First Direct Measurements of Superheavy-Element Mass Numbers.

An experiment was performed at Lawrence Berkeley National Laboratory's 88-in. Cyclotron to determine the mass number of a superheavy element. The measurement resulted in the observation of two α-decay chains, produced via the ^{243}Am(^{48}Ca,xn)^{291-x}Mc reaction, that were separated by mass-to-charge ratio (A/q) and identified by the combined BGS+FIONA apparatus. One event occurred at A/q=284 and was assigned to ^{284}Nh (Z=113), the α-decay daughter of ^{288}Mc (Z=115), while the second occurred at A/q=288 and was assigned to ^{288}Mc. This experiment represents the first direct measurements of the mass numbers of superheavy elements, confirming previous (indirect) mass-number assignments.

Further evidence of a cumulative effect of social disadvantage on risk of psychosis.

BACKGROUND: A growing body of evidence suggests that indicators of social disadvantage are associated with an increased risk of psychosis. However, only a few studies have specifically looked at cumulative effects and long-term associations. The aims of this study are: To compare the prevalence of specific indicators of social disadvantage at, and prior to, first contact with psychiatric services in patients suffering their first episode of psychosis and in a control sample. To explore long-term associations, cumulative effects, and direction of effects. METHOD: We collected information on social disadvantage from 332 patients and from 301 controls recruited from the local population in South London. Three indicators of social disadvantage in childhood and six indicators of social disadvantage in adulthood were analysed. RESULTS: Across all the domains considered, cases were more likely to report social disadvantage than were controls. Compared with controls, cases were approximately two times more likely to have had a parent die and approximately three times more likely to have experienced a long-term separation from one parent before the age of 17 years. Cases were also more likely than controls to report two or more indicators of adult social disadvantage, not only at first contact with psychiatric services [odds ratio (OR) 9.5], but also at onset of psychosis (OR 8.5), 1 year pre-onset (OR 4.5), and 5 years pre-onset (OR 2.9). CONCLUSIONS: Greater numbers of indicators of current and long-term exposure are associated with progressively greater odds of psychosis. There is some evidence that social disadvantage tends to cluster and accumulate.

Psychological processes underlying the association between childhood trauma and psychosis in daily life: an experience sampling study.

BACKGROUND: Evidence has accumulated that implicates childhood trauma in the aetiology of psychosis, but our understanding of the putative psychological processes and mechanisms through which childhood trauma impacts on individuals and contributes to the development of psychosis remains limited. We aimed to investigate whether stress sensitivity and threat anticipation underlie the association between childhood abuse and psychosis. METHOD: We used the Experience Sampling Method to measure stress, threat anticipation, negative affect, and psychotic experiences in 50 first-episode psychosis (FEP) patients, 44 At-Risk Mental State (ARMS) participants, and 52 controls. Childhood abuse was assessed using the Childhood Trauma Questionnaire. RESULTS: Associations of minor socio-environmental stress in daily life with negative affect and psychotic experiences were modified by sexual abuse and group (all p FWE < 0.05). While there was strong evidence that these associations were greater in FEP exposed to high levels of sexual abuse, and some evidence of greater associations in ARMS exposed to high levels of sexual abuse, controls exposed to high levels of sexual abuse were more resilient and reported less intense negative emotional reactions to socio-environmental stress. A similar pattern was evident for threat anticipation. CONCLUSIONS: Elevated sensitivity and lack of resilience to socio-environmental stress and enhanced threat anticipation in daily life may be important psychological processes underlying the association between childhood sexual abuse and psychosis.

Determination of dopamine, serotonin, and their metabolites in pediatric cerebrospinal fluid by isocratic high performance liquid chromatography coupled with electrochemical detection.

A method to rapidly measure dopamine (DA), dihydroxyindolphenylacetic acid, homovanillic acid, serotonin (5-HT) and 5-hydroxyindoleacetic acid concentrations in cerebrospinal fluid (CSF) has not yet been reported. A rapid, sensitive, and specific HPLC method was therefore developed using electrochemical detection. CSF was mixed with an antioxidant solution prior to freezing to prevent neurotransmitter degradation. Separation of the five analytes was obtained on an ESA MD-150 x 3.2 mm column with a flow rate of 0.37 mL/min and an acetonitrile-aqueous (5 : 95, v/v) mobile phase with 75 mM monobasic sodium phosphate buffer, 0.5 mM EDTA, 0.81 mM sodium octylsulfonate and 5% tetrahydrofuran. The optimal electrical potential settings were: guard cell +325 mV, E1 -100 mV and E2 +300 mV. Within-day and between-day precisions were <10% for all analytes and accuracies ranged from 91.0 to 106.7%. DA, 5-HT, and their metabolites were stable in CSF with antioxidant solution at 4 degrees C for 8 h in the autoinjector. This method was used to measure neurotransmitters in CSF obtained from children enrolled on an institutional medulloblastoma treatment protocol.

Application of a highly specific and sensitive fluorescent HPLC method for topotecan lactone in whole blood.

