Evolution of hypoxia and hypoxia-inducible factor asparaginyl hydroxylase regulation in chronic kidney disease

Background The roles of hypoxia and hypoxia inducible factor (HIF) during chronic kidney disease (CKD) are much debated. Interventional studies with HIF-α activation in rodents have yielded contradictory results. The HIF pathway is regulated by prolyl and asparaginyl hydroxylases. While prolyl hydroxylase inhibition is a well-known method to stabilize HIF-α, little is known about the effect asparaginyl hydroxylase factor inhibiting HIF (FIH). Methods We used a model of progressive proteinuric CKD and a model of obstructive nephropathy with unilateral fibrosis. In these models we assessed hypoxia with pimonidazole and vascularization with three-dimensional micro-computed tomography imaging. We analysed a database of 217 CKD biopsies from stage 1 to 5 and we randomly collected 15 CKD biopsies of various severity degrees to assess FIH expression. Finally, we modulated FIH activity in vitro and in vivo using a pharmacologic approach to assess its relevance in CKD. Results In our model of proteinuric CKD, we show that early CKD stages are not characterized by hypoxia or HIF activation. At late CKD stages, some areas of hypoxia are observed, but these are not colocalizing with fibrosis. In mice and in humans, we observed a downregulation of the HIF pathway, together with an increased FIH expression in CKD, according to its severity. Modulating FIH in vitro affects cellular metabolism, as described previously. In vivo, pharmacologic FIH inhibition increases the glomerular filtration rate of control and CKD animals and is associated with decreased development of fibrosis. Conclusions The causative role of hypoxia and HIF activation in CKD progression is questioned. A pharmacological approach of FIH downregulation seems promising in proteinuric kidney disease

Purkinje cells activities in the vestibulo-cerebellum in freely moving rats

Un cadre théorique classique pour expliquer comment les mouvements volontaires sont générés et optimisés implique l'existence d'un modèle interne basé sur les conséquences sensorielles de ses propres actions. Le cervelet est souvent considéré comme une structure où ces modèles pourraient être efficacement stockés et mis-à-jour. Parmi tous les systèmes sensoriels, le système vestibulaire est probablement celui où la plus grande proportion de stimuli est auto-générés et pourtant peu étudié en conditions actifs. Pour appréhender le rôle du vestibulo-cervelet, nous avons enregistré des cellules de Purkinje du nodulus en condition active chez le rongeur, associé à l'enregistrement quantitatif des signaux inertiels produits par les mouvements de la tête. Cela a nécessité le développent d'outils de mesure adaptés au petit animal. Ces outils, absents du commerce, sont capable d'enregistrer, et cela sans aucun câble, les mouvements inertiels (accélération linéaire et vitesse angulaire) de celui ci offrant une représentation des informations vestibulaires. Les résultats présentés dans cette thèse montrent que, au moins dans des conditions actives, les cellules de Purkinje présentent une sensibilité sélective à certaines composantes du mouvement de la tête. La diversité des réponses observées démontre de plus que chaque cellule possède son propre " champ récepteur vestibulaire ". Il a ainsi été montré que certaines cellules avaient un champ récepteur en coordonnées égocentriques et d'autres allocentriques. Cette distinction s'inscrit dans le problème général de la transformation par le cervelet des coordonnées vestibulaires et de la représentation de l'environnement.A classical and theoretical explaining framework how voluntary movements are generated and optimized implies the existence of an internal model based on the sensory consequences of own actions. The cerebellum is often considered as a structure where the models could be effectively stored and made-to-day. Of all the sensory systems, the vestibular system is probably one where the largest proportion of stimuli are self-generated but yet little studied in active conditions. To understand the role of the vestibular-cerebellum, we recorded Purkinje cells from nodulus in active condition in rodents associated with quantitative recording of inertial signals produced by head motion. This required developing the measurement tools adapted to small animals. These tools, absent of trade, are capable of recording, without any cables, the inertial movement (linear acceleration and angular velocity) of this one as a representation of vestibular information. The results presented in this thesis show that, at least in active condition, Purkinje cells exhibit selective sensitivity to certain components of the head movement. The diversity of responses observed further demonstrates that each cell has its own "vestibular receptive field". It has thus been shown that some cells have a receptive field in egocentric coordinates while others allocentric. This results is part of the general problem of the coordinate transformation and of the environment representation by the vestibular cerebellum

Bazedoxifene as a novel strategy for treatment of pancreatic and gastric adenocarcinoma

