A triple-targeting inhibitory activity of Rose Bengal on polysaccharide biosynthesis of Burkholderia pseudomallei.

Sugar nucleotidyltransferases (SNTs) participate in various biosynthesis pathways constructing polysaccharides in Gram-negative bacteria. In this study, a triple-targeting inhibitory activity of Rose Bengal against SNTs such as d-glycero-α-d-manno-heptose-1-phosphate guanylyltransferase (HddC), d-glycero-ß-d-manno-heptose-1-phosphate adenylyltransferase (HldC), and 3-deoxy-d-manno-oct-2-ulosonic acid cytidylyltransferase (KdsB) from Burkholderia pseudomallei is provided. Rose Bengal effectively suppresses the nucleotidyltransferase activity of the three SNTs, and its IC50 values are 10.42, 0.76, and 5.31 µM, respectively. Interestingly, Rose Bengal inhibits the three enzymes regardless of their primary, secondary, tertiary, and quaternary structural differences. The experimental results indicate that Rose Bengal possesses the plasticity to shape its conformation suitable to interact with the three SNTs. As HddC functions in the formation of capsular polysaccharides and HldC and KdsB produce building blocks to constitute the inner core of lipopolysaccharide, Rose Bengal is a potential candidate to design antibiotics in a new category. In particular, it can be developed as a specific antimelioidosis agent. As the mortality rate of the infected people caused by B. pseudomallei is quite high, there is an urgent need for specific antimelioidosis agents. Therefore, a further study is being carried out with derivatives of Rose Bengal.

PD-L1 expression and infiltration by CD4+ and FoxP3+ T cells are increased in Xp11 translocation renal cell carcinoma and indicate poor prognosis.

AIMS: Interaction between programmed death-1 ligand (PD-L1) and its receptor programmed death 1 (PD-1) on T cells inactivates antitumour immune responses. PD-L1 expression has been associated with poor prognosis in renal cell carcinoma (RCC) and predicts adverse outcome. This study was designed to evaluate the impact of PD-L1 expression and the immune microenvironment on the clinical outcome in Xp11 translocation renal cell carcinoma (TRCC) and, therefore, their potential relevance as prognostic biomarkers. METHODS AND RESULTS: The present retrospective analysis investigated expression of PD-L1 and immune cells CD8, CD4, CD3, forkhead box protein 3 (FoxP3) and PD-1 in TRCC compared to other types of RCC. FFPE specimens were collected between 2011 and 2017 from 311 patients who underwent nephrectomy at our institution for RCC. Specimens were immunostained for PD-L1, CD8, CD4, CD3, FoxP3 and PD-1, and an outcome analysis was conducted. PD-L1 expression rate was highest in TRCC (68%, 16 of 25), followed by mucinous tubular and spindle cell RCC and collecting duct carcinoma (33%, one of three), papillary RCC (27%, seven of 26), clear cell RCC (16%, 29 of 233), chromophobe RCC (11%, two of 18) and multilocular cystic RCC (0%, none of three). In TRCC, PD-L1 expression was associated with poor recurrence-free survival (RFS) (P = 0.041). The CD4high and FoxP3high groups showed a significantly shorter RFS (P = 0.05 and P = 0.031, respectively) compared to CD4low and FOXPlow groups. CONCLUSION: PD-L1 expression was higher in TRCC than in other types of RCC. High PD-L1 tumour cell expression and tumour infiltration by CD4+ and FoxP3+ immune cells were associated with poor RFS in TRCC.

A prospective association between dietary folate intake and type 2 diabetes risk among Korean adults aged 40 years or older: the Korean Multi-Rural Communities Cohort (MRCohort) Study.

