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1.  Tamponade in surgery for retinal detachment associated with proliferative vitreoretinopathy 
Retinal detachment (RD) with proliferative vitreoretinopathy (PVR) often requires surgery to restore normal anatomy and to stabilize or improve vision. PVR usually occurs in association with recurrent RD (that is, after initial retinal re-attachment surgery) but occasionally may be associated with primary RD. Either way, a tamponade agent (gas or silicone oil) is needed during surgery to reduce the rate of postoperative recurrent RD.
The objective of this review was to assess the relative safety and effectiveness of various tamponade agents used with surgery for retinal detachment (RD) complicated by proliferative vitreoretinopathy (PVR).
Search methods
We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 5), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2013), EMBASE (January 1980 to June 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to June 2013), the metaRegister of Controlled Trials (mRCT) (, ( and the WHO International Clinical Trials Registry Platform (ICTRP) ( We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 26 June 2013.
Selection criteria
We included randomized controlled trials (RCTs) of participants undergoing surgery for RD associated with PVR that compared various tamponade agents.
Data collection and analysis
Two review authors screened the search results independently. We used the standard methodological procedures expected by The Cochrane Collaboration.
PMCID: PMC3990035  PMID: 24532038
Fluorocarbons [*administration & dosage]; Randomized Controlled Trials as Topic; Recurrence [prevention & control]; Retinal Detachment [etiology; prevention & control; *therapy]; Silicone Oils [*administration & dosage]; Sulfur Hexafluoride [*administration & dosage]; Vitreoretinopathy, Proliferative [*complications]; Humans
2.  UBE3C Promotes Growth and Metastasis of Renal Cell Carcinoma via Activating Wnt/β-Catenin Pathway 
PLoS ONE  2015;10(2):e0115622.
Renal cell carcinoma (RCC) is the most common primary malignancy of the kidney and one of the most lethal genitourinary malignancies. Clear-cell renal cell carcinoma (ccRCC) has an extremely poor prognosis because of a high potential for tumor growth, vascular invasion, metastasis and recurrence. Unfortunately, the mechanism of RCC growth and metastasis is not well understood. In this report, we for the first time demonstrated ubiquitin protein ligase E3C (UBE3C) as a driving factor for RCC growth and metastasis. UBE3C expression was increased in ccRCC tissues compared with adjacent normal tissues. ccRCC patients with high UBE3C protein expression in tumors were associated with significantly worse postoperative survival. Knockdown of UBE3C expression in ACHN cells inhibited cell proliferation, migrations and invasiveness in vitro while overexpression of UBE3C in 786-O cells exerted the opposite effects. UBE3C up-regulated β-catenin protein levels and promoted β-catenin nuclear accumulation, leading to the activation of the Wnt/β-catenin signal pathway in RCC cells. Collectively, these observations suggest that UBE3C plays an important role in RCC development and progression, and UBE3C may be a novel target for prevention and treatment of ccRCC.
PMCID: PMC4319909  PMID: 25658088
3.  Effects of transcutaneous electrical nerve stimulation on pain in patients with spinal cord injury: a randomized controlled trial 
[Purpose] To investigate the effects of transcutaneous electrical nerve stimulation (TENS) on pain in patients with spinal cord injury. [Subjects and Methods] Fifty-two spinal cord injury patients with central pain were randomly allocated into two groups TENS and control with 26 subjects per group. The patients in TENS and control groups were treated with TENS and sham TENS for 20 min (three times a week) for 12 consecutive weeks, respectively. The two group’s pain was assessed using visual analog scale (VAS) and the McGill Pain Questionnaire (including pain rating index-total, pain rating index-affective, pain rating index-sensory, present pain intensity, and number of words chosen) before and after the treatment. [Results] After the intervention, we found significant differences in VAS, pain rating index-total, pain rating index-affective, pain rating index-sensory, present pain intensity, and number of words chosen between the TENS group and the control group. [Conclusion] Our results suggest that TENS effectively decreases pain in patients with spinal cord injury.
PMCID: PMC4305569  PMID: 25642029
Transcutaneous electrical nerve stimulation; Pain; Spinal cord injury
4.  Topical corticosteroids as adjunctive therapy for bacterial keratitis 
Bacterial keratitis is a serious ocular infectious disease that can lead to severe visual disability. Risk factors for bacterial corneal infection include contact lens wear, ocular surface disease, corneal trauma, and previous ocular or eyelid surgery. Topical antibiotics constitute the mainstay of treatment in cases of bacterial keratitis, whereas the use of topical corticosteroids as an adjunctive therapy to antibiotics remains controversial. Topical corticosteroids are usually used to control inflammation using the smallest amount of the drug. Their use requires optimal timing, concomitant antibiotics, and careful follow-up.
The objective of the review was to assess the effectiveness and safety of corticosteroids as adjunctive therapy for bacterial keratitis. Secondary objectives included evaluation of health economic outcomes and quality of life outcomes.
Search methods
We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 6), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to July 2014), EMBASE (January 1980 to July 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to July 2014), the metaRegister of Controlled Trials (mRCT) (, ( and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) ( We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 14 July 2014. We also searched the Science Citation Index to identify additional studies that had cited the only trial included in the original version of this review, reference lists of included trials, earlier reviews, and the American Academy of Ophthalmology guidelines. We also contacted experts to identify any unpublished and ongoing randomized trials.
Selection criteria
We included randomized controlled trials (RCTs) that had evaluated adjunctive therapy with topical corticosteroids in people with bacterial keratitis who were being treated with antibiotics.
Data collection and analysis
We used the standard methodological procedures expected by The Cochrane Collaboration.
