Near Normalization of Metabolic and Functional Features of the Central Nervous System in Type 1 Diabetic Patients With End-Stage Renal Disease After Kidney-Pancreas Transplantation

OBJECTIVE The pathogenesis of brain disorders in type 1 diabetes (T1D) is multifactorial and involves the adverse effects of chronic hyperglycemia and of recurrent hypoglycemia. Kidney-pancreas (KP), but not kidney alone (KD), transplantation is associated with sustained normoglycemia, improvement in quality of life, and reduction of morbidity/mortality in diabetic patients with end-stage renal disease (ESRD). RESEARCH DESIGN AND METHODS The aim of our study was to evaluate with magnetic resonance imaging and nuclear magnetic resonance spectroscopy (1H MRS) the cerebral morphology and metabolism of 15 ESRD plus T1D patients, 23 patients with ESRD plus T1D after KD (n = 9) and KP (n = 14) transplantation, and 8 age-matched control subjects. RESULTS Magnetic resonance imaging showed a higher prevalence of cerebrovascular disease in ESRD plus T1D patients (53% [95% CI 36–69]) compared with healthy subjects (25% [3–6], P = 0.04). Brain 1H MRS showed lower levels of N-acetyl aspartate (NAA)-to-choline ratio in ESRD plus T1D, KD, and KP patients compared with control subjects (control subjects vs. all, P < 0.05) and of NAA-to-creatine ratio in ESRD plus T1D compared with KP and control subjects (ESRD plus T1D vs. control and KP subjects, P ≤ 0.01). The evaluation of the most common scores of psychological and neuropsychological function showed a generally better intellectual profile in control and KP subjects compared with ESRD plus T1D and KD patients. CONCLUSIONS Diabetes and ESRD are associated with a precocious form of brain impairment, chronic cerebrovascular disease, and cognitive decline. In KP-transplanted patients, most of these features appeared to be near normalized after a 5-year follow-up period of sustained normoglycemia

Development of a Multidisciplinary Program to Expedite Care of Esophageal Emergencies

Background Level 1 programs have improved outcomes by expediting the multidisciplinary care of critically ill patients. We established a novel level 1 program for the management of esophageal emergencies. Methods After institutional review board approval, we performed a retrospective analysis of patients referred to our level 1 esophageal emergency program from April 2013 through November 2015. A historical comparison group of patients treated for the same diagnosis in the previous 2 years was used. Results Eighty patients were referred and transported an average distance of 56 miles (range, 1–163 miles). Median time from referral to arrival was 2.4 hours (range, 0.4-12.9 hours). Referrals included 6 (7%) patients with esophageal obstruction and 71 (89%) patients with suspected esophageal perforation. Of the patients with suspected esophageal perforation, causes included iatrogenic (n = 26), Boerhaave’s syndrome (n = 32), and other (n = 13). Forty-six percent (n = 33) of patients were referred because of pneumomediastinum, but perforation could not be subsequently demonstrated. Initial management of patients with documented esophageal perforation included operative treatment (n = 25), endoscopic intervention (n = 8), and supportive care (n = 5). Retrospective analysis demonstrated a statistically significant difference in mean Pittsburgh severity index score (PSS) between esophageal perforation treatment groups (p < 0.01). In patients with confirmed perforations, there were 3 (8%) mortalities within 30 days. More patients in the esophageal level 1 program were transferred to our institution in less than 24 hours after diagnosis than in the historical comparison group (p < 0.01). Conclusions Development of an esophageal emergency referral program has facilitated multidisciplinary care at a high-volume institution, and early outcomes appear favorable

How does toxoplasmosis affect the maternal-foetal immune interface and pregnancy?

Toxoplasma gondii is a zoonotic parasite which, depending on the geographical location, can infect between 10 to 90% of humans. Infection during pregnancy mayresult in congenital toxoplasmosis. The effects on the fetus vary depending on the stage of gestation in which primary maternal infection arises. A large body of research has focused on understanding immune response to toxoplasmosis, although few studies have addressed how it is affected by pregnancy or the pathological consequences of infection at the maternal-fetal interface. There isa lack of knowledge about how maternal immune cells, specifically macrophages are modulated during infection and the resulting consequences for parasite control and pathology. Herein, we discuss the potential of T. gondii infection to affect the maternal-fetal interface and the potential of pregnancy to disrupt maternal immunity to T. gondii infection

Effect of TIM-3 Blockade on the Immunophenotype and Cytokine Profile of Murine Uterine NK Cells

