Ionizing radiation has long been known to induce heritable mutagenic change in DNA sequence. However, the genome-wide effect of radiation is not well understood. Here we report the molecular properties and frequency of mutations in phenotypically selected mutant lines isolated following exposure of the genetic model flowering plant Arabidopsis thaliana to fast neutrons (FNs). Previous studies suggested that FNs predominantly induce deletions longer than a kilobase in A. thaliana. However, we found a higher frequency of single base substitution than deletion mutations. Whilst the overall frequency and molecular spectrum of fast-neutron (FN)-induced single base substitutions differed substantially from those of "background" mutations arising spontaneously in laboratory-grown plants, G:C>A:T transitions were favored in both. We found that FN-induced G:C>A:T transitions were concentrated at pyrimidine dinucleotide sites, suggesting that FNs promote the formation of mutational covalent linkages between adjacent pyrimidine residues. In addition, we found that FNs induced more single base than large deletions, and that these single base deletions were possibly caused by replication slippage. Our observations provide an initial picture of the genome-wide molecular profile of mutations induced in A. thaliana by FN irradiation, and are particularly informative of the nature and extent of genome-wide mutation in lines selected on the basis of mutant phenotypes from FN-mutagenized A. thaliana populations.

This study identified the subtypes of psychosocial functioning in children who had sustained traumatic brain injury using the Behavior Assessment System for Children, Second Edition. Participants (N = 91) were aged 6-20. Using hierarchical agglomerative clustering techniques, a reliable typology emerged that consisted of two subtypes, which were labeled as Normal and Pervasive Emotional Difficulties. Using further exploratory analyses, other less statistically reliable subtypes were also observed, which were thought to have clinical significance. These were labeled as Mild Externalizing/Depression, Mild Externalizing/Attention Problems, Mild Depression, and Mild Anxiety. The majority of participants were assigned to the Normal subtype. Relationships between subtypes and other variables, including gender, time elapsed since injury, age at injury, and age at testing were also analyzed, with time elapsed since injury being the only variable to significantly differentiate the subtypes.

BACKGROUND Exenatide twice daily is a first-in-class glucagon-like peptide receptor agonist approved for the treatment of type 2 diabetes. The objective of this analysis was to evaluate the safety profile of exenatide twice daily and to compare its profile with that of a pooled comparator (placebo and insulin) in patients with type 2 diabetes. METHODS Data from 19 completed, randomized, controlled clinical trials of exenatide twice daily (5 μg and 10 μg) were pooled and analyzed; the pooled data included 5594 intent-to-treat patients who were followed for 12-52 weeks. Incidence rates, exposure-adjusted incidence rates, and 95% confidence intervals around risk differences between groups were calculated. RESULTS Baseline demographics and exposure time were comparable between groups (exenatide, N = 3261; pooled comparator, N = 2333; mean exposure time 166-171 days). Transient, mild- to-moderate nausea was the most frequent adverse event with exenatide (36.9% versus 8.3% in the pooled comparator). The incidence of hypoglycemia (minor or major) with concomitant sulfonylurea (exenatide 26.5%, pooled comparator 20.7%) was higher than that without sulfonylurea (exenatide 3.1%, pooled comparator 2.7%) in all groups. Serious adverse events, discontinuations due to serious adverse events, and deaths were reported with similar frequency in the exenatide and pooled comparator groups. Composite exposure-adjusted incidence rates were not statistically different between groups for pancreatitis, renal impairment, or major adverse cardiac events; there was a difference in incidence rates for benign thyroid neoplasm (0.3% versus 0%). CONCLUSION Overall, this analysis, representing over 1500 patient-years of exposure, demonstrated that exenatide twice daily was safe and generally well tolerated in patients with type 2 diabetes. The incidence of most adverse events, including serious adverse events, was similar in both exenatide-treated and comparator-treated patients. The most distinct differences between groups were in gastrointestinal-related adverse events, which is consistent with other therapies within the glucagon-like peptide class.

Background.  Cosmetic products are not tested with the same rigour as medical treatments, but recent high-quality studies have shown significant reductions in changes of skin ageing with use of cosmetic antiageing products. Aim.  To test whether a cosmetic 'anti-spot' two-step treatment containing a complex of seaweed-derived oligosaccharide and zinc would produce a significant improvement in mild acne. Methods.  A double-blind, vehicle-controlled trial of this treatment was performed for 8 weeks on 60 age-matched participants with mild acne. They were divided into two groups: 30 participants were treated with vehicle control and 30 with the active treatment containing a seaweed-derived oligosaccharide complexed with 0.1% zinc pyrrolidone. Results.  After 8 weeks, both groups had a reduction in comedones, papules and pustules, and this was significantly greater in the active than control group at 2, 4 and 8 weeks. Conclusions.  Cosmetic products may offer some benefit for mild acne and still meet the requirements of the European Cosmetic Directive. In particular, the seaweed-derived oligosaccharide complexed with 0.1% zinc pyrrolidone used in this study produced a significant reduction in acne vs. a control treatment. Cosmetic companies should conduct blinded controlled trials of their product's efficacy and publish the results.

