Comparison of Long-Term Survival of Patients with Solitary Large Hepatocellular Carcinoma of BCLC Stage A after Liver Resection or Transarterial Chemoembolization: A Propensity Score Analysis

Background

The aim of this study was to compare the long-term outcome of patients with a solitary large (>5 cm) hepatocellular carcinoma (HCC) in Barcelona Clinic Liver Cancer (BCLC) stage A who received liver resection (LR) or transarterial chemoembolization (TACE).

Methods

Our study examined 128 patients treated by LR and 90 treated by TACE. To reduce bias in patient selection, we conducted propensity score analysis in the present study and 54 pairs of patients after propensity score matching were generated, their long-term survival was compared using the Kaplan–Meier method. Independent predictors of survival were identified by multivariate analysis.

Results

Long-term survival was significantly better for the LR group by log-rank test (P<0.001). In multivariate analysis, tumor size, serum ALT level and TACE independently predicted survival. Despite similar baseline characteristics after propensity score matching, LR group still had significantly better survival (1 year, 68.5 vs. 55.0%; 3 years, 47.6 vs. 21.2%; 5 years, 41.3 vs. 18.5%; P = 0.007) than TACE group. The LR and TACE groups had comparable 30- and 90-day post-treatment mortality. Multivariate analysis showed that serum ALT level, serum AFP level and TACE independently predicted survival by multivariate analysis after propensity score matching.

Conclusion

Our propensity-score-matched study suggested that LR provided significantly better long-term survival than TACE for a solitary large HCC of the BCLC stage A, regardless of tumor size.     

DIC Score in Pregnant Women – A Population Based Modification of the International Society on Thrombosis and Hemostasis Score

Objectives

The objectives of this study were: 1) To determine the component needed to generate a validated DIC score during pregnancy. 2) To validate such scoring system in the identification of patients with clinical diagnosis of DIC.

Material and Methods

This is a population based retrospective study, including all women who gave birth at the ‘Soroka University Medical Center’ during the study period, and have had blood coagulation tests including complete blood cell count, prothrombin time (PT)(seconds), partial thromboplastin time (aPTT), fibrinogen, and D-dimers. Nomograms for pregnancy were established, and DIC score was constructed based on ROC curve analyses.

Results

1) maternal plasma fibrinogen concentrations increased during pregnancy; 2) maternal platelet count decreased gradually during gestation; 3) the PT and PTT values did not change with advancing gestation; 4) PT difference had an area under the curve (AUC) of 0.96 (p<0.001), and a PT difference ≥1.55 had an 87% sensitivity and 90% specificity for the diagnosis of DIC; 5) the platelet count had an AUC of 0.87 (p<0.001), an 86% sensitivity and 71% specificity for the diagnosis of DIC; 6) fibrinogen concentrations had an AUC of 0.95 (p<0.001) and a cutoff point ≤3.9 g/L had a sensitivity of 87% and a specificity of 92% for the development of DIC; and 7) The pregnancy adjusted DIC score had an AUC of 0.975 (p<0.001) and at a cutoff point of ≥26 had a sensitivity of 88%, a specificity of 96%, a LR(+) of 22 and a LR(−) of 0.125 for the diagnosis of DIC.

Conclusion

We could establish a sensitive and specific pregnancy adjusted DIC score. The positive likelihood ratio of this score suggests that a patient with a score of ≥26 has a high probability to have DIC.     

Changepoint detection in base-resolution methylome data reveals a robust signature of methylated domain landscape

Background

Base-resolution methylome data generated by whole-genome bisulfite sequencing (WGBS) is often used to segment the genome into domains with distinct methylation levels. However, most segmentation methods include many parameters to be carefully tuned and/or fail to exploit the unsurpassed resolution of the data. Furthermore, there is no simple method that displays the composition of the domains to grasp global trends in each methylome.

