Evaluation of Visible Diffuse Reflectance Spectroscopy in Liver Tissue: Validation of Tissue Saturations Using Extracorporeal Circulation

Significance: Real-time information about oxygen delivery to the hepatic graft is important to direct care and diagnose vascular compromise in the immediate post-transplant period. Aim: The current study was designed to determine the utility of visible diffuse reflectance spectroscopy (vis-DRS) for measuring liver tissue saturation in vivo. Approach: A custom-built vis-DRS probe was calibrated using phantoms with hemoglobin (Hb) and polystyrene microspheres. Ex vivo (extracorporeal circulation) and in vivo protocols were used in a swine model (n=15) with validation via blood gas analysis. Results: In vivo absorption and scattering measured by vis-DRS with and without biliverdin correction correlated closely between analyses. Lin’s concordance correlation coefficients are 0.991 for μa and 0.959 for μs\u27. Hb measured by blood test and vis-DRS with (R2=0.81) and without (R2=0.85) biliverdin correction were compared. Vis-DRS data obtained from the ex vivo protocol plotted against the PO2 derived from blood gas analysis showed a good fit for a Hill coefficient of 1.67 and P50=34  mmHg (R2=0.81). A conversion formula was developed to account for the systematic deviation, which resulted in a goodness-of-fit (R2=0.76) with the expected oxygen dissociation curve. Conclusions: We show that vis-DRS allows for real-time measurement of liver tissue saturation, an indicator for liver perfusion and oxygen delivery

Predicting lymphoma in Sjögren's syndrome and the pathogenetic role of parotid microenvironment through precise parotid swelling recording

Objective: Parotid swelling (PSW) is a major predictor of non-Hodgkin lymphoma (NHL) in primary Sjögren's syndrome (pSS). However, since detailed information on the time of onset and duration of PSW is scarce, this was investigated to verify whether it may lead to further improved prediction. NHL localisation was concomitantly studied to evaluate the role of the parotid gland microenvironment in pSS-related lymphomagenesis. Methods: A multicentre study was conducted among patients with pSS who developed B cell NHL during follow-up and matched controls that did not develop NHL. The study focused on the history of salivary gland and lachrymal gland swelling, evaluated in detail at different times and for different durations, and on the localisation of NHL at onset. Results: PSW was significantly more frequent among the cases: at the time of first referred pSS symptoms before diagnosis, at diagnosis, and from pSS diagnosis to NHL. The duration of PSW was evaluated starting from pSS diagnosis, and the NHL risk increased from PSW of 2-12 months to > 12 months. NHL was prevalently localised in the parotid glands of the cases. Conclusion: A more precise clinical recording of PSW can improve lymphoma prediction in pSS. PSW as a very early symptom is a predictor, and a longer duration of PSW is associated with a higher risk of NHL. Since lymphoma usually localises in the parotid glands, and not in the other salivary or lachrymal glands, the parotid microenvironment appears to be involved in the whole history of pSS and related lymphomagenesis

Lipoprotein-Associated Phospholipase A2: A Novel Contributor in Sjögren’s Syndrome-Related Lymphoma?