Main results
We found four RCTs that met the inclusion criteria of this review. The total number of included participants was 611 (612 eyes), ranging from 30 to 500 participants per trial. One trial was included in the previous version of the review, and we identified three additional trials through the updated searches in July 2014. One of the three smaller trials was a pilot study of the largest study: the Steroids for Corneal Ulcers Trial (SCUT). All trials compared the treatment of bacterial keratitis with topical corticosteroid and without topical corticosteroid and had follow-up periods ranging from two months to one year. These trials were conducted in the USA, Canada, India, and South Africa.
All trials reported data on visual acuity ranging from three weeks to one year, and none of them found any important difference between the corticosteroid group and the control group. The pilot study of the SCUT reported that time to re-epithelialization in the steroid group was 53% slower than the placebo group after adjusting for baseline epithelial defect size (hazard ratio (HR) 0.47; 95% confidence interval (CI) 0.23 to 0.94). However, the SCUT did not find any important difference in time to re-epithelialization (HR 0.92; 95% CI 0.76 to 1.11). For adverse events, none of the three small trials found any important difference between the two treatment groups. The investigators of the largest trial reported that more patients in the control group developed intraocular pressure (IOP) elevation (risk ratio (RR) 0.20; 95% CI 0.04 to 0.90). One trial reported quality of life and concluded that there was no difference between the two groups (data not available). We did not find any reports regarding economic outcomes.
Although the four trials were generally of good methodological design, all trials had considerable losses to follow-up (10% or more) in the final analyses. Further, three of the four trials were underpowered to detect treatment effect differences between groups and inconsistency in outcome measurements precluded meta-analyses for most outcomes relevant to this review.
Authors’ conclusions
There is inadequate evidence as to the effectiveness and safety of adjunctive topical corticosteroids compared with no topical corticosteroids in improving visual acuity, infiltrate/scar size, or adverse events among participants with bacterial keratitis. Current evidence does not support a strong effect of corticosteroid, but may be due to insufficient power to detect a treatment effect.
PMCID: PMC4269217  PMID: 25321340
Adrenal Cortex Hormones [*therapeutic use]; Chemotherapy, Adjuvant [methods]; Eye Infections, Bacterial [*drug therapy]; Keratitis [*drug therapy; microbiology]; Humans
5.  The relationship between glycemic variability and diabetic peripheral neuropathy in type 2 diabetes with well-controlled HbA1c 
Diabetic peripheral neuropathy (DPN) is one of the most common microvascular complications of diabetes. Glycemic variability could be an independent risk factor for diabetes complications in addition to average glucose. Type 2 diabetes with well-controlled glycosylated hemoglobin A1c (HbA1c) may have different terms of glycemic variability and vascular complication consequences. The aim of the study is to investigate the relationship between glycemic variability and DPN in type 2 diabetes with well-controlled HbA1c (HbA1c < 7.0%).
45 type 2 diabetes with well-controlled HbA1c(HbA1c < 7.0%) and with DPN (DM/DPN group) were recruited in the study, and 45 type 2 diabetes with well-controlled HbA1c and without DPN (DM/–DPN group) were set as controls. The two groups were also matched for age and diabetic duration. Blood pressure, body mass index(BMI), insulin sensitivity index (Matsuda index, ISI), total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDLC), and low density lipoprotein cholesterol (LDLC) were tested in the two groups. And all patients were monitored using the continuous glucose monitoring (CGM) system for consecutive 72 hours. The multiple parameters of glycemic variability included the standard deviation of blood glucose (SDBG), mean of daily differences (MODD) and mean amplitude of glycemic excursions (MAGE).
The DM/DPN group had a greater SDBG, MODD and MAGE, when compared to the DM/–DPN group (p < 0.05). BMI, TC, and LDLC of DM/DPN group were lower than those of DM/–DPN group (p < 0.05). The patients with hypoglycemia were comparable between the two groups (p > 0.05). Univariate analysis showed DPN was closely associated with BMI (OR 0.82, CI 0.72–0.94, p = 0.005), TC (OR 0.63, CI 0.42–0.93, p = 0.02), LDLC (OR 0.4, CI 0.20–0.80, p = 0.009), SDBG (OR 2.95, CI 1.55–5.61, p = 0.001), MODD (OR 4.38, CI 1.48–12.93, p = 0.008), MAGE (OR 2.18, CI 1.47–3.24, p < 0.001). Multivariate logistic regression analysis showed that MAGE (OR 2.05, CI 1.36–3.09, p = 0.001) and BMI (OR 0.85, CI 0.73–0.99, p = 0.033) were significantly correlating with DPN. Glycemic variability, evaluated by MAGE, was the most significantly independent risk factor for DPN.
There was a close relationship between glycemic variability evaluated by MAGE and DPN in type 2 diabetes with well-controlled HbA1c.
PMCID: PMC4272789  PMID: 25530811
Glycemic variability; Continuous glucose monitoring; Diabetic peripheral neuropathy; Type 2 diabetes
6.  A Hypothetical Model of Crossing Bombyx mori Nucleopolyhedrovirus through Its Host Midgut Physical Barrier 
PLoS ONE  2014;9(12):e115032.
Bombyx mori nucleopolyhedrovirus (BmNPV) is a primary pathogen of silkworm (B. mori) that causes severe economic losses each year. However, the molecular mechanisms of silkworm-BmNPV interactions, especially the silkworm proteins that can interact with the virus, are still largely unknown. In this study, the total and membrane proteins of silkworm midguts were displayed using one- and two-dimensional electrophoresis. A virus overlay assay was used to detect B. mori proteins that specifically bind to BmNPV particles. Twelve proteins were located and identified using mass spectrometry, and the different expression of the corresponding genes in BmNPV susceptible and resistant silkworm strains also indicated their involvement in BmNPV infection. The 12 proteins are grouped based on their potential roles in viral infection, for example, endocytosis, intracellular transportation, and host responses. Based on these results, we hypothesize the following: I) vacuolar ATP synthase catalytic subunit A and subunit B may be implicated in the process of the membrane fusion of virus and the release of the nucleocapsid into cytoplasm; II) actin, enolase and phosphoglycerate kinase are cytoskeleton associated proteins and may play an important role in BmNPV intracellular transportation; III) mitochondrial prohibitin complex protein 2, ganglioside-induced differentiation-associated protein, calreticulin, regucalcin-like isoform X1 and 60 kDa heat shock protein are involved in cell apoptosis regulation during BmNPV infection in larvae midguts; IV) ribosomal P0 may be associated with BmNPV infection by regulating gene expression of BmNPV; V) arginine kinase has a role in the antiviral activities against BmNPV. Our work should prove informative by providing multiple protein targets and a novel direction to investigate the molecular mechanisms of the interactions between silkworms and BmNPV.
