Background

Glaucoma is an optic neuropathy that leads to vision loss and blindness. It is the second most common cause of irreversible blindness worldwide. The main treatment for glaucoma aims to reduce intraocular pressure (IOP) in order to slow or prevent further vision loss. IOP can be lowered with medications, and laser or incisional surgeries. Trabeculectomy is the most common incisional surgical procedure to treat glaucoma. Device-modified trabeculectomy is intended to improve drainage of the aqueous humor to lower IOP. Trabeculectomy-modifying devices include Ex-PRESS, Ologen, amniotic membrane, expanded polytetrafluoroethylene (E-PTFE) membrane, Gelfilm and others. However, the effectiveness and safety of these devices are uncertain.

Objectives

To assess the relative effectiveness, primarily with respect to IOP control and safety, of the use of different devices as adjuncts to trabeculectomy compared with standard trabeculectomy in eyes with glaucoma.

Search methods

We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2014, Issue 12), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to December 2014), EMBASE (January 1980 to December 2014), PubMed (1948 to December 2014), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to December 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 22 December 2014.

Selection criteria

We included randomized controlled trials comparing devices used during trabeculectomy with trabeculectomy alone. We also included studies where antimetabolites were used in either or both treatment groups.

Data collection and analysis

We used standard procedures expected by Cochrane.

Main results

We found 33 studies that met our inclusion criteria, of which 30 were published as full-length journal articles and three as conference abstracts. Only five studies have been registered. The 33 studies included a total of 1542 participants with glaucoma, and compared five types of devices implanted during trabeculectomy versus trabeculectomy alone. Five studies reported the use of Ex-PRESS (386 participants), eight studies reported the use of Ologen (327 participants), 18 studies reported the use of amniotic membrane (726 participants), one study reported the use of E-PTFE (60 participants), and one study reported the use of Gelfilm (43 participants). These studies were conducted in North America, South America, Europe, Asia, and the Middle East. Planned participant follow-up periods ranged from three months to five years. The studies were reported poorly which limited our ability to judge risk of bias for many domains. Only two studies explicitly masked outcome assessment so, we rated 31 studies at high risk of detection bias.Low-quality evidence from three studies showed that use of Ex-PRESS compared with trabeculectomy alone may be associated with a slightly lower IOP at one year (mean difference (MD) -1.58 mm Hg, 95% confidence interval (CI) -2.74 to -0.42; 165 eyes). Cataract surgery and hyphema may be less frequent in the Ex-PRESS group than in the trabeculectomy-alone group (cataract surgery: risk ratio (RR) 0.32, 95% CI 0.14 to 0.74, 3 studies, low-quality evidence; hyphema: RR 0.33, 95% CI 0.12 to 0.94, 4 studies, low-quality evidence). The effect of whether Ex-PRESS prevents hypotony was uncertain (RR 0.92, 95% CI 0.63 to 1.33, 2 studies, very low-quality evidence). All these studies received funding from the device manufacturer.Very low-quality evidence from five studies suggests that use of Ologen compared with trabeculectomy alone is associated with slightly higher IOP at one year (MD 1.40 mm Hg, 95% CI -0.57 to 3.38; 177 eyes). The effect of Ologen on preventing hypotony was uncertain (RR 0.75, 95% CI 0.47 to 1.19, 5 studies, very low-quality evidence). Differences between the two treatment groups for other reported complications also were inconclusive.Low-quality evidence from nine studies suggests that use of amniotic membrane with trabeculectomy may be associated with lower IOP at one year compared with trabeculectomy alone (MD -3.92 mm Hg, 95% CI -5.41 to -2.42; 356 eyes). Low-quality evidence showed that use of amniotic membrane may prevent adverse events and complications, such as hypotony (RR 0.40, 95% CI 0.17 to 0.94, 5 studies, low-quality evidence).The report from the only E-PTFE study (60 eyes) showed no important differences for postoperative IOP at one year (MD -0.44 mm Hg, 95% CI -1.76 to 0.88) between the trabeculectomy + E-PTFE versus the trabeculectomy-alone groups. Hypotony was the only postoperative complication observed less frequently in the E-PTFE group compared to the trabeculectomy-alone group (RR 0.29, 95% CI 0.11 to 0.77).The one Gelfilm study reported uncertainty in the difference in IOP and complication rates between the two groups at one year; no further data were provided in the study report.

