23 research outputs found
Recent Advances and the Potential for Clinical Use of Autofluorescence Detection of Extra-Ophthalmic Tissues
The autofluorescence (AF) characteristics of endogenous fluorophores allow the label-free assessment and visualization of cells and tissues of the human body. While AF imaging (AFI) is well-established in ophthalmology, its clinical applications are steadily expanding to other disciplines. This review summarizes clinical advances of AF techniques published during the past decade. A systematic search of the MEDLINE database and Cochrane Library databases was performed to identify clinical AF studies in extra-ophthalmic tissues. In total, 1097 articles were identified, of which 113 from internal medicine, surgery, oral medicine, and dermatology were reviewed. While comparable technological standards exist in diabetology and cardiology, in all other disciplines, comparability between studies is limited due to the number of differing AF techniques and non-standardized imaging and data analysis. Clear evidence was found for skin AF as a surrogate for blood glucose homeostasis or cardiovascular risk grading. In thyroid surgery, foremost, less experienced surgeons may benefit from the AF-guided intraoperative separation of parathyroid from thyroid tissue. There is a growing interest in AF techniques in clinical disciplines, and promising advances have been made during the past decade. However, further research and development are mandatory to overcome the existing limitations and to maximize the clinical benefits
A prospective, observational, multicenter cohort study
Background Graft-derived cell-free DNA (GcfDNA), which is released into the
blood stream by necrotic and apoptotic cells, is a promising noninvasive organ
integrity biomarker. In liver transplantation (LTx), neither conventional
liver function tests (LTFs) nor immunosuppressive drug monitoring are very
effective for rejection monitoring. We therefore hypothesized that the
quantitative measurement of donor-derived cell-free DNA (cfDNA) would have
independent value for the assessment of graft integrity, including damage from
acute rejection. Methods and findings Traditional LFTs were performed and
plasma GcfDNA was monitored in 115 adults post-LTx at three German transplant
centers as part of a prospective, observational, multicenter cohort trial.
GcfDNA percentage (graft cfDNA/total cfDNA) was measured using droplet digital
PCR (ddPCR), based on a limited number of predefined single nucleotide
polymorphisms, enabling same-day turn-around. The same method was used to
quantify blood microchimerism. GcfDNA was increased >50% on day 1 post-LTx,
presumably from ischemia/reperfusion damage, but rapidly declined in patients
without graft injury within 7 to 10 d to a median <10%, where it remained for
the 1-y observation period. Of 115 patients, 107 provided samples that met
preestablished criteria. In 31 samples taken from 17 patients during biopsy-
proven acute rejection episodes, the percentage of GcfDNA was elevated
substantially (median 29.6%, 95% CI 23.6%â41.0%) compared with that in 282
samples from 88 patients during stable periods (median 3.3%, 95% CI 2.9%â3.7%;
p < 0.001). Only slightly higher values (median 5.9%, 95% CI 4.4%â10.3%) were
found in 68 samples from 17 hepatitis C virus (HCV)âpositive, rejection-free
patients. LFTs had low overall correlations (r = 0.28â0.62) with GcfDNA and
showed greater overlap between patient subgroups, especially between acute
rejection and HCV+ patients. Multivariable logistic regression modeling
demonstrated that GcfDNA provided additional LFT-independent information on
graft integrity. Diagnostic sensitivity and specificity were 90.3% (95% CI
74.2%â98.0%) and 92.9% (95% CI 89.3%â95.6%), respectively, for GcfDNA at a
threshold value of 10%. The area under the receiver operator characteristic
curve was higher for GcfDNA (97.1%, 95% CI 93.4%â100%) than for same-day
conventional LFTs (AST: 95.7%; ALT: 95.2%; Îł-GT: 94.5%; bilirubin: 82.6%). An
evaluation of microchimerism revealed that the maximum donor DNA in
circulating white blood cells was only 0.068%. GcfDNA percentage can be
influenced by major changes in host cfDNA (e.g., due to leukopenia or
leukocytosis). One limitation of our study is that exact time-matched GcfDNA
and LFT samples were not available for all patient visits. Conclusions In this
study, determination of GcfDNA in plasma by ddPCR allowed for earlier and more
sensitive discrimination of acute rejection in LTx patients as compared with
conventional LFTs. Potential blood microchimerism was quantitatively low and
had no significant influence on GcfDNA value. Further research, which should
