Steatosis drives monocyte-derived macrophage accumulation in human metabolic dysfunction-associated fatty liver disease.

Background & Aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common complication of obesity with a hallmark feature of hepatic steatosis. Recent data from animal models of MAFLD have demonstrated substantial changes in macrophage composition in the fatty liver. In humans, the relationship between liver macrophage heterogeneity and liver steatosis is less clear. Methods: Liver tissue from 21 participants was collected at time of bariatric surgery and analysed using flow cytometry, immunofluorescence, and H&E microscopy. Single-cell RNA sequencing was also conducted on a subset of samples (n = 3). Intrahepatic triglyceride content was assessed via MRI and tissue histology. Mouse models of hepatic steatosis were used to investigate observations made from human liver tissue. Results: We observed variable degrees of liver steatosis with minimal fibrosis in our participants. Single-cell RNA sequencing revealed four macrophage clusters that exist in the human fatty liver encompassing Kupffer cells and monocyte-derived macrophages (MdMs). The genes expressed in these macrophage subsets were similar to those observed in mouse models of MAFLD. Hepatic CD14+ monocyte/macrophage number correlated with the degree of steatosis. Using mouse models of early liver steatosis, we demonstrate that recruitment of MdMs precedes Kupffer cell loss and liver damage. Electron microscopy of isolated macrophages revealed increased lipid accumulation in MdMs, and ex vivo lipid transfer experiments suggested that MdMs may serve a distinct role in lipid uptake during MAFLD. Conclusions: The human liver in MAFLD contains macrophage subsets that align well with those that appear in mouse models of fatty liver disease. Recruited myeloid cells correlate well with the degree of liver steatosis in humans. MdMs appear to participate in lipid uptake during early stages of MALFD. Impact and implications: Metabolic dysfunction associated fatty liver disease (MAFLD) is extremely common; however, the early inflammatory responses that occur in human disease are not well understood. In this study, we investigated macrophage heterogeneity in human livers during early MAFLD and demonstrated that similar shifts in macrophage subsets occur in human disease that are similar to those seen in preclinical models. These findings are important as they establish a translational link between mouse and human models of disease, which is important for the development and testing of new therapeutic approaches for MAFLD.

Distinct Inflammatory Milieu in Patients With Right Heart Failure.

BACKGROUND: Right heart failure (RHF) is associated with worse clinical outcomes. In addition to hemodynamic perturbations, the syndrome of RHF involves liver congestion and dysfunction. The mechanisms that underlie heart-liver interactions are poorly understood and may involve secreted factors. As a first step to understand the cardiohepatic axis, we sought to elucidate the circulating inflammatory milieu in patients with RHF. METHODS: Blood samples were collected from the inferior vena cava and hepatic veins during right heart catheterization from 3 groups of patients: (1) controls with normal cardiac function, (2) patients with heart failure who did not meet all criteria of RHF, and (3) patients who met prespecified criteria for RHF defined by hemodynamic and echocardiographic parameters. We performed a multiplex protein assay to survey levels of several circulating markers and analyzed their association with mortality and the need for a left ventricular assist device or heart transplant. Finally, we leveraged publicly available single-cell RNA sequencing data and performed tissue imaging to evaluate the expression of these factors in the liver. RESULTS: In this study, RHF was associated with elevated levels of a subset of cytokines/chemokines/growth factors compared with controls. In particular, soluble CD163 (cluster of differentiation 163) and CXCL12 (chemokine [C-X-C motif] ligand 12) were higher in RHF and predicted left ventricular assist device/transplant-free survival in an independent validation cohort. Furthermore, single-cell RNA sequencing and immunohistochemistry of human liver biopsies suggest that these factors are expressed by Kupffer cells and may be liver derived. CONCLUSIONS: RHF is associated with a distinct circulating inflammatory profile. Soluble CD163 and CXCL12 are novel biomarkers that can prognosticate patient outcomes. Future studies to define how these molecules influence heart failure phenotypes and disease progression may lead to new approaches to the management of patients with RHF.

A Distinct Inflammatory Milieu in Patients with Right Heart Failure.

