Doppler ultrasound triggering for cardiac MRI at 7T.

PURPOSE: A prerequisite for cardiac MR (CMR) imaging is adequate synchronization of image acquisition with the cardiac cycle. Electrocardiogram triggering may be hampered by electromagnetic interferences at high field strength. The purpose of this work is to evaluate the feasibility of Doppler ultrasound triggering for CMR image synchronization at 7T ultra-high-field MRI. METHODS: A custom-built Doppler ultrasound (DUS) trigger device was developed. Magnetic resonance compatibility was evaluated using E- and H-field probes and flip angle maps prior to the study. Cardiac MR was performed at 7T in 13 healthy subjects using DUS and pulse oximetry for triggering. For validation of the trigger signal, the electrocardiogram, pulse, and DUS signals were compared outside of the MR room. Breath-hold cine fast low-angle-shot sequences were acquired in short-axis and four-chamber view. Image quality was assessed by two senior radiologists and by measurement of endocardial blurring. RESULTS: The maximal change in E- and H-field distributions with and without transducer was 5%. No interferences were observed between DUS and MRI in the B1 maps and during CMR imaging. Validation of the DUS trigger signal resulted in a high correlation to the electrocardiographic signal of r = 0.99. Analysis of image and trigger quality revealed no significant differences. CONCLUSION: Doppler ultrasound was applied as a new trigger method in CMR at 7T. The transmission line and transducer were locally approved as 7T MR conditional, and were successfully tested for image synchronization at 7T. In the future, this method needs to be evaluated in a larger patient population. Magn Reson Med 80:239-247, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Detection of early infarction signs with machine learning-based diagnosis by means of the Alberta Stroke Program Early CT score (ASPECTS) in the clinical routine.

PURPOSE: New software solutions emerged to support radiologists in image interpretation in acute ischemic stroke. This study aimed to validate the performance of computer-aided assessment of the Alberta Stroke Program Early CT score (ASPECTS) for detecting signs of early infarction. METHODS: ASPECT scores were assessed in 119 CT scans of patients with acute middle cerebral artery ischemia. Patient collective was differentiated according to (I) normal brain, (II) leukoencephalopathic changes, (III) infarcts, and (IV) atypical parenchymal defects (multiple sclerosis, etc.). ASPECTS assessments were automatically provided by the software package e-ASPECTS (Brainomix®, UK) (A). Subsequently, three neuroradiologists (B), (C), and (D) examined independently 2380 brain regions. Interrater comparison was performed with the definite infarct core as reference standard after best medical care (thrombolysis and/or thrombectomy). RESULTS: Interrater comparison revealed higher correlation coefficient of (B) 0.71, (C) 0.76, and of (D) 0.80 with definite infarct core compared to (A) 0.59 for ASPECTS assessment in the acute ischemic stroke setting. While (B), (C), and (D) showed a significant correlation for individual patient groups (I), (II), (III), and (IV), except for (D) (II), (A) was not significant in patient groups with pre-existing changes (II), (III), and (IV). The following sensitivities, specificities, PPV, NPV, and accuracies given in percent were achieved: (A) 83, 57, 55, 82, and 67; (B) 74, 76, 69, 83, and 77; (C) 80.8, 85.2, 76, 84, and 80; (D) 63, 90.7, 82, 79, and 80, respectively. CONCLUSION: For ASPECTS assessment, the examined software may provide valid data in case of normal brain. It may enhance the work of neuroradiologists in clinical decision making. A final human check for plausibility is needed, particularly in patient groups with pre-existing cerebral changes.

Outcomes of Pediatric Kidney Transplantation in Recipients of a Previous Non-Renal Solid Organ Transplant.

Children who receive a non-renal solid organ transplant may develop secondary renal failure requiring kidney transplantation. We investigated outcomes of 165 pediatric kidney transplant recipients who previously received a heart, lung, or liver transplant using data from 1988 to 2012 reported to the United Network for Organ Sharing. Patient and allograft survival were compared with 330 matched primary kidney transplant (PKT) recipients. Kidney transplantation after solid organ transplant (KASOT) recipients experienced similar allograft survival: 5- and 10-year graft survival was 78% and 60% in KASOT recipients, compared to 80% and 61% in PKT recipients (p = 0.69). However, KASOT recipients demonstrated worse 10-year patient survival (75% KASOT vs. 97% PKT, p < 0.001). Competing risks analysis indicated that KASOT recipients more often experienced graft loss due to patient death (p < 0.001), whereas allograft failure per se was more common in PKT recipients (p = 0.01). To study more recent outcomes, kidney transplants performed from 2006 to 2012 were separately investigated. Since 2006, KASOT and PKT recipients had similar 5-year graft survival (82% KASOT vs. 83% PKT, p = 0.48), although 5-year patient survival of KASOT recipients remained inferior (90% KASOT vs. 98% PKT, p < 0.001). We conclude that despite decreased patient survival, kidney allograft outcomes in pediatric KASOT recipients are comparable to those of PKT recipients.

