Outcomes of endovascular treatment of ruptured abdominal aortic aneurysms

IntroductionThe successful application of endovascular techniques for the elective repair of abdominal aortic aneurysms (AAAs) has stimulated a strong interest in their possible use in dealing with a long-standing surgical challenge: the ruptured abdominal aortic aneurysm (RAAA). The use of a conventional open procedure to repair ruptured aneurysms is associated with a high operative mortality of 45% to 50%. In this study, we evaluated the current frequency of endovascular repair of RAAAs in four large states and the impact of this technique on patient outcome.MethodsWe examined discharge data sets from 2000 through 2003 from the four states of California, Florida, New Jersey, and New York, whose combined population represents almost a third of the United States population. Proportions and trends were analyzed by χ2 analysis and continuous variables by the Student’s t test.ResultsWe found that since the year 2000, endovascular repair has begun to emerge as a viable treatment option for RAAAs, accounting for the repair of 6.2% of cases in 2003. During the same period, the use of open procedures for RAAAs declined. The overall mortality rate for the 4-year period was significantly lower for endovascular vs open repair (39.3% vs. 47.7%, P = .005). Moreover, compared with open repair, endovascular repair resulted in a significantly lower rate of pulmonary, renal, and bleeding complications. Survival after endovascular repair correlated with hospital experience, as assessed by the overall volume of elective and nonelective endovascular procedures. For endovascular repairs, mortality ranged from 45.9% for small volume hospitals to 26% for large volume hospitals (P = .0011). Volume was also a determinant of mortality for open repairs, albeit to a much lesser extent (51.5% for small volume hospitals, 44.3% for large volume hospitals; P < .0001).ConclusionWe observed a benefit to using endovascular procedures for RAAAs in institutions with significant endovascular experience; however, the analysis of administrative data cannot rule out selection bias as an explanation of better outcomes. These data strongly endorse the need for prospective studies to clarify to what extent the improved survival in RAAA patients is to be attributed to the endovascular approach rather than the selection of low-risk patients

Open Versus Laparoscopic Adrenalectomy for Adrenocortical Carcinoma: A Meta-analysis of Surgical and Oncological Outcomes

PURPOSE: This study was designed to determine the role of laparoscopic adrenalectomy (LA) in the surgical management of adrenocortical carcinoma (ACC). METHODS: A systematic literature review was performed on January 2, 2015 using PubMed. Article selection proceeded according to PRISMA criteria. Studies comparing open adrenalectomy (OA) to LA for ACC and including at least 10 cases per each surgical approach were included. Odds ratio (OR) was used for all binary variables, and weight mean difference (WMD) was used for the continuous parameters. Pooled estimates were calculated with the fixed-effect model, if no significant heterogeneity was identified; alternatively, the random-effect model was used when significant heterogeneity was detected. Main demographics, surgical outcomes, and oncological outcomes were analyzed. RESULTS: Nine studies published between 2010 and 2014 were deemed eligible and included in the analysis, all of them being retrospective case-control studies. Overall, they included 240 LA and 557 OA cases. Tumors treated with laparoscopy were significantly smaller in size (WMD -3.41 cm; confidence interval [CI] -4.91, -1.91; p &lt; 0.001), and a higher proportion of them (80.8 %) more at a localized (I-II) stage compared with open surgery (67.7 %) (odds ratio [OR] 2.8; CI 1.8, 4.2; p &lt; 0.001). Hospitalization time was in favor of laparoscopy, with a WMD of -2.5 days (CI -3.3, -1.7; p &lt; 0.001). There was no difference in the overall recurrence rate between LA and OA (relative risk [RR] 1.09; CI 0.83, 1.43; p = 0.53), whereas development of peritoneal carcinomatosis was higher for LA (RR 2.39; CI 1.41, 4.04; p = 0.001). No difference could be found for time to recurrence (WMD -8.2 months; CI -18.2, 1.7; p = 0.11), as well as for cancer specific mortality (OR 0.68; CI 0.44, 1.05; p = 0.08). CONCLUSIONS: OA should still be considered the standard surgical management of ACC. LA can offer a shorter hospital stay and possibly a faster recovery. Therefore, this minimally invasive approach can certainly play a role in this setting, but it should be only offered in carefully selected cases to avoid jeopardizing the oncological outcome.PURPOSE: This study was designed to determine the role of laparoscopic adrenalectomy (LA) in the surgical management of adrenocortical carcinoma (ACC). METHODS: A systematic literature review was performed on January 2, 2015 using PubMed. Article selection proceeded according to PRISMA criteria. Studies comparing open adrenalectomy (OA) to LA for ACC and including at least 10 cases per each surgical approach were included. Odds ratio (OR) was used for all binary variables, and weight mean difference (WMD) was used for the continuous parameters. Pooled estimates were calculated with the fixed-effect model, if no significant heterogeneity was identified; alternatively, the random-effect model was used when significant heterogeneity was detected. Main demographics, surgical outcomes, and oncological outcomes were analyzed. RESULTS: Nine studies published between 2010 and 2014 were deemed eligible and included in the analysis, all of them being retrospective case-control studies. Overall, they included 240 LA and 557 OA cases. Tumors treated with laparoscopy were significantly smaller in size (WMD -3.41 cm; confidence interval [CI] -4.91, -1.91; p &lt; 0.001), and a higher proportion of them (80.8 %) more at a localized (I-II) stage compared with open surgery (67.7 %) (odds ratio [OR] 2.8; CI 1.8, 4.2; p &lt; 0.001). Hospitalization time was in favor of laparoscopy, with a WMD of -2.5 days (CI -3.3, -1.7; p &lt; 0.001). There was no difference in the overall recurrence rate between LA and OA (relative risk [RR] 1.09; CI 0.83, 1.43; p = 0.53), whereas development of peritoneal carcinomatosis was higher for LA (RR 2.39; CI 1.41, 4.04; p = 0.001). No difference could be found for time to recurrence (WMD -8.2 months; CI -18.2, 1.7; p = 0.11), as well as for cancer specific mortality (OR 0.68; CI 0.44, 1.05; p = 0.08). CONCLUSIONS: OA should still be considered the standard surgical management of ACC. LA can offer a shorter hospital stay and possibly a faster recovery. Therefore, this minimally invasive approach can certainly play a role in this setting, but it should be only offered in carefully selected cases to avoid jeopardizing the oncological outcome

