Early Conversion From Calcineurin Inhibitor- to Everolimus-Based Therapy Following Kidney Transplantation: Results of the Randomized ELEVATE Trial.

In a 24-month, multicenter, open-label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10-14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI: mean (standard error) 0.3(1.5) mL/min/1.732 versus -1.5(1.5) mL/min/1.732 (p = 0.116). Biopsy-proven acute rejection (BPAR) at month 12 was more frequent under everolimus versus CNI overall (9.7% vs. 4.8%, p = 0.014) and versus tacrolimus-treated patients (2.6%, p < 0.001) but similar to cyclosporine-treated patients (8.8%, p = 0.755). Reporting on de novo donor-specific antibodies (DSA) was limited but suggested more frequent anti-HLA Class I DSA under everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI (8.4%). In conclusion, conversion to everolimus at 10-14 weeks posttransplant was associated with renal function similar to that with standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus than everolimus.

Prolonged Ischemic Time, Delayed Graft Function, and Graft and Patient Outcomes in Live Donor Kidney Transplant Recipients.

The association between prolonged cold ischemic time (CIT) and graft and patient outcomes in live donor kidney transplant recipients remains unclear. The aims of this study were to examine the association of CIT with delayed graft function and graft loss in live donor kidney transplant recipients and those who participated in the Australian Paired Kidney Exchange program using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry. Of 3717 live donor transplant recipients between 1997 and 2012 who were followed for a median of 6.6 years (25 977 person-years), 224 (25%) experienced CIT >4-8 h. Donor age was an effect modifier between CIT and graft outcomes. In recipients who received kidneys from older donors aged >50 years, every hour of increase in CIT was associated with adjusted odds of 1.28 (95% confidence interval [CI] 1.07-1.53, p = 0.007) for delayed graft function, whereas CIT >4-8 h was associated with adjusted hazards of 1.93 (95% CI 1.21-3.09, p = 0.006) and 1.91 (95% CI 1.05-3.49, p = 0.035) for overall and death-censored graft loss, respectively, compared with CIT of 1-2 h. Attempts to reduce CIT in live donor kidney transplants involving older donor kidneys may lead to improvement of graft outcomes.

Evaluation of the effect of tofacitinib exposure on outcomes in kidney transplant patients.

Tofacitinib fixed-dose regimens attained better kidney function and comparable efficacy to cyclosporine (CsA) in kidney transplant patients, albeit with increased risks of certain adverse events. This post-hoc analysis evaluated whether a patient subgroup with an acceptable risk-benefit profile could be identified. Tofacitinib exposure was a statistically significant predictor of serious infection rate. One-hundred and eighty six kidney transplant patients were re-categorized to above-median (AME) or below-median (BME) exposure groups. The 6-month biopsy-proven acute rejection rates in AME, BME and CsA groups were 7.8%, 15.7% and 17.7%, respectively. Measured glomerular filtration rate was higher in AME and BME groups versus CsA (61.2 and 67.9 vs. 53.9 mL/min) at Month 12. Fewer patients developed interstitial fibrosis and tubular atrophy (IF/TA) at Month 12 in AME (20.5%) and BME (27.8%) groups versus CsA (48.3%). Serious infections occurred more frequently in the AME group (53.0%) than in BME (28.4%) or CsA (25.5%) groups. Posttransplant lymphoproliferative disorder (PTLD) only occurred in the AME group. In kidney transplant patients, the BME group preserved the clinical advantage of comparable acute rejection rates, improved renal function and a lower incidence of IF/TA versus CsA, and with similar rates of serious infection and no PTLD.

Modulation of Energy Transfer into Sequential Electron Transfer upon Axial Coordination of Tetrathiafulvalene in an Aluminum(III) Porphyrin-Free-Base Porphyrin Dyad.