Evaluation of a low-carbohydrate diet-based preparation protocol without fasting for cardiac PET/MR imaging.

OBJECTIVE: Assessment of increased glucose uptake in inflammatory or malignant myocardial disease using PET/MRI relies on uptake suppression in normal myocardium. We evaluated the efficacy of a ≥24 hours high-fat, low-carbohydrate, and protein-permitted diet (HFLCPP) in combination with unfractionated heparin for suppression of "physiologic" myocardial glucose uptake. METHODS: PET/MRI was successfully performed in 89 patients. HFLCPP was started ≥24 hours prior to PET/MRI. All patients received i.v. injection of unfractionated heparin (50 IU·kg-1) 15 minutes prior to FDG administration. Left ventricular FDG uptake was visually evaluated by two readers. Diffuse myocardial uptake exceeding liver uptake, isolated uptake in the lateral wall, or diffuse uptake in the entire circumference of the heart base were defined as failed suppression. Homogeneous myocardial uptake below liver uptake with/without focal uptake was defined as successful suppression. RESULTS: Success rate was 84%. Suppression was unsuccessful in 14 patients. No significant influence of gender (P = .40) or age (P = .21) was found. However, insufficient suppression was more common in patients younger than 45 years (20% vs 7%). PET/MR imaging completion rate was >97%. CONCLUSION: A HFLCPP diet in combination with unfractionated heparin was successfully implemented for cardiac PET/MRI and resulted in a sufficient suppression of myocardial FDG uptake in 84% of patients.

[Diagnostic criteria for Menière's disease according to the Classification Committee of the Bárány Society]. / M. Menière: Diagnostische Kriterien des Internationalen Klassifikationskomitees der Bárány-Gesellschaft.

This paper presents diagnostic criteria for Menière's disease jointly formulated by the Classification Committee of the Bárány Society, The Japan Society for Equilibrium Research, the European Academy of Otology and Neurotology (EAONO), the Equilibrium Committee of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) and the Korean Balance Society. The classification includes two categories: definite Menière's disease and probable Menière's disease. The diagnosis of definite Menière's disease is based on clinical criteria and requires the observation of an episodic vertigo syndrome associated with low- to medium-frequency sensorineural hearing loss and fluctuating aural symptoms (hearing, tinnitus and/or fullness) in the affected ear. Duration of vertigo episodes is limited to a period between 20 min and 12 h. Probable Menière's disease is a broader concept defined by episodic vestibular symptoms (vertigo or dizziness) associated with fluctuating aural symptoms occurring in a period from 20 min to 24 h.

Interferon Gamma ELISPOT Testing as a Risk-Stratifying Biomarker for Kidney Transplant Injury: Results From the CTOT-01 Multicenter Study.

Previous studies suggest that quantifying donor-reactive memory T cells prior to kidney transplantation by interferon gamma enzyme-linked immunosorbent spot assay (IFNγELISPOT) can assist in assessing risk of posttransplant allograft injury. Herein, we report an analysis of IFNγELISPOT results from the multicenter, Clinical Trials in Organ Transplantation-01 observational study of primary kidney transplant recipients treated with heterogeneous immunosuppression. Within the subset of 176 subjects with available IFNγELISPOT results, pretransplant IFNγELISPOT positivity surprisingly did not correlate with either the incidence of acute rejection (AR) or estimated glomerular filtration rate (eGFR) at 6- or 12-month. These unanticipated results prompted us to examine potential effect modifiers, including the use of T cell-depleting, rabbit anti-thymocyte globulin (ATG). Within the no-ATG subset, IFNγELISPOT(neg) subjects had higher 6- and 12-month eGFRs than IFNγELISPOT(pos) subjects, independent of biopsy-proven AR, peak PRA, human leukocyte antigen mismatches, African-American race, donor source, and recipient age or gender. In contrast, IFNγELISPOT status did not correlate with posttransplant eGFR in subjects given ATG. Our data confirm an association between pretransplant IFNγELISPOT positivity and lower posttransplant eGFR, but only in patients who do not receive ATG induction. Controlled studies are needed to test the hypothesis that ATG induction is preferentially beneficial to transplant candidates with high frequencies of donor-reactive memory T cells.

