Diagnosis and treatment of pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia: An overview.

Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease is an autosomic dominant disorder, which is characterized by the development of multiple arteriovenous malformations in either the skin, mucous membranes, and/or visceral organs. Pulmonary arteriovenous malformations (PAVMs) may either rupture, and lead to life-threatening hemoptysis/hemothorax or be responsible for a right-to-left shunting leading to paradoxical embolism, causing stroke or cerebral abscess. PAVMs patients should systematically be screened as the spontaneous complication rate is high, by reaching almost 50%. Neurological complications rate is considerably higher in patients presenting with diffuse pulmonary involvement. PAVM diagnosis is mainly based upon transthoracic contrast echocardiography and CT scanner examination. The latter also allows the planification of treatments to adopt, which consists of percutaneous embolization, having replaced surgery in most of the cases. The anchor technique consists of percutaneous coil embolization of the afferent pulmonary arteries of the PAVM, by firstly placing a coil into a small afferent arterial branch closely upstream the PAVM. Enhanced contrast CT scanner is the key follow-up examination that depicts the PAVM enlargement, indicating the various mechanisms of PAVM reperfusion. When performed by experienced operators as the prime treatment, percutaneous embolization of PAVMs, is a safe, efficient and sustained therapy in the great majority of HHT patients.

[Neurological symptoms with Bartonella henselae infection: report on 2 pediatric cases]. / Atteintes neurologiques àBartonella henselae : à propos de 2 cas pédiatriques.

Cat scratch disease (CSD) is usually a benign, self-limited regional lymphadenopathy, caused by Bartonella henselae. However, systemic complications have been described. We report on 2 children who developed neurological symptoms of acute encephalitis or neuroretinitis. Cat scratch disease should be suspected when neurological symptoms of undetermined cause occur in children, whether or not anamnesis is significant.

Radio-anatomy of the superior vena cava syndrome and therapeutic orientations.

Superior vena cava syndrome (SVCS) groups all the signs secondary to the obstruction of superior vena cava drainage and the increase in the venous pressure in the territories upstream. There are two major causes of SVCS: malignant, dominated by bronchopulmonary cancer, and benign, often secondary to the presence of poorly positioned implantable venous devices. CT scan is the key examination for the exploration of SVCS. It specifies the characteristics of the stenosis, its aetiology and detects collateral venous routes. Scannography reconstructions provide a true map of the obstacle, indispensable in planning the endovascular treatment.

ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension.

Germline mutations in genes encoding members of the transforming growth factor-ß (TGF-ß)/bone morphogenetic protein (BMP) superfamily are causal for two hereditary vascular disorders, hereditary hemorrhagic telangiectasia (HHT) and heritable pulmonary arterial hypertension (PAH). When the two diseases coexist, activin A receptor type II-like kinase-1 (ACVRL1) gene mutations are usually identified. We report a remarkable ACVRL1 germinal and somatic mosaicism characterized by the presence of two distinct mutant alleles and a non-mutant ACVRL1 allele in a woman diagnosed with PAH at the age 40. She also met the Curaçao diagnostic criteria for HHT based on additional findings of telangiectases, epistaxis and arteriovenous malformations. Mutation analysis of ACVRL1 identified two adjacent heterozygous deleterious mutations within exon 10: c.1388del (p.Gly463fsX2) and c.1390del (p.Leu464X) in a region enriched by mutation-associated DNA motifs. The mother transmitted the c.1388del to one child and the c.1390del to two children confirming germinal mosaicism. Allele-specific polymerase chain reaction analysis showed that c.1388del is the predominant mutation in lymphocytes of the index case. Haplotype analysis revealed that both mutant alleles have a common chromosomal origin which is distinct from that of the mother's non-mutant ACVRL1 allele. These distinct mutant alleles in tissues and germline could have arisen by DNA structure-mediated events occurring in the early stages of the mother's embryogenesis, prior to the segregation of her germline, which ultimately led to the independent transmission of each allele. These highlight the complexity of genomic events occurring during early embryogenesis and the consequences of mutational mosaicism upon pathogenic variability.

