Determination of the

We report the first measurement of the parity-violating elastic electron scattering asymmetry on ^{27}Al. The ^{27}Al elastic asymmetry is A_{PV}=2.16±0.11(stat)±0.16(syst) ppm, and was measured at ⟨Q^{2}⟩=0.02357±0.00010 GeV^{2}, ⟨θ_{lab}⟩=7.61°±0.02°, and ⟨E_{lab}⟩=1.157 GeV with the Q_{weak} apparatus at Jefferson Lab. Predictions using a simple Born approximation as well as more sophisticated distorted-wave calculations are in good agreement with this result. From this asymmetry the ^{27}Al neutron radius R_{n}=2.89±0.12 fm was determined using a many-models correlation technique. The corresponding neutron skin thickness R_{n}-R_{p}=-0.04±0.12 fm is small, as expected for a light nucleus with a neutron excess of only 1. This result thus serves as a successful benchmark for electroweak determinations of neutron radii on heavier nuclei. A tree-level approach was used to extract the ^{27}Al weak radius R_{w}=3.00±0.15 fm, and the weak skin thickness R_{wk}-R_{ch}=-0.04±0.15 fm. The weak form factor at this Q^{2} is F_{wk}=0.39±0.04.

Precision Measurement of the Beam-Normal Single-Spin Asymmetry in Forward-Angle Elastic Electron-Proton Scattering.

A beam-normal single-spin asymmetry generated in the scattering of transversely polarized electrons from unpolarized nucleons is an observable related to the imaginary part of the two-photon exchange process. We report a 2% precision measurement of the beam-normal single-spin asymmetry in elastic electron-proton scattering with a mean scattering angle of θ_{lab}=7.9° and a mean energy of 1.149 GeV. The asymmetry result is B_{n}=-5.194±0.067(stat)±0.082 (syst) ppm. This is the most precise measurement of this quantity available to date and therefore provides a stringent test of two-photon exchange models at far-forward scattering angles (θ_{lab}→0) where they should be most reliable.

Production of Highly Polarized Positrons Using Polarized Electrons at MeV Energies.

The Polarized Electrons for Polarized Positrons experiment at the injector of the Continuous Electron Beam Accelerator Facility has demonstrated for the first time the efficient transfer of polarization from electrons to positrons produced by the polarized bremsstrahlung radiation induced by a polarized electron beam in a high-Z target. Positron polarization up to 82% have been measured for an initial electron beam momentum of 8.19 MeV/c, limited only by the electron beam polarization. This technique extends polarized positron capabilities from GeV to MeV electron beams, and opens access to polarized positron beam physics to a wide community.

Delayed refractory hyperventilation following endoscopic third ventriculostomy in a 5-year-old boy.

We present the case of a 5-year-old boy who developed a delayed onset intractable hyperventilation following endoscopic third ventriculostomy. The proposed aetiology of this exceptionally rare phenomenon is discussed. To our knowledge, previous cases have only been reported in the adult population.

Carboplatin/taxane-induced gastrointestinal toxicity: a pharmacogenomics study on the SCOTROC1 trial.

Carboplatin/taxane combination is first-line therapy for ovarian cancer. However, patients can encounter treatment delays, impaired quality of life, even death because of chemotherapy-induced gastrointestinal (GI) toxicity. A candidate gene study was conducted to assess potential association of genetic variants with GI toxicity in 808 patients who received carboplatin/taxane in the Scottish Randomized Trial in Ovarian Cancer 1 (SCOTROC1). Patients were randomized into discovery and validation cohorts consisting of 404 patients each. Clinical covariates and genetic variants associated with grade III/IV GI toxicity in discovery cohort were evaluated in replication cohort. Chemotherapy-induced GI toxicity was significantly associated with seven single-nucleotide polymorphisms in the ATP7B, GSR, VEGFA and SCN10A genes. Patients with risk genotypes were at 1.53 to 18.01 higher odds to develop carboplatin/taxane-induced GI toxicity (P<0.01). Variants in the VEGF gene were marginally associated with survival time. Our data provide potential targets for modulation/inhibition of GI toxicity in ovarian cancer patients.

Cavity design for high-frequency axion dark matter detectors.