Axially assembled aluminum(III) porphyrin based dyads and triads have been constructed to investigate the factors that govern the energy and electron transfer processes in a perpendicular direction to the porphyrin plane. In the aluminum(III) porphyrin-free-base porphyrin (AlPor-Ph-H2Por) dyad, the AlPor occupies the basal plane, while the free-base porphyrin (H2Por) with electron withdrawing groups resides in the axial position through a benzoate spacer. The NMR, UV-visible absorption, and steady-state fluorescence studies confirm that the coordination of pyridine appended tetrathiafulvalene (TTF) derivative (TTF-py or TTF-Ph-py) to the dyad in noncoordinating solvents afford vertically arranged supramolecular self-assembled triads (TTF-py→AlPor-Ph-H2Por and TTF-Ph-py→AlPor-Ph-H2Por). Time-resolved studies revealed that the AlPor in dyad and triads undergoes photoinduced energy and/or electron transfer processes. Interestingly, the energy and electron donating/accepting nature of AlPor can be modulated by changing the solvent polarity or by stimulating a new competing process using a TTF molecule. In modest polar solvents (dichloromethane and o-dichlorobenzene), excitation of AlPor leads singlet-singlet energy transfer from the excited singlet state of AlPor ((1)AlPor*) to H2Por with a moderate rate constant (k(EnT)) of 1.78 × 10(8) s(-1). In contrast, excitation of AlPor in the triad results in ultrafast electron transfer from TTF to (1)AlPor* with a rate constant (k(ET)) of 8.33 × 10(9)-1.25 × 10(10) s(-1), which outcompetes the energy transfer from (1)AlPor* to H2Por and yields the primary radical pair TTF(+•)-AlPor(-•)-H2Por. A subsequent electron shift to H2Por generates a spatially well-separated TTF(+•)-AlPor-H2Por(-•) radical pair.

A systematic review of conversion from calcineurin inhibitor to mammalian target of rapamycin inhibitors for maintenance immunosuppression in kidney transplant recipients.

This was a systematic review of randomized controlled trials comparing delayed conversion of mammalian target of rapamycin inhibitors (mTORi) for calcineurin inhibitors (CNIs) versus CNI continuation in kidney transplantation. Databases (2000-2012) and conference abstracts (2009-2012) were searched giving a total of 29 trials. Outcomes analyzed included GFR, graft loss, rejection and adverse events and were expressed as weighted mean differences (WMDs) or as risk ratios (RRs). Patients converted to mTORi up to 1 year posttransplant in intention-to-treat analysis had higher GFR compared with those remaining on CNI (WMD 0.28 mL/min/1.73 m(2) , 95% confidence interval [CI] 0.21-0.36; I(2) = 68%, p < 0.001). Stratifying trials by time posttransplant or type of mTORi did not change the overall heterogeneity. For on-treatment population, mTORi was associated with higher GFR (14.21 mL/min/1.73 m(2) , 10.34-18.08; I(2) = 0%, p = 0.970) 2-5 years posttransplant. The risk of rejection at 1 year was higher in mTORi trials (RR 1.72, 1.34-2.22; I(2) = 12%, p = 0.330). Discontinuation secondary to adverse events was more common in patients on mTORi, whereas the incidence of skin cancers and cytomegalovirus infection was lower in patients on mTORi. Conversion from CNI to mTORi is associated with short-term improvements in GFR in a number of studies but longer-term follow-up data of graft and patient survival are required.

Spatial variation in the effects of size and age on reproductive dynamics of common coral trout Plectropomus leopardus.

