Identification and validation of the dopamine agonist bromocriptine as a novel therapy for high-risk myelodysplastic syndromes and secondary acute myeloid leukemia

Myelodysplastic syndromes (MDS) represent a broad spectrum of diseases characterized by their clinical manifestation as one or more cytopenias, or a reduction in circulating blood cells. MDS is predominantly a disease of the elderly, with a median age in the UK of around 75. Approximately one third of MDS patients will develop secondary acute myeloid leukemia (sAML) that has a very poor prognosis. Unfortunately, most standard cytotoxic agents are often too toxic for older patients. This means there is a pressing unmet need for novel therapies that have fewer side effects to assist this vulnerable group. This challenge was tackled using bioinformatic analysis of available transcriptomic data to establish a gene-based signature of the development and progression of MDS. This signature was then used to identify novel therapeutic compounds via statistically-significant connectivity mapping. This approach suggested re-purposing an existing and widely-prescribed drug, bromocriptine as a novel potential therapy in these disease settings. This drug has shown selectivity for leukemic cells as well as synergy with current therapies.

Spectacle design preferences among Chinese primary and secondary students and their parents: A qualitative and quantitative study

Purpose: To identify the specific characteristics making glasses designs, particularly those compatible with adjustable glasses, more or less appealing to Chinese children and their parents. Patients and Methods: Primary and secondary school children from urban and rural China with < = -1.00 diopters of bilateral myopia and their parents ranked four conventional-style frames identified by local optical shops as popular versus four child-specific frames compatible with adjustable spectacles. Scores based on the proportion of maximum possible ranking were computed for each style. Selected children and their parents also participated in Focus Groups (FGs) discussing spectacle design preference. Recordings were transcribed and coded by two independents reviewers using NVivo software. Results: Among 136 urban primary school children (age range 9-11 years), 290 rural secondary school children (11-17 years) and 16 parents, all adjustable-style frames (scores on 0-100 scale 25.7-62.4) were ranked behind all conventional frames (63.0-87.5). For eight FGs including 12 primary children, 26 secondary children and 16 parents, average kappa values for NVivo coding were 0.81 (students) and 0.70 (parents). All groups agreed that the key changes to make adjustable designs more attractive were altering the round lenses to rectangular or oval shapes and adding curved earpieces for more stable wear. The thick frames of the adjustable designs were considered stylish, and children indicated they would wear them if the lens shape were modified. Conclusions: Current adjustable lens designs are unattractive to Chinese children and their parents, though this study identified specific modifications which would make them more appealing.

In-the-Bag Intraocular Lens Placement via Secondary Capsulorhexis with Radiofrequency Diathermy in Pediatric Aphakic Eyes

Pediatric ophthalmologists increasingly recognize that the ideal site for intraocular lens (IOL) implantation is in the bag for aphakic eyes, but it is always very difficult via conventional technique. We conducted a prospective case series study to investigate the success rate and clinical outcomes of capsular bag reestablishment and in-the-bag IOL implantation via secondary capsulorhexis with radiofrequency diathermy (RFD) in pediatric aphakic eyes, in which twenty-two consecutive aphakic pediatric patients (43 aphakic eyes) enrolled in the Childhood Cataract Program of the Chinese Ministry of Health were included. The included children underwent either our novel technique for secondary IOL implantation (with RFD) or the conventional technique (with a bent needle or forceps), depending on the type of preoperative proliferative capsular bag present. In total, secondary capsulorhexis with RFD was successfully applied in 32 eyes (32/43, 74.4%, age 5.6±2.3 years), of which capsular bag reestablishment and in-the-bag IOL implantation were both achieved in 30 eyes (30/43, 70.0%), but in the remaining 2 eyes (2/32, 6.2%) the IOLs were implanted in the sulcus with a capsular bag that was too small. Secondary capsulorhexis with conventional technique was applied in the other 11 eyes (11/43, 25.6%, age 6.9±2.3 years), of which capsular bag reestablishment and in-the-bag IOL implantation were both achieved only in 3 eyes(3/43, 7.0%), and the IOLs were implanted in the sulcus in the remaining 8 eyes. A doughnut-like proliferative capsular bag with an extensive Soemmering ring (32/43, 74.4%) was the main success factor for secondary capsulorhexis with RFD, and a sufficient capsular bag size (33/43, 76.7%) was an additional factor in successful in-the-bag IOL implantation. In conclusion, RFD secondary capsulorhexis technique has 70% success rate in the capsular bag reestablishment and in-the-bag IOL implantation in pediatric aphakic eyes, particularly effective in cases with a doughnut-like, extensively proliferative Soemmering ring. © 2013 Luo et al.