BackgroundB-cell non-Hodgkin’s lymphoma (B-NHL) is one of the major complications of primary Sjögren’s syndrome (SS). Chronic inflammation and macrophages in SS minor salivary glands have been previously suggested as significant predictors for lymphoma development among SS patients. Lipoprotein-associated phospholipase A2 (Lp-PLA2)—a product mainly of tissue macrophages—is found in the circulation associated with lipoproteins and has been previously involved in cardiovascular, autoimmune, and malignant diseases, including lymphoma.ObjectiveThe purpose of the current study was to investigate the contributory role of Lp-PLA2 in B-NHL development in the setting of primary SS.MethodsLp-PLA2 activity in serum samples collected from 50 primary SS patients with no lymphoma (SS-nL), 9 primary SS patients with lymphoma (SS-L), and 42 healthy controls (HC) was determined by detection of [3H]PAF degradation products by liquid scintillation counter. Moreover, additional sera from 50 SS-nL, 28 SS-L, and 32 HC were tested for Lp-PLA2 activity using a commercially available ELISA kit. Lp-PLA2 mRNA, and protein expression in minor salivary gland (MSG) tissue samples derived from SS-nL, SS-L patients, and sicca controls (SC) were analyzed by real-time PCR, Western blot, and immunohistochemistry.ResultsSerum Lp-PLA2 activity was significantly increased in SS-L compared to both SS-nL and HC by two independent methods implemented [mean ± SD (nmol/min/ml): 62.0 ± 13.4 vs 47.6 ± 14.4 vs 50.7 ± 16.6, p-values: 0.003 and 0.04, respectively, and 19.4 ± 4.5 vs 15.2 ± 3.3 vs 14.5 ± 3.0, p-values: <0.0001, in both comparisons]. ROC analysis revealed that the serum Lp-PLA2 activity measured either by radioimmunoassay or ELISA has the potential to distinguish between SS-L and SS-nL patients (area under the curve [AUC]: 0.8022, CI [95%]: 0.64–0.96, p-value: 0.004 for radioimmunoassay, and AUC: 0.7696, CI [95%]: 0.66–0.88, p-value: <0.0001, for ELISA). Lp-PLA2 expression in MSG tissues was also increased in SS-L compared to SS-nL and SC at both mRNA and protein level. ROC analysis revealed that both MSG mRNA and protein Lp-PLA2 have the potential to distinguish between SS-nL and SS-L patients (area under the curve [AUC] values of 0.8490, CI [95%]: 0.71–0.99, p-value: 0.0019 and 0.9444, CI [95%]: 0.79–1.00, p- value: 0.0389 respectively). No significant difference in either serum Lp-PLA2 activity or MSG tissue expression was observed between SS-nL and HC.ConclusionsLp-PLA2 serum activity and MSG tissue mRNA/protein expression could be a new biomarker and possibly a novel therapeutic target for B-cell lymphoproliferation in the setting of SS

Aplastic anemia associated with interferon alpha 2a in a patient with chronic hepatitis C virus infection: a case report

<p>Abstract</p> <p>Introduction</p> <p>Hepatitis-associated aplastic anemia is a common syndrome in patients with bone marrow failure. However, hepatitis-associated aplastic anemia is an immune-mediated disease that does not appear to be caused by any of the known hepatitis viruses including hepatitis C virus. In addition, to the best of our knowledge there are no reported cases of patients with chronic hepatitis C virus infection developing aplastic anemia associated with pegylated interferon alpha 2a treatment.</p> <p>Case presentation</p> <p>We report the case of a 46-year-old Greek man who developed severe aplastic anemia during treatment with pegylated interferon alpha 2a for chronic hepatitis C virus infection. He presented with generalized purpura and bruising, as well as pallor of the skin and mucous membranes. His blood tests showed pancytopenia. He underwent allogeneic bone marrow transplantation after completing two courses of immunosuppressive therapy with antithymocyte globulin and cyclosporin A.</p> <p>Conclusions</p> <p>The combination of a specific environmental precipitant represented by the hepatitis C virus infection, an altered metabolic detoxification pathway due to treatment with pegylated interferon alpha 2a and a facilitating genetic background such as polymorphism in metabolic detoxification pathways and specific human leukocyte antigen genes possibly conspired synergistically in the development of aplastic anemia in this patient. Our case clearly shows that the causative role of pegylated interferon alpha 2a in the development of aplastic anemia must not be ignored.</p

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

A randomized trial of ciprofloxacin in the empirical therapy of febrile neutropenic patients