It has not been well established whether dietary folate intake reduces the risk of diabetes development. We aimed to clarify the prospective association between dietary folate intake and type 2 diabetes (T2D) risk among 7333 Korean adults aged 40 years or older who were included in the Multi-Rural Communities Cohort. Dietary folate intake was estimated from all 106 food items listed on a FFQ, not including folate intake from supplements. Two different measurements of dietary folate intake were used: the baseline consumption and the average consumption from baseline until just before the end of follow-up. The association between folate intake and T2D risk was determined through a modified Poisson regression model with a robust error estimator controlling for potential confounders. For 29 745 person years, 319 cases of diabetes were ascertained. In multivariable analyses, dietary folate intake was inversely associated with risk of T2D for women, not for men. For women, the incidence rate ratio of diabetes in the third tertile compared with the first tertile was 0·57 (95 % CI 0·38-0·87, P for trend=0·0085) in the baseline consumption model and 0·64 (95 % CI 0·43-0·95, P for trend=0·0244) in the average consumption model. These inverse associations was found in both normal fasting blood glucose group and impaired fasting glucose group among women. Among non-users of multinutrients and vitamin supplements, the significant inverse association remained. Thus, higher dietary intake of folate is prospectively associated with lower risk of diabetes for women.

MUC5AC and MUC5B enhance the characterization of mucinous adenocarcinomas of the lung and predict poor prognosis.

AIMS: From the viewpoint of histogenesis, lung adenocarcinoma can be subdivided into two groups: terminal respiratory unit (TRU) and non-TRU types. We recently reported a non-TRU type adenocarcinoma designated as ciliated adenocarcinoma (we now prefer central type adenocarcinoma). We suggest reasons that mucinous adenocarcinoma should encompass central type adenocarcinoma to represent its biological characteristics as non-TRU type adenocarcinoma. METHODS AND RESULTS: Mucin (MUC)5AC and MUC5B were expressed more significantly in non-TRU type adenocarcinoma (P < 0.01). Thirty-five (76.1%) and 45 cases (97.8%) of 46 non-TRU type adenocarcinoma showed positivity for MUC5AC and MUC5B. Twelve (7.6%) and eight (5.1%) cases of 157 TRU type adenocarainoma showed positivity for MUC5B and MUC5AC. NKX2-1 gene expression was measured with quantitative reverse transcription-polymerase chain reaction (qRT-PCR). ΔΔCt of NKX2-1 gene expression was 6.79 for TRU type adenocarcinoma and 0.6 for non-TRU type adenocarcinoma. Overall survival and disease-free survival were poorer in non-TRU type adenocarcinoma (P = 0.02 and P = 0.03). A multivariate test also showed that non-TRU type adenocarcinoma is an independent prognostic factor (P = 0.04). CONCLUSION: MUC5AC and MUC5B were specific makers for non-TRU adenocarcinoma, including both central type adenocarcinoma and mucinous adenocarcinoma. We suggest that non-TRU type adenocarcinoma presents a poorer prognosis, so it should be regarded separately from TRU type adenocarcinoma.

Estimation of surface-level PM concentration from satellite observation taking into account the aerosol vertical profiles and hygroscopicity.

Surface-level PM10 distribution was estimated from the satellite aerosol optical depth (AOD) products, taking the account of vertical profiles and hygroscopicity of aerosols over Jeju, Korea during March 2008 and October 2009. In this study, MODIS AOD data from the Terra and Aqua satellites were corrected with aerosol extinction profiles and relative humidity data. PBLH (Planetary Boundary Layer Height) was determined from MPLNET lidar-derived aerosol extinction coefficient profiles. Through statistical analysis, better agreement in correlation (R = 0.82) between the hourly PM10 concentration and hourly average Sunphotometer AOD was the obtained when vertical fraction method (VFM) considering Haze Layer Height (HLH) and hygroscopic growth factor f(RH) was used. The validity of the derived relationship between satellite AOD and surface PM10 concentration clearly demonstrates that satellite AOD data can be utilized for remote sensing of spatial distribution of regional PM10 concentration.

Comparison of long-term outcomes of selective laser trabeculoplasty versus argon laser trabeculoplasty in open-angle glaucoma.