Metabolism of mineral-sorbed organic matter depends upon microbial lifestyle in fluvial ecosystems

In fluvial ecosystems mineral erosion, carbon (C) and nitrogen (N) fluxes are linked via organo-mineral complexation, where dissolved organic molecules bind to mineral surfaces. Biofilms and suspended aggregates represent major aquatic microbial lifestyles whose relative importance changes predictably through fluvial networks. We tested how organo-mineral sorption affects aquatic microbial metabolism, using organo-mineral particles containing a mix of ¹³C, ¹⁵N-labelled amino acids. We traced ¹³C and ¹⁵N retention within biofilm and suspended aggregate biomass and its mineralisation. Organo-mineral complexation restricted C and N retention within biofilms and aggregates and also their mineralisation. This reduced the efficiency with which biofilms mineralise C and N by 30 % and 6 %. By contrast, organo-minerals reduced the C and N mineralisation efficiency of suspended aggregates by 41 % and 93 %. Our findings show how organo-mineral complexation affects microbial C:N stoichiometry, potentially altering the biogeochemical fate of C and N within fluvial ecosystems.

Inhibition of O-GlcNAc transferase activity reprograms prostate cancer cell metabolism

Metabolic networks are highly connected and complex, but a single enzyme, O-GlcNAc transferase (OGT) can sense the availability of metabolites and also modify target proteins. We show that inhibition of OGT activity inhibits the proliferation of prostate cancer cells, leads to sustained loss of c-MYC and suppresses the expression of CDK1, elevated expression of which predicts prostate cancer recurrence (p=0.00179). Metabolic profiling revealed decreased glucose consumption and lactate production after OGT inhibition. This decreased glycolytic activity specifically sensitized prostate cancer cells, but not cells representing normal prostate epithelium, to inhibitors of oxidative phosphorylation (rotenone and metformin). Intra-cellular alanine was depleted upon OGT inhibitor treatment. OGT inhibitor increased the expression and activity of alanine aminotransferase (GPT2), an enzyme that can be targeted with a clinically approved drug, cycloserine. Simultaneous inhibition of OGT and GPT2 inhibited cell viability and growth rate, and additionally activated a cell death response. These combinatorial effects were predominantly seen in prostate cancer cells, but not in a cell-line derived from normal prostate epithelium. Combinatorial treatments were confirmed with two inhibitors against both OGT and GPT2. Taken together, here we report the reprogramming of energy metabolism upon inhibition of OGT activity, and identify synergistically lethal combinations that are prostate cancer cell specific.

Spectacle acceptance among secondary school students in rural China: the Xichang Pediatric Refractive Error Study (X-PRES)--report 5.

PURPOSE: To assess determinants of spectacle acceptance and use among rural Chinese children. METHODS: Children with uncorrected acuity < or = 6/12 in either eye and whose presenting vision could be improved > or = 2 lines with refraction were identified from a school-based sample of 1892 students. Information on obtaining glasses and the benefits of spectacles was provided to children, families, and teachers. Purchase of new spectacles and reasons for nonpurchase were assessed by direct inspection and interview 3 months later. RESULTS: Among 674 (35.6%) children requiring spectacles (mean age, 14.7 +/- 0.8 years), 597 (88.6%) were followed up. Among 339 children with no glasses at baseline, 30.7% purchased spectacles, whereas 43.2% of 258 children with inaccurate glasses replaced them. Most (70%) subjects paid US$13 to $26. Among children with bilateral vision < or = 6/18, 45.6% bought glasses. In multivariate models, presenting vision < 6/12 (P < 0.009), refractive error < -2.0 D (P < 0.001), and amount willing to pay for glasses (P = 0.01) were predictors of purchase. Reasons for nonpurchase included satisfaction with current vision (78% of those with glasses at baseline, 49% of those without), concerns over price or parental refusal (18%), and fear glasses would weaken the eyes (13%). Only 26% of children stated that they usually wore their new glasses. CONCLUSIONS: Many families in rural China will pay for glasses, though spectacle acceptance was < 50%, even among children with poor vision. Acceptance could be improved by price reduction, education showing that glasses will not harm the eyes, and parent-focused interventions.