[Benign but not harmless intracranial hypertension: a case report]. / Hypertension intracrânienne bénigne, mais pas anodine. À propos d'un cas.

Benign intracranial hypertension (BIH) is characterized as an intracranial pressure increase occurring in the absence of brain tumour, sinus thrombosis or hydrocephaly. But contrary to what its designation might suggest, it threatens the visual prognosis. We report the case of a 15-year-old girl with lymphocytic meningitis, developing secondary a BIH. Cerebrospinal fluid pressure was 70cm water, without enlargement of the cerebral ventricles. Along with the progression, bilateral 6th nerve palsy, impairment of visual acuity and bilateral papilledema appeared. No cause was found after a complete assessment. Treatment consisted in oral acetazolamide and 9 depletive spinal taps. Clinical examination, fundus examination and Goldmann visual field normalized after 8 weeks. No relapse occurred after a 1-year follow-up. This case shows that BIH, which is not a well-known disorder, is incorrectly referred to as benign: both prompt diagnosis and proper management are of major importance.

Fatal rupture of pulmonary arteriovenous malformation in hereditary haemorrhagic telangiectasis and severe PAH.

A 29-yr-old patient with hereditary haemorrhagic telangiectasia was referred to the present authors' centre with progressive exertional dyspnoea. Pulmonary arterial hypertension (PAH) was suspected on Doppler echocardiography and confirmed by right heart catheterisation demonstrating severe PAH. Genetic analysis found an activin receptor-like kinase-1 gene missense mutation. Chest radiography and computed tomodensitometry of the chest revealed a pulmonary arteriovenous malformation with a 5-mm diameter feeding artery in the right lower lobe. Embolisation of the arteriovenous malformation was discussed, but was considered a very high-risk procedure that could aggravate PAH and was therefore not performed. Haemodynamics were improved by dual endothelin receptor antagonist and inhaled iloprost but the patient subsequently died suddenly of a rupture of the arteriovenous malformation into the pleural cavity. Severe PAH is generally considered a contraindication to performing pulmonary arteriovenous malformation embolisation because of the risk of worsening of PAH. However, given the significant risk of rupture, paradoxical embolism and haemoptysis, and the lack of data regarding the evolution of pulmonary pressure after embolisation in PAH, pulmonary arteriovenous malformation embolisation should not be absolutely contraindicated and might be considered in patients with stable PAH.

Liver metastasis of a mucinous colonic carcinoma mimicking a haemangioma in T2-weighted sequences.

We report the case of a patient with a single liver metastasis of a mucinous colonic carcinoma that mimics a haemangioma in T2-weighted sequences. Although a very high T2 signal in non-cystic lesions is highly specific for the diagnostic of haemangioma, the use of gadolinium-enhancement MRI is recommended. In patients with a history of neoplasia, the diagnosis of benign liver nodules should be made with caution.

[Embolization of localized pulmonary arteriovenous malformations in adults]. / Embolisation des malformations artérioveineuses pulmonaires localisées de l'adulte.

OBJECTIVES: To report our experience using embolization in managing localized pulmonary arteriovenous malformations in adults. MATERIAL: and methods. All patients presenting with localized pulmonary arteriovenous malformations treated with embolization were included in the study. Clinical presentation (respiratory symptoms and previous history of paradoxical embolism) and the characteristics of pulmonary arteriovenous malformations (single or multiple, location, diameter of the afferent artery and simple or complex angioarchitecture) before embolization were analyzed. The details of the procedure, including the number of pulmonary arteriovenous malformations embolized, the number of coils used, and the type of intraoperative complications were recorded. Postembolization clinical and imaging follow-up were described. RESULTS: Forty-two patients (26 women, 16 men; mean age, 45 years), including 36 with hereditary hemorrhagic telangiectasia were treated with embolization. Twenty-two patients (53%) were dyspneic and 12 (29%) had a previous history of paradoxical embolism prior to embolization. Forty-seven procedures were carried out on a total of 99 pulmonary arteriovenous malformations (mean, 2.3 per patient), using 530 coils (12.6 per patient). The pulmonary arteriovenous malformations were located in the lower lobes in 60% of cases and a simple architecture was reported in 81% of cases. The average diameter of the afferent artery was 6mm. No preoperative complications were reported. After embolization, two patients (5%) presented with a paradoxical embolism and five patients out of 22 (23%) remained dyspneic. The rate of complete occlusion of treated arteriovenous malformations was 92% using computer tomography. CONCLUSION: Embolization is a highly effective and safe technique for treating pulmonary arteriovenous malformations. Improvement in dyspnea and prevention of paradoxical embolism can be expected. A high technical success rate can be obtained by experienced interventional radiologists.

