Donor-specific antibodies in a pediatric kidney transplant population-Prevalence and association with antiproliferative drug dosing.

Prevalence and implications of anti-HLA class I and class II antibodies are beginning to be better characterized in pediatric kidney transplant recipients. dnDSA formation is predictive of AMR and downstream diminished graft function and survival. However, risk factors for the development of dnDSA are not well defined in this patient population. After introducing DSA surveillance into our pediatric kidney transplant program, we are reporting the prevalence of class I and class II DSA in 67 otherwise stable recipients. Secondary end-points included risk factors for DSA development and assessment of graft function. Significantly, lower median daily MMF doses were observed in patients with DSAs compared to patients without DSAs (371 vs 617 mg/m2 /d, respectively; P = 0.035). Class II DSA formation was more common, with a prevalence of 17.9%, as compared to 10.4% for class I DSA. Estimated glomerular filtration rate was also decreased in patients with positive DSA vs those with negative titers (71, SD 25 vs 78, SD 29 mL/min/1.73 m2 , respectively; P = 0.034). We conclude that reduced-dose MMF is associated with dnDSA and DSA is associated with diminished graft function in stable pediatric kidney transplant recipients.

Adherence in pediatric kidney transplant recipients: solutions for the system.

Non-adherence remains a significant problem among pediatric (and adult) renal transplant recipients. Non-adherence among solid organ transplant recipients results in US$15-100 million annual costs. Estimates of non-adherence range from 30 to 70% among pediatric patients. Research demonstrates that a 10% decrement in adherence is associated with 8% higher hazard of graft failure and mortality. Focus has begun to shift from patient factors that impact adherence to the contributing healthcare and systems factors. The purpose of this review is to describe problems within the systems implicated in non-adherence and potential solutions that may be related to positive adherence outcomes. Systems issues include insurance and legal regulations, provider and care team barriers to optimal care, and difficulties with transitioning to adult care. Potential solutions include recognition of how systems can work together to improve patient outcomes through improvements in insurance programs, a multi-disciplinary care team approach, evidence-based medical management, pharmacy-based applications and interventions to simplify medication regimens, improved transition protocols, and telehealth/technology-based multi-component interventions. However, there remains a significant lack of reliability in the application of these potential solutions to systems issues that impact patient adherence. Future efforts should accordingly focus on these efforts, likely by leveraging quality improvement and related principles, and on the investigation of the efficacy of these interventions to improve adherence and graft outcomes.

Complications of trans arterial embolization during the resuscitation of pelvic fractures.

INTRODUCTION: Trans arterial embolization (TAE) can stem uncontrolled bleeding associated with pelvic fractures, but is associated with potential complications. This study investigated and compared the early to midterm complications in two patient cohorts: one who did and one who did not undergo TAE. METHODOLOGY: The results of 14 patients who underwent TAE in the resuscitation phase, and then had their pelvic fractures managed non-operatively, the study group (Group 1), were compared with those of a control group (Group 2) of 14 patients matched for age, sex, injury and management, that did not undergo TAE. All patients were examined clinically and answered a questionnaire on bowel and urinary function, pain and limp. Gluteus medius structure and volume were assessed on MRI. The hip girdle muscle function was assessed using a hand held dynamometer, surface electromyography as well as quantitative gait analysis. RESULTS: Seven patients in Group 1 (50%), but none in Group 2, had persistent urological dysfunctions, in the absence of any recognized previous pathology or urologic trauma at the time of injury. No gluteal muscle demonstrated fibrosis or fatty infiltration. The median gluteal muscle volume was not significantly decreased compared with the uninjured side in either group (P=0.421). The muscle strengths of gluteus maximus, gluteus medius, tensor fasciae latae and iliopsoas when compared to the uninjured side were significantly less in Group 1 compared to Group 2. However, no patient had a discernable limp and gait analysis showed no significant differences between the left and right sides in the study and control groups in the gluteal activation timing (p=0.171 and 0.354) and duration (p=0.622 and 0.435). There were no skin complications, and no patient reported any persistent bowel dysfunction. CONCLUSION: TAE was associated with a high rate of persistent urological dysfunction. TAE could lead to decreased hip muscles strength, however this does not seem to affect gait.