The effects of size and age on reproductive dynamics of common coral trout Plectropomus leopardus populations were compared between coral reefs open or closed (no-take marine reserves) to fishing and among four geographic regions of the Great Barrier Reef (GBR), Australia. The specific reproductive metrics investigated were the sex ratio, the proportion of vitellogenic females and the spawning fraction of local populations. Sex ratios became increasingly male biased with length and age, as expected for a protogyne, but were more male biased in southern regions of the GBR (Mackay and Storm Cay) than in northern regions (Lizard Island and Townsville) across all lengths and ages. The proportion of vitellogenic females also increased with length and age. Female P. leopardus were capable of daily spawning during the spawning season, but on average spawned every 4·3 days. Mature females spawned most frequently on Townsville reserve reefs (every 2·3 days) and Lizard Island fished reefs (every 3·2 days). Females on Mackay reefs open to fishing showed no evidence of spawning over 4 years of sampling, while females on reserve reefs spawned only once every 2-3 months. No effect of length on spawning frequency was detected. Spawning frequency increased with age on Lizard Island fished reefs, declined with age on Storm Cay fished reefs, and declined with age on reserve reefs in all regions. It is hypothesized that the variation in P. leopardus sex ratios and spawning frequency among GBR regions is primarily driven by water temperature, while no-take management zones influence spawning frequency depending on the region in which the reserve is located. Male bias and lack of spawning activity on southern GBR, where densities of adult P. leopardus are highest, suggest that recruits may be supplied from central or northern GBR. Significant regional variation in reproductive traits suggests that a regional approach to management of P. leopardus is appropriate and highlights the need for considering spatial variation in reproduction where reserves are used as fishery or conservation management tools.

Normal Parathyroid Glands Are Most Often Seen on Neck Ultrasound.

RATIONALE AND OBJECTIVES: The dogma is that normal parathyroid glands (PTGs) are not visible on ultrasound (US). Recently, several studies have shown that PTGs present these US features: ovoid structure, homogeneous and hyperechoic. The primary objective was to assess the detection rate, standard size and locations of normal PTGs in a population of patients consulting for thyroid US exam. The secondary objective was to determine if the presence of a goiter or a thyroiditis could modify the visualization of normal PTGs. METHOD: Single-center prospective study on 192 patients based on the typical US appearance previously described to identify one or more PTGs. RESULTS: One or more PTGs were visualized in 75% of patients (144/192). They were visualized preferentially at the lower pole of the thyroid gland and in the infra-thyroid region (66%). The mean (± SD) size of normal PTGs was 5.68 mm (± 1,42 mm)×4.05 mm (± 1,03 mm)×2,68 mm (± 0,61 mm) and mean volume was 33.3 mm3 (± 17.75 mm3). The presence of a goiter made the search for PTGs more difficult whereas the presence of thyroiditis facilitated it. CONCLUSION: The US detection rate of PTGs is high (75%). The identification of PTGs could be particularly useful in the preoperative assessment before total thyroidectomy or parathyroid surgery. It could reduce the risk of postoperative hypoparathyroidism and improve the accuracy of postoperative US surveillance of thyroid cancer. Better knowledge of the usual anatomical location of normal PTGs could also enable better detection of abnormal glands.

Sotrastaurin in calcineurin inhibitor-free regimen using everolimus in de novo kidney transplant recipients.

Sotrastaurin, a novel selective protein-kinase-C inhibitor, inhibits early T cell activation via a calcineurin-independent pathway. Efficacy and safety of sotrastaurin in a calcineurin inhibitor-free regimen were evaluated in this two-stage Phase II study of de novo kidney transplant recipients. Stage 1 randomized 131 patients (2:1) to sotrastaurin 300 mg or cyclosporine A (CsA). Stage 2 randomized 180 patients (1:1:1) to sotrastaurin 300 or 200 mg or CsA. All patients received basiliximab, everolimus (EVR) and prednisone. Primary endpoint was composite efficacy failure rate of treated biopsy-proven acute rejection, graft loss, death or lost to follow-up. Main safety assessment was estimated glomerular filtration rate (eGFR) by MDRD-4 at Month 12. Composite efficacy failure rates at 12 months were higher in sotrastaurin arms (Stage 1: 16.5% and 10.9% for sotrastaurin 300 mg and CsA; Stage 2: 27.2%, 34.5% and 19.4% for sotrastaurin 200 mg, 300 mg and CsA). eGFR was significantly better in sotrastaurin groups versus CsA at most time points, except at 12 months. Gastrointestinal and cardiac adverse events were more frequent with sotrastaurin. Higher treatment discontinuation, deaths and graft losses occurred with sotrastaurin 300 mg. Sotrastaurin combined with EVR showed higher efficacy failure rates and some improvement in renal allograft function compared to a CsA-based therapy.

