Transcatheter embolization as the new reference standard for endoscopically unmanageable upper gastrointestinal bleeding

Acute nonvariceal upper gastrointestinal bleeding(UGIB) is a major medical emergency problem associated with significant morbidity and mortality.Endoscopy is considered the first method of choice to detect and treat UGIB.Endoscopic therapy usually achieves primary hemostasis,but 10%-30% of these patients have repeat bleeding.In patients in whom hemostasis is not achieved with endoscopic techniques,treatment with transcatheter angiographic embolization(TAE) or surgery is needed.Surgical intervention is usually an expeditious and gratifying endeavor,but it can be associated with high operative mortality rates.A large number of studies support the use of TAE as salvage therapy as an alternative to surgery.However,few studies have compared the results of TAE with that of emergency surgery in terms of efficiency,the frequency of repeat bleeding,and complications.Recently,Ang et al retrospectively compared the outcome of TAE and surgery as salvage therapy of UGIB after failed endoscopic treatment.There were no significant differences in 30 d mortality,complication rates and length of stay although higher rebleeding rates were observed after TAE compared with surgery.In this commentary,we discuss the advantages and drawbacks of these two therapeutic strategies for UGIB.We also attempt to define the exact role of TAE for acute nonvariceal UGIB.     

Évaluation du bullying scolaire (harcèlement scolaire) chez les adolescents français : validité de l’adaptation française du questionnaire Agresseur/Victime révisé d’Olweus (1996)

Bullying is a widespread problem in schools. There would be a benefit in the availability of a valid instrument for its measurement in France. The Olweus Bully/Victim Questionnaire revised (BVQr) (Olweus, 1996) [21] is one of the most widely used bullying self-report in the world, but no data are available on its validity for its use with French adolescents.     

An indirect treatment comparison of the efficacy of patisiran and tafamidis for the treatment of hereditary transthyretin-mediated amyloidosis with polyneuropathy

Background: Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a progressive, life-threatening disease. Until recently, tafamidis was the only approved pharmacotherapy. Patisiran significantly improved polyneuropathy and quality of life (QoL) in the phase III APOLLO trial. In the absence of direct comparisons, this analysis aimed to evaluate the comparative efficacy of tafamidis and patisiran in hATTR amyloidosis with polyneuropathy.

Research design and methods: Randomized controlled trial evidence for tafamidis was identified by systematic literature review. Indirect treatment comparisons were performed using the standard pairwise Bucher method for endpoints used in both APOLLO and the tafamidis Fx-005 trial: change from baseline in Neuropathy Impairment Score-lower limbs (NIS-LL), Norfolk QoL-Diabetic Neuropathy questionnaire (QoL-DN), NIS-LL response, and mBMI vs. placebo. Inter-trial population differences were assessed by sensitivity analysis.

Results: The base-case analysis (FAP Stage 1 APOLLO patients vs. intent-to-treat Fx-005 population) suggested patisiran had a greater treatment effect vs. tafamidis for all endpoints, with significant improvements in mean change in NIS-LL (–5.49) and QoL-DN (–13.10) from baseline to Month 18. Similar trends were observed in all sensitivity analyses.

Conclusions: In the absence of direct comparisons, this analysis suggests patisiran has a greater treatment effect than tafamidis in patients with hATTR amyloidosis with polyneuropathy.     