Individualization of topotecan dosing reduces inter-patient variability in topotecan exposure, presumably reducing toxicity and increasing efficacy. However, logistical limitations (e.g. requirement for plasma, intensive bedside plasma processing) have prevented widespread application of this approach to dosing topotecan. Thus, the objectives of the present study were to develop and validate an HPLC with fluorescence detection method to measure topotecan lactone in whole blood samples and to evaluate its application to individualizing topotecan dosing. Plasma samples (200 microL) were prepared using methanolic precipitation, a filtration step and then injection of 100 microL of the methanolic extract onto a Novapak C(18), 4 microm, 3.9 x 150 mm column with an isocratic mobile phase. Analytes were detected with a Shimadzu Fluorescence RF-10AXL detector with an excitation and emission wavelength of 370 and 520 nm, respectively. This method had a lower limit of quantification of 1 ng/mL (S/N >or= 5; RSD 4.9%) and was validated over a linear range of 1-100 ng/mL. Results from a 5-day validation study demonstrated good within-day and between-day precision and accuracy. Data are presented to demonstrate that the present method can be used with whole blood samples to individualize topotecan dosing in children with cancer.

Short communication: The effect of feeding high protein distillers dried grains on milk production of Holstein cows.

The objectives of this study were to evaluate the effects of feeding high-protein distillers dried grains (HPDDG) on rumen degradability, dry matter intake, milk production, and milk composition. Sixteen lactating Holstein cows (12 multiparous and 4 primiparous) averaging 80 +/- 14 d in milk were randomly assigned to 1 of 2 dietary treatments in a 2 x 2 crossover design. A portion of forage and all soy-based protein in the control diet were replaced by HPDDG (20% dry matter). Milk production and dry matter intake were recorded daily and averaged for d 19 to 21 of each 21-d period. Milk samples were collected on d 20 to 21 of each period. Milk yield increased with the inclusion of HPDDG (33.4 vs. 31.6 +/- 2.13 kg/d), and 3.5% FCM was higher for the ration containing HPDDG (36.3 vs. 33.1 +/- 2.24 kg/d). Percentage protein was not affected by treatment (average 3.04 +/- 0.08%), but protein yield increased with inclusion of HPDDG (0.95 to 1.00 +/- 0.05 kg/d). Milk fat concentration was not different between treatments (average 3.95 +/- 0.20%), but fat yield increased for the ration containing HPDDG (1.35 vs. 1.21 +/- 0.09 kg/d). Dry matter intake was not affected and averaged 21.9 +/- 0.80 kg across treatments. Because of greater milk production, feed conversion was improved by the inclusion of HPDDG (1.47 to 1.73 +/- 0.09). Milk urea N was greater for the HPDDG ration than the control (14.5 vs. 12.8 +/- 0.67 mg/dL). This research suggests that HPDDG may effectively replace soy-based protein in lactating dairy cow diets.

Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor.

A potential strategy to increase the efficacy of topotecan to treat central nervous system (CNS) malignancies is modulation of the activity of ATP-binding cassette (ABC) transporters at the blood-brain and blood-cerebrospinal fluid barriers to enhance topotecan CNS penetration. This study focused on topotecan penetration into the brain extracellular fluid (ECF) and ventricular cerebrospinal fluid (CSF) in a mouse model and the effect of modulation of ABC transporters at the blood-brain and blood-cerebrospinal fluid barriers by a tyrosine kinase inhibitor (gefitinib). After 4 and 8 mg/kg topotecan i.v., the brain ECF to plasma AUC ratio of unbound topotecan lactone was 0.21 +/- 0.04 and 0.61 +/- 0.16, respectively; the ventricular CSF to plasma AUC ratio was 1.18 +/- 0.10 and 1.30 +/- 0.13, respectively. To study the effect of gefitinib on topotecan CNS penetration, 200 mg/kg gefitinib was administered orally 1 hour before 4 mg/kg topotecan i.v. The brain ECF to plasma AUC ratio of unbound topotecan lactone increased by 1.6-fold to 0.35 +/- 0.04, which was significantly different from the ratio without gefitinib (P < 0.05). The ventricular CSF to plasma AUC ratio significantly decreased to 0.98 +/- 0.05 (P < 0.05). Breast cancer resistance protein 1 (Bcrp1), an efficient topotecan transporter, was detected at the apical aspect of the choroid plexus in FVB mice. In conclusion, topotecan brain ECF penetration was lower compared with ventricular CSF penetration. Gefitinib increased topotecan brain ECF penetration but decreased the ventricular CSF penetration. These results are consistent with the possibility that expression of Bcrp1 and P-glycoprotein at the apical side of the choroid plexus facilitates an influx transport mechanism across the blood-cerebrospinal fluid barrier, resulting in high topotecan CSF penetration.

SEN6, a locus for SV40-mediated immortalization of human cells, maps to 6q26-27.

Normal cells show a limited lifespan in culture and the phenotype of cellular senescence. Tumors and tumor cell lines have typically overcome this form of growth suppression and grow continuously as immortal cell lines in culture. We have exploited the DNA virus SV40 to study the mechanism by which human fibroblasts overcome senescence and become immortal. Multiple steps have now been identified, including inactivation of cellular growth suppressors through direct interaction with SV40 large T antigen and through mutation of a gene on chromosome 6 (designated SEN6). In this study, we sublocalize the site of SEN6 to 6q26-27 based on molecular genetic analysis. Twelve SV40-immortalized fibroblast cell lines share a deletion in this area based on assessment for loss of heterozygostiy (LOH) for seven informative markers on 6q. Two immortal cell lines (AR5 and HALneo) appeared to have retained separate single copies of chromosome 6 despite the fact that they are both derived from the same preimmortal SV40-transformant and should share the same mutated allele of SEN6 (Hubbard-Smith et al., 1992). Detailed analysis by polymerase chain reaction, restriction fragment length polymorphism and fluorescence in situ hybridization shows, however, that although they differ for 17 markers from the centromere to 6q26, they share AR5 derived sequences (eight markers) distal to 6q26 including the minimal deletion region, further