L-454,560, a potent and selective PDE4 inhibitor with in vivo efficacy in animal models of asthma and cognition.

Type 4 phosphodiesterases (PDE4) inhibitors are emerging therapeutics in the treatment of a number of chronic disorders including asthma, chronic obstructive pulmonary disease (COPD) and cognitive disorders. This study delineates the preclinical profile of L-454,560, which is a potent, competitive and preferential inhibitor of PDE4A, 4B, and 4D with IC50 values of 1.6, 0.5 and 1.2 nM, respectively. In contrast to the exclusive binding of cilomilast and the preferential binding of roflumilast to the PDE4 holoenzyme state (Mg2+-bound form), L-454,560 binds to both the apo-(Mg2+-free) and holoenzyme states of PDE4. The intrinsic enzyme potency for PDE4 inhibition by L-454,560 also results in an effective blockade of LPS-induced TNFalpha formation in whole blood (IC50 = 161 nM) and is comparable to the human whole blood potency of roflumilast. The cytokine profile of inhibition of L-454,560 is mainly a Th1 profile with significant inhibition of IFNgamma and no detectable inhibition of IL-13 formation up to 1 microM. L-454,560 was also found to be efficacious in two models of airway hyper-reactivity, the ovalbumin (OVA) sensitized and challenged guinea pig and the ascaris sensitized sheep model. Furthermore, L-454560 was also effective in improving performance in the delayed matching to position (DMTP) version of the Morris watermaze, at a dose removed from that associated with potential emesis. Therefore, L-454,560 is a novel PDE4 inhibitor with an overall in vivo efficacy profile at least comparable to roflumilast and clearly superior to cilomilast.

[The role of spiral computerized tomography in the diagnosis of pulmonary embolism]. / Place actuelle de l'angioscanner spiralé dans l'embolie pulmonaire.

The diagnostic strategy of pulmonary embolism has changed in the last few years with the use of the pulmonary spiral angio-scan. It has become the investigation of first intention for the positive diagnosis of pulmonary embolism. Its limitations are known, essentially the difficulties in visualisation of distal pulmonary embolism. However, the introduction of new 64-slice scanners has considerably improved the resolution. The indications of the spiral angioscanner have recently increased with the study of pulmonary artery vascularisation and the calculation of Qanadli's obstruction index, the study of the peripheral venous system and the evaluation of right ventricular dysfunction by the calculation of the ratio of surfaces (or diameters) of RV/LV.

Pioglitazone does not increase cerebral glucose utilisation in a murine model of Alzheimer's disease and decreases it in wild-type mice.

AIMS/HYPOTHESIS: Clinical trials are in progress to test thiazolidinediones in neurodegenerative diseases such as Alzheimer's disease that involve deficiencies in brain glucose metabolism. While thiazolidinediones enhance glucose uptake in non-cerebral tissues, their impact on brain energy metabolism has not been investigated in vivo. We thus determined whether the thiazolidinedione pioglitazone reverses the decrease in cerebral glucose utilisation (CGU) in a model of brain metabolic deficiency related to Alzheimer's disease. Results are relevant to diabetes because millions of diabetic patients take pioglitazone as an insulin-sensitising drug, and diabetes increases the risk of developing Alzheimer's disease. MATERIALS AND METHODS: The regional pattern of CGU was measured with the 2-deoxy [(14)C] glucose autoradiographic technique in adult awake mice overexpressing transforming growth factor beta1 (TGFbeta1), and in wild-type littermates. Mice were treated with pioglitazone for 2 months. RESULTS: Measurement of CGU in 27 brain regions confirmed that TGFbeta1 overexpression induced hypometabolism across the brain. Pioglitazone did not reverse the effect of TGFbeta1 overexpression and decreased regional CGU in control animals by up to 23%. The extent of the regional CGU decrease induced by pioglitazone, but not that induced by TGFbeta1, correlated strongly with basal CGU, suggesting that the higher the local metabolic rate the greater the reduction of CGU effected by pioglitazone. CONCLUSIONS/INTERPRETATION: In contrast to its stimulatory effect in non-cerebral tissues, chronic treatment with pioglitazone decreases CGU in vivo. This evidence does not support the hypothesis that pioglitazone could act as a metabolic enhancer in Alzheimer's disease, and raises the question of how thiazolidinediones could be beneficial in neurodegenerative diseases.