Efficacy of sotrastaurin plus tacrolimus after de novo kidney transplantation: randomized, phase II trial results.

Sotrastaurin, a novel immunosuppressant, blocks early T cell activation through protein kinase C inhibition. Efficacy and safety of sotrastaurin with tacrolimus were assessed in a dose-ranging non-inferiority study in renal transplant recipients. A total of 298 patients were randomized 1:1:1:1 to receive sotrastaurin 100 (n = 77; discontinued in December 2011) or 200 mg (n = 73) b.i.d. plus standard tacrolimus (sTAC; 5-12 ng/mL), sotrastaurin 300 mg (n = 75) b.i.d. plus reduced tacrolimus (rTAC; 2-5 ng/mL) or enteric-coated mycophenolic acid (MPA) plus sTAC (n = 73); all patients received basiliximab and corticosteroids. Composite efficacy failure (treated biopsy-proven acute rejection ≥ grade IA, graft loss, death or loss to follow up) rates at Month 12 were 18.8%, 12.4%, 10.9% and 14.0% for the sotrastaurin 100, 200 and 300 mg, and MPA groups, respectively. The median estimated glomerular filtration rates were 55.7, 53.3, 64.9 and 59.2 mL/min, respectively. Mean heart rates were faster with higher sotrastaurin doses and discontinuations due to adverse events and gastrointestinal adverse events were more common. Fewer patients in the sotrastaurin groups experienced leukopenia than in the MPA group (1.3-5.5% vs. 16.5%). Sotrastaurin 200 and 300 mg had comparable efficacy to MPA in prevention of rejection with no significant difference in renal function between the groups.

Polyomavirus BK replication in de novo kidney transplant patients receiving tacrolimus or cyclosporine: a prospective, randomized, multicenter study.

Polyomavirus BK (BKV)-associated nephropathy causes premature kidney transplant (KT) failure. BKV viruria and viremia are biomarkers of disease progression, but associated risk factors are controversial. A total of 682 KT patients receiving basiliximab, mycophenolic acid (MPA), corticosteroids were randomized 1:1 to cyclosporine (CsA) or tacrolimus (Tac). Risk factors were analyzed in 629 (92.2%) patients having at least 2 BKV measurements until month 12 posttransplant. Univariate analysis associated CsA-MPA with lower rates of viremia than Tac-MPA at month 6 (10.6% vs. 16.3%, p = 0.048) and 12 (4.8% vs. 12.1%, p = 0.004) and lower plasma BKV loads at month 12 (3.9 vs. 5.1 log(10) copies/mL; p = 0.028). In multivariate models, CsA-MPA remained associated with less viremia than Tac-MPA at month 6 (OR 0.60; 95% CI 0.36-0.99) and month 12 (OR 0.33; 95% CI 0.16-0.68). Viremia at month 6 was also independently associated with higher steroid exposure until month 3 (OR 1.19 per 1 g), and with male gender (OR 2.49) and recipient age (OR 1.14 per 10 years) at month 12. The data suggest a dynamic risk factor evolution of BKV viremia consisting of higher corticosteroids until month 3, Tac-MPA compared to CsA-MPA at month 6 and Tac-MPA, older age, male gender at month 12 posttransplant.

Decadal trends in marine reserves reveal differential rates of change in direct and indirect effects.

