly reduced serum osmolality due to an unbalanced rapid blood sugar decrease and serum sodium increase may have lead to the neurological disease. We propose that a reserved and well-defined rehydration strategy in the first 6 (-12) h of therapy is crucial for recovery and can reduce neurological complications of patients with DKA.     

Deletion of psychiatric risk gene Cacna1c impairs hippocampal neurogenesis in cell‐autonomous fashion

Ca²⁺ is a universal signal transducer which fulfills essential functions in cell development and differentiation. CACNA1C, the gene encoding the alpha‐1C subunit (i.e., Ca_v1.2) of the voltage‐dependent l ‐type calcium channel (LTCC), has been implicated as a risk gene in a variety of neuropsychiatric disorders. To parse the role of Ca_v1.2 channels located on astrocyte‐like stem cells and their descendants in the development of new granule neurons, we created Tg^{GLAST‐CreERT2}/Cacna1c^fl/fl/RCE:loxP mice, a transgenic tool that allows cell‐type‐specific inducible deletion of Cacna1c. The EGFP reporter was used to trace the progeny of recombined type‐1 cells. FACS‐sorted Cacna1c‐deficient neural precursor cells from the dentate gyrus showed reduced proliferative activity in neurosphere cultures. Moreover, under differentiation conditions, Cacna1c‐deficient NPCs gave rise to fewer neurons and more astroglia. Similarly, under basal conditions in vivo, Cacna1c gene deletion in type‐1 cells decreased type‐1 cell proliferation and reduced the neuronal fate‐choice decision of newly born cells, resulting in reduced net hippocampal neurogenesis. Unexpectedly, electroconvulsive seizures completely compensated for the proliferation deficit of Cacna1c deficient type‐1 cells, indicating that there must be Ca_v1.2‐independent mechanisms of controlling proliferation related to excitation. In the aggregate, this is the first report demonstrating the presence of functional L‐type 1.2 channels on type‐1 cells. Ca_v1.2 channels promote type‐1 cell proliferation and push the glia‐to‐neuron ratio in the direction of a neuronal fate choice and subsequent neuronal differentiation. Ca_v1.2 channels expressed on NPCs and their progeny possess the ability to shape neurogenesis in a cell‐autonomous fashion.     

Cat Scratch Disease Due to Bartonella henselae Infection Mimicking Parotid Malignancy

An unusual Bartonella henselae infection presenting clinically as a putative parotid cancer was diagnosed based on serological tests, histomorphology and amplification of a 16S-rDNA sequence of Bartonella henselae. The patient improved greatly upon antibiotic treatment and did not require surgery. Although uncommon, infection with Bartonella spp., particularly Bartonella henselae, should be included in the differential diagnosis of parotid tumors. Electronic Publication     

Diffusion imaging-based subdivision of the human hypothalamus: a magnetic resonance study with clinical implications

The hypothalamus and its subdivisions are involved in many neuropsychiatric conditions such as affective disorders, schizophrenia, or narcolepsy, but parcellations of hypothalamic subnuclei have hitherto been feasible only with histological techniques in postmortem brains. In an attempt to map subdivisions of the hypothalamus in vivo, we analyzed the directionality information from high-resolution diffusion-weighted magnetic resonance images of healthy volunteers. We acquired T1-weighted and diffusion-weighted scans in ten healthy subjects at 3 T. In the T1-weighted images, we manually delineated an individual mask of the hypothalamus in each subject and computed in the co-registered diffusion-weighted images the similarity of the principal diffusion direction for each pair of mask voxels. By clustering the similarity matrix into three regions with a k-means algorithm, we obtained an anatomically coherent arrangement of subdivisions across hemispheres and subjects. In each hypothalamus mask, we found an anterior region with dorsoventral principal diffusion direction, a posteromedial region with rostro-caudal direction, and a lateral region with mediolateral direction. A comparative analysis with microstructural hypothalamus parcellations from the literature reveals that each of these regions corresponds to a specific group of hypothalamic subnuclei as defined in postmortem brains. This is to our best knowledge the first in vivo study that attempts a delineation of hypothalamic subdivisions by clustering diffusion-weighted magnetic resonance imaging data. When applied in a larger sample of neuropsychiatric patients, a structural analysis of hypothalamic subnuclei should contribute to a better understanding of the pathogenesis of neuropsychiatric conditions such as affective disorders.     

Impact of body composition, fat distribution and sustained weight loss on cardiac function in obesity

Background

Older age is an independent predictor of all-cause mortality in patients with mild to moderate heart failure (HF). Whether older age is also an independent predictor of mortality in patients with more advanced HF is unknown.

Methods

Of the 2707 Beta-Blocker Evaluation of Survival Trial (BEST) participants with ambulatory chronic HF (New York Heart Association class III/IV and left ventricular ejection fraction < 35%), 1091 were elderly (≥ 65 years). Propensity scores for older age, estimated for each of the 2707 patients, were used to assemble a cohort of 603 pairs of younger and older patients, balanced on 66 baseline characteristics.

Results

All-cause mortality occurred in 33% and 36% of younger and older matched patients respectively during 4 years of follow-up (hazard ratio {HR} associated with age ≥65 years, 1.05; 95% confidence interval {CI}, 0.87-1.27; P = 0.614). HF hospitalization occurred in 38% and 40% of younger and older matched patients respectively (HR, 1.01; 95% CI, 0.84-1.21; P = 0.951). Among 603 pairs of unmatched and unbalanced patients, all-cause mortality occurred in 28% and 36% of younger and older patients respectively (HR, 1.34; 95% CI, 1.10-1.64; P = 0.004) and HF hospitalization occurred in 34% and 40% of younger and older unmatched patients respectively (HR, 1.24; 95% CI, 1.03-1.50; P = 0.024).

Conclusion

Significant bivariate associations suggest that older age is a useful marker of poor outcomes in patients with advanced chronic systolic HF. However, lack of significant independent associations suggests that older age per se has no intrinsic effect on outcomes in these patients.