Amyloid fibrils contained in semen, known as SEVI, or semen derived enhancer of viral infection, have been shown to dramatically increase the infectivity of HIV. However, previous work with these fibrils has suggested that extensive time and non-physiologic levels of agitation are necessary to induce amyloid formation from the precursor peptide (a proteolytic cleavage product of prostatic acid phosphatase, PAP(248-286)). Here, we show that fibril formation by PAP(248-286) is dramatically accelerated in the presence of seminal plasma (SP), and that agitation is not required for fibrillization in this setting. Analysis of the effects of specific SP components on fibril formation by PAP(248-286) revealed that this effect is primarily due to the anionic buffer components of SP (notably inorganic phosphate and sodium bicarbonate). Divalent cations present in SP had little effect on the kinetics of fibril formation, but physiologic levels of Zn(2+) strongly protected SEVI fibrils from degradation by seminal proteases. Taken together, these data suggest that in the in vivo environment, PAP(248-286) is likely to efficiently form fibrils - thus providing an explanation for the presence of SEVI in human semen.

BACKGROUND The optimal chest tube size for the drainage of traumatic hemothoraces and pneumothoraces is unknown. The purpose of this study was to compare the efficacy of small versus large chest tubes for use in thoracic trauma. Our hypothesis was that (1) there would be no difference in clinically relevant outcomes including retained hemothoraces, the need for additional tube insertion, and invasive procedures and (2) there would be an increase in pain with the insertion of large versus small tubes. METHODS This is a prospective, institutional review board-approved observational study. All patients requiring open chest tube drainage within 12 hours of admission (January 2007-January 2010) were identified at a Level I trauma center. Clinical demographic data and outcomes including efficacy of drainage, complications, retained hemothoraces, residual pneumothoraces, need for additional tube insertion, video-assisted thoracoscopy, and thoracotomy were collected and analyzed by tube size. Small chest tubes (28-32 Fr) were compared with large (36-40 Fr). RESULTS During the study period, a total of 353 chest tubes (small: 186; large: 167) were placed in 293 patients. Of the 275 chest tubes inserted for a hemothorax, 144 were small (52.3%) and 131 were large (47.7%). Both groups were similar in age, gender, and mechanism; however, large tubes were placed more frequently in patients with a Glasgow Coma Scale ≤8, severe head injury, a systolic blood pressure <90 mm Hg, and Injury Severity Score ≤25. The volume of blood drained initially and the total duration of tube placement were similar for both groups (small: 6.3 ± 3.9 days vs. large: 6.2 ± 3.6 days; adjusted (adj.) p = 0.427). After adjustment, no statistically significant difference in tube-related complications, including pneumonia (4.9% vs. 4.6%; adj. p = 0.282), empyema (4.2% vs. 4.6%; adj. p = 0.766), or retained hemothorax (11.8% vs. 10.7%; adj. p = 0.981), was found when comparing small versus large chest tubes. The need for tube reinsertion, image-guided drainage, video-assisted thoracoscopy, and thoracotomy was likewise the same (10.4% vs. 10.7%; adj. p = 0.719). For patients with a pneumothorax requiring chest tube drainage (n = 238), there was no difference in the number of patients with an unresolved pneumothorax (14.0% vs. 13.0%; adj. p = 0.620) or those needing reinsertion of a second chest tube. The mean visual analog pain score was similar for small and large tubes (6.0 ± 3.3 and 6.7 ± 3.0; p = 0.237). CONCLUSIONS For injured patients with chest trauma, chest tube size did not impact the clinically relevant outcomes tested. There was no difference in the efficacy of drainage, rate of complications including retained hemothorax, need for additional tube drainage, or invasive procedures. Furthermore, tube size did not affect the pain felt by patients at the site of insertion. LEVEL OF EVIDENCE : II.

BACKGROUND: In the CALYPSO trial, carboplatin-pegylated liposomal doxorubicin (CD) demonstrated superior therapeutic index versus carboplatin-paclitaxel (CP) in patients with recurrent ovarian cancer. This paper reports the health-related quality of life (HRQoL) findings.Materials and methods:HRQoL was measured with the EORTC QoL-QC30 questionnaire and OV28 ovarian cancer module. Mean change scores from baseline in HRQoL subscales (five functional scales and global health status) in each arm and the proportion of patients improved or worsened were calculated every 3 months until 12 months. RESULTS: Compliance was 90% at baseline and 76%, 64%, 57% at 3, 6, and 9 months, respectively. Baseline HRQoL showed already impaired global scores (mean 62/100) and considerable symptom burden (90% of patients reporting nonzero scores). Global QoL and abdominal symptom scores improved over time in both arms; at 6 months, 36% of patients met criteria for improved symptoms. Treatment with CD resulted in less peripheral neuropathy (9.8 versus 24.2), fewer other chemotherapy side-effects (9.5 versus 16.2), and less impact on body image (3.8 versus 10.4) versus CP (all P < 0.02) at 6 months. CONCLUSIONS: These patient-reported outcomes confirm the overall lower toxicity of CD versus CP. The improved disease-related outcomes achieved with CD were not at the expense of QoL.

