A therapeutic DNA vaccination strategy for autoimmunity and transplantation

De novo autoimmunity induced by an allograft may play a significant role in chronic organ rejection, which remains a major barrier to successful transplantation. Accordingly, immunization with non-polymorphic antigens found in both donor allograft and recipient would be an attractive means to prevent long-term graft rejection, because it would rely on recipient mechanisms of immune homeostasis and could minimize the need to identify appropriate donor polymorphic antigens for induction of graft tolerance. Here we show that intradermal injection of plasmid DNA encoding glutamic acid decarboxylase (GAD) polypeptide, which is synthesized in both pancreatic islet and skin tissue, ameliorated new-onset type 1 diabetes in NOD mice and increased skin allograft survival in a BALB/c-C57BL/6 model system in a donor-specific manner. Successful therapy of autoimmune diabetes required CpG-methylation of plasmid DNA and co-delivery of a cDNA coding for the pro-apoptotic BAX protein, which was shown previously to induce Foxp3⁺ regulatory T cells in NOD mice. In contrast, significantly increased skin allograft survival after immunization of recipient only required CpG-methylation of plasmid DNA coding for GAD alone. Injection of unmethylated plasmid DNA coding for BAX alone near the allograft also promoted graft survival, but induced a pro-inflammatory response to self-antigens. Our results reveal a promising potential for autoimmunity-targeting DNA vaccination to be applied to transplantation.     

The impact of intercurrent EBV infection on ATP levels in CD4+ T cells of pediatric kidney transplant recipients

Abstract: ImmuKnow^® measures ATP (ng/mL) in PHA‐activated CD4+ T cells from patient’s whole blood. According to published reports, median ImmuKnow^® is 258 ng/mL in stable pediatric kidney transplant (PKT) recipients ≥12 yr, and 165 ng/mL in those <12 yr. However, data on the effect of infection or AR on ImmuKnow^® are scarce. We studied the effect of Epstein‐Barr virus (EBV) viremia on ImmuKnow^® in PKT with GD. Twenty‐eight PKT with GD were reviewed. Group 1 has 19 PKT ≥12 yr, and group 2 has nine PKT <12 yr. Mean follow‐up was 19.4 ± 12 months. All ImmuKnow^® values discussed in this study were measured during GD ± fever. None had ImmuKnow^® pretransplant. EBV DNA was isolated from patient blood by real‐time PCR. Group 1 has eight boys and 11 girls (mean age = 16.6 ± 2.4 yr). Group 2 has two boys and seven girls (mean age = 6 ± 3.1 yr). Median ImmuKnow^® was 292 ng/mL in group 1, and 370 ng/mL in group 2. Nine children developed EBV viremia: two in group1 (median ImmuKnow^® = 273 ng/mL), and seven in group 2 (median ImmuKnow^® = 475 ng/mL). Overall mean ImmuKnow^® in the nine EBV viremic patients was higher than that in the 19 non‐viremic ones (422 ± 176 ng/mL, and 302 ± 113 ng/mL, respectively, unequal variance t‐test, p = 0.08). Eight children developed AR (all in G1, median ImmuKnow^® = 272 ng/mL). In group 1, one patient developed concurrent EBV viremia and rejection, while another patient developed EBV viremia six months following a rejection episode. In group 2, none developed simultaneous AR, CMV, or BK virus infection with EBV viremia. None developed post‐transplant lymphoproliferative disease. In summary, EBV viremia was paradoxically associated with high ImmuKnow^® in PKT <12 yr. This suggests strong co‐stimulation of PHA‐activated CD4+ T cells by EBV‐transformed B cells.     

A comparison of opioid use between WCB recipients and other Manitobans for knee,shoulder, back and carpal tunnel release procedures

Background

This study's objectives were to evaluate whether WCB claimants with conditions requiring certain surgical procedures are more likely to be prescribed outpatient opioids than other Manitobans and whether those prescribed opioids are more likely to still be on opioid medications 6 months post procedure.

Methods

We compared 7,246 WCB claims for a number of surgical procedures to 65,032 similar procedures performed in other Manitobans. Logistic regression was used to explore the association between being a WCB claimant and being prescribed opioids, while controlling for type of surgical procedure and other potential confounders.

Results

WCB claimants were more likely than other Manitobans to be prescribed opioids (adjusted OR 1.38; 95%CI 1.30–1.47). Amongst those prescribed opioids, the odds of being still on opioids 6 months post‐procedure were not significantly elevated for WCB claimants (adjusted OR 1.09 95%CI 0.97–1.23).

Conclusions

WCB claimants are prescribed opioids more often than non‐claimants for similar procedures. Am. J. Ind. Med. 59:257–263, 2016. © 2016 The Authors. American Journal of Industrial Medicine Published by Wiley Periodicals, Inc.     