In an effort to extend the usefulness of microwave cavity detectors to higher axion masses, above ∼8 µeV (∼2 GHz), a numerical trade study of cavities was conducted to investigate the merit of using variable periodic post arrays and regulating vane designs for higher-frequency searches. The results show that both designs could be used to develop resonant cavities for high-mass axion searches. Multiple configurations of both methods obtained the scanning sensitivity equivalent to approximately 4 coherently coupled cavities with a single tuning rod.

First determination of the weak charge of the proton.

The Q(weak) experiment has measured the parity-violating asymmetry in ep elastic scattering at Q(2)=0.025(GeV/c)(2), employing 145 µA of 89% longitudinally polarized electrons on a 34.4 cm long liquid hydrogen target at Jefferson Lab. The results of the experiment's commissioning run, constituting approximately 4% of the data collected in the experiment, are reported here. From these initial results, the measured asymmetry is A(ep)=-279±35 (stat) ± 31 (syst) ppb, which is the smallest and most precise asymmetry ever measured in ep scattering. The small Q(2) of this experiment has made possible the first determination of the weak charge of the proton Q(W)(p) by incorporating earlier parity-violating electron scattering (PVES) data at higher Q(2) to constrain hadronic corrections. The value of Q(W)(p) obtained in this way is Q(W)(p)(PVES)=0.064±0.012, which is in good agreement with the standard model prediction of Q(W)(p)(SM)=0.0710±0.0007. When this result is further combined with the Cs atomic parity violation (APV) measurement, significant constraints on the weak charges of the up and down quarks can also be extracted. That PVES+APV analysis reveals the neutron's weak charge to be Q(W)(n)(PVES+APV)=-0.975±0.010.

Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas.

Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in gliomas, myeloid leukemias, chondrosarcomas and thyroid cancer. We discovered IDH1 and IDH2 mutations in 34 of 326 (10%) intrahepatic cholangiocarcinomas. Tumor with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine and higher 5-methylcytosine levels, as well as increased dimethylation of histone H3 lysine 79 (H3K79). Mutations in IDH1 or IDH2 were associated with longer overall survival (P=0.028) and were independently associated with a longer time to tumor recurrence after intrahepatic cholangiocarcinoma resection in multivariate analysis (P=0.021). IDH1 and IDH2 mutations were significantly associated with increased levels of p53 in intrahepatic cholangiocarcinomas, but no mutations in the p53 gene were found, suggesting that mutations in IDH1 and IDH2 may cause a stress that leads to p53 activation. We identified 2309 genes that were significantly hypermethylated in 19 cholangiocarcinomas with mutations in IDH1 or IDH2, compared with cholangiocarcinomas without these mutations. Hypermethylated CpG sites were significantly enriched in CpG shores and upstream of transcription start sites, suggesting a global regulation of transcriptional potential. Half of the hypermethylated genes overlapped with DNA hypermethylation in IDH1-mutant gliobastomas, suggesting the existence of a common set of genes whose expression may be affected by mutations in IDH1 or IDH2 in different types of tumors.

Environmental lithium exposure in the North of Chile--I. Natural water sources.

Lithium as an essential element for human life is still a subject of controversy. However, it is accepted that it does have profound neurological effects and is a valuable treatment for bipolar disease. Generally, it occurs in barely trace amounts in groundwater with few major exceptions. One of these is the Northern area of Chile where all potable water and many of the food stuffs contain high levels of lithium; between 100 and 10,000 times higher than most rivers in North America. Inevitably, the local population has been exposed to these levels in their drinking water for as long as the region has been populated. The present report details lithium levels in all the surface water sources of Northern Chile with comparison to that elsewhere. The implications for the local population are discussed and their situation compared to those exposed to other sources of lithium pollution.

Methylenetetrahydrofolate reductase genetic polymorphisms and toxicity to 5-FU-based chemoradiation in rectal cancer.