Results

We propose to use changepoint detection for domain demarcation based on base-resolution methylome data. While the proposed method segments the methylome in a largely comparable manner to conventional approaches, it has only a single parameter to be tuned. Furthermore, it fully exploits the base-resolution of the data to enable simultaneous detection of methylation changes in even contrasting size ranges, such as focal hypermethylation and global hypomethylation in cancer methylomes. We also propose a simple plot termed methylated domain landscape (MDL) that globally displays the size, the methylation level and the number of the domains thus defined, thereby enabling one to intuitively grasp trends in each methylome. Since the pattern of MDL often reflects cell lineages and is largely unaffected by data size, it can serve as a novel signature of methylome.

Conclusions

Changepoint detection in base-resolution methylome data followed by MDL plotting provides a novel method for methylome characterization and will facilitate global comparison among various WGBS data differing in size and even species origin.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1809-5) contains supplementary material, which is available to authorized users.     

Clinical Prediction Rule for Stratifying Risk of Pulmonary Multidrug-Resistant Tuberculosis

Background

Multidrug-resistant tuberculosis (MDR-TB), resistance to at least isoniazid and rifampin, is a worldwide problem.

Objective

To develop a clinical prediction rule to stratify risk for MDR-TB among patients with pulmonary tuberculosis.

Methods

Derivation and internal validation of the rule among adult patients prospectively recruited from 37 health centers (Perú), either a) presenting with a positive acid-fast bacillus smear, or b) had failed therapy or had a relapse within the first 12 months.

Results

Among 964 patients, 82 had MDR-TB (prevalence, 8.5%). Variables included were MDR-TB contact within the family, previous tuberculosis, cavitary radiologic pattern, and abnormal lung exam. The area under the receiver-operating curve (AUROC) was 0.76. Selecting a cut-off score of one or greater resulted in a sensitivity of 72.6%, specificity of 62.8%, likelihood ratio (LR) positive of 1.95, and LR negative of 0.44. Similarly, selecting a cut-off score of two or greater resulted in a sensitivity of 60.8%, specificity of 87.5%, LR positive of 4.85, and LR negative of 0.45. Finally, selecting a cut-off score of three or greater resulted in a sensitivity of 45.1%, specificity of 95.3%, LR positive of 9.56, and LR negative of 0.58.

Conclusion

A simple clinical prediction rule at presentation can stratify risk for MDR-TB. If further validated, the rule could be used for management decisions in resource-limited areas.     

Regulation of root morphogenesis in arbuscular mycorrhizae: what role do fungal exudates,phosphate, sugars and hormones play in lateral root formation?

Background

Arbuscular mycorrhizae (AMs) form a widespread root–fungus symbiosis that improves plant phosphate (Pi) acquisition and modifies the physiology and development of host plants. Increased branching is recognized as a general feature of AM roots, and has been interpreted as a means of increasing suitable sites for colonization. Fungal exudates, which are involved in the dialogue between AM fungi and their host during the pre-colonization phase, play a well-documented role in lateral root (LR) formation. In addition, the increased Pi content of AM plants, in relation to Pi-starved controls, as well as changes in the delivery of carbohydrates to the roots and modulation of phytohormone concentration, transport and sensitivity, are probably involved in increasing root system branching.

Scope

This review discusses the possible causes of increased branching in AM plants. The differential root responses to Pi, sugars and hormones of potential AM host species are also highlighted and discussed in comparison with those of the non-host Arabidopsis thaliana.

Conclusions

Fungal exudates are probably the main compounds regulating AM root morphogenesis during the first colonization steps, while a complex network of interactions governs root development in established AMs. Colonization and high Pi act synergistically to increase root branching, and sugar transport towards the arbusculated cells may contribute to LR formation. In addition, AM colonization and high Pi generally increase auxin and cytokinin and decrease ethylene and strigolactone levels. With the exception of cytokinins, which seem to regulate mainly the root:shoot biomass ratio, these hormones play a leading role in governing root morphogenesis, with strigolactones and ethylene blocking LR formation in the non-colonized, Pi-starved plants, and auxin inducing them in colonized plants, or in plants grown under high Pi conditions.     

