Characterization of greater middle eastern genetic variation for enhanced disease gene discovery

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia1-3, has resulted in an elevated burden of recessive disease4. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized ‘genetic purging’. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics

Réanimation en hépatologie, insuffisance hépatique aigüe de cause indéterminée (caractéristiques, profil évolutif et facteurs pronostiques)

L insuffisance hépatique aiguë (IHA) est un syndrome rare résultant d une altération brutale des fonctions hépatiques. Son évolution est variable mais s accompagne d une morbi-mortalité importante. La transplantation hépatique reste le seul traitement lorsque la guérison n est pas spontanée. Malgré une enquête étiologique exhaustive, aucune cause n est trouvée dans 15% des cas. Ce travail est le premier à établir les caractéristiques propres, le profil évolutif et les facteurs pronostiques des patients atteints d IHA de cause indéterminée (IHAI).De 1986 à 2006, 541 patients ont été admis à l hôpital Paul Brousse, en réanimation pour IHA. Parmi eux, 71 patients (13%) présentaient une IHAI. L âge moyen était de 32 ans, principalement des femmes (60,6%). Dix patients (14,2%) se sont spontanément améliorés, 6 sont décédés (8,4%) et 55 (77,5%) ont été transplantés La mortalité globale est de 67,6 % et celle des patients transplantés de 30,9 %. Les critères de transplantation de Clichy-Paul Brousse s avèrent performants dans cette indication (sensibilité : 90%, spécificité : 100%). Le taux de prothrombine (p=0,018), la bilirubinémie (p=0,003) et l absence d encéphalopathie hépatique (p<0,0001) sont des facteurs pronostiques d amélioration spontanée. Ces paramètres ne permettent de prédire ni la mortalité globale et ni la mortalité post-transplantation, contrairement aux marqueurs de défaillance d organes dont le score de SOFA (p=0,0005). Ces résultats encouragent à adresser les patients atteints d IHAI dans des centres spécialisés disposant de l accès à la transplantation hépatique mais également d un secteur de réanimation prenant en charge la défaillance multiviscérale.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

Effects of dopamine and norepinephrine on systemic and hepatosplanchnic hemodynamics, oxygen exchange, and energy balance in vasoplegic septic patients.

International audienceDopamine is widely used to improve systemic and hepatosplanchnic hemodynamics and oxygenation during sepsis. However, some studies have suggest that norepinephrine may have beneficial effects on regional blood flow and metabolism, whereas dopamine might have deleterious effects related to redistribution of blood flow away from the intestinal mucosa or by decreasing directly the cell redox state. In 12 vasoplegic septic patients, we compared the effects of norepinephrine and dopamine on systemic and hepatosplanchnic hemodynamics, oxygenation, and energy metabolism. Catecholamines were administered in a crossover randomized order to maintain mean arterial pressure (MAP) at 80 mmHg. Hepatosplanchnic blood flow (Qspl) was determined using a continuous infusion of indocyanine green dye. Despite a similar MAP, the cardiac index was higher with dopamine than with norepinephrine (6.3 [5.3-7.3] vs. 4.3 [3.8-4.9] L.min.m) (P <0.001). Qspl was similar with both catecholamines, but the ratio of Qspl to cardiac output was significantly lower with dopamine (23.9% [17.5-33.5]) than with norepinephrine (33.5% [25.8-37]) (P <0.05). Although global O2 delivery and O2 consumption were higher with dopamine (782 [707-859] vs. 553 [512-629] mL.min.m, P <0.001 and 164 [134-192] vs. 128 [111-149] mL.min.m, P <0.001, respectively), hepatosplanchnic O2 delivery and consumption were not different. Hepatic lactate uptake was lower (0.47 [0.3-0.89] vs. 1.01 [0.69-1.34] mmol.min) (P <0.01), and hepatic venous lactate-to-pyruvate ratio was higher (15.3 [7.6-21.1] vs. 11.2 [6.6-15.1], P <0.05) with dopamine than with norepinephrine. In vasoplegic septic patients, maintaining mean arterial pressure, hepatosplanchnic hemodynamics, and oxygen exchange with dopamine requires a consequent increased cardiac output, which is responsible for an increased global oxygen demand when compared with norepinephrine. In addition, dopamine impairs the hepatic energy balance. Its position as a preferential treatment compared with norepinephrine in this context may therefore be questionable