PURPOSE: To compare the long-term success rate of selective laser trabeculoplasty (SLT) versus argon laser trabeculoplasty (ALT). DESIGN: Retrospective chart review. PARTICIPANTS: One hundred ninety-five eyes of 195 patients with uncontrolled open-angle glaucoma (OAG), of which 154 eyes underwent ALT and 41 eyes underwent SLT and were followed up for a maximum of 5 years. INTERVENTION: The SLT patients were treated with the frequency-doubled q-switched neodymium:yytrium-aluminum-garnet laser (532 nm). Approximately 50 to 55 nonoverlapping spots were placed over 180 degrees of the trabecular meshwork at energy levels ranging from 0.6 to 1.0 mJ per pulse. The ALT patients were treated with the argon blue-green laser with between 45 to 55 adjacent, nonoverlapping spots over 180 degrees of the trabecular meshwork at 470 to 1150 mW of energy per pulse. MAIN OUTCOME MEASURES: The success rates were defined by criterion I and criterion II. Success by criterion I was defined as a decrease in intraocular pressure (IOP) of 3 mmHg or more with no additional medications, laser, or glaucoma surgery. Criterion II had the same requirements as criterion I, except that a 20% or more IOP reduction was required for success. RESULTS: The mean follow-up time was 37.4+/-14.7 months for patients in the SLT group and 33.6+/-17.0 months for patients in the ALT group. The long-term success rate was not significantly different between the ALT and SLT groups by either criterion (Kaplan-Meier survival analysis log-rank P = 0.20 by criterion I and P = 0.12 by criterion II). When comparing patients with and without previous ALT, there was not a statistically significant difference in the patients treated with SLT by either criterion (log-rank P = 0.37 by criterion I and P = 0.39 by criterion II). CONCLUSIONS: In eyes with primary OAG that are receiving maximally tolerated medical therapy, SLT was found to be as effective as ALT in lowering IOP over a 5-year period. However, long-term data reveal that many of the glaucoma patients treated with SLT and ALT required further medical or surgical intervention. Whether SLT has better long-term success than ALT in repeat laser trabeculoplasty treatments remains unclear.

Comparison of long-term incidence of posterior capsular opacification between phacoemulsification and phacotrabeculectomy.

PURPOSE: To investigate the long-term incidence of posterior capsular opacification after phacoemulsification compared with phacotrabeculectomy with or without adjunctive subconjunctival mitomycin C. METHODS: This was a retrospectively conducted long-term, observational, case-control study. One hundred eyes of 100 cataract patients who underwent phacoemulsification and posterior chamber intraocular lens implantation and 100 eyes of 100 primary open-angle glaucoma patients with cataract that underwent phacotrabeculectomy and posterior chamber intraocular lens implantation, matched with respect to age, intraocular lens type, prevalence of diabetes mellitus, and length of follow-up. The main outcome measure was the rate of clinically significant posterior capsular opacification as determined by slit-lamp biomicroscopy and necessity to perform neodynium:yttrium aluminum garnet (Nd:YAG) capsulotomy and as calculated by Kaplan-Meier survival analysis. Postoperative visual acuity and maintenance of intraocular pressure control were also measured. RESULTS: There was no significant difference in the rate of posterior capsular opacification requiring Nd:YAG capsulotomy between the phacoemulsification and phacotrabeculectomy groups (P =.77). However, a significant difference in the rate of posterior capsular opacification was found between those patients without diabetes mellitus and those with a preoperative diagnosis of diabetes mellitus (P =.016). Also, survival analysis comparing use of mitomycin C with no use of mitomycin C in the phacotrabeculectomy group showed a higher survival in the mitomycin C subgroup (P =.03). CONCLUSION: There was no significant difference in long-term posterior capsular opacification between phacoemulsification and phacotrabeculectomy in the study population. Intraoperative, adjunctive use of mitomycin C in the phacotrabeculectomy group and the presence of diabetes mellitus in the overall patients were beneficial (protective) factors against posterior capsular opacification.

Effects of 2-bromopropane on pregnant dams and embryo-fetal development in the ICR mouse.