Experimental studies have shown that the IL6/GP130/STAT3 pathway is involved in pancreatic cancer tumorigenesis and progression as well as in the development of other tumors. Bazedoxifene, a selective estrogene receptor modulator clinically available for the treatment of osteoporosis, has been shown to be an effective GP130/STAT3 signaling inhibitor through in vitro and small animal studies. Our aim was to investigate the effect of bazedoxifene on tumor progression in patients with advanced pancreatic and gastric tumors. We analyzed the data of 7 patients (5 suffering from pancreatic and 2 from gastric adenocarcinoma), with locally advanced and/or metastatic disease, median age 73 years old (range 48 - 86 years). Bazedoxifene was given orally at a dose of 20 mg per day for a median duration of 9 months (range 5 - 14 months). Two patients received bazedoxifene as monotherapy, 5 patients were under concomitant chemotherapy. Results showed tumor marker reduction in 5 patients, stable disease on CT in 5 patients and metabolic regression on PET-CT in 3 patients. Weight was gained in 4 patients. Two patients developed deep vein thrombosis and one pulmonary embolism, the treatment was otherwise well tolerated. An immunhistochemical study of pSTAT3 was performed in 6 patients, out of which 3 were positive. Our preliminary data indicate that bazedoxifene is a potential new therapeutic option for pancreatic and gastric cancer therapy, safe to use and at low cost. It might be administrated at an early stage with current strategies. Based on these preliminary results, we will initiate a prospective clinical study

Gangrenous gas necrosis of the spleen: a case report

BACKGROUND: Splenic abscess usually arises from hematogenous spread. Causative pathogens are various and anaerobic pathogens are rarely reported. CASE PRESENTATION: We report the case of a 50-year-old male patient who was admitted for sepsis due to gangrenous necrosis of the spleen associated with bacteremia. Causative pathogens were Clostridium perfringens and Streptococcus gallolyticus. The patient was successfully treated by splenectomy and targeted intravenous antibiotics. No underlying or predisposing disease was found. CONCLUSION: Gangrenous necrosis of the spleen is a rare entity that can be successfully treated by splenectomy and antibiotics

Clearing Steatosis Prior to Liver Surgery for Colorectal Metastasis: A Narrative Review and Case Illustration

Over recent years, non-alcoholic fatty liver disease (NAFLD) has become the most common liver disorder in the developed world, accounting for 20% to 46% of liver abnormalities. Steatosis is the hallmark of NAFLD and is recognized as an important risk factor for complication and death after general surgery, even more so after liver resection. Similarly, liver steatosis also impacts the safety of live liver donation and transplantation. We aim to review surgical outcomes after liver resection for colorectal metastases in patients with steatosis and discuss the most common pre-operative strategies to reduce steatosis. Finally, as illustration, we report the favorable effect of a low-caloric, hyper-protein diet during a two-stage liver resection for colorectal metastases in a patient with severe steatosis

Large Desmoid Tumor of the Pancreas: A Report of a Rare Case and Review of the Literature

BACKGROUND Desmoid tumor (DT), also known as aggressive fibromatosis or desmoid-type fibromatosis, is a rare disease. It can occur in anyone at any age, and is more likely to appear in female patients. DTs are sometimes associated with familial adenomatous polyposis and rare syndromes such as Gardner syndrome. Arising from specific cells, fibroblasts, they tend to develop in patients with a history of abdominal surgery and rarely produce metastases. CASE REPORT We present a case of a 41-year-old man who was referred for abdominal discomfort with no digestive or general symptoms. An abdominal CT scan revealed a mass in the left hypochondrium, corresponding to an intraperitoneal tumor extending to left colon. Based on MRI, we suspected a gastrointestinal stromal tumor. Colonoscopy showed no intraluminal tumor in the colon. A PET-CT scan revealed tumor hypermetabolism and no metastases. The mass was diagnosed as a DT after percutaneous biopsy. Six weeks after diagnosis and as the tumor continued increasing despite pharmacological treatment, the patient underwent surgical pancreatic tail resection with splenectomy and left colonic segmentectomy. Histological examination revealed a 7.047-g DT with severe infiltration of pancreatic parenchyma and transmural colic barrier, with no high-grade differentiation and negative resection margins. The postoperative recovery was uneventful, and we proposed surveillance with MRI. CONCLUSIONS The DT was surgically removed and patient remains under MRI surveillance. Other reported management approaches consist of radiotherapy, tyrosine kinase inhibitors, anti-hormonal therapies/non-steroidal anti-inflammatory drugs, chemotherapy, or close surveillance only. This is, to our knowledge, the largest and heaviest DT reported in the modern literature.</p