Comparison of Long-Term Survival of Patients with BCLC Stage B Hepatocellular Carcinoma after Liver Resection or Transarterial Chemoembolization

Background and Aims

Treatment of patients with Barcelona Clinic Liver Cancer Stage B hepatocellular carcinoma (BCLC-B HCC) is controversial. This study compared the long-term survival of patients with BCLC-B HCC who received liver resection (LR) or transarterial chemoembolization (TACE).

Methods

A total of 257 and 135 BCLC-B HCC patients undergoing LR and TACE, respectively, were retrospectively evaluated. Kaplan–Meier method was used for long-term survival analysis. Independent prognostic predictors were determined by the Cox proportional hazards model.

Results

The hospital mortality rate was similar between groups (3.1% vs. 3.7%; P = 0.76). However, the LR group showed a significantly higher postoperative complication rate than the TACE group (28 vs. 18.5%; P = 0.04). At the same time, the LR group showed significantly higher overall survival rates (1 year, 84 vs. 69%; 3 years, 59 vs. 29%; 5 years, 37 vs. 14%; P<0.001). Moreover, similar results were observed in the propensity score model. Three independent prognostic factors were associated with worse overall survival: serum AFP level (≥400 ng/ml), serum ALT level, and TACE.

Conclusions

LR appears to be as safe as TACE for patients with BCLC-B HCC, and it provides better long-term overall survival. However, prospective studies are needed to disclose if LR may be regarded as the preferred treatment for these patients as long as liver function is preserved.     

Identification of novel biomarkers in seasonal allergic rhinitis by combining proteomic, multivariate and pathway analysis

Background

Glucocorticoids (GCs) play a key role in the treatment of seasonal allergic rhinitis (SAR). However, some patients show a low response to GC treatment. We hypothesized that proteins that correlated to discrimination between symptomatic high and low responders (HR and LR) to GC treatment might be regulated by GCs and therefore suitable as biomarkers for GC treatment.

Methodology/Principal Findings

We identified 953 nasal fluid proteins in symptomatic HR and LR with a LC MS/MS based-quantitative proteomics analysis and performed multivariate analysis to identify a combination of proteins that best separated symptomatic HR and LR. Pathway analysis showed that those proteins were most enriched in the acute phase response pathway. We prioritized candidate biomarkers for GC treatment based on the multivariate and pathway analysis. Next, we tested if those candidate biomarkers differed before and after GC treatment in nasal fluids from 40 patients with SAR using ELISA. Several proteins including ORM (P<0.0001), APOH (P<0.0001), FGA (P<0.01), CTSD (P<0.05) and SERPINB3 (P<0.05) differed significantly before and after GC treatment. Particularly, ORM (P<0.01), FGA (P<0.05) and APOH (P<0.01) that belonged to the acute phase response pathway decreased significantly in HR but not LR before and after GC treatment.

Conclusions/Significance

We identified several novel biomarkers for GC treatment response in SAR with combined proteomics, multivariate and pathway analysis. The analytical principles may be generally applicable to identify biomarkers in clinical studies of complex diseases.     

Cruciate Ligament Reconstruction and Risk of Knee Osteoarthritis: The Association between Cruciate Ligament Injury and Post-Traumatic Osteoarthritis. A Population Based Nationwide Study in Sweden, 1987–2009

Objective

To study the association between Cruciate Ligament (CL) injury and development of post-traumatic osteoarthritis in the knee in patients treated operatively with CL reconstruction compared with patients treated non-operatively.

Design

Population based cohort study; level of evidence II-2.

Setting

Sweden, 1987–2009.

Participants

All patients aged between 15–60 years being diagnosed and registered with a CL injury in The National Swedish Patient Register between 1987 and 2009.