2-Bromopropane (2-BP), a halogenated propane analogue, is a substitute for chlorofluorocarbones (CFCs) which have a great potential to destroy the ozone layer and to warm the earth's environment. The present study was carried out to investigate the potential adverse effects of 2-BP on pregnant dams and embryo-fetal development after maternal exposure during the gestational days (GD) 6-17 in ICR mice. The test chemical was administered subcutaneously to pregnant mice at dose levels of 0, 500, 1000, and 1500mg/kg per day. All dams were subjected to caesarean section on GD 18 and their fetuses were examined for external, visceral and skeletal abnormalities. Throughout the study period, no treatment-related deaths were found in the groups treated with 2-BP. Pregnant mice of the 1000 and 1500mg/kg groups showed treatment-related clinical signs such as rough fur and swelling, induration, crust formation, and ulceration in the injection sites which were dose dependent in incidence and severity. A decrease in fetal weight, an increase in fetal malformation, and an increase in fetal ossification delay were found at a dose level of 1500mg/kg per day in a dose-dependent manner. On the contrary, there were no adverse effects on body weight, body weight gain, gravid uterine weight, food consumption, gross finding at any dose tested. In addition, no treatment-related effects on the number of corpora lutea, implantations, resorptions, dead fetuses, live fetuses, and sex ratio of live fetuses were observed. These findings suggest that 2-BP was embryotoxic and teratogenic at a minimally maternally toxic dose (i.e., 1500mg/kg per day) in ICR mice. In the present experimental conditions, the no-observed-adverse-effect level of 2-BP is considered to be 500mg/kg per day for dams and 1000mg/kg per day for fetuses, respectively.

Axotomy-induced dopaminergic neurodegeneration is accompanied with c-Jun phosphorylation and activation transcription factor 3 expression.

Accumulating evidence has shown that both phosphorylated c-Jun (pc-Jun) and activating transcription factor 3 (ATF3) were upregulated in a variety of tissue injuries and proposed to play an important role in cell death/survival. To elucidate the significance and functional role of these immediate-early genes during neuronal damage in the central nervous system, we examined temporal and spatial profiles of pc-Jun and ATF3 in dopaminergic neurons of the substantia nigra (SN) following transection of the medial forebrain bundle (MFB) in adult rats. Morphological characteristics of pc-Jun-positive dopaminergic neurons as well as microglial reaction in response to the axotomy-induced neurodegeneration were also investigated. Following MFB transection, both c-Jun phosphorylation and ATF3 were found in the nuclei of tyrosine hydroxylase-immunoreactive (TH-ir) neurons of the ipsilateral SN, but not in those of the contralateral SN. In the ipsilateral SN, the number of pc-Jun- and ATF3-positive nuclei was increased by 5-7 days post-lesion, and then progressively decreased probably due to the loss of neurons. Retrograde tracing with FluoroGold (FG) in hemi-axotomized rat brain demonstrated that none of the intact, unaxotomized (FG-ir) neurons was pc-Jun-positive, indicating phosphorylation of c-Jun occurs only in axotomized neurons. Concomitant co-localization of pc-Jun and ATF3 in the same TH-ir neuron was also demonstrated by triple immunofluorescence labeling. Many TH-ir neurons that underwent various steps of consecutive neurodegenerative changes retained pc-Jun in the condensed or fragmented nuclei. Moreover, numerous activated microglia, identified by both phagocytic (ED1) and MHC II (OX6) markers, closely apposed to these neurons throughout the entire neurodegenerative process, suggesting that they are actively phagocytosing dying neurons. Taken together, these results support the idea that pc-Jun and its putative dimeric partner ATF3 may be closely participating in axotomy-induced neurodegeneration.

Pathological dynamics of activated microglia following medial forebrain bundle transection.

