Role of lung ornithine aminotransferase in idiopathic pulmonary fibrosis: regulation of mitochondrial ROS generation and TGF-ß1 activity.

Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung remodeling and the excessive accumulation of extracellular matrix (ECM) proteins. In a previous study, we found that the levels of ornithine aminotransferase (OAT), a principal enzyme in the proline metabolism pathway, were increased in the lungs of patients with IPF. However, the precise role played by OAT in the pathogenesis of IPF is not yet clear. The mechanism by which OAT affects fibrogenesis was assessed in vitro using OAT-overexpressing and OAT-knockdown lung fibroblasts. The therapeutic effects of OAT inhibition were assessed in the lungs of bleomycin-treated mice. OAT expression was increased in fibrotic areas, principally in interstitial fibroblasts, of lungs affected by IPF. OAT levels in the bronchoalveolar lavage fluid of IPF patients were inversely correlated with lung function. The survival rate was significantly lower in the group with an OAT level >75.659 ng/mL than in the group with an OAT level ≤75.659 ng/mL (HR, 29.53; p = 0.0008). OAT overexpression and knockdown increased and decreased ECM component production by lung fibroblasts, respectively. OAT knockdown also inhibited transforming growth factor-ß1 (TGF)-ß1 activity and TGF-ß1 pathway signaling. OAT overexpression increased the generation of mitochondrial reactive oxygen species (ROS) by activating proline dehydrogenase. The OAT inhibitor L-canaline significantly attenuated bleomycin-induced lung injury and fibrosis. In conclusion, increased OAT levels in lungs affected by IPF contribute to the progression of fibrosis by promoting excessive mitochondrial ROS production, which in turn activates TGF-ß1 signaling. OAT may be a useful target for treating patients with fibrotic lung diseases, including IPF.

CKD-516 potentiates the anti-cancer activity of docetaxel against epidermal growth factor receptor tyrosine kinase inhibitor-resistant lung cancer.

Lung cancer is the leading cause of cancer death. Although docetaxel has been used as a second- or third-line treatment for non-small cell lung cancer (NSCLC), the objective response rate is less than 10%. Hence, there is a need to improve the clinical efficacy of docetaxel monotherapy; combination therapy should be considered. Here, we show that CKD-516, a vascular disruption agent, can be combined with docetaxel to treat epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)-resistant NSCLC. CKD-516 was orally bioavailable; neither CKD-516 nor docetaxel affected the mean plasma concentration-time profile or pharmacokinetic parameters of the other drug. CKD-516 and docetaxel synergistically inhibited the growth of H1975 (with an L858R/T790M double mutation of EGFR) and A549 (with a KRAS mutation) lung cancer cell lines. In addition, docetaxel plus CKD-516 delayed tumor growth in-and extended the lifespan of-tumor-bearing mice. Thus, combination CKD-516 and docetaxel therapy could be used to treat EGFR-TKI-resistant NSCLC.

CKD-581 Downregulates Wnt/ß-Catenin Pathway by DACT3 Induction in Hematologic Malignancy.

The present study evaluated the anti-cancer activity of histone deacetylase (HDAC)-inhibiting CKD-581 in multiple myeloma (MM) and its pharmacological mechanisms. CKD-581 potently inhibited a broad spectrum of HDAC isozymes. It concentration-dependently inhibited proliferation of hematologic cancer cells including MM (MM.1S and RPMI8226) and T cell lymphoma (HH and MJ). It increased the expression of the dishevelled binding antagonist of ß-catenin 3 (DACT3) in T cell lymphoma and MM cells, and decreased the expression of c-Myc and ß-catenin in MM cells. Additionally, it enhanced phosphorylated p53, p21, cleaved caspase-3 and the subG1 population, and reversely, downregulated cyclin D1, CDK4 and the anti-apoptotic BCL-2 family. Finally, administration of CKD-581 exerted a significant anti-cancer activity in MM.1S-implanted xenografts. Overall, CKD-581 shows anticancer activity via inhibition of the Wnt/ß-catenin signaling pathway in hematologic malignancies. This finding is evidence of the therapeutic potential and rationale of CKD-581 for treatment of MM.