Discontinuous epitopes on the C2 domain of coagulation Factor VIII mapped by computer-designed synthetic peptides

The occurrence of alloantibodies against Factor VIII (FVIII) is the main iatrogenic complication in haemophilia A (HA). Anti-FVIII autoantibodies may also spontaneously appear in non-HA patients, leading to acquired haemophilia A. In both contexts, the antibody response against FVIII is complex and difficult to analyse due to the lack of suitable tools. Our purpose was to comprehensively map, at the amino acid level, discontinuous epitopes of the C2 domain of FVIII targeted by patients' antibodies. We synthesized 33 synthetic peptides, which were predicted by the bioinformatic algorithm PEPOP to mimic C2 domain discontinuous epitopes. Using an inhibition assay based on the x-MAP technology, we evaluated their ability to block the binding to the C2 domain of anti-C2 domain antibodies from pooled plasma samples. Nine peptides were thus selected and tested again in individual plasma samples. Our results support the view that C2 domain epitopes are organized as an epitopic mosaic distributed around the molecule, showed that each patient displayed a specific anti-C2 epitopic profile, and confirmed the complexity and variability of the immune response against the C2 domain of FVIII. This ability to finely map epitopes could be further used to follow the antibody specificity modifications over time.     

Transjugular intrahepatic portosystemic shunt as bridge-to-surgery in refractory gastric antral vascular ectasia

Gastric antral vascular ectasia(GAVE) may cause gastrointestinal bleeding(GIB). The treatment of GAVE relies on endoscopic approaches such as electrocoagulation(argon plasma coagulation, laser therapy, heater probe therapy, radiofrequency ablation), cryotherapy, and band ligation. In refractory cases, antrectomy may be considered. In the event of an associated cirrhosis and portal hypertension, it has been suggested that antrectomy could be an option, provided the mortality risk isn't considered too great. We report the case of a 67-year-old cirrhotic patient who presented with GAVE related GIB, unresponsive to multiple endoscopic treatments. The patient had a good liver function(model for end-stage disease 10). After a multidisciplinary meeting, a transjugular intrahepatic portosystemic shunt(TIPS) procedure was performed, in order to treat the cirrhosis associated ascites. The outcome was successful. An antrectomy was then performed, with no recurrence of GIB and no transfusion need during three months of follow up. In this case, the TIPS procedure achieved a complete ascites regression, allowing a safer surgical treatment of the GAVE-related GIB.     

Gonadotropin-releasing hormone couples to 3',5'-cyclic adenosine-5'-monophosphate pathway through novel protein kinase Cdelta and -epsilon in LbetaT2 gonadotrope cells

GnRH regulates the reproductive system by stimulating synthesis and release of gonadotropins. GnRH acts through a receptor coupled to multiple intracellular events including a rapid phosphoinositide turnover. Although the cAMP pathway is essential for gonadotrope function, the ability of GnRH to induce cAMP, as well as the coupling mechanisms involved, remain controversial. In this study, we established that GnRH increases intracellular cAMP levels in a concentration-dependent manner in LbetaT2 gonadotrope cells (maximal increase, 2.5-fold; EC(50), 0.30 nm), and this was further evidenced by GnRH activation of a cAMP-sensitive reporter gene. The GnRH effect was Ca(2+) independent, mimicked by the phorbol ester phorbol 12-myristate 13-acetate, and blocked by the protein kinase C (PKC) inhibitor bisindolylmaleimide, indicating that the GnRH effect was mediated by PKC. Pharmacological inhibition of conventional PKC isoforms with G?6976 did not prevent GnRH-induced cAMP production, whereas down-regulation of novel PKCdelta, -epsilon, and -theta by a long-term treatment with GnRH markedly reduced it. Expression of dominant-negative (DN) mutants of PKCdelta or -epsilon but not PKCtheta impaired GnRH activation of a cAMP-sensitive promoter, demonstrating that PKCdelta and -epsilon are the two endogenous isoforms mediating GnRH activation of the adenylyl cyclase (AC) pathway in LbetaT2 cells. Accordingly, we identified by RT-PCR and immunocytochemical analysis, two PKC-sensitive AC isoforms, i.e. AC5 and AC7 as potential targets for GnRH. Lastly, we showed that only sustained stimulation of GnRH receptor significantly increased cAMP, suggesting that in vivo, the cAMP signaling pathway may be selectively recruited under intense GnRH release such as the preovulatory GnRH surge.