Innate immunity alone is not sufficient for chronic rejection but predisposes healed allografts to T cell-mediated pathology

BackgroundAcute allograft rejection is dependent on adaptive immunity, but it is unclear whether the same is true for chronic rejection. Here we asked whether innate immunity alone is sufficient for causing chronic rejection of mouse cardiac allografts.MethodsWe transplanted primarily vascularized cardiac grafts to recombinase activating gene-knockout (RAG^?/?) mice that lack T and B cells but have an intact innate immune system. Recipients were left unmanipulated, received adjuvants that stimulate innate immunity, or were reconstituted with B-1 lymphocytes to generate natural IgM antibodies. In a second model, we transplanted cardiac allografts to mice that lack secondary lymphoid tissues (splenectomized aly/aly recipients) and studied the effect of NK cell inactivation on T cell-mediated chronic rejection.ResultsAcute cardiac allograft rejection was not observed in any of the recipients. Histological analysis of allografts harvested 50 to 90 days after transplantation to RAG^?/? mice failed to identify chronic vascular or parenchymal changes beyond those observed in control syngeneic grafts. Chronic rejection of cardiac allografts parked in splenectomized aly/aly mice was observed only after the transfer of exogenously activated T cells. NK inactivation throughout the experiment, or during the parking period alone, reduced the severity of T cell-dependent chronic rejection.ConclusionsThe innate immune system alone is not sufficient for causing chronic rejection. NK cells predispose healed allografts to T cell-dependent chronic rejection and may contribute to chronic allograft pathology.     

Worldwide variability in deceased organ donation registries

The variability in deceased organ donation registries worldwide has received little attention. We considered all operating registries, where individual wishes about organ donation were recorded in a computerized database. We included registries which recorded an individual's decision to be a donor (donor registry), and registries which only recorded an individual's objection (non-donor registry). We collected information on 15 characteristics including history, design, use and number of registrants for 27 registries (68%). Most registries are nationally operated and government-owned. Registrations in five nations expire and require renewal. Some registries provide the option to make specific organ selections in the donation decision. Just over half of donor registries provide legally binding authorization to donation. In all national donor registries, except one, the proportion of adults (15+) registered is modest (<40%). These proportions can be even lower when only affirmative decisions are considered. One nation provides priority status on the transplant waiting list as an incentive to affirmative registration, while another nation makes registering a donation decision mandatory to obtain a driver's license. Registered objections in non-donor registries are rare (<0.5%). The variation in organ donor registries worldwide necessitates public discourse and quality improvement initiatives, to identify and support leading practices in registry use.     

Reoperative Lymph Node Dissection for Recurrent Papillary Thyroid Cancer and Effect on Serum Thyroglobulin

Background

Papillary thyroid cancer (PTC) has an excellent prognosis with current treatment methods. However, the rates of locoregional recurrence after initial surgical management remain significant. This study evaluates the effect of reoperative neck dissection for locoregional recurrence of PTC after initial total thyroidectomy and radioiodine therapy on the incidence of cervical recurrence and postoperative serum thyroglobulin (Tg) levels.

Methods

This is a retrospective cohort study conducted in a single academic medical center of patients with recurrent or persistent PTC isolated to the neck after previous total thyroidectomy with or without lymph node dissection and adjuvant I¹³¹ therapy who were treated with reoperative lymph node dissection. Outcomes including operative complications, pathologic findings, and effect of surgery on Tg levels and rates of recurrent disease were analyzed.

Results

From 2001 to 2010, a total of 61 patients had reoperative neck dissections for recurrent cervical PTC with a complication rate of 5?%. Seventy-two percent of patients were clinically free of detectable disease, and 28?% of patients had recurrent, persistent, or newly metastatic disease detected during the follow-up period. All patients had significant decreases in Tg levels, with a median 98?% reduction in preoperative levels. However, only 21?% of patients had an undetectable stimulated Tg (<0.5?ng/mL) during the follow-up period of 15.5?months.

