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Activation of the coagulation cascade contributes to early graft loss and intraportal thrombotic events in clinical islet transplantation. Although these complications were shown to be related to the presence of tissue factor in human islet preparations, the contribution of duct cells, which represent a major contaminant of clinical islet isolates, has not been specified so far. Herein, we used flow cytometry, immunohistochemistry, RT-PCR, and functional coagulation assays to demonstrate that duct cells exert a potent factor VII-dependent procoagulant activity related to their expression of tissue factor. Both the classical membrane-bound and the recently described soluble form of tissue factor were shown to be synthesized by duct cells. We conclude that contaminating duct cells contribute to early β-cell damage after islet transplantation through their involvement in tissue factor-mediated thrombotic and inflammatory events., Early loss of functional β-cells after islet transplantation represents a major limitation of this therapeutic modality for type 1 diabetes, even with the most efficient protocols currently available (1,2). Recent [...]

ABSTRACTBackground: Ectopic Cushing’s syndrome is a very rare condition caused by an ACTH-secreting tumor outside the pituitary or adrenal glands, and the majority of these cases are encountered in the context of paraneoplastic syndromes. The ectopic source of ACTH secretion is not always obvious to detection and can be challenging. We report a rare case, in which a hidden ACTH-secreting carcinoid tumor of the lung caused a severe refractory hypokalemia, leading us to a race against time to locate the tumor.Case presentation: A 33-year-old young male was admitted to the ICU for the management of a severe hypokalemia, and complains from several months of depression, increased weight, disabling non-radiating dorsal lower back pain and refractory arterial hypertension. The physical examination immediately suggested a Cushing’s syndrome. The 24-h cortisoluria confirmed hypercortisolism and the increased ACTH level was oriented towards ACTH-dependent Cushing’s syndrome. Thereafter, a dexamethasone suppression test was negative, indicating in favor of ectopic ACTH secretion. The etiological assessment via imaging and isotopes revealed a solitary pulmonary nodule at the right lower lobe estimated at 18 mm, the resection and anatomopathological analysis of which led to the diagnosis of carcinoid pulmonary tumor, and resolved hypercortisolism and its complications.Conclusion: A delayed diagnosis of Cushing’s syndrome result in a consequent morbi-mortality, mainly due to cardiovascular events. The optimal treatment for ectopic Cushing’s syndrome is surgical resection, thus making the localization of the tumor a key element.

We report on a pilot study investigating the feasibility of early immunosuppression withdrawal after liver transplantation (LT) using antithymocyte globulin (ATG) induction and rapamycin.

We previously reported on the partial prevention of experimental shunt-induced pulmonary arterial hypertension (PAH) by the nonselective endothelin (ET) ET-A/ET-B receptor antagonist bosentan. As the respective roles of the ET-A and ET-B receptor signaling in the pathobiology of the disease remain undefined, we investigated the effects of selective ET-A receptor blockade by sitaxsentan in the same early stage PAH model. Twenty-one 3-wk-old piglets were randomized to placebo or sitaxsentan therapy (1.5 mg/kg/d), after anastomosis of the left subclavian artery to the pulmonary arterial trunk or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation, followed by pulmonary tissue sampling for morphometry and real-time-quantitative-PCR for ET-1, angiopoietin-1, and bone morphogenetic receptor (BMPR) signaling molecules. Three months of left to right shunting induced an increase in pulmonary vascular resistance (PVR) and medial thickness, an overexpression of ET-1, ET-B receptor, and angiopoietin-1, and a decreased expression of BMPR-2 and BMPR-1A. Pretreatment with sitaxsentan prevented shunt-induced increase in PVR and decreased medial thickness by 64%. Sitaxsentan therapy completely prevented the decreased expression of BMPR-2 and limited the overexpression of ET-1, ET-B and angiopoietin-1, and the decreased expression of BMPR-1A. In conclusion, selective ET-A receptor blockade partially prevents shunt-induced PAH.

