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This study reports initial results of the development of the SIAM, a non-adherence risk assessment system for tacrolimus and sirolimus for the pediatric kidney transplant population. Forty-eight youths between 10 and 25 yr of age diagnosed with chronic kidney disease or a kidney transplant used an electronic pill bottle (EM; time stamps each bottle opening) to dispense their medication for at least 30 days or until their next clinic appointment. Youth also completed a self-report adherence measure, and standard deviations were calculated for the last four medication serum trough levels obtained for each patient. Estimation models were developed for each medication (i.e., SIAM(TACRO) and SIAM(SIRO) ) to assign weights to these clinically available adherence measures (self-report and trough levels) for the calculation of a non-adherence risk composite score. SIAM(TACRO) models included both self-report and tacrolimus trough levels and significantly predicted EM. For sirolimus, the model predictive of adherence as measured by EM consisted of the standard deviation of sirolimus trough levels only (SIAM(SIRO) ). Non-adherence risk can be effectively assessed using clinically available assessment tools. However, the best methods for using self-report and trough levels to predict non-adherence likely differ based on the medication for which adherence is being assessed., (© 2012 John Wiley & Sons A/S.)

While it is known that sirolimus affects sex hormones in adult kidney transplant patients, there is a scarcity of data on its effects on sex hormone levels in adolescent kidney recipients. The objective of this study is to describe the impact of sirolimus on the sex hormones in this patient population. This is a retrospective review of male adolescent renal transplant patients transitioned to sirolimus. Baseline and subsequent annual testosterone levels were collected. Linear regression was undertaken to determine the predictors of testosterone levels. Four African Americans and 11 Caucasians, median age of 15 yr (11-18) in 2008, were included. Mean time post-transplant was 81 ± 37 months. Mean testosterone values were the following: 336 ± 135 ng/dL (n = 8) at baseline, 349 ± 130 ng/dL (n = 15) one yr later, and 360 ± 132 ng/dL (n = 13) two yr later (normal range for adult males: 350-970 ng/dL). Seven (47%) patients experienced a decrease in testosterone levels. Time on sirolimus was associated with decreased testosterone (r = 0.643, p = 0.010). Testosterone levels in pubertal male kidney transplant recipients on sirolimus may be suppressed, especially if they have been treated with sirolimus for several years. These data need to be confirmed in a larger study., (© 2012 John Wiley & Sons A/S.)

Background: Tacrolimus is commonly prescribed for immunosuppression, yet it can cause acute and chronic kidney injury. Continuous intravenous nicardipine (CIVN), prescribed for posttransplant hypertension, inhibits tacrolimus metabolism by cytochrome P450 (CYP) 3A4 and could lead to tacrolimus overexposure in patients genetically lacking the alternative pathway for tacrolimus metabolism, CYP3A5., Methods: We compared maximum 12-hr tacrolimus trough levels (MaxC0) and dose-adjusted MaxC0 in 12 cases treated with CIVN immediately after kidney transplantation with 26 controls (no CIVN). CYP3A5 genotype was determined for all cases., Results: Eight cases not expressing CYP3A5 (CYP3A5*3/*3) had higher median MaxC0 (24.3 ng/mL) than four cases expressing CYP3A5 (CYP3A5*1/*1; 13.9 ng/mL, P=0.028) and controls (14.6 ng/mL, P=0.003). Compared with the other two groups combined, CYP3A5*3/*3 cases had higher median dose-adjusted MaxC0 (330 vs. 175, P=0.012), less time to MaxC0 (42 vs. 72 hr, P<0.001), and more scheduled tacrolimus doses held per patient (1.75 vs. 0.4, P=0.007). Six of eight (75%) CYP3A5*3/*3 cases had potentially toxic MaxC0 (>20 ng/mL) compared with none of four CYP3A5*1/*1 cases and 3 of 26 (11.5%) controls (P<0.001, CYP3A5*3/*3 cases vs. all others)., Conclusion: CYP3A5 nonexpressors simultaneously treated with tacrolimus and CIVN may be at increased risk for tacrolimus toxicity.

TA-TMA is a serious complication of hematopoietic stem cell transplantation, presenting as microangiopathic hemolytic anemia with severe renal injury and mortality as high as 60%. Diagnosis and treatment of TA-TMA is very challenging after HSCT because anemia, thrombocytopenia, hypertension, and renal impairment are multifactorial, leading to delayed recognition and management of this complication. We report a successful outcome following early intervention for hyperacute TA-TMA after allogeneic HSCT., (© 2010 John Wiley & Sons A/S.)

To present the preliminary psychometric properties of the PAT2.0&#95;GEN, a brief, caregiver completed screener of psychosocial for children who were recipients of kidney transplants. Caregivers of 45 children and adolescents with kidney transplants completed the PAT2.0&#95;GEN and the PedsQL. Internal consistency and predictive validity of the PAT2.0 were examined. Internal consistency for the PAT2.0&#95;GEN Total score was strong. Internal consistency for the PAT2.0&#95;GEN subscales ranged from 0.31 to 0.82. Evidence supporting convergent validity was observed; higher PAT2.0&#95;GEN scores were significantly associated with lower caregiver- and self-rated patient quality of life and poorer family communication. PAT2.0&#95;GEN scores were also associated with an increased likelihood that a patient received or had been independently referred for psychological services within two yr of completing the PAT2.0&#95;GEN. The PAT2.0&#95;GEN Total score is a promising screening tool for psychosocial risk in the pediatric kidney transplant population., (© 2011 John Wiley & Sons A/S.)

Heart and kidney dysfunction often coexist, and increasing evidence supports the interaction of these two organs, as demonstrated by the clinical condition known as cardiorenal syndrome (CRS). We report a pediatric patient with end-stage renal disease (ESRD) who developed a dilated cardiomyopathy and decompensated heart failure after undergoing unilateral nephrectomy and while on maintenance peritoneal dialysis. He showed marked improvement in his cardiac function with the addition of intensive hemodialysis. We discuss the pathophysiology of cardiorenal syndrome in patients with ESRD and suggest that intensive dialysis may be an effective therapy for this condition.

