The folliculin-FNIP1 pathway deleted in human Birt-Hogg-Dube syndrome is required for murine B-cell development

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder characterized by cutaneous fibrofolliculomas, pulmonary cysts, and kidney malignancies. Affected individuals carry germ line mutations in folliculin (FLCN), a tumor suppressor gene that becomes biallelically inactivated in kidney tumors by second-hit mutations. Similar to other factors implicated in kidney cancer, FLCN has been shown to modulate activation of mammalian target of rapamycin (mTOR). However, its precise in vivo function is largely unknown because germ line deletion of Flcn results in early embryonic lethality in animal models. Here, we describe mice deficient in the newly characterized folliculin-interacting protein 1 (Fnip1). In contrast to Flcn, Fnip1(-/-) mice develop normally, are not susceptible to kidney neoplasia, but display a striking pro-B cell block that is entirely independent of mTOR activity. We show that this developmental arrest results from rapid caspase-induced pre-B cell death, and that a Bcl2 transgene reconstitutes mature B-cell populations, respectively. We also demonstrate that conditional deletion of Flcn recapitulates the pro-B cell arrest of Fnip1(-/-) mice. Our studies thus demonstrate that the FLCN-FNIP complex deregulated in BHD syndrome is absolutely required for B-cell differentiation, and that it functions through both mTOR-dependent and independent pathways.     

Clinical significance of clonality assessment in JAK2V617F-negative essential thrombocythemia

JAK2V617F-negative essential thrombocythemia (ET) is a heterogeneous disease including clonal cases and others without evidence of clonality. However, it is unknown if the detection of myeloid clonality in JAK2V617F-negative ET patients confers a different clinical outcome than those in whom clonal hematopoiesis cannot be demonstrated. The objective of the present study was to evaluate the clinical significance of clonality assessment in patients with JAK2V617F-negative ET. Clonality investigation including mutational status of MPL, TET2, and ASXL1 genes and human androgen receptor (HUMARA) assay was performed in 73 JAK2V617F-negative cases out of 186 subjects consecutively diagnosed with ET in a single institution, at diagnosis or during follow-up. Mutations in MPL, TET2, and ASXL1 were observed in 7, 4, and 2 cases, respectively, whereas clonality by HUMARA assay was demonstrated in 21 out of 46 (46?%) female patients. With a median follow-up of 8?years, death, thrombosis, bleeding, and disease transformation were registered in 7, 10, 8, and 6 patients, respectively. No differences in thrombosis, bleeding or survival were observed according to clonality assessment. The probability of disease transformation at 10?years was higher in patients showing clonal hematopoiesis by presenting mutations in either MPL, TET2, or ASXL1 (64 versus 2?% in patients without mutations, p?相似文献   

Endosonography-guided drainage of pancreatic fluid collections with a novel lumen-apposing stent

Background

The purpose of this study is to report our initial experience with a new fully covered metallic stent with a novel design (AXIOS) to prevent migration and fluid leakage, in the drainage of pancreatic fluid collections (PFC).

Methods

We included nine patients from four Spanish centers undergoing endoscopic ultrasound (EUS)-guided drainage of PFC with placement of an AXIOS stent. The lesions were accessed via transgastric (n = 7), transesophageal (n = 1), and transduodenal (n = 1) by using a novel access device (NAVIX) in six cases or a 19-G needle in three. Patients were individually followed prospectively for procedure indications, demographic data, previous imaging techniques, technical aspects, clinical outcomes, complications, and follow-up after endoscopic drainage.

Results

The mean size of lesions was 105 ± 26.3 mm (range, 70–150). In six cases, cystoscopy was performed through the stent, including necrosectomy in two. Median procedure time was 25 ± 13 min. A median number of two sessions were performed. The technical success rate was 88.8 % (8/9) due to one failure of the delivery system. One patient developed a tension pneumothorax immediately after transesophageal drainage. No migrations were reported, and all stents were removed easily. All patients had a successful treatment outcome achieving complete cyst resolution. Mean time to stent retrieval was 33 ± 40 days. Mean follow-up was 50 ± 1.3 weeks (range, 45–55), and only one patient presented a recurrence 4 weeks after the stent removal. Furthermore, comparison with ten previous consecutively recruited PFC cases drained by EUS-guided using plastic pigtail stents was done. Technical and clinical successes were similar. However, two stent migrations, two recurrences, and two complications were found. The number of stents used (n = 15) and the median procedure time (42.8 ± 3.1 min) were significantly higher.

Conclusions

Drainage of PFC using dedicated devices as this novel metallic stent with special design seems to be an effective, feasible and safe alternative technique.     

Cutaneous leishmaniases in French Guiana

Cutaneous leishmaniases are endemic over the entire territory of French Guiana. At least 5 distinct Leishmania species coexist in the sylvatic ecotopes of this French territory. The present paper checks the advances in the ecological research field during the past 5 years. The current epidemiological situation and trends are detailed successively Links between the recrudescence of leishmaniases and gold-mining are highlighted. The potential adaptation of the pathogenic complexes to the newly anthropized habitats is also described.     

