Differences in the vascular tree of the femoral trochlear growth cartilage at osteochondrosis‐susceptible sites in foals revealed by SWI 3T MRI

Focal ischemic chondronecrosis of epiphyseal growth cartilage (EGC) during endochondral ossification is believed to be a key early event on the pathway to osteochondrosis (OC) in both animals and humans. The lateral ridge of the equine trochlea is a site where severe osteochondritis dissecans lesions frequently arise and is a model for the study of naturally occurring disease. Non‐invasive imaging to investigate EGC vascularity may help elucidate why focal ischemia occurs. 3T MRI susceptibility‐weighted imaging (SWI) of femoral trochlea of OC predisposed (n = 10) and control (n = 6) day‐old foals, with minimal joint loading after birth, was performed. SWI and 3D images revealed the EGC vascular architecture without a contrast agent, and matched histologic observations. No vascular lesions were identified. There was no difference in the vascular density and architecture between control and OC specimens, but a striking difference in vascular pattern was seen at the OC‐predilected site in the lateral ridge of the trochlea in all specimens, when compared to the medial ridge of the trochlea, where OC lesions are rarely observed. This site was less ossified with more perichondrial vessels not yet bridging with the subchondral bone. Furthermore, the mean vascular density of all specimens was significantly higher at this site. We speculate that joint morphology and focal internal trauma on this site with a unique vascular architecture may trigger ischemic events at this site. SWI permitted visualization of EGC in young foals with a clinical 3T MRI and paves the way for non‐destructive longitudinal studies to improve understanding of OC in all species. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1539–1546, 2016.     

Minimization of maintenance immunosuppressive therapy after renal transplantation comparing cyclosporine A/azathioprine or cyclosporine A/mycophenolate mofetil bitherapy to cyclosporine A monotherapy: a 10‐year postrandomization follow‐up study

Long‐term outcomes in renal transplant recipients withdrawn from steroid and submitted to further minimization of immunosuppressive regimen after 1 year are lacking. In this multicenter study, 204 low immunological risk kidney transplant recipients were randomized 14.2 ± 3.7 months post‐transplantation to receive either cyclosporine A (CsA) + azathioprine (AZA; n = 53), CsA + mycophenolate mofetil (MMF; n = 53), or CsA monotherapy (n = 98). At 3 years postrandomization, the occurrence of biopsy for graft dysfunction was similar in bitherapy and monotherapy groups (21/106 vs. 26/98; P = 0.25). At 10 years postrandomization, patients’ survival was 100%, 94.2%, and 95.8% (P = 0.25), and death‐censored graft survival was 94.9%, 94.7%, and 95.2% (P = 0.34) in AZA, MMF, and CsA groups, respectively. Mean estimated glomerular filtration rate was 70.4 ± 31.1, 60.1 ± 22.2, and 60.1 ± 19.0 ml/min/1.73 m², respectively (P = 0.16). The incidence of biopsy‐proven acute rejection was 1.4%/year in the whole cohort. None of the patients developed polyomavirus‐associated nephropathy. The main cause of graft loss (n = 12) was chronic antibody‐mediated rejection (n = 6). De novo donor‐specific antibodies were detected in 13% of AZA‐, 21% of MMF‐, and 14% of CsA‐treated patients (P = 0.29). CsA monotherapy after 1 year is safe and associated with prolonged graft survival in well‐selected renal transplant recipient ( ClinicalTrials.gov number: 980654).     

The association between killer‐cell immunoglobulin‐like receptor (KIR) and KIR ligand genotypes and the likelihood of BK virus replication after kidney transplantation

BK virus is a common opportunistic post‐transplantation viral infection. Although some risk factors have been studied in this context, the contribution of NK cells has not been assessed in detail. In a group of kidney transplant recipients, we studied the association between (i) the likelihood of BK virus replication during the two‐year period after kidney transplantation and (ii) the genotypes of the killer cell immunoglobulin‐like receptor (KIR) repertoire and their human leukocyte antigen (HLA) ligands. Other clinical factors (such as defective organ recovery and immunosuppressive treatment) were also assessed. BK virus replication was observed in 43 of the 103 recipients (41%). Patients with BK virus replication in the plasma were more likely to display defective organ recovery in the first seven days post‐transplantation. BK virus replication was not associated with Missing KIR ligands. However, BK virus replication was more frequent in patients with responsive NK cells (i.e. when a ligand for activating KIRs was not homozygous in the recipient and present in the donor). Our results suggest that defective organ recovery and the recipient's activating KIR repertoire may be related (depending on HLA ligands present in the couple recipient / donor) to the reactivation of BK virus replication after kidney transplantation.     