BK virus is a significant cause of hemorrhagic cystitis after hematopoietic stem cell transplantation (HSCT). However, its role in nephropathy post-HSCT is less studied. We retrospectively evaluated clinical outcomes in pediatric HSCT patients with hemorrhagic cystitis. Although most of these patients had very high urine BK viral loads (viruria), patients with higher BK plasma loads (viremia) had significant renal dysfunction, a worse clinical course, and decreased survival. Patients with a peak plasma BK viral load of >10,000 copies/mL (high viremia) were more likely to need dialysis and aggressive treatment for hemorrhagic cystitis compared to patients with ≤ 10,000 copies/mL (low viremia). Conversely, most patients with low viremia had only transient elevations in creatinine, and less severe hemorrhagic cystitis that resolved with supportive therapy. Overall survival (OS) at 1 year post-HSCT was 89% in the low viremia group and 48% in the high viremia group. We conclude that the degree of BK viremia, and not viruria, may predict renal, urologic, and overall outcome in the post-HSCT population., (Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a challenging diagnosis after hematopoietic stem cell transplantation. Although endothelial injury represents the final common pathway of disease, the exact pathophysiology of TA-TMA remains unclear. Potential causes include infections, chemotherapy, radiation, and calcineurin inhibitors. Recent literature addresses the roles of cytokines, graft-versus-host disease, the coagulation cascade, and complement in the pathogenesis of TA-TMA. Current diagnostic criteria are unsatisfactory, because patients who have received a transplant can have multiple other reasons for the laboratory abnormalities currently used to diagnose TA-TMA. Moreover, our lack of understanding of the exact mechanism of disease limits the development and evaluation of potential treatments. Short- and long-term renal complications contribute to TA-TMA's overall poor prognosis. In light of these challenges, future research must validate novel markers of disease to aid in early diagnosis, guide current and future treatments, prevent long-term morbidity, and improve outcomes. We focus on TA-TMA as a distinct complication of hematopoietic stem cell transplantation, emphasizing the central role of the kidney in this disease.

Patients undergoing auto-SCT for neuroblastoma present a unique population to study transplant-associated thrombotic microangiopathy (TA-TMA), due to standardized chemotherapy and later exposure to radiation and cis-retinoic acid (cis-RA). We retrospectively analyzed 20 patients after auto-SCT to evaluate early clinical indicators of TA-TMA. A total of 6 patients developing TA-TMA (30% prevalence) were compared with 14 controls. Four of six patients were diagnosed with TA-TMA by 25 days after auto-SCT. Compared with controls, TA-TMA patients had higher average systolic and diastolic blood pressure levels during high-dose chemotherapy and developed hypertension by day 13 after auto-SCT. Proteinuria was a significant marker for TA-TMA, whereas blood and platelet transfusion requirements were not. Serum creatinine did not differ between groups post transplant. However, patients with TA-TMA had a 60% decrease in renal function from baseline by nuclear glomerular filtration rate, compared with a 25% decrease in those without TA-TMA (P=0.001). There was no TA-TMA-related mortality. Significant complications included end-stage renal disease (n=1) and polyserositis (n=3). Patients with TA-TMA were unable to complete cis-RA therapy after auto-SCT. We suggest that careful attention to blood pressure and urinalysis will assist in the early diagnosis of TA-TMA, whereas serum creatinine seems to be an insensitive marker for this condition.

Background: Although nonadherence is well documented and strategies for adherence have been shown to be critical to overcoming barriers and improving overall adherence rates, it is unknown how family strategy use is related to adherence in the pediatric renal transplant population., Objectives: The aims of this study were to assess (a) the strategies used by adolescents with kidney transplants and their caregivers to adhere to the posttransplant oral medication regimen and (b) the relationship of these strategies to objective adherence rates., Methods: Semistructured interviews to assess self-management were administered to 17 adolescents (14-18 years) and 17 caregivers. Adherence to oral immunosuppressant medication, measured via electronic monitors, was determined also for a subset of 13 dyads., Results: Common strategies endorsed by families included the following: making it part of the routine (88.2%), verbal reminders by caregiver (82.4%), caregiver verifying medication was taken (76.5%), placing medication in a convenient location (76.5%), and using a pillbox (70.6%). A greater number of family-endorsed strategies were correlated with higher levels of adherence. Of those strategies spontaneously endorsed, only caregiver reminders to take medication and caregiver verification that medications were taken were related significantly to higher adherence rates., Discussion: The findings highlight the importance of identification and use of specific strategies to improve adherence rates of pediatric renal transplant recipients and emphasize the need for continued caregiver involvement in the promotion of adherence to the treatment regimen.

Here we report an unbiased analysis of the cytotoxic T lymphocyte (CTL) serine-threonine phosphoproteome by high-resolution mass spectrometry. We identified approximately 2,000 phosphorylations in CTLs, of which approximately 450 were controlled by T cell antigen receptor (TCR) signaling. A significantly overrepresented group of molecules identified included transcription activators, corepressors and chromatin regulators. A focus on chromatin regulators showed that CTLs had high expression of the histone deacetylase HDAC7 but continually phosphorylated and exported this transcriptional repressor from the nucleus. Dephosphorylation of HDAC7 resulted in its accumulation in the nucleus and suppressed expression of genes encoding key cytokines, cytokine receptors and adhesion molecules that determine CTL function. Screening of the CTL phosphoproteome has thus identified intrinsic pathways of serine-threonine phosphorylation that target chromatin regulators and determine the CTL functional program.

Mycophenolate mofetil (MMF) is widely used for maintenance immunosuppressive therapy in pediatric renal and heart transplant recipients. Children undergo developmental changes (ontogeny) of drug disposition, which may affect drug metabolism of the active compound mycophenolic acid (MPA). Therefore, a detailed characterization of MPA pharmacokinetics and pharmacodynamics in this patient population is required. In general, the overall efficacy and tolerability of MMF in pediatric patients appear to be comparable with those in adults, except for a higher prevalence of gastrointestinal adverse effects in children younger than 6 years. The currently recommended dose in pediatric patients with concomitant cyclosporine is 1200 mg/m(2) per day in 2 divided doses; the recommended MMF dose with concomitant tacrolimus or without a concurrent calcineurin inhibitor is 900 mg/m(2) per day in 2 divided doses. Recent data suggest that fixed MMF dosing results in MPA underexposure (MPA-area under the concentration-time curve (AUC(0-12)), <30 mg × h/L) early posttransplant in approximately 60% of patients. To achieve adequate MPA exposure in most patients, an initial MMF dose of 1800 mg/m(2) per day with concomitant cyclosporine and 1200 mg/m(2) per day with concomitant tacrolimus for the first 2 to 4 weeks posttransplant has been suggested. As in adults, there is an approximately 10-fold variability in dose-normalized MPA-AUC(0-12) values between pediatric patients after renal transplantation, strengthening the argument for concentration-controlled dosing of the drug. Although the clinical utility of therapeutic drug monitoring of MPA for graft outcome and patient survival is still controversial, potential indications are the avoidance of underimmunosuppression, particularly in patients with high immunologic risk in the initial period posttransplant, in patients who are treated with protocols that explore the possibilities of calcineurin inhibitor minimization, withdrawal or even complete avoidance, and steroid withdrawal or avoidance regimens that might also benefit from intensified therapeutic drug monitoring of MPA. An additional indication especially in adolescent patients is the monitoring of drug adherence. Therapeutic drug monitoring of MPA in pediatric solid organ transplantation using limited sampling strategies is preferable over drug dosing based on trough level monitoring only. Several validated pediatric limited sampling strategies are available. Clearly, more research is required to determine whether pediatric patients will benefit from therapeutic drug monitoring of MPA for long-term maintenance immunosuppression with MMF., (Copyright © 2011 Elsevier Inc. All rights reserved.)

BK virus (BKV) is an increasingly identified cause of pathology in immunocompromised transplant recipients. BKV is a well-known cause of graft dysfunction following renal transplantation and has also been reported in the native kidneys of other solid organ recipients. Less commonly, BKV nephropathy occurs in allogeneic stem-cell transplant (SCT) recipients. We now describe the first reported case of BKV nephropathy after pediatric autologous SCT., (Copyright © 2010 Wiley-Liss, Inc.)

