Growth factor restriction impedes progression of wound healing following cataract surgery: identification of VEGF as a putative therapeutic target

Secondary visual loss occurs in millions of patients due to a wound-healing response, known as posterior capsule opacification (PCO), following cataract surgery. An intraocular lens (IOL) is implanted into residual lens tissue, known as the capsular bag, following cataract removal. Standard IOLs allow the anterior and posterior capsules to become physically connected. This places pressure on the IOL and improves contact with the underlying posterior capsule. New open bag IOL designs separate the anterior capsule and posterior capsules and further reduce PCO incidence. It is hypothesised that this results from reduced cytokine availability due to greater irrigation of the bag. We therefore explored the role of growth factor restriction on PCO using human lens cell and tissue culture models. We demonstrate that cytokine dilution, by increasing medium volume, significantly reduced cell coverage in both closed and open capsular bag models. This coincided with reduced cell density and myofibroblast formation. A screen of 27 cytokines identified nine candidates whose expression profile correlated with growth. In particular, VEGF was found to regulate cell survival, growth and myofibroblast formation. VEGF provides a therapeutic target to further manage PCO development and will yield best results when used in conjunction with open bag IOL designs

Evaluation of the role of glutathione in the lead-induced toxicity in Saccharomyces cerevisiae

The effect of intracellular reduced glutathione (GSH) in the lead stress response of Saccharomyces cerevisiae was investigated. Yeast cells exposed to Pb, for 3 h, lost the cell proliferation capacity (viability) and decreased intracellular GSH level. The Pb-induced loss of cell viability was compared among yeast cells deficient in GSH1 (∆gsh1) or GSH2 (∆gsh2) genes and wild-type (WT) cells. When exposed to Pb, ∆gsh1 and ∆gsh2 cells did not display an increased loss of viability, compared with WT cells. However, the depletion of cellular thiols, including GSH, by treatment of WT cells with iodoacetamide (an alkylating agent, which binds covalently to thiol group), increased the loss of viability in Pb-treated cells. In contrast, GSH enrichment, due to the incubation of WT cells with amino acids mixture constituting GSH (l-glutamic acid, l-cysteine and glycine), reduced the Pb-induced loss of proliferation capacity. The obtained results suggest that intracellular GSH is involved in the defence against the Pb-induced toxicity; however, at physiological concentration, GSH seems not to be sufficient to prevent the Pb-induced loss of cell viability

An Estimate of Avian Mortality at Communication Towers in the United States and Canada

Avian mortality at communication towers in the continental United States and Canada is an issue of pressing conservation concern. Previous estimates of this mortality have been based on limited data and have not included Canada. We compiled a database of communication towers in the continental United States and Canada and estimated avian mortality by tower with a regression relating avian mortality to tower height. This equation was derived from 38 tower studies for which mortality data were available and corrected for sampling effort, search efficiency, and scavenging where appropriate. Although most studies document mortality at guyed towers with steady-burning lights, we accounted for lower mortality at towers without guy wires or steady-burning lights by adjusting estimates based on published studies. The resulting estimate of mortality at towers is 6.8 million birds per year in the United States and Canada. Bootstrapped subsampling indicated that the regression was robust to the choice of studies included and a comparison of multiple regression models showed that incorporating sampling, scavenging, and search efficiency adjustments improved model fit. Estimating total avian mortality is only a first step in developing an assessment of the biological significance of mortality at communication towers for individual species or groups of species. Nevertheless, our estimate can be used to evaluate this source of mortality, develop subsequent per-species mortality estimates, and motivate policy action

Horizontal DNA transfer mechanisms of bacteria as weapons of intragenomic conflict