Diagnostic accuracy of GATA6 immunostaining in sebaceous tumors of the skin

The accurate diagnosis of skin adnexal neoplasms is sometimes challenging but is necessary because medical management and follow-up may differ between tumors. GATA6 transcription factor has been identified as a new marker of the upper folliculosebaceous compartment (lower infundibulum, junctional zone and isthmus, and upper sebaceous gland) in the human skin. We aimed to determine the diagnostic accuracy of GATA6 immunostaining to diagnose sebaceous tumors compared with that to diagnose other adnexal and nonadnexal cutaneous neoplasms. We conducted a retrospective, evaluator-nonblinded study comparing the reference standard (diagnosis by an expert dermatopathologist) with GATA6 immunostaining to identify sebaceous tumors in a cohort containing 234 different tumors. The GATA6 expression score was significatively higher in sebaceous than that in nonsebaceous tumors. In addition, tumors originating from the upper hair follicle showed positive results for GATA6 staining; however, they showed lower GATA6 expression scores. Detection of sebaceous tumors using GATA6 positivity had a sensitivity of 95.7% (95% confidence interval [95% CI], 85.8-99.2), specificity of 80.8% (95% CI, 74.5-85.8), positive predictive value of 55.6% (95% CI, 44.7-65.9), and negative predictive value of 98.7% (95% CI, 95.4-99.8). GATA6 showed similar sensitivity to adipophilin, the reference marker; however, the specificity of GATA6 was higher, as observed in a cohort of 106 tumors enriched in squamous cell carcinomas with clear-cell histology. In addition, GATA6 positivity was assessed in 39 sebaceous carcinomas and compared with epithelial membrane antigen (EMA), CK7, and androgen receptor (AR) staining results. Although CK7 staining displayed lower diagnostic performances, GATA6 staining showed comparable results as EMA and AR. Finally, we found GATA6 expression in skin metastases of gastrointestinal origin, whereas GATA6 was absent in metastases originating from breast or lung cancers. Overall, our work identified GATA6 immunostaining as a new diagnostic tool for sebaceous tumors

Clinicopathological features of cutaneous reactions after mRNA-based COVID-19 vaccines

Background: Cutaneous reactions, mostly on injection site after mRNA-based COVID-19 vaccines, have been reported but not with detailed histopathological characterization.Objectives: Characterization and classification of these reactions in a clinical and pathological point of view.Methods: Monocentric case series of 11 patients with cutaneous manifestations, clinically and histologically characterized after COVID-19 vaccination.Results: From January to June 2021, we recorded 11 cutaneous reactions to mRNA COVID-19 vaccines from BNT162b2 (n = 8) and mRNA-1273 (n = 3). Generalized reactions showing erythematous rash or purpura were the most common clinical presentation, and drug-reaction-like pattern was the most common histological finding.Conclusions: A proper clinicopathological classification will be helpful in the early diagnosis and management of the cutaneous reactions to mRNA COVID-19 vaccines.</p

Disulfiram-induced acute liver injury

Disulfiram is a drug used to treat alcohol dependence since many years. It interferes with the metabolism of alcohol, may be associated with neurological and dermatological symptoms, and can be hepatotoxic. Due to the frequent coexistent liver test alterations due to alcohol, the true incidence of disulfiram-associated liver injury is unclear and severity of injury may vary from mildly elevated liver enzymes to fulminant hepatitis leading to death. There are several reported cases of disulfiram hepatitis in the literature. Liver histology, when available, demonstrates some degree of portal inflammation with eosinophils and hepatocyte necrosis. We present here a well-documented case of acute hepatitis due to disulfiram with typical histological lesions, favorable outcome following drug withdrawal, and a brief steroid course. The risk of hepatotoxicity should be kept in mind when prescribing disulfiram

Anti-CD122 antibody restores specific CD8+ T cell response in nonalcoholic steatohepatitis and prevents hepatocellular carcinoma growth

ABSTRACTNonalcoholic steatohepatitis (NASH) can lead to hepatocellular carcinoma (HCC). Although immunotherapy is used as first-line treatment for advanced HCC, the impact of NASH on anticancer immunity is only partially characterized. We assessed the tumor-specific T cell immune response in the context of NASH. In a mouse model of NASH, we observed an expansion of the CD44+CXCR6+PD-1+CD8+ T cells in the liver. After intra-hepatic injection of RIL-175-LV-OVA-GFP HCC cells, NASH mice had a higher percentage of peripheral OVA-specific CD8+ T cells than control mice, but these cells did not prevent HCC growth. In the tumor, the expression of PD-1 on OVA-specific CD44+CXCR6+CD8+ cells was higher in NASH mice suggesting lowered immune activity. Treating mice with an anti-CD122 antibody, which reduced the number of CXCR6+PD-1+ cells, we restored OVA-specific CD8 activity, and reduced HCC growth compared to untreated NASH mice. Human dataset confirmed that NASH-affected livers, NASH tissues adjacent to HCC and HCC in patients with NASH exhibited gene expression patterns supporting mouse observations. Our findings demonstrate the immune system fails to prevent HCC growth in NASH, primarily linked to a higher representation of CD44+CXCR6+PD-1+CD8+ T cells. Treatment with an anti-CD122 antibody reduces the number of these cells and prevents HCC growth