Shahla Namak

PGE2 suppresses intestinal T cell function in thermal injury : A cause of enhanced bacterial translocation

Increased gut bacterial translocation in burn and trauma patients has been demonstrated in a number of previous studies, however, the mechanism for such an increased gut bacterial translocation in injured patients remains poorly understood. Utilizing a rat model of burn injury, in the present study we examined the role of intestinal immune defense by analyzing the T cell functions. We investigated if intestinal T cells dysfunction contributes to bacterial translocation after burn injury. Also our study determined if burn-mediated alterations in intestinal T cell functions are related to enhanced release of PGE2. Finally, we examined whether or not burn-related alterations in intestinal T cell function are due to inappropriate activation of signaling molecule P59fyn, which is required for T cell activation and proliferation. The results presented here showed an increase in gut bacterial accumulation in mesenteric lymph nodes after thermal injury. This was accompanied by a decrease in the intestinal T cell proliferative responses. Furthermore, the treatments of burn-injured animals with PGE2 synthesis blocker (indomethacin or NS398) prevented both the decrease in intestinal T cell proliferation and enhanced bacterial translocation. Finally, our data suggested that the inhibition of intestinal T cell proliferation could result via PGE2-mediated down-regulation of the T cell activation-signaling molecule P59fyn. These findings support a role of T cell-mediated immune defense against bacterial translocation in burn injury.

Effects of burn with and without Escherichia coli infection in rats on intestinal vs. splenic T-cell responses.

Objective To evaluate the effect of burn injury with and without an Escherichia coli septic complication on T-cell proliferation, interleukin-2 production, and Ca2+ signaling responses in intestinal Peyer’s patch and splenic T cells. Design Prospective, randomized, sham-controlled animal study. Setting University medical center research laboratory. Subjects Adult male Sprague-Dawley rats. Interventions Rats were subjected to a 30% total body surface area, full skin thickness burn. Infection in rats was induced via intraperitoneal inoculation of E. coli, 109 colony forming units/kg, with or without a prior burn. Measurements and Main Results Rat Peyer’s patch and splenic T lymphocytes were isolated by using a nylon wool cell purification protocol. T-cell proliferation, interleukin-2 production, and Ca2+ signaling responses were measured after stimulation of cells with the mitogen, concanavalin A. T-cell proliferation was determined by measuring incorporation of 3H-thymidine into T-cell cultures. Interleukin-2 production by T-cell cultures was measured by using enzyme-linked immunosorbent assay. Intracellular T-cell Ca2+ concentration, [Ca2+]i, was measured by the use of Ca2+-specific fluorescent label, fura-2, and its fluorometric quantification. [Ca2+]i was also evaluated by the use of digital video imaging of fura-2 loaded individual T cells. T-cell proliferation and interleukin-2 production were suppressed substantially in both Peyer’s patch and splenic T cells 3 days after either the initial burn alone or burn followed by the E. coli inoculation at 24 hrs after the initial burn. There seemed to be no demonstrable additive effects of E. coli infection on the effects produced by burn injury alone. The T-cell proliferation and interleukin-2 production suppressions with burn or burn-plus-infection insults were correlated with attenuated Ca2+ signaling. E. coli infection alone suppressed T-cell proliferation in Peyer’s patch but not in splenic T cells at 2 days postbacterial inoculation;E. coli infection had no effect on Peyer’s patch or splenic T cells at 1 day postinjury. On the other hand, burn injury alone caused a substantial T-cell proliferative suppression at 2 days postburn in both Peyer’s patch and splenic cells and a significant suppression in T-cell proliferation on day 1 postburn in Peyer’s patch but not in the spleen. Conclusion An initial burn injury suppressed T-cell proliferation at a level that it would not be further affected by a subsequent infection even if the infection by itself has the potential of suppressing T-cell proliferation. An earlier onset of T-cell suppression in Peyer’s patch cells than in the spleen with burn could be attributable to an initial hypoperfusion-related intestinal mucosal tissue injury. Overall, our study supports the concept that burn injury per se can significantly suppress T-cell mediated immunity and that the intestine is an early tissue site of such suppression.