ideally include protocol biopsies, will be needed to establish the practical
value of GcfDNA measurements in the management of LTx patients
Expression Analysis of Fibronectin Type III Domain-Containing (FNDC) Genes in Inflammatory Bowel Disease and Colorectal Cancer
Background. Fibronectin type III domain-containing (FNDC) proteins fulfill manifold functions in tissue development and regulation of cellular metabolism. FNDC4 was described as anti-inflammatory factor, upregulated in inflammatory bowel disease (IBD). FNDC signaling includes direct cell-cell interaction as well as release of bioactive peptides, like shown for FNDC4 or FNDC5. The G-protein-coupled receptor 116 (GPR116) was found as a putative FNDC4 receptor. We here aim to comprehensively analyze the mRNA expression of FNDC1, FNDC3A, FNDC3B, FNDC4, FNDC5, and GPR116 in nonaffected and affected mucosal samples of patients with IBD or colorectal cancer (CRC). Methods. Mucosa samples were obtained from 30 patients undergoing diagnostic colonoscopy or from surgical resection of IBD or CRC. Gene expression was determined by quantitative real-time PCR. In addition, FNDC expression data from publicly available Gene Expression Omnibus (GEO) data sets (GDS4296, GDS4515, and GDS5232) were analyzed. Results. Basal mucosal expression revealed higher expression of FNDC3A and FNDC5 in the ileum compared to colonic segments. FNDC1 and FNDC4 were significantly upregulated in IBD. None of the investigated FNDCs was differentially expressed in CRC, just FNDC3A trended to be upregulated. The GEO data set analysis revealed significantly downregulated FNDC4 and upregulated GPR116 in microsatellite unstable (MSI) CRCs. The expression of FNDCs and GPR116 was independent of age and sex. Conclusions. FNDC1 and FNDC4 may play a relevant role in the pathobiology of IBD, but none of the investigated FNDCs is regulated in CRC. GPR116 may be upregulated in advanced or MSI CRC. Further studies should validate the altered FNDC expression results on protein levels and examine the corresponding functional consequences
Metabolic heterogeneity of human hepatocellular carcinoma: implications for personalized pharmacological treatment
Metabolic reprogramming is a characteristic feature of cancer cells, but there is no unique metabolic program for all tumors. Genetic and gene expression studies have revealed heterogeneous inter- and intratumor patterns of metabolic enzymes and membrane transporters. The functional implications of this heterogeneity remain often elusive. Here, we applied a systems biology approach to gain a comprehensive and quantitative picture of metabolic changes in individual hepatocellular carcinoma (HCC). We used protein intensity profiles determined by mass spectrometry in samples of 10 human HCCs and the adjacent noncancerous tissue to calibrate Hepatokin1, a complex mathematical model of liver metabolism. We computed the 24-h profile of 18 metabolic functions related to carbohydrate, lipid, and nitrogen metabolism. There was a general tendency among the tumors toward downregulated glucose uptake and glucose release albeit with large intertumor variability. This finding calls into question that the Warburg effect dictates the metabolic phenotype of HCC. All tumors comprised elevated ÎČ-oxidation rates. Urea synthesis was found to be consistently downregulated but without compromising the tumor's capacity for ammonia detoxification owing to increased glutamine synthesis. The largest intertumor heterogeneity was found for the uptake and release of lactate and the size of the cellular glycogen content. In line with the observed metabolic heterogeneity, the individual HCCs differed largely in their vulnerability against pharmacological treatment with metformin. Taken together, our approach provided a comprehensive and quantitative characterization of HCC metabolism that may pave the way for a computational a priori assessment of pharmacological therapies targeting metabolic processes of HCC
Pharmacokinetics of tigecycline in critically ill patients with liver failure defined by maximal liver function capacity test (LiMAx)
Background:
In critically ill patients, tigecycline (TGC) remains an important therapeutic option due to its efficacy against multiresistant Gram-positive and Gram-negative bacteria. TGC is metabolized and eliminated predominantly by the liver. Critical illness-induced liver failure may have a profound impact on the pharmacokinetic of TGC. In the present study, we aimed to establish a link between the degree of liver dysfunction and TGC plasma concentration using the novel maximum liver function capacity (LiMAx) test, as a dynamic liver function test.