Monitoring inosine monophosphate dehydrogenase (IMPDH) activity as a biomarker of mycophenolic acid (MPA)-induced immunosuppression may serve as a novel approach in pharmacokinetics (PK)/pharmacodynamics (PD)-guided therapy. The authors prospectively studied MPA pharmacokinetics and IMPDH inhibition in 28 pediatric de novo kidney transplant recipients. Pretransplant IMPDH activity and full PK/PD profiles were obtained at 3 different occasions: 1 to 3 days, 4 to 9 days, and approximately 6 months after transplant. Large intra- and interpatient variability was noted in MPA pharmacokinetics and exposure and IMPDH inhibition. MPA exposure (AUC(0-12 h)) was low early posttransplant and increased over time and stabilized at months 3 to 6. Mean pretransplant IMPDH activity (6.4 ± 4.6 nmol/h/mg protein) was lower than previously reported in adults. In most of the patients, IMPDH enzyme activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory E(max) model (EC(50) = 0.97 mg/L). This study suggests the importance of early PK/PD monitoring to improve drug exposure. Because IMPDH inhibition is well correlated to MPA concentration, pretransplant IMPDH activity may serve as an early marker to guide the initial level of MPA exposure required in a pediatric population.

Aim: To investigate the therapeutic value of azathioprine as monotherapy or combined with other immunosuppressive drugs for uveitis in patients with juvenile idiopathic arthritis (JIA)., Methods: A retrospective multicentre study including 41 children with JIA (28 (68.2%) female) with unilateral or bilateral (n=28) chronic anterior uveitis. Azathioprine was used to treat uveitis that was active in patients receiving topical or systemic corticosteroids, methotrexate or other immunosuppressive drugs. The primary end point was assessment of uveitis inactivity. Secondary end points comprised dose sparing of topical steroids and systemic corticosteroids, and immunosuppression., Results: At 1 year, uveitis inactivity was achieved in 13/17 (76.5%) patients by using azathioprine as systemic monotherapy and in 5/9 (56.6%) as combination therapy. During the entire azathioprine treatment period (mean 26 months), inactivity was obtained in 16/26 patients (61.5%) with monotherapy and in 10/15 (66.7%) when combined with other immunosuppressives (p=1.0). With azathioprine, dosages of systemic immunosuppression and steroids could be reduced by ≥ 50% (n=12) or topical steroids reduced to ≤ 2 drops/eye/day in six patients. In three patients (7.3%), azathioprine was discontinued because of nausea and stomach pain. Conclusions Azathioprine may be reconsidered in the stepladder approach for the treatment of JIA-associated uveitis. The addition of azathioprine may also be beneficial for patients not responding properly to methotrexate.

TAC is commonly prescribed in KTX recipients, though overexposure can be nephrotoxic. CIVN, used to treat post-KTX hypertension, may inhibit TAC metabolism resulting in overexposure and potential toxicity. We present two case reports and analysis of 2068 KTXs from the PHIS to characterize post-KTX intravenous anti-hypertensive use and to determine whether CIVN in TAC-treated patients would predict "immunosuppressive drug causing adverse effects in therapeutic use" (E-code E9331). CIVN was ordered in 11% of KTXs and prescribing increased from 6.2% in 2003 to 10.3% in 2008 (p=0.003, Mantel-Haenszel chi-square test). AEI were reported in 7.1% of TAC-treated patients with CIVN orders compared to 3% of those without (p=0.003, chi-square test). In univariate analysis using GEEs, AEI were twofold more likely in patients with CIVN orders than patients without (AOR 2.1, 95% CI 1.03-4.17) and threefold more likely than patients with orders for other continuous intravenous anti-hypertensives (AOR 3.2, 95% CI 1.09-9.08). In multivariate analysis, only CIVN significantly predicted AEI (AOR 2.8, 95% CI 1.29-6.04). Thus, until clinical studies to fully characterize this interaction are completed, CIVN should be used with caution in TAC-treated individuals., (© 2010 John Wiley & Sons A/S.)

A mixed-methods design was utilized to examine strategies that families use to manage the post-transplant oral medication regimen of adolescents with renal transplants. Seventeen adolescents and their caregivers were administered structured interviews assessing the tasks that families identified as comprising the oral medication regimen, how tasks were allocated across family members and how the dyad decided on the allocation of tasks. Adherence was assessed via electronic pill bottles and calculated by dividing the number of doses taken by those prescribed. Patients and their caregivers identified the following tasks as part of the oral medication regimen: filling the pillbox (71%), calling for refills (65%) and verifying that the pillbox is filled correctly (47%). Adult caregivers were primarily responsible for managing the medication regimen for the majority of adolescents (70%). Secondary analyses revealed that the number of oral medication regimen tasks identified by the dyad was significantly associated with patient adherence. Our findings highlight the need to bolster efforts to develop methods to quantitatively assess and promote self-management skills among adolescents with renal transplants., (© 2010 John Wiley & Sons A/S.)

With the increasing use of mycophenolic acid (MPA) as an immunosuppressant in solid organ transplantation and in treating autoimmune diseases such as systemic lupus erythematosus, the need for strategies to optimize therapy with this agent has become increasingly apparent. This need is largely based on MPA's significant between-subject and between-occasion (within-subject) pharmacokinetic variability. While there is a strong relationship between MPA exposure and effect, the relationship between drug dose, plasma concentration and exposure (area under the concentration-time curve [AUC]) is very complex and remains to be completely defined. Population pharmacokinetic models using various approaches have been proposed over the past 10 years to further evaluate the pharmacokinetic and pharmacodynamic behaviour of MPA. These models have evolved from simple one-compartment linear iterations to complex multi-compartment versions that try to include various factors, which may influence MPA's pharmacokinetic variability, such as enterohepatic recycling and pharmacogenetic polymorphisms. There have been major advances in the understanding of the roles transport mechanisms, metabolizing and other enzymes, drug-drug interactions and pharmacogenetic polymorphisms play in MPA's pharmacokinetic variability. Given these advances, the usefulness of empirical-based models and the limitations of nonlinear mixed-effects modelling in developing mechanism-based models need to be considered and discussed. If the goal is to individualize MPA dosing, it needs to be determined whether factors which may contribute significantly to variability can be utilized in the population pharmacokinetic models. Some pharmacokinetic models developed to date show promise in being able to describe the impact of physiological processes such as enterohepatic recycling. Most studies have historically been based on retrospective data or poorly designed studies which do not take these factors into consideration. Modelling typically has been undertaken using non-controlled therapeutic drug monitoring data, which do not have the information content to support the development of complex mechanistic models. Only a few recent modelling approaches have moved away from empiricism and have included mechanisms considered important, such as enterohepatic recycling. It is recognized that well thought-out sampling schedules allow for better evaluation of the pharmacokinetic data. It is not possible to undertake complex absorption modelling with very few samples being obtained during the absorption phase (which has often been the case). It is important to utilize robust AUC monitoring which is now being propagated in the latest consensus guideline on MPA therapeutic drug monitoring. This review aims to explore the biological factors that contribute to the clinical pharmacokinetics of MPA and how these have been introduced in the development of population pharmacokinetic models. An overview of the processes involved in the enterohepatic recycling of MPA will be provided. This will summarize the components that complicate absorption and recycling to influence MPA exposure such as biotransformation, transport, bile physiology and gut flora. Already published population pharmacokinetic models will be examined, and the evolution of these models away from empirical approaches to more mechanism-based models will be discussed.