Essential role of ICAM-1 in aldosterone-induced atherosclerosis.

OBJECTIVE: Elevated aldosterone is associated with increased risk of atherosclerosis complications, whereas treatment with mineralocorticoid receptor (MR) antagonists decreases the rate of cardiovascular events. Here we test the hypothesis that aldosterone promotes early atherosclerosis by modulating intercellular adhesion molecule-1 (ICAM-1) expression and investigate the molecular mechanisms by which aldosterone regulates ICAM-1 expression. METHODS AND RESULTS: Apolipoprotein-E (ApoE)-/- mice fed an atherogenic diet and treated with aldosterone for 4weeks showed increased vascular expression of ICAM-1, paralleled by enhanced atherosclerotic plaque size in the aortic root. Moreover, aldosterone treatment resulted in increased plaque lipid and inflammatory cell content, consistent with an unstable plaque phenotype. ApoE/ICAM-1 double knockout (ApoE-/-/ICAM-1-/-) littermates were protected from the aldosterone-induced increase in plaque size, lipid content and macrophage infiltration. Since aldosterone is known to regulate ICAM-1 transcription via MR in human endothelial cells, we explored MR regulation of the ICAM-1 promoter. Luciferase reporter assays performed in HUVECs using deletion constructs of the human ICAM-1 gene promoter showed that a region containing a predicted MR-responsive element (MRE) is required for MR-dependent transcriptional regulation of ICAM-1. CONCLUSIONS: Pro-atherogenic effects of aldosterone are mediated by increased ICAM-1 expression, through transcriptional regulation by endothelial MR. These data enhance our understanding of the molecular mechanism by which MR activation promotes atherosclerosis complications.

Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia.

Preeclampsia is a hypertensive disorder of pregnancy in which patients develop profound sensitivity to vasopressors, such as angiotensin II, and is associated with substantial morbidity for the mother and fetus. Enhanced vasoconstrictor sensitivity and elevations in soluble fms-like tyrosine kinase 1 (sFLT1), a circulating antiangiogenic protein, precede clinical signs and symptoms of preeclampsia. Here, we report that overexpression of sFlt1 in pregnant mice induced angiotensin II sensitivity and hypertension by impairing endothelial nitric oxide synthase (eNOS) phosphorylation and promoting oxidative stress in the vasculature. Administration of the NOS inhibitor l-NAME to pregnant mice recapitulated the angiotensin sensitivity and oxidative stress observed with sFlt1 overexpression. Sildenafil, an FDA-approved phosphodiesterase 5 inhibitor that enhances NO signaling, reversed sFlt1-induced hypertension and angiotensin II sensitivity in the preeclampsia mouse model. Sildenafil treatment also improved uterine blood flow, decreased uterine vascular resistance, and improved fetal weights in comparison with untreated sFlt1-expressing mice. Finally, sFLT1 protein expression inversely correlated with reductions in eNOS phosphorylation in placental tissue of human preeclampsia patients. These data support the concept that endothelial dysfunction due to high circulating sFLT1 may be the primary event leading to enhanced vasoconstrictor sensitivity that is characteristic of preeclampsia and suggest that targeting sFLT1-induced pathways may be an avenue for treating preeclampsia and improving fetal outcomes.

Mineralocorticoid Receptors in the Pathophysiology of Vascular Inflammation and Atherosclerosis.