To elucidate the role and pathological dynamics of activated microglia, this study assessed the phagocytic, immunophenotypic, morphological, and migratory properties of activated microglia in the medial forebrain bundle (MFB) axotomized rat brain. Activated microglia were identified using two different monoclonal antibodies: ED1 for phagocytic activity and OX6 for major histocompatibility complex (MHC) class II. Phagocytic microglia, characterized by ED1-immunoreactivity or ED1- and OX6-immunoreactivity, appeared in the MFB and substantia nigra (SN) as early as 1-3 days post-lesion (dpl), when there was no apparent loss of SN dopamine (DA) neurons. Thereafter, a great number of activated microglia selectively adhered to degenerating axons, dendrites and DA neuronal somas of the SN. This was followed by significant loss of these fibers and nigral DA neurons. Activation of microglia into phagocytic stage was most pronounced between 14 approximately 28 dpl and gradually subsided, but phagocytic microglia persisted until 70 dpl, the last time point examined. ED1 expression preceded MHC II expression in phagocytic microglia. All phagocytic microglia sticking to DA neurons showed activated but ramified form with enlarged somas and thickened processes. They were recruited to the SNc from cranial, dorsal and ventral aspects along various structures and finally stuck to DA neurons of the SNc. Characteristic rod-shaped microglia in the white matter were thought to migrate a long distance. The present study strongly suggests that neurons undergoing delayed neurodegeneration may be phagocytosed by numerous phagocytic, ramified microglia at various sites where specific surface signals are exposed or diffusible molecules are released.

Pulmonary involvement in Erdheim-Chester disease.

Erdheim-Chester disease is a disseminated non-Langerhans' cell histiocytosis involving multiple organs with characteristic sclerotic musculoskeletal lesions. This is the report of the case of a 53-year-old woman with extensive and progressive pulmonary disease. Computed tomography scans revealed diffuse infiltrative lung disease. Thoracoscopic lung biopsy and a biopsy of the right femur lesion were performed. The histopathology revealed that she had non-Langerhans' cell histiocytosis; Erdheim-Chester disease. The characteristic lesions of Erdheim-Chester disease, including involvement of the orbit, pericardium, periaorta, and bone were detected. This helped to further confirm that the patient had Erdheim-Chester disease with associated pulmonary involvement. As Erdheim-Chester disease is a rare non-Langerhans' cell histiocytosis that may be misdiagnosed as interstitial lung disease or other pulmonary disorders, this diagnosis should be considered in the differential diagnosis of such lung lesions.

Efficacy and safety of the fixed combinations latanoprost/timolol versus dorzolamide/timolol in patients with elevated intraocular pressure.

PURPOSE: To compare the efficacy and safety of the fixed combination of latanoprost and timolol with those of the fixed combination of dorzolamide and timolol in patients with elevated intraocular pressure (IOP). DESIGN: Three-month, randomized, parallel group, evaluator-masked, multicenter study. PARTICIPANTS: Patients with primary open-angle glaucoma or ocular hypertension with elevated IOP insufficiently responsive to monotherapy; 253 randomized: 125 to receive a fixed combination of latanoprost 0.005% and timolol 0.5% once daily, and 128 to receive a fixed combination of dorzolamide 2% and timolol 0.5% twice daily. METHODS: Visits were at screening (current ocular hypotensive therapy was discontinued), 2 weeks (if needed for an IOP-safety check), baseline (randomization), and after 1 and 3 months of therapy. Intraocular pressure was measured in triplicate at 8 am, 12 pm, and 4 pm at each study visit, and diurnal IOP was calculated as the mean value of these recordings. Adverse events were recorded at each visit. MAIN OUTCOME MEASURE: The difference between treatment groups in the change in mean diurnal IOP from baseline to month 3. RESULTS: Mean diurnal IOP levels were similar at baseline. Mean (+/- standard error of the mean) reductions in diurnal IOP from baseline to month 3 were 9.4+/-0.27 mmHg in the latanoprost/timolol fixed-combination group, versus 8.4+/-0.26 mmHg in patients receiving the dorzolamide/timolol fixed combination. The mean difference in diurnal IOP reduction between treatments was 1.00 mmHg (95% confidence interval, 0.31-1.69; P = 0.005) in favor of the latanoprost/timolol fixed combination. Both treatments generally were well tolerated. CONCLUSIONS: The fixed combination of latanoprost and timolol was slightly more effective than that of dorzolamide and timolol in reducing mean diurnal IOP, and both treatments were generally well tolerated.

