Final Measurement of the

This Letter reports one of the most precise measurements to date of the antineutrino spectrum from a purely ^{235}U-fueled reactor, made with the final dataset from the PROSPECT-I detector at the High Flux Isotope Reactor. By extracting information from previously unused detector segments, this analysis effectively doubles the statistics of the previous PROSPECT measurement. The reconstructed energy spectrum is unfolded into antineutrino energy and compared with both the Huber-Mueller model and a spectrum from a commercial reactor burning multiple fuel isotopes. A local excess over the model is observed in the 5-7 MeV energy region. Comparison of the PROSPECT results with those from commercial reactors provides new constraints on the origin of this excess, disfavoring at 2.0 and 3.7 standard deviations the hypotheses that antineutrinos from ^{235}U are solely responsible and noncontributors to the excess observed at commercial reactors, respectively.

Measurement of the Antineutrino Spectrum from

This Letter reports the first measurement of the ^{235}U ν[over ¯]_{e} energy spectrum by PROSPECT, the Precision Reactor Oscillation and Spectrum experiment, operating 7.9 m from the 85 MW_{th} highly enriched uranium (HEU) High Flux Isotope Reactor. With a surface-based, segmented detector, PROSPECT has observed 31678±304(stat) ν[over ¯]_{e}-induced inverse beta decays, the largest sample from HEU fission to date, 99% of which are attributed to ^{235}U. Despite broad agreement, comparison of the Huber ^{235}U model to the measured spectrum produces a χ^{2}/ndf=51.4/31, driven primarily by deviations in two localized energy regions. The measured ^{235}U spectrum shape is consistent with a deviation relative to prediction equal in size to that observed at low-enriched uranium power reactors in the ν[over ¯]_{e} energy region of 5-7 MeV.

First measurement of the form factors in the decays D0 → ρ- e+ ν(e) and D+ → ρ0 e+ ν(e).

The beauty to up quark coupling constant |V(ub)| can be extracted from B → ρ e+ ν(e) combined with the form factors for D → K* e+ ν(e) and B → V ℓ+ ℓ- and D → ρ e+ ν(e). Using the entire CLEO-c ψ(3770) → DD event sample, corresponding to an integrated luminosity of 818 pb(-1) and approximately 5.4×10(6) DD events, we measure the form factors for the decays D0 → ρ- e+ ν(e) and D+ → ρ0 e+ ν(e) for the first time and the branching fractions with improved precision. A four-dimensional unbinned maximum likelihood fit determines the form factor ratios to be V(0)/A1(0)=1.48±0.15±0.05 and A2(0)/A1(0)=0.83±0.11±0.04. Assuming Cabibbo-Kobayashi-Maskawa unitarity, the known D meson lifetimes, and our measured branching fractions we obtain the form factor normalizations A1(0), A2(0), and V(0). We also present a measurement of the branching fraction for D+ → ω e+ ν(e) with improved precision.

Observation of the h(c)(1P) Using e+ e- collisions above the DD threshold.

Using 586 pb(-1) of e+ e- collision data at E(c.m.) = 4170 MeV, produced at the Cornell Electron Storage Ring collider and collected with the CLEO-c detector, we observe the process e+ e- → π+ π- h(c)(1P). We measure its cross section to be 15.6±2.3±1.9±3.0 pb, where the third error is due to the external uncertainty on the branching fraction of ψ(2S) → π0 h(c)(1P), which we use for normalization. We also find evidence for e+ e- → ηh(c)(1P) at 4170 MeV at the 3σ level and see hints of a rise in the e+ e- → π+ π- h(c)(1P) cross section at 4260 MeV.

Nonfuel Antineutrino Contributions in the High Flux Isotope Reactor.