Atherosclerosis is a chronic inflammatory disease of the vasculature that causes significant morbidity and mortality from myocardial infarction, stroke, and peripheral vascular disease. Landmark clinical trials revealed that mineralocorticoid receptor (MR) antagonists improve outcomes in cardiovascular patients. Conversely, enhanced MR activation by the hormone aldosterone is associated with increased risk of MI, stroke, and cardiovascular death. This review summarizes recent advances in our understanding of the role of aldosterone and the MR in the pathogenesis of vascular inflammation and atherosclerosis as it proceeds from risk factor-induced endothelial dysfunction and inflammation to plaque formation, progression, and ultimately rupture with thrombosis, the cause of acute ischemia. The role of the MR in converting cardiac risk factors into endothelial dysfunction, in enhancing leukocyte adhesion and infiltration into the vasculature, in promoting systemic inflammation and vascular oxidative stress, and in plaque destabilization and thrombosis are discussed. A greater understanding of the mechanisms by which the MR promotes atherosclerosis has substantial potential to identify novel treatment targets to improve cardiovascular health and decrease mortality.

Retrospective evaluation of the clinical use of prothrombin complex concentrate for the reversal of anticoagulation with vitamin K antagonists.

Anticoagulation reversal is a time-sensitive intervention for the prevention of life-threatening hemorrhagic events occurring with bleeding or surgery. Recommendations for the most effective and well tolerated reversal agent in these settings remain controversial. Several clinical guidelines for the management of intracerebral hemorrhage support use of prothrombin complex concentrates (PCCs) for the rapid reversal of warfarin-associated coagulopathy despite limited clinical data. The purpose of this investigation was to evaluate the efficacy and safety of PCC for the rapid reversal of anticoagulation by vitamin K antagonists for life-threatening bleeding or emergent surgery and to assess adherence to a hospital-based protocol. A retrospective chart review was conducted of adult patients receiving PCC for the reversal of anticoagulation. Patients were assessed according to indication for anticoagulation reversal. The primary outcome measure was adequacy of international normalized ratio reversal. Other outcomes included cessation of bleeding, thrombotic complications, and adherence to an institutional-based guideline for the use of PCC. ICU and hospital length of stay and 30-day mortality was assessed. There were 70 patients included in this study. Mean international normalized ratio was reduced from 3.1 to 1.6 following administration of at least one dose of PCC. Cessation of bleeding occurred in 65.7% of patients. Clinical assessment was unclear in 18.6%. Thrombotic complications were observed in 7.1% of patients. The 30-day mortality rate was found to be 14.3%. These data demonstrate that PCC is a well tolerated and effective method for anticoagulation reversal associated with a relatively high 30-day survival rate.

Therapeutic levels of lopinavir in late pregnancy and abacavir passage into breast milk in the Mma Bana Study, Botswana.

BACKGROUND: Pharmacokinetic data for lopinavir in late pregnancy and in breastfeeding are limited, and no data for abacavir in breast milk are available. METHODS: Women in the Mma Bana Study initiated HAART from 18 to 34 weeks of gestation. We determined trough plasma and whole breast milk concentrations of lopinavir (LPV), abacavir (ABC), nevirapine (NVP), lamivudine (3TC) and zidovudine (ZDV) among separate subsets of pregnant and breastfeeding women, and in plasma of exposed infants. Lopinavir was measured 1 month after starting HAART or 1 month postpartum, and other drugs were measured 1 month postpartum. RESULTS: Sampling occurred a median of 14 h (range 11-17) from last maternal drug ingestion. Although 50% higher median LPV levels were seen in postpartum than antepartum plasma (8.29 µg/ml versus 5.51 µg/ml; P = 0.02), antepartum levels with standard LPV dosing were therapeutic for all women (> 1.0 µg/ml). Very low LPV levels (< 0.25 µg/ml) were detected in breast milk. Median ABC levels in breast milk were 85% of those in plasma (0.057 µg/ml versus 0.067 µg/ml). Breast milk concentrations of NVP and 3TC were 27% and 74% of plasma levels, respectively. At these trough maternal time points, only NVP was detectable in potentially inhibitory levels in breastfeeding infants, and most infants had non-detectable levels of LPV, ABC, ZDV and 3TC via maternal breast milk. CONCLUSIONS: Standard LPV dosing achieved therapeutic levels in pregnancy and no appreciable concentrations in breast milk. ABC is detectable in breast milk at similar concentrations to plasma, but does not result in appreciable infant exposure.

