Hnf1b renal expression directed by a distal enhancer responsive to Pax8.

Xenopus provides a simple and efficient model system to study nephrogenesis and explore the mechanisms causing renal developmental defects in human. Hnf1b (hepatocyte nuclear factor 1 homeobox b), a gene whose mutations are the most commonly identified genetic cause of developmental kidney disease, is required for the acquisition of a proximo-intermediate nephron segment in Xenopus as well as in mouse. Genetic networks involved in Hnf1b expression during kidney development remain poorly understood. We decided to explore the transcriptional regulation of Hnf1b in the developing Xenopus pronephros and mammalian renal cells. Using phylogenetic footprinting, we identified an evolutionary conserved sequence (CNS1) located several kilobases (kb) upstream the Hnf1b transcription start and harboring epigenomic marks characteristics of a distal enhancer in embryonic and adult renal cells in mammals. By means of functional expression assays in Xenopus and mammalian renal cell lines we showed that CNS1 displays enhancer activity in renal tissue. Using CRISPR/cas9 editing in Xenopus tropicalis, we demonstrated the in vivo functional relevance of CNS1 in driving hnf1b expression in the pronephros. We further showed the importance of Pax8-CNS1 interaction for CNS1 enhancer activity allowing us to conclude that Hnf1b is a direct target of Pax8. Our work identified for the first time a Hnf1b renal specific enhancer and may open important perspectives into the diagnosis for congenital kidney anomalies in human, as well as modeling HNF1B-related diseases.

[Diagnostic approach and therapeutic management of hyperthyroidism]. / Démarche diagnostique et prise en charge thérapeutique de l'hyperthyroïdie.

Hyperthyroidism is a frequent clinical situation that can be expressed by various signs and it is generally easy to diagnose. This review proposes to explain the diagnostic approach that affects therapeutic management by separating diseases with homogeneous and nodular thyroid.

tBid mediated activation of the mitochondrial death pathway leads to genetic ablation of the lens in Xenopus laevis.

Xenopus is a well proven model for a wide variety of developmental studies, including cell lineage. Cell lineage in Xenopus has largely been addressed by injection of tracer molecules or by micro-dissection elimination of blastomeres. Here we describe a genetic method for cell ablation based on the use of tBid, a direct activator of the mitochondrial apoptotic pathway. In mammalian cells, cross-talk between the main apoptotic pathways (the mitochondrial and the death domain protein pathways) involve the pro-death protein BID, the active form of which, tBID, results from protease truncation and translocation to mitochondria. In transgenic Xenopus, restricting tBID expression to the lens-forming cells enables the specific ablation of the lens without affecting the development of other eye structures. Thus, overexpression of tBid can be used in vivo as a tool to eliminate a defined cell population by apoptosis in a developing organism and to evaluate the degree of autonomy or the inductive effects of a specific tissue during embryonic development.

Generation of trangenic Xenopus laevis using the Sleeping Beauty transposon system.

Using the Sleeping Beauty (SB) transposon system, we have developed a simple method for the generation of Xenopus laevis transgenic lines. The transgenesis protocol is based on the co-injection of the SB transposase mRNA and a GFP-reporter transposon into one-cell stage embryos. Transposase-dependent reporter gene expression was observed in cell clones and in hemi-transgenic animals. We determined an optimal ratio of transposase mRNA versus transposon-carrying plasmid DNA that enhanced the proportion of hemi-transgenic tadpoles. The transgene is integrated into the genome and may be transmitted to the F1 offspring depending on the germline mosaicism. Although the transposase is necessary for efficient generation of transgenic Xenopus, the integration of the transgene occurred by an non-canonical transposition process. This was observed for two transgenic lines analysed. The transposon-based technique leads to a high transgenesis rate and is simple to handle. For these reasons, it could present an attractive alternative to the classical Restriction Enzyme Mediated Integration (REMI) procedure.

Developmental cell death during Xenopus metamorphosis involves BID cleavage and caspase 2 and 8 activation.