Decadal-scale observations of marine reserves suggest that indirect effects on taxa that occur through cascading trophic interactions take longer to develop than direct effects on target species. Combining and analyzing a unique set of long-term time series of ecologic data in and out of fisheries closures from disparate regions, we found that the time to initial detection of direct effects on target species (±SE) was 5.13 ± 1.9 years, whereas initial detection of indirect effects on other taxa, which were often trait mediated, took significantly longer (13.1 ± 2.0 years). Most target species showed initial direct effects, but their trajectories over time were highly variable. Many target species continued to increase, some leveled off, and others decreased. Decreases were due to natural fluctuations, fishing impacts from outside reserves, or indirect effects from target species at higher trophic levels. The average duration of stable periods for direct effects was 6.2 ± 1.2 years, even in studies of more than 15 years. For indirect effects, stable periods averaged 9.1 ± 1.6 years, although this was not significantly different from direct effects. Populations of directly targeted species were more stable in reserves than in fished areas, suggesting increased ecologic resilience. This is an important benefit of marine reserves with respect to their function as a tool for conservation and restoration.

PB1-F2 expedition from the whole protein through the domain to aa residue function.

More than decade ago during systematic search for alternative reading frame derived peptides encoded by influenza A virus recognized by CD8+ T cells, PB1-F2 protein was discovered serendipitously by Chen et al. (2001). Since that time, an increasing body of evidence has continued to highlight the multifunctional meaning of this unusual influenza A protein. After twelve years of intensive research with 56 pubmed records for PB1-F2 in the title there is still a lot yet to explore. Is it a proapoptotic "explosive" protein that suppresses the mechanisms of early innate immune response or does it function as an NS1 antagonist? What is the root of its strain and cell specificity? What is the relationship between PB1-F2 and pathogenicity or secondary bacterial infection? Here we attempt to "take a trip" from the whole protein level through domains and regions to very particular aminoacid residues in correlation with its function in different virus isolates, cell type or animal model.

Randomized controlled trial of sirolimus for renal transplant recipients at high risk for nonmelanoma skin cancer.

Sirolimus has antineoplastic effects and may reduce skin cancer rates in kidney transplant patients. This prospective, multicenter, randomized, open-label, controlled trial randomized 86 kidney transplant recipients (≥1 year posttransplant) with history of nonmelanoma skin cancer (NMSC) to continue calcineurin inhibitor (CNI) or convert to sirolimus. Patients were stratified by number of NMSC lesions (0-5, 6-20) in previous year. Primary end point was number of biopsy-confirmed new NMSC lesions per patient-year. Yearly NMSC rate was significantly lower with sirolimus (1.31 vs. 2.48 lesions/patient-year; p = 0.022). Squamous cell carcinoma occurred at a lower rate in the sirolimus versus CNI group (p = 0.038); basal cell carcinoma rate was similar in both. A lower proportion of patients receiving sirolimus developed new or recurrent NMSC (56.4% vs. 80.9%; p = 0.015) or new squamous cell carcinoma (41.0% vs. 70.2%; p = 0.006). No sirolimus patients and one CNI continuation patient experienced acute rejection. Incidence of treatment-emergent adverse events was similar between groups; however, discontinuation rates related to adverse events were significantly higher with sirolimus (46.2% vs. 0%; p < 0.001). In kidney transplant recipients with history of NMSC, conversion from CNI to sirolimus reduced rates of NMSC, without increasing acute rejection risk.

The ORION study: comparison of two sirolimus-based regimens versus tacrolimus and mycophenolate mofetil in renal allograft recipients.

