Improved survival in steroid-refractory acute graft versus host disease after non-myeloablative allogeneic transplantation using a daclizumab-based strategy with comprehensive infection prophylaxis

Approximately 15% of patients undergoing non-myeloablative allogeneic haematopoietical cell transplantation (NMHCT) develop steroid-refractory acute-graft versus host disease (aGVHD), a usually fatal complication. We encountered 18 cases of steroid-refractory aGVHD in 146 patients, undergoing NMHCT from a related human leucocyte antigen-compatible donor following cyclophosphamide/fludarabine-based conditioning. Our initial cohort of steroid-refractory aGVHD patients treated with antithymocyte globulin (ATG) and mycophenolate mofetil (regimen-1: n = 6) had high GVHD-related mortality. Therefore, we investigated an alternative strategy for subsequent patients developing this complication (regimen-2: n = 12), consisting of daclizumab (alone or combined with infliximab/ATG) and targeted broad spectrum antibacterial and aspergillus prophylaxis in conjunction with rapid tapering of steroids to minimize opportunistic infections. In a retrospective analysis, patients receiving regimen-2 were significantly more likely to have complete resolution of GVHD compared with those receiving regimen-1 [12/12 (100%) vs. 1/6 (17%); P < 0.001]. When compared with those receiving regimen-1, regimen-2 patients also had a higher probability of survival at day 100 (100% vs. 50%) and day 200 (73% vs. 17%) post-transplant, and improved overall survival (median 453 d vs. 42 d from aGVHD onset; P < 0.0001). GVHD-related mortality was 89% for regimen-1 patients vs. 17% for regimen-2 patients (P < 0.0001). These data suggest that a co-ordinated approach using immunoregulatory monoclonal antibodies, pre-emptive antimicrobial therapy and judicious steroid withdrawal can dramatically improve outcome in steroid-refractory aGVHD.     

Green fluorescent protein expression in dendritic cells enhances their immunogenicity and elicits specific cytotoxic T-cell responses in humans

OBJECTIVE: Green fluorescent protein (GFP) has been used to monitor and select cells transduced with vectors encoding other transgenes of interest. We investigated the immunogenic nature of GFP in humans and further explored whether this xenoprotein could be used as a functional adjuvant to enhance T-cell immunity to the melanoma tumor antigen MART1. METHODS: Peripheral blood lymphocytes from healthy donors were stimulated by autologous dendritic cells expressing GFP, then cloned by limiting dilution and tested for antigen specificity following coculture with GFP-expressing or GFP-negative targets. In a parallel experiment, lymphocytes from HLA A 0201+ healthy donors were stimulated with four different Melan-A/MART1(27-35) peptide-pulsed stimulators: 1) MART1 peptide-pulsed DCs, 2) MART1 peptide-pulsed DCs loaded with GFP protein, 3) MART1 peptide-pulsed GFP adenovirus-transduced DCs, and 4) MART1 peptide-pulsed null adenovirus-transduced DCs. The percentage of CD3+/CD8+ MART1 peptide-specific T cells was determined by intracellular cytokine staining for gamma-IFN. RESULTS: Multiple CD4+ and CD8+ T cell clones were expanded which secreted gamma-IFN and demonstrated high levels of cytotoxicity to GFP-expressing targets as assessed by ELISA and Cr51 release respectively. We next investigated the impact of GFP expression on DCs used to stimulate cytotoxic T cells specific for a tumor-associated peptide. The percentage of MART1- specific CD8+ T cells that were generated was higher when MART1-pulsed GFP adenovirus-transduced DCs were used as stimulators (28%) compared to MART1-pulsed DCs alone (11%, p = 0.01), MART1-pulsed null adenovirus-transduced DCs (11.7%, p = 0.02), or MART1-pulsed DCs loaded with GFP protein (12.2%). CONCLUSIONS: These findings further support GFP's immunogenicity and suggest this xenoprotein might further be used to enhance the expansion of tumor-specific T cells.     

Low density lipoprotein retention by aortic tissue. Contribution of extracellular matrix

We compared in vitro heparin binding activity and in vivo intravascular clearance and aortic uptake in rabbits of native, reductively methylated and heparin-complexed low density lipoprotein (LDL) in order to explore the extracellular matrix binding vs cellular metabolism of LDL. Reductively methylated LDL formed soluble and insoluble complexes with heparin which was comparable to native LDL. Reductive methylation of LDL produced only 30% reduction in aortic uptake vs 60% reduction in plasma clearance, reflecting the relatively smaller contribution of receptor-mediated pathway in aortic tissue vs whole animal. The intravascular clearance of native and heparin-complexed LDL remained essentially the same, indicating similarities in cellular metabolism of LDL in both cases. But the aortic uptake of the heparin bound LDL was 30% less than the native LDL, suggesting an inhibition in binding of heparin-complexed LDL to tissue proteoglycans. Saline extraction accounted for only part (53-66%) of the LDL preparations that were retained by the tissue while subsequent collagenase and elastase treatments extracted 3-5% and 17-22% of the materials respectively. These results favor the contribution of arterial extracellular matrix components to the retention of LDL.     

Serum lipoprotein profile in children from a biracial community: the Bogalusa Heart Study.