Dyslipidemia, a known risk factor for atherosclerosis, is frequent among both adults and children with chronic kidney disease. Here, we describe the prevalence and pattern of dyslipidemia from a cross-sectional analysis of 391 children aged 1-16 years, enrolled in the multicenter Chronic Kidney Disease in Children (CKiD) study, with a median glomerular filtration rate (GFR), measured by the plasma disappearance of iohexol, of 43 ml/min per 1.73 m2. Multivariate analysis was applied to adjust for age, gender, body mass index (BMI), GFR, and the urinary protein/creatinine ratio. Proteinuria was in the nephrotic range in 44 and the BMI exceeded the 95th percentile in 57 patients of this cohort. Baseline lipid analysis found a high prevalence of hypertriglyceridemia in 126, increased non-HDL-C in 62, and reduced HDL-C in 83. Overall, 177 children had dyslipidemia, of whom 79 had combined dyslipidemia. Lower GFR was associated with higher triglycerides, lower HDL-C, and higher non-HDL-C. Nephrotic-range proteinuria was significantly associated with dyslipidemia and combined dyslipidemia. Compared with children with a GFR>50, children with a GFR<30 had significantly increased odds ratios for any dyslipidemia or for combined dyslipidemia. Hence, among children with moderate chronic kidney disease, dyslipidemia is common and is associated with lower GFR, nephrotic proteinuria, and non-renal factors including age and obesity.

Impaired kidney function is a well-recognized complication following liver transplantation (LT). Studies of this complication in children have been limited by small numbers and insensitive outcome measures. Our aim was to define the prevalence of, and identify risk factors for, post-LT kidney dysfunction in a multicenter pediatric cohort using measured glomerular filtration rate (mGFR). We conducted a cross-sectional study of 397 patients enrolled in the Studies in Pediatric Liver Transplantation (SPLIT) registry, using mGFR < 90 mL/min/1.73 m(2) as the primary outcome measure. Median age at LT was 2.2 years. Primary diagnoses were biliary atresia (44.6%), fulminant liver failure (9.8%), metabolic liver disease (16.4%), chronic cholestatic liver disease (13.1%), cryptogenic cirrhosis (4.3%) and other (11.8%). At a mean of 5.2 years post-LT, 17.6% of patients had a mGFR < 90 mL/min/1.73 m(2) . In univariate analysis, factors associated with this outcome were transplant center, age at LT, primary diagnosis, calculated GFR (cGFR) at LT and 12 months post-LT, primary immunosuppression, early post-LT kidney complications, age at mGFR, height and weight Z-scores at 12 months post-LT. In multivariate analysis, independent variables associated with a mGFR <90 mL/min/1.73 m(2) were primary immunosuppression, age at LT, cGFR at LT and height Z-score at 12 months post-LT., (©2010 The Authors Journal compilation©2010 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The purpose of the current study is to report preliminary psychometric properties of the ATR scale, a brief measure of the distribution of treatment tasks across the family members of children with a kidney transplant. Pediatric patients with renal transplants (ages 7-18 yr) and their caregivers completed the ATR and measures of adherence and family functioning. Internal consistency for the ATR (total score and subscales) was strong (range α = 0.75-0.93). Validity for the ATR was supported by significant correlations between the ATR caregiver total score of patient responsibility and patient age, as well as the ATR caregiver total score of patient responsibility and adherence. The ATR scale is a promising new tool for assessing the distribution of medical regimen tasks between patients and their caregivers. The availability of a standardized measure of ATR could assist in monitoring patient preparation for transition and identifying factors contributing to non-adherence., (© 2010 John Wiley & Sons A/S.)

Life-span psychological research has long been interested in the contextual embeddedness of individual development. To examine whether and how regional variables relate to between-person disparities in the progression of late-life well-being, we applied three-level growth curve models to 24-year longitudinal data from deceased participants of the German Socio-Economic Panel Study (N = 3,427; age at death = 18 to 101 years). Results indicated steep declines in well-being with impending death, with some 8% of the between-person differences in both level and decline of well-being reflecting between-county differences. Exploratory analyses revealed that individuals living and dying in less affluent counties reported lower late-life well-being, controlling for key individual predictors, including age at death, gender, education, and household income. The regional variables examined did not directly relate to well-being change but were found to moderate (e.g., amplify) the disparities in change attributed to individual variables. Our results suggest that resource-poor counties provide relatively less fertile grounds for successful aging until the end of life and may serve to exacerbate disparities. We conclude that examinations of how individual and residential characteristics interact can further our understanding of individual psychological outcomes and suggest routes for future inquiry., ((c) 2010 APA, all rights reserved.)

Background: Pain is a common, often undertreated problem among patients with palliative needs., Objectives: To evaluate clinician factors associated with intention to address diverse aspects of pain., Design: Clinicians reviewed a clinical vignette describing a frail elderly patient with advanced hormone-refractory metastatic prostate cancer, depression, and pain not on analgesic therapy. Clinicians were surveyed about their intentions for treatment., Participants: All 280 primary care and specialist clinicians working in 19 hospital and community-based primary care, oncology, and cardiology clinics at eight geographically dispersed sites in two large VA hospital systems., Main Measures: Endpoints were clinician intention to deliver guideline-concordant care: prescribe opioids/antidepressants, assess existential wellbeing, and offer mental health referral. Demographic and behavioral measures were evaluated in association with endpoints., Key Results: Of 208 (74%) responding practitioners, 189 were responsible for prescribing decisions. Of those, 86, 77, 75, and 69 were "very"/"somewhat likely" to prescribe opioids, antidepressants, refer to a mental health specialist, or assess existential wellbeing, respectively. Factors associated with greater intent to prescribe an opioid or antidepressant included female gender, being an attending physician, being a primary care clinician, and greater confidence in pain management skills. Greater trust in the validity of pain ratings was associated with intent to prescribe an antidepressant and assess existential wellbeing. Prescribing opioids was less likely if perceived as an administrative burden. Assessing existential wellbeing was less likely if time constraints were perceived a barrier to evaluating pain. Female gender was the only factor associated with intent to refer to a mental health specialist., Conclusions: Our findings suggest useful targets for improving pain management include bolstering clinician confidence in pain management and their trust in pain ratings., (Wiley Periodicals, Inc.)