Corneal hysteresis and axial length among Chinese secondary school children: the Xichang Pediatric Refractive Error Study (X-PRES) report no. 4.

PURPOSE: To evaluate the association between corneal hysteresis and axial length/refractive error among rural Chinese secondary school children. DESIGN: Cross-sectional cohort study. METHODS: Refractive error (cycloplegic auto-refraction with subjective refinement), central corneal thickness (CCT) and axial length (ultrasonic measurement), intraocular pressure (IOP), and corneal hysteresis (Reichert Ocular Response Analyzer) were measured on a rural school-based cohort of children. RESULTS: Among 1,233 examined children, the mean age was 14.7 +/- 0.8 years and 699 (56.7%) were girls. The mean spherical equivalent (n = 1,232) was -2.2 +/- 1.6 diopters (D), axial length (n = 643) was 23.7 +/- 1.1 mm, corneal hysteresis (n = 1,153) was 10.7 +/- 1.6 mm Hg, IOP (n = 1,153) was 17.0 +/- 3.4 mm Hg, and CCT (n = 1,226) was 553 +/- 33 microns. In linear regression models, longer axial length was significantly (P < .001 for both) associated with lower corneal hysteresis and higher IOP. Hysteresis in this population was significantly (P < .001) lower than has previously been reported for normal White children (n = 42, 12.3 +/- 1.3 mm Hg), when adjusting for age and gender. This difference did not appear to depend on differences in axial length between the populations, as it persists when only Chinese children with normal uncorrected vision are included. CONCLUSIONS: Prospective studies will be needed to determine if low hysteresis places eyes at risk for axial elongation secondary or if primary elongation results in lower hysteresis.

Visual disability, visual function, and myopia among rural chinese secondary school children: the Xichang Pediatric Refractive Error Study (X-PRES)--report 1.

PURPOSE: To evaluate visual acuity, visual function, and prevalence of refractive error among Chinese secondary-school children in a cross-sectional school-based study. METHODS: Uncorrected, presenting, and best corrected visual acuity, cycloplegic autorefraction with refinement, and self-reported visual function were assessed in a random, cluster sample of rural secondary school students in Xichang, China. RESULTS: Among the 1892 subjects (97.3% of the consenting children, 84.7% of the total sample), mean age was 14.7 +/- 0.8 years, 51.2% were female, and 26.4% were wearing glasses. The proportion of children with uncorrected, presenting, and corrected visual disability (< or = 6/12 in the better eye) was 41.2%, 19.3%, and 0.5%, respectively. Myopia < -0.5, < -2.0, and < -6.0 D in both eyes was present in 62.3%, 31.1%, and 1.9% of the subjects, respectively. Among the children with visual disability when tested without correction, 98.7% was due to refractive error, while only 53.8% (414/770) of these children had appropriate correction. The girls had significantly (P < 0.001) more presenting visual disability and myopia < -2.0 D than did the boys. More myopic refractive error was associated with worse self-reported visual function (ANOVA trend test, P < 0.001). CONCLUSIONS: Visual disability in this population was common, highly correctable, and frequently uncorrected. The impact of refractive error on self-reported visual function was significant. Strategies and studies to understand and remove barriers to spectacle wear are needed.

Strategies to improve the accuracy of vision measurement by teachers in rural Chinese secondary schoolchildren: Xichang Pediatric Refractive Error Study (X-PRES) report no. 6.