Transforming growth factor-β1 in the urine of young children with urinary tract infection

Urinary tract infection (UTI) is a frequent cause of morbidity during the first years of life and may lead to renal insufficiency. Transforming growth factor-1 (TGF-) is both immunoregulatory and an important mediator of interstitial fibrosis. TGF- was detected in the urine of 52% of 48 children aged 1–24 months with a first episode of UTI (94% due to Escherichia coli) and no obstructive nephropathy compared with 0 of 20 healthy young children (P<0.001). TGF- was detected in the urine only during the early stage (<1 day) after initiation of treatment. It was detected more frequently (P=0.06) and in significantly higher concentrations (P=0.046) in children with a normal ^99m Tc-dimercaptosuccinic acid scan compared with those with abnormal scans performed 3–14 days after the diagnosis of UTI, suggesting a regulatory role in fibrogenesis and outcome of pyelonephritis in childhood.     

Poor Intraoperative Blood Glucose Control Is Associated with a Worsened Hospital Outcome after Cardiac Surgery in Diabetic Patients

Background: Tight perioperative control of blood glucose improves the outcome of diabetic patients undergoing cardiac surgery. Because stress response and cardiopulmonary bypass can induce profound hyperglycemia, intraoperative glycemic control may become difficult. The authors undertook a prospective cohort study to determine whether poor intraoperative glycemic control is associated with increased intrahospital morbidity.

Methods: Two hundred consecutive diabetic patients undergoing on-pump heart surgery were enrolled. A standard insulin protocol based on subcutaneous intermediary insulin was given the morning of the surgery. Intravenous insulin therapy was initiated intraoperatively from blood glucose concentrations of 180 mg/dl or greater and titrated according to a predefined protocol. Poor intraoperative glycemic control was defined as four consecutive blood glucose concentrations greater than 200 mg/dl without any decrease in despite insulin therapy. Postoperative blood glucose concentrations were maintained below 140 mg/dl by using aggressive insulin therapy. The main endpoints were severe cardiovascular, respiratory, infectious, neurologic, and renal in-hospital morbidity.

Results: Insulin therapy was required intraoperatively in 36% of patients, and poor intraoperative glycemic control was observed in 18% of patients. Poor intraoperative glycemic control was significantly more frequent in patients with severe postoperative morbidity (37% vs. 10%; P < 0.001). The adjusted odds ratio for severe postoperative morbidity among patients with a poor intraoperative glycemic control as compared with patients without was 7.2 (95% confidence interval, 2.7-19.0).     

Kidney Transplant in Black Recipients: Are African Europeans Different from African Americans?

Despite recent improvement, significant racial disparities in outcome still persist after renal transplantation among African American patients in the United States. This study evaluated the association of race and ethnicity with allograft outcomes in a French population of 952 Caucasian (Cauc) patients and 140 African European (AE) patients who underwent renal transplantation in our center between 1987 and 2003. Demographic characteristics were similar for the two cohorts other than cause of end-stage renal failure (more hypertension among AE and more polycystic kidney disease among Cauc) and cold ischemia time (significantly longer for AE). Immunosuppressive treatment was comparable between groups. There were no significant differences between AE and Cauc in the incidence of acute rejection (31% vs. 30%). At 5 years post-transplant, patient survival (93% vs. 92%), graft survival (83% in both groups) and graft function (creatinine clearance 48 mL/min vs. 45 mL/min) were also similar among the AE and Cauc patients. We demonstrate that ethnic origin does not affect outcome after renal transplantation in France. Therefore, differences observed in the United States cannot be only related to immunologic or pharmacologic factors. The results of renal transplantation in patients of African origin could be improved with universal immunosuppressive drug coverage.     

Early local intracoronary platelet activation after drug-eluting stent placement

Background Early local platelet activation after coronary intervention identifies patients at increased risk of acute stent thrombosis （AST）. However, early changes in platelet activation in coronary circulation following drug-eluting stent （DES） implantation have never been reported. Methods In a prospective study of 26 consecutive elective stable angina patients, platelet activation was analyzed by measuring soluble glycoprotein V （sGPV） and P-selectin （CD62P） before and after implantation of either DES or bare metal stent （BMS）. All patients were pretreated with clopidogrel （300 mg loading dose） and aspirin （75 mg orally） the day before the procedure. Blood samples were drawn from the coronary ostium and 10 - 20 mm distal to the lesion site. Results Consistent with the lower baseline clinical risk, the levels of CD62P and sGPV were within normal reference range, both in the coronary ostium and distal to the lesion before percutaneous coronary intervention （PCI） procedure. The levels of CD62P and sGPV did not change significantly （CD62P： （31.1 ± 9.86） ng/ml vs （29.5 ± 9.02） ng/ml, P=0.319 and sGPV： （52.4 ± 13.5） ng/ml vs （51.8 ± 11.7） ng/ml, P=0.674, respectively） after stent implantation when compared with baseline. Changes in these platelet activation markers did not differ between stent types. Conclusions Intracoronary local platelet activation does not occur in stable angina patients before and immediately followina DES implantation when dual anti-Dlatelet is administered.     

