Human liver derived mesenchymal stromal cells ameliorate murine ischemia-induced inflammation through macrophage polarization.

Introduction: The immunomodulatory properties of mesenchymal stromal cells (MSC) have been well-characterized in in-vitro and in-vivo models. We have previously shown that liver MSC (L-MSC) are superior inhibitors of T-cell activation/proliferation, NK cell cytolytic function, and macrophage activation compared to adipose (A-MSC) and bone marrow MSC (BM-MSC) in-vitro. Method: To test these observations in-vivo, we infused these types of MSC into mice with unilateral renal artery stenosis (RAS), an established model of kidney inflammation. Unilateral RAS was induced via laparotomy in 11-week-old, male 129-S1 mice under general anesthesia. Control mice had sham operations. Human L-MSC, AMSC, and BM-MSC (5x105 cells each) or PBS vehicle were injected intra-arterially 2 weeks after surgery. Kidney morphology was studied 2 weeks after infusion using micro-MRI imaging. Renal inflammation, apoptosis, fibrosis, and MSC retention were studied ex-vivo utilizing western blot, immunofluorescence, and immunohistological analyses. Results: The stenotic kidney volume was smaller in all RAS mice, confirming significant injury, and was improved by infusion of all MSC types. All MSC-infused groups had lower levels of plasma renin and proteinuria compared to untreated RAS. Serum creatinine improved in micetreated with BM- and L-MSC. All types of MSC located to and were retained within the stenotic kidneys, but L-MSC retention was significantly higher than A- and BM-MSC. While all groups of MSC-treated mice displayed reduced overall inflammation and macrophage counts, L-MSC showed superior potency in-vivo at localizing to the site of inflammation and inducing M2 (reparative) macrophage polarization to reduce inflammatory changes. Discussion: These in-vivo findings extend our in-vitro studies and suggest that L-MSC possess unique anti-inflammatory properties that may play a role in liver-induced tolerance and lend further support to their use as therapeutic agents for diseases with underlying inflammatory pathophysiology.

Liver fibrosis in children: a comprehensive review of mechanisms, diagnosis, and therapy.

Chronic liver disease incidence is increasing among children worldwide due to a multitude of epidemiological changes. Most of these chronic insults to the pediatric liver progress to fibrosis and cirrhosis to different degrees. Liver and immune physiology differs significantly in children from adults. Because most of pediatric liver diseases have no definitive therapy, a better understanding of population and disease-specific fibrogenesis is mandatory. Furthermore, fibrosis development has prognostic significance and often guide treatment. Evaluation of liver fibrosis continues to rely on the gold-standard liver biopsy. However, many high-quality studies put forward the high diagnostic accuracy of numerous diagnostic modalities in this setting. Herein, we summarize and discuss the recent literature on fibrogenesis with an emphasis on pediatric physiology along with a detailed outline of disease-specific signatures, noninvasive diagnostic modalities, and the potential for antifibrotic therapies.

Liver mesenchymal stem cells are superior inhibitors of NK cell functions through differences in their secretome compared to other mesenchymal stem cells.

Liver-resident mesenchymal stem cells (L-MSCs) are superior inhibitors of alloreactive T cell responses compared to their counterparts from bone marrow (BM-MSCs) or adipose tissue (A-MSCs), suggesting a role in liver's overall tolerogenic microenvironment. Whether L-MSCs also impact NK cell functions differently than other MSCs is not known. We generated and characterized L-MSCs, A-MSCs and BM-MSCs from human tissues. The mass spectrometry analysis demonstrated that L-MSC secretome is uniquely different than that of A-MSC/BM-MSC, with enriched protein sets involved in IFNγ responses and signaling. When co-cultured with primary human NK cells, L-MSCs but not other MSCs, decreased surface expression of activating receptors NKp44 and NKG2D. L-MSCs also decreased IFNγ secretion by IL-2-stimulated NK cells more effectively than other MSCs. Cytolytic function of NK cells were reduced significantly when co-cultured with L-MSCs, whereas A-MSCs or BM-MSCs did not have a major impact. Mechanistic studies showed that the L-MSC-mediated reduction in NK cell cytotoxicity is not through changes in secretion of the cytotoxic proteins Perforin, Granzyme A or B, but through increased production of HLA-C1 found in L-MSC secretome that inhibits NK cells by stimulating their inhibitory receptor KIRDL2/3. L-MSCs are more potent inhibitors of NK cell functions than A-MSC or BM-MSC. Combined with their T cell inhibitory features, these results suggest L-MSCs contribute to the tolerogenic liver microenvironment and liver-induced systemic tolerance often observed after liver transplantation.