BKVNP is an increasingly recognized cause of graft dysfunction and loss in kidney transplant recipients. Protocols for BKV screening and for the diagnosis of BKVNP are still evolving. PCR-based BKV detection became available at our institution in 2007, when we began using it according to published guidelines. We subsequently reviewed our experience with urine and plasma BKV PCR testing in our pediatric kidney transplant recipient population. We found rates of viruria, viremia, and BKVNP that were similar to the published literature. We also conducted a cost analysis suggesting that urine PCR testing, as used by us, is not cost efficient in the detection of BKV. We conclude that plasma only-based PCR testing for BKV may be sufficient in most clinical settings.

Purpose: To evaluate the outcomes after dose-escalated radiotherapy (RT) for spinal metastases and paraspinal tumors., Methods and Materials: A total of 14 patients, 12 with spinal metastases and a long life expectancy and 2 with paraspinal tumors, were treated for 16 lesions with intensity-modulated, image-guided RT. A median biologic effective dose of 74 Gy(10) (range, 55-86) in a median of 20 fractions (range, 3-34) was prescribed to the target volume. The spinal canal was treated to 40 Gy in 20 fractions using a second intensity-modulated RT dose level in the case of epidural involvement., Results: After median follow-up of 17 months, one local recurrence was observed, for an actuarial local control rate of 88% after 2 years. Local control was associated with rapid and long-term pain relief. Of 11 patients treated for a solitary spinal metastasis, 6 developed systemic disease progression. The actuarial overall survival rate for metastatic patients was 85% and 63% after 1 and 2 years, respectively. Acute Grade 2-3 skin toxicity was seen in 2 patients with no late toxicity greater than Grade 2. No radiation-induced myelopathy was observed., Conclusion: Dose-escalated irradiation of spinal metastases was safe and resulted in excellent local control. Oligometastatic patients with a long life expectancy and epidural involvement are considered to benefit the most from fractionated RT.

Objectives: : To study synovial membrane (SM) inflammation near the patella with different magnetic resonance imaging (MRI) approaches performed using a T1-injected sequence in knee osteoarthritis (OA), and to compare MRI results with macroscopic, microscopic and clinical findings., Methods: Fifteen patients fulfilling American College of Rheumatology (ACR) criteria for knee OA and requiring joint lavage completed a functional index (Lequesne's functional index) and a pain visual analog scale (VAS). SM inflammation near the patella was assessed on axial fat saturation post-injected T1 MRI images using three different methods: (1) semi-quantitative score=MRI synovitis score; (2) synovial membrane volume (SMV) analysis; (3) SMV with low (SMVL) (<0.3%/s(-1)), intermediate (SMVI) (0.3%/s(-1) to 1%/s(-1)) and high (SMVH) (> or =1%/s(-1)) speed of enhancement. Chondral lesions and SM inflammation were macroscopically graded and SM biopsies performed for microscopic scoring., Results: All MRI approaches exhibited excellent intra- and inter-observer reproducibility. MRI synovitis score correlated well with macroscopic (r=0.61, P=0.003) and total microscopic scores (r=0.55, P=0.03). Correlations between SMV and macroscopic (r=0.60, P=0.02) and microscopic congestion (r=0.63, P=0.01) were good. SMVH was correlated only with microscopic congestion (r=0.79, P=0.01). Low SMV was associated with neither macroscopic nor microscopic scores. However, it did correlate well with pain-VAS score (r=0.61, P=0.03) and moderately with a functional index (r=0.46, P=0.10)., Conclusion: The three MRI approaches used here provided highly reproducible information on SM inflammation near the patella in knee OA. Compared to SMV, MRI synovitis score seems sufficient to assess synovial inflammation but high SMV is an appropriate indicator of vascular congestion, and low SMV reflects pain in knee OA.

Background: Osteonecrosis of the femoral head has become increasingly common after steroid therapy and as a consequence of improved survival in children with sickle cell anemia and leukemia. Multiple operative and nonoperative treatments have been explored in the pediatric patient population, and core decompression is a relatively safe and possibly effective option. To optimize core decompression further, we have tested a new technique involving thorough decompression of the osteonecrotic zone under endoscopic visualization (TDEV) combined with cancellous bone grafting and stabilization with a nail plate device., Methods: We retrospectively reviewed 16 hips in 13 patients (< or =20 years old) with femoral head osteonecrosis related to steroid treatment, sickle cell anemia, or leukemia. The Steinberg classification system was used to classify all cases. Each patient underwent TDEV, bone grafting, and stabilization of the grafting site. Patients were followed up postoperatively for changes in pain level, functional ability, and Steinberg radiologic stage., Results: The mean follow-up was 28 months (range, 18-49 months). All patients in whom the procedure was successful had improvement in pain symptoms at latest follow-up, except for 1. Radiologically, all Steinberg stage II cases (B and C), except for 1, demonstrated good incorporation of graft without further progression of disease. Seven of the 8 patients that showed radiologic progression and deterioration of function or progressive symptoms had grade IIIB disease or higher at the time of procedure., Conclusions: Our initial results demonstrate that TDEV combined with cancellous bone grafting and stabilization produces encouraging early results for pediatric patients with lesions graded lower than Steinberg stage IIIB. Our findings were less optimistic for patients with higher-grade lesions. Our recommendation, therefore, is to use TDEV by trained surgeons for treatment of early-stage lesions, preferably less than Steinberg stage IIIB., Level of Evidence: Level IV, Therapeutic Study.

Leukopenia and diarrhea are the predominant adverse events associated with mycophenolate mofetil (MMF), leading to dose reduction or discontinuation in children. Polymorphisms of the drug's main metabolizing enzyme, uridine diphosphate-glucuronosyl transferase (UGT), confer alteration in drug exposure. We studied the incidence of these polymorphisms in pediatric kidney transplant recipients experiencing MMF-associated leukopenia and diarrhea. UGT genotypes of 16 affected children who recovered after MMF dose reduction or discontinuation were compared with those of 22 children who tolerated the drug at standard doses. DNA was extracted and sequenced using standard procedures to detect polymorphisms associated with increased (e.g., UGT1A9 -331T>C) or decreased drug exposure. All three patients who were homozygous for UGT1A9 -331T>C developed leukopenia, and heterozygotes also had significantly more toxicity (P = 0.04). A weaker association (P = 0.08) existed in UGT2B7 -900G>A carriers. Our data implicate UGT polymorphisms associated with altered drug exposure as potential predictors of MMF adverse events.

In 2005, kidney allocation rules in the United States were updated to enhance access to kidneys from young adult deceased donors (DDs) for pediatric recipients. We studied how this rule change affected transplant activity at our pediatric center. We retrospectively compared kidney transplant activity at our center since the rule change (until December 31, 2007) to before the change (n = 36 each), focusing on those recipients directly affected by it, that is, younger than 18 years. There were no significant differences in recipients' age, gender or ethnicity before versus after the rule change. Percentages of preemptive transplants and retransplants were similar in both groups, as was the percentage of sensitized patients. There was a significant decrease in overall, but not DD, mean donor age. Mean wait time for DD kidneys decreased for pediatric recipients. Increases were found in percentage of DD transplants and in mean HLA mismatches after the rule change. Patient and short-term graft survival were not significantly different. These data suggest that the allocation rule change was not only followed by improvement in overall access to kidney transplantation for children, but also by decreases in living donor transplants and HLA matching. Larger studies are needed to evaluate the long-term impact of the change.