Multicenter validation of urinary CXCL9 as a risk-stratifying biomarker for kidney transplant injury.

Noninvasive biomarkers are needed to assess immune risk and ultimately guide therapeutic decision-making following kidney transplantation. A requisite step toward these goals is validation of markers that diagnose and/or predict relevant transplant endpoints. The Clinical Trials in Organ Transplantation-01 protocol is a multicenter observational study of biomarkers in 280 adult and pediatric first kidney transplant recipients. We compared and validated urinary mRNAs and proteins as biomarkers to diagnose biopsy-proven acute rejection (AR) and stratify patients into groups based on risk for developing AR or progressive renal dysfunction. Among markers tested for diagnosing AR, urinary CXCL9 mRNA (odds ratio [OR] 2.77, positive predictive value [PPV] 61.5%, negative predictive value [NPV] 83%) and CXCL9 protein (OR 3.40, PPV 67.6%, NPV 92%) were the most robust. Low urinary CXCL9 protein in 6-month posttransplant urines obtained from stable allograft recipients classified individuals least likely to develop future AR or a decrement in estimated glomerular filtration rate between 6 and 24 months (92.5-99.3% NPV). Our results support using urinary CXCL9 for clinical decision-making following kidney transplantation. In the context of acute dysfunction, low values can rule out infectious/immunological causes of injury. Absent urinary CXCL9 at 6 months posttransplant defines a subgroup at low risk for incipient immune injury.

Outcomes of steroid-avoidance protocols in pediatric kidney transplant recipients.

Advances in immunosuppression have facilitated increased use of steroid-avoidance protocols in pediatric kidney transplantation. To evaluate such steroid avoidance, a retrospective cohort analysis of pediatric kidney transplant recipients between 2002 and 2009 in the United Network for Organ Sharing database was performed. Outcomes (acute rejection and graft loss) in steroid-based and steroid-avoidance protocols were assessed in 4627 children who received tacrolimus and mycophenolate immunosuppression and did not have multiorgan transplants. Compared to steroid-based protocols, steroid avoidance was associated with decreased risk of acute rejection at 6 months posttransplant (8.3% vs. 10.9%, p = 0.02) and improved 5-year graft survival (84% vs. 78%, p < 0.001). However, patients not receiving steroids experienced less delayed graft function (p = 0.01) and pretransplant dialysis, were less likely to be African-American and more frequently received a first transplant from a living donor (all p < 0.001). In multivariate analysis, steroid avoidance trended toward decreased acute rejection at 6 months, but this no longer reached statistical significance, and there was no association of steroid avoidance with graft loss. We conclude that, in clinical practice, steroid avoidance appears safe with regard to graft rejection and loss in pediatric kidney transplant recipients at lower immunologic risk.

Differing effects of rapamycin or calcineurin inhibitor on T-regulatory cells in pediatric liver and kidney transplant recipients.

In a cross-sectional study, we assessed effects of calcineurin inhibitor (CNI) or rapamycin on T-regulatory (Treg) cells from children with stable liver (n = 53) or kidney (n = 9) allografts several years posttransplant. We analyzed Treg number, phenotype, suppressive function, and methylation at the Treg-specific demethylation region (TSDR) using Tregs and peripheral blood mononuclear cells. Forty-eight patients received CNI (39 as monotherapy) and 12 patients received rapamycin (9 as monotherapy). Treg numbers diminished over time on either regimen, but reached significance only with CNI (r =-0.424, p = 0.017). CNI levels inversely correlated with Treg number (r =-0.371, p = 0.026), and positively correlated with CD127+ expression by Tregs (r = 0.437, p = 0.023). Patients with CNI levels >3.6 ng/mL had weaker Treg function than those with levels <3.6 ng/mL, whereas rapamycin therapy positively correlated with Treg numbers (r = 0.628, p = 0.029) and their expression of CTLA4 (r = 0.726, p = 0.041). Overall, CTLA4 expression, TSDR demethylation and an absence of CD127 were important for Treg suppressive function. We conclude that rapamycin has beneficial effects on Treg biology, whereas long-term and high dose CNI use may impair Treg number, function and phenotype, potentially acting as a barrier to attaining host hyporesponsiveness to an allograft.