Donor‐specific chimeric antigen receptor Tregs limit rejection in naive but not sensitized allograft recipients

Cell therapy with autologous donor‐specific regulatory T cells (Tregs) is a promising strategy to minimize immunosuppression in transplant recipients. Chimeric antigen receptor (CAR) technology has recently been used successfully to generate donor‐specific Tregs and overcome the limitations of enrichment protocols based on repetitive stimulations with alloantigens. However, the ability of CAR‐Treg therapy to control alloreactivity in immunocompetent recipients is unknown. We first analyzed the effect of donor‐specific CAR Tregs on alloreactivity in naive, immunocompetent mice receiving skin allografts. Tregs expressing an irrelevant or anti‐HLA‐A2‐specific CAR were administered to Bl/6 mice at the time of transplanting an HLA‐A2⁺ Bl/6 skin graft. Donor‐specific CAR‐Tregs, but not irrelevant‐CAR Tregs, significantly delayed skin rejection and diminished donor‐specific antibodies (DSAs) and frequencies of DSA‐secreting B cells. Donor‐specific CAR‐Treg–treated mice also had a weaker recall DSA response, but normal responses to an irrelevant antigen, demonstrating antigen‐specific suppression. When donor‐specific CAR Tregs were tested in HLA‐A2‐sensitized mice, they were unable to delay allograft rejection or diminish DSAs. The finding that donor‐specific CAR‐Tregs restrain de novo but not memory alloreactivity has important implications for their use as an adoptive cell therapy in transplantation.     

Detection of the sentinal node in squamous-cell carcinoma of the oral cavity and oropharynx. Preliminary study

INTRODUCTION: The sentinel lymph node is defined as the first relay of the lymphatic drainage of the tumor. Isotopic detection of the sentinel lymph node and absence of its metastatic invasion should theoretically be predictive of total drainage of the tumor. The goal of this study was to evaluate sentinel lymph node detectability by lymphoscintigraphy in N0 and/or N1 squamous-cell carcinoma of oral cavity and oropharynx and to determine its negative predictive value. MATERIAL AND METHOD: Lymphoscintigraphy was used for sentinel lymph node detection. The procedure required peritumoral injection of technicium-labeled colloids to enable anatomical and cutaneous location of the sentinel lymph node. A one-way Tyco-Mallinckrodt probe was used for intraoperative detection of the sentinel lymph node. This prospective study included 21 patients with N0 or N1 squamous-cell carcinoma of the oral cavity and the oropharynx. The surgical attitude based on T and N was not modified in this prospective study without direct individual benefit for the patient. Neck dissection was achieved without difficulty. RESULTS: The sentinel lymph node was identified in 20 out of 21 subjects. The sentinel lymph node was not identified in one patient with recurrence T2N0M0 squamous-cell carcinoma of the oropharynx radiated 3 years earlier. The percentage of false-negatives was 12.5% (1 false-negative out of 8 positive patients), giving a sensibility of the detection method of 87.5% (IC (95%)=[47.35-99.68]). This false-negative patient had a T3N0M0 squamous-cell carcinoma of the oropharynx with a sentinel lymph node removed in territory III. Neck dissection revealed 1 N + R- in the sub-mandibular territory associated with 27 N-R-. The probability of not finding a metastatic node at neck dissection when the sentinel lymph node is not metastatic (negative predictive value) was 92.3% (12/13) (IC (95)=[63.97-99.81]). The specificity of the method was 100%, as was the positive predictive value, because no sentinel node was diagnosed positive wrongly on frozen sections among patients without true histological node metastasis. DISCUSSION: For routine care of patients with squamous-cell carcinoma of the oral cavity and the oropharynx detection of the sentinel lymph node is proposed primarily for patients with T1T2N0 staging. Larger tumors can modify the architecture and flow within the lymphatic ducts, and consequently even the concept of a sentinel lymph node. Systematic neck dissection is required or T3T4, even when N0. Our series of T1T2N0 tumors is too small to enable statistically significant conclusions. A low level of false-negative in a larger series would be necessary to propose this technique instead of convention neck dissection for T1T2 tumors of the oral cavity and oropharynx.     

Follicular lymphoma international prognostic index

The prognosis of follicular lymphomas (FL) is heterogeneous and numerous treatments may be proposed. A validated prognostic index (PI) would help in evaluating and choosing these treatments. Characteristics at diagnosis were collected from 4167 patients with FL diagnosed between 1985 and 1992. Univariate and multivariate analyses were used to propose a PI. This index was then tested on 919 patients. Five adverse prognostic factors were selected: age (> 60 years vs 60 years), Ann Arbor stage (III-IV vs I-II), hemoglobin level (< 120 g/L vs 120 g/L), number of nodal areas (> 4 vs 4), and serum LDH level (above normal vs normal or below). Three risk groups were defined: low risk (0-1 adverse factor, 36% of patients), intermediate risk (2 factors, 37% of patients, hazard ratio [HR] of 2.3), and poor risk ( 3 adverse factors, 27% of patients, HR = 4.3). This Follicular Lymphoma International Prognostic Index (FLIPI) appeared more discriminant than the International Prognostic Index proposed for aggressive non-Hodgkin lymphomas. Results were very similar in the confirmation group. The FLIPI may be used for improving treatment choices, comparing clinical trials, and designing studies to evaluate new treatments.