Understanding the molecular mechanisms underlying dysregulated immune responses in human immunodeficiency virus type 1 (HIV-1) infection is crucial for the control of HIV/AIDS. Despite the postulate that HIV envelope glycoprotein gp120-CD4 interactions lead to impaired T-cell responses, the precise mechanisms underlying such association are not clear. To address this, we analyzed Lck and F-actin redistribution into the immunological synapse in stimulated human primary CD4(+) T cells from HIV-1-infected donors. Similar experiments were performed with CD4(+) T cells from HIV-uninfected donors, which were exposed to anti-CD4 domain 1 antibodies, as an in vitro model of gp120-CD4 interactions, or aldithriol-inactivated HIV-1 virions before stimulation. CD4(+) T cells from HIV-infected patients exhibited a two- to threefold inhibition of both Lck and F-actin recruitment into the synapse, compared to cells from uninfected donors. Interestingly, defective recruitment of Lck was ameliorated following suppressive highly active antiretroviral therapy. Engagement of the CD4 receptor on T cells from HIV-uninfected donors before anti-CD3/CD28 stimulation led to similar defects. Furthermore, the redistribution of Lck into lipid rafts was abrogated by CD4 preengagement. Our results suggest that the engagement of CD4 by HIV gp120 prior to T-cell receptor stimulation leads to dysregulation of early signaling events and could consequently play an important role in impaired CD4(+) T-cell function.

Purpose: To evaluate intra-fractional uncertainties during intensity-modulated radiotherapy (IMRT) of prostate cancer., Patients and Methods: During IMRT of 21 consecutive patients, kilovolt (kV) cone-beam computed tomography (CBCT) images were acquired prior to and immediately after treatment: a total of 252 treatment fractions with 504 CBCT studies were basis of this analysis. The prostate position in anterior-posterior (AP) direction was determined using contour matching; patient set-up based on the pelvic bony anatomy was evaluated using automatic image registration. Internal variability of the prostate position was the difference between absolute prostate and patient position errors. Intra-fractional changes of prostate position, patient position, rectal distension in AP direction and bladder volume were analyzed., Results: With a median treatment time of 16 min, intra-fractional drifts of the prostate were >5 mm in 12% of all fractions and a margin of 6 mm was calculated for compensation of this uncertainty. Mobility of the prostate was independent from the bony anatomy with poor correlation between absolute prostate motion and motion of the bony anatomy (R2=0.24). A systematic increase of bladder filling by 41 ccm on average was observed; however, these changes did not influence the prostate position. Small variations of the prostate position occurred independently from intra-fractional changes of the rectal distension; a weak correlation between large internal prostate motion and changes of the rectal volume was observed (R2=0.55)., Conclusion: Clinically significant intra-fractional changes of the prostate position were observed and margins of 6 mm were calculated for this intra-fractional uncertainty. Repeated or continuous verification of the prostate position may allow further margin reduction.

Equinovarus of the foot is the most common lower extremity deformity following traumatic brain injury. We evaluated outcomes of the split anterior tibialis tendon transfer (SPLATT) for correction of equinovarus in 47 patients with hemiplegic traumatic brain injury and specifically studied differences in outcomes with two tendon fixation techniques. Seventeen patients constituting Group I underwent fixation with one technique and 30 constituting Group II had another technique. Patients in both groups had appropriate procedures based on dynamic electromyography and gait analyses. Both groups were demographically comparable. All 47 feet were corrected to plantigrade position. Thirty-six of 47 patients became brace-free at final followup. There was a notable decrease in the use of ambulatory aids and ambulatory status improved in both groups. There were three fixation-related complications in Group I and none in Group II. Surgical correction of the spastic equinovarus with SPLATT, in the appropriate patient, with or without associated tendon procedures helps to achieve and maintain correction, improves the ambulatory status of the patient, and eliminates the need for bracing in as much as 77% of patients. We recommend the Group II construct owing to the considerably lower complication rate.

Mycophenolate mofetil (MMF) has become a standard component of immunosuppressive regimens in adult and pediatric renal transplantation. Especially in children, MMF is known to have clinically obvious gastrointestinal side effects such as diarrhea or abdominal pain that can be dose-limiting or require drug discontinuation. In contrast, we report isolated weight loss unaccompanied by obvious clinical gastrointestinal symptoms in two pediatric renal transplant patients taking MMF. Both patients began gaining weight again after conversion to azathioprine. Accordingly, subspecialists and generalists caring for pediatric kidney transplant recipients taking MMF should be aware of this clinically "silent" complication.

Objective: To retrospectively examine the diagnostic accuracy of prenatal RhD blood type genotyping on amniotic fluid, using a combination of two polymerase chain reaction (PCR) methods in daily practice., Methods: Amniotic fluid was obtained from women undergoing amniocentesis. Two PCR protocols were carried out in two different laboratories. We obtained the postnatal serological RhD status. In cases with differing prenatal and postnatal test results, we investigated the possible error source by different methods. Sensitivity, specificity and the predictive values were calculated., Results: Prenatal RhD genotyping was applied in 1,640 cases, of which the postnatal serologic RhD status was obtained in 927. No discordance between both PCR methods occurred. In nine out of 927 cases differing results between PCR and serologic status were encountered. The sensitivity was 99.5%, the specificity 98.6%, and both positive and negative predictive values 99.1%., Conclusion: Prenatal diagnosis of the fetal RhD blood type with PCR from amniotic fluid is highly accurate in daily practice and associated with a minimal sensitivity of 99.5% and a minimal specificity of 98.6%.

Background: The developmental anatomy and biomechanics of the upper cervical spine are unique in children. Congenital osseous anomalies in this region may be associated with an increased risk for subsequent neurological compromise from instability and/or spinal cord encroachment. We performed a double-cohort study evaluating congenital osseous anomalies of the upper cervical spine in children who presented with one or more clinical problems, and we attempted to outline the risk of possible neurological compromise., Methods: We reviewed the medical records and imaging studies of all children seen and treated for osseous anomalies of the upper cervical spine at our institution between 1988 and 2003. Patients were divided into two cohorts on the basis of the presence or absence of associated syndromes. Parameters reviewed included demographic data, clinical presentation, and imaging features. All anomalies involving the central nervous system, the occipitocervical junction, and the upper cervical osseous canal were included. Complicating sequelae such as canal stenosis, segmental instability, and other anomalies of the central nervous system and spine were identified., Results: Sixty-eight consecutive children were identified. Twenty-one patients had an underlying described syndrome. There were 234 osseous anomalies (average, 3.4 per patient). Three or more anomalies were noted in 79% of the patients. There was no significant difference in the mean number of anomalies (p = 0.80) or in the frequency of any specific anomaly (p > 0.20 for all) between syndromic and nonsyndromic patients. The variety of clinical presentations included neck pain (twenty-six patients), neurological changes (twenty-one patients), and torticollis and/or stiffness (twenty-one patients). Twenty-three patients had more than one complaint. Six patients had isolated spinal instability, twenty-eight had isolated spinal cord encroachment, and six had a combination of both. Forty-four (65%) of the sixty-eight patients underwent surgical decompression and/or arthrodesis principally focused from the foramen magnum to the second cervical vertebra., Conclusions: As a result of these findings, we recommend a thorough evaluation and advanced imaging of the upper cervical spine in all children who present with symptoms related to the upper cervical spine, to identify associated anomalies and further define the nature of canal encroachment including any potential for neurologic compromise.