PMCID: PMC4264868  PMID: 25502928
7.  Endothelial keratoplasty versus penetrating keratoplasty for Fuchs endothelial dystrophy 
Fuchs endothelial dystrophy (FED) is a condition in which there is premature degeneration of corneal endothelial cells. When the number of endothelial cells is reduced to a significant degree, fluid begins to accumulate within the cornea. As a result, the cornea loses its transparency and the individual suffers a reduction in vision. The only successful surgical treatment for this condition is replacement of part or all of the cornea with healthy tissue from a donor. The established procedure, penetrating keratoplasty (PKP), has been used for many years and its safety and efficacy are well known. Endothelial keratoplasty (EK) techniques are relatively new surgical procedures and their safety and efficacy relative to PKP are uncertain.
The objective of this review was to compare the benefits and complications related to two surgical methods (EK and PKP) of replacing the diseased endothelial layer of the cornea with a healthy layer in people with FED.
Search methods
We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2014, Issue 1), MEDLINE (January 1950 to January 2014), EMBASE (January 1980 to January 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to January 2014), the metaRegister of Controlled Trials (mRCT) ( and ( There were no date or language restrictions in the electronic searches for trials. The electronic databases were last searched on 27 January 2014.
Selection criteria
We included all randomised controlled trials (RCTs) comparing EK versus PKP for people (of any age and gender) who had been clinically diagnosed with FED.
Data collection and analysis
Two authors independently screened the search results, assessed trial quality and extracted data using the standard methodological procedures expected by The Cochrane Collaboration.
Main results
We included three RCTs that enrolled a total of 139 eyes of 136 participants and analysed 123 (88%) eyes. Two RCTs randomised eyes into either the endothelial keratoplasty (EK) group or penetrating keratoplasty (PKP) group and one RCT randomised eyes into either the femtosecond laser-assisted endothelial keratoplasty (FLEK) group or PKP group. The RCTs comparing EK with PKP did not show any significant differences between procedures with respect to best corrected visual acuity (BCVA) at two years (mean difference (MD) 0.14 logMAR; 95% confidence interval (CI) −0.08 to 0.36; P = 0.23) or at one year (MD 0.09 logMAR; 95% CI −0.05 to 0.23; P = 0.22), whereas the trial comparing FLEK with PKP showed significantly better BCVA after PKP (MD 0.20 logMAR; 95% CI 0.10 to 0.30; P = 0.0001). Only one RCT reported on irregular astigmatism (higher-order aberration), which was less with EK than PKP (MD −1.20 µm; 95% CI −1.53 to −0.87; P < 0.001). Only one RCT reported on endothelial cell counts (lower after FLEK than PKP: MD −969 cells/mm²; 95% CI −1161 to −777; P < 0.001), primary graft failure (higher after FLEK than PKP: RR 7.76; 95% CI 0.41 to 145.22; P = 0.10), and graft rejection (more after FLEK than PKP: RR 1.11; 95% CI 0.07 to 17.12; P = 0.94). Only one RCT reported that 27.8% of participants had graft dislocation, 2.8% had epithelial ingrowth and postoperative pupillary block, and 13.9% had intraocular pressure (IOP)-related problems in the FLEK group compared with the PKP group, in whom 10% had suture-related problems, 5% had wound dehiscence and 10% had suture revision to correct astigmatism. Overall, the adverse events in the FLEK group appeared to be more frequent than in the PKP group. No trials reported information about quality of life or economic data. The overall methodological quality of the three trials was not satisfactory as most did not perform allocation concealment or masking of participants and outcome assessors, and all trials had a small sample size.
Authors’ conclusions
The rapid growth of endothelial keratoplasty as the treatment of choice for FED is based upon the belief that visual recovery is more rapid, surgically induced astigmatism (regular and irregular) is less and rates of transplant rejection are lower with EK. This change in practice also assumes that the rates of long term transplant survival are equal for the two procedures. The practical differences between the surgical procedures mean that visual recovery is inherently more rapid following EK, but this review found no strong evidence from RCTs of any difference in the final visual outcome between EK and PKP for people with FED. This review also found that higher order aberrations are fewer following EK but endothelial cell loss is greater following EK. The RCTs that we included employed different EK techniques, which may have a bearing on these findings. EK procedures have evolved over the years and can be performed using different techniques, for example deep lamellar endothelial keratoplasty, Descemets stripping endothelial keratoplasty (DSEK), Descemets stripping automated endothelial keratoplasty (DSAEK), femtosecond laser-assisted endothelial keratoplasty and Descemet membrane endothelial keratoplasty (DMEK). More RCTs are needed to compare PKP with commonly performed EK procedures such as DSEK, DSAEK and DMEK in order to determine the answers to two key questions, whether there is any difference in the final visual outcome between these techniques and whether there are differences in the rates of graft survival in the long term?
PMCID: PMC4260402  PMID: 24526345
8.  Vitamin A and fish oils for retinitis pigmentosa 
Retinitis pigmentosa (RP) comprises a group of hereditary eye diseases characterized by progressive degeneration of retinal photoreceptors. It results in severe visual loss that may lead to legal blindness. Symptoms may become manifest during childhood or adulthood, and include poor night vision (nyctalopia) and constriction of peripheral vision (visual field loss). This field loss is progressive and usually does not reduce central vision until late in the disease course. The worldwide prevalence of RP is one in 4000, with 100,000 patients affected in the USA. At this time, there is no proven therapy for RP.