Long-term filtration and visual field outcomes after primary glaucoma triple procedure with and without mitomycin-C.

OBJECTIVE: To evaluate the long-term effectiveness of glaucoma management in patients undergoing primary glaucoma triple procedure (PGTP) with and without adjunctive subconjunctival mitomycin-C (MMC). DESIGN: Case-controlled study. PARTICIPANTS: Of the 203 eyes of 203 primary open-angle glaucoma (POAG) patients who had undergone PGTP and in whom reliable Humphrey visual fields had been obtained both before and after surgery at 13.5 +/- 8.9 and 27.9 +/- 8.9 months, 124 of the 144 eyes that received MMC during surgery were matched to the other 59 eyes that did not with respect to cup-to-disc ratio and risk factors for filtration failure in addition to other variables. MAIN OUTCOME MEASURES: Both preoperative and postoperative intraocular pressure (IOP), Humphrey visual fields and their global indices, number of glaucoma medications, and best-corrected visual acuity (BCVA). RESULTS: There were no significant differences in demographics between the two groups (P > 0.05 for each). Whereas both the control and the MMC groups attained significant decreases of mean IOP (18.5 +/- 5.7 mmHg-;15.6 +/- 4.6 mmHg, P = 0.0014; 19.3 +/- 7.0 mmHg-13.7 +/- 4.9 mmHg, P = 0.0001) and mean number of medications (2.1 +/- 1.3-1.3 +/- 1.3, P = 0.0001; 2.3 +/- 1.2-1.0 +/- 1.3, P = 0.0001) at 36 months after surgery, the MMC group had significantly lower mean IOP than the control group at all postoperative visits (P < 0.05 for each). The MMC group also tended to have less medical dependency after surgery than the control group. There was no significant difference in postoperative BCVA between the two groups. Patients in both groups had mean visual acuity of 20/30 or better. There was a significant worsening of corrected pattern standard deviation (CPSD) in the control group (3.97 +/- 3.18-5.17 +/- 3.36, P = 0.001) compared with no significant change in the MMC group (5.07 +/- 4.11-5.23 +/- 3.36, P = 0.93). The mean deviation did not change significantly in either group. CONCLUSIONS: The long-term glaucoma management in POAG patients with cataract undergoing PGTP indicates a successful outcome in final IOP, medical dependency, and BCVA. Furthermore, the MMC group had better IOP control and stable visual fields (CPSD), whereas the control group had a significant worsening of CPSD.

Minocycline enhances MPTP toxicity to dopaminergic neurons.

Minocycline has been shown previously to have beneficial effects against ischemia in rats as well as neuroprotective properties against excitotoxic damage in vitro, nigral cell loss via 6-hydroxydopamine, and to prolong the life-span of transgenic mouse models of Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). We investigated whether minocycline would protect against toxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that selectively destroys nigrostriatal dopaminergic (DA) neurons and produces a clinical state similar to Parkinson's disease (PD) in rodents and primates. We found that although minocycline inhibited microglial activation, it significantly exacerbated MPTP-induced damage to DA neurons. We present evidence suggesting that this effect may be due to inhibition of DA and 1-methyl-4-phenylpridium (MPP+) uptake into striatal vesicles.

Use of NSE/PS2m-transgenic mice in the study of the protective effect of exercise on Alzheimer's disease.

In its late stage, Alzheimer's disease results in progressive muscle weakness in the arms and legs. The aim of this study was to determine whether mice expressing the skeletal muscle-specific mutant PS2 gene (a model of Alzheimer's disease) are a useful experimental system to study the protective effect of exercise on A beta-42 reduction, improvement of behavioural function and changes in metabolic parameters. With this aim in mind, the transgenic mice were subjected to treadmill exercise for 3 months. The results showed that in transgenic mice, but not in normal mice, treadmill exercise resulted in a reduction of A beta-42 deposits and an improvement in behavioural function, thereby restoring normal concentrations of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglyceride. Thus, exercise may represent a practical therapeutic strategy for use with human patients with Alzheimer's disease.