Corticosteroid-induced drug reaction with eosinophilia and systematic symptoms successfully treated with a tumor necrosis factor alpha inhibitor.

BACKGROUND: Despite recent advances in the treatment of drug reaction with eosinophilia and systemic symptoms (DRESS), the mainstay of treatment involves discontinuing the culprit drugs and administering topical or systemic corticosteroid. OBJECTIVE: The clinical use of a tumor necrosis factor (TNF)-alpha inhibitor was rarely explored in treatment of DRESS. METHODS: We present a case of corticosteroid-induced DRESS that was successfully treated with a TNF-alpha inhibitor without sequalae. RESULTS: This is the first case report that showed the clinical use of a TNF alpha inhibitor in treating corticosteroids- induced DRESS and immediate hypersensitivity reactions. The HLA-B*5801 was identified as a possible genetic factor associated with a corticosteroid-induced DRESS. CONCLUSIONS: A TNF-alpha inhibitor could be a primary option in treating DRESS, especially in patients with hypersensitivity reaction to corticosteroids.

Effects of melatonin receptor expression on prognosis and survival in oral squamous cell carcinoma patients.

Melatonin receptors can inhibit breast and prostate cancers; however, little is known regarding their effects on oral squamous cell carcinoma. In this study, we collected specimens from 81 patients with oral squamous cell carcinoma and analysed clinicopathological data retrospectively. In addition, the expression of the melatonin receptor was analysed immunohistochemically. Survival rates were calculated using the Kaplan-Meier method and log-rank test. Multivariate analysis was performed based on the Cox proportional-hazards model. Further, an in vitro study was performed using YD15 cells. The cells were transfected with siRNA targeting melatonin receptor 1A and 1B for evaluating the malignancy of melatonin receptors by western blotting, trypan blue-exclusion, colony-forming, wound-healing, and invasion assays. Survival decreased as melatonin receptor expression and clinical and pathological tumour-node-metastasis stages increased. A Cox proportional-hazard model showed that melatonin receptor 1A may serve as a significant predictor of the survival rate of patients with oral squamous cell carcinoma [hazard ratio = 1.423, 95% confidence interval (CI) = 1.019-1.988, p = 0.038]. Melatonin receptor 1A and 1B knockdown significantly suppressed proliferation, migration ability, and invasion ability of YD15 cells in vitro. Our findings reveal that inhibiting melatonin receptor expression may suppress oral squamous cell carcinoma development.

Anti-Cancer Effects of CKD-581, a Potent Histone Deacetylase Inhibitor against Diffuse Large B-Cell Lymphoma.

Double-hit lymphoma (DHL) and double-expressor lymphoma (DEL) are aggressive forms of lymphoma that require better treatments to improve patient outcomes. CKD-581 is a new histone deacetylase (HDAC) inhibitor that exhibited a better safety profile in clinical trials compared to other HDAC inhibitors. Here, we demonstrate that CKD-581 inhibited the class I-II HDAC family via histone H3 and tubulin acetylation. CKD-581 treatment also up-regulated the phosphorylation of histone H2AX (γH2AX, DNA double-strand break marker), and reduced levels of MYC and anti-apoptotic proteins such as BCL-2, BCL-6, BCL-XL, and MCL-1 in DH/DE-diffuse large B cell lymphoma (DLBCL) cell lines. Ultimately, CKD-581 also induced apoptosis via poly(ADP ribose) polymerase 1 (PARP1) cleavage. In a DLBCL SCID mouse xenograft model, CKD-581 exhibited anti-cancer effects comparable with those of rituximab (CD20 mAb). Our findings suggest that CKD-581 could be a good candidate for the treatment of DLBCL.