The oxidative-stress-responsive kinase 1 (OSR1) and the STE20/SPS1-related proline/alanine-rich kinase (SPAK) are key enzymes in a signalling cascade regulating the activity of Na(+)/K(+)/2Cl(-) co-transporters (NKCCs) in response to osmotic stress. Both kinases have a conserved carboxy-terminal (CCT) domain, which recognizes a unique peptide (Arg-Phe-Xaa-Val) motif present in OSR1- and SPAK-activating kinases (with-no-lysine kinase 1 (WNK1) and WNK4) as well as its substrates (NKCC1 and NKCC2). Here, we describe the structural basis of this recognition event as shown by the crystal structure of the CCT domain of OSR1 in complex with a peptide containing this motif, derived from WNK4. The CCT domain forms a novel protein fold that interacts with the Arg-Phe-Xaa-Val motif through a surface-exposed groove. An intricate web of interactions is observed between the CCT domain and an Arg-Phe-Xaa-Val motif-containing peptide derived from WNK4. Mutational analysis shows that these interactions are required for the CCT domain to bind to WNK1 and NKCC1. The CCT domain structure also shows how phosphorylation of a Ser/Thr residue preceding the Arg-Phe-Xaa-Val motif results in a steric clash, promoting its dissociation from the CCT domain. These results provide the first molecular insight into the mechanism by which the SPAK and OSR1 kinases specifically recognize their upstream activators and downstream substrates.

Despite that on clinical systems phased array technology is now widely used, the high field MRI experimental systems with multiple receiver channels just became available few years ago. For this reason and due to the large range of magnetic field (frequencies between 200 and 500 MHz for proton resonance), commercial phased arrays implemented in narrow bore for high field applications are rare and relatively expensive. Array coil imaging is an advanced method for acquiring high resolution images with enhanced Signal-to-Noise Ratio (SNR) and/or enlarged Field Of View (FOV) compared for example to single loop surface coil. The volume of interest is then covered by several coil elements and images reconstructed for every single channel are combined afterwards. The goal of this work was to develop a dedicated two-element array coil operating at 300 MHz (7T) for high-resolution imaging of rat knee joint in order to quantify cartilage thickness and volume. A dedicated two-element array coil with two square elements encompassing knee joint was designed and built. Decoupling between elements was achieved with a capacitor inserted on the common leg of the two elements. The average gain in SNR compared to a 15 mm reference single loop coil was 2.2. This SNR gain was used to improve spatial resolution of 3D acquisition by decreasing the voxel size from 59 x 59 x 156 microm(3) to 51 x 51 x 94 microm(3) without time penalty.

In this report, we describe a newborn infant who presented with congenital nephrotic syndrome and renal insufficiency, as well as bilateral microcoria. This constellation of findings is a hallmark of Pierson syndrome, a newly recognized genetic disorder that is caused by a deficiency of beta2 laminin in the basement membrane. Our patient demonstrated classic histopathologic findings of Pierson syndrome on renal biopsy, including absence of beta2 laminin on immunofluorescent staining, and genetic testing confirmed the diagnosis. We conclude that Pierson syndrome should be included in the differential diagnosis for congenital nephrotic syndrome, especially in patients with ocular abnormalities.

Few data exist on the modulation of cytokine receptor signaling by the actin or tubulin cytoskeleton. Therefore, we studied interleukin-2 receptor (IL-2R) signaling in phytohemagglutinine (PHA)-pretreated human T cells in the context of alterations in the cytoskeletal system induced by cytochalasin D (CyD), jasplaklinolide (Jas), taxol (Tax), or colchicine (Col). We found that changes in cytoskeletal tubulin polymerization altered the strength of several IL-2-triggered signals. Moreover, Tax-induced tubulin hyperpolymerization augmented the surface expression of the IL-2R ss -chain and enhanced the association of the IL-2R beta -chain with cytoskeletal tubulin. The IL-2R beta-chain, in turn, was constitutively associated with tubulin and, more weakly, actin. To exclude the possibility that these associations are artifacts caused by PHA, we confirmed them in T cells from TCR-transgenic DO 11.10 mice stimulated with their nominal antigen. We conclude that altered polymerization of cytoskeletal components, especially tubulin, is accompanied by modulation of IL-2 signaling at the receptor level.

Although the immunomodulatory properties of statins are in part independent of their lipid-lowering effects, cholesterol is a major component of lipid rafts. We therefore studied the effects of atorvastatin (AS) on the raft enrichment of the interleukin-2 receptor (IL-2R) beta chain previously described by us and on early IL-2R signaling events in activated human T cells. We found that concomitant AS exposure during a 3-day stimulation with phytohemagglutinin (PHA) attenuates activation-associated events, such as the enhanced surface expression of the raft marker GM-1 and the induced expression of the activation marker CD25 (the IL-2R alpha chain). In contrast, brief AS treatment after PHA stimulation increased GM-1 surface expression and virtually abolished the selective raft enrichment of the IL-2R beta chain. Although this AS-associated increase in GM-1 expression resembled that seen in the presence of the raft-disrupting cholesterol chelator methyl-beta-cyclodextrin (MBCD), the two agents had contrasting effects on the tyrosine phosphorylation of the IL-2R beta chain by exogenous IL-2: MBCD essentially abolished this event, whereas AS tended to enhance it and shifted its occurrence out of rafts. We conclude that AS affects IL-2R signaling by altering the raft enrichment of the IL-2R beta chain and propose that this effect is one mechanism underlying the immunomodulatory properties of statins.

Anemia status at 1-year post-kidney transplant was documented retrospectively in 231 pediatric recipients (mean age: 12.6 +/- 5.0, range: 1.9-20.7 years) at Cincinnati Children's Hospital Medical Center between 1978 and 2003. Anemia was present in 59 (25.5%) patients. The prevalence of anemia has increased in the more recent eras (1978-1985: 7.8%, 1986-1997: 29%; 1998-2003: 32%, p < 0.01). Logistic regression analysis determined that the use of calcineurin inhibitors or impaired allograft function predicted anemia at 1-year post-transplant. Kaplan-Meier analysis showed that children with anemia at 1-year post-transplant had a significantly worse overall allograft survival than children without anemia (p = 0.02). However, when data were analyzed using a Cox proportional hazards model, only lower allograft function at 1-year post-transplant, black race and older era, but not anemia, independently predicted worse graft survival in children. This study suggests that the recent increase in the incidence of anemia post-kidney transplant is related to modern immunosuppressive therapy and that post-transplant anemia is more likely a marker of allograft dysfunction in children rather than its cause.