The objective of this review was to synthesize the best available evidence regarding the effectiveness and safety of vitamin A and fish oils (docosahexaenoic acid (DHA)) in preventing the progression of RP.
Search methods
We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2013, Issue 7),Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to August 2013), EMBASE (January 1980 to August 2013), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to August 2013), the meta Register of Controlled Trials (mRCT) (, ( and the WHO International Clinical Trials Registry Platform (ICTRP) ( did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 20 August 2013.
Selection criteria
We included randomized controlled trials (RCTs) evaluating the effectiveness of vitamin A, fish oils (DHA) or both, as a treatment for RP. We excluded cluster-randomized trials and cross-over trials.
Data collection and analysis
We pre-specified the following outcomes: mean change from baseline visual field, mean change from baseline electroretinogram (ERG) amplitudes, and anatomic changes as measured by optical coherence tomography (OCT), at one year; as well as mean change in visual acuity at five-year follow-up. Two authors independently evaluated risk of bias for all included trials and extracted data from the publications. We also contacted study investigators for further information on trials with publications that did not report outcomes on all randomized patients.
Main results
We reviewed 394 titles and abstracts and nine records and included three RCTs that met our eligibility criteria. The three trials included a total of 866 participants aged four to 55 years with RP of all forms of genetic predisposition. One trial evaluated the effect of vitamin A alone, one trial evaluated DHA alone, and a third trial evaluated DHA and vitamin A versus vitamin A alone. None of the RCTs had protocols available, so selective reporting bias was unclear for all. In addition, one trial did not specify the method for random sequence generation, so there was an unclear risk of bias. All three trials were graded as low risk of bias for all other domains. We did not perform meta-analysis due to clinical heterogeneity of participants and interventions across the included trials.
The primary outcome, mean change of visual field from baseline at one year, was not reported in any of the studies. No toxicity or adverse events were reported in these three trials. No trial reported a statistically significant benefit of vitamin supplementation on the progression of visual field loss or visual acuity loss. Two of the three trials reported statistically significant differences in ERG amplitudes among some subgroups of participants, but these results have not been replicated or substantiated by findings in any of the other trials.
Authors’ conclusions
Based on the results of three RCTs, there is no clear evidence for benefit of treatment with vitamin A and/or DHA for people with RP, in terms of the mean change in visual field and ERG amplitudes at one year and the mean change in visual acuity at five years follow-up. In future RCTs, since some of the studies in this review included unplanned subgroup analysis that suggested differential effects based on previous vitamin A exposure, investigators should consider examining this issue. Future trials should take into account the changes observed in ERG amplitudes and other outcome measures from trials included in this review, in addition to previous cohort studies, when calculating sample sizes to assure adequate power to detect clinically and statistically meaningful difference between treatment arms.
PMCID: PMC4259575  PMID: 24357340
9.  Spectacle correction versus no spectacles for prevention of strabismus in hyperopic children 
Hyperopia (far-sightedness) in infancy requires accommodative effort to bring images into focus. Prolonged accommodative effort has been associated with an increased risk of strabismus (eye misalignment). Strabismus makes it difficult for the eyes to work together and may result in symptoms of asthenopia (eye strain) and intermittent diplopia (double vision), and makes near work tasks difficult to complete. Untreated strabismus may result in the development of amblyopia (lazy eye). The prescription of spectacles to correct hyperopic refractive error is believed to prevent the development of strabismus.
To assess the effectiveness of prescription spectacles compared with no intervention for the prevention of strabismus in infants and children with hyperopia.
Search methods
We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 4), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to April 2014), EMBASE (January 1980 to April 2014), PubMed (1966 to April 2014), the metaRegister of Controlled Trials (mRCT) (, ( and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) ( We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 3 April 2014. We also searched the Science Citation Index database in September 2013.
Selection criteria
We included randomized controlled trials and quasi-randomized trials investigating the assignment to spectacle intervention or no treatment for children with hyperopia. The definition of hyperopia remains subjective, but we required it to be at least greater than +2.00 diopters (D) of hyperopia.
Data collection and analysis
Two review authors independently extracted data using the standard methodologic procedures expected by The Cochrane Collaboration. One review author entered data into Review Manager and a second review author verified the data entered. The two review authors resolved discrepancies at all stages of the review process.
Main results
We identified three randomized controlled trials (855 children enrolled) in this review. These trials were all conducted in the UK with follow-up periods ranging from one to 3.5 years. We judged the included studies to be at high risk of bias, due to use of quasi-random methods for assigning children to treatment, no masking of outcomes assessors, and high proportions of drop-outs. None of the three trials accounted for missing data and analyses were limited to the available-case data (674 (79%) of 855 children enrolled for the primary outcome). These factors impair our ability to assess the effectiveness of treatment.
Analyses incorporating the three trials we identified in this review (674 children) suggested the effect of spectacle correction initiated prior to the age of one year in hyperopic children between three and four years of age is uncertain with respect to preventing strabismus (risk ratio (RR) 0.71; 95% confidence interval (CI) 0.44 to 1.15). Based on a meta-analysis of three trials (664 children), the risk of having visual acuity worse than 20/30 at three years of age was also uncertain for children with spectacles compared with those without spectacle correction irrespective of compliance (RR 0.87; 95% CI 0.60 to 1.26).
Emmetropization was reported in two trials: one trial suggested that spectacles impede emmetropization, and the second trial reported no difference in the rate of refractive error change.
Authors’ conclusions
Although children who were allocated to the spectacle group were less likely to develop strabismus and less likely to have visual acuity worse than 20/30 children allocated to no spectacles, these effects may have been chance findings, or due to bias. Due to the high risk of bias and poor reporting of included trials, the true effect of spectacle correction for hyperopia on strabismus is still uncertain.
