Strategies for B-lymphocyte repertoire remodeling in transplantation tolerance

Transplantation tolerance remains an elusive goal as B-cell-initiated chronic humoral rejection evades current immunosuppression. B-cell-directed therapy is thus emerging as a key component in achieving transplantation tolerance and long-term graft survival. Here, we propose strategies of B-cell repertoire remodeling to achieve humoral unresponsiveness to donor antigens with implementation of fundamental B-cell immunobiology and use of newly developed B-cell-directed agents.     

Neonatal Hyperbilirubinemia in infants with G6PD c.563C > T Variant

ABSTRACT: BACKGROUND: There is a strong correlation between glucose-6-phosphate dehydrogenase (G6PD) deficiency and neonatal hyperbilirubinemia with a rare but potential threat of devastating acute bilirubin encephalopathy. G6PD deficiency was observed in 4-14% of hospitalized icteric neonates in Pakistan. G6PD c.563C > T is the most frequently reported variant in this population. The present study was aimed at evaluating the time to onset of hyperbilirubinemia and the postnatal bilirubin trajectory in infants having G6PD c.563C > T. METHODS: This was a case-control study conducted at The Aga Khan University, Pakistan during the year 2008. We studied 216 icteric male neonates who were re-admitted for phototherapy during the study period. No selection was exercised. Medical records showed that 32 were G6PD deficient while 184 were G6PD normal. Each infant was studied for birth weight, gestational age, age at the time of presentation, presence of cephalhematoma, sepsis and neurological signs, peak bilirubin level, age at peak bilirubin level, days of hospitalization, whether phototherapy or exchange blood transfusion was initiated, and the outcome. During hospital stay, each baby was tested for complete blood count, reticulocyte count, ABO and Rh blood type, direct antiglobulin test and quantitative G6PD estimation [by kinetic determination of G6PDH]. G6PDgenotype was analyzed in 32 deficient infants through PCRRFLP analysis and gene sequencing. RESULTS: G6PD variants c.563C > T and c.131 C > G were observed in 21 (65%) and three (9%) of the 32 G6PD deficient infants, respectively. DNA of eight (25%) newborns remained uncharacterized. In contrast to G6PD normal neonates, infants with c.563C > T variant had significantly lower enzyme activity (mean +/- 1SD; 0.3 +/- 0.2 U/gHb vs. 14.0 +/- 4.5 U/gHb, p < 0.001) experienced higher peak levels of total serum bilirubin (mean +/- 1SD; 16.8 +/- 5.4 mg/dl vs. 13.8 +/- 4.6 mg/dl, p = 0.008) which peaked earlier after birth (mean +/- 1SD 2.9 +/- 1.6 vs. 4.3 +/- 2.3 days, p = 0.007). No statistically significant difference was observed in mean weight, age at presentation, hemoglobin, reticulocyte count, TSH level, hospital stay or in the frequency of initiation of phototherapy or blood exchange between the two groups. CONCLUSIONS: We concluded that infants with G6PD c.563C > T variant developed jaundice earlier than infants with normal G6PD enzyme levels. Compared to G6PD normal infants, G6PD c.563C > T carrying infants had significantly low G6PD activity.     

Critical analysis of literature on low-dose synergy for use in screening chemical mixtures for risk assessment

There is increasing interest in the use of tiered approaches in risk assessment of mixtures or co-exposures to chemicals for prioritization. One possible screening-level risk assessment approach is the threshold of toxicological concern (TTC). To date, default assumptions of dose or response additivity have been used to characterize the toxicity of chemical mixtures. Before a screening-level approach could be used, it is essential to know whether synergistic interactions can occur at low, environmentally relevant exposure levels. Studies demonstrating synergism in mammalian test systems were identified from the literature, with emphasis on studies performed at doses close to the points of departure (PODs) for individual chemicals. This search identified 90 studies on mixtures. Few included quantitative estimates of low-dose synergy; calculations of the magnitude of interaction were included in only 11 papers. Quantitative methodology varied across studies in terms of the null hypothesis, response measured, POD used to test for synergy, and consideration of the slope of the dose-response curve. It was concluded that consistent approaches should be applied for quantification of synergy, including that synergy be defined in terms of departure from dose additivity; uniform procedures be developed for assessing synergy at low exposures; and the method for determining the POD for calculating synergy be standardized. After evaluation of the six studies that provided useful quantitative estimates of synergy, the magnitude of synergy at low doses did not exceed the levels predicted by additive models by more than a factor of 4.     

In-hospital acute upper gastrointestinal bleeding: What is the scope of the problem?

