Late pulmonary metastases of renal cell carcinoma immediatelyafter post-transplantation immunosuppressive treatment: a case report

INTRODUCTION We report a case of pulmonary metastatic recurrence of renal adenocarcinoma soon after radical nephrectomy that was followed by renal transplant and immunosuppressive medication. Increased risk of metastatic recurrence of renal cell carcinoma should be considered in the immediate post-transplant period when immunosuppressive medication is administered, even if nephrectomy had been performed many years earlier. CASE PRESENTATION In 1986 the patient demonstrated renal insufficiency secondary to mesangial glomerulonephritis. In 1992 he underwent left side radical nephrectomy with histopathological diagnosis of clear cell adenocarcinoma. Mesangial glomerulonephritis in the remaining right kidney progressed to end-stage renal failure. In October 2000 he received a kidney transplant from a cadaver and commenced immunosuppressive medication. Two months later, several nodules were found in his lungs, which were identified as metastases from the primary renal tumor that had been removed with the diseased kidney 8 years earlier. CONCLUSION Recurrence of renal cell carcinoma metastases points to tumor dormancy and reflects a misbalance between effective tumor immune surveillance and immune escape. This case demonstrates that a state of tumor dormancy can be interrupted soon after administration of immunosuppressant medication.

Usefulness of late enhancement MRI as diagnostic tool to differentiate myocardial infarction from myocarditis

Introduction: Residual pulmonary artery (PA) anomalies are a major concern after surgery for cono-truncal malformations. This study sought to assess residual PA anomalies using MRI/MRA. Methods: 43 MRI/MRA studies were performed in 37 patients after corrective surgery for cono-truncal malformations. MRI/MRA studies comprised spin-echo, cine, velocity-encoded and 3D Gadolinium-enhanced MRA sequences. Residual PA anomalies were searched in ail patients; angiographie data were available in 13 patients and a comparison with MRI/MRA was made. Results: 32/37 patients had postoperative anomalies of the pulmonary arterial tree. Left pulmonary artery stenosis was the most common finding (14/32), followed by stenosis at multiple sites (11/32). Isolated right pulmonary artery stenosis was rare (2/32). The median time interval between MRI/MRA and angiography in the 13 patients undergoing both types of studies was 54 days. The findings between the two examinations were identical regarding stenoses and collateral vessels. In 4 patients, the MRI/MRA study allowed to plan interventional catheterization with balloon dilatation and/or stenting of the obstructed arteries or co il-occlusion of systemic collaterals. Eleven patients had additional surgery based on MRI/MRA findings. Conclusions: Post-operative anomalies of the PA in cono-truncal malformations can reliably be detected with MRI/MRA. This technique allows planning of the intervention al or surgical procedure to correct the residual anomalies and may th us replace or precede catheterization during the follow-up of surgically corrected cono-truncal malformations.

Early and late skin reactions to radiotherapy for breast cancer and their correlation with radiation-induced DNA damage in lymphocytes

INTRODUCTION Radiotherapy outcomes might be further improved by a greater understanding of the individual variations in normal tissue reactions that determine tolerance. Most published studies on radiation toxicity have been performed retrospectively. Our prospective study was launched in 1996 to measure the in vitro radiosensitivity of peripheral blood lymphocytes before treatment with radical radiotherapy in patients with breast cancer, and to assess the early and the late radiation skin side effects in the same group of patients. We prospectively recruited consecutive breast cancer patients receiving radiation therapy after breast surgery. To evaluate whether early and late side effects of radiotherapy can be predicted by the assay, a study was conducted of the association between the results of in vitro radiosensitivity tests and acute and late adverse radiation effects. METHODS Intrinsic molecular radiosensitivity was measured by using an initial radiation-induced DNA damage assay on lymphocytes obtained from breast cancer patients before radiotherapy. Acute reactions were assessed in 108 of these patients on the last treatment day. Late morbidity was assessed after 7 years of follow-up in some of these patients. The Radiation Therapy Oncology Group (RTOG) morbidity score system was used for both assessments. RESULTS Radiosensitivity values obtained using the in vitro test showed no relation with the acute or late adverse skin reactions observed. There was no evidence of a relation between acute and late normal tissue reactions assessed in the same patients. A positive relation was found between the treatment volume and both early and late side effects. CONCLUSION After radiation treatment, a number of cells containing major changes can have a long survival and disappear very slowly, becoming a chronic focus of immunological system stimulation. This stimulation can produce, in a stochastic manner, late radiation-related adverse effects of varying severity. Further research is warranted to identify the major determinants of normal tissue radiation response to make it possible to individualize treatments and improve the outcome of radiotherapy in cancer patients.

Intracoronary injection of bone marrow-derived mononuclear cells early or late after acute myocardial infarction: effects on global left ventricular function.