PMCID: PMC4259577  PMID: 25133974
10.  A CRISPR/Cas9 toolkit for multiplex genome editing in plants 
BMC Plant Biology  2014;14(1):327.
To accelerate the application of the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/ CRISPR-associated protein 9) system to a variety of plant species, a toolkit with additional plant selectable markers, more gRNA modules, and easier methods for the assembly of one or more gRNA expression cassettes is required.
We developed a CRISPR/Cas9 binary vector set based on the pGreen or pCAMBIA backbone, as well as a gRNA (guide RNA) module vector set, as a toolkit for multiplex genome editing in plants. This toolkit requires no restriction enzymes besides BsaI to generate final constructs harboring maize-codon optimized Cas9 and one or more gRNAs with high efficiency in as little as one cloning step. The toolkit was validated using maize protoplasts, transgenic maize lines, and transgenic Arabidopsis lines and was shown to exhibit high efficiency and specificity. More importantly, using this toolkit, targeted mutations of three Arabidopsis genes were detected in transgenic seedlings of the T1 generation. Moreover, the multiple-gene mutations could be inherited by the next generation.
We developed a toolkit that facilitates transient or stable expression of the CRISPR/Cas9 system in a variety of plant species, which will facilitate plant research, as it enables high efficiency generation of mutants bearing multiple gene mutations.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-014-0327-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4262988  PMID: 25432517
CRISPR/Cas9; Genome editing; Multiple gene mutations; Assembly of multiple gRNAs
11.  Berberine Improves Kidney Function in Diabetic Mice via AMPK Activation 
PLoS ONE  2014;9(11):e113398.
Diabetic nephropathy is a major cause of morbidity and mortality in diabetic patients. Effective therapies to prevent the development of this disease are required. Berberine (BBR) has several preventive effects on diabetes and its complications. However, the molecular mechanism of BBR on kidney function in diabetes is not well defined. Here, we reported that activation of AMP-activated protein kinase (AMPK) is required for BBR-induced improvement of kidney function in vivo. AMPK phosphorylation and activity, productions of reactive oxygen species (ROS), kidney function including serum blood urea nitrogen (BUN), creatinine clearance (Ccr), and urinary protein excretion, morphology of glomerulus were determined in vitro or in vivo. Exposure of cultured human glomerulus mesangial cells (HGMCs) to BBR time- or dose-dependently activates AMPK by increasing the thr172 phosphorylation and its activities. Inhibition of LKB1 by siRNA or mutant abolished BBR-induced AMPK activation. Incubation of cells with high glucose (HG, 30 mM) markedly induced the oxidative stress of HGMCs, which were abolished by 5-aminoimidazole-4-carboxamide ribonucleoside, AMPK gene overexpression or BBR. Importantly, the effects induced by BBR were bypassed by AMPK siRNA transfection in HG-treated HGMCs. In animal studies, streptozotocin-induced hyperglycemia dramatically promoted glomerulosclerosis and impaired kidney function by increasing serum BUN, urinary protein excretion, and decreasing Ccr, as well as increased oxidative stress. Administration of BBR remarkably improved kidney function in wildtype mice but not in AMPKα2-deficient mice. We conclude that AMPK activation is required for BBR to improve kidney function in diabetic mice.
PMCID: PMC4237447  PMID: 25409232
12.  N-acetylcysteine attenuates reactive-oxygen-species-mediated endoplasmic reticulum stress during liver ischemia-reperfusion injury 
World Journal of Gastroenterology : WJG  2014;20(41):15289-15298.
AIM: To investigate the effects of N-acetylcysteine (NAC) on endoplasmic reticulum (ER) stress and tissue injury during liver ischemia reperfusion injury (IRI).
METHODS: Mice were injected with NAC (300 mg/kg) intraperitoneally 2 h before ischemia. Real-time polymerase chain reaction and western blotting determined ER stress molecules (GRP78, ATF4 and CHOP). To analyze the role of NAC in reactive oxygen species (ROS)-mediated ER stress and apoptosis, lactate dehydrogenase (LDH) was examined in cultured hepatocytes treated by H2O2 or thapsigargin (TG).
RESULTS: NAC treatment significantly reduced the level of ROS and attenuated ROS-induced liver injury after IRI, based on glutathione, malondialdehyde, serum alanine aminotransferase levels, and histopathology. ROS-mediated ER stress was significantly inhibited in NAC-treated mice. In addition, NAC treatment significantly reduced caspase-3 activity and apoptosis after reperfusion, which correlated with the protein expression of Bcl-2 and Bcl-xl. Similarly, NAC treatment significantly inhibited LDH release from hepatocytes treated by H2O2 or TG.
CONCLUSION: This study provides new evidence for the protective effects of NAC treatment on hepatocytes during IRI. Through inhibition of ROS-mediated ER stress, NAC may be critical to inhibit the ER-stress-related apoptosis pathway.
PMCID: PMC4223262  PMID: 25386077
N-acetylcysteine; Reactive oxygen species; Endoplasmic reticulum stress; Apoptosis; Liver ischemia-reperfusion
13.  Identification of novel multitargeted PPARα/γ/δ pan agonists by core hopping of rosiglitazone 
The thiazolidinedione class peroxisome proliferator-activated receptor gamma (PPARγ) agonists are restricted in clinical use as antidiabetic agents because of side effects such as edema, weight gain, and heart failure. The single and selective agonism of PPARγ is the main cause of these side effects. Multitargeted PPARα/γ/δ pan agonist development is the hot topic in the antidiabetic drug research field. In order to identify PPARα/γ/δ pan agonists, a compound database was established by core hopping of rosiglitazone, which was then docked into a PPARα/γ/δ active site to screen out a number of candidate compounds with a higher docking score and better interaction with the active site. Further, absorption, distribution, metabolism, excretion, and toxicity prediction was done to give eight compounds. Molecular dynamics simulation of the representative Cpd#1 showed more favorable binding conformation for PPARs receptor than the original ligand. Cpd#1 could act as a PPARα/γ/δ pan agonist for novel antidiabetic drug research.