Bone marrow derived long-lived plasma cell phenotypes are heterogeneous and can change in culture.

Bone marrow-derived long-lived plasma cells (LLPCs) are thought to be a major source of alloantibody in sensitized transplant patients. However, studies of LLPCs have been hampered not only by the fact that they are rare and difficult to isolate and culture but also due to the lack of consensus regarding a definitive cell-surface phenotype. The goal of the current study was to determine if LLPCs have a specific, stable cell-surface phenotype. PCs were isolated from high-volume (120cc) bone marrow aspirates that were enriched first by negative selection then positive selection using anti-CD38 antibody-coated beads and purified by cell sorting. A typical isolation resulted in >100,000 PCs that were sorted into 4 populations with variable numbers of PCs: CD19+/CD138+/CD38Hi (64.1% of the PCs), CD19-/CD138+/CD38Hi (20.9%), CD19+/CD138-/CD38Hi (10.7%), and CD19-/CD138-/CD38Hi (4.3%). The purity of each subset was 96-99%. Each subset contained PCs secreting IgG and IgA. Measles- and tetanus-specific PCs (i.e. putative IgG secreting, antigen-specific LLPCs). LLPCs were identified in both the CD19+/CD138+/CD38Hi and CD19-/CD138+/CD38Hi subsets and in the smaller CD138- subsets (when pooled). Thus, all CD38Hi subsets contained LLPCs. Cultured PCs maintained viability (>50%) and function and could be retrieved for analyses. During 7 days of culture, cell surface expression changed from baseline in many PCs. For example, approximately 20% of CD19 + CD138+/CD38Hi cells (the largest PC subset) became CD19-. CFSE assays showed no division and only a small percentage of LLPCs were Ki-67 positive suggesting that the cells did not divide in culture and that the antibody detected was not from plasmablasts. We conclude that human bone marrow LLPCs have a heterogeneous expression of CD19 and CD138, which can change during cell culture. The fact that LLPCs were found in all four subsets raises the possibility that a large percentage of PCs in the bone marrow may be LLPCs.

Liver involvement in neuroblastoma amplified sequence gene deficiency is not limited to acute injury: Fibrosis silently continues.

Biallelic mutations in neuroblastoma amplified sequence gene (NBAS) is a rare disease which is characterized by recurrent liver failure (RALF). We reported the novel mutations, clinical characteristics and long-term outcomes of 5 patients with novel biallelic NBAS variants. Four patients (80%) had acute, episodic liver crises (LC) triggered by fever, with a median age of onset of 8.5 months. The median age in the last episode was 34 months. Median number of liver episodes was 4. The course of ALF was complicated by hepatic encephalopathy and hypoglycaemia in all patients with ALF. Two patients recovered with conservative treatment, 2 required liver transplantation (LT) and 1 died during the fourth episode. Long-term post-transplant follow-up showed normal liver function and histology. There is no hepatic or extrahepatic recurrence after LT. Non-transplanted patients exhibited fibrosis in either biopsy or elastography. Despite a reduction in the frequency of clinically significant episodes, patients may exhibit ongoing liver injury and fibrosis. An acute on chronic liver failure with predominant cholestasis can be an alternative presentation.

Disease Course and Treatment Response of Eosinophilic Gastrointestinal Diseases in Children With Liver Transplantation: Long-Term Follow-Up.