Main Outcome Measures

Knee osteoarthritis.

Results

A total of 64,614 patients diagnosed with CL injury during 1987 to 2009 in Sweden were included in the study. Seven percent of the patients were diagnosed with knee OA in specialized healthcare during the follow-up (mean 9 years). Stratified analysis by follow-up showed that while those with shorter follow-up had a non-significant difference in risk (0.99, 95%CI 0.90–1.09 for follow-up less than five years compared with the non-operated cohort), those with longer follow-up had an increased risk of knee OA after CL reconstruction (HR = 1.42, 95%CI 1.27–1.58 for follow-up more than ten years compared with non-operated cohort). The risk to develop OA was not affected by sex.

Conclusion

CL reconstructive surgery does not seem to have a protective effect on long term OA in either men or women.     

Structural correlates of taste and smell loss in encephalitis disseminata

Background

Olfactory dysfunction in MS patients is reported in the literature. MRI of the olfactory bulb (OB) is discussed as a promising new testing method for measuring olfactory function (OF).Aim of this study was to explore reasons for and optimize the detection of olfactory dysfunction in MS patients with MRI.

Materials and Methods

OB and olfactory brain volume was assessed within 34 MS patients by manual segmentation. Olfactory function was tested using the Threshold-Discrimination-Identification-Test (TDI), gustatory function was tested using Taste Strips (TST).

Results

41% of the MS patients displayed olfactory dysfunction (8% of the control group), 16% displayed gustatory dysfunction (5% of the control group). There was a correlation between the OB volume and the number and volume of MS lesions in the olfactory brain. Olfactory brain volume correlated with the volume of lesions in the olfactory brain and the EDSS score. The TST score correlated with the number and volume of lesions in the olfactory brain.

Conclusion

The correlation between a higher number and volume of MS lesions with a decreased OB and olfactory brain volume could help to explain olfactory dysfunction.     

Tumefactive Multiple Sclerosis in Taiwan

Background

Multiple sclerosis (MS) is less common in Asia, including Taiwan, and some characteristics of MS in Asians differ from those of Caucasians. Tumefactive brain lesion is even rarer in MS patients.

Objective

To review patients with tumefactive MS and compare them with those in other studies investigating tumefactive demyelinating lesions and our Taiwanese typical MS patients.

Methods

Twelve patients (6.3%) from the 190 MS patients visiting Taipei Veterans General Hospital from 1985 to 2010 were enrolled. They all fulfilled the McDonald or Poser criteria for MS and had at least one brain lesion larger than 2 centimeters with or without a mass effect.

Results

Eleven patients (91.7%) were female and presented tumefactive brain lesions during the first attack. The clinical course of all patients was relapsing-remitting with a second attack within 2 years. Their initial extended disability status score was higher, but the prognosis was better after more than 2 years of follow-up, than in other studies. Moreover, our patients did not have optic or spinal involvement as well as positive neuromyelitis optica immunoglobulin or aquaporin-4 antibody, which is very common in Taiwanese MS patients.

Conclusion

Tumefactive MS is not common in Taiwan. Although the tumefactive demyelinating lesions seem to be terrible initially, their prognosis is relatively more favorable than expected.     

Comparison of artificial neural network and logistic regression models for predicting in-hospital mortality after primary liver cancer surgery

Background

Since most published articles comparing the performance of artificial neural network (ANN) models and logistic regression (LR) models for predicting hepatocellular carcinoma (HCC) outcomes used only a single dataset, the essential issue of internal validity (reproducibility) of the models has not been addressed. The study purposes to validate the use of ANN model for predicting in-hospital mortality in HCC surgery patients in Taiwan and to compare the predictive accuracy of ANN with that of LR model.

