Potentially harmful excipients in neonatal medicines: A pan-European observational study

Objectives We aimed to describe administration of eight potentially harmful excipients of interest (EOI)-parabens, polysorbate 80, propylene glycol, benzoates, saccharin sodium, sorbitol, ethanol and benzalkonium chloride-to hospitalised neonates in Europe and to identify risk factors for exposure. Methods All medicines administered to neonates during 1 day with individual prescription and demographic data were registered in a web-based point prevalence study. Excipients were identified from the Summaries of Product Characteristics. Determinants of EOI administration (geographical region, gestational age (GA), active pharmaceutical ingredient, unit level and hospital teaching status) were identified using multivariable logistical regression analysis. Results Overall 89 neonatal units from 21 countries participated. Altogether 2095 prescriptions for 530 products administered to 726 neonates were recorded. EOI were found in 638 (31%) prescriptions and were administered to 456 (63%) neonates through a relatively small number of products (n=142; 27%). Parabens, found in 71 (13%) products administered to 313 (43%) neonates, were used most frequently. EOI administration varied by geographical region, GA and route of administration. Geographical region remained a significant determinant of the use of parabens, polysorbate 80, propylene glycol and saccharin sodium after adjustment for the potential covariates including anatomical therapeutic chemical class of the active ingredient. Conclusions European neonates receive a number of potentially harmful pharmaceutical excipients. Regional differences in EOI administration suggest that EOI-free products are available and provide the potential for substitution to avoid side effects of some excipients.

Co-tape casting fabrication, field assistant sintering and evaluation of a coke resistant La0.2Sr0.7TiO3-Ni/YSZ functional gradient anode supported solid oxide fuel cell

The ability to directly utilize hydrocarbons and other renewable liquid fuels is one of the most important issues affecting the large scale deployment of solid oxide fuel cells (SOFCs). Herein we designed La_0.2Sr_0.7TiO₃-Ni/YSZ functional gradient anode (FGA) supported SOFCs, prepared with a co-tape casting method and sintered using the field assisted sintering technique (FAST). Through SEM observations, it was confirmed that the FGA structure was achieved and well maintained after the FAST process. Distortion and delamination which usually results after conventional sintering was successfully avoided. The La_0.2Sr_0.7TiO₃-Ni/YSZ FGA supported SOFCs showed a maximum power density of 600mWcm^-2 at 750°C, and was stable for 70h in CH₄. No carbon deposition was detected using Raman spectroscopy. These results confirm the potential coke resistance of La_0.2Sr_0.7TiO₃-Ni/YSZ FGA supported SOFCs.

WS02.7 Initial and chronic MRSA infection in cystic fibrosis

Objectives Chronic MRSA infection, which affects approximately 26% of CF patients in the USA, is associated with declining lung function and poor outcomes (Dasenbrook, 2010). Anaerobic niches have been described within the CF lung, potentially influencing the virulence of MRSA. This study aims to compare initial and chronic CF MRSA isolates, following aerobic and anaerobic culture. Methods Isolates, obtained from CF sputum at first isolation [“early” (n = 10)] or up to 5 years later, during chronic infection [“late” (n = 15)] were cultured in aerobic and anaerobic conditions. Differences in virulence were compared using the Galleria mellonella infection model. Biofilm formation of each isolate was assessed following staining with crystal violet. Production of Δ-haemolysin (Δ-hly), a surrogate marker for expression of the virulence regulator agr, was determined by haemolysis assay. Results MRSA grown in anaerobic conditions had significantly increased virulence in the G. mellonella model (p = 0.007), increased biofilm formation (p = 0.006) and increased Δ-hly production (p<0.0001). No significant difference between Δ-hly production or biofilm formation were observed between early and late isolates; however late isolates were found to be more virulent in the G. mellonella model (p = 0.0002). Conclusion These results suggest that an anaerobic environment, as found in the CF lung, may increase virulence of MRSA and aid in the establishment of chronic infection. Further clinical studies are required to determine how these phenotypic changes are associated with transition to chronic infection and patient outcome.