Background: Right heart failure (RHF) is associated with worse clinical outcomes. In addition to hemodynamic perturbations, the syndrome of RHF involves liver congestion and dysfunction. The mechanisms that underlie heart-liver interactions are poorly understood and may involve secreted factors. As a first step to understand the cardiohepatic axis, we sought to elucidate the circulating inflammatory milieu in patients with RHF. Methods: Blood samples were collected from the IVC and hepatic veins during right heart catheterization from 3 groups of patients: 1) controls with normal cardiac function, 2) patients with heart failure (HF) who did not meet all criteria of RHF, and 3) patients who met prespecified criteria for RHF defined by hemodynamic and echocardiographic parameters. We performed multiplex protein assay to survey levels of several circulating markers and analyzed their association with mortality and need for left ventricular assist device or heart transplant. Finally, we leveraged publicly available single cell RNA sequencing (scRNAseq) data and performed tissue imaging to evaluate expression of these factors in the liver. Results: In this study of 43 patients, RHF was associated with elevated levels of a subset of cytokines/chemokines/growth factors compared to controls. In particular, soluble CD163 (sCD163) and CXCL12 were higher in RHF and predicted survival in an independent validation cohort. Furthermore, scRNAseq and immunohistochemistry of human liver biopsies suggest that these factors are expressed by Kupffer cells and may be liver derived. Conclusions: RHF is associated with a distinct circulating inflammatory profile. sCD163 and CXCL12 are novel biomarkers that can prognosticate patient outcomes. Future studies to define how these molecules influence HF phenotypes and disease progression may lead to new approaches to management of patients with RHF.

Established Clinical Prediction Rules for Bleeding Had Mediocre Discrimination in Left Ventricular Assist Device Recipients.

Left ventricular assist devices (LVAD) reduce mortality in patients with end-stage heart failure, but LVAD management is frequently complicated by bleeding. Bleeding prediction post-LVAD implantation is challenging as prediction rules for hemorrhage have not been rigorously studied in this population. We aimed to validate clinical prediction rules for bleeding, derived in the atrial fibrillation and venous thromboembolism populations, in an LVAD cohort. This was a retrospective cohort study of LVAD recipients at an academic center. The primary end-point was time to gastrointestinal bleed or intracranial hemorrhage after implant; the secondary end-point was time to any major hemorrhage after hospital discharge. Four hundred and eighteen patients received an LVAD (135 HeartMate II, 125 HeartMate 3, 158 HVAD) between November 2009 and January 2019. The primary end-point occurred in 169 (40.4%) patients with C -statistics ranging 0.55-0.58 (standard deviation [SD] 0.02 for all models). The secondary end-point occurred in 167 (40.0%) patients with C -statistics ranging 0.53-0.58 (SD 0.02 for all models). Modifying the age and liver function thresholds increased the C -statistic range to 0.56-0.60 for the primary and secondary end-points. In a sensitivity analysis of HeartMate 3 patients, prediction rules performed similarly. Existing prediction rules for major bleeding had mediocre discrimination in an LVAD cohort.

Dietary lipids inhibit mitochondria transfer to macrophages to divert adipocyte-derived mitochondria into the blood.

Adipocytes transfer mitochondria to macrophages in white and brown adipose tissues to maintain metabolic homeostasis. In obesity, adipocyte-to-macrophage mitochondria transfer is impaired, and instead, adipocytes release mitochondria into the blood to induce a protective antioxidant response in the heart. We found that adipocyte-to-macrophage mitochondria transfer in white adipose tissue is inhibited in murine obesity elicited by a lard-based high-fat diet, but not a hydrogenated-coconut-oil-based high-fat diet, aging, or a corn-starch diet. The long-chain fatty acids enriched in lard suppress mitochondria capture by macrophages, diverting adipocyte-derived mitochondria into the blood for delivery to other organs, such as the heart. The depletion of macrophages rapidly increased the number of adipocyte-derived mitochondria in the blood. These findings suggest that dietary lipids regulate mitochondria uptake by macrophages locally in white adipose tissue to determine whether adipocyte-derived mitochondria are released into systemic circulation to support the metabolic adaptation of distant organs in response to nutrient stress.

COVID-19 in orthotopic heart transplant recipients and association with donor specific antibodies.