OBJECTIVE: To assess and improve the accuracy of lay screeners compared with vision professionals in detecting visual impairment in secondary schoolchildren in rural China. METHODS: After brief training, 32 teachers and a team of vision professionals independently measured vision in 1892 children in Xichang. The children also underwent vision measurement by health technicians in a concurrent government screening program. RESULTS: Of 32 teachers, 28 (87.5%) believed that teacher screening was worthwhile. Sensitivity (93.5%) and specificity (91.2%) of teachers detecting uncorrected presenting visual acuity of 20/40 or less were better than for presenting visual acuity (sensitivity, 85.2%; specificity, 84.8%). Failure of teachers to identify children owning but not wearing glasses and teacher bias toward better vision in children wearing glasses explain the worse results for initial vision. Wearing glasses was the student factor most strongly predictive of inaccurate teacher screening (P < .001). The sensitivity and specificity of the government screening program detecting low presenting visual acuity were 86.7% and 28.7%, respectively. CONCLUSIONS: Teacher vision screening after brief training can achieve accurate results in this setting, and there is support among teachers for screening. Screening of uncorrected rather than presenting visual acuity is recommended in settings with a high prevalence of corrected and uncorrected refractive error. Low specificity in the government program renders it ineffective.

Prevalence and determinants of spectacle nonwear among rural Chinese secondary schoolchildren: the Xichang Pediatric Refractive Error Study Report 3.

OBJECTIVE: To study spectacle wear among rural Chinese children. METHODS: Visual acuity, refraction, spectacle wear, and visual function were measured. RESULTS: Among 1892 subjects (84.7% of the sample), the mean (SD) age was 14.7 (0.8) years. Among 948 children (50.1%) potentially benefiting from spectacle wear, 368 (38.8%) did not own them. Among 580 children owning spectacles, 17.9% did not wear them at school. Among 476 children wearing spectacles, 25.0% had prescriptions that could not improve their visual acuity to better than 6/12. Therefore, 62.3% (591 of 948) of children needing spectacles did not benefit from appropriate correction. Children not owning and not wearing spectacles had better self-reported visual function but worse visual acuity at initial examination than children wearing spectacles and had a mean (SD) refractive error of -2.06 (1.15) diopter (D) and -2.78 (1.32) D, respectively. Girls (P < .001) and older children (P = .03) were more likely to be wearing their spectacles. A common reason for nonwear (17.0%) was the belief that spectacles weaken the eyes. Among children without spectacles, 79.3% said their families would pay for them (mean, US $15). CONCLUSIONS: Although half of the children could benefit from spectacle wear, 62.3% were not wearing appropriate correction. These children have significant uncorrected refractive errors. There is potential to support programs through spectacle sales.

Myopia, spectacle wear, and risk of bicycle accidents among rural Chinese secondary school students: the Xichang Pediatric Refractive Error Study report no. 7.

OBJECTIVE: To study the effect of myopia and spectacle wear on bicycle-related injuries in rural Chinese students. Myopia is common among Chinese students but few studies have examined its effect on daily activities. METHODS: Data on visual acuity, refractive error, current spectacle wear, and history of bicycle use and accidents during the past 3 years were sought from 1891 students undergoing eye examinations in rural Guangdong province. RESULTS: Refractive and accident data were available for 1539 participants (81.3%), among whom the mean age was 14.6 years, 52.5% were girls, 26.8% wore glasses, and 12.9% had myopia of less than -4 diopters in both eyes. More than 90% relied on bicycles to get to school daily. A total of 2931 accidents were reported by 423 participants, with 68 requiring medical attention. Male sex (odds ratio, 1.55; P < .001) and spectacle wear (odds ratio, 1.38; P = .04) were associated with a higher risk of accident, but habitual visual acuity and myopia were unassociated with the crash risk, after adjusting for age, sex, time spent riding, and risky riding behaviors. CONCLUSION: These results may be consistent with data on motor vehicle accidents implicating peripheral vision (potentially compromised by spectacle wear) more strongly than central visual acuity in mediating crash risk.

The effect of polyphosphate kinase gene deletion on polyhydroxyalkanoate accumulation and carbon metabolism in Pseudomonas putida KT2440.