Selective induction of apoptosis by the pyrrolo-1,5-benzoxazepine 7-[[dimethylcarbamoyl]oxy]-6-(2-naphthyl)pyrrolo-[2,1-d] (1,5)-benzoxazepine (PBOX-6) in Leukemia cells occurs via the c-Jun NH2-terminal kinase-dependent phosphorylation and inactivation of Bcl-2 and Bcl-XL

Overexpression of the Bcl-2 proto-oncogene in tumor cells confers resistance against chemotherapeutic drugs. In this study, we describe how the novel pyrrolo-1,5-benzoxazepine compound 7-[[dimethylcarbamoyl]oxy]-6-(2-naphthyl)pyrrolo-[2,1-d] (1,5)-benzoxazepine (PBOX-6) selectively induces apoptosis in Bcl-2-overexpressing cancer cells, whereas it shows no cytotoxic effect on normal peripheral blood mononuclear cells. PBOX-6 overcomes Bcl-2-mediated resistance to apoptosis in chronic myelogenous leukemia (CML) K562 cells by the time- and dose-dependent phosphorylation and inactivation of antiapoptotic Bcl-2 family members Bcl-2 and Bcl-XL. PBOX-6 also induces Bcl-2 phosphorylation and apoptosis in wild-type T leukemia CEM cells and cells overexpressing Bcl-2. This is in contrast to chemotherapeutic agents such as etoposide, actinomycin D, and ultraviolet irradiation, whereby overexpression of Bcl-2 confers resistance against apoptosis. In addition, PBOX-6 induces Bcl-2 phosphorylation and apoptosis in wild-type Jurkat acute lymphoblastic leukemia cells and cells overexpressing Bcl-2. However, Jurkat cells containing a Bcl-2 triple mutant, whereby the principal Bcl-2 phosphorylation sites are mutated to alanine, demonstrate resistance against Bcl-2 phosphorylation and apoptosis. PBOX-6 also induces the early and transient activation of c-Jun NH2-terminal kinase (JNK) in CEM cells. Inhibition of JNK activity prevents Bcl-2 phosphorylation and apoptosis, implicating JNK in the upstream signaling pathway leading to Bcl-2 phosphorylation. Collectively, these findings identify Bcl-2 phosphorylation and inactivation as a critical step in the apoptotic pathway induced by PBOX-6 and highlight its potential as an effective antileukemic agent.

A let-7 microRNA-binding site polymorphism in 3'-untranslated region of KRAS gene predicts response in wild-type KRAS patients with metastatic colorectal cancer treated with cetuximab monotherapy

PURPOSE: recent studies have found that KRAS mutations predict resistance to monoclonal antibodies targeting the epidermal growth factor receptor in metastatic colorectal cancer (mCRC). A polymorphism in a let-7 microRNA complementary site (lcs6) in the KRAS 3' untranslated region (UTR) is associated with an increased cancer risk in non-small-cell lung cancer and reduced overall survival (OS) in oral cancers. We tested the hypothesis whether this polymorphism may be associated with clinical outcome in KRAS wild-type (KRASwt) mCRC patients treated with cetuximab monotherapy.

PATIENTS AND METHODS: the presence of KRAS let-7 lcs6 polymorphism was evaluated in 130 mCRC patients who were enrolled in a phase II study of cetuximab monotherapy (IMCL-0144). Genomic DNA was extracted from dissected formalin-fixed paraffin-embedded tumor tissue, KRAS mutation status and polymorphism were assessed using direct sequencing and PCR restriction fragment length polymorphism technique.

RESULTS: KRAS let-7 lcs6 polymorphism was found to be related to object response rate (ORR) in mCRC patients whose tumors had KRASwt. The 12 KRASwt patients harboring at least a variant G allele (TG or GG) had a 42% ORR compared with a 9% ORR in 55 KRASwt patients with let-7 lcs6 TT genotype (P = 0.02, Fisher's exact test). KRASwt patients with TG/GG genotypes had trend of longer median progression-free survival (3.9 versus 1.3 months) and OS (10.7 versus 6.4 months) compared to those with TT genotypes.

CONCLUSIONS: these results are the first to indicate that the KRAS 3'UTR polymorphism may predict for cetuximab responsiveness in KRASwt mCRC patients, which warrants validation in other clinical trials.