Uncovering Biosynthetic Relationships Between Antifungal Nonadrides and Octadrides

Maleidrides are a class of bioactive secondary metabolites unique to filamentous fungi, which contain one or more maleic anhydrides fused to a 7-, 8- or 9- membered carbocycle (named heptadrides, octadrides and nonadrides respectively). Herein structural and biosynthetic studies on the antifungal octadride, zopfiellin, and nonadrides scytalidin, deoxyscytalidin and castaneiolide are described. A combination of genome sequencing, bioinformatic analyses, gene disruptions, biotransformations, isotopic feeding studies, NMR and X-ray crystallography revealed that they share a common biosynthetic pathway, diverging only after the nonadride deoxyscytalidin. 5-Hydroxylation of deoxyscytalidin occurs prior to ring contraction in the zopfiellin pathway of Diffractella curvata. In Scytalidium album, 6-hydroxylation-confirmed as being catalysed by the α-ketoglutarate dependent oxidoreductase ScyL2-converts deoxyscytalidin to scytalidin, in the final step in the scytalidin pathway. Feeding scytalidin to a zopfiellin PKS knockout strain led to the production of the nonadride castaneiolide and two novel ring-open maleidrides. © The Royal Society of Chemistry

The Cardiac TBX5 Interactome Reveals a Chromatin Remodeling Network Essential for Cardiac Septation

Human mutations in the cardiac transcription factor gene TBX5 cause Congenital Heart Disease (CHD), however the underlying mechanism is unknown. We report characterization of the endogenous TBX5 cardiac interactome and demonstrate that TBX5, long considered a transcriptional activator, interacts biochemically and genetically with the Nucleosome Remodeling and Deacetylase (NuRD) repressor complex. Incompatible gene programs are repressed by TBX5 in the developing heart. CHD missense mutations that disrupt the TBX5-NuRD interaction cause depression of a subset of repressed genes. Furthermore, the TBX5-NuRD interaction is required for heart development. Phylogenetic analysis showed that the TBX5-NuRD interaction domain evolved during early diversification of vertebrates, simultaneous with the evolution of cardiac septation. Collectively, this work defines a TBX5-NuRD interaction essential to cardiac development and the evolution of the mammalian heart, and when altered may contribute to human CHD

Structure revision of cryptosporioptides and determination of the genetic basis for dimeric xanthone biosynthesis in fungi

Three novel dimeric xanthones, cryptosporioptides A–C were isolated from Cryptosporiopsis sp. 8999 and their structures elucidated. Methylation of cryptosporioptide A gave a methyl ester with identical NMR data to cryptosporioptide, a compound previously reported to have been isolated from the same fungus. However, HRMS analysis revealed that cryptosporioptide is a symmetrical dimer, not a monomer as previously proposed, and the revised structure was elucidated by extensive NMR analysis. The genome of Cryptosporiopsis sp. 8999 was sequenced and the dimeric xanthone (dmx) biosynthetic gene cluster responsible for the production of the cryptosporioptides was identified. Gene disruption experiments identified a gene (dmxR5) encoding a cytochrome P450 oxygenase as being responsible for the dimerisation step late in the biosynthetic pathway. Disruption of dmxR5 led to the isolation of novel monomeric xanthones. Cryptosporioptide B and C feature an unusual ethylmalonate subunit: a hrPKS and acyl CoA carboxylase are responsible for its formation. Bioinformatic analysis of the genomes of several fungi producing related xanthones, e.g. the widely occurring ergochromes, and related metabolites allows detailed annotation of the biosynthetic genes, and a rational overall biosynthetic scheme for the production of fungal dimeric xanthones to be proposed