Hypothesis: Anatomic differences may render the superior division of the vestibular nerve more susceptible to injury during vestibular neuritis., Background: Neural degeneration has been identified in temporal bone studies of vestibular neuritis. Previous anatomic and physiologic studies of vestibular neuritis have demonstrated that the superior division of the vestibular nerve is preferentially affected, with sparing of the inferior division. A preliminary temporal bone study has implicated neural entrapment as a possible cause for this preferential injury., Methods: Two independent unbiased observers performed histologic analysis of 184 temporal bones from our temporal bone library. Measurements of the medial, midpoint, and lateral portions of the superior vestibular, inferior vestibular, and the singular nerves and their bony channels lateral to the internal auditory canal were made. These measurements included the length and width of each bony channel and an estimated percent of each channel occupied by bony spicules at each location., Results: The lengths of the bony channels of the singular nerve (0.598 mm) and the inferior vestibular nerve (0.277 mm) were significantly shorter than the average length of the superior vestibular channel (1.944 mm; p < 0.0001). The total percent of the channel occupied by bone at the midpoint was significantly greater for the superior vestibular (28%) compared with either the singular (0%) or the inferior vestibular channel (18%) (p < 0.0001)., Conclusion: The lateral bony channel of the superior vestibular nerve is seven times longer than the inferior vestibular and more than three times longer than the singular channel. There are a larger percentage of bony spicules occupying the superior vestibular compared with the inferior vestibular or singular channels. In addition, the superior nerve passes through a longer area of severe narrowing compared with the inferior or singular nerves. This anatomic arrangement of a longer bony channel with more interspersed bony spicules could make the superior vestibular nerve more susceptible to entrapment and ischemia.

Stimulated human T cells from healthy volunteers demonstrate attenuated early interleukin (IL)-2 receptor (R) signaling in the presence of daclizumab (Dac). Aiming to confirm that this ex-vivo effect of Dac is also observed in-vivo, we studied T cells from 3 kidney transplant recipients before and 2-3 weeks and 4-6 months after transplantation. We found by flow cytometry that T cells obtained pre-transplant and stimulated ex-vivo with phytohemeagglutinine upregulated the IL-2R alpha-(CD25) and beta-(CD122) chains as expected. Moreover, exogenous IL-2 induced characteristic tyrosine phosphorylation events detectable by immunoblotting in these cells. However, T cells studied post-transplant neither exhibited CD25 or -122 upregulation nor IL-2-induced tyrosine phosphorylation events, indicating broad, persistent suppression of the IL-2R signaling machinery which thus appears largely inaccessible for Dac in actual transplant recipients. We therefore conclude that the clinical efficacy of this agent may depend on additional mechanisms in-vivo other than those identified ex-vivo.

Lipid rafts are established as critical structures for a variety of cellular processes, including immune cell activation. Beyond their importance for initial immune cell activation at the immunological synapse, lipid rafts are now also being recognized as important sites for cytokine and growth factor signal transduction, both in immune cells as part of secondary regulatory processes, and in non-immune cells. This review summarizes current knowledge regarding the roles of rafts in cytokine signaling and emphasizes the need for measures to better standardize the study of rafts.

Objective: This study was undertaken to investigate the origin and pathophysiological importance of plasminogen activator inhibitor (PAI-1) in atherosclerosis., Methods and Results: We used the ferric chloride model to induce carotid artery injury in apolipoprotein E knockout (apoE-/-) and wild-type (WT) mice. ApoE-/- mice fed high-fat diet for 4 months developed severe hypercholesterolemia and had significantly elevated plasma PAI-1 levels (2.3+/-0.3 versus 0.6+/-0.1 ng/mL in WT mice; P<0.05). These mice exhibited a prothrombotic phenotype with shortened times to thrombotic arterial occlusion (8.6 versus 11.5 minutes; P<0.001) and reduced recanalization rates (12% versus 51%; P<0.0001) compared with WT mice. In situ hybridization, reverse transcriptase-polymerase chain reaction, and immunohistochemistry showed a significantly upregulated PAI-1 expression in P-selectin-positive (activated) endothelial cells lining normal-appearing arterial segments and within the advanced atherosclerotic lesions of apoE-/- mice. No significant upregulation of PAI-1 expression was found in the other organs studied, and only trace amounts of PAI-1 mRNA were detected in murine platelets. Importantly, deletion of the PAI-1 gene reversed the prothrombotic tendency and reduced neointimal growth after injury in apoE-/- mice despite the persistence of excessive hypercholesterolemia., Conclusions: These results suggest that increased vascular expression of PAI-1 may contribute to the elevated circulating levels of the inhibitor and be responsible, at least in part, for the prothrombotic phenotype in apoE-/- mice.

In this paper, the detailed morphology of Prorocentrum donghaiense was studied. Taxonomic comparison was made between P. donghaiense and other relevant Prorocentrum species. The results suggested that distinct differences existed among them with respect to their conservative characteristics of morphology and cell sizes. This kind of discrepancy was far beyond that of individual variations within same species due to environmental factors. Therefore, the high biomass bloom-forming species in the East China Sea was not real Prorocentrum "dentatum" Stein, but P. donghaiense Lu that was re-described in the present paper. P. donghaiense appeared in the East China Sea, and P. "dentatum" occurred in Japanese and Korean waters should be the same species.

Tacrolimus-based immunosuppression with steroid withdrawal in pediatric kidney transplantation was pioneered at the University of Pittsburgh but is not broadly practiced at other centers. We present our 4-year experience with a modified Pittsburgh protocol at our own moderate-volume center. Seventeen pediatric kidney transplant recipients were treated with a tacrolimus-based immunosuppressive regimen involving steroid withdrawal over 6-12 post-transplant months in most cases and followed for up to 49 months. Patient and graft survival as well as graft function were excellent, and beneficial effects on several cardiovascular parameters were noted. Complications included fungal infections, glucose intolerance and post-transplant lymphoproliferative disease and were generally managed successfully. While awaiting longer-term follow-up data, we conclude that tacrolimus-based immunosuppression with steroid withdrawal in pediatric kidney transplantation is potentially beneficial and feasible even at centers managing a rather small number of recipients.

Glycolipid-enriched membrane microdomains ("rafts") are critical sites for signal transduction and other processes such as intracellular transport. While the participation of T-cell rafts in the formation of the immunological synapse is well established, the role of rafts on antigen-presenting cells (APCs) as well as the relationship between these domains and major histocompatibility complex (MHC) molecules is less clearly defined. We therefore investigated whether MHC class I or II molecules are found in rafts of the human macrophage-monocytic cell line U937. We detected the preferential localization of MHC class II, but not class I, molecules in rafts. Furthermore, raft disruption resulted in a decrease in constitutive protein tyrosine phosphorylation events in U937 cells. Our findings are reviewed in the context of results from other groups who also found important associations of MHC class II molecules with APC rafts. Additional, and at times contradictory, findings by others regarding the relationship between rafts and MHC molecules are also discussed. It is concluded that class II MHC molecules can localize in rafts of APCs and that this localization may be relevant for APC function and thus immune regulation.