Non-structural cancellous bone graft and headless compression screw fixation for treatment of scaphoid waist non-union.

PURPOSE: Scaphoid fracture commonly occurs around the mid-third of the scaphoid, and non-union of this fracture has several treatment options. The authors performed autologous cancellous bone graft from the iliac crest and headless compression screw fixation for the treatment of Mack-Lichtman type II scaphoid waist non-union. The purpose of this study was to determine whether this procedure was effective in achieving bony union and restoration of alignment. METHODS: Medical records and radiographs of 30 patients who underwent cancellous bone graft and headless compression screw fixation for non-union of scaphoid waist fracture were retrospectively reviewed. There were 28 men and 2 women, with a mean age of 32.8 years (range: 21-63). The mean time to surgery was 10 months (range: 3-25) and mean follow-up was 37.5 months (range: 15-52). The authors analyzed bony union, lateral intrascaphoid angle, scapholunate angle, radiolunate angle and scaphoid length on radiographs and evaluated the Modified Mayo wrist score (MMWS) as a functional outcome. RESULTS: Bony union was achieved in all cases. The lateral intrascaphoid angle improved from 40° to 32° (P<0.001). The scapholunate angle also improved from 61° to 56° (P=0.009). The radiolunate angle decreased from 8° to 4° (P=0.048) and scaphoid length increased from 22mm to 26mm (P<0.001) postoperatively. Wrist motion and MMWS improved significantly at last follow-up. However, there were no significant differences between scaphoid deformity correction angle and pre- to post-operative difference in MMWS. CONCLUSIONS: Non-structural autologous cancellous bone graft from the iliac crest and headless screw fixation provided reliable results and can be one of the effective treatment options for patients with symptomatic Mack-Lichtman type II non-union in the mid-third of the scaphoid. LEVEL OF EVIDENCE: Level III.

Hyperopic refractive errors as a prognostic factor in intermittent exotropia surgery.

UNLABELLED: Purpose: To evaluate and compare surgical outcomes with respect to refractive errors in strabismus surgery for the treatment of intermittent exotropia (IXT). METHODS: The medical records of patients with IXT who were treated by one surgeon from January 2005 and June 2011 were reviewed. Three hundred and thirty-three IXT patients were included and divided into three groups according to preoperative refractive error: IXT with hyperopia (group I), IXT with emmetropia (group II), and IXT with myopia (group III). The surgical outcomes with respect to sensory and motor criteria were compared among the three groups. RESULTS: The surgical success rates according to motor criteria and sensory and motor criteria combined were higher in groups I (29 patients) and III (124 patients) than in group II (180 patients) at postoperative 3 and 6 months and at the last follow-up. Stereopsis was significantly better in groups II and III than in group I preoperatively (P=0.002 by one-way analysis of variance test); however, the difference was not significant postoperatively. Twenty patients in group I (69.0%) were prescribed undercorrected hyperopic spectacles postoperatively, while only 22 patients in group III (17.7%) were prescribed spectacles with more myopic power than their refractive errors. CONCLUSION: In the surgical treatment of IXT, hyperopia was not an indicator of poor prognosis. Taking into consideration the age effect, follow-up period after IXT surgery, and stereopsis improvement, hyperopic refractive error is rather a good prognostic factor.

Results of conservative management for consecutive esotropia after intermittent exotropia surgery.