Conclusions

Reoperative treatment of recurrent or persistent PTC can be performed with low complication rates, and Tg levels greatly decrease in most patients; however, few achieve undetectable stimulated Tg.     

Treatment of critical defects produced in calvaria of mice with mesenchymal stem cells

Mesenchymal stem cells (MSC) are present in specialized niches in perivascular regions of adult tissues and are able to differentiate into various cell types, such as those committed to repairing. Bone marrow derived MSC from eight young mice C57BL/ 6 gfp+ were expanded in culture for repairing critical defects in calvarial bone produced in twenty-four young isogenic adult C57BL/6 mice. The animals were subjected to a cranial defect of 6.0mm diameter and divided into two equal experimental groups. Control group did not receive any treatment and the treated group received a MSC pellet containing 1.0 x 10(7) cells/mL into the defects. The group treated with MSC showed increased angiogenesis and amount of new bone deposited on the defect limits than that observed in the control group. The results demonstrated that transplantation of bone marrow-derived MSC of C57BL/6 gfp+ mice to bone critical defects produced in mice calvarial contributes positively to the bone repair process. MSC presets ability to influence the correct functioning of osteoblasts, increases the amount of mobilized cells for the repairing process, speeds up growth, and increases deposition of bone matrix.     

Oral bisphosphonate use in the elderly is not associated with acute kidney injury

Intravenous bisphosphonates can cause acute kidney injury; however, this risk was not found with oral bisphosphonates in randomized clinical trials with restrictive eligibility criteria. In order to provide complementary safety data, we studied the risk of acute kidney injury in a population-based cohort of 122,727 patients aged 66 years and older discharged from hospital following a new fragility fracture and no history of bisphosphonate use in the prior year. Bisphosphonate treatment was identified within 120 days after discharge and event rates were measured from 90 days of therapy initiation. The primary outcome was hospitalization with acute kidney injury with secondary outcomes of new nephrology consultation and, in a subset of patients with laboratory values, acute kidney injury was defined as an increase in serum creatinine. We identified 18,286 bisphosphonate users and 104,441 non-users with a mean age of 81 years. Of 5772 patients with laboratory values, 40% had chronic kidney disease (eGFR <60?ml/min per 1.73?m(2)). Overall, there was no statistically significant difference in the risk of acute kidney injury among bisphosphonate users compared to non-users (adjusted odds ratio 1.03), and no significant differences in other outcomes or in subgroups of patients with baseline chronic kidney disease. Thus, in this older population-based cohort, oral bisphosphonate use was not associated with acute kidney injury.     

Neuronal nitric oxide synthase: its role and regulation in macula densa cells

Macula densa (MD) cells detect changes in distal tubular sodium chloride concentration ([NaCl](L)), at least in part, through an apical Na:2Cl:K co-transporter. This co-transporter may be a site for regulation of tubuloglomerular feedback (TGF), and recently angiotensin II (Ang II) was shown to regulate the MD Na:2Cl:K co-transporter. In addition, nitric oxide (NO) produced via neuronal NO synthase (nNOS) in MD cells attenuates MD-TGF signaling. This study investigated [NaCl](L)-dependent MD-NO production, the regulation of co-transporter activity by NO, and the possible interaction of NO with Ang II. MD cell Na(+) concentration ([Na(+)](i)) and NO production were measured using sodium-binding benzofuran isophthalate and 4-amino-5-methylamino-2',7'-difluorescein diacetate, respectively, using fluorescence microscopy. Na:2Cl:K co-transport activity was assessed as the initial rate of increase in [Na(+)](i) when [NaCl](L) was elevated from 25 to 150 mM. 10(-4) M 7-nitroindazole, a specific nNOS blocker, significantly increased by twofold the initial rate of rise in [Na(+)](i) when [NaCl](L) was increased from 25 to 150 mM, indicating co-transporter stimulation. There was no evidence for an interaction between the stimulatory effect of Ang II and the inhibitory effect of NO on co-transport activity, and, furthermore, Ang II failed to alter MD-NO production. NO production was sensitive to [NaCl](L) but increased only when [NaCl](L) was elevated from 60 to 150 mM. These studies indicate that MD-NO directly inhibits Na:2Cl:K co-transport and that NO and Ang II independently alter co-transporter activity. In addition, generation of MD-NO seems to occur only at markedly elevated [NaCl](L), suggesting that NO may serve as a buffer against high rates of MD cell transport and excessive TGF-mediated vasoconstriction.     