De novo donor-specific antibodies (DSAs) are associated with increased risk of antibody-mediated rejection and worse clinical outcomes after orthotopic heart transplant (OHT). No study has reported the production of DSAs after infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in an OHT population. In this retrospective study, we described coronavirus disease 2019 (COVID-19) incidence and clinical course in a large, contemporary OHT cohort. We showed that the case-fatality rate has significantly decreased since the early days of the pandemic, although remains higher than that of the general population. In addition, we found that 10% of OHT recipients developed de novo DSAs or experienced an increase in pre-existing DSAs after COVID-19, with the majority occurring in unvaccinated patients (15% vs 2%). Further studies are necessary to substantiate our findings in an external cohort.

Reproducibility of pathologic scoring systems for periprosthetic adverse local tissue reactions: A cross-sectional study.

BACKGROUND: Several previous studies have described broad histologic classifications of peri-prosthetic reactions that likely reflect the underlying mechanism of arthroplasty failure; however, a consensus has not yet been reached about the relative importance of individual observations. QUESTION/PURPOSE: The purpose of this study was to evaluate the inter-examiner repeatability of commonly used histopathologic grading methods, and to determine the utility of assigning a more simple, global categorization in patients undergoing revision THA surgery of implants with a variety of bearing combinations. METHODS: Between March 2013 and February 2020, a total of 2131 patients underwent revision hip arthroplasty surgery at a one center, of which 12% (248 of 2131) of patients were enrolled. Two pathologists independently reviewed microscope slides of periprosthetic tissue from these patients, of which 425 slides (229 hips, 222 subjects) were reviewed by both pathologists. Separate slides were used for a priori training of the pathologists. Slides were evaluated with the Campbell Aseptic Lymphocyte-dominant Vasculitis-Associated Lesion (ALVAL) score, the Oxford ALVAL score as modified by Grammatopolous, the Fujishiro and Natu scores, and a proposed simplified pattern classification, similar to that of Krenn et al., that incorporates individual factors of these existing scoring methods and was previously shown to correspond to Magnetic Resonance Imaging findings. Inter-rater agreement was assessed using Gwet's AC1 and AC2 coefficients and correspondence analysis was used to examine associations between individual factors of prior scoring methods with the proposed major pattern. RESULTS: Almost perfect inter-rater repeatability (Gwet's AC2 > 0.8) was found for 71% (15/21) of the individual factors, and substantial interrater agreement was found for the proposed major overall pattern (Gwet's AC1: 0.80, 95%CI: 0.72-0.85). Correspondence analysis was able to explain 89-91% of data variability and was able to identify individual features not commonly associated with a major pattern, but discriminatory of the major pattern, such as "Lymph Cuff Thickness 0.25-0.5″ with ALVAL. CONCLUSION: In contrast to prior examinations, excellent interrater agreement was found that may be attributable to a priori training of raters with a test set of slides or difficulty of interpreting grading criteria. The proposed simplified major pattern classification may facilitate evaluation of histopathologic tissue samples.

Adverse Local Tissue Reactions are Common in Asymptomatic Individuals After Hip Resurfacing Arthroplasty: Interim Report from a Prospective Longitudinal Study.