PURPOSE: To examine the clinical course of consecutive esotropia (ET) using conservative management, after intermittent exotropia (IXT) surgery. METHODS: This study included 149 out of 151 consecutive patients with ET after IXT surgery, who were managed conservatively. The clinical course of consecutive ET was examined and the patients were classified into two groups based on the duration of esodeviation: (1) >3 weeks (persistent ET group, n=56) and (2) <3 weeks (transient ET group, n=93). Patient characteristics and treatment outcomes, including the recurrence of exotropia and stereopsis, were compared between the two groups. RESULTS: All patients with ET were managed with full-time alternate occlusion and/or with a Fresnel prism. In 149 patients out of 151 consecutive patients, 82% of ET disappeared at 12-month follow-up and all at the last follow-up visit (31.4±23.5 months). At the final visit, a recurrence of exotropia of >10 prism dioptres was significantly less frequent in the persistent ET group than in the transient ET group (25% vs 62%, respectively; P=0.01). However, stereopsis outcome was not significantly different between the two groups, and stereopsis change was not affected by age. CONCLUSIONS: By using conservative management only, persistent consecutive ET after IXT surgery disappeared in most cases by the 1-year follow-up visit after surgery. Recurrence of exotropia was significantly less frequent in patients with persistent ET, yet the sensory outcome was not affected by the duration of consecutive ET or age.

Improvement in vision-related function with intravitreal aflibercept: data from phase 3 studies in wet age-related macular degeneration.

PURPOSE: To evaluate the effect of intravitreal aflibercept injection on visual function in wet age-related macular degeneration (AMD). DESIGN: Prospective, multicenter, double-masked, active-controlled, parallel-group, randomized phase 3 clinical studies (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD [VIEW] 1 and 2 [clinicaltrials.gov identifiers, NCT00509795 and NCT00637377, respectively]). PARTICIPANTS: Patients (n=2419) with active, treatment-naïve, exudative AMD. This analysis included patients who received intravitreal aflibercept 2.0 mg every 8 weeks (2q8; n=607) or ranibizumab 0.5 mg every 4 weeks (0.5q4; n=595). INTERVENTION: Patients were randomized 1:1:1:1 to receive intravitreal aflibercept 2q8 (after 3 initial monthly doses), intravitreal aflibercept 2q4, intravitreal aflibercept 0.5q4, or ranibizumab 0.5q4 in the study eye. Patients in the intravitreal aflibercept 2q8 group received a sham injection alternating with active treatment. MAIN OUTCOME MEASURES: The 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) was administered at baseline and at weeks 12, 24, 36, and 52. The NEI VFQ-25 subscale scores were compared between intravitreal aflibercept 2q8 and ranibizumab 0.5q4 treatment arms, the approved dosing for each agent worldwide. Change in composite NEI VFQ-25 score was evaluated based on categorical change in visual acuity (worsened, unchanged, improved). RESULTS: Baseline NEI VFQ-25 scores were similar for both treatments in both studies. Mean change from baseline to 52 weeks was similar for ranibizumab 0.5q4 and intravitreal aflibercept 2q8 across all 12 subscales, with the greatest improvements noted for mental health and general vision (9.0-11.6 points, both treatments, both studies). Improvement of 4 points or more (both treatments, both studies) also was observed for subscales near vision, distance vision, role difficulties, and dependency. Mean change from baseline to 52 weeks in NEI VFQ-25 composite score (pooled data) stratified by clinical response showed meaningful improvement only in patients who gained 5 Early Treatment Diabetic Retinopathy letters or more (7.3 and 7.8 points for intravitreal aflibercept 2q8 and ranibizumab 0.5q4, respectively). CONCLUSIONS: Visual function outcomes were similar across all NEI VFQ-25 subscales over 52 weeks for intravitreal aflibercept 2q8 and ranibizumab 0.5q4, with clinically meaningful improvement recorded in 6 of 12 subscales.

A prospective, observational, open-label, multicentre study to investigate the daily treatment practice of ranibizumab in patients with neovascular age-related macular degeneration.