Long-lasting successful dissemination of resistance to oxazolidinones in MDR Staphylococcus epidermidis clinical isolates in a tertiary care hospital in France

International audienceObjectives: Patient-and procedure-related changes in modern medicine have turned CoNS into one of the major nosocomial pathogens. Treatments of CoNS infections are challenging owing to the large proportion of MDR strains and oxazolidinones often remain the last active antimicrobial molecules. Here, we have investigated a long-lasting outbreak (2010-13) due to methicillin-and linezolid-resistant (LR) CoNS (n " 168), involving 72 carriers and 49 infected patients. Methods: Antimicrobial susceptibilities were tested by the disc diffusion method and MICs were determined by broth microdilution or Etest. The clonal relationship of LR Staphylococcus epidermidis (LRSE) was first determined using a semi-automated repetitive element palindromic PCR (rep-PCR) method. Then, WGS was performed on all cfr-positive LRSE (n " 30) and LRSE isolates representative of each rep-PCR-defined clone (n " 17). Self-transferability of cfr-carrying plasmids was analysed by filter-mating experiments. Results: This outbreak was caused by the dissemination of three clones (ST2, ST5 and ST22) of LRSE. In these clones, linezolid resistance was caused by (i) mutations in the chromosome-located genes encoding the 23S RNA and L3 and L4 ribosomal proteins, but also by (ii) the dissemination of two different self-conjugative plasmids carrying the cfr gene encoding a 23S RNA methylase. By monitoring linezolid prescriptions in two neighbouring hospitals, we highlighted that the spread of LR-CoNS was strongly associated with linezolid use. Conclusions: Physicians should be aware that plasmid-encoded linezolid resistance has started to disseminate among CoNS and that rational use of oxazolidinones is critical to preserve these molecules as efficient treatment options for MDR Gram-positive pathogens

Intention-to-treat analysis of liver transplantation for hepatocellular carcinoma: living versus deceased donor transplantation

For patients who have cirrhosis with hepatocellular carcinoma (HCC), living donor liver transplantation (LDLT) reduces waiting time and dropout rates. We performed a comparative intention-to-treat analysis of recurrence rates and survival outcomes after LDLT and deceased donor liver transplantation (DDLT) in HCC patients. Our study included 183 consecutive patients with HCC who were listed for liver transplantation over a 9-year period at our institution. Tumor recurrence was the primary endpoint. At listing, patient and tumor characteristics were comparable in the two groups (LDLT, n = 36; DDLT, n = 147). Twenty-seven (18.4%) patients dropped out, all from the DDLT waiting list, mainly due to tumor progression (19/27 [70%] patients). The mean waiting time was shorter in the LDLT group (2.6 months versus 7.9 months; P = 0.001). The recurrence rates in the two groups were similar (12.9% and 12.7%, P = 0.78), and there was a trend toward a longer time to recurrence after LDLT (38 ± 27 months versus 16 ± 13 months, P = 0.06). Tumors exceeding the University of California, San Francisco (UCSF) criteria, tumor grade, and microvascular invasion were independent predictive factors for recurrence. On an intention-to-treat basis, the overall survival (OS) in the two groups was comparable. Patients beyond the Milan and UCSF criteria showed a trend toward worse outcomes with LDLT compared with DDLT (P = 0.06). CONCLUSION: The recurrence and survival outcomes after LDLT and DDLT were comparable on an intent-to-treat analysis. Shorter waiting time preventing dropouts is an additional advantage with LDLT. LDLT for HCC patients beyond validated criteria should be proposed with caution