NK cells are the most abundant lymphocyte population in the feto-maternal interface during gestation. The uterine NK cells (uNK) are transient, have a unique immunophenotype and produce a number of cytokines. These cytokines play an important role in establishment and maintenance of vascular remodeling and tolerance associated with successful pregnancy. The uNK cells also express TIM-3 during gestation and blockade of TIM-3 expression results in fetal loss in mice. In this study we determined the effect of TIM-3 blockade on uNK cells. Specifically we observed surface receptor phenotype and cytokine production by uNK cells following TIM-3 blockade. Our results show that TIM-3 plays a role in regulating the uNK cells and contributes to the maintenance of tolerance at the feto-maternal interface

The link between the PDL1 costimulatory pathway and Th17 in fetomaternal tolerance

Fetomaternal tolerance has been shown to depend both on regulatory T cells (Tregs) and negative signals from the PD1-PDL1 costimulatory pathway. More recently, IL-17-producing T cells (Th17) have been recognized as a barrier in inducing tolerance in transplantation. In this study, we investigate the mechanisms of PDL1-mediated regulation of fetomaternal tolerance using an alloantigen-specific CD4 + TCR transgenic mouse model system (ABM-tg mouse). PDL1 blockade led to an increase in embryo resorption and a reduction in litter size. This was associated with a decrease in Tregs, leading to a lower Treg/effector T cell ratio. Moreover, PDL1 blockade inhibited Ag-specific alloreactive T cell apoptosis and induced apoptosis of Tregs and a shift toward higher frequency of Th17 cells, breaking fetomaternal tolerance. These Th17 cells arose predominantly from CD4 +Foxp3 - cells, rather than from conversion of Tregs. Locally in the placenta, similar decrease in regulatory and apoptotic markers was observed by real-time PCR. Neutralization of IL-17 abrogated the anti-PDL1 effect on fetal survival rate and restored Treg numbers. Finally, the adoptive transfer of Tregs was also able to improve fetal survival in the setting of PDL1 blockade. This is to our knowledge the first report using an alloantigen-specific model that establishes a link between PDL1, Th17 cells, and fetomaternal tolerance

Expression of NK cell markers in the uNK and pNK population from non-pregnant and pregnant mice.

<p>Expression of NK1.1, DX5, DBA and NKp46 were determined on CD3^-CD122⁺ cells isolated from the uteri of non-pregnant (A) syngeneically mated pregnant (B) and allogeneically mated (C) pregnant CBA mice. Expression of NK1.1, DX5, DBA and NKp46 on CD3^-CD122⁺ cells from spleen of non-pregnant CBA mouse (D), syngeneically mated (E) and allogeneically mated (F) pregnant CBA mouse. Red-boxed areas denote uNK populations positive for NK1.1 and DBA in allogeneically mated pregnant CBA mouse (C) and DBA positive uNK population in syngeneically mated pregnant CBA mouse (B). These positive populations are absent in the splenic NK cell population in the same mouse. Data is representative of at least 3 experiments.</p

Effect of GM-CSF on the uNK cells and uMDSC from pregnant mice.

<p>A. CBA/CaJ female mice were mated with C57BL/6 allogeneic male mice. Uterine NK cells were flow sorted to obtain a NK1.1^- DX5^- DBA⁺ cell population that was incubated with GMCSF (20ng/ml) ± IL-2 (20ng/ml) for 5–7 days. Expression of uNK and CD11b⁺Ly6G^hiLy6C^lo and CD11b⁺Ly6G^loLy6C^hi cell populations were analyzed using a flow cytometer. GMCSF treatment resulted in no significant change in the NK1.1^- DX5^- DBA⁺ cell population from the CBA mice (p = 0.1164). However, an increase of the CD11b⁺Ly6G^loLy6C^hi population was observed (p = 0.0592). An inverse correlation was observed between the uNK cells and uMDSC in presence of both GMCSF and IL-2 treatment but was not statistically significant. B. C57BL/6 female mice were mated with allogeneic CBA/CaJ male mice. Uterine NK cells were flow sorted to obtain a NK1.1⁺ DX5^- DBA⁺ cell population that was incubated with GMCSF (20ng/ml) ± IL-2 (20ng/ml) for 5–7 days. Expression of uNK and CD11b⁺Ly6G^hiLy6C^lo and CD11b⁺Ly6G^loLy6C^hi cell populations were analyzed using a flow cytometer. GMCSF treatment resulted in a significant change in the NK1.1⁺ DX5^- DBA⁺ cell population from the C57BL/6 female mice (p = 0.0310). However, the change in the CD11b⁺Ly6G^loLy6C^hi population was not significant (p = 0.2410). The effect of GMCSF was more pronounced in the uNK cells from the C57BL/6 female mice and a significant inverse correlation between uNK and uMDSC was also observed (p = 0.0158). Data are presented as mean± SEM and are representative of at least 3 experiments. Statistical analysis was done by one-way analysis of variance (ANOVA) using Kruskal-Wallis test and two way ANOVA.</p