PMCID: PMC4232041  PMID: 25422585
PPARs; diabetes; docking; molecular dynamics simulation; ADMET
14.  Analysis of COQ2 gene in multiple system atrophy 
Loss of function COQ2 mutations results in primary CoQ10 deficiency. Recently, recessive mutations of the COQ2 gene have been identified in two unrelated Japanese families with multiple system atrophy (MSA). It has also been proposed that specific heterozygous variants in the COQ2 gene may confer susceptibility to sporadic MSA. To assess the frequency of COQ2 variants in patients with MSA, we sequenced the entire coding region and investigated all exonic copy number variants of the COQ2 gene in 97 pathologically-confirmed and 58 clinically-diagnosed MSA patients from the United States.
We did not find any homozygous or compound heterozygous pathogenic COQ2 mutations including deletion or multiplication within our series of MSA patients. In two patients, we identified two heterozygous COQ2 variants (p.S54W and c.403 + 10G > T) of unknown significance, which were not observed in 360 control subjects. We also identified one heterozygous carrier of a known loss of function p.S146N substitution in a severe MSA-C pathologically-confirmed patient.
The COQ2 p.S146N substitution has been previously reported as a pathogenic mutation in primary CoQ10 deficiency (including infantile multisystem disorder) in a recessive manner. This variant is the third primary CoQ10 deficiency mutation observed in an MSA case (p.R387X and p.R197H). Therefore it is possible that in the heterozygous state it may increase susceptibility to MSA. Further studies, including reassessing family history in patients of primary CoQ10 deficiency for the possible occurrence of MSA, are now warranted to resolve the role of COQ2 variation in MSA.
Electronic supplementary material
The online version of this article (doi:10.1186/1750-1326-9-44) contains supplementary material, which is available to authorized users.
PMCID: PMC4233093  PMID: 25373618
COQ2; Multiple system atrophy; Genetics; CoQ10 deficiency
16.  Decreased SIRT3 in aged human mesenchymal stromal/stem cells increases cellular susceptibility to oxidative stress 
Sirtuin3 (SIRT3) is an important member of the sirtuin family of protein deacetylases that is localized to mitochondria and linked to lifespan extension in organisms ranging from yeast to humans. As aged cells have less regenerative capacity and are more susceptible to oxidative stress, we investigated the effect of ageing on SIRT3 levels and its correlation with antioxidant enzyme activities. Here, we show that severe oxidative stress reduces SIRT3 levels in young human mesenchymal stromal/stem cells (hMSCs). Overexpression of SIRT3 improved hMSCs resistance to the detrimental effects of oxidative stress. By activating manganese superoxide dismutase (MnSOD) and catalase (CAT), SIRT3 protects hMSCs from apoptosis under stress. SIRT3 expression, levels of MnSOD and CAT, as well as cell survival showed little difference in old versus young hMSCs under normal growth conditions, whereas older cells had a significantly reduced capacity to withstand oxidative stress compared to their younger counterparts. Expression of the short 28 kD SIRT3 isoform was higher, while the long 44 kD isoform expression was lower in young myocardial tissues compared with older ones. These results suggest that the active short isoform of SIRT3 protects hMSCs from oxidative injury by increasing the expression and activity of antioxidant enzymes. The expression of this short isoform decreases in cardiac tissue during ageing, leading to a reduced capacity for the heart to withstand oxidative stress.
PMCID: PMC4224562  PMID: 25210848
SIRT3; oxidative stress; ageing; mesenchymal stromal/stem cells; myocardium; antioxidants
17.  A Unique Evolution of the S2 Gene of Equine Infectious Anemia Virus in Hosts Correlated with Particular Infection Statuses 
Viruses  2014;6(11):4265-4279.
Equine infectious anemia virus (EIAV) is a member of the Lentivirus genus in the Retroviridae family that exhibits a genomic structure similar to that of HIV-1. The S2 accessory proteins play important roles in viral replication in vivo and in viral pathogenicity; however, studies on S2 evolution in vivo are limited. This study analyzed the evolutionary characteristics of the S2 gene of a pathogenic EIAV strain, EIAVLN40, in four experimentally infected horses. The results demonstrated that 14.7% (10 of 68 residues) of the stable amino acid mutations occurred longitudinally in S2 during a 150-day infection period. Further analysis revealed that six of the ten mutated residues were positively selected during the infection. Alignment and phylogenetic analyses showed that the S2 gene sequences of viruses isolated from the infected horses at the early stage of EIAVLN40 infection were highly homologous and similar to the vaccine-specific sequence. The S2 gene variants isolated from the febrile episodes and late phase of infection became homologous to the S2 gene sequence of the inoculating EIAVLN40 strain. Our results indicate that the S2 gene evolves in diversity and divergence in vivo in different stages of EIAV infection and that this evolution correlates with the pathogenicity of the virus.
PMCID: PMC4246221  PMID: 25390683
equine infectious anemia virus; EIAV; S2 gene; evolution; diversity
18.  Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism Is Not a Major Determining Factor in the Development of Sporadic Alzheimer Disease: Evidence from an Updated Meta-Analysis 
PLoS ONE  2014;9(10):e111406.