ΣΚΟΠΟΣ ΤΗΣ ΕΡΓΑΣΙΑΣ ΑΥΤΗΣ ΗΤΑΝ ΝΑ ΑΠΟΔΕΙΧΘΕΙ ΕΑΝ Η ΜΟΝΟΘΕΡΑΠΕΙΑ ΜΕ ΜΕΓΑΛΗ ΔΟΣΗ (400 MG X 31V) ΣΙΠΡΟΦΛΟΞΑΣΙΝΗΣ ΕΙΝΑΙ ΑΠΟΤΕΛΕΣΜΑΤΙΚΗ ΣΑΝ ΑΡΧΙΚΗ ΕΜΠΕΙΡΙΚΗ ΑΝΤΙΜΙΚΡΟΒΙΑΚΗ ΘΕΡΑΠΕΙΑ ΣΕ ΛΟΙΜΩΞΕΙΣ ΟΥΔΕΤΕΡΟΠΕΝΙΚΩΝ ΑΣΘΕΝΩΝ ΣΕ ΣΥΓΚΡΙΣΗ ΜΕ ΤΟΝ ΚΛΑΣΙΚΟ ΣΥΝΔΥΑΣΜΟ "ΚΕΦΤΑΖΙΝΤΙΜΗ-ΑΜΙΚΑΣΙΝΗ"(ΟΜΑΔΑ ΜΑΡΤΥΡΩΝ)ΜΕΛΕΤΗΘΗΚΑΝ 120 ΕΜΠΥΡΕΤΑ ΟΥΔΕΤΕΡΟΠΕΝΙΚΑ ΕΠΕΙΣΟΔΙΑ ΕΠΙ 91 ΑΣΘΕΝΩΝ ΟΙ ΟΠΟΙΟΙ ΕΠΑΣΧΑΝ ΚΥΡΙΩΣ ΑΠΟ ΟΞΕΙΑ ΛΕΥΧΑΙΜΙΑ ΚΑΙ ΜΗ HODGKIN ΛΕΜΦΩΜΑ ΥΨΗΛΗΣ ΚΑΟΗΘΕΙΑΣ.ΕΠΙΤΥΧΗΣ ΕΚΒΑΣΗ ΧΩΡΙΣ ΤΡΟΠΟΠΟΙΗΣΗ ΤΗΣ ΑΝΤΙΜΙΚΡΟΒΙΑΚΗΣ ΘΕΡΑΠΕΙΑΣ ΠΑΡΑΤΗΡΗΘΗΚΕ ΣΕ 25/60 (41,7%)ΓΙΑ ΤΗΝ ΟΜΑΔΑ ΤΗΣ ΣΙΠΡΟΦΛΟΞΑΣΙΝΗΣ ΚΑΙ 27/60(45%) ΓΙΑ ΤΗΝ ΟΜΑΔΑ ΤΩΝ ΜΑΡΤΥΡΩΝ (Ρ=0,70).ΣΕ 25/60 (41,7%) ΤΩΝ ΕΠΕΙΣΟΔΙΩΝ ΣΤΗΝ ΟΜΑΔΑ ΤΗΣ ΣΙΠΡΟΦΛΟΞΑΣΙΝΗΣ ΕΓΙΝΕ ΕΠΙΤΥΧΗΣ ΑΝΤΙΚΑΤΑΣΤΑΣΗ ΤΗΣ ΕΝΔΟΦΛΕΒΙΑΣ ΜΕ ΑΠΟ ΤΟΥ ΣΤΟΜΑΤΟΣ ΧΟΡΗΓΗΣΗ ΜΕΤΑ ΑΠΟ ΜΕΣΗ ΤΙΜΗ 4.4 ΗΜΕΡΩΝ ΕΝΔΟΦΛΕΒΙΑΣ ΑΓΩΓΗΣ.ΜΙΚΡΟΒΙΟΛΟΓΙΚΑ ΑΠΟΔΕΔΕΙΓΜΕΝΕΣ ΛΟΙΜΩΞΕΙΣ ΠΑΡΑΤΗΡΗΘΗΚΑΝ ΣΕ 19/60 (31,7%) ΤΩΝ ΕΠΕΙΣΟΔΙΩΝ ΓΙΑ ΤΗΝ ΟΜΑΔΑ ΤΗΣ ΣΙΠΡΟΦΛΟΞΑΣΙΝΗΣ ΚΑΙ 19/60 (31,7%) ΓΙΑ ΤΗΝ ΟΜΑΔΑ ΜΑΡΤΥΡΩΝ ΜΕ ΕΠΙΤΥΧΗ ΕΚΒΑΣΗ ΧΩΡΙΣ ΤΡΟΠΟΠΟΙΗΣΗ ΤΗΣ ΑΝΤΙΜΙΚΡΟΒΙΑΚΗΣ ΘΕΡΑΠΕΙΑΣ ΣΕ 9/19 (47,4%) ΚΑΙ ΣΤΙΣ ΔΥΟ ΟΜΑΔΕΣ (Ρ=0,84).ΟΙ GRAM-ΑΡΝΗΤΙΚΟΙ ΜΙΚΡΟΟΡΓΑΝΙΣΜΟΙ ΚΥΡΙΑΡΧΟΥΣΑΝ ΣΕ ΠΟΣΟΣΤΟ 61,4%.ΣΤΑ ΕΠΕΙΣΟΔΙΑ ΟΠΟΥ Η ΟΥΔΕΤΕΡΟΠΕΝΙΑ (<500/ΜL) ΔΙΗΡΚΗΣΕ ΠΕΡΙΣΣΟΤΕΡΟ ΑΠΟ 14 ΗΜΕΡΕΣ Η ΜΟΝΟΘΕΡΑΠΕΙΑ ΜΕ ΣΙΠΡΟΦΛΟΞΑΣΙΝΗ ΠΑΡΟΥΣΙΑΖΕΤΑΙ 2,54 ΦΟΡΕΣ ΛΙΓΟΤΕΡΟ Η ΜΟΝΟΘΕΡΑΠΕΙΑ ΜΕ ΣΙΠΡΟΦΛΟΞΑΣΙΝΗ ΠΑΡΟΥΣΙΑΖΕΤΑΙ 2,54 ΦΟΡΕΣ ΛΙΓΟΤΕΡΟ ΑΠΟΤΕΛΕΣΜΑΤΙΚΗ ΣΕ ΣΥΓΚΡΙΣΗ ΜΕ ΤΟΝ ΣΥΝΔΥΑΣΜΟ ΚΕΦΤΑΖΙΝΤΙΜΗ + ΑΜΙΚΑΣΙΝΗ (Ρ=0,0191)