HYPOTHESIS Infusion of ethyl pyruvate (EP) solution can improve outcome in a clinically relevant, large- animal model of septic shock resulting from fecal peritonitis. DESIGN Prospective randomized animal study. SETTING University hospital animal research laboratory. SUBJECTS Fourteen female sheep. INTERVENTIONS Fourteen fasted, anesthetized, invasively monitored, mechanically ventilated female sheep weighing (mean ± SD) 30.4 ± 3.8 kg received 0.5 g/kg of feces intraperitoneally to induce peritonitis, without administration of antibiotic agents or vasoactive drugs. After surgical preparation, the ewes were randomized to receive a continuous intravenous infusion at 15 mg/kg per hour of either EP combined with Ringer lactate solution or Ringer lactate solution only. Fluid resuscitation was titrated to maintain the pulmonary artery occlusion pressure at baseline levels throughout the experiment. All animals were monitored until they died spontaneously or for a maximum of 30 hours. RESULTS Compared with Ringer lactate solution alone, EP administration resulted in less tachycardia, longer time to development of arterial hypotension and oliguria (median, 27 vs 15 hours and 24 vs 16 hours, respectively; both P<.01), and prolonged survival time (median, 29.5 vs 17.0 hours; P<.001). Animals who received EP also had a smaller decrease in colloid osmotic pressure (P<.05) and a tendency for lower serum interleukin 6 concentrations (P = .08). CONCLUSIONS In this clinically relevant model of septic shock in ewes, continuous EP infusion prolonged time to development of organ dysfunction and markedly prolonged survival. These findings suggest a potential use for EP in the treatment of severe sepsis and septic shock.Arch Surg. 2007;142:166-171--

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We describe a fatal primary human herpesvirus 6 (HHV-6) variant A infection in a kidney transplanted adult woman. On day 20 post transplantation (TX), after rejection therapy, the patient presented an acute hemophagocytic syndrome with hepatitis and central nervous system involvement. HHV-6 IgG and IgM antibodies seroconversion was demonstrated. HHV-6 variant A was the sole pathogen detected by nested PCR and/or culture in blood, bone marrow aspiration, liver biopsy, cerebrospinal fluid and bronchoalveolar lavage. The graft was HHV-6 seropositive and the patient was not transfused before day 28 post TX, suggesting that the virus was transmitted by the graft. Despite immunoglobulins, ganciclovir and foscarnet therapy, the HHV-6 infection progressed and led to severe aplasia. The patient developed Aspergillus fumigatus pneumonia and died from fulminant candidemia. This case demonstrated for the first time that HHV-6 variant A primary infection can cause life-threatening disseminated infection in immunosuppressed patients.

Abstract: Purpose : The aim of our study is to investigate the in vitro effects of plant lectins, galectins and neoglycoconjugates on the proliferation of three human sarcoma cell lines. Methods : Proliferation was assessed by means of the tetrazolium derivative reduction (MTT) assay. In addition, glycohistochemistry was used to make visible the plant-lectin-specific binding sites; the intensity of the lectin binding pattern was quantified by means of image analysis. Results : Depending on the cell lines, the staining intensity and the percentage of labelled cells were different. With respect to growth modulation, the cell lines also responded differently to the probes used. Besides a predominant inhibitory effect elicited by the probes at 50 μg/ml, dose-dependent effects, including growth stimulation, were detectable in several instances. These effects relate to the animal galectins tested and several neoglycoconjugates, e.g. the lactose- and blood-group-A-trisaccharide-bearing probes. Conclusions : Endogenous lectins and lectin-reactive cellular glycoconjugates can apparently affect the regulation of the growth of human sarcoma cells. We suggest that these results are relevant for further histopathological monitoring in correlation with prognosis and in vitro assays to reveal possible clinical applications.