Background:CA-125 as a tumour progression criterion in relapsing ovarian cancer (ROC) trials remains controversial. CALYPSO is a large randomised trial incorporating CA-125 (GCIG criteria) and symptomatic deterioration in addition to Response Evaluation Criteria in Solid Tumours (RECIST) criteria (radiological) to determine progression.Methods:In all, 976 patients with platinum-sensitive ROC were randomised to carboplatin-paclitaxel (C-P) or carboplatin-pegylated liposomal doxorubicin (C-PLD). CT-scan and CA-125 were performed every 3 months until progression.Results:In all, 832 patients (85%) progressed, with 60% experiencing a first radiological progression, 10% symptomatic progression, and 28% CA-125 progression without evidence of radiological or symptomatic progression. The benefit of C-PLD vs C-P in progression-free survival was not influenced by type of first progression (hazard ratio 0.85 (95% confidence interval (CI): 0.66-1.10) and 0.84 (95% CI: 0.72-0.98) for CA-125 and RECIST, respectively). In patients with CA-125 first progression who subsequently progressed radiologically, a delay of 2.3 months was observed between the two progression types. After CA-125 first progression, median time to new treatment was 2.0 months. In all, 81%of the patients with CA-125 or radiological first progression and 60% with symptomatic first progression received subsequent treatment.Conclusion:CA-125 and radiological tests performed similarly in determining progression with C-PLD or C-P. Additional follow-up with CA-125 measurements was not associated with overtreatment.British Journal of Cancer advance online publication, 12 January 2012; doi:10.1038/bjc.2011.593 www.bjcancer.com.

This paper evaluates the use of oligovalent amyloid-binding molecules as potential agents that can reduce the enhancement of human immunodeficiency virus-1 (HIV-1) infection in cells by semen-derived enhancer of virus infection (SEVI) fibrils. These naturally occurring amyloid fibrils found in semen have been implicated as mediators that can facilitate the attachment and internalization of HIV-1 virions to immune cells. Molecules that are capable of reducing the role of SEVI in HIV-1 infection may, therefore, represent a novel strategy to reduce the rate of sexual transmission of HIV-1 in humans. Here, we evaluated a set of synthetic, oligovalent derivatives of benzothiazole aniline (BTA, a known amyloid-binding molecule) for their capability to bind cooperatively to aggregated amyloid peptides and to neutralize the effects of SEVI in HIV-1 infection. We demonstrate that these BTA derivatives exhibit a general trend of increased binding to aggregated amyloids as a function of increasing valence number of the oligomer. Importantly, we find that oligomers of BTA show improved capability to reduce SEVI-mediated infection of HIV-1 in cells compared to a BTA monomer, with the pentamer exhibiting a 65-fold improvement in efficacy compared to a previously reported monomeric BTA derivative. These results, thus, support the use of amyloid-targeting molecules as potential supplements for microbicides to curb the spread of HIV-1 through sexual contact.

Background:Locally advanced inoperable pancreatic cancer (LAPC) has a poor prognosis. By increasing intensity of systemic therapy combined with an established safe chemoradiation technique, our intention was to enhance the outcomes of LAPC. In preparation for phase III evaluation, the feasibility and efficacy of our candidate regimen gemcitabine-oxaliplatin chemotherapy with sandwich 5-fluorouracil (5FU) and three-dimensional conformal radiotherapy (3DCRT) needs to be established.Methods:A total of 48 patients with inoperable LAPC without metastases were given gemcitabine (1000 mg m(-2) d1 + d15 q28) and oxaliplatin (100 mg m(-2) d2 + d16 q28) in induction (one cycle) and consolidation (three cycles), and 5FU 200 mg m(-2) per day over 6 weeks during 3DCRT 54 Gy.Results:Median duration of sustained local control (LC) was 15.8 months, progression-free survival (PFS) was 11.0 months, and overall survival was 15.7 months. Survival rates for 1, 2, and 3 years were 70.2%, 21.3%, and 12.8%, respectively. Global quality of life did not significantly decline from baseline during treatment, which was associated with modest treatment-related toxicity.Conclusion:Fixed-dose gemcitabine and oxaliplatin, combined with an effective and safe regimen of 5FU and 3DCRT radiotherapy, was feasible and reasonably tolerated. The observed improved duration of LC and PFS with more intensive therapy over previous trials may be due to patient selection, but suggest that further evaluation in phase III trials is warranted.British Journal of Cancer advance online publication, 1 December 2011; doi:10.1038/bjc.2011.526 www.bjcancer.com.