[Erythema nodosum and adenopathy in a 15-year-old boy: uncommon signs of cat scratch disease]. / Erythème noueux et adénopathies chez un adolescent: mode de révélation rare de la maladie des griffes du chat.

UNLABELLED: Erythema nodosum rarely occurs in childhood and can be caused by cat scratch disease, as a result of agent Bartonella henselae. We report the case of a teenager who presented erythema nodosum and bilateral inguinal adenitis. Cat scratch disease diagnosis was confirmed by anti-Bartonella henselae serologies. Despite an appropriate antibiotic therapy, evolution was unfavourable with adenitis abcédation requiring surgical drainage. CONCLUSION: Erythema nodosum in children must let think to cat scratch disease among others etiologies.

[Embolization of uterine fibroids and infertility: is a clinical trial conceivable?]. / Embolisation des fibromes utérins et infertilité: un essai clinique est-il envisageable?

Uterine artery embolization is a recent technique intended for treating uterine fibroids, as an alternative to hysterectomy. The possible side effects putting at stake the prognosis of fertility after embolization are considered as a brake to its use for the treatment of infertility associated with myoma. Secondary hysterectomy and permanent amenorrhea are the two main risks. But they are not so frequent and can be prevented. To date, the experience in the field of fertility and pregnancy after arterial embolization for fibroids is quite limited. However, first results are encouraging and not very different from those observed after surgical myomectomy. A therapeutic trial using arterial embolization for the management of fibroids within a context of infertility can be devised in the presence of submucosal or intramural myomas responsible for metromenorrhagia and with no major infertility factors associated. It is likely that uterine artery embolization should provide results equivalent or superior to those of surgical myomectomy in case of numerous and intramural fibroids with no prevailing myoma. Arterial embolization could be also interesting in case of recurrent myoma after laparotomic myomectomy.

[Negative D-dimers and peripheral pulmonary embolism]. / D-dimères négatifs et embolies pulmonaires périphériques.

The measurement of D-dimers is a recent addition to the diagnostic strategy of pulmonary embolism and has been shown to be a valuable tool with excellent sensitivity. However, there have been rare reports of patients with pulmonary embolism but negative D-dimer tests. The object of this study was to study patients with pulmonary embolism but negative D-dimers and to compare them with a population of patients with pulmonary embolism and raised D-dimers. One hundred and fifty consecutive patients admitted for pulmonary embolism were included in this study. All underwent measurement of D-dimers (normal <500 ng/ml) by an ELISA technique. The data of clinical examination and complementary investigations were analysed with respect to the D-dimers result. The sensitivity of raised D-dimers for pulmonary embolism was 96% (6 patients had results <500 ng/ml). The finding of chest pain was statistically greater in the group with negative D-dimers (p=0.01). In these cases, the emboli were all distal (p=0.0003), the average Miller index was significantly lower than in patients with high D-dimers (p=0.04) and the diagnostic value of ultrasound investigations (echocardiography, ultrasonography of lower limb veins) was less (p<0.0001). The authors conclude that measurement of D-dimers by the ELISA method may be non-diagnostic in distal pulmonary embolism and one explanation could be the less extensive thromboembolic process. In cases with negative D-dimers, a strong clinical suspicion of pulmonary embolism should lead to the request for further investigations.