BACKGROUND: The evaluation of the natural history prevalence of adverse local tissue reactions (ALTRs) using MRI has focused only on metal-on-metal (MoM) bearing surfaces without comparison to nonMoM bearing surfaces. QUESTIONS/PURPOSES: To determine (1) the longitudinal changes and differences in blood metal ion levels in patients with hip resurfacing arthroplasty (HRA), ceramic-on-ceramic (CoC) THA, and metal-on-polyethylene (MoP) THA compared with those undergoing ceramic-on-polyethylene (CoP) THA; (2) how the longitudinal change of synovial reaction classification in patients with HRA, CoC THA, and MoP THA compares with those undergoing CoP THA, and whether there is an association between the presence of an ALTR or metallosis on MRI with corresponding patient-reported outcomes, or the presence of capsular dehiscence; and (3) differences in blood metal ion levels between patients undergoing HRA with an ALTR or metallosis on MRI and those with HRA without these conditions. METHODS: Between March 2014 and February 2019, 22,723 patients underwent primary HRA and THA at one center. Patients received an HRA based on their desired athletic level after surgery and the presence of normal acetabular and proximal femoral bone morphology without osteopenia or osteoporosis. Two percent (342 of 22,723) of patients were contacted to participate, and 71% (243 of 342 hips in 206 patients) were enrolled for analysis at baseline. The patients underwent arthroplasty for degenerative joint disease, and 25 patients withdrew over the course of the study. We included patients who were more than 1 year postarthroplasty. All participants had an MRI examination and blood serum ion testing and completed a Hip Disability and Osteoarthritis Outcome Score survey annually for four years (baseline, year 1, year 2, year 3). Morphologic and susceptibility-reduced MR images were evaluated by a single radiologist not involved in the care of patients for the presence and classification of synovitis (Gwet AC1: 0.65 to 0.97), synovial thickness, and volume (coefficient of repeatability: 1.8 cm3). Linear mixed-effects models were used to compare the mean synovial thickness, synovial volume, and Hip Disability and Osteoarthritis Outcome Score subscales between bearing surfaces at each timepoint and within each bearing surface over time. Marginal Cox proportional hazards models were used to compare the time to and the risk of developing ALTR only, metallosis only, and ALTR or metallosis between bearing surfaces. All models were adjusted for age, sex, BMI, and length of implantation based on known confounders for hip arthroplasty. Adjustment for multiple comparisons was performed using the Dunnett-Hsu method. RESULTS: Patients with unilateral HRA had higher cobalt and chromium serum ion levels (baseline: 1.8 ± 0.8 ppb, year 1: 2.0 ± 1.5 ppb, year 2: 2.1 ± 1.2 ppb, year 3: 1.6 ± 0.7 ppb) than those with unilateral CoP bearings (baseline: 0.0 ± 0.1 ppb, year 1: 0.1 ± 0.3 ppb, year 2: 0.0 ± 0.2 ppb, year 3: 0.0 ± 0.0 ppb) at all timepoints (p < 0.001 for each time point). More patients who received an HRA developed ALTR or metallosis on MRI than did patients with CoP bearings (hazard ratio 4.8 [95% confidence interval 1.2 to 18.4]; p = 0.02). There was no association between the longitudinal change of synovial reaction to ALTR or metallosis on MRI with patient-reported outcomes. In addition, there was no association between the presence of dehiscence at baseline and the subsequent development of ALTR or metallosis, as seen on MRI. There were elevated cobalt (4.7 ± 3.5 ppb) and chromium (4.7 ± 2.6 ppb) serum levels in patients with unilateral HRA who had an ALTR or metallosis present on MRI at year 1 compared with patients without an ALTR or metallosis on MRI (cobalt: 1.8 ± 1.0 ppb, mean difference 4.7 ppb [95% CI 3.3 to 6.0]; p < 0.001; chromium: 2.3 ± 0.5 ppb, mean difference 3.6 ppb [95% CI 2.2 to 5.0]; p < 0.001) as well as for chromium at year 3 (3.9 ± 2.4 ppb versus 2.2 ± 1.1 ppb, mean difference 1.3 ppb [95% CI 0.3 to 2.4]; p = 0.01). CONCLUSION: We found a higher proportion of ALTR or metallosis on MRI in patients with HRA compared with patients with CoP, even when patient self-assessed symptomatology of those with an ALTR or metallosis on MRI was not different than the absence of these features. MRI detected ALTRs in high-function patients, emphasizing that an annual clinical assessment dependent on survey or blood ion testing alone may not detect soft tissue complications. The results of this study are in line with prior consensus recommendations of using MRI as part of a routine follow-up protocol for this patient population. LEVEL OF EVIDENCE: Level III, therapeutic study.

Differences in the magnetic resonance imaging parameter T2* may be identified during the course of canine patellar tendon healing: a pilot study.

BACKGROUND: Previous studies have utilized ultrashort echo (UTE) magnetic resonance imaging (MRI), and derived T2* maps, to evaluate structures with highly ordered collagen structures such as tendon. T2* maps may provide a noninvasive means to assess tendon damage and healing. This pilot study evaluated the longitudinal relationship of an induced mechanical strain on the patellar tendon with corresponding UTE T2* metrics, histologic and biomechanical evaluation at two post-operative time points. METHODS: A total of 27 patellar tendons in male Beagles were surgically subjected to stretching by a small diameter (SmD) or a large diameter (LgD) diameter rod to induce damage due to strain, and evaluated at 4- and 8-week intervals using quantitative MRI (qMRI), biomechanical testing, and histology. A separate set of 16 limbs were used as controls. RESULTS: The tendons experienced a 67% and 17% prolongation of short T2* values as compared to controls at 4 and 8 weeks post-operatively, respectively. Histologic analysis displayed a trend of increased collagen disruption at 4 weeks followed by presence of greater organization at 8 weeks. Biomechanical evaluation found a reduction of tendon modulus and failure strain at both time points, and an increase in cross-sectional area at 4 weeks as compared to controls. CONCLUSIONS: These findings display tendon healing in response to an imposed strain and present the utility of qMRI to evaluate longitudinal differences of patellar tendon T2* values in a model of induced subclinical tendon damage. The qMRI technique of UTE provides a means to non-invasively evaluate the healing process of a mechanically damaged tendon.