Entertainment or Health? Exploring the Internet Usage Patterns of the Urban Poor: A Secondary Analysis of a Randomized Controlled Trial

BackgroundImportant gaps remain in our knowledge of how individuals from low socioeconomic position (SEP) use the Internet for resources and in understanding the full range of activities they perform online. Although self-report data indicate that low SEP individuals use the Internet less than high SEP people for health information and for other beneficial capital-enhancing activities, these results may not provide an accurate overall view of online use.ObjectiveThe aim of this study was to determine the ways in which low SEP individuals use the Internet, including for entertainment, social networking, and capital-enhancing functions, and how they are associated with health information seeking.MethodsDetailed Web tracking data were collected from 118 low SEP individuals who participated in the intervention group of a randomized controlled trial that provided Internet access. Websites were grouped by topic, including categories of capital-enhancing websites that provided access to resources and information. Different types of online activities were summed into an Internet use index. Single and multiple negative binomial regression models were fitted with the Internet use index as the predictor and health information seeking as the outcome. Next, models were fitted with low, medium, and high Web usage in capital-enhancing, entertainment, and social network categories to determine their associations with health information seeking.ResultsParticipants used the Web for diverse purposes, with 63.6% (75/118) accessing the Internet for all defined types of Internet use. Each additional category of Internet use was associated with 2.12 times the rate of health information seeking (95% CI 1.84-2.44, P<.001). Higher use of each type of capital-enhancing information was associated with higher rates of health information seeking, with high uses of government (incident rate ratio [IRR] 8.90, 95% CI 4.82-16.42, P<.001) and news (IRR 11.36, 95% CI 6.21-20.79, P<.001) websites associated with the highest rates of health information seeking compared to their lowest use categories. High entertainment website use (IRR 3.91, 95% CI 2.07-7.37, P<.001) and high social network use (IRR 2.06, 95% CI 1.08-3.92, P=.03) were also associated with higher health information seeking.ConclusionsThese data clearly show that familiarity and skills in using the Internet enhance the capacity to use it for diverse purposes, including health and to increase capital, and that Internet usage for specific activities is not a zero sum game. Using it for one type of topic, such as entertainment, does not detract from using it for other purposes. Findings may inform ways to engage low SEP groups with Internet resources.     

Pro-apoptotic DNA vaccination ameliorates new onset of autoimmune diabetes in NOD mice and induces foxp3+ regulatory T cells in vitro

We have shown previously that incorporation of a cDNA coding for the pro-apoptotic protein BAX into plasmid DNA coding for a secreted form of the pancreatic beta-cell antigen glutamic acid decarboxylase (GAD) promotes prevention of type 1 diabetes in non-obese diabetic (NOD) mice. Here we present evidence indicating that injection of the same vaccine at time of early diabetes onset could ameliorate the disease with efficacy, with 42% of mice overtly diabetic by 40 weeks of age compared to 92% in control groups. In addition, immunological analysis revealed that the DNA vaccine induced CD4(+)CD25(+) T cells cultured from draining lymph nodes that had immunosuppressive function in vitro. The induced regulatory T cells (Tregs) expressed the foxp3 gene and showed cell-contact-dependent as well as TGF-beta- and IL-10-independent immunosuppressive activity. Data also revealed that CD4(+)CD25(-) T cells from mice immunized with the DNA vaccine yielded a cell population that was foxp3(+), showed increased expression of CD25 compared to control, and had immunosuppressive function in vitro, indicating that Tregs could have developed from antigen-induced, peripheral T lymphocytes. In contrast, injection of DNA coding for SGAD55 or BAX alone did not induce Tregs. Altogether, our data confirm that pro-apoptotic DNA vaccination can be used as an immunosuppressive strategy and demonstrate its potential for therapy of pathological autoimmunity.     

Adult Surgical Emergencies in a Developing Country: The Experience of Nnamdi Azikiwe University Teaching Hospital, Nnewi, Anambra State, Nigeria

The goal of this study was to examine the adult surgical emergencies seen at the Nnamdi Azikiwe University Teaching Hospital (NAUTH), Nnewi, with a view to proffering preventive solutions where appropriate and improving outcome. From the register of patients seen at the Casualty department and from the operations register in the main operation room of NAUTH, names and hospital numbers of adult patients treated as emergencies over a 5-year period, from 7 September 1998 to 6 September 2003, were obtained. The hospital folders were then retrieved from the Records Department. From each folder, the following details about each patient were extracted: age, sex, diagnosis at presentation, causative factors, treatment given, and outcome. A total of 902 adult patients were treated during the period. The commonest emergency operation was appendectomy for acute appendicitis in 139 patients (97 women and 42 men), followed closely by road traffic accidents (RTAs) involving 137 patients (103 men and 34 women). Gunshot injuries, which resulted mainly from armed robbery attacks, accounted for 127 cases. More men (113) sustained gunshot injuries than women (14). Of the 92 cases of acute intestinal obstruction seen, 62 occurred in women and 30 in men. Some 126 men presented with acute urinary retention, and two others presented with priapism. Governments at various levels should provide modern diagnostic tools for the accurate preoperative diagnosis of surgical emergencies in hospitals. Governments should also inculcate strict discipline into drivers using the highways, particularly in relation to abuse of alcohol and drugs. Good roads and adequate security should be provided for the people. The need for Pre-Hospital Care for the efficient evacuation of accident victims is emphasized. These measures will help to improve the management and outcome of surgical emergencies, and decrease the number of surgical emergencies resulting from RTAs and gunshot wounds.