Horizontal DNA transfer (HDT) is a pervasive mechanism of diversification in many microbial species, but its primary evolutionary role remains controversial. Much recent research has emphasised the adaptive benefit of acquiring novel DNA, but here we argue instead that intragenomic conflict provides a coherent framework for understanding the evolutionary origins of HDT. To test this hypothesis, we developed a mathematical model of a clonally descended bacterial population undergoing HDT through transmission of mobile genetic elements (MGEs) and genetic transformation. Including the known bias of transformation toward the acquisition of shorter alleles into the model suggested it could be an effective means of counteracting the spread of MGEs. Both constitutive and transient competence for transformation were found to provide an effective defence against parasitic MGEs; transient competence could also be effective at permitting the selective spread of MGEs conferring a benefit on their host bacterium. The coordination of transient competence with cell-cell killing, observed in multiple species, was found to result in synergistic blocking of MGE transmission through releasing genomic DNA for homologous recombination while simultaneously reducing horizontal MGE spread by lowering the local cell density. To evaluate the feasibility of the functions suggested by the modelling analysis, we analysed genomic data from longitudinal sampling of individuals carrying Streptococcus pneumoniae. This revealed the frequent within-host coexistence of clonally descended cells that differed in their MGE infection status, a necessary condition for the proposed mechanism to operate. Additionally, we found multiple examples of MGEs inhibiting transformation through integrative disruption of genes encoding the competence machinery across many species, providing evidence of an ongoing "arms race." Reduced rates of transformation have also been observed in cells infected by MGEs that reduce the concentration of extracellular DNA through secretion of DNases. Simulations predicted that either mechanism of limiting transformation would benefit individual MGEs, but also that this tactic's effectiveness was limited by competition with other MGEs coinfecting the same cell. A further observed behaviour we hypothesised to reduce elimination by transformation was MGE activation when cells become competent. Our model predicted that this response was effective at counteracting transformation independently of competing MGEs. Therefore, this framework is able to explain both common properties of MGEs, and the seemingly paradoxical bacterial behaviours of transformation and cell-cell killing within clonally related populations, as the consequences of intragenomic conflict between self-replicating chromosomes and parasitic MGEs. The antagonistic nature of the different mechanisms of HDT over short timescales means their contribution to bacterial evolution is likely to be substantially greater than previously appreciated

Intracameral bevacizumab and mitomycin C Trabeculectomy for eyes with neovascular glaucoma: a case series

The purpose of this study was to describe the surgical outcomes and safety of intracameral bevacizumab during trabeculectomy in eyes with neovascular glaucoma. Pilot study included four eyes (four patients) with refractory neovascular glaucoma submitted to fornix-based trabeculectomy with adjunctive use of bevacizumab in the anterior chamber during the procedure. Patients were previously treated with panretinal photocoagulation as standard therapy. Variables evaluated were intraocular pressure, bleb appearance, iris neovascularization, intraoperative/postoperative complications, and visual outcomes. No intraoperative complication was observed. The mean follow-up period was 12.75 (range, 12–15 months). All eyes showed significant intraocular pressure control postoperatively. Iris neovascularization reduced significantly within 1 month after surgery. Mild anterior chamber inflammation was observed during follow-up in all eyes. No significant postoperative complication was observed, and no patient presented visual acuity deterioration. Intracameral bevacizumab may be used as an adjunctive therapy during trabeculectomy in eyes with neovascular glaucoma

Modified Pilates as an adjunct to standardphysiotherapy care for urinaryincontinence: a mixed methods pilot for arandomised controlled trial

Background Urinary incontinence (UI) is a distressing condition affecting at least 5 million women in England and Wales. Traditionally, physiotherapy for UI comprises pelvic floor muscle training, but although evidence suggests this can be effective it is also recognised that benefits are often compromised by patient motivation and commitment. In addition, there is increasing recognition that physical symptoms alone are poor indicators of the impact of incontinence on individuals’ lives. Consequently, more holistic approaches to the treatment of UI, such as Modified Pilates (MP) have been recommended. This study aimed to provide preliminary findings about the effectiveness of a 6-week course of MP classes as an adjunct to standard physiotherapy care for UI, and to test the feasibility of a randomised controlled trial (RCT) design. Methods The study design was a single centre pilot RCT, plus qualitative interviews. 73 women referred to Women’s Health Physiotherapy Services for UI at Colchester Hospital University NHS Foundation Trust were randomly assigned to two groups: a 6-week course of MP classes in addition to standard physiotherapy care (intervention) or standard physiotherapy care only (control). Main outcome measures were self-reported UI, quality of life and self-esteem at baseline (T1), completion of treatment (T2), and 5 months after randomisation (T3). Qualitative interviews were conducted with a subgroup at T2 and T3. Due to the nature of the intervention blinding of participants, physiotherapists and researchers was not feasible. Results Post-intervention data revealed a range of benefits for women who attended MP classes and who had lower symptom severity at baseline: improved self-esteem (p = 0.032), decreased social embarrassment (p = 0.026) and lower impact on normal daily activities (p = 0.025). In contrast, women with higher symptom severity showed improvement in their personal relationships (p = 0.017). Qualitative analysis supported these findings and also indicated that MP classes could positively influence attitudes to exercise, diet and wellbeing. Conclusions A definitive RCT is feasible but will require a large sample size to inform clinical practice. Trial registration ISRCTN74075972 Registered 12/12/12 (Retrospectively registered)