Angiotensin-converting enzyme gene (ACE) insertion/deletion (I/D) polymorphism have long been linked to sporadic Alzheimer disease (SAD), but the established data remained controversial. To clarify this inconsistency, a comprehensive meta-analysis was conducted. Through searching of Pubmed, Embase, Alzgene, China National Knowledge Infrastructure (CNKI) and manually searching relevant references, 53 independent studies from 48 articles were included, involving a total of 8153 cases and 14932 controls. The strength of association was assessed by using odds ratios (ORs) with 95% confidence intervals (CIs). Further stratified analyses and heterogeneity analyses were tested, as was publication bias. Overall, significant associations were revealed between I/D polymorphism and SAD risk using allelic comparison (OR = 1.09, 95%CI = 1.01–1.17, p = 0.030), homozygote comparison (OR = 1.17, 95%CI = 1.01–1.34, p = 0.030) and the dominant model (OR = 1.16, 95%CI = 1.04–1.29, p = 0.008), but they were not sufficiently robust to withstand the false-positive report probability (FPRP) analyses. Otherwise, in subgroup analyses restricted to the high quality studies, the large sample size studies and studies with population-based controls, no significant association was observed in any genetic models. In summary, the current meta-analysis suggested that the ACE I/D polymorphism is unlikely to be a major determining factor in the development of SAD.
PMCID: PMC4216072  PMID: 25360660
19.  Outcomes in Cochrane Systematic Reviews Addressing Four Common Eye Conditions: An Evaluation of Completeness and Comparability 
PLoS ONE  2014;9(10):e109400.
Choice of outcomes is critical for clinical trialists and systematic reviewers. It is currently unclear how systematic reviewers choose and pre-specify outcomes for systematic reviews. Our objective was to assess the completeness of pre-specification and comparability of outcomes in all Cochrane reviews addressing four common eye conditions.
We examined protocols for all Cochrane reviews as of June 2013 that addressed glaucoma, cataract, age-related macular degeneration (AMD), and diabetic retinopathy (DR). We assessed completeness and comparability for each outcome that was named in ≥25% of protocols on those topics. We defined a completely-specified outcome as including information about five elements: domain, specific measurement, specific metric, method of aggregation, and time-points. For each domain, we assessed comparability in how individual elements were specified across protocols.
We identified 57 protocols addressing glaucoma (22), cataract (16), AMD (15), and DR (4). We assessed completeness and comparability for five outcome domains: quality-of-life, visual acuity, intraocular pressure, disease progression, and contrast sensitivity. Overall, these five outcome domains appeared 145 times (instances). Only 15/145 instances (10.3%) were completely specified (all five elements) (median = three elements per outcome). Primary outcomes were more completely specified than non-primary (median = four versus two elements). Quality-of-life was least completely specified (median = one element). Due to largely incomplete outcome pre-specification, conclusive assessment of comparability in outcome usage across the various protocols per condition was not possible.
Outcome pre-specification was largely incomplete; we encourage systematic reviewers to consider all five elements. This will indicate the importance of complete specification to clinical trialists, on whose work systematic reviewers depend, and will indirectly encourage comparable outcome choice to reviewers undertaking related research questions. Complete pre-specification could improve efficiency and reduce bias in data abstraction and analysis during a systematic review. Ultimately, more completely specified and comparable outcomes could make systematic reviews more useful to decision-makers.
PMCID: PMC4199623  PMID: 25329377
20.  Down-regulated miR-22 as predictive biomarkers for prognosis of epithelial ovarian cancer 
Diagnostic Pathology  2014;9(1):178.
Recent studies have demonstrated that microRNA-22 (miR-22) was deregulated in many types of cancers and was involved in various cellular processes related to carcinogenesis. However, the clinical significance and prognostic value of miR-22 in epithelial ovarian cancer (EOC) haven’t been investigated.
109 pairs of fresh EOC tissue and matched adjacent normal tissue specimens were collected between May 2007 and March 2013. Real-time quantitative RT-PCR assay was performed to evaluate the expression levels of miR-22. The chi-square test was used to assess miR-22 expression with respect to clinicopathological parameters. The survival curves of the patients were determined using the Kaplan-Meier method and Cox regression, and the log-rank test was used for statistical evaluations.
miR-22 expression in EOC tissues was significantly lower than that in matched normal adjacent tissues (mean ± SD: 1.944 ± 1.026 vs. 4.981 ± 1.507, P < 0.0001). Low miR-22 expression level was correlated with FIGO stage (P = 0.006), tumor grade (P = 0.03), and lymph node metastases (P = 0.01). Kaplan-Meier analysis with the log-rank test indicated that low miR-22 expression had a significant impact on overall survival (44.4% vs. 64.5%; P = 0.005) and progression-free survival (23.5% vs. 52.6%; P = 0.004).
Our data demonstrated that the expression of miR-22 was downregulated in EOC, and associated with overall survival as well as progression-free survival, suggesting that miR-22 could serve as an efficient prognostic factor for EOC patients.
Virtual slides
The virtual slide(s) for this article can be found here:
PMCID: PMC4180346  PMID: 25257702
miR-22; Biomarkers; Prognosis; Epithelial ovarian cancer
21.  Expression and function of SIRT6 in muscle invasive urothelial carcinoma of the bladder 
SIRT6, a member of the class III histone deacetylase, has been shown to inhibit glycolysis and promote DNA double strand break repairs. Despite of its proposed tumor suppressor role, no significant differences in SIRT6 mRNA levels among normal bladder urothelium, non-muscle invasive, and muscle invasive urothelial carcinoma were noted in the two largest bladder cancer gene expression datasets available in OncomineTM. We therefore studied the expression and function of SIRT6 in muscle invasive urothelial carcinoma of the bladder. Immunohistochemistry studies of SIRT6 on radical cystectomy samples showed a dramatic decline of SIRT6 expression when bladder cancer progressed from T2 to T4. Functional study with bladder cancer cell lines confirmed its role in inhibiting glycolysis and cell proliferation. Reducing SIRT6 with siRNA, however, did not sensitize bladder cancer cells to drug induced DNA damage. The differential expression patterns of SIRT6 amongst different T stages of muscle invasive bladder cancers indicate less reliance on glycolysis when urothelial carcinoma invades deeper through the bladder and into the adjacent tissues.