Elimination of tadpole organs during Xenopus metamorphosis is largely achieved through apoptosis, and recent evidence suggest involvement of the mitochondrial death route and bax-initiated caspase-3 and -9 deployment. However, events upstream of the activation of Bax are unknown. In other models, proteins of the BH3-only group such as BID are known to assure this function. We show that Xenopus bid transcript levels increase at metamorphosis in larval cells destined to disappear. This increase correlates with an abrupt rise in Caspase-2 and -8 mRNA levels and an enhanced activity of Caspase-2 and -8. In BIDGFP transgenic animal's tail regression is accelerated. The cleavage of BIDGFP fusion protein during natural or T(3)-induced metamorphosis was specifically inhibited by caspase-8 inhibitors. Our results show that tail regression at metamorphosis implicates an apoptotic pathway inducible by T(3) hormone in an organ autonomous manner and involving the cell death executioners BID and Caspases-2 and -8.

[Familial orthochromatic leukodystrophy: clinicopathological study of two cases]. / Leucodystrophies orthochromatiques familiales.

This paper reports the clinico-pathological data in a French family with orthochromatic leukodystrophy. The parents were first cousins and had seven children. Among those, two sisters and one brother presented with neurological signs, with onset around the 5(th) decade, including a dementing syndrome of frontal type, a tetrapyramidal syndrome, seizures, and, in one sibling, a cerebellar syndrome. CT scan or MRI showed diffuse involvement of the white matter. The neurological signs worsened progressively leading to death within 11 and 22 months. Neuropathological examination was performed in two cases. It revealed characteristic orthochromatic leukodystrophy. In one case, the presence of pigmented macrophages and astrocytes was suggestive of Van Bogaert and Nyssen disease. However there were some atypical features including the absence of pigmented cells in the second case whose clinical course was shorter, and the cavitary appearance of the white matter changes with a relative increase in the number of oligodendrocytes raising the issue of a possible link between this condition and cavitary orthochromatic leukodystrophies.

Adult Henoch-Schönlein purpura associated with malignancy.

OBJECTIVE: Malignancies are among the well-established causes of vasculitis. We studied the association between adult Henoch-Schonlein purpura (HSP) and malignant neoplasms. METHODS: We retrospectively reviewed 14 cases of adult HSP diagnosed during a 6-year period and found a malignant neoplasm in four. Fifteen reports of adult HSP with malignant disease were identified in the literature. These 19 cases were compared with 158 adults who had HSP but no malignancy and who where reported in the literature. RESULTS: Most (63%) of the malignant neoplasms associated with adult HSP were solid tumors: lung, n = 6; prostate, n = 2; breast, n = 1; renal, n = 1; stomach, n = 1; and small bowel, n = 1. Hematologic malignancies (37%) included non-Hodgkin lymphoma, n = 2; Hodgkin disease, n = 2; IgA multiple myeloma, n = 1; myeloproliferative disease, n = 1; and myelodysplastic syndrome, n = 1. Patients with malignancy were older (median age, 59 years), were more likely to be male (M/F = 8.5), had joint involvement more frequently (95%), and had a lower frequency of prior acute infection than those without malignancy. A typical paraneoplastic course was documented in only two cases. CONCLUSIONS: Epidemiological studies are needed to determine the association between adult HSP and malignancy. In practice, it may be wise to suspect a malignancy in men older than 40 years of age who develop HSP in the absence of a precipitating factor. Pathogenic hypotheses involve tumor antigens or abnormal IgA production leading to immune complex formation.

[Ulcer of the esophagus disclosing probable malignant histiocytofibroma of the posterior mediastinum]. / Ulcère suspendu de l'oesophage révélant un probable histiocytofibrome malin du médiastin postérieur.

We report the case of a 72-year-old woman hospitalized for dysphagia and odynophagia due to an ulcer of the esophagus. Thoracic CT-scan and esophageal endosonography revealed a tumour of the mediastinum which invaded the esophagus. Per-operative biopsies concluded to a probable malignant fibrous histiocytoma.

[Neuromeningeal sites of multiple myeloma: 3 cases and review of the literature]. / Localisations neuroméningées du myélome multiple: trois observations et revue de la littérature.