Comparisons of mortality and pre-discharge respiratory outcomes in small-for-gestational-age and appropriate-for-gestational-age premature infants

BACKGROUND: There are differences in the literature regarding outcomes of premature small-for-gestational-age (SGA) and appropriate-for gestational-age (AGA) infants, possibly due to failure to take into account gestational age at birth. OBJECTIVE: To compare mortality and respiratory morbidity of SGA and AGA premature newborn infants. DESIGN/METHODS: A retrospective study was done of the 2,487 infants born without congenital anomalies at ≤36 weeks of gestation and admitted to the neonatal intensive care unit (NICU) at John Dempsey Hospital, between Jan. 1992 and Dec. 1999. Recent (1994–96) U.S. birth weight percentiles for gestational age (GA), race and gender were used to classify neonates as SGA (<10th percentile for GA) or AGA (10(th)–90th percentile for GA). Using multivariate logistic regression and survival analyses to control for GA, SGA and AGA infants were compared for mortality and respiratory morbidity. RESULTS: Controlling for GA, premature SGA infants were at a higher risk for mortality (Odds ratio 3.1, P = 0.001) and at lower risk of respiratory distress syndrome (OR = 0.71, p = 0.02) than AGA infants. However multivariate logistic regression modeling found that the odds of having respiratory distress syndrome (RDS) varied between SGA and AGA infants by GA. There was no change in RDS risk in SGA infants at GA ≤ 32 wk (OR = 1.27, 95% CI 0.32 – 1.98) but significantly decreased risk for RDS at GA > 32 wk (OR = 0.41, 95% CI 0.27 – 0.63; p < 0.01). After controlling for GA, SGA infants were observed to be at a significantly higher risk for developing chronic lung disease as compared to AGA infants (OR = 2.2, 95% CI = 1.2 – 3.9, P = 0.01). There was no significant difference between SGA and AGA infants in total days on ventilator. Among infants who survived, mean length of hospital stay was significantly higher in SGA infants born between 26–36 wks GA than AGA infants. CONCLUSIONS: Premature SGA infants have significantly higher mortality, significantly higher risk of developing chronic lung disease and longer hospital stay as compared to premature AGA infants. Even the reduced risk of RDS in infants born at ≥32 wk GA, (conferred possibly by intra-uterine stress leading to accelerated lung maturation) appears to be of transient effect and is counterbalanced by adverse effects of poor intrauterine growth on long term pulmonary outcomes such as chronic lung disease

Biochemical Properties of a Novel Cysteine Protease of Plasmodium vivax, Vivapain-4

Plasmodium vivax affects hundreds of millions each year and results in severe morbidity and mortality. Plasmodial cysteine proteases (CPs) play crucial roles during the progression of malaria since inhibition of these molecules impairs parasite growth. These CPs might be targeted for new antimalarial drugs. We characterized a novel P. vivax CP, vivapain-4 (VX-4), which appeared to evolve differentially among primate Plasmodium species. VX-4 showed highly unique substrate preference depending on surrounding micro-environmental pH. It effectively hydrolyzed benzyloxycarbonyl-Leu-Arg-4-methyl-coumaryl-7-amide (Z-Leu-Arg-MCA) and Z-Phe-Arg-MCA at acidic pH and Z-Arg-Arg-MCA at neutral pH. Three amino acids (Ala90, Gly157 and Glu180) that delineate the S2 pocket were found to be substituted in VX-4. Alteration of Glu180 abolished hydrolytic activity against Z-Arg-Arg-MCA at neutral pH, indicating Glu180 is intimately involved in the pH-dependent substrate preference. VX-4 hydrolyzed actin at neutral pH and hemoglobin at acidic pH, and participated in plasmepsin 4 activation at neutral/acidic pH. VX-4 was localized in the food vacuoles and cytoplasm of the erythrocytic stage of P. vivax. The differential substrate preferences depending on pH suggested a highly efficient mechanism to enlarge biological implications of VX-4, including hemoglobin degradation, maturation of plasmepsin, and remodeling of the parasite architecture during growth and development of P. vivax