Impact of New UNOS Allocation Criteria on Heart Transplant Practices and Outcomes.

BACKGROUND: In October 2018, a new heart allocation policy was implemented with intent of prioritizing the sickest patients and decreasing waitlist time. We examined the effects of the new policy on transplant practices and outcomes 1 year before and 1 year after the change. METHODS: Transplant recipients from October 2017 to September 2019 at our institution were identified and divided into 2 cohorts, a preallocation and postallocation criteria change. Patient demographics, clinical data, and bridging strategy were assessed. Early outcomes including ischemic time, severe primary graft dysfunction, need for renal replacement therapy, and duration of hospital stay were investigated. RESULTS: In the 12 months before the change, 38 patients were transplanted as compared to 33 patients in the 12 months after the change. The average wait-time to transplant decreased after the allocation change (49 versus 313 d, P = 0.02). Patients were more likely to be bridged with an intra-aortic balloon pump (45% versus 3%) and less likely to be supported with a durable left ventricular assist device (LVAD) after the change (24% versus 82%). There was an increase in total ischemic time after the change (177 versus 117 min, P ≤ 0.01). There were no significant differences in other early posttransplant outcomes. CONCLUSIONS: Implementation of the new allocation system for heart transplantation resulted in dramatic changes in the bridging strategy utilized at our institution. Temporary mechanical support usage increased following the change and the number of recipients supported with durable LVADs decreased. Early posttransplant outcomes appear similar.

Post-Contrast 3D Inversion Recovery Magnetic Resonance Neurography for Evaluation of Branch Nerves of the Brachial Plexus.

PURPOSE: To compare 3.0 Tesla brachial plexus three-dimensional (3D) T2-weighted short tau inversion recovery fast spin echo (STIR-FSE) MRI sequences before (pre-contrast STIR) and after (post-contrast STIR) administration of gadolinium intravenous contrast. METHOD: Eighteen patients were included. Each patient was imaged before and after intravenous contrast administration during the same session. 3D STIR-FSE sequences were obtained at 3.0 Tesla using two 16-channel flexible coils positioned over the lower neck and chest wall region. Three musculoskeletal radiologists qualitatively assessed degree of vascular signal suppression, visualization of the axillary, musculocutaneous, and suprascapular nerves, diagnostic confidence in nerve evaluation, and lesion conspicuity. Marginal ordinal logistic regression models were used to compare subjective ratings between sequences. Pre- and post-STIR lesion conspicuity was compared using Wilcoxon signed-rank test. Inter- and intra-observer agreements were assessed using Gwet's agreement coefficient. RESULTS: Vascular signal suppression significantly improved following contrast administration (odds ratio, OR = 209.9, 95% confidence interval, CI: 21.0-2094.6, p < .001). The post-contrast STIR technique significantly improved nerve visualization (OR = 8.4, 95% CI: 3.6-19.9, p < .001) and diagnostic confidence in evaluation (OR = 13.2, 95% CI: 4.8-36.0, p < .001) across all nerve segments. Post-contrast STIR improved lesion conspicuity by 1 point, but statistical significance was not reached (Reader 1: p = 0.5, Reader 2: p = 0.063). Post-contrast STIR imaging demonstrated substantial to near-perfect inter- and intra-rater agreement coefficients for both nerve visualization (inter-rater: 0.74-1.0, intra-rater: 0.94-1.0) and diagnostic confidence (inter-rater: 0.79-1.0, intra-rater: 0.94-1.0). Quantitatively, post-contrast STIR demonstrated a 24% increase in mean C6 nerve-to-muscle signal intensity ratio (p = 0.017). CONCLUSIONS: Post-contrast STIR improved nerve-to-muscle contrast ratio, allowing for enhanced visualization and diagnostic confidence in evaluation of branch nerves of the brachial plexus.