BACKGROUND: There is a large degree of variation in tumour response and host toxicities associated with neoadjuvant chemoradiation for rectal cancer patients. We performed a complimentary pharmacogenetic study to investigate germline polymorphisms of genes involved in 5-fluorouracil (5-FU) and irinotecan pathways and their potential association with clinical outcomes and toxicities from neoadjuvant chemoradiation in patients with rectal cancer treated in a prospective genotype-directed study. METHODS: The germline DNA of 131 patients was genotyped for 10 variants in TYMS, MTHFR, DPYD, UGT1A1, ABCC1 and SLCO1B1 genes. Ninety-six patients were treated with 5-FU/radiotherapy (RT) and 35 received 5-FU/RT/irinotecan. Relationships between genetic variants and adverse events, tumour response, overall and disease-free survivals were assessed. RESULTS: MTHFR 1298A>C and MTHFR diplotypes (for 677C>T and 1298A>C) were associated with chemoradiation-related toxicity when 5-FU was used alone. MTHFR haplotypes (677C-1298C) and diplotypes (CA-TA and TA-TA) showed, respectively, a protective and a negative effect on the incidence of severe diarrhoea or mucositis. No association was observed between genetic markers and drug response. CONCLUSION: MTHFR polymorphisms can potentially predict toxicity in patients treated with 5-FU as a single chemotherapeutic drug.

Search for chameleon scalar fields with the axion dark matter experiment.

Scalar fields with a "chameleon" property, in which the effective particle mass is a function of its local environment, are common to many theories beyond the standard model and could be responsible for dark energy. If these fields couple weakly to the photon, they could be detectable through the afterglow effect of photon-chameleon-photon transitions. The ADMX experiment was used in the first chameleon search with a microwave cavity to set a new limit on scalar chameleon-photon coupling ßγ excluding values between 2×10(9) and 5×10(14) for effective chameleon masses between 1.9510 and 1.9525 µeV.

SQUID-based microwave cavity search for dark-matter axions.

Axions in the microeV mass range are a plausible cold dark-matter candidate and may be detected by their conversion into microwave photons in a resonant cavity immersed in a static magnetic field. We report the first result from such an axion search using a superconducting first-stage amplifier (SQUID) replacing a conventional GaAs field-effect transistor amplifier. This experiment excludes KSVZ dark-matter axions with masses between 3.3 microeV and 3.53 microeV and sets the stage for a definitive axion search utilizing near quantum-limited SQUID amplifiers.

Search for hidden sector photons with the ADMX detector.

Hidden U(1) gauge symmetries are common to many extensions of the standard model proposed to explain dark matter. The hidden gauge vector bosons of such extensions may mix kinetically with standard model photons, providing a means for electromagnetic power to pass through conducting barriers. The axion dark matter experiment detector was used to search for hidden vector bosons originating in an emitter cavity driven with microwave power. We exclude hidden vector bosons with kinetic couplings χ>3.48×10⁻8 for masses less than 3 µeV. This limit represents an improvement of more than 2 orders of magnitude in sensitivity relative to previous cavity experiments.

Sciatic hernia: laparoscopic transabdominal extraperitoneal repair with plug and patch.

Sciatic hernia is a rare pelvic floor hernia that occurs through the greater or lesser sciatic foramen. Sciatic hernias often present as pelvic pain, particularly in women, and diagnosis can be difficult. Transabdominal and transgluteal operative approaches, including laparoscopic repair, have been reported. We show a laparoscopic technique using a plug of human allogeneic dermal matrix and lightweight polypropylene extraperitoneal patch avoiding fixation. The patient had significant improvement of her symptoms and no complications at 12 months follow-up.

Influence of ethnicity on pharmacogenetic variation in the Ghanaian population.

It has been well established that the frequencies of genomic variants can vary greatly between the populations of different countries. We sought to quantify the intra-population variability in Ghana to determine the value of genotyping studies done at a nationwide level. Further, we investigated the differences between the Ghanaian and other African populations to determine the quality of genomic representation provided by a small subgroup within the continent with regard to the general population. We genotyped 934 unrelated Ghanaian individuals for 15 single nucleotide polymorphisms (SNPs) from genes defined as clinically relevant based on their reported roles in the transport of, metabolism of, or as targets of the medicines listed in the World Health Organization Essential Medicines list. Populations within Ghana and between nations in Western Africa were genetically cohesive. In contrast, populations in other areas of Africa were genetically divergent. Gene allele frequency also differed significantly between the populations in African nations and the United States for several of the SNPs. These results demonstrate that national populations in similar geographic regions, like Africa, may have widely varying genetic allele frequencies for clinically relevant SNPs. Further genotyping studies of specific populations are necessary to provide the best medical care to all individuals.