PURPOSE: The HELIOS (Health Economics with Lucentis in Observational Settings) study was designed on request of the Dutch Health Authority for an observational study to assess the effectiveness and safety of ranibizumab for neovascular age-related macular degeneration (wet AMD) in daily practice. METHODS: The HELIOS study was a 2-year prospective, observational, open-label, multicentre study involving 14 sites. Patients with wet AMD were enrolled and observed for a period of 24 months. The data were collected at baseline and at the visits closest around the time-points 3, 6, 12, 18 and 24 months after inclusion. RESULTS: Treatment with ranibizumab resulted in prevention of vision loss. The mean ETDRS score increased from 45.1 letters at baseline to 48.5 letters at 24 months. This was achieved with a mean of 7.8 injections over 24 months. Stabilization of visual acuity was also reflected by the scores on the quality of life EQ-5D questionnaire, which did not significantly change over the study period. The more subjective EQ-VAS questionnaire showed an overall improvement. The VFQ-25 questionnaire was also mostly stable over time. After 24 months, 32.2% of the patients gained ≥1 letter and 17.1% gained >15 letters. Patients completing the loading phase were better responders, as demonstrated by increased long-term visual acuity. In addition, ranibizumab was well tolerated and had a safety profile commonly seen in routine clinical practice. CONCLUSION: This study demonstrates that also in daily practice ranibizumab was effective in preventing vision loss over a period of 24 months. No new safety findings were identified.

Correlation between genotype and phenotype in patients with bi-allelic SLC26A4 mutations.

Mutation of SLC26A4 is the most common cause of prelingual hearing loss in East Asia. Patients with SLC26A4 mutations have variable phenotypes ranging from non-syndromic hearing loss to Pendred syndrome. Here, we analyzed the correlation between genotype and various inner ear phenotypes and found a possible underlying mechanism. This study included 111 patients with bi-allelic SLC26A4 mutations who had bilateral enlarged vestibular aqueduct (EVA) and hearing loss. p.H723R (61%), c.919-2A>G (24%), and p.T410M (4%) were the most common mutations in Korean patients with EVAs. Residual hearing in patients with c.919-2A>G or p.T410M mutations was better than that of patients with p.H723R homozygous mutations. Interestingly, quantitative polymerase chain reaction showed normal pendrin transcript (6-17% of normal levels) was produced from patients with c.919-2A>G homozygous mutations. Surface expression ratio of pendrin and residual anion exchange activity were higher in cells transfected with p.T410M in comparison to cells transfected with p.H723R. These results suggest that there is a correlation between degree of residual hearing and the SLC26A4 genotype commonly found in the East Asian population.

Impact of estradiol valerate/dienogest on work productivity and activities of daily living in women with heavy menstrual bleeding.

OBJECTIVES: To quantify the change in work productivity and activities of daily living in North American women with heavy menstrual bleeding (HMB) treated with estradiol valerate/dienogest (E2V/DNG; Qlaira(®)/Natazia(®)) compared to placebo. METHODS: Women in the United States and Canada, aged 20-53 years with an objective diagnosis of HMB and no recognizable anatomical pathology, were treated with E2V/DNG or placebo for seven cycles (196 days). Main outcome measures included work productivity (i.e., productivity while at work) and activities of daily living measured using a modified Work Productivity and Activity Impairment Questionnaire (mWPAI) on a Likert scale from 0 to 10 (higher values denote higher impairment levels). RESULTS: In both countries, significant improvement was observed between baseline and end of treatment in work productivity and activities of daily living impairment. The improvements in work productivity and activities of daily living with E2V/DNG treatment relative to placebo ranged from 37.2% to 39.2% across both countries. Monthly gains due to E2V/DNG treatment (net of placebo improvement) associated with improvement in work productivity were estimated to be US$80.2 and Can$70.8 (US$58.5) and those associated with improvement in activities of daily living were estimated to be US$84.9 and Can$73.5 (US$60.7). CONCLUSIONS: E2V/DNG was shown to have a consistent positive impact on work productivity and activities of daily living in U.S. and Canadian women with HMB. In addition, these improvements in work productivity and activities of daily living were associated with a reduction in HMB-related monetary burden compared to the placebo group.

Potential economic impact of increasing low dose aspirin usage on CVD in the US.