Toll-Like Receptors, Tissue Injury, and Tumourigenesis

Toll-like receptors (TLRs) belong to a class of molecules known as pattern recognition receptors, and they are part of the innate immune system, although they modulate mechanisms that impact the development of adaptive immune responses. Several studies have shown that TLRs, and their intracellular signalling components, constitute an important cellular pathway mediating the inflammatory process. Moreover, their critical role in the regulation of tissue injury and wound healing process as well as in the regulation of apoptosis is well established. However, interest in the role of these receptors in cancer development and progression has been increasing over the last years. TLRs are likely candidates to mediate effects of the innate immune system within the tumour microenvironment. A rapidly expanding area of research regarding the expression and function of TLRs in cancer cells and its association with chemoresistance and tumourigenesis, and TLR-based therapy as potential immunotherapy in cancer treatment is taking place over the last years

MDR1 mRNA expression and MDR1 gene variants as predictors of response to chemotherapy in patients with acute myeloid leukaemia: a meta-analysis

Data from 30 pharmacogenomic studies that investigated MDR1 mRNA expression or gene variants (C3435T, G2677TA, C1236T) and response to therapy in acute myeloid leukaemia (AML) were synthesized. Anthracycline-based regimens were mainly used. MDR1 mRNA overexpression was associated with poor response to therapy [odds ratio (OR) = 2.49 95% confidence interval (Cl) 1.38-4.50]. The gene variants were not associated with response to treatment; the generalized ORs, a genetic model-free approach, for the variants C3435T, G2677TA and C1236T were ORG = 0.86 (95% CI 0.55-1.37), ORG = 0.97 (95% CI 0.58-1.64) and ORG = 1.17 (95% CI 0.75-1.83), respectively. There is indication that MDR1 mRNA expression may be considered as a potential marker for response to chemotherapy in AML patients