Methodology/Principal Findings

Patients who underwent a HCC surgery during the period from 1998 to 2009 were included in the study. This study retrospectively compared 1,000 pairs of LR and ANN models based on initial clinical data for 22,926 HCC surgery patients. For each pair of ANN and LR models, the area under the receiver operating characteristic (AUROC) curves, Hosmer-Lemeshow (H-L) statistics and accuracy rate were calculated and compared using paired T-tests. A global sensitivity analysis was also performed to assess the relative significance of input parameters in the system model and the relative importance of variables. Compared to the LR models, the ANN models had a better accuracy rate in 97.28% of cases, a better H-L statistic in 41.18% of cases, and a better AUROC curve in 84.67% of cases. Surgeon volume was the most influential (sensitive) parameter affecting in-hospital mortality followed by age and lengths of stay.

Conclusions/Significance

In comparison with the conventional LR model, the ANN model in the study was more accurate in predicting in-hospital mortality and had higher overall performance indices. Further studies of this model may consider the effect of a more detailed database that includes complications and clinical examination findings as well as more detailed outcome data.     

Partial mechanical stimulation facilitates the growth of the rhizomatous plant Leymus secalinus: modulation by clonal integration

Background and Aims

Mechanical stimulation (MS) often induces plants to undergo thigmomorphogenesis and to synthesize an array of signalling substances. In clonal plants, connected ramets often share resources and hormones. However, little is known about whether and how clonal integration influences the ability of clonal plants to withstand MS. We hypothesized that the effects of MS may be modulated by clonal integration.

Methods

We conducted an experiment in which ramet pairs of Leymus secalinus were subjected to three treatments: (1) connected ramet pairs under a homogeneous condition [i.e. the proximal (relatively old) and distal (relatively young) ramets were not mechanically stressed]; (2) connected ramet pairs under a heterogeneous condition (i.e. the proximal ramet was mechanically stressed but the distal ramet was not); and (3) disconnected ramet pairs under the same condition as in treatment 2. At the end of the experiment, we harvested all plants and determined their biomass and allocation.

Key Results

Clonal integration had no significant influence on measured traits of distal L. secalinus ramets without MS. However, under MS, plants with distal ramets that were connected to a mother ramet produced more total plant biomass, below-ground biomass, ramets and total rhizome length than those that were not connected. Partial MS exerted local effects on stimulated ramets and remote effects on connected unstimulated ramets. Partial MS increased total biomass, root/shoot ratio, number of ramets and total rhizome length of stimulated proximal ramets, and increased total biomass, root weight ratio, number of ramets and total rhizome length of connected unstimulated ramets due to clonal integration.

Conclusions

These findings suggest that thigmomorphogenesis may protect plants from the stresses caused by high winds or trampling and that thigmomorphogenesis can be strongly modulated by the degree of clonal integration.     

A Comparison of Vasopressin,Terlipressin, and Lactated Ringers for Resuscitation of Uncontrolled Hemorrhagic Shock in an Animal Model

Aim

The aim of this study is to compare the effect of lactated ringer (LR), vasopressin (Vaso) or terlipressin (Terli) on uncontrolled hemorrhagic shock (UHS) in rats.

Methods

48 rats were divided into four treatment groups for UHS study. Vaso group was given bolus vasopressin (0.8 U/kg); the Terli group was given bolus terlipressin (15 mcg/kg); LR group was given LR and the sham group was not given anything. Mean arterial pressure (MAP), serum lactate level, plasma cytokine levels, lung injury and mortality are investigated for these different treatment groups.

Results

Compared with LR group, vasopressin and terlipressin-treated groups were associated with higher MAP, lowered mortality rates, less lung injury, lowered serum lactate level, less proinflammatory and more anti-inflammatory cytokine production at certain time points. Comparing between vasopressin and terlipressin treated groups, there is no statistical difference in mortality rates, lung injury, serum lactate level and cytokine level. However, there is a difference in the length of time in maintaining a restored level of MAP (80 to 110 mmHg). The terlipressin treated rats can maintain this restored level of MAP for 45 minutes, but the vasopressin treated rats can only maintain this restored level of MAP for 5 minutes before decreasing gradually to the MAP observed in LR group (40 mmHg).