INTRODUCTION: To describe the clinical and laboratory profile, natural course, treatment outcome, and risk factors of posttransplant esophageal and nonesophageal eosinophilic gastrointestinal disorders (EGIDs). METHODS: All children (aged <18 years) who underwent liver transplantation, between 2011 and 2019, in a single transplant center with a follow-up period of 1 year or more posttransplant and with a history of posttransplant endoscopic evaluation were included in this study. RESULTS: During the study period, 89 children met the inclusion criteria. Patients were followed for a median of 8.0 years. A total of 39 (44%) patients were diagnosed with EGID after transplantation. Of these, 29 (33%) had eosinophilic esophagitis (EoE), and 10 (11%) had eosinophilic gastritis, gastroenteritis or enterocolitis. In comparison with the non-EGID group, patients with EGID were younger at transplant (P ≤ 0.0001), transplanted more frequently due to biliary atresia (P ≤ 0.0001), and had higher rates of pretransplant allergy (P = 0.019). In the posttransplant period, they had higher rates of mammalian Target of Rapamycin inhibitor use (P = 0.006), Epstein-Barr virus viremia (P = 0.03), post-transplant lymphoproliferative disease (P = 0.005), and allergen sensitization (P ≤ 0.0001). In regression analysis, young age at transplant, age at diagnosis, pretransplant atopic dermatitis, and post-transplant lymphoproliferative disease were associated with an increased risk of EGID or EoE. Laboratory abnormalities such as anemia (P = 0.007), thrombocytosis (P = 0.012), and hypoalbuminemia (P = 0.031) were more commonly observed in the eosinophilic gastritis, gastroenteritis or enterocolitis group than in the EoE group. Following treatment, most patients had symptomatic resolution at 3 months and histologic resolution at 6 months postdiagnosis. Among the patients who had 5 years of follow-up, none recurred. DISCUSSION: EGID is a common posttransplant diagnosis, which seems to affect patients who are transplanted earlier and who have pretransplant atopy. Posttransplant EGID is responsive to treatment, but as histologic remission occurs after symptomatic resolution, the decision to perform control endoscopy should be delayed.

Serum osmolarity as a potential predictor for contrast-induced nephropathy following elective coronary angiography.

BACKGROUND AND OBJECTIVES: Contrast-induced nephropathy (CIN) is a relatively common complication following primary coronary angiography (CAG) or percutaneous coronary intervention (PCI), especially in at-risk patients. The goal of this study is to evaluate the role of pre-procedural serum osmolarity as a risk factor for CIN in patients undergoing elective CAG for stable coronary artery disease (CAD). MATERIALS AND METHODS: A total of 356 stable CAD patients scheduled to undergo CAG or PCI were included in this two-center study. Serum osmolarity was calculated on admission. CIN was defined according to the KDIGO criteria. RESULTS: There were 45 (12.6%) patients who developed CIN 48-72 h after CAG or PCI. CIN patients had a higher prevalence of diabetes (51.1% in those with CIN vs 24.4% in those without CIN, p < 0.001), higher serum glucose (129 mg/dL in those with CIN vs 108 mg/dL in those without CIN, p < 0.001), blood urea nitrogen (22.4 mg/dL in those with CIN vs 19.0 mg/dL in those without CIN, p = 0.01) and serum osmolarity (294.2 mOsm in those with CIN vs 290.1 mOsm in those without CIN, p < 0.001) levels, had received a higher dose of contrast (250 mL in those with CIN vs 200 mL in those without CIN, p = 0.03) but had lower hemoglobin (12.9 g/dL in those with CIN vs 13.6 g/dL in those without CIN, p = 0.04) level. In multivariate analysis, serum osmolarity [odds ratio (OR) 1.11; 95% confidence interval (CI) 1.04-1.18 for each mOsm/L increase; p = 0.001], diabetes (OR 2.43, 95% CI 1.26-4.71; p = 0.01), C-reactive protein (OR 1.04, 95% CI 1.01-1.08 for each mg/dL increase; p = 0.02) and contrast volume (OR 34.66, 95% CI 1.25-962.22 for each L increase; p = 0.04) remained as independent predictors of CIN. Serum sodium, glucose and blood urea nitrogen contributed to the excess serum osmolarity of CIN patients. CONCLUSION: Serum osmolarity is a cheap and widely available marker that can reliably predict CIN after CAG or PCI. Future research should focus on determining a clinically optimal cutoff for serum osmolarity that would warrant preventive interventions. Furthermore, later research may investigate the role of serum osmolarity not only as a risk factor but also as a pathogenetic mechanism underlying CIN.

Elevation in serum uric acid levels predicts favourable response to erlotinib treatment in patients with metastatic non-small-cell lung cancer.