PMCID: PMC4230126  PMID: 25400728
SIRT6; bladder cancer; glycolysis; metabolism
22.  Retrieval-balloon-assisted enterography for ERCP after Billroth II gastroenterostomy and Braun anastomosis 
World Journal of Gastroenterology : WJG  2014;20(31):10921-10926.
AIM: To describe an optimal route to the Braun anastomosis including the use of retrieval-balloon-assisted enterography.
METHODS: Patients who received a Billroth II gastroenterostomy (n = 109) and a Billroth II gastroenterostomy with Braun anastomosis (n = 20) between January 2009 and May 2013 were analyzed in this study. Endoscopic retrograde cholangiopancreatography (ERCP) was performed under fluoroscopic control using a total length of 120 cm oblique-viewing duodenoscope with a 3.7-mm diameter working channel. For this procedure, we used a triple-lumen retrieval balloon catheter in which a 0.035-inch guidewire could be inserted into the “open-channel” guidewire lumen while the balloon could be simultaneously injected and inflated through the other 2 lumens.
RESULTS: For the patients with Billroth II gastroenterostomy and Braun anastomosis, successful access to the papilla was gained in 17 patients (85%) and there was therapeutic success in 16 patients (80%). One patient had afferent loop perforation, but postoperative bleeding did not occur. For Billroth II gastroenterostomy, there was failure in accessing the papilla in 15 patients (13.8%). ERCP was unsuccessful because of tumor infiltration (6 patients), a long afferent loop (9 patients), and cannulation failure (4 patients). The papilla was successfully accessed in 94 patients (86.2%), and there was therapeutic success in 90 patients (82.6%). Afferent loop perforation did not occur in any of these patients. One patient had hemorrhage 2 h after ERCP, which was successfully managed with conservative treatment.
CONCLUSION: Retrieval-balloon-assisted enterography along an optimal route may improve the ERCP success rate after Billroth II gastroenterostomy and Braun anastomosis.
PMCID: PMC4138472  PMID: 25152595
Retrieval-balloon-assisted enterography; Billroth II gastroenterostomy; Braun anastomosis; Optimal enterography route; Gastrojejunal anastomosis; Efferent loop; Endoscopic retrograde cholangiopancreatography; Duodenoscope; Enterography success rate; Therapeutic success rate
23.  High performance current and spin diode of atomic carbon chain between transversely symmetric ribbon electrodes 
Scientific Reports  2014;4:6157.
We demonstrate that giant current and high spin rectification ratios can be achieved in atomic carbon chain devices connected between two symmetric ferromagnetic zigzag-graphene-nanoribbon electrodes. The spin dependent transport simulation is carried out by density functional theory combined with the non-equilibrium Green's function method. It is found that the transverse symmetries of the electronic wave functions in the nanoribbons and the carbon chain are critical to the spin transport modes. In the parallel magnetization configuration of two electrodes, pure spin current is observed in both linear and nonlinear regions. However, in the antiparallel configuration, the spin-up (down) current is prohibited under the positive (negative) voltage bias, which results in a spin rectification ratio of order 104. When edge carbon atoms are substituted with boron atoms to suppress the edge magnetization in one of the electrodes, we obtain a diode with current rectification ratio over 106.
PMCID: PMC4139955  PMID: 25142376
24.  Activated microglia contribute to neuronal apoptosis in Toxoplasmic encephalitis 
Parasites & Vectors  2014;7(1):372.
A plethora of evidence shows that activated microglia play a critical role in the pathogenesis of the central nervous system (CNS). Toxoplasmic encephalitis (TE) frequently occurs in HIV/AIDS patients. However, knowledge remains limited on the contributions of activated microglia to the pathogenesis of TE.
A murine model of reactivated encephalitis was generated in a latent infection with Toxoplasma gondii induced by cyclophosphamide. The neuronal apoptosis in the CNS and the profile of pro-inflammatory cytokines were assayed in both in vitro and in vivo experiments.
Microglial cells were found to be activated in the cortex and hippocampus in the brain tissues of mice. The in vivo expression of interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS) were up-regulated in TE mice, and accordingly, the neuronal apoptosis was significantly increased. The results were positively correlated with those of the in vitro experiments. Additionally,apoptosis of the mouse neuroblastoma type Neuro2a (N2a) remarkably increased when the N2a was co-cultured in transwell with microglial cells and Toxoplasma tachyzoites. Both in vivo and in vitro experiments showed that minocycline (a microglia inhibitor) treatment notably reduced microglial activation and neuronal apoptosis.
Activated microglia contribute to neuronal apoptosis in TE and inhibition of microglia activation might represent a novel therapeutic strategy of TE.
PMCID: PMC4143554  PMID: 25128410
Toxoplasmic encephalitis; Microglia; Neuronal apoptosis; Minocycline
25.  Acute acalculous cholecystitis immediately after gastric operation: Case report and literatures review 
World Journal of Gastroenterology : WJG  2014;20(30):10642-10650.
Acute acalculous cholecystitis (AAC) is a rare complication of gastric surgery. The most commonly accepted concepts regarding its pathogenesis are bile stasis, sepsis and ischemia, but it has not been well described how to identify and manage this disease in the early stage. We report three cases of AAC in elderly patients immediately after gastric surgery, which were treated with three different strategies. One patient died 42 d after emergency cholecystectomy, and the other two finally recovered through timely cholecystostomy and percutaneous transhepatic gallbladder drainage, respectively. These cases informed us of the value of early diagnosis and proper treatment for perioperative AAC after gastric surgery. We further reviewed reported cases of AAC immediately after gastric operation, which may expand our knowledge of this disease.
PMCID: PMC4130878  PMID: 25132787
Acute acalculous cholecystitis; Postoperative complication; Gastric surgery

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