BACKGROUND: Intracoronary administration of autologous bone marrow-derived mononuclear cells (BM-MNC) may improve remodeling of the left ventricle (LV) after acute myocardial infarction. The optimal time point of administration of BM-MNC is still uncertain and has rarely been addressed prospectively in randomized clinical trials. METHODS AND RESULTS: In a multicenter study, we randomized 200 patients with large, successfully reperfused ST-segment elevation myocardial infarction in a 1:1:1 pattern into an open-labeled control and 2 BM-MNC treatment groups. In the BM-MNC groups, cells were administered either early (ie, 5 to 7 days) or late (ie, 3 to 4 weeks) after acute myocardial infarction. Cardiac magnetic resonance imaging was performed at baseline and after 4 months. The primary end point was the change from baseline to 4 months in global LV ejection fraction between the 2 treatment groups and the control group. The absolute change in LV ejection fraction from baseline to 4 months was -0.4±8.8% (mean±SD; P=0.74 versus baseline) in the control group, 1.8±8.4% (P=0.12 versus baseline) in the early group, and 0.8±7.6% (P=0.45 versus baseline) in the late group. The treatment effect of BM-MNC as estimated by ANCOVA was 1.25 (95% confidence interval, -1.83 to 4.32; P=0.42) for the early therapy group and 0.55 (95% confidence interval, -2.61 to 3.71; P=0.73) for the late therapy group. CONCLUSIONS: Among patients with ST-segment elevation myocardial infarction and LV dysfunction after successful reperfusion, intracoronary infusion of BM-MNC at either 5 to 7 days or 3 to 4 weeks after acute myocardial infarction did not improve LV function at 4-month follow-up. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00355186.

Middle and Late Jurassic carbon stable-isotope stratigraphy and radiolarite sedimentation of the Umbria-Marche basin (Central Italy)

A continuous carbon isotope curve from Middle-Upper Jurassic pelagic carbonate rocks was acquired from two sections in the southern part of the Umbria-Marche Apennines in central Italy. At the Colle Bertone section (Terni) and the Terminilletto section (Rieti), the Upper Toarcian to Bajocian Calcari e Marne a Posidonia Formation and the Aalenian to Kimmeridgian Calcari e Marne a Posidonia and Calcari Diasprigni formations were sampled, respectively. Biostratigraphy in both sections is based on rich assemblages of calcareous nannofossils and radiolarians, as well as some ammonites found in the upper Toarcian-Bajocian interval. Both sections revealed a relative minimum of delta(13)C(PDB) close to + 2 parts per thousand in the Aalenian and a maximum around 3.5 parts per thousand in early Bajocian, associated with an increase in visible chert. In basinal sections in Umbria-Marche, this interval includes the very cherry base of the Calcari Diasprigni Formation (e.g. at Valdorbia) or the chert-rich uppermost portion of the Calcari a Posidonia (e.g at Bosso). In the Terminilletto section, the Bajocian-early Barthonian interval shows a gradual decrease in delta(13)C(PDB) values and a low around 2.3 parts per thousand. This part of the section is characterised by more than 40 m of almost chart-free limestones and correlates with a recurrence of limestone-rich facies in basinal sections at Valdorbia. A double peak with values of delta(13)C(PDB) around + 3 parts per thousand was observed in the Callovian and Oxfordian, constrained by well preserved radiolarian faunas. The maxima lie in the Callovian and the middle Oxfordian, and the minimum between the two peaks should be near the Callovian/Oxfordian boundary. In the Terminilletto section, visible chert increases together with delta(13)C(PDB) values from the middle Bathonian and reaches peak values in the Callovian-Oxfordian. In basinal sections in Umbria-Marche, a sharp increase in visible chert is observed at this level within the Calcari Diasprigni. A drop of delta(13)C values towards + 2 parts per thousand occurs in the Kimmeridgian and coincides with a decrease of visible chert in outcrop. The observed delta(13)C positive anomalies during the early Bajocian and the Callovian-Oxfordian may record changes in global climate towards warmer, more humid periods characterised by increased nutrient mobilisation and increased carbon burial. High biosiliceous (radiolarians, siliceous sponges) productivity and preservation appear to coincide with the delta(13)C positive anomalies, when the production of platform carbonates was subdued and ceased in many areas, with a drastic reduction of periplatform ooze input in many Tethyan basins. The carbon and silica cycles appear to be linked through global warming and increased continental weathering. Hydrothermal events related to extensive rifting and/or accelerated oceanic spreading may be the endogenic driving force that created a perturbation of the exogenic system (excess CO2 into the atmosphere and greenhouse conditions) reflected by the positive delta(13)C shifts and biosiliceous episodes.