WHAT IS KNOWN AND OBJECTIVE: Erlotinib is a small molecule tyrosine kinase inhibitor which blocks the activation of epidermal growth factor receptor (EGFR), a transmembrane receptor that is upregulated in many cancer types. Inhibition of angiogenesis with consequent impairments in intratumoral microcirculation is one of the mechanisms through which EGFR inhibition halts the progression of cancer. A consequence of impaired microcirculation is intratumoral hypoxia, which results in increases in serum uric acid levels. The goal of this study was to investigate the relationship between serum uric acid levels and response to erlotinib in metastatic non-small-cell lung cancer (NSCLC). METHODS: A total of 56 patients with metastatic non-small-cell lung cancer who received erlotinib for a duration of at least 3 months were included in this retrospective cohort study. Demographic characteristics, progression status, baseline serum uric levels and 3-month serum uric acid levels were recorded and analysed. RESULTS AND DISCUSSION: Of the study population, 21 (37.5%) were female and 35 (62.5%) were male patients. No significant difference in above demographic characteristics was observed among exitus, survivor with progression and survivor without progression groups. Patients who responded favourably to erlotinib with no progression of their disease had significantly increased uric acid levels at 3-month follow-up (P = .01). Such a correlation was not observed if the patient was exitus (P = .47) or had progressed on erlotinib therapy (P = .19). WHAT IS NEW AND CONCLUSION: In conclusion, this study is the first to demonstrate significant increases in serum uric acid levels in patients with metastatic NSCLC who responded favourably to erlotinib and had no progression under erlotinib therapy. Further studies are required to confirm and characterize serum uric acid as a novel biomarker in predicting the outcome in those with metastatic NSCLC.

Bladder Artery Embolization for Massive Hematuria Treatment in a Patient With Ataxia-Telangiectasia Acute Lymphoblastic Leukemia.

Ataxia-telangiectasia (AT) is a hereditary recessive autosomal disorder following a course of progressive cerebellar ataxia, and oculocutaneous telangiectasia. Disease-specific telangiectasias are generally localized in the oculocutaneous region, while telangiectasias located within the bladder are rarely seen in patients with AT. The patient who had been followed-up with a diagnosis of AT since the age of 3 years was later diagnosed with acute lymphoblastic leukemia at the age of 8 years. The patient developed hematuria approximately in the 29th month of treatment. The cystoscopy revealed regions of extensive hemorrhagic telangiectasis, which was interpreted as the bladder involvement of AT. The case presented here underwent several cycles of intravesical steroid and tranexamic acid treatments and intravesical cauterization procedures, but the patient was unresponsive to all medical treatment approaches. The patient was consequently evaluated by an interventional radiology unit for a selective arterial embolization. The patient's hematuria resolved after embolization. Bladder wall telangiectasia may, on rare occasions, develop in patients with AT, and can result in life-threatening hemorrhages. We also suggest that a selective arterial embolectomy can be safely carried out in pediatric patients with treatment-resistant intravesical bleeding.

The Role of Liver Transplantation in Alcoholic Hepatitis.

Acute alcoholic hepatitis is a syndrome of jaundice and hepatic decompensation that occurs with excessive alcohol consumption. The diagnosis can be made with a combination of clinical characteristics and laboratory studies, though biopsy may be required in unclear cases. Acute alcoholic hepatitis can range from mild to severe disease, as determined by a Maddrey discriminant function ≥32. Mild forms can be managed with supportive care and abstinence from alcohol. While mild form has an overall good prognosis, severe alcoholic hepatitis is associated with an extremely high short-term mortality of up to 50%. Additional complications of severe alcoholic hepatitis can include hepatic encephalopathy, gastrointestinal bleeding, renal failure, and infection; these patients frequently require intensive care unit admission. Corticosteroids may have short-term benefit in this group of patients if there are no contraindications; however, a subset of patients do not respond to steroids. New emerging therapies, which target hepatic regeneration, bile acid metabolism, and extracorporeal liver support, are being investigated. Liver transplantation for alcoholic liver disease was traditionally only considered in patients who have achieved 6 months of abstinence, in part due to social and ethical concerns regarding the use of a limited resource. However, the majority of patients with severe alcoholic hepatitis who fail medical therapy will not live long enough to meet this requirement. Recent studies have demonstrated that early liver transplantation in carefully selected patients with severe alcoholic hepatitis who fail medical therapy can provide a significant survival benefit and yields survival outcomes comparable to liver transplantation for other indications, with 6-month survival rates ranging from 77% to 100%. Alcohol relapse posttransplantation remains an important challenge, and heavy consumption can contribute to graft loss and mortality. Future investigation should address the substantial post-liver transplantation recidivism rate, from improving selection criteria to increasing posttransplantation substance abuse treatment resources.

An unusual cause of terminal hematuria in a child: Eosinophilic cystitis.

Eosinophilic cystitis is a rare inflammatory disease of the bladder; it rarely occurs in children. Patients typically show irritative urination symptoms frequently, with a possible need for urgency, alongside dysuria, gross haematuria, suprapubic pain and painful urination. Sometimes bladder mass accumulation with the possibility of malignancy is also observed. We present an 8-year-old male patient who gained admission for terminal hematuria and discuss the management of eosinophilic cystitis.