Serum lipoprotein profiles in 3182 children, ages 5-14 years, were studied in a biracial community as part of the Bogalusa Heart Study to describe the early natural history of atherosclerosis. White and black children showed similar mean levels of beta-lipoproteins. Pre-beta-lipoprotein levels, however, were significantly higher in white shildren, while significantly higher levels of alpha-lipoprotein were found in black children. Girls had generally higher levels of beta- and pre-beta-lipoprotein and lower levels of alpha-lipoprotein than boys, although the differences were not significant at each age group. With age there was little change in alpha-lipoprotein levels, a significant increase in pre-beta-lipoprotein levels and a slight but significant decrease between 11 and 14 years in beta-lipoprotein levels. The correlation of alpha-lipoprotein was negative with beta-lipoprotein and, to a greater extent, with pre-beta-lipoprotein. The above inverse relationships were significantly greater in white children than in black children, suggesting differences in lipoprotein profiles in the two groups. Lipoprotein values from a total community study are now available for comparison with the currently recommended upper normal limits for lipoproteins. Since only a very small percentage of children could be considered as hyperlipoproteinemic by those specific levels in this community, we suggest that distributions and percentiles be used to evaluate children for hyperlipoproteinemia.     

Rate of change in adiposity and its relationship to concomitant changes in cardiovascular risk variables among biracial (black-white) children and young adults: The Bogalusa Heart Study

To assess the annual rate of change in adiposity and its relationship to concomitant changes in cardiovascular risk variables during childhood and young adulthood, serial data on black and white children (n = 3,459; initial and follow-up mean age, 8.1 and 14.4 years) and young adults (n = 1,263; initial and follow-up mean age, 22.5 and 30.9 years) enrolled in the Bogalusa Heart Study were examined. Body mass index (BMI) and sum of subscapular and triceps skinfolds were used as indicators of adiposity. In addition, measurements were made of systolic and diastolic blood pressure and fasting levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, insulin, and glucose. Annualized rate of change for each variable was estimated. The rate of increase in adiposity was significantly more pronounced during childhood versus adulthood. Race difference (blacks > whites) in the rate of increase in adiposity was seen only among females. Females, black females in particular, displayed greater rate of increase in adiposity than males. In a multivariate analysis, the rate of increase in adiposity was related independently of baseline age and baseline adiposity to adverse changes in measured cardiovascular risk variables, except glucose. Many of these associations were modulated significantly by race, sex, and age group. The impact was relatively greater for blood pressure and LDL cholesterol in adults and for triglycerides in children. The changes in blood pressure, LDL cholesterol, and HDL cholesterol were greater in whites, while the rate of increase in insulin was greater in blacks. Females displayed greater changes in blood pressure, HDL cholesterol, and insulin. On the other hand, the rate of increase in triglycerides was greater in males. These results indicate that increases in adiposity regardless of initial status of body fatness alter cardiovascular risk variables towards increased risk beginning in childhood, and that this deleterious trend underscores the importance of weight control early in life.     

Aberrant retropharyngeal (submucosal) internal carotid artery: an under-recognized, clinically significant variant

We present a case of a 71-year-old woman who was incidentally found to have aberrant retropharyngeal internal carotid artery, lying very close to the pharyngeal mucosa, on imaging. Radiologists, otolaryngologists and anaesthetists should be aware of this clinically significant variant which can result in life-threatening bleeding during procedures in the oral cavity or oropharynx.     

Clinical profile of acute kidney injury in a pediatric intensive care unit from Southern India: A prospective observational study

Background:

Although the term acute renal failure was replaced by acute kidney injury (AKI) recently, there is a paucity of data on the incidence and profile of AKI in critically ill children from the developing world.

Objectives:

The objective of this study is to determine the incidence, etiology, short term outcome and predictors of fatality in critically ill children admitted to the pediatric intensive care unit (PICU) with AKI, aged 1 month to 13 years.

Materials and Methods:

In this prospective observational study, from June 2010 to March 2011, 215 children admitted to the PICU were screened for AKI, defined according to the AKI Network criteria. The patients with AKI were followed-up until discharge/death. Their clinical and biochemical data were recorded.

Results:

The incidence of AKI among 215 patients screened was 54 (25.1%). The common etiologies were infections, [34 (62.9%)], acute glomerulonephritis (7.6%), snake envenomation (5.7%), hemolytic uremic syndrome (3.8%) and congestive cardiac failures (3.8%). Among infections, pneumonia and septicemia constituted 26.5% each, meningoencephalitis accounted for 23.5%, and dengue, scrub typhus, tuberculosis and malaria constituted 9.3% of children with AKI. 27.8% of patients required dialysis. Overall mortality was 46.3%. On logistic regression analysis, requirement of mechanical ventilation was an independent predictor of fatality in AKI.

Conclusions:

Besides the high incidence of AKI in critically ill-children admitted to the PICU (25.1%), the condition was associated with adverse outcomes, including high mortality (46.3%) and need for dialysis (27.8%). Infections dominated the etiological profile. Requirement of mechanical ventilation predicted an adverse outcome in our patient population.     

Novel CD3Z and CD3E Deficiency in Two Unrelated Females

Journal of Clinical Immunology -     

The Diagnostic Dilemma of a Parasympathetic Schwannoma in the Submandibular Gland

Schwannomas are benign soft tissue tumours that arise from nerve sheath cells. They are rare in the salivary glands and are thought to arise from the parasympathetic nerves. We report the case of a 69-year-old man who presented with a painless right submandibular mass that appeared to resemble a pleomorphic adenoma on ultrasonography and, on this basis, proceeded to surgical excision of the gland. We review the relevant literature and highlight the diagnostic pitfalls.