BACKGROUND: Cardiovascular disease (CVD) is a leading cause of death in the US and Western Europe, but regular use of preventive low-dose aspirin has proven effective in preventing CVD events. The purpose of this study was to explore the potential economic impact in the US if preventive aspirin usage were to be increased in line with clinical guidelines for primary and secondary prevention. METHODS: The risk profile of the US population was characterized using NHANES data, and Framingham cardiovascular risk equations were applied to calculate risk for myocardial infarction, angina and ischemic stroke according to age and gender. Primary and secondary patients were considered separately. Using publicly available unit costs, a budget impact model calculated the annual impact of increased preventive aspirin usage considering gastrointestinal bleeding and hemorrhagic stroke adverse events and diminishing aspirin adherence over a 10-year time horizon. RESULTS: In a base population of 1,000,000 patients, full implementation of clinical guidelines would potentially prevent an additional 1273 myocardial infarctions, 2184 angina episodes and 565 ischemic strokes in primary prevention patients and an additional 578 myocardial infarctions, and 607 ischemic strokes in secondary prevention patients. This represents a total savings of $79.6 million for primary prevention and $32.2 million for secondary and additional out-of-pocket expense to patients of $29.0 million for primary prevention and $2.6 million for secondary prevention for the cost of aspirin. CONCLUSIONS: This budgetary model suggests that there is a strong economic case, both for payers and society, to encourage aspirin use for patients at appropriate risk and per clinical guidelines. It also provides an example of how minimizing costs do not necessarily have to imply a rationing of care. Limitations include the exclusion of other CVD interventions in the analysis.

Elastic properties and apparent density of human edentulous maxilla and mandible.

The aim of this study was to determine whether elastic properties and apparent density of bone differ in different anatomical regions of the maxilla and mandible. Additional analyses assessed how elastic properties and apparent density were related. Four pairs of edentulous maxilla and mandibles were retrieved from fresh human cadavers. Bone samples from four anatomical regions (maxillary anterior, maxillary posterior, mandibular anterior, mandibular posterior) were obtained. Elastic modulus (EM) and hardness (H) were measured using the nano-indentation technique. Bone samples containing cortical and trabecular bone were used to measure composite apparent density (cAD) using Archimedes' principle. Statistical analyses used repeated measures ANOVA and Pearson correlations. Bone physical properties differed between regions of the maxilla and mandible. Generally, mandible had higher physical property measurements than maxilla. EM and H were higher in posterior than in anterior regions; the reverse was true for cAD. Posterior maxillary cAD was significantly lower than that in the three other regions.

Advances in the diagnosis and management of persistent pulmonary hypertension of the newborn.

Rapid evaluation of a neonate who is cyanotic and in respiratory distress is essential for achieving a good outcome. Persistent pulmonary hypertension of the newborn (PPHN) can be a primary cause or a contributing factor to respiratory failure, particularly in neonates born at 34 weeks or more of gestation. PPHN represents a failure of normal postnatal adaptation that occurs at birth in the pulmonary circulation. Rapid advances in therapy in recent years have led to a remarkable decrease in mortality for the affected infants. Infants who survive PPHN are at significant risk for long-term hearing and neurodevelopmental impairments, however. This review focuses on the diagnosis, recent advances in management, and recommendations for the long-term follow-up of infants who have PPHN.

FOXO3a induces differentiation of Bcr-Abl-transformed cells through transcriptional down-regulation of Id1.