BACKGROUND Acute upper gastrointestinal bleeding(AUGIB) is a frequently encountered condition in the Gastroenterology field with a mortality rate of 10-14%. Despite recent newer innovations and advancements in endoscopic techniques and available medications, the mortality rate associated with AUGIB remained persistently elevated.AIM To explore mortality, characteristics and outcome differences between hospitalized patients who develop AUGIB while in-hospital, and patients who initially present with AUGIB.METHODS This is a retrospective of patients who presented to Northwell Health Staten Island University Hospital from October 2012 to October 2016 with AUGIB that was confirmed endoscopically. Patients were divided in two groups: Group 1 comprised patients who developed AUGIB during their hospital stay; group 2 consisted of patients who initially presented with AUGIB as their main complaint. Patient characteristics, time to endoscopy, endoscopy findings andinterventions, and clinical outcomes were collected and compared between groups.RESULTS A total of 336 patients were included. Group 1 consisted of 139 patients and group 2 of 196 patients. Mortality was significantly higher in the 1 st group compared to the 2 nd(20% vs 3.1%, P ≤ 0.05). Increased length of stay(LOS) was noted in the 1 st group(13 vs 6, P ≤ 0.05). LOS post-endoscopy, vasopressor use,number of packed red blood cell units and patients requiring fresh frozen plasma were higher in group 1. Inpatients were more likely to be on corticosteroids,antiplatelets and anticoagulants. Conversely, the mean time from bleeding to undergoing upper endoscopy was significantly lower in group 1 compared to group 2.CONCLUSION In-hospital AUGIB is associated with high mortality and morbidity despite a shorter time to endoscopy. Larger scale studies assessing the role of increased comorbidities and antithrombotic use in this setting are warranted.     

Tissue Repair Response as a Function of Dose during Trichloroethylene Hepatotoxicity

Trichloroethylene (TCE), a widely used organic solvent and degreasingagent, is regarded as a hepatotoxicant. The objective of thepresent studies was to investigate whether the extent and timelinessof tissue repair has a determining influence on the ultimateoutcome of hepatotoxicity. Male Sprague-Dawley rats (200–250g) were injected with a 10-fold dose range of TCE and hepatotoxicityand tissue repair were studied during a time course of 0 to96 h. Light microscopic changes as evaluated by H&E-stainedliver sections revealed a dose-dependent necrosis of hepaticcells. Maximum liver cell necrosis was observed at 48 h afterthe TCE administration. However, liver injury as assessed byplasma sorbitol dehydrogenase (SDH) showed a dose response overa 10-fold dose range only at 6 h, whereas alanine aminotrans-ferase(ALT) did not show a dose response at any of the time pointsstudied. A low dose of TCE (250 mg/kg) showed an increase inSDH at all time points up to 96 h without peak levels, whereashigher doses showed peak only at 6 h. At later time points SDHdeclined but remained above normal. In vitro addition of trichloroaceticacid, a metabolite of TCE to plasma, decreased the activitiesof SDH and ALT indicating that metabolites formed during TCEtoxicity may interfere with plasma enzyme activities in vivo.This indicates that the lack of dose-related increase in SDHand ALT activities may be because of interference by the TCEmetabolite. Tissue regeneration response as measured by [³H]thymidineincorporation into hepatocellular nuclear DNA was stimulatedmaximally at 24 h after 500 mg/kg TCE administration. A higherdose of TCE led to a delay and diminishment in [³H]thymidineincorporation. At a low dose of TCE (250 mg/kg) [³H]thymidineincorporation peaked at 48 h and this could be attributed tovery low or minimal injury caused by this dose. With higherdoses tissue repair was delayed and attenuated allowing forunrestrained progression of liver injury. These results supportthe concept that the toxicity and repair are opposing responsesand that a dose-related increase in tissue repair representsa dynamic, quantifiable compensatory mechanism.     

A systemic downregulation of gamma interferon production is associated with acute shigellosis.

Production of cytokines by peripheral blood mononuclear cells from Shigella-infected patients was assessed. The frequencies of tumor necrosis factor alpha (TNF-alpha), TNF-beta, and transforming growth factor beta mRNA-expressing cells were persistently upregulated during the course of shigellosis in comparison to those of healthy controls. In contrast, the frequency of gamma interferon (IFN-gamma) mRNA-expressing cells was significantly reduced during the acute stage compared to that during the convalescent stage and to that of healthy Bangladeshi controls (P < 0.01). Constitutive IFN-gamma production in Bangladeshi controls was significantly upregulated compared to that in Swedish controls.