The high-energy environment in the super-Earth system CoRoT-7

High-energy irradiation of exoplanets has been identified to be a key influence on the stability of these planets' atmospheres. So far, irradiation-driven mass-loss has been observed only in two Hot Jupiters, and the observational data remain even more sparse in the super-Earth regime. We present an investigation of the high-energy emission in the CoRoT-7 system, which hosts the first known transiting super-Earth. To characterize the high-energy XUV radiation field into which the rocky planets CoRoT-7b and CoRoT-7c are immersed, we analyzed a 25 ks XMM-Newton observation of the host star. Our analysis yields the first clear (3.5σ) X-ray detection of CoRoT-7. We determine a coronal temperature of ≈ 3 MK and an X-ray luminosity of 3 × 1028 erg s-1. The level of XUV irradiation on CoRoT-7b amounts to ≈37 000 erg cm-2 s-1. Current theories for planetary evaporation can only provide an order-of-magnitude estimate for the planetary mass loss; assuming that CoRoT-7b has formed as a rocky planet, we estimate that CoRoT-7b evaporates at a rate of about 1.3 × 1011 g s-1 and has lost ≈4-10 earth masses in total.

Protocol-driven adjustment of ocular hypotensive medication in patients at low risk of conversion to glaucoma

AIM: To investigate the safety and potential savings of decreasing medication use in low-risk patients with ocular hypertension (OH).
METHODS: Patients with OH receiving pressure-lowering medication identified by medical record review at a university hospital underwent examination by a glaucoma specialist with assessment of visual field (VF), vertical cup-to-disc ratio (vCDR), central corneal thickness and intraocular pressure (IOP). Subjects with estimated 5-year risk of glaucoma conversion <15% were asked to discontinue ≥1 medication, IOP was remeasured 1 month later and risk was re-evaluated at 1 year.
RESULTS: Among 212 eyes of 126 patients, 44 (20.8%) had 5-year risk >15% and 14 (6.6%) had unreliable baseline VF. At 1 month, 15 patients (29 eyes, 13.7%) defaulted follow-up or refused to discontinue medication and 11 eyes (5.2%) had risk >15%. The remaining 69 patients (107 eyes, 50.7%) successfully discontinued 141 medications and completed 1-year follow-up. Mean IOP (20.5±2.65 mm Hg vs 20.3±3.40, p=0.397) did not change, though mean VF pattern SD (1.58±0.41 dB vs 1.75±0.56 dB, p=0.001) and glaucoma conversion risk (7.31±3.74% vs 8.76±6.28%, p=0.001) increased at 1 year. Mean defect decreased (-1.42±1.60 vs -1.07±1.52, p=0.022). One eye (0.47%) developed a repeatable VF defect and 13 eyes (6.1%) had 5-year risk >15% at 1 year. The total 1-year cost of medications saved was US$4596.
CONCLUSIONS: Nearly half (43.9%) of low-risk OH eyes in this setting could safely reduce medications over 1 year, realising substantial savings.Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Visual outcomes and astigmatism after sutureless, manual cataract extraction in rural China: study of cataract outcomes and up-take of services (SCOUTS) in the caring is hip project, report 1.

OBJECTIVE: To study the visual acuity and astigmatism of persons undergoing cataract extraction by local surgeons in rural China. METHODS: Visual acuity, keratometry, and refraction were measured 10 to 14 months postoperatively for all cataract cases during 4 months in Sanrao, China. RESULTS: Among 313 eligible subjects, 242 (77%) could be contacted, of whom 176 (73%) were examined. Of those who were examined, mean +/- SD age was 69.3 +/- 10.5 years, 66.5% were female, 35 had been operated on bilaterally at Sanrao, and 85.2% had a preoperative presenting visual acuity of 6/60 or worse. Presenting and best-corrected postoperative acuity in the eye that was operated on were 6/18 or better in 83.4% and 95.7%, respectively. Among 27 fellow eyes operated on elsewhere, 40.7% had a presenting acuity of 6/18 or better and 40.7% were blind (P < .001). Mean +/- SD postoperative astigmatism did not differ between 211 eyes that were operated on (-1.13 +/- 0.84 diopters) and 109 eyes that were not (-1.13 +/- 1.17 diopters; P = .27). Presence of operative complications (8.5%) and older age were associated with worse vision; bilateral surgery was associated with better vision. CONCLUSIONS: These results confirm the effectiveness of skill transfer in this setting, with superior outcomes to most studies in rural Asia and to eyes in this cohort operated on at other facilities.

Ocular comorbidities among cataract-operated patients in rural China: the caring is hip Study of Cataract Outcomes and Uptake of Services (SCOUTS), report No. 3.