Leukemic transformation often requires activation of protein kinase B (PKB/c-Akt) and is characterized by increased proliferation, decreased apoptosis, and a differentiation block. PKB phosphorylates and inactivates members of the FOXO subfamily of Forkhead transcription factors. It has been suggested that hyperactivation of PKB maintains the leukemic phenotype through actively repressing FOXO-mediated regulation of specific genes. We have found expression of the transcriptional repressor Id1 (inhibitor of DNA binding 1) to be abrogated by FOXO3a activation. Inhibition of PKB activation or growth factor deprivation also resulted in strong down-regulation of Id1 promoter activity, Id1 mRNA, and protein expression. Id1 is highly expressed in Bcr-Abl-transformed K562 cells, correlating with high PKB activation and FOXO3a phosphorylation. Inhibition of Bcr-Abl by the chemical inhibitor STI571 resulted in activation of FOXO3a and down-regulation of Id1 expression. By performing chromatin immunoprecipitation assays and promoter-mutation analysis, we demonstrate that FOXO3a acts as a transcriptional repressor by directly binding to the Id1 promoter. STI571 treatment, or expression of constitutively active FOXO3a, resulted in erythroid differentiation of K562 cells, which was inhibited by ectopic expression of Id1. Taken together our data strongly suggest that high expression of Id1, through PKB-mediated inhibition of FOXO3a, is critical for maintenance of the leukemic phenotype.

Chronic protein kinase B (PKB/c-akt) activation leads to apoptosis induced by oxidative stress-mediated Foxo3a transcriptional up-regulation.

Increased protein kinase B (PKB; c-Akt) activation is a hallmark of diverse neoplasias providing both proliferative and antiapoptotic survival signals. In this study, we investigated the effect of chronic PKB activation on cellular survival and proliferation using cytokine-dependent bone marrow-derived Ba/F3 cells, in which PKBalpha activation can be directly, and specifically, induced by addition of 4-hydroxytamoxifen (4-OHT). Direct activation of PKB rescued Ba/F3 cells from cytokine withdrawal-induced apoptosis; however, surprisingly, these antiapoptotic effects were short lived, cells only being protected for up to 48 hours. We observed that activation of PKB in survival factor-deprived cells led to a dramatic increase of Foxo3a on both the transcriptional and protein level leading to expression of its transcriptional targets Bim and p27(kip1). High levels of PKB activity result in increased aerobic glycolysis and mitochondrial activity resulting in overproduction of reactive oxygen species. To determine whether oxidative stress might itself be responsible for Foxo3a up-regulation, we utilized hydrogen peroxide (H(2)O(2)) as an artificial inducer of oxidative stress and N-acetylcysteine (NAC), a thiol-containing radical oxygen scavenger. Addition of NAC to the culture medium prolonged the life span of cells treated with 4-OHT and prevented the up-regulation of Foxo3a protein levels caused by PKB activation. Conversely, treatment of Ba/F3 cells with H(2)O(2) caused an increase of Foxo3a on both transcriptional and protein levels, suggesting that deregulated PKB activation leads to oxidative stress resulting in Foxo3a up-regulation and subsequently cell death. Taken together, our data provide novel insights into the molecular consequences of uncontrolled PKB activation.

The Antioxidants in Prevention of Cataracts Study: effects of antioxidant supplements on cataract progression in South India.

AIM: To determine if antioxidant supplements (beta carotene and vitamins C and E) can decrease the progression of cataract in rural South India. METHODS: The Antioxidants in Prevention of Cataracts (APC) Study was a 5 year, randomised, triple masked, placebo controlled, field based clinical trial to assess the ability of interventional antioxidant supplements to slow cataract progression. The primary outcome variable was change in nuclear opalescence over time. Secondary outcome variables were cortical and posterior subcapsular opacities and nuclear colour changes; best corrected visual acuity change; myopic shift; and failure of treatment. Annual examinations were performed for each subject by three examiners, in a masked fashion. Multivariate modelling using a general estimating equation was used for analysis of results, correcting for multiple measurements over time. RESULTS: Initial enrolment was 798 subjects. Treatment groups were comparable at baseline. There was high compliance with follow up and study medications. There was progression in cataracts. There was no significant difference between placebo and active treatment groups for either the primary or secondary outcome variables. CONCLUSION: Antioxidant supplementation with beta carotene, vitamins C and E did not affect cataract progression in a population with a high prevalence of cataract whose diet is generally deficient in antioxidants.