Distinct cytokine profiles of circulating mononuclear cells stimulated with Staphylococcus aureus enterotoxin A in vitro during early and late episodes of chronic osteomyelitis

We investigated the cytokine profile of peripheral mononuclear cells from chronic osteomyelitis (OST) patients following in vitro stimulation with staphylococcal enterotoxin A (SEA). We demonstrate that stimulation with SEA induced prominent lymphocyte proliferation and high levels of tumour necrosis factor (TNF)-α, interleukin (IL)-4 and IL-10 secretion in both OST and non-infected individuals (NI). Even though stimulation with SEA had no impact on IL-6 production in either patient group, the baseline level of IL-6 production by cells from OST patients was always significantly less than that produced by cells from NI. After classifying the osteomyelitic episodes based on the time after the last reactivation event as "early" (1-4 months) or "late" osteomyelitis (5-12 months), we found that increased levels of TNF-α and IL-4 in combination with decreased levels of IL-6 were observed in the early episodes. By contrast, increased levels of IL-10, IL-2 and IL-6 were hallmarks of late episodes. Our data demonstrate that early osteomyelitic episodes are accompanied by an increased frequency of "high producers" of TNF-α and IL-4, whereas late events are characterised by increased frequencies of "high producers" of IL-10, IL-6 and IL-2. These findings demonstrate the distinct cytokine profiles in chronic osteomyelitis, with a distinct regulation of IL-6 production during early and late episodes.

Roles of PPARβ and PPARγ in mouse placental development

RESUME Les gènes des PPARs jouent des rôles importants dans la régulation du métabolisme énergétique, lipidique et glucidique. Le présent travail, caractérise et analyse les défauts placentaires responsables de la mort embryonnaire des souris mutantes pour PPARβ et pour PPARγ, entre le jour E9.5 et E10.5. Les placentas issus d'embryons PPARP présentent un sévère retard de croissance, alors que les placentas mutants PPARγ montrent de graves défauts vasculaires. Nous montrons que les placentas issus d'embryons PPARβ-/-, au jour E9.5 présentent une réduction prononcée de la couche de cellules géantes, associée à une diminution des niveaux de protéines exprimées par les cellules géantes, tel que le placenta lactogène-I et la « proliferin ». Par ailleurs, nous montrons que le traitement d'un lignée trophoblastique par un ligand spécifique de PPARP augmente considérablement leur différentiation en cellules géantes. Cette différentiation dépendante de la voie de signalisation P13-kinase, s'accompagne d'une élévation de l'expression de l'ADRP, une protéine de structure associée aux vésicules lipidiques. Ainsi nous démontrons que PPAR5 est un régulateur majeur de la différentiation des cellules géantes, lesquelles sont primordiales aussi bien pour l'établissement de la structure placentaire, que pour la fonction endocrine. Par contre, les placentas PPARγ-/- présentent un défaut de vascularisation. Le niveau d'une protéine anti-angiogénique, la « proliferin-related protein », est très basse et ne peut pas contre-balancer l'élévation normale de la protéine pro-angiogénique « proliferin ». La formation des vaisseaux se trouve alors altérée. Ainsi, PPARγ constitue un régulateur majeur de l'activité anti-angiogénique. En conclusion, ce travail fournit de nouveaux éléments sur le rôle complémentaires de PPARβet PPARγ dans les événements complexes qui régissent le développement placentaire. SUMMARY Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors involved in energy homeostasis and growth. Herein, we characterize the placental defects that cause embryonic lethality around E9.5/E10.5 in PPARβ- and in PPARγ-deficient mouse lines. Most but not all PPARβ-null mutants die around E9.5/E10.5 with severe growth retardation. The placentas from PPARβ-/- embryos at E9.5 exhibit a strongly reduced giant cell layer, associated with reduced levels of proteins expressed by giant cells such as Placental lactogen-I and Proliferin. Ectopic treatment of a rat trophoblast cell line with PPARβ ligand markedly accelerated PI3 kinase-dependent giant cell differentiation. In addition, we demonstrate that ADRP, a pen-related lipid droplet-bound protein, is up-regulated by PPARβ in differentiated Rcho-1 cells. These results indicate that PPARβ is a crucial regulator of the differentiation secondary giant cells, which play a major role in the establishment of the placental structure as well as an important endocrine function. In contrast, the main alteration of the PPARγ-null placentas concerns the vasculogenesis. We show that in these placentas, the level of the anti-angiogenic proliferin-related protein is very low, and cannot balance the normal elevation of the pro-angiogenic proliferin expression, leading to the defective placental vessel formation. Consistently, the dramatic increase of PPARγ expression in late stage of gestation in wild-type mice is likely a major regulator of the anti-angiogenic activity, particularly important at the end of the pregnancy. This work emphasizes the important and complementary roles of PPARβ and PPARγ in mouse placental development and provides new tools for understanding the complex regulatory events that governs placental development and function. Understanding the function of PPARβ and PPARγ are of crucial interest with respect to human placental development and associated pathologies.