Reactor neutrino experiments have seen major improvements in precision in recent years. With the experimental uncertainties becoming lower than those from theory, carefully considering all sources of ν ¯ e is important when making theoretical predictions. One source of ν ¯ e that is often neglected arises from the irradiation of the nonfuel materials in reactors. The ν ¯ e rates and energies from these sources vary widely based on the reactor type, configuration, and sampling stage during the reactor cycle and have to be carefully considered for each experiment independently. In this article, we present a formalism for selecting the possible ν ¯ e sources arising from the neutron captures on reactor and target materials. We apply this formalism to the High Flux Isotope Reactor (HFIR) at Oak Ridge National Laboratory, the ν ¯ e source for the the Precision Reactor Oscillation and Spectrum Measurement (PROSPECT) experiment. Overall, we observe that the nonfuel ν ¯ e contributions from HFIR to PROSPECT amount to 1% above the inverse beta decay threshold with a maximum contribution of 9% in the 1.8-2.0 MeV range. Nonfuel contributions can be particularly high for research reactors like HFIR because of the choice of structural and reflector material in addition to the intentional irradiation of target material for isotope production. We show that typical commercial pressurized water reactors fueled with low-enriched uranium will have significantly smaller nonfuel ν ¯ e contribution.

Basis for the selective cytotoxicity of rhodamine 123.

Using rat liver mitochondria we determined that the primary biochemical target for inhibition of mitochondrial bioenergetic function by rhodamine 123 (Rh123) was FoF1-ATPase and that the amount of Rh123 associated with mitochondria is proportional to the mitochondrial membrane potential. Inhibition of coupled respiration by Rh123 in mitochondria isolated from CX-1, a Rh123-sensitive carcinoma cell type, and CV-1, a Rh123-insensitive normal epithelial cell type, was linearly related to the amount of Rh123 added (micrograms/mg protein) with CX-1 mitochondria exhibiting 2-fold greater inhibition compared to CV-1 mitochondria at any given amount of dye. The inhibition pattern for mitochondria isolated from MIP101, a Rh123-insensitive carcinoma cell type, was nonlinear, exhibiting greater sensitivity than CV-1 mitochondria at very low amounts of Rh123 but becoming less sensitive than either CV-1 or CX-1 at higher amounts. Rh123 inhibited FoF1-ATPase activity to a similar extent and in a concentration-dependent manner in both CV-1 and CX-1 mitochondria, but a different and complex pattern of inhibition was apparent for MIP101 mitochondria. Moreover, mitochondria from the 2 carcinoma cell types, CX-1 and MIP101, had higher membrane potentials (163 +/- 7 and 158 +/- 8 mV, respectively) than did mitochondria from the normal epithelial cell type, CV-1 (104 +/- 9 mV). It was concluded that differences in both mitochondrial membrane potential and sensitivity of FoF1-ATPase contribute to the selective cytotoxicity exhibited by Rh123 for certain cell types in vitro.

Aberrant mitochondria in two human colon carcinoma cell lines.

Electron micrographs of CCL237 and FET cells (two slowly growing, differentiated human colon carcinoma lines) revealed enlarged mitochondria with few cristae. Polarographic measurement of respiratory activity in mitochondria isolated from these cell lines was compared to that of CV-1 cells (a normal monkey kidney epithelial line) and MIP101 cells (another human colon carcinoma line), both of which have mitochondria with a "normal" appearance. The respiratory control ratios of CCL237 and FET mitochondria were found to be considerably lower than those of CV-1 and MIP101 mitochondria (approximately 3 as compared to greater than 10, respectively), indicating that in CCL237 and FET mitochondria the processes of substrate oxidation and phosphorylation of ADP are only loosely coupled. In intact cells, differences in radiolabeled tetraphenylphosphonium uptake showed that the mitochondrial membrane potential in CCL237 and FET cells was less than that in CV-1 and MIP101 cells, and that nigericin failed to hyperpolarize the mitochondria of CCL237 and FET cells. In addition, FET mitochondria exhibited significantly lower ADP-stimulated and uncoupled respiratory rates than mitochondria isolated from the other cell types, indicating that in the former, the capacity for oxidative phosphorylation is somehow impaired. Selective toxicity of FET cells was obtained by treatment with 2-deoxyglucose, an inhibitor of glycolysis, suggesting the possibility of exploiting the phenotype of impaired oxidative metabolism for chemotherapy.

Photoactivation enhances the mitochondrial toxicity of the cationic rhodacyanine MKT-077.