The significance of disulfide bonding in biological activity of HB-EGF, a mutagenesis approach.

A site-directed mutagenesis approach was taken to disrupt each of 3 disulfide bonds within human HB-EGF by substituting serine for both cysteine residues that contribute to disulfide bonding. Each HB-EGF disulfide analogue (HB-EGF-Cys/Ser(108/121), HB-EGF-Cys/Ser(116/132), and HB-EGF-Cys/Ser(134/143)) was cloned under the regulation of the mouse metallothionein (MT) promoter and stably expressed in mouse fibroblasts. HB-EGF immunoreactive proteins with M(r) of 6.5, 21 and 24 kDa were observed from lysates of HB-EGF and each HB-EGF disulfide analogue. HB-EGF immunohistochemical analyses of each HB-EGF stable cell line demonstrated ubiquitous protein expression except HB-EGF-Cys/Ser(108/121) and HB-EGF-Cys/Ser(116/132) stable cell lines which exhibited accumulated expression immediately outside the nucleus. rHB-EGF, HB-EGF, and HB-EGF(134/143) proteins competed with 125I-EGF in an A431 competitive binding assay, whereas HB-EGF-Cys/Ser(108/121) and HB-EGF-Cys/Ser(116/132) failed to compete. Each HB-EGF disulfide analogue lacked the ability to stimulate tyrosine phosphorylation of the 170 kDa EGFR. These results suggest that HB-EGF-Cys/Ser(134/143) antagonizes EGFRs.

Imatinib disposition and ABCB1 (MDR1, P-glycoprotein) genotype.

The aim of this study was to explore the impact of individual variation in drug elimination on imatinib disposition. Twenty-two patients with gastrointestinal stromal tumor or chronic myeloid leukemia initially received imatinib 600 mg daily with dosage subsequently toxicity adjusted. Pharmacokinetic parameters on day 1 and at steady-state were compared with elimination phenotype and single-nucleotide polymorphisms of CYP3A5 and ABCB1. A fivefold variation in estimated imatinib clearance (CL/F) was present on day 1 and mean CL/F had fallen by 26% at steady state. This reduction in imatinib CL/F was associated with ABCB1 genotype, being least apparent in thymidine homozygotes at the 1236T>C, 2677G>T/A and 3435C>T loci. Toxicity-related dose reduction also tended to be less common in these individuals. ABCB1 genotype was associated with steady-state CL/F due to an apparent genotype-specific influence of imatinib on elimination. Further evaluation of ABCB1 genotype and imatinib dosage is warranted.

The effects of cannabinoids on P-glycoprotein transport and expression in multidrug resistant cells.

Cannabis is the most widely used illicit drug in the world. Cannabinoids are used therapeutically by some patients as they have analgesic, anti-emetic and appetite stimulant properties which palliate adverse symptoms. Use of these agents in an oncology setting raises the question of whether they act to modulate the effectiveness of concurrently administered anti-cancer drugs. The transporter, P-glycoprotein (P-gp) confers multiple drug resistance (MDR) by effluxing a diverse array of anti-cancer agents. This study was undertaken to examine the effect of cannabinoids on P-gp. Unlike the known P-gp inhibitor, PSC833, short 1h exposure to three plant-derived cannabinoids, cannabinol (CBN), cannabidiol (CBD) and Delta(9)-tetrahydrocannabinol (THC) and the synthetic cannabinoid receptor agonist, WIN55, 212-2 (WIN) did not inhibit the efflux of the P-gp substrate Rhodamine 123 (Rh123) in either a drug-selected human T lymphoblastoid leukaemia cell line (CEM/VLB(100)) or in a mouse fibroblast MDR1 transfected cell line (77.1). However, in CEM/VLB(100) cells, prolonged 72 h exposure to the cannabinoids, THC and CBD, decreased P-gp expression to a similar extent as the flavonoid, curcumin (turmeric). This correlated with an increase in intracellular accumulation of Rh123 and enhanced sensitivity of the cells to the cytotoxic actions of the P-gp substrate, vinblastine. Taken together, these results provide preliminary evidence that cannabinoids do not exacerbate P-gp mediated MDR. Further, plant-derived cannabinoids are moderately effective in reversing MDR in CEM/VLB(100) cells by decreasing P-gp expression.