Abstract: Little is known about the regulation of sarcoma proliferation by hormones and/or growth factors. We therefore characterised the in vitro proliferative influence on eight sarcoma cell lines of the platelet-derived growth factor, the insulin-like growth factor 1, triiodothyronine, the epidermal growth factor, the luteinising-hormone-releasing hormone, progesterone, gastrin and 17 β-oestradiol. The influence of the different factors on the proliferation of sarcoma cell lines was measured by the colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test. Two culture media were studied: (1) a nutritionally poor medium containing 2% of fetal calf serum and (2) a nutritionally rich one containing 5% or 10% FCS both with and without the addition of non-essential amino acids. The results were analysed either by conventional statistical analyses or by a classification method based on a decision-tree approach developed in Machine Learning. This latter method was also compared to other classifiers (such as logistic regression and k nearest neighbours) with respect to its accuracy of classification. Monovariate statistical analysis showed that each of the eight cell lines exhibited sensitivity to at least one factor, and each factor significantly modified the proliferation of five or six of the eight cell lines under study. Of these eight lines one of fibrosarcoma origin was the most “factor-sensitive”. Decision-tree-related data analysis enabled the specific pattern of factor sensitivity to be characterised for the three histological types of cell line under study. The effects of hormone and growth factors are significantly influenced by the type of culture medium used. The method used appeared to be an accurate classifier for the kind of data analysed. Sarcoma proliferation can be modulated, at least in vitro, by various hormones and growth factors, and the proliferation of each histopathological type exhibited a distinct sensitivity to different hormone and/or growth-factors.

Implementation of SARS-CoV-2 testing in the daily practice of pathology laboratories requires procedure adaptation to formalin-fixed and paraffin-embedded (FFPE) samples. So far, one study reported the feasibility of SARS-CoV-2 genome sequencing on FFPE tissues with only one contributory case out of two. The present study aimed to optimize SARS-CoV-2 genome sequencing using the Ion AmpliSeq SARS-CoV-2 Panel on 22 FFPE lung tissues from 16 deceased COVID-19 patients. SARS-CoV-2 was detected in all FFPE blocks using a real-time RT-qPCR targeting the Egene with Crossing Point (Cp) values ranging from 16.02 to 34.16. Sequencing was considered as contributory (i.e. with a uniformity >55%) for 17 FFPE blocks. Adapting the number of target amplification PCR cycles according to the RT-qPCR Cp values allowed to optimize the sequencing quality for the contributory blocks; i.e. 20 PCR cycles for blocks with a Cp value <28 and 25 PCR cycles for blocks with a Cp value between 28 and 30. The majority of blocks with a Cp value >30 were non-contributory. Comparison of matched frozen and FFPE tissues revealed discordance for only three FFPE blocks, all with a Cp value >28. Variant identification and clade classification was possible for 13 patients. The present study validates SARS-CoV-2 genome sequencing on FFPE blocks and opens the possibility to explore correlation between virus genotype and histopathological lesions.

La granulomatose avec polyangéite (GPA/Wegener) est une vascularite nécrosante systémique des petits vaisseaux. L’atteinte neurologique centrale combine classiquement une méningite lymphocytaire et une atteinte multiple de nerfs crâniens.

Using a series of 105 renal cell carcinomas (RCCs) we investigated whether features quantitatively describing the appearance of Feulgen‐stained nuclei and, more particularly, of their chromatin (on the basis of computer‐assisted microscopy) can contribute any significant prognostic information. Thirty morphonuclear and 8 nuclear DNA content‐related variables were thus generated. The actual prognostic values of this set of cytometric variables was compared (by means of discriminant statistical analysis) to conventional diagnostic and/or prognostic markers including histopathological grades, tumour invasion levels and the presence or absence of metastases. We obtained complete clinical follow‐ups for 49 of the 105 RCC patients under study, making it possible to define a subset of patients with a bad prognosis (i.e., who died in the 12 months following nephrectomy) and a subset of patients with a good prognosis (i.e., who survived at least 24 months following nephrectomy). An original method of data analysis related to artificial intelligence (decision tree induction) enabled a strong prognostic model to be set up. In the case of 10 new patients, this model identified all the dead patients as having a bad survival status, with a total of 8 correct predictions. Another prognostic model similarly generated enabled the correct predictions to be confirmed.