Human Monocytic Ehrlichiosis Associated With Myocarditis and Hemophagocytic Lymphohistiocytosis.

We present 3 cases at a single institution of human monocytic ehrlichiosis resulting in myocarditis and hemophagocytic lymphohistiocytosis. Contrary to previously published studies in which case fatalities were only as high as 1%, 2 of the 3 patients we discuss experienced a fulminant course resulting in death despite appropriate doxycycline treatment. Human monocytic ehrlichiosis is rarely a cause of myocarditis and hemophagocytic lymphohistiocytosis, but a high degree of suspicion is important because early empirical therapy may decrease morbidity and mortality. (Level of Difficulty: Intermediate.).

Racial differences in patients referred for right heart catheterization and risk of pulmonary hypertension.

African Americans (AA) have a higher incidence of pulmonary hypertension (PH) risk factors. Few studies have examined the racial differences in the prevalence and etiology of PH and direct comparison of invasive hemodynamics between AAs and Caucasians has rarely been reported. In this study, we examined whether racial differences exist in patients referred for right heart catheterization (RHC) and hypothesized that AA race is an independent risk factor for PH and is associated with increased adjusted mortality. We extracted data for AA and Caucasian patients who underwent RHC at Vanderbilt between 1998 and 2014. Clinical information was obtained from Vanderbilt's Synthetic Derivative, a de-identified mirror of our Electronic Medical Record. A total of 4576 patients were analyzed, including 586 (13%) AAs and 3990 (87%) Caucasians. AAs were younger than Caucasians by an average of eight years, but had more prevalent heart failure, features of metabolic syndrome, and higher creatinine. AAs also had higher mean pulmonary artery pressure and pulmonary vascular resistance. After adjusting for relevant co-morbidities, the AA race is associated with 41% increased risk of PH (odds ratio [OR] = 1.41, 95% confidence interval [CI] = 1.12-1.79). Among patients with PH, AA race is associated with 24% increased adjusted mortality (hazard ratio [HR] = 1.24, 95% CI = 1.09-1.45). AAs were younger but had more prevalent cardiometabolic and renal disease and worse pulmonary hemodynamics. The AA race is an independent risk factor for PH. Among patients with PH, the AA race is associated with increased adjusted mortality. Future studies should focus on delineating whether genetic or environmental factors contribute to PH risk in AAs.

[Expression of porforin and granzyme B in familial hemophagocytic lymphohistiocytosis].

OBJECTIVE: To analyze the correlation between genetic variants of PRF1 and expression level of perforin and granzyme B protein, and further determine the relationship between PRF1 gene variants and cytotoxic T lymphocyte/natural killer (CTL/NK) cell function in famililal hemophagocytic lymphohistiocytosis (FHL2). METHODS: Eight children of FHL2 (P1-P8) after treatment, as well as parents and siblings of P1-P5 were included, and thirty healthy children came for physical examination were designated as controls. PRF1, Unc13D, STX11, STXBP2, RAB27A, LYST, SH2D1A, BIRC4 exons were amplified by PCR and followed by direct sequencing. Bioinformatics analysis of mutant PRF1 was performed by ExPASy online system. Perforin and granzyme B expression on cytotoxic lymphocyte was detected by flow cytometry. RESULTS: ① Three of eight FHL2 children harbored heterozygous missense of PRF1 exons: P1 had compound heterozygous missense mutations (R4C and R33H) and P2 had heterozygous mutations (V50L), P3 had heterozygous mutations (R489W), which confirmed the diagnosis of FHL2. The father (F1) and younger brother (B1) of P1 also had compound heterozygous missense mutation (R4C/R33H), the mother (M2) and younger brother (B2) of P2 had V50L mutation, the father (F3) of P3 had no R489W mutation and the mother of P3 did not participate in this research, so mutation of R4C/R33H of P1 inherited from paternal line, and V50L mutation of P2 came from maternal line, R489W mutation of P3 came from maternal line. ② Comparing to control group, perforin expression of CD8(+) T cells and natural killer (NK) cells of P1, F1, B1, P2, M2 and B2 decreased significantly, but there was no significant difference between two groups in terms of granzyme B expression. CONCLUSIONS: R4C/R33H compound heterozygous mutation and V50L heterozygous mutation all cause lower expression of perforin on CTL/NK cells, and may be causative mutations for familial hemophagocytic lymphohistiocytosis.