Clan, language, and migration history has shaped genetic diversity in Haida and Tlingit populations from Southeast Alaska.

The linguistically distinctive Haida and Tlingit tribes of Southeast Alaska are known for their rich material culture, complex social organization, and elaborate ritual practices. However, much less is known about these tribes from a population genetic perspective. For this reason, we analyzed mtDNA and Y-chromosome variation in Haida and Tlingit populations to elucidate several key issues pertaining to the history of this region. These included the genetic relationships of Haida and Tlingit to other indigenous groups in Alaska and Canada; the relationship between linguistic and genetic data for populations assigned to the Na-Dene linguistic family, specifically, the inclusion of Haida with Athapaskan, Eyak, and Tlingit in the language family; the possible influence of matrilineal clan structure on patterns of genetic variation in Haida and Tlingit populations; and the impact of European entry into the region on the genetic diversity of these indigenous communities. Our analysis indicates that, while sharing a "northern" genetic profile, the Haida and the Tlingit are genetically distinctive from each other. In addition, Tlingit groups themselves differ across their geographic range, in part due to interactions of Tlingit tribes with Athapaskan and Eyak groups to the north. The data also reveal a strong influence of maternal clan identity on mtDNA variation in these groups, as well as the significant influence of non-native males on Y-chromosome diversity. These results yield new details about the histories of the Haida and Tlingit tribes in this region.

Imaging periprosthetic osteolysis around total knee arthroplasties using a human cadaver model.

We examined the sensitivity and accuracy of measuring osteolysis around total knee arthroplasty (TKA) on radiographs, computed tomography (CT), and magnetic resonance imaging (MRI) in a cadaver model. Fifty-four simulated osteolytic defects ranging from 0.7 to 14 cm(3) were created in 6 cadaver knees implanted with either a cemented or an uncemented TKA. Three blinded investigators assessed the presence, location, and volume of defects on radiographs and CT and MRI scans with metal reduction protocols. Both CT and MRI had significantly higher sensitivities and specificities than did plain radiographs (P < .005). Overall, there was no difference in the accuracy of defect volume measurements between CT and MRI (P = .574). This study demonstrates the limitations of radiographs and the high sensitivity and specificity of both CT and MRI in assessing osteolysis around TKA.

Imaging recognition of morphological variants at the midcarpal joint.

PURPOSE: To compare the imaging methods for identifying the various morphological variations of the articular surfaces at the midcarpal joint. METHODS: Thirteen cadaveric wrists were examined by plain neutral anteroposterior radiographs; 2-dimensional computed tomography (CT); 3-dimensional CT reconstruction, and 3-tesla magnetic resonance imaging (MRI). Carpal measurements were performed, and the parameters that defined the scaphoid, lunate, hamate, and capitate morphological types were investigated, with dissection being used as the definitive measure of morphology. The dissection findings were compared to the results of each imaging technique to determine the accuracy of morphological determination from each technique. RESULTS: Lunate type was the most accurately identified morphological variant amongst all imaging techniques. Lunate type was most accurately determined from coronal MRI. A lunate with a small, cartilaginous ulnar facet (intermediate type) could be differentiated only by coronal MRI and dissection. Scaphoid type could not be determined accurately using any of the imaging modalities described. Capitate type was most accurately determined from coronal MRI. However, flat and spherical-type capitates could not be routinely differentiated from V-shaped capitates. Hamate type was most accurately determined from 3-dimensional CT reconstruction. CONCLUSIONS: Accurate identification of carpal bone morphology is required to improve our understanding of carpal mechanics and pathology. Not all morphological features can be identified radiographically. Direct visualization is required to differentiate types of scaphoid, and to differentiate V-type capitates. MRI provides the most accurate identification of lunate type, and 3-dimensional CT provides the best method of differentiating hamate types.

Complications of occipital bone pneumatization.

Four cases of occipital bone pneumatization and subsequent complications are described, which include a pathological fracture of C1 and the occipital bone, spontaneous subcutaneous emphysema and pneumatocele formation. Reviews of the published literature and possible aetiological factors have been discussed.