Sleep-wake sensitive mechanisms of adenosine release in the basal forebrain of rodents : an in vitro study

Adenosine acting in the basal forebrain is a key mediator of sleep homeostasis. Extracellular adenosine concentrations increase during wakefulness, especially during prolonged wakefulness and lead to increased sleep pressure and subsequent rebound sleep. The release of endogenous adenosine during the sleep-wake cycle has mainly been studied in vivo with microdialysis techniques. The biochemical changes that accompany sleep-wake status may be preserved in vitro. We have therefore used adenosine-sensitive biosensors in slices of the basal forebrain (BFB) to study both depolarization-evoked adenosine release and the steady state adenosine tone in rats, mice and hamsters. Adenosine release was evoked by high K+, AMPA, NMDA and mGlu receptor agonists, but not by other transmitters associated with wakefulness such as orexin, histamine or neurotensin. Evoked and basal adenosine release in the BFB in vitro exhibited three key features: the magnitude of each varied systematically with the diurnal time at which the animal was sacrificed; sleep deprivation prior to sacrifice greatly increased both evoked adenosine release and the basal tone; and the enhancement of evoked adenosine release and basal tone resulting from sleep deprivation was reversed by the inducible nitric oxide synthase (iNOS) inhibitor, 1400 W. These data indicate that characteristics of adenosine release recorded in the BFB in vitro reflect those that have been linked in vivo to the homeostatic control of sleep. Our results provide methodologically independent support for a key role for induction of iNOS as a trigger for enhanced adenosine release following sleep deprivation and suggest that this induction may constitute a biochemical memory of this state

Angiogenesis in cancer of unknown primary: clinicopathological study of CD34, VEGF and TSP-1

BACKGROUND: Cancer of unknown primary remains a mallignancy of elusive biology and grim prognosis that lacks effective therapeutic options. We investigated angiogenesis in cancer of unknown primary to expand our knowledge on the biology of these tumors and identify potential therapeutic targets. METHODS: Paraffin embedded archival material from 81 patients diagnosed with CUP was used. Tumor histology was adenocarcinoma (77%), undifferentiated carcinoma (18%) and squamous cell carcinoma (5%). The tissue expression of CD34, VEGF and TSP-1 was assessed immunohistochemically by use of specific monoclonal antibodies and was analyzed against clinicopathological data. RESULTS: VEGF expression was detected in all cases and was strong in 83%. Stromal expression of TSP-1 was seen in 80% of cases and was strong in 20%. The expression of both proteins was not associated with any clinical or pathological parameters. Tumor MVD was higher in tumors classified as unfavorable compared to more favorable and was positively associated with VEGF and negatively with TSP-1. CONCLUSION: Angiogenesis is very active and expression of VEGF is almost universal in cancers of unknown primary. These findings support the clinical investigation of VEGF targeted therapy in this clinical setting

Histone deacetylases suppress cgg repeat-induced neurodegeneration via transcriptional silencing in models of Fragile X Tremor Ataxia Syndrome

Fragile X Tremor Ataxia Syndrome (FXTAS) is a common inherited neurodegenerative disorder caused by expansion of a CGG trinucleotide repeat in the 59UTR of the fragile X syndrome (FXS) gene, FMR1. The expanded CGG repeat is thought to induce toxicity as RNA, and in FXTAS patients mRNA levels for FMR1 are markedly increased. Despite the critical role of FMR1 mRNA in disease pathogenesis, the basis for the increase in FMR1 mRNA expression is unknown. Here we show that overexpressing any of three histone deacetylases (HDACs 3, 6, or 11) suppresses CGG repeat-induced neurodegeneration in a Drosophila model of FXTAS. This suppression results from selective transcriptional repression of the CGG repeat-containing transgene. These findings led us to evaluate the acetylation state of histones at the human FMR1 locus. In patient-derived lymphoblasts and fibroblasts, we determined by chromatin immunoprecipitation that there is increased acetylation of histones at the FMR1 locus in pre-mutation carriers compared to control or FXS derived cell lines. These epigenetic changes correlate with elevated FMR1 mRNA expression in pre-mutation cell lines. Consistent with this finding, histone acetyltransferase (HAT) inhibitors repress FMR1 mRNA expression to control levels in pre-mutation carrier cell lines and extend lifespan in CGG repeat-expressing Drosophila. These findings support a disease model whereby the CGG repeat expansion in FXTAS promotes chromatin remodeling in cis, which in turn increases expression of the toxic FMR1 mRNA. Moreover, these results provide proof of principle that HAT inhibitors or HDAC activators might be used to selectively repress transcription at the FMR1 locus.open293