Examining intrinsic thalamic resting state networks using graph theory analysis: implications for mTBI detection.

A major challenge associated with understanding mild traumatic brain injury (mTBI) is the absence of biomarkers in standard clinical imaging modalities. Furthermore, the inhomogeneity of mTBI location and intensity, combined with latent symptoms further complicates identification and treatment. A growing body of evidence suggests that the thalamus may be injured or susceptible to change as the result of mTBI. A significant number of connections to and from cortical, subcortical, cerebellar and brain stem regions converge at the thalamus. Furthermore, the thalamus is also involved with information processing, integration and the regulation of specific behaviors. We use graph theory analysis to evaluate intrinsic functional networks of the left and right thalamus in mTBI subjects (N=15) and neurologically intact healthy controls (N=12). We also explore neural correlates of the thalamic network architecture with clinical assessments. Our results suggest the presence of distinct unilateral thalamic differences in mTBI subjects. We also observe correlations of the thalamic changes with clinical assessments. The findings from this study have implications for functional networks in the thalamus and its projections for application as a potential biomarker for mTBI detection.

Oral uracil-tegafur plus leucovorin vs fluorouracil bolus plus leucovorin for advanced colorectal cancer: a meta-analysis of five randomized controlled trials.

AIM: The aim of this study was to evaluate systematically the efficacy and safety of oral uracil-tegafur (UFT) plus leucovorin (LV) compared with infusional fluorouracil (5-FU) plus LV for advanced colorectal cancer. METHOD: Eligible studies were identified from Medline, Embase and the Cochrane Library. The end-points included overall survival and overall tumour response rate, and toxicity including leucopenia, febrile neutropenia, stomatitis/mucositis and diarrhoea. RESULTS: Five randomized controlled trials were identified. Pooled data demonstrated no difference in overall survival between the oral UFT plus LV regimen and the 5-FU bolus plus LV regimen [hazard ratio 1.013; 95% confidence interval (CI) 0.911-1.127].The fixed-effect pooled estimate for overall tumour response rate showed no significant difference between the two regimens (relative risk 0.893; 0.672-1.187). Grade 3-4 leucopenia [odds ratio (OR) 0.126; 955 CI 0.048-0.326], grade 1-4 leucopenia (OR 0.089; 95% CI 0.067-0.119) and grade1-4 febrile neutropenia (OR 0.020; 95% CI 0.004-0.102) were significantly less prominent in the oral UFT regimens. For nonhaematological toxicities, grade 3-4 stomatitis/mucositis (OR 0.075; 95% CI 0.039-0.146), grade 3-4 infection (OR 0.484; 95% CI 0.310-0.758), grade 1-4 infection (OR 0.672; 95% CI 0.547-0.826, P < 0.001), grade 1-4 diarrhoea (OR 0.743; 95% CI 0.626-0.881) were also less likely to happen in patients in the oral UFT plus LV regimen, while there was no significant difference between the two treatment regimens with respect to grade 1-4 stomatitis/mucositis (OR 0.278; 95% CI 0.053-1.456) and grade 3-4 (OR 1.174; 95% CI 0.983-1.403) diarrhoea. CONCLUSION: Oral UFT or 5-FU bolus combined with LV results in similar overall survival and tumour response rates for advanced colorectal cancer. The former treatment regimen is greatly superior in terms of toxicity, especially haematological toxicity.

Electrofusion of a weakly immunogenic neuroblastoma with dendritic cells produces a tumor vaccine.

The absence of surface costimulatory molecules explains in part the lack of an effective anti-tumor immune response in tumor-bearing animals, even though unique tumor antigens may be presented by class I MHC. We determined that the immunogenicity of a murine neuroblastoma, Neuro-2a, which lacks surface costimulatory molecules, could be increased by electrically induced fusion with dendritic cells. Electrofusion induced a higher level of cell fusion than polyethylene glycol, and tumor/dendritic cell heterokaryons expressed high levels of costimulatory molecules. While Neuro-2a was unable to induce the proliferation of syngeneic or allogeneic T cells in vitro, fused cells were able to induce T cell responses both in vitro and in vivo. When fused dendritic tumor cells were used as a cancer vaccine, immunized mice were significantly protected from challenge with Neuro-2a. We propose that electrofusion with patient-derived tumor and dendritic cells may provide a rapid means to produce patient-specific tumor vaccines.