In this study, the mitochondrial phototoxicity of the cationic rhodacyanine MKT-077 was investigated by comparing its effects on the inhibition of mitochondrial respiration and the structural integrity of mitochondrial DNA (mtDNA) in the presence and absence of added high-intensity visible light (7.5 J/cm2). Results indicate that photoirradiation significantly enhances the mitochondrial toxicity of MKT-077 at both the biochemical and DNA levels. For example, the concentration of MKT-077 required to achieve one-half maximal inhibition of ADP-stimulated respiration was observed to be 6-fold lower in the presence versus absence of high-intensity light (one-half maximal inhibition at 2.5 versus 15 microg MKT-077/ mg, respectively). In addition, photoirradiation produced a 25-fold increase in inhibition of succinate-cytochrome c reductase activity by MKT-077 (one-half maximal inhibition at 2 versus 50 microg MKT-077/ml, +/-light, respectively) and a 6-fold increase in inhibition of cytochrome oxidase activity (one-half maximal inhibition at 5 versus 30 microg MKT-077/ml, +/-light, respectively). Furthermore, the combination of 25 microg/ml MKT-077 and 7.5 J/cm2 visible light caused significant degradation of mtDNA in isolated rat liver mitochondria, whereas the same concentration of dye in the absence of light had only a modest effect on mtDNA. Evaluation of light-induced MKT-077 lipid peroxidation in mitochondrial membrane fragments by the thiobarbituric acid test and by measurement of nonrespiratory-linked oxygen uptake suggests that mitochondrial phototoxicity by MKT-077 may be the result of lipid peroxidation via reactive oxygen species. These results have important implications with regard to the potential use of MKT-077 in photochemotherapy.

Mitochondrial toxicity of cationic photosensitizers for photochemotherapy.

The triarylmethane derivative Victoria Blue-BO (VB-BO) and the chalcogenapyrylium (CP) dyes have potential for use in photochemotherapy, because they are taken up by the mitochondria of malignant cells and cause cell death. To clarify the mechanism of cell killing we examined the phototoxic effects of VB-BO and a series of three CP dyes on bioenergetic function in isolated rat liver mitochondria. Without photoirradiation, and irrespective of the respiratory substrate used, each of the compounds tested induced some uncoupling of oxidative phosphorylation. Visible irradiation of VB-BO produced an inhibition of mitochondrial respiration when glutamate plus malate, but not succinate, was used as the respiratory substrate. With photoirradiation VB-BO was also shown to inhibit rotenone-sensitive NADH-cytochrome c reductase activity, but it had no effect on succinate-cytochrome c reductase activity. These data indicate that photoactivation of VB-BO produces selective inhibition of mitochondrial respiratory complex I. Photoirradiation of the CP dyes inhibited both complex I and complex II initiated respiratory activity. With photoirradiation, the CP dyes also inhibited both NADH- and succinate-cytochrome c reductase activities, as well as other membrane-bound enzymes, cytochrome c oxidase and succinate dehydrogenase, but not the mitochondrial matrix enzyme, citrate synthetase, or the cytosolic enzyme, lactate dehydrogenase. alpha-Tocopherol protected bioenergetic activities against CP dye photodamage. These results suggest that mitochondrial photosensitization by CP compounds is mediated by the production of membrane-damaging singlet oxygen which causes nonspecific damage to membranes and membrane-bound enzymes.

Selective damage to carcinoma mitochondria by the rhodacyanine MKT-077.

We investigated the mitochondrial toxicity of the lipophilic cation, MKT-077, and the role of mitochondria in selective malignant cell killing by this compound by examining the effect of MKT-077 on mitochondrial structure and function in treated cells and in isolated organelles. Results of this study demonstrate changes in mitochondrial ultrastructure that are induced by MKT-077 treatment in carcinoma cells but not in similarly treated normal epithelial cells. In addition, MKT-077 was found to inhibit respiratory activity in isolated intact mitochondria and electron transport activity in freeze-thawed mitochondrial membrane fragments in a dose-dependent manner. The concentration of MKT-077 necessary to obtain half-maximal inhibition of ADP-stimulated respiration was approximately 4-fold greater in mitochondria isolated from cells of the normal epithelial cell line, CV-1 (15 micrograms MKT-077/mg protein), as compared to the human colon carcinoma cell line, CX-1 (4 micrograms MKT-077/mg protein). Further, the data show a selective loss of mitochondrial DNA in CX-1 and CRL1420 cells (carcinoma) but not CV-1 cells (normal epithelial) treated with 3 microgram/ml MKT-077 for up to 3 days. Under the same conditions, nuclear DNA was unaffected in all three cell lines. The sensitivity of the cell lines tested to mitochondrial damage by MKT-077 correlates well with their sensitivity to cytotoxicity by MKT-077. These results demonstrate selective mitochondrial damage by MKT-077 at the cellular, biochemical, and molecular levels and suggest that selective effects on mitochondrial structure and function may provide a basis for the selective malignant cell killing exhibited by this compound.