Conclusion

Early optimization of hemodynamics with terlipressin or vasopressin in an animal model of UHS was associated with improved hemodynamics and inflammatory cytokine profile than the LR control. Compared with vasopressin, terlipressin has the advantage of ease of use and sustained effects.     

Cannabinoids Alleviate Experimentally Induced Intestinal Inflammation by Acting at Central and Peripheral Receptors

Background and Aims

In an attempt to further investigate the role of cannabinoid (CB) system in the pathogenesis of inflammatory bowel diseases, we employed two recently developed ligands, AM841 (a covalently acting CB agonist) and CB13 (a peripherally-restricted CB agonist) to establish whether central and peripheral CB sites are involved in the anti-inflammatory action in the intestine.

Methods and Results

AM841 (0.01, 0.1 and 1 mg/kg, i.p.) significantly decreased inflammation scores in dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-treated mice when administered before induction of colitis or as a treatment of existing intestinal inflammation. The effect was absent in CB₁, CB₂ and CB_1/2-deficient mice. A peripherally-restricted agonist CB13 did not alleviate colitis when given i.p. (0.1 mg/kg), but significantly decreased inflammation score after central administration (0.1 µg/animal).

Conclusions

This is the first evidence that central and peripheral CB receptors are responsible for the protective and therapeutic action of cannabinoids in mouse models of colitis. Our observations provide new insight to CB pharmacology and validate the use of novel ligands AM841 and CB13 as potent tools in CB-related research.     

Comparison of Prediction Model for Cardiovascular Autonomic Dysfunction Using Artificial Neural Network and Logistic Regression Analysis

Background

This study aimed to develop the artificial neural network (ANN) and multivariable logistic regression (LR) analyses for prediction modeling of cardiovascular autonomic (CA) dysfunction in the general population, and compare the prediction models using the two approaches.

Methods and Materials

We analyzed a previous dataset based on a Chinese population sample consisting of 2,092 individuals aged 30–80 years. The prediction models were derived from an exploratory set using ANN and LR analysis, and were tested in the validation set. Performances of these prediction models were then compared.

Results

Univariate analysis indicated that 14 risk factors showed statistically significant association with the prevalence of CA dysfunction (P<0.05). The mean area under the receiver-operating curve was 0.758 (95% CI 0.724–0.793) for LR and 0.762 (95% CI 0.732–0.793) for ANN analysis, but noninferiority result was found (P<0.001). The similar results were found in comparisons of sensitivity, specificity, and predictive values in the prediction models between the LR and ANN analyses.

Conclusion

The prediction models for CA dysfunction were developed using ANN and LR. ANN and LR are two effective tools for developing prediction models based on our dataset.     

Autoantibodies and Sjogren’s Syndrome in Multiple Sclerosis,a Reappraisal

Background

Rheumatologic diseases may cause neurologic disorders that mimic multiple sclerosis (MS). A panel of serum autoantibodies is often obtained as part of the evaluation of patients suspected of having MS.

Objectives

To determine, in light of recently revised diagnostic criteria for MS, neuromyelitis optica, and Sjogren’s Syndrome, if testing for autoantibodies in patients with a confirmed diagnosis of MS would reveal a frequency or demonstrate a clinical utility divergent from previous reports or lead to identification of undiagnosed cases of Sjogren’s Syndrome.

Methods

Convenience sample cross-sectional study of MS patients recruited from the OHSU Multiple Sclerosis Center.

Results

Autoantibodies were detected in 38% (35/91) of patients with MS and were not significantly associated with disease characteristics or severity. While four patients had SSA antibodies, none met diagnostic criteria for Sjogren’s Syndrome.