Neurologic manifestations are not unusual in multiple myeloma. Conversely meningeal and cerebral involvement have been very rarely reported. We report here on three patients with multiple myeloma and meningeal or cerebral involvement (two of them with autopsy study): one case of cerebellar involvement associated with secondary plasma cell leukemia and two cases of meningeal involvement. We reviewed the characteristics of 20 cases of meningeal involvement with demonstration of plasma cells at cerebrospinal fluid analysis (18 previously reported cases and our two patients). Meningeal involvement occurs in patients with initially stage III multiple myeloma in 85% of cases and is associated with the occurrence of plasma cell leukemia in 20% of cases. The most frequent neurologic signs are: confusion (60%), altered consciousness (25%), gait disorder (25%), cranial nerve palsy (25%). Meningismus is rarely present. Diagnosis is based on cerebrospinal fluid analysis after lumbar puncture which should be made after cranial magnetic resonance imaging. The diagnosis of intra-cranial haemorrhage and infectious meningitis have to be cautiously ruled out. Despite treatments (systemic and/or intrathecal chemotherapy, radiation therapy), prognosis is very poor: mean time of survival after the occurrence of neurologic signs is about 2 months.

Chondromyxosarcoma: a rare form of bone neoplasm in children.

The case described is interesting for its unusual presentation related to its uncommon onset in youth and its revelation by a fracture which led to a first erroneous pathological diagnosis. In fact, retrospective analysis of the CT showing peripheral condensation could suggest the malignant chondroïd nature of the tumor. Subsequent radiological follow-up demonstrated the rapid growth of the tumor hence exhibiting a very invasive form. Myxoïd differentiation is commonly related to aggressive chondrosarcoma.

[Surgically treated syphilitic gumma of the brain. Computerized tomography findings]. / Gomme syphilitique cérébrale opérée. Données du scanner X.

Syphilitic gumma is now exceptional. Symptomatology is non-specific and frequently, as in the case reported here, the onset is marked by a localized or generalized convulsion. A space-occupying lesion is recognized by angiography and CT. The precise diagnosis is suggested by evidence of arteritis or of a hypodense mass outlined by contrast or slight calcifications and confirmed by positive serology in a patient with a suspected cerebral tumor. In some cases a positive diagnosis can be made only by pathological examination after surgical ablation of the gumma. An area of central necrosis is surrounded by a granulomatous layer rich in plasmocytes (the polyclonal nature of the secretion is shown by immunocytochemistry) and a peripheral fibroblastic zone. The arteries are ensheathed by a dense inflammatory infiltrate constituted almost entirely by plasmocytes and their lumens are either stenosed or filled with endarteritic debris. Surgical treatment should be combined with penicillin administration. For a patient in good general condition with a suspected gumma, medical treatment can be given initially, with follow-up by CT, neurosurgery being indicated only in case of failure of medical therapy. The rarity of gummata in relation to other tertiary syphilitic lesions remains unexplained. The patient reported here had multiple infections including one due to cytomegalovirus after ablation of the gumma, highly suggesting an immunity disorder.

[Polyradiculopathy associated with bullous pemphigoid (author's transl)]. / Polyradiculonévrite associée à une pemphigoïde bulleuse.

A sensorio-motor polyradiculopathy of subacute onset and a bullous pemphigoid form of herpetiform dermatitis (Dühring-Brocq disease) developed simultaneously in a 71-year-old man. Both conditions regressed under the influence of prednisone and azathioprine. The immediate cortico-dependence of the skin condition should be noted. Death occurred 9 months later, related to diffuse pulmonary aspergillosis. A paraneoplastic aetiology was sought unsuccessfully.

[Aortic ruptures in traffic accident traumatology]. / Les ruptures aortiques en traumatologie routière

8 cases of rupture of the aorta seen in a series of 62 autopsies were studied in the context of a multidisciplinary enquiry into road accidents. In the light of these cases, the literature and experimental findings, different mechanisms are described, an essential step in the prevention of this lesion which is the main cause of death in 15 p. cent of cases.

[Circular fractures of the skull base during traffic accidents]. / Les fractures circulaires de la base du crâne au cours des accidents de la route

With reference to 5 cases of circular fracture of the base of the skull occurring in relation to road accidents, the literature is reviewed. Two different types may be distinguished: --"compression" fractures, --"hyperextension' fractures, the latter being special on the basis of the site of the fracture line and the application of forces via the face or chin. Reconstruction of trajectories during accidents, on the basis of the anatomical lesions and the damage caused to vehicles, as well as the study of films made during the experimental reproduction of similar lesions, make it possible to explain the mode of production of these hyperextension fractures. Such understanding is essential to the study of safety precautions for vehicle occupants.