In vivo administration of MKT-077 causes partial yet reversible impairment of mitochondrial function.

The effects of in vivo administration of a pharmacologically toxic dose of the lipophilic cationic compound, MKT-077, were investigated in selected vital organs of the rat. MKT-077 (15 mg/kg body weight), administered by bolus i.v. injection every day for 5 days, did not detectably influence rat heart and kidney mitochondrial respiration. Although the same dosage of MKT-077 significantly decreased respiratory rates in rat liver mitochondria relative to untreated controls, complete recovery was evident within 3 days following drug withdrawal. Whereas the mitochondrial DNA of rat kidney and liver appeared to be unaffected by MKT-077 treatment, levels of heart mtDNA were noticeably less than control levels in the immediate interval following drug administration. However, this latter effect was partially reversed as early as 10 days following treatment and completely reversed within a 30-day posttreatment period. These results strongly suggest that a pharmacologically toxic dose of MKT-077 minimally affects the overall functional integrity of mitochondria in such critical, although highly vulnerable, tissues as the heart, liver, and kidney.

Delocalized lipophilic cations selectively target the mitochondria of carcinoma cells.

Traditional chemotherapies, aimed at DNA replication in rapidly dividing cells, have achieved only limited success in the treatment of carcinomas due largely to their lack of specificity for cells of tumorigenic origin. It is important, therefore, to investigate treatment strategies aimed at novel cellular targets that are sufficiently different between normal cells and cancer cells so as to provide a basis for selective tumor cell killing. Delocalized lipophilic cations (DLCs) are concentrated by cells and into mitochondria in response to negative inside transmembrane potentials. The higher plasma and/or mitochondrial membrane potentials of carcinoma cells compared to normal epithelial cells account for the selective accumulation of DLCs in carcinoma mitochondria. Since most DLCs are toxic to mitochondria at high concentrations, their selective accumulation in carcinoma mitochondria and consequent mitochondrial toxicity provide a basis for selective carcinoma cell killing. Several of these compounds have already displayed some degree of efficacy as chemotherapeutic agents in vitro and in vivo. The effectiveness of DLCs can also be enhanced by their use in photochemotherapy or combination drug therapy. Discovery of the biochemical differences that account for the higher membrane potentials in carcinoma cells is expected to lead to the design of new DLCs targeted specifically to those differences, resulting in even greater selectivity and efficacy for tumor cell killing.

Low incidence of persistent tardive dyskinesia in elderly patients with dementia treated with risperidone.

OBJECTIVE: The authors studied the incidence of tardive dyskinesia in elderly institutionalized patients with dementia being treated with risperidone. METHOD: After participating in a 12-week multicenter double-blind study during which they received placebo or one of three doses of risperidone, 330 patients (mean age=82.5 years) with Alzheimer's, vascular, or mixed dementia were enrolled in a 1-year open-label study during which they received flexible doses of risperidone. Persistent emergent tardive dyskinesia was defined according to scores on the dyskinesia subscale of the Extrapyramidal Symptom Rating Scale. RESULTS: The mean modal risperidone dose was 0.96 mg/day (SD=0.53), and the median length of risperidone use was 273 days. The 1-year cumulative incidence of persistent emergent tardive dyskinesia among the 255 patients without dyskinesia at baseline was 2.6%. Patients with dyskinetic symptoms at baseline experienced significant reductions in the severity of dyskinesia. Patients who received 0.75-1.5 mg/day of risperidone showed a significant improvement in psychopathologic symptoms over the 1-year period. CONCLUSIONS: Although there was no control group, the observed incidence of persistent tardive dyskinesia with risperidone seemed to be much lower than that seen in elderly patients treated with conventional neuroleptics. The average optimal dose of risperidone in elderly dementia patients was found to be 0.75-1.5 mg/day.