Safety and efficacy of two sirolimus (SRL)-based regimens were compared with tacrolimus (TAC) and mycophenolate mofetil (MMF). Renal transplantation recipients were randomized to Group 1 (SRL+TAC; week 13 TAC elimination [n = 152]), Group 2 (SRL + MMF [n = 152]) or Group 3 (TAC + MMF [n = 139]). Group 2, with higher-than-expected biopsy-confirmed acute rejections (BCARs), was sponsor-terminated; therefore, Group 2 two-year data were limited. At 1 and 2 years, respectively, graft (Group 1: 92.8%, 88.5%; Group 2: 90.6%, 89.9%; Group 3: 96.2%, 95.4%) and patient (Group 1: 97.3%, 94.4%; Group 2: 95.2%, 94.5%; Group 3: 97.0%, 97.0%) survival rates were similar. One- and 2-year BCAR incidence was: Group 1, 15.2%, 17.4%; Group 2, 31.3%, 32.8%; Group 3, 8.2%, 12.3% (Group 2 vs. 3, p < 0.001). Mean 1- and 2-year modified intent-to-treat glomerular filtration rates (mL/min) were similar. Primary reason for discontinuation was adverse events (Group 1, 34.2%; Group 2, 33.6%; Group 3, 22.3%; p < 0.05). In Groups 1 and 2, delayed wound healing and hyperlipidemia were more frequent. One-year post hoc analysis of new-onset diabetes posttransplantation was greater in TAC recipients (Groups 1 and 3 vs. 2, 17% vs. 6%; p = 0.004). Between-group malignancy rates were similar. The SRL-based regimens were not associated with improved outcomes for kidney transplantation patients.

Impact of blood processing on estimation of soluble HLA-G.

HLA-G is a non-classical MHC class I antigen that functions as an immunomodulatory molecule. There are two forms of HLA-G antigens, soluble and membrane bound. Soluble HLA-G can be produced by translation of HLA-G transcripts (HLA-G5, -G6, -G7) and by shedding/proteolytic cleavage of membrane bound antigens (HLA-G1, -G2, -G3, -G4). Soluble as well as membrane bound HLA-G molecules have a direct inhibitory effect on immune responses. The relevance of soluble HLA-G in various pathologic conditions, such as transplantation, autoimmunity, infectious and malignant diseases, has been extensively investigated, however interpretation remains controversial. In this work we analyzed the levels of sHLA-G (sHLA-G1 and HLA-G5) in different blood samples of healthy donors as serum, and blood plasma isolated using anti-coagulant EDTA and heparin, respectively. We found that the levels of sHLA-G (sHLA-G1 and HLA-G5) in blood plasma prepared with EDTA were significantly higher than those observed in plasma with heparin or in serum. Finally we detected the average levels of sHLA-G in females exceeded those of males.

N-terminal region of the PB1-F2 protein is responsible for increased expression of influenza A viral protein PB1.

Influenza A virus (IAV) PB1-F2 protein is encoded by an alternative reading frame (+1) within the PB1 gene. PB1-F2 has been shown to contribute to the pathogenesis of influenza virus infection as well as to the secondary bacterial infection. More recently has been shown that PB1-F2 protein may regulate a viral RNA (vRNA) polymerase activity by the interaction with PB1 protein. We proved that PB1-F2 protein increased the level of expression of PB1 protein and vRNA in the infected cells. Moreover, we demonstrated that a higher level of vRNA expression resulted in the increase of expression of multiple viral proteins, including NP, M1, and NS1. Finally, we used plasmids expressing N-terminal (1-50 aa) or C-terminal (51-87 aa) region of the PB1-F2 molecule for transfection of MDCK cells co-infected with influenza A/Puerto Rico/8/34 (H1N1) virus deficient in the PB1-F2 protein expression (PR8ΔPB1-F2). These experiments clearly showed that N-terminal region of PB1-F2 protein was responsible for the increase in PB1 protein expression. C-terminal region of PB1-F2 protein had no effect. Thus, we have identified the important function for N-terminal region of PB1-F2 protein.

Outcomes of active surveillance of EU-TIRADS 5 thyroid nodules.