Conclusions

Rheumatologic autoantibodies are frequently found in MS patients and are not associated with disease severity or systemic rheumatologic disease. Our demonstration of the low specificity of these autoantibodies suggests that the diagnostic utility and cost-effectiveness of testing is not supported when there is strong clinical suspicion of MS and low clinical suspicion of rheumatologic disease.     

Safety and Tolerability of Lactobacillus reuteri DSM 17938 and Effects on Biomarkers in Healthy Adults: Results from a Randomized Masked Trial

Background

There are few carefully-designed studies investigating the safety of individual probiotics approved under Investigational New Drug policies.

Objectives

The primary aim of this prospective, double-blind placebo-controlled trial was to investigate if daily treatment of adults with Lactobacillus reuteri DSM 17938 (LR) for 2 months is safe and well-tolerated. Our secondary aim was to determine if LR treatment has immune effects as determined by regulatory T cell percentages, expression of toll-like receptors (TLR)-2 and −4 on circulating peripheral blood mononuclear cells (PMBCs), cytokine expression by stimulated PBMC, and intestinal inflammation as measured by fecal calprotectin.

Methods

Forty healthy adults were randomized to a daily dose of 5×10⁸ CFUs of LR (n = 30) or placebo (n = 10) for 2 months. Participants completed a daily diary card and had 7 clinic visits during treatment and observation.

Results

There were no severe adverse events (SAEs) and no significant differences in adverse events (AEs). There were no differences in PBMC subclasses, TLRs, or cytokine expression after treatment. The probiotic-treated group had a significantly higher fecal calprotectin level than the placebo group after 2 months of treatment: 50 µg/g (IQR 24–127 µg/g) vs. 17 µg/g (IQR 11–26 µg/g), p = 0.03, although values remained in the normal clinical range (0–162.9 µg/g). LR vials retained >10⁸ CFUs viable organisms/ml.

Conclusions

LR is safe and well tolerated in adults, without significant changes in immunologic markers. There was a small but significant increase in fecal calprotectin, perhaps indicating some element of immune recognition at the intestinal level.

Trial Registration

Clinical Trials.gov {"type":"clinical-trial","attrs":{"text":"NCT00922727","term_id":"NCT00922727"}}NCT00922727     

Optimizing Exchange Transfusion for Severe Unconjugated Hyperbilirubinemia: Studies in the Gunn Rat

Background

Severe unconjugated hyperbilirubinemia carries the risk of neurotoxicity. Phototherapy (PT) and exchange transfusion (ET) are cornerstones in the treatment of unconjugated hyperbilirubinemia. Studies to improve ET efficacy have been hampered by the low application of ET in humans and by the lack of an in vivo model. The absence of an appropriate animal model has also prevented to determine the efficacy of adjunct or alternative treatment options such as albumin (Alb) administration.

Aim

To establish an in vivo model for ET and to determine the most effective treatment (combination) of ET, PT and Alb administration.

Methods

Gunn rats received either PT, PT+Alb, ET, ET+PT, ET+PT+Alb or sham operation (each n = 7). ET was performed via the right jugular vein in ∼20 min. PT (18 µW/cm²/nm) was started after ET or at T₀. Albumin i.p. injections (2.5 g/kg) were given after ET or before starting PT. Plasma unconjugated bilirubin (UCB), plasma free bilirubin (Bf), and brain bilirubin concentrations were determined.

Results

We performed ET in 21 Gunn rats with 100% survival. At T₁, ET was profoundly more effective in decreasing both UCB −44%, p<0.01) and Bf −81%, p<0.05) than either PT or PT+Alb. After 48 h, the combination of ET+PT+Alb showed the strongest hypobilirubinemic effect (−54% compared to ET).

Conclusions

We optimized ET for severe unconjugated hyperbilirubinemia in the Gunn rat model. Our data indicate that ET is the most effective treatment option, in the acute as well as the follow-up situation.