Glomerular filtration rate following pediatric liver transplantation--the SPLIT experience.

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.

Ethical considerations for participation of nondirected living donors in kidney exchange programs.

Kidneys from nondirected donors (NDDs) have historically been allocated directly to the deceased donor wait list (DDWL). Recently, however, NDDs have participated in kidney exchange (KE) procedures, including KE 'chains', which have received considerable media attention. This increasing application of KE chains with NDD participation has occurred with limited ethical analysis and without ethical guidelines. This article aims to provide a rigorous ethical evaluation of NDDs and chain KEs. NDDs and bridge donors (BDs) (i.e. living donors who link KE procedures within KE chains) raise several ethical concerns including coercion, privacy, confidentiality, exploitation and commercialization. In addition, although NDD participation in KE procedures may increase transplant numbers, it may also reduce NDD kidney allocation to the DDWL, and disadvantage vulnerable populations, particularly O blood group candidates. Open KE chains (also termed 'never-ending' chains) result in a permanent diversion of NDD kidneys from the DDWL. The concept of limited KE chains is discussed as an ethically preferable means for protecting NDDs and BDs from coercion and minimizing 'backing out', whereas 'honor systems' are rejected because they are coercive and override autonomy. Recent occurrences of BDs backing out argue for adoption of ethically based protective measures for NDD participation in KE.

Cost-efficient screening for BK virus in pediatric kidney transplantation: a single-center experience and review of the literature.

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.

Is Histologic Thrombus Composition in Acute Stroke Linked to Stroke Etiology or to Interventional Parameters?

BACKGROUND AND PURPOSE: Detailed insight into the composition of thrombi retrieved from patients with ischemic stroke by mechanical thrombectomy might improve pathophysiologic understanding and therapy. Thus, this study searched for links between histologic thrombus composition and stroke subtypes and mechanical thrombectomy results. MATERIALS AND METHODS: Thrombi from 85 patients who had undergone mechanical thrombectomy for acute ischemic stroke between December 2016 and March 2018 were studied retrospectively. Thrombi were examined histologically. Preinterventional imaging features, stroke subtypes, and interventional parameters were re-analyzed. Statistical analysis was performed with the Kruskal-Wallis test, Mann-Whitney U test, or Spearman correlation as appropriate. RESULTS: Cardioembolic thrombi had a higher percentage of macrophages and a tendency toward more platelets than thrombi of large-artery atherosclerotic stenosis (P = .021 and .003) or the embolic stroke of undetermined source (P = .037 and .099) subtype. Thrombi prone to fragmentation required the combined use of contact aspiration and stent retrieval (P = .021) and were associated with an increased number of retrieving maneuvers (P = .001), longer procedural times (P = .001), and a higher lymphocyte content (P = .035). CONCLUSIONS: We interpreted the higher macrophage and platelet content in cardioembolic thrombi compared with large-artery atherosclerotic stenosis or embolic stroke of undetermined source thrombi as an indication that the latter type might be derived from an atherosclerotic plaque rather than from an undetermined cardiac source. The extent of thrombus fragmentation was associated with a more challenging mechanical thrombectomy and a higher lymphocyte content of the thrombi. Thus, thrombus fragmentation not only might be caused by the recanalization procedure but also might be a feature of a lymphocyte-rich, difficult-to-retrieve subgroup of thrombi.

Current kidney allocation rules and their impact on a pediatric transplant center.

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.

Magnetic resonance imaging in osteoarthritis: which method best reflects synovial membrane inflammation? Correlations with clinical, macroscopic and microscopic features.

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.

The nature of the near-infrared features on the venus night side.

Near-infrared images of the Venus night side show bright contrast features that move from east to west, in the direction of the cloud-top atmospheric superrotation. Recently acquired images of the Venus night side along with earlier spectroscopic observations allow identification of the mechanisms that produce these features, their level of formation, and the wind velocities at those levels. The features are detectable only at wavelengths near 1.74 and 2.3 micrometers, in narrow atmospheric windows between the CO(2) and H(2)O bands. The brightest features have brightness temperatures near 480 Kelvin, whereas the darkest features are more than 50 Kelvin cooler. Several factors suggest that this radiation is emitted by hot gases at altitudes below 35 kilometers in the Venus atmosphere. The feature contrasts are produced as this thermal radiation passes through a higher, cooler, atmospheric layer that has horizontal variations in transparency. The 6.5-day east-west rotation period of the features indicates that equatorial wind speeds are near 70 meters per second in this upper layer. Similar wind speeds have been measured by entry probes and balloons at altitudes between 50 and 55 kilometers in the middle cloud layer. The bright features indicate that there are partial clearings in this cloud deck. The presence of these clearings could decrease the efficiency of the atmospheric greenhouse that maintains the high surface temperatures on Venus.