Reversible coma secondary to cefepime neurotoxicity

OBJECTIVE: To describe a case of cefepime neurotoxicity associated with acute renal failure that resulted in nonconvulsive status epilepticus. CASE SUMMARY: A 66-year-old woman with acute myeloid leukemia had fever on the third day of the initial chemotherapy cycle. Empiric antibiotic treatment with cefepime 2 g every 8 hours was started; fluconazole and vancomycin were subsequently added due to the persistence of fever. Ten days after initiation of cefepime, the patient developed acute renal failure followed by altered consciousness (Glasgow coma scale 6) associated with nonconvulsive status epilepticus. Cefepime was discontinued. Epileptiform activity in the electroencephalogram disappeared with clonazepam, and the patient regained consciousness 48 hours after cefepime withdrawal. DISCUSSION: Acute renal impairment combined with the use of cefepime may account for nonconvulsive status epilepticus. An objective causality assessment revealed that the adverse event was probably due to cefepime. Cefepime's neurotoxic effects derive from high serum concentrations resulting from decreased renal clearance, increased unbound antibiotic, and blood-brain barrier dysfunction during uremia. CONCLUSIONS: The combination of cefepime treatment and acute renal failure may induce drug-related neurotoxicity. Nonconvulsive status epilepticus frequently passes unnoticed in severely ill patients without a history of epilepsy. This disorder should be included in the list of potential causes of coma. In this patient, early detection of nonconvulsive status epilepticus and withdrawal of the antibiotic resulted in full recovery.     

Cortical thinning associated with mild cognitive impairment in Parkinson's disease

The aim of this study was to investigate patterns of cortical atrophy associated with mild cognitive impairment in a large sample of nondemented Parkinson's disease (PD) patients, and its relation with specific neuropsychological deficits. Magnetic resonance imaging (MRI) and neuropsychological assessment were performed in a sample of 90 nondemented PD patients and 32 healthy controls. All underwent a neuropsychological battery including tests that assess different cognitive domains: attention and working memory, executive functions, memory, language, and visuoperceptual‐visuospatial functions. Patients were classified according to their cognitive status as PD patients without mild cognitive impairment (MCI; n = 43) and PD patients with MCI (n = 47). Freesurfer software was used to obtain maps of cortical thickness for group comparisons and correlation with neuropsychological performance. Patients with MCI showed regional cortical thinning in parietotemporal regions, increased global atrophy (global cortical thinning, total gray matter volume reduction, and ventricular enlargement), as well as significant cognitive impairment in memory, executive, and visuospatial and visuoperceptual domains. Correlation analyses showed that all neuropsychological tests were associated with cortical thinning in parietotemporal regions and to a lesser extent in frontal regions. These results provide neuroanatomic support to the concept of MCI classified according to Movement Disorders Society criteria. The posterior pattern of atrophy in temporoparietal regions could be a structural neuroimaging marker of cognitive impairment in nondemented PD patients. All of the neuropsychological tests reflected regional brain atrophy, but no specific patterns were seen corresponding to impairment in distinct cognitive domains. © 2014 International Parkinson and Movement Disorder Society     

Molecular Imaging of Tumor-Associated Angiogenesis Using a Novel Magnetic Resonance Imaging Contrast Agent Targeting αvβ3 Integrin

Background

The recent introduction of biological anticancer therapy has renewed the interest in functional imaging of tumor-associated angiogenesis (TAA) as a tool to monitor early therapy response. The present study evaluated imaging of TAA using P1227, a novel, small molecular magnetic resonance imaging (MRI) probe targeting α_vβ₃ integrin.

Methods

HT29 human colorectal cancers were grown in athymic mice. Dynamic MRI was performed using a three-dimensional VIBE sequence up to 110 min after injection of P1227 or gadolinium–tetraazacyclododecane tetraacetic acid (Gd–DOTA). Specificity was assessed by using P1227 1 h after intravenous administration of the α_vβ₃ inhibitor cilengitide. Regions of interest were drawn encompassing the tumor rim and normal muscle. Imaging data were compared with microvessel density and α_vβ₃ expression.

Results

Using P1227, specific enhancement of the angiogenic tumor rim, but not of normal muscle, was observed, whereas Gd–DOTA enhanced tumor and normal muscle. After administering cilengitide, enhancement with P1227, but not with DOTA, was significantly suppressed during the first 20 min. When using P1227, a significant correlation was observed between normalized enhancement of the tumor rim and immunohistochemical α_vβ₃ integrin expression.

Conclusions

Molecular MRI using a small monogadolinated tracer targeting α_vβ₃ integrin and moderate magnetic field strength holds promise in assessing colorectal TAA.