T-Cell Proliferative Responses following Sepsis in Neonatal Rats

Both experimental and clinical evidence suggest a suppression of T-cell function in burn and sepsis. The objective of the present study was to evaluate splenocyte and purified T-cell proliferative response and IL-2 production in septic neonatal rats. We also examined if alterations in T-cell proliferation and IL-2 production in neonatal sepsis is due to elevation in PGE2. PGE2 is known to play a significant role in T-cell suppression during sepsis in adults. Sepsis was induced in 15-day-old neonatal Sprague-Dawley rats by implanting 0.1 cm3 of fecal pellet impregnated with Escherichia coli (50 CFU) and Bacteroides fragilis (103 CFU). Animals receiving fecal pellets without the bacteria were designated as sterile. A group of septic and sterile rats were treated with PGE2 synthesis inhibitors, NS398 and resveratrol. These treatments of animals allowed us to evaluate the role of PGE2 in T-cell suppression during neonatal sepsis. Splenocytes as well as purified T cells were prepared and then proliferative response and IL-2 productive capacities were measured. A significant suppression of splenocyte proliferation and IL-2 production was noticed in both sterile and septic animals compared to the T cells from unoperated control rats. In contrast, the proliferation and IL-2 production by nylon wool purified T cells in sterile rats was not significantly different from control rats, whereas, a significant suppression in Con A-mediated T-cell proliferation and IL-2 production noticed in septic rat T cells compared to the sterile and control rat T cells. Such decrease in T-cell proliferation and IL-2 production was accompanied with 20–25% deaths in neonates implanted with septic pellets. No mortality was noted in sterile-implanted neonates. Treatment of animals with COX-1 inhibitor had no effect on T-cell proliferation response in both septic and sterile groups, whereas COX-2 inhibitor abrogated the decrease in T-cell proliferative response in the septic group. The treatment of animals with COX-2 inhibitor also significantly prevented the sepsis-associated mortality in neonates. In conclusion, the present study demonstrated T-cell suppression during neonatal sepsis is accompanied by a decrease in IL-2 production. Such suppressions were ameliorated with COX-2 inhibitor suggesting a role for PGE2 in the suppressed T-cell-mediated immune function in neonatal sepsis.

Biosimilars for Immune-Mediated Chronic Diseases in Primary Care: What a Practicing Physician Needs to Know

ABSTRACT The introduction of biologics has revolutionized the treatment of immune‐mediated diseases, but high cost and limited patient access remain hurdles, and some physicians are concerned that biosimilars are not similar enough. The purpose of this narrative review is to describe biosimilar safety, efficacy, nomenclature, extrapolation and interchangeability. In the United States, the Biologics Price Competition and Innovation Act created an abbreviated pathway for licensing of a biologic that is biosimilar to another licensed product (i.e., the reference product). This approval pathway differs from that of generic small‐molecule drugs because biologics are too complex to be perfectly duplicated, and follows a process designed to demonstrate that any differences between the biosimilar and its reference product have no significant impact on safety and efficacy. The US approval process requires extensive analytical assessments, animal studies and clinical trials, assuring that biosimilar products provide clinical results similar to those of the reference product.

Examining the evidence for self-monitoring of blood glucose in non-insulin Type 2 diabetes

Self-monitoring of blood glucose (SMBG) can be a tool to provide feedback information to patients and clinicians to consider in the management of diabetes mellitus. SMBG is clearly useful to detect...

Sepsis-Induced Alteration in T-Cell Ca2+ Signaling in Neonatal Rats

Sepsis-induced suppression in T-cell proliferation follows deranged Ca2+ signaling in adult rats. In preliminary studies, we observed suppression in T-cell proliferation in septic neonatal rats as well. In this study, we assessed splenic T-cell cytosolic Ca2+ concentration, [Ca2+]i, as its elevation plays an important role in T-cell proliferation. Also, we investigated the role of PGE2 in sepsis-related changes in T-cell [Ca2+]i in animals pretreated with cyclooxygenase-1 (COX-1) inhibitor (resveratrol) and cyclooxygenase-2 (COX-2) inhibitor (NS-398). Sepsis was induced in 15-day-old rat pups by intraperitoneal implantation of fecal pellets containing Escherichia coli and Bacteroides fragilis. The sham group consisted of pups implanted with sterile fecal pellets. Septic and sham pups were sacrificed 24 h after implantation and their spleens were removed. The spleens from sham and septic pups, along with spleens from unoperated control pups, were processed for single cell suspensions, and T cells were isolated using nylon wool columns. Fura-2 fluorophotometry was employed for the measurement of [Ca2+]i (in nM units) in T cells stimulated with concanavalin A (ConA). Our results show that ConA-mediated T-cell [Ca2+]i response is significantly suppressed in septic neonatal rats. Pretreatment of pups with COX-2, but not COX-1 inhibitor, prevented the decrease in the [Ca2+]i response. These findings suggest that PGE2 might induce the attenuation in T-cell Ca2+ signaling during sepsis in neonatal rats.

Connecting Refugees to Medical Homes Through Multi-Sector Collaboration

As increasing numbers of refugees have resettled globally, an interdisciplinary group of stakeholders in Forsyth, North Carolina, recognized obstacles preventing coordinated medical care, which inspired the development of our Refugee Health Collaborative. This study assessed the Collaborative’s impact on access to coordinated care within patient-centered medical homes (PCMH). A Collaborative-developed novel algorithm guided the process by which refugees establish care in PCMHs. All refugees who established medical care in the two primary health systems in our county (n = 285) were included. Logistic non-linear mixed models were used to estimate the differences between three time frames: pre-algorithm, algorithm implementation and refinement, and ongoing algorithm implementation. After algorithm implementation, there has been a significant decrease in the time required to establish care in PCMHs, increased provider acknowledgment of refugee status, and decreased emergency department (ED) visits. Multi-disciplinary, organized collaboration can facilitate enhanced access to care for refugee families at the population level.