A study of suicides in Londonderry, Northern Ireland, for the year period spanning 2000-2005

This study reports on 60 cases of suicide in Londonderry, Northern Ireland from January 2000 to December 2005. The research focused on a number of factors associated with the occurrence of suicide. These included age, gender, employment status, method used and possible predisposing factors. Additionally, the seasonality of occurrence was also investigated. Notably, over the period of the study, the number of suicides almost doubled. The results demonstrated that 83.3% of suicides were male. The largest proportion of these, over one third, occurred in men between the ages 21 and 30 years. This high rate of young male suicides was in marked contrast to any other group. The most frequent method of suicide recorded in this study was hanging (55%). The next most frequent methods were drowning (25%) and overdose (13.3%). Three times as many males (6) overdosed compared to females.     

Differential modulation of CD4 and CD8 T-cell proliferation by induction of nitric oxide synthesis in antigen presenting cells

BACKGROUND: On antigenic stimulation, CD4 T cells generally proliferate more readily than CD8 T cells. The purpose of the present experiments was to determine whether nitric oxide (NO) might differentially modulate CD4 vs. CD8 T-cell proliferation. METHODS: Various concentrations of C57BL/6 iNOS +/+ and -/- bone marrow (BM)-derived antigen presenting cells (APC) (obtained by culture in granulocyte-macrophage colony-stimulating factor [GM-CSF] and interleukin [IL]-4) were cultured with purified BALB/c CD4 or CD8 T cells. RESULTS: Proliferation of CD4 T cells was similar in the presence of both NO synthase (iNOS) +/+ and -/- APC, whereas CD8 T cell proliferation was inhibited at the higher concentrations of iNOS +/+ dendritic cells (DC), coincident with increased levels of NO in the culture supernatant. Analysis of cytokine levels revealed that more interferon (IFN)-gamma, a potent inducer of NO synthesis in many cell types, was present in CD8 T cell than in CD4 T-cell-APC cultures. Addition of IFN-gamma to CD4 T-cell-APC cultures resulted in induction of NO synthesis and inhibition of proliferation at higher levels of NO than that required to inhibit CD8 T cell proliferation. However, CD4 T-cell proliferation was moderately inhibited in the presence of lipopolysaccharide (LPS)-stimulated CD11c DC, coincident with production of IFN-gamma and induction of NO synthesis. CONCLUSIONS: These findings indicate that CD8 T-cell proliferation can be inhibited by lesser amounts of APC-derived NO than is necessary to inhibit CD4 T cell proliferation. NO synthesis was not initiated in CD4 T cell-DC cultures unless costimulatory molecules were up-regulated and IFN-gamma was produced.     

Post-Traumatic Periprosthetic Tibial and Fibular Fracture After Total Ankle Arthroplasty: A Case Report

Periprosthetic fractures after total ankle arthroplasty are uncommon, with most cases occurring intraoperatively. We describe a post-traumatic periprosthetic fracture of the distal tibia and fibula after total ankle arthroplasty that was treated with minimally invasive plate osteosynthesis. It is important for orthopedic surgeons not only to recognize the risk factors for postoperative periprosthetic total ankle arthroplasty fractures, but also to be familiar with the treatment options available to maximize function and minimize complications. The design of the tibial prosthesis and surgical techniques required to prepare the ankle joint for implantation are important areas of future research to limit the risk of periprosthetic fractures.