OBJECTIVE: Active surveillance of cytologically proven microcarcinomas has been shown as a safe procedure. However, fine needle aspiration biopsy (FNAB) is not recommended by European Thyroid Association (ETA) and American Thyroid Association (ATA) guidelines for highly suspicious nodules ≤ 10 mm. The aim of the study was to assess the outcomes of active surveillance of EU-TIRADS 5 nodules ≤ 10 mm not initially submitted to FNAB. PATIENTS AND METHODS: 80 patients with at least one EU-TIRADS 5 nodule ≤ 10 mm and no suspicious lymph nodes, accepting active surveillance, were included. RESULTS: Mean baseline diameter and volume were 5.4 mm (±2.0) and 64.4 mm3 (±33.5), respectively. After a median follow-up of 36.1 months, a volumetric increase ≥ 50% occurred in 28 patients (35.0%) and a suspicious lymph node in 3 patients (3.8%). Twenty-four patients underwent an FNAB (30.0%) after at least a 1 year follow-up of which 45.8% were malignant, 8.3% benign, 33.3% undetermined and 8.3% nondiagnostic. Sixteen patients (20.0%) underwent conversion surgery after a median follow-up of 57.2 months, confirming the diagnosis of papillary carcinoma in 15/16 cases (not described in 1 histology report), all in remission at 6-12 months postoperative follow-up. CONCLUSION: Applying ETA and ATA guidelines to avoid FNA of EU-TIRADS 5 sub-centimeter nodules and proceeding to active surveillance of such nodules in selected patients is a safe procedure. Thus, US-FNAB could be postponed until the nodule shows signs of progression or a suspicious lymph node appears, with no added risk for the patient.

Introduction of a glycosylation site into a secreted protein provides evidence for an alternative antigen processing pathway: transport of precursors of major histocompatibility complex class I-restricted peptides from the endoplasmic reticulum to the cytosol.

We found that the presentation of a H-2Kd-restricted determinant from influenza virus nucleoprotein (NP) to T cells is strictly dependent on expression of the transporter associated with antigen presentation (TAP), regardless of whether NP is expressed as a cytosolic or secreted NP (SNP). Introducing an N-linked glycosylation site into the determinant selectively reduced presentation of SNP. This indicates that glycosylation does not interfere with TAP-transported peptides, and therefore that cytosolic peptides derived from SNP must have been exposed to the glycosylation machinery of the endoplasmic reticulum (ER) before their existence in the cytosol. Based on these findings, we propose that TAP-dependent processing of at least some ER-targeted proteins entails the reimportation of protein from the secretory pathway to the cytosol, where the protein is processed via the classical pathway.

Cystic form of cervical lymphadenopathy in adults. Guidelines of the French Society of Otorhinolaryngology (short version). Part 2-etiological diagnosis procedure: Clinical and imaging assessment.

INTRODUCTION: The authors present the guidelines of the French Society of Otorhinolaryngology (SFORL) for clinical and radiological assessment of cystic neck lymphadenopathy of unknown primary in adults. Most cases concern head and neck carcinoma metastasis, often in the oropharyngeal area, or less frequently differentiated thyroid carcinoma or non-keratinizing nasopharyngeal carcinoma. METHODS: A multidisciplinary task force was commissioned to carry out a review of the literature on the etiological work-up in cystic neck lymphadenopathy in adults: clinical examination, conventional imaging (ultrasound, CT, MRI) and metabolic imaging. Guidelines were drafted based on the articles retrieved, and graded A, B, C or expert opinion according to decreasing level of evidence. RESULTS: Oriented clinical examination, cervical and thyroid ultrasound scan and contrast-enhanced neck and chest CT scan are recommended in the assessment of cystic neck lymphadenopathy of unknown primary in adult patients. PET-CT is recommended prior to panendoscopy, to identify the primary tumor. CONCLUSION: Clinical and radiological assessment is fundamental for etiologic diagnosis of cystic neck lymphadenopathy in adult patients, and should be completed by cytological examination before in initiating treatment.