PURPOSE: To determine the prevalence and impact on vision and visual function of ocular comorbidities in a rural Chinese cataract surgical program, and to devise strategies to reduce their associated burden. DESIGN: Cross-sectional cohort study. PARTICIPANTS: Persons undergoing cataract surgery by one of two recently trained local surgeons at a government-run village-level hospital in rural Guangdong between August 8 and December 31, 2005. INTERVENTIONS: Eligible subjects were invited to return for a comprehensive ocular examination and visual function interview 10 to 14 months after surgery. Prevalent ocular comorbid conditions were identified. MAIN OUTCOME MEASURES: Presenting and best-corrected vision, visual function, and treatability of the comorbidity. RESULTS: Of 313 persons operated within the study window, 242 (77%) could be contacted by telephone; study examinations and interviews were performed on 176 (74%). Examined subjects had a mean age of 69.4+/-10.5 years, 116 (66%) were female, and 149 (85%) had been blind (presenting vision < or = 6/60) in the operative eye before surgery. Among unoperated eyes, 89 of 109 (81.7%) had > or =1 ocular comorbidities, whereas for operated eyes the corresponding proportion was 72 of 211 (34.1%). The leading comorbidity among operated eyes was refractive error (43/72 [59.7%]), followed by glaucoma/glaucoma suspect (14/72 [19.4%]), whereas for unoperated eyes, it was cataract (80/92 [87.0%]), followed by refractive error (12/92 [13.0%]). Among operated eyes with comorbidities, 90.3% (65/72) had > or =1 comorbidities that were treatable. In separate models adjusting for age and gender, persons with > or =1 comorbidities in the operated eye had significantly worse presenting vision (P<0.001) than those without such findings, but visual function (P = 0.197) and satisfaction with surgery (P = 0.796) were unassociated with comorbidities. CONCLUSIONS: Ocular comorbidities are highly prevalent among persons undergoing cataract surgery in this rural Asian setting, and their presence is significantly associated with poorer visual outcomes. The fact that the great majority of comorbidities encountered in this program are treatable suggests that strategies to reduce their impact can be successful.

Impact of posterior subcapsular opacification on vision and visual function among subjects undergoing cataract surgery in rural China: Study of Cataract Outcomes and Up-Take of Services (SCOUTS) in the Caring is Hip Project, report 5.

AIM: To study the effect of posterior capsular opacification (PCO) on vision and visual function in patients undergoing cataract surgery in rural China, and to compare this with the effect of refractive error. METHODS: Patients undergoing cataract surgery in at least one eye by local surgeons in a rural setting between 8 August and 31 December 2005 were examined with slit lamp grading of PCO 10-14 months after surgery. Subjects with any PCO associated with best-corrected visual acuity of 6/7.5 or worse, or with grade 2+ or worse PCO without visual decrement, were offered YAG laser capsulotomy. Vision and self-reported visual function were assessed, and various demographic and clinical factors potentially associated with PCO were recorded. RESULTS: Of 313 patients operated on within the study window, 239 (76%) could be contacted by telephone; study examinations were performed on 176 (74%). Examined subjects had a mean (SD) age of 69.4 (10.5) years, 116 (67%) were female, and 149 (86%) had been blind (presenting visual acuity < or = 6/60) in the operated eye before surgery. PCO of grade 1 or above was present in 34 of 204 operated eyes (16.7%). Those with PCO had significantly worse presenting vision (p = 0.007) but not visual function (p>0.3) than those without PCO. Women had a significantly higher prevalence of PCO (20.9%) than did men (8.6%, p<0.05). Of 19 eyes undergoing capsulotomy with best-corrected visual acuity measured the next day, 13 (68%) improved by one or more lines, and seven (37%) improved by two or more lines. Despite a higher uptake of capsulotomy (95%) as opposed to refraction (35%) in this cohort, the yield in terms of eyes with poor presenting visual acuity (< 6/18) that could be improved was higher for refraction (26% = 9/35) than for capsulotomy (9% = 3/35). CONCLUSION: The prevalence of PCO and impact on vision and visual function in this cohort was modest 1 year after surgery. However, PCO prevalence increases with time. Follow-up of this cohort is underway to determine the effectiveness of this early intervention in identifying and treating subjects who will eventually experience clinically significant PCO.

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.