Pharmacokinetics, Pharmacodynamics, and Safety of Lisinopril in Pediatric Kidney Transplant Patients: Implications for Starting Dose Selection.

Hypertension in pediatric kidney transplant recipients contributes to long-term graft loss, yet treatment options--including angiotensin-converting enzyme inhibitors--are poorly characterized in this vulnerable population. We conducted a multicenter, open-label pharmacokinetic (PK) study of daily oral lisinopril in 22 children (ages 7-17 years) with stable kidney transplant function. Standard noncompartmental PK analyses were performed at steady state. Effects on blood pressure were examined in lisinopril-naïve patients (n = 13). Oral clearance declined in proportion to underlying kidney function; however, in patients with low estimated glomerular filtration rate (30-59 ml/min per 1.73m(2)), exposure (standardized to 0.1 mg/kg/day dose) was within the range reported previously in children without a kidney transplant. In lisinopril-naïve patients, 85% and 77% had a ≥ 6 mmHg reduction in systolic and diastolic blood pressure, respectively. Lisinopril was well tolerated. Our study provides initial insight on lisinopril use in children with a kidney transplant, including starting dose considerations.

STAT5 pathway: target of anti-CD4 antibody in attenuation of IL-2 receptor signaling.

BACKGROUND: Anti-CD4 antibodies induce long-term graft survival by incompletely understood mechanisms, and CD4-ligation with HIV gp120-derivatives attenuates interleukin (IL)-2 receptor signaling. We examined the latter in the context of the CD4-modulating antibody 16H5. MATERIALS AND METHODS: We performed immunoblots to assess the IL-2-induced phosphorylation of signal transducer and activator of transcription (STAT)5 and Akt in the presence or absence of 16H5. Furthermore, we documented the effects of 16H5 on the induction of STAT5, activating protein (AP)-1, and myc by IL-2 in DNA-binding assays. 3H-thymidine incorporation of the human lymphoid cell line CMO, which exhibits constitutive activation of the STAT5 pathway and IL2-independent growth, was also measured during 16H5 treatment. RESULTS: In human T lymphocytes, 16H5 attenuated both the tyrosine phosphorylation of STAT5 by IL-2 and the IL-2-induced DNA-binding of this transcription factor. In contrast, 16H5 had no effect on the serine phosphorylation of Akt by IL-2 or on the IL-2-induced DNA-binding of myc. Signal transduction involving AP-1 was unaffected by 16H5 and IL-2. 16H5 also attenuated CMO cell proliferation. CONCLUSIONS: 16H5 targets the STAT5 signaling pathway to attenuate IL-2 receptor signal transduction in human T cells. This observation provides a molecular explanation for the immunomodulatory actions of anti-CD4 antibodies.

Interstitial nephritis, hepatic failure, and systemic eosinophilia after minocycline treatment.

This report describes a 15-year-old white boy who presented with fever, back pain, a disseminated exanthematous rash, renal failure, and hepatopathy 3 weeks after the initiation of oral minocycline therapy for facial acne. Marked peripheral and urine eosinophilia were noted. A bone marrow aspiration showed more than 50% eosinophils without any evidence of malignancy, and a simultaneous kidney biopsy showed acute interstitial nephritis (AIN). The patient's symptoms and laboratory findings improved after high-dose steroid therapy was initiated, worsened when it was withheld, and improved again after it was reinitiated in view of the biopsy findings. The patient recovered completely, and steroids were tapered to discontinuation over 3 months. Over a year later, the patient's peripheral blood mononuclear cells (PBMCs) were cultured for 2 weeks in the presence or absence of minocycline ex vivo, and minocycline was found to induce the emergence of CD4(+) cells after 1 week in culture. In conclusion, this article shows for the first time several new aspects of minocycline-induced morbidity: renal and hepatic failure can occur together, and AIN and elevated blood eosinophil counts can be accompanied by marked bone marrow eosinophilia, suggesting a systemic allergic response as the underlying pathomechanism. Furthermore, the initial phase of such a response appears to involve CD4(+) T cells detectable ex vivo. Lastly, high-dose treatment with corticosteroids appears to be beneficial in this setting.