Authors' conclusions

Overall, the use of devices with standard trabeculectomy may help with greater IOP reduction at one-year follow-up than trabeculectomy alone; however, due to potential biases and imprecision in effect estimates, the quality of evidence is low. When we examined outcomes within subgroups based on the type of device used, our findings suggested that the use of an Ex-PRESS device or an amniotic membrane as an adjunct to trabeculectomy may be slightly more effective in reducing IOP at one year after surgery compared with trabeculectomy alone. The evidence that these devices are as safe as trabeculectomy alone is unclear. Due to various limitations in the design and conduct of the included studies, the applicability of this evidence synthesis to other populations or settings is uncertain. Further research is needed to determine the effectiveness and safety of other devices and in subgroup populations, such as people with different types of glaucoma, of various races and ethnicity, and with different lens types (e.g. phakic, pseudophakic).

Five CHB(11)X(6)Y(5)(-) carborane anions from the series X = Br, Cl, I and Y = H, Cl, CH(3) were generated by electrospray ionization, and their reactivity with a series of Brønsted acids and electron transfer reagents were examined in the gas phase. The undecachlorocarborane acid, H(CHB(11)Cl(11)), was found to be far more acidic than the former record holder, (1-C(4)F(9)SO(2))(2)NH (i.e., DeltaH degrees (acid) = 241 +/- 29 vs 291.1 +/- 2.2 kcal mol(-1)) and bridges the gas-phase acidity and basicity scales for the first time. Its conjugate base, CHB(11)Cl(11)(-), was found by photoelectron spectroscopy to have a remarkably large electron binding energy (6.35 +/- 0.02 eV) but the value for the (1-C(4)F(9)SO(2))(2)N(-) anion is even larger (6.5 +/- 0.1 eV). Consequently, it is the weak H-(CHB(11)Cl(11)) BDE (70.0 kcal mol(-1), G3(MP2)) compared to the strong BDE of (1-C(4)F(9)SO(2))(2)N-H (127.4 +/- 3.2 kcal mol(-1)) that accounts for the greater acidity of carborane acids.

The present prospective, randomized, double-blind study aimed to determine the impact of transversus abdominis plane (TAP) block on propofol and remifentanil consumption, when administered by closed-loop titration guided by processed electroencephalography, i.e., bispectral index (BIS) values. Following institutional review board approval, 60 patients were scheduled for laparoscopic colectomy under general anesthesia. Patients were randomly assigned to receive bilateral TAP block with 20 ml 0.375% ropivacaine (TAP group) or 20 ml 0.9% saline [control (CON) group]. General anesthesia was maintained with propofol and remifentanil administration using closed-loop titration guided by BIS values. The primary outcome was perioperative propofol and remifentanil consumption. The secondary outcomes were hypertensive or hypotensive events requiring treatment, recovery time in PACU and time to first rescue analgesia following surgery. A total of 58 patients participated in the present study. At similar depths of anesthesia, as measured by BIS during the maintenance phase (45-55), patients who received TAP blocks required less propofol (4.2±1.3 vs. 5.5±1.6 mg/kg/h; P<0.001) and remifentanil (0.16±0.05 vs. 0.21±0.05 µg/kg/min; P<0.001). Time to extubation was significantly shorter in the TAP group (9.8±3.2 min) than in the CON group (14.2±4.9 min) (P<0.05). The requirement to treat hemodynamic change was also significantly lower (P<0.05). Pain score at 2 h after surgery was also significantly reduced in the TAP group compared with the CON group (P<0.05), whereas the time to first rescue analgesia was delayed in patients who received TAP block (P<0.05). Postoperative nausea and vomiting occurred at comparable rates in each group (P>0.05). In conclusion, TAP block combined with general anesthesia reduced propofol and remifentanil consumption, shortened time to tracheal extubation and promoted hemodynamic stability in laparoscopic colectomy.

Air-breathing marine predators have been essential components of the marine ecosystem since the Triassic. Many of them are considered the apex predators but without direct evidence-dietary inferences are usually based on circumstantial evidence, such as tooth shape. Here we report a fossil that likely represents the oldest evidence for predation on megafauna, i.e., animals equal to or larger than humans, by marine tetrapods-a thalattosaur (∼4 m in total length) in the stomach of a Middle Triassic ichthyosaur (∼5 m). The predator has grasping teeth yet swallowed the body trunk of the prey in one to several pieces. There were many more Mesozoic marine reptiles with similar grasping teeth, so megafaunal predation was likely more widespread than presently conceived. Megafaunal predation probably started nearly simultaneously in multiple lineages of marine reptiles in the Illyrian (about 242-243 million years ago).