Antroduodenal manometry in the evaluation of chronic functional gastrointestinal symptoms.

Intraluminal pressure in the gastric antrum and duodenum was studied in 44 children and adolescents referred for evaluation because of functional symptoms, including vomiting, abdominal distension, and abdominal pain. Manometric abnormalities were found in 39 patients (89%). Abnormalities during fasting included absence of the migrating motor complex; retrograde, phase 3-like episodes; increased frequency, decreased duration, and decreased amplitude of phase 3 episodes; tonic duodenal contractions; nonpropagated bursts of duodenal contractions; and consistently low-amplitude or absent contractions. Postprandial abnormalities included a phase 1-like pattern (postprandial hypomotility) and phase 3-like episodes (failure to induce a fed pattern). The presence or absence of the migrating motor complex was a predictor of disability. Parenteral alimentation was needed by only 4 of 28 patients with the migrating motor complex, but by 13 of 16 patients without the migrating motor complex (P less than .001). In 15 of 18 patients studied on consecutive days, oral cisapride was associated with increases in the number and amplitude of duodenal contractions after a complex-liquid meal (P less than .02). It is concluded that antroduodenal manometry is a useful technique that elucidates the underlying gastrointestinal motility disorder present in the majority of children and adolescents with severe functional symptoms.

Cisapride 20 mg b.d. for preventing symptoms of GERD induced by a provocative meal. The CIS-USA-89 Study Group.

BACKGROUND: Cisapride is a substituted piperidinyl benzamide indicated for the symptomatic treatment of patients with nocturnal heartburn due to gastro-oesophageal reflux disease (GERD). The currently recommended dosing regimen for cisapride is 10 mg q.d.s., but the elimination half-life of 8-10 h supports b.d. dosing with 20 mg. METHODS: This multicentre, randomized, double-blind, placebo-controlled trial was undertaken to determine the efficacy and safety of cisapride 20 mg b.d. dosing in reducing or preventing heartburn and other meal-related symptoms after challenge with a provocative fatty meal. In phase 1 of the study, 137 patients with at least a 3-month history of symptoms suggestive of GERD and at least five episodes of GERD on 7-day diary were eligible to receive single-blind treatment with placebo for 7 (range +/- 3) days and then ingested a provocative meal. One hundred and twenty-two patients (45 men and 77 women, 22-65 years of age) who experienced heartburn during the 3 h after ingestion of the meal qualified for the double-blind phase of the study and were randomly assigned to either cisapride 20 mg or matching placebo b.d. for 7 (+/-3) days. At the end of this period, 118 patients again ate a fatty meal and were assessed for symptoms of GERD. RESULTS: Heartburn was prevented in a significantly higher percentage of cisapride-treated patients (40%; 24 out of 60) than placebo-treated patients (21%; 12 out of 58) after the repeat provocative meal at the end of the double-blind phase (P = 0.017). Cisapride was also significantly more effective in reducing the severity of postprandial heartburn, belching, and regurgitation (P < 0.05). Twice-daily dosing with cisapride 20 mg was well tolerated; the number of cisapride- and placebo-treated patients who experienced at least one adverse event was similar (31% and 22%, respectively). The most common adverse events were diarrhoea (cisapride, 18%; placebo, 0%) and rhinitis (cisapride, 2%; placebo, 5%). CONCLUSIONS: These results demonstrate that cisapride 20 mg b.d. is effective in preventing or reducing symptoms of heartburn in patients who developed heartburn after ingesting a provocative fatty meal. Cisapride was also effective in reducing the severity of heartburn-related symptoms such as belching and regurgitation.

Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. Risperidone Study Group.