Microstructural, chemical and isotopic evidence for the origin of late neolithic leather recovered from an ice field in the Swiss Alps

Archaeological leather samples recovered from the ice field at the Schnidejoch Pass (altitude 2756 m amsl) in the western Swiss Alps were studied using optical, chemical molecular and isotopic (delta(13)C and delta(15)N of the bulk leather, and compound-specific delta(13)C analyses of the organic-solvent extracted fatty acids) methods to obtain insight into the origin of the leather and ancient tanning procedures. For comparison, leathers from modern native animals in alpine environment (red deer, goat, sheep, chamois, and calf/cow) were analyzed using the same approach. Optical and electron microscopically comparisons of Schnidejoch and modern leathers showed that the gross structure (pattern of collagen fibrils and intra-fibrils material) of archaeological leather had survived essentially intact for five millennia. The SEM studies of the hairs from the most important archaeological find, a Neolithic leather legging, show a wave structure of the hair cuticle, which is a diagnostic feature for goatskins. The variations of the bulk delta(13)C and delta(15)N values, and delta(13)C values of the main fatty acids are within the range expected for pre-industrial temperate C(3) environment. The archaeological leather samples contain a mixture of indigenous (from the animal) and exogenous plant/animal lipids. An important amount of waxy n-alkanes, n-alkan-1-ols and phytosterols (beta-sitosterol, sitostanol) in all samples, and abundant biomarker of conifers (nonacosan-10-01) in the legging leathers clearly indicate that the Neolithic people were active in a subalpine coniferous forest, and that they used an aqueous extract of diverse plant material for tanning leather. (C) 2010 Elsevier Ltd. All rights reserved.

Survival-independent function of NF-kappaB/Rel during late stages of thymocyte differentiation.

Transcription factors of the NF-kappaB/Rel family are important mediators of extracellular signals. Their implication in positive selection of thymocytes is suggested by a defective thymic development in transgenic mice that over-express IkappaB in thymocytes. These mice exhibit an accumulation of an unusually prominent population of TCRhigh/CD4/CD8 double positive cells in the thymus and a dramatic reduction of CD4+ and CD8+ cells in the periphery. The present study addresses the role of NF-kappaB in survival and differentiation processes of maturing thymocytes using IkappaB/bcl-2 and IkappaB/HY double-transgenic mice. Neither the introduction of the anti-apoptosis gene bcl-2 nor the positively selecting background in female HY transgenic mice resulted in a rescue of the maturational defects observed in the thymus of IkappaB transgenic mice. Thus, rather than promoting survival the main role of NF-kappaB/Rel proteins during positive selection of thymocytes appears to be the mediation of differentiation signals.

Early Cretaceous (late Berriasian to early Aptian) palaeoceanographic change along the northwestern Tethyan margin (Vocontian Trough, southeastern France): δ13C, δ18O and Sr-isotope belemnite and whole-rock records

Stable carbon, oxygen, and strontium isotope records were obtained from uppermost Hauterivian to lowermost Aptian belemnite rostra, which were collected in well-dated sections from the Vocontian Trough (southeastern France). This data set complements previously published belemnite-isotope records from the uppermost Berriasian-Hauterivian interval from the same basin. The belemnite carbon and oxygen isotope record is compared to the carbonate bulk-rock isotope record from the same sections, and from additional Italian sections. With regards to their long-term trends, both belemnite and whole-rock delta O-18 records are well correlated, except for the uppermost Hauterivian-lower Barremian interval, within which they deviate. This discrepancy is interpreted to be linked to the latest Hauterivian Faraoni oceanic anoxic event and its early Barremian aftermath. The Faraoni level is characterized by enhanced sea-water stratification, probably induced by the onset of a warmer and more humid climate along the northern Tethyan margin. The early Barremian was characterized by stronger vertical sea-water mixing reflected by a decrease in density contrast between sea-surface and deeper waters. The belemnite oxygen isotope record shows a more stable evolution with smaller fluctuations than its bulk-rock counterpart, which indicates that deeper water masses were not as much subjected to density fluctuations as sea-surface water. The comparison of belemnite and bulk-rock carbon isotope records allows observing the impact of regional influence exerted by platform carbonate ooze shedding on the carbon cycle. Discrepancies in the two records are observed during time of photozoan carbonate platform growth. The strontium isotopic record shows a gradual increase from the uppermost Berriasian to the uppermost lower Barremian followed by a rapid decrease until the uppermost Barremian and a renewed small increase within the lowermost Aptian. The major inflection point in the uppermost lower Barremian appears to predate the onset in the formation of the Ontong-Java volcanic plateau.