Materials/methods:
The prospective study included 33 patients from a surgical ICU with the clinical indication for antibiotic therapy with TGC. The patients received 100 mg loading dose of TGC followed by intermittent standard doses of 50 mg q12. Blood samples for TGC plasma concentration were collected at 0.3, 2, 5, 8 and 11.5 h in a steady-state condition after at least 36 h post-standard dosage. The results were analyzed by means of a high-performance liquid chromatography (HPLC) method. Within the same day, the LiMAx test was carried out and routine blood parameters were measured.
Results:
Peak plasma concentrations of TGC were significantly higher in patients with severe liver failure (LiMAxââ300 ”g/kg/h). The pharmacokinetic curves revealed higher values in severe liver failure at any measured point. Moreover, LiMAx and total bilirubin were the only liver-related parameters that correlated with TGC Cmax.
Conclusions:
The present study demonstrates a high variability of TGC plasma concentrations in critically ill patients. The results show a significant correlation between the degree of liver dysfunction, measured by the LiMAx test, and TGC Cmax. LiMAx test may be a helpful tool beyond others for adjusting the required dosage of hepatic metabolized antibiotics in critically ill patients.
Trial registry DRKSâGerman clinical trials register; Trial registration number: DRKS00008888; Date of registration: 07-17-2015; Date of enrolment of the first participant to the trial: 12-10-201
Hepatic CYP1A2 activity in liver tumors and the implications for preoperative volume-function analysis
Correlation between plasma endothelin-1 levels and severity of septic liver failure quantified by maximal liver function capacity (LiMAx test). A prospective study
<div><p>Aim</p><p>To investigate the relationship between the degree of liver dysfunction, quantified by maximal liver function capacity (LiMAx test) and endothelin-1, TNF-α and IL-6 in septic surgical patients.</p><p>Methods</p><p>28 septic patients (8 female, 20 male, age range 35â80y) were prospectively investigated on a surgical intensive care unit. Liver function, defined by LiMAx test, and measurements of plasma levels of endothelin-1, TNF-α and IL-6 were carried out within the first 24 hours after onset of septic symptoms, followed by day 2, 5 and 10. Patients were divided into 2 groups (group A: LiMAx â„100 ÎŒg/kg/h, moderate liver dysfunction; group B: LiMAx <100 ÎŒg/kg/h, severe liver dysfunction) for analysis and investigated regarding the correlation between endothelin-1 and the severity of liver failure, quantified by LiMAx test.</p><p>Results</p><p>Group B showed significant higher results for endothelin-1 than patients in group A (P = 0.01, d5; 0.02, d10). For TNF-α, group B revealed higher results than group A, with a significant difference on day 10 (P = 0.005). IL-6 showed a non-significant trend to higher results in group B. The Spearman's rank correlation coefficient revealed a significant correlation between LiMAx and endothelin-1 (-0.434; P <0.001), TNF-α (-0.515; P <0.001) and IL-6 (-0.590; P <0.001).</p><p>Conclusions</p><p>Sepsis-related hepatic dysfunction is associated with elevated plasma levels of endothelin-1, TNF-α and IL-6. Low LiMAx results combined with increased endothelin-1 and TNF-α and a favourable correlation between LiMAx and cytokine values support the findings of a crucial role of Endothelin-1 and TNF-α in development of septic liver failure.</p></div
Relationship between liver function and cytokines in septic patients using Spearmanâs rank correlation coefficient.
<p><b>(A)</b> LiMAx vs. CT-proET-1, <b>(B)</b> LiMAx vs. TNF-a, <b>(C)</b> LiMAx vs. IL-6.</p
Clinical characteristics and severity of illness in the study groups.
<p>Clinical characteristics and severity of illness in the study groups.</p