BACKGROUND: We report the findings from the first large, double-blind, placebo-controlled study conducted to evaluate the efficacy and safety of risperidone in the treatment of psychotic and behavioral symptoms in institutionalized elderly patients with dementia. METHOD: 625 patients (67.8% women; mean age = 82.7 years) with DSM-IV diagnoses of Alzheimer's disease (73%), vascular dementia (15%), or mixed dementia (12%) and significant psychotic and behavioral symptoms were included. Each patient was randomly assigned to receive placebo or 0.5 mg/day, 1 mg/day, or 2 mg/day of risperidone for 12 weeks. The primary outcome measure was the Behavioral Pathology in Alzheimer's Disease rating scale (BEHAVE-AD). RESULTS: The study was completed by 70% of the patients. Baseline Functional Assessment Staging scores were 6 or 7 in more than 95% of the patients, indicating severe dementia. At endpoint, significantly greater reductions in BEHAVE-AD total scores and psychosis and aggressiveness subscale scores were seen in patients receiving 1 and 2 mg/day of risperidone than in placebo patients (p = .005 and p < .001, respectively). At week 12, 0.5 mg/day of risperidone was superior to placebo in reducing BEHAVE-AD aggression scores (p = .02). More adverse events were reported by patients receiving 2 mg/day of risperidone than 1 mg/day. The most common dose-related adverse events were extrapyramidal symptoms, somnolence, and mild peripheral edema. The frequency of extrapyramidal symptoms in patients receiving 1 mg/day of risperidone was not significantly greater than in placebo patients. CONCLUSION: Risperidone significantly improved symptoms of psychosis and aggressive behavior in patients with severe dementia. Results show that 1 mg/day of risperidone is an appropriate dose for most elderly patients with dementia.

Photoproduction of straight phi(1020) mesons on the proton at large momentum transfer

The cross section for straight phi meson photoproduction on the proton has been measured for the first time up to a four-momentum transfer -t = 4 GeV2, using the CLAS detector at the Thomas Jefferson National Accelerator Facility. At low four-momentum transfer, the differential cross section is well described by Pomeron exchange. At large four-momentum transfer, above -t = 1.8 GeV2, the data support a model where the Pomeron is resolved into its simplest component, two gluons, which may couple to any quark in the proton and in the straight phi.

Actinic keratosis and dysplasia of the conjunctiva: a clinicopathological study of 45 cases.

OBJECTIVE: To characterize precancerous conjunctival intraepithelial tumours on file at the Armed Forces Institute of Pathology (AFIP). DESIGN: Chart review. SETTING: Registry of Ophthalmic Pathology of the AFIP. NUMBERS: Forty-five patients with intraepithelial neoplastic lesions of the conjunctiva followed for at least 2 years. MAIN OUTCOME MEASURES: Extent; papillomatous pattern; degree of parakeratosis, hyperkeratosis and atypia; and amount of solar elastosis. RESULTS: Based on their histologic appearance, 24 cases were classified as actinic keratosis and 21 cases as dysplasia. Clinically, lesions classified as actinic keratosis tended to be focal and leukoplakic, whereas those classified as dysplasia tended to be diffuse and gelatinous. Two of the lesions classified as actinic keratosis recurred, compared with 13 of the lesions classified as dysplasia. In one patient with dysplasia locally invasive squamous cell carcinoma developed after numerous recurrences, requiring orbital exenteration. The degree of atypia was not correlated with recurrence in either group. CONCLUSIONS: Most intraepithelial neoplastic lesions of the conjunctiva can be readily diagnosed by the ophthalmic pathologist as either actinic keratosis or dysplasia.

Dentin biomodification potential depends on polyphenol source.

Although proanthocyanidins (PACs) modify dentin, the effectiveness of different PAC sources and the correlation with their specific chemical composition are still unknown. This study describes the chemical profiling of natural PAC-rich extracts from 7 plants using ultra high pressure/performance liquid chromatography (UHPLC) to determine the overall composition of these extracts and, in parallel, comprehensively evaluate their effect on dentin properties. The total polyphenol content of the extracts was determined (as gallic acid equivalents) using Folin-Ciocalteau assays. Dentin biomodification was assessed by the modulus of elasticity, mass change, and resistance to enzymatic biodegradation. Extracts with a high polyphenol and PAC content from Vitis vinifera, Theobroma cacao, Camellia sinensis, and Pinus massoniana induced a significant increase in modulus of elasticity and mass. The UHPLC analysis showed the presence of multiple types of polyphenols, ranging from simple phenolic acids to oligomeric PACs and highly condensed tannins. Protective effect against enzymatic degradation was observed for all experimental groups; however, statistically significant differences were observed between plant extracts. The findings provide clear evidence that the dentin bioactivities of PACs are source dependent, resulting from a combination of concentration and specific chemical constitution of the complex PAC mixtures.