The primary enzyme involved in polyphosphate (polyP) synthesis, polyP kinase (ppk), has been deleted in Pseudomonas putida KT2440. This has resulted in a threefold to sixfold reduction in polyhydroxyalkanoate (PHA) accumulation compared with the wild type under conditions of nitrogen limitation, with either temperature or oxidative (H2O2) stress, when grown on glucose. The accumulation of PHA by Δppk mutant was the same as the wild type under nitrogen-limiting growth conditions. There was no difference in polyP levels between wild-type and Δppk strains under all growth conditions tested. In the Δppk mutant proteome, polyP kinase (PPK) was undetectable, but up-regulation of the polyp-associated proteins polyP adenosine triphosphate (ATP)/nicotinamide adenine dinucleotide (NAD) kinase (PpnK), a putative polyP adenosine monophosphate (AMP) phosphotransferase (PP_1752), and exopolyphosphatase was observed. Δppk strain exhibited significantly retarded growth with glycerol as carbon and energy source (42 h of lag period compared with 24 h in wild-type strain) but similar growth to the wild-type strain with glucose. Analysis of gene transcription revealed downregulation of glycerol kinase and the glycerol facilitator respectively. Glycerol kinase protein expression was also downregulated in the Δppk mutant. The deletion of ppk did not affect motility but reduced biofilm formation. Thus, the knockout of the ppk gene has resulted in a number of phenotypic changes to the mutant without affecting polyP accumulation.

Organophosphonates revealed: new insights into the microbial metabolism of ancient molecules.

Organophosphonates are ancient molecules that contain the chemically stable C–P bond, which is considered a relic of the reducing atmosphere on primitive earth. Synthetic phosphonates now have a wide range of applications in the agricultural, chemical and pharmaceutical industries. However, the existence of C–P compounds as contemporary biogenic molecules was not discovered until 1959, with the identification of 2-aminoethylphosphonic acid in rumen protozoa. Here, we review advances in our understanding of the biochemistry and genetics of microbial phosphonate metabolism, and discuss the role of these compounds and of the organisms engaged in their turnover within the P cycle.

Physiology and metabolic profile of Moringa olifera and Eucalyptus globulus plants subjected to climate changes

As alterações climáticas emergentes têm um grande impacto no crescimento e desenvolvimento de espécies florestais, nomeadamente em espécies de valor industrial e medicinal, como é o caso do eucalipto (Eucalyptus globulus) e da moringa (Moringa oleifera). Assim, é urgente conhecer as respostas fisiológicas e entender as variações que ocorrem nos perfis metabólicos de espécies vegetais. Neste trabalho, plantas jovens de Eucalyptus globulus foram expostas a radiação UVB (12kJ/m2) e foram avaliadas as respostas fisiológicas e o perfil metabólico, um e onze dias após a aplicação da radiação. A dose de UVB usada não afetou as reações fotoquímicas nem as trocas gasosas, contudo ao nível do metabolismo do carbono (AST e amido) e do conteúdo de pigmentos verificaram-se pequenas alterações (AST e pigmentos). Através da análise do perfil metabólico de E. globulus foram encontrados compostos voláteis e semi-voláteis pertencentes às famílias dos terpenos, sesquiterpenos e aldeídos. Em geral, os sesquiterpenos e os álcoois monoterpénicos apresentaram uma tendência para manter e, em alguns casos, diminuir com o stress, enquanto que o grupos dos aldeídos aumentou e os monoterpenos apresentaram um comportamento mais heterogéneo. O E. globulus mostrou ser uma espécie tolerante à aplicação da dose de UVB usada neste trabalho. Por outro lado, plantas jovens de M. oleifera foram expostas a défice hídrico (DH). Um grupo de plantas foi recolhido um dia após o final da exposição e o outro grupo após onze dias do final da exposição. Foi avaliado o perfil metabólico desta espécie através de GC/MS. Os dados cromatográficos indicaram que em condições de stress (DH(1) e DH(11)), as quantidades de compostos associados a vias primárias e secundárias de defesa (como os alcanos, álcoois, ácidos carboxílicos, esteróis, aminoácidos e açucares) sofreram algumas alterações. As plantas analisadas 11 dias após a remoção do stress mostraram maiores variações do perfil de metabolitos. No entanto, tanto um como onze dias após a remoção do stress, as plantas apresentaram a formação de novos rebentos. Apesar do perfil de metabolitos ter sofrido algumas alterações, por não se registarem casos de morte, conclui-se que as plantas de moringa mostraram ser tolerantes aos tratamentos aplicados.