Hematophagous mosquitoes require vertebrate blood for their reproductive cycles, making them effective vectors for transmitting dangerous human diseases. Thus, high-intensity metabolism is needed to support reproductive events of female mosquitoes. However, the regulatory mechanism linking metabolism and reproduction in mosquitoes remains largely unclear. In this study, we found that the expression of estrogen-related receptor (ERR), a nuclear receptor, is activated by the direct binding of 20-hydroxyecdysone (20E) and ecdysone receptor (EcR) to the ecdysone response element (EcRE) in the ERR promoter region during the gonadotropic cycle of Aedes aegypti (named AaERR). RNA interference (RNAi) of AaERR in female mosquitoes led to delayed development of ovaries. mRNA abundance of genes encoding key enzymes involved in carbohydrate metabolism (CM)-glucose-6-phosphate isomerase (GPI) and pyruvate kinase (PYK)-was significantly decreased in AaERR knockdown mosquitoes, while the levels of metabolites, such as glycogen, glucose, and trehalose, were elevated. The expression of fatty acid synthase (FAS) was notably downregulated, and lipid accumulation was reduced in response to AaERR depletion. Dual luciferase reporter assays and electrophoretic mobility shift assays (EMSA) determined that AaERR directly activated the expression of metabolic genes, such as GPI, PYK, and FAS, by binding to the corresponding AaERR-responsive motif in the promoter region of these genes. Our results have revealed an important role of AaERR in the regulation of metabolism during mosquito reproduction and offer a novel target for mosquito control.

In anautogenous mosquitoes, juvenile hormone III (JH) plays an essential role in female post-eclosion (PE) development, preparing them for subsequent blood feeding and egg growth. We re-examined the JH titer during the reproductive cycle of female Aedes aegypti mosquitoes. Using liquid chromatography coupled with triple tandem mass spectrometry (LC-MS/MS/MS), we have shown that it reaches its peak at 48-54 h PE in the female hemolymph and at 72 h PE in whole body extracts. This method represents an effective assay for determination of JH titers. The 2.1-kb 5' promoter region of the Early Trypsin (ET) gene, which is specifically expressed in the female midgut under the control of JH during the PE phase, was utilized to genetically engineer the Ae. aegypti mosquito line with the ET-Gal4 activator. We then established the ET-GAL4>UAS-enhanced green fluorescent protein (EGFP) system in Ae. aegypti. In ET-Gal4>UAS-EGFP female mosquitoes, the intensity of the midgut-specific EGFP signal was observed to correspond to the ET gene transcript level and follow the JH titer during the PE phase. The EGFP signal and the EGFP transcript level were significantly diminished in midguts of transgenic female mosquitoes after RNA interference depletion of the JH receptor Methoprene-tolerant (Met), providing evidence of the control of ET gene expression by Met. Topical JH application caused premature enhancement of the EGFP signal and the EGFP transcript level in midguts of newly eclosed ET-Gal4>UAS-EGFP female mosquitoes, in which endogenous JH titer is still low. Hence, this novel ET-Gal4>UAS system permits JH-dependent gene overexpression in the midgut of Ae. aegypti female mosquitoes prior to a blood meal.

Dioxygenases of the Ten-Eleven Translocation (TET) family are 5-methylcytosine oxidases that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidation products in DNA. We show that Tet1 and Tet2 have distinct roles in regulating 5hmC in mouse embryonic stem cells (mESC). Tet1 depletion diminishes 5hmC levels at transcription start sites (TSS), whereas Tet2 depletion is predominantly associated with decreased 5hmC in gene bodies. Enrichment of 5hmC is observed at the boundaries of exons that are highly expressed, and Tet2 depletion results in substantial loss of 5hmC at these boundaries. In contrast, at promoter/TSS regions, Tet2 depletion results in increased 5hmC, potentially because of the redundant activity of Tet1. Together, the data point to a complex interplay between Tet1 and Tet2 in mESC, and to distinct roles for these two proteins in regulating promoter, exon, and polyadenylation site usage in cells.

Despite the large number of reports on colloidal nanocrystals, very little is known about the mechanistic details in terms of nucleation and growth at the atomistic level. Taking bimetallic core-shell nanocrystals as an example, here we integrate in situ liquid-cell transmission electron microscopy with first-principles calculations to shed light on the atomistic details involved in the nucleation and growth of Pt on Pd cubic seeds. We elucidate the roles played by key synthesis parameters, including capping agent and precursor concentration, in controlling the nucleation site, diffusion path, and growth pattern of the Pt atoms. When the faces of a cubic seed are capped by Br^-, Pt atoms preferentially nucleate from corners and then diffuse to edges and faces for the creation of a uniform shell. The diffusion does not occur until the Pt deposited at the corner has reached a threshold thickness. At a high concentration of the precursor, self-nucleation takes place and the Pt clusters then randomly attach to the surface of a seed for the formation of a non-uniform shell. These atomistic insights offer a general guideline for the rational synthesis of nanocrystals with diverse compositions, structures, shapes, and related properties.

Hepatocellular carcinoma (HCC) is a deadly form of liver malignancy with limited treatment options. Amplification and/or overexpression of c-MYC is one of the most frequent genetic events in human HCC. The mammalian target of Rapamycin Complex 1 (mTORC1) is a major functional axis regulating various aspects of cellular growth and metabolism. Recently, we demonstrated that mTORC1 is necessary for c-Myc driven hepatocarcinogenesis as well as for HCC cell growth in vitro. Among the pivotal downstream effectors of mTORC1, upregulation of Fatty Acid Synthase (FASN) and its mediated de novo lipogenesis is a hallmark of human HCC. Here, we investigated the importance of FASN on c-Myc-dependent hepatocarcinogenesis using in vitro and in vivo approaches. In mouse and human HCC cells, we found that FASN suppression by either gene silencing or soluble inhibitors more effectively suppressed proliferation and induced apoptosis in the presence of high c-MYC expression. In c-Myc/Myeloid cell leukemia 1 (MCL1) mouse liver tumor lesions, FASN expression was markedly upregulated. Most importantly, genetic ablation of Fasn profoundly delayed (without abolishing) c-Myc/MCL1 induced HCC formation. Liver tumors developing in c-Myc/MCL1 mice depleted of Fasn showed a reduction in proliferation and an increase in apoptosis when compared with corresponding lesions from c-Myc/MCL1 mice with an intact Fasn gene. In human HCC samples, a significant correlation between the levels of c-MYC transcriptional activity and the expression of FASN mRNA was detected. Altogether, our study indicates that FASN is an important effector downstream of mTORC1 in c-MYC induced HCC. Targeting FASN may be helpful for the treatment of human HCC, at least in the tumor subset displaying c-MYC amplification or activation.

The arthropod-specific juvenile hormone (JH) controls numerous essential functions. Its involvement in gene activation is known to be mediated by the transcription factor Methoprene-tolerant (Met), which turns on JH-controlled genes by directly binding to E-box-like motifs in their regulatory regions. However, it remains unclear how JH represses genes. We used the Aedes aegypti female mosquito, in which JH is necessary for reproductive maturation, to show that a repressor, Hairy, is required for the gene-repressive action of JH and Met. The RNA interference (RNAi) screen for Met and Hairy in the Aedes female fat body revealed a large cohort of Met- and Hairy-corepressed genes. Analysis of selected genes from this cohort demonstrated that they are repressed by JH, but RNAi of either Met or Hairy renders JH ineffective in repressing these genes in an in vitro fat-body culture assay. Moreover, this JH action was prevented by the addition of the translational inhibitor cycloheximide (CHX) to the culture, indicating the existence of an indirect regulatory hierarchy. The lack of Hairy protein in the CHX-treated tissue was verified using immunoblot analysis, and the upstream regions of Met/Hairy-corepressed genes were shown to contain common binding motifs that interact with Hairy. Groucho (gro) RNAi silencing phenocopied the effect of Hairy RNAi knockdown, indicating that it is involved in the JH/Met/Hairy hierarchy. Finally, the requirement of Hairy and Gro for gene repression was confirmed in a cell transfection assay. Thus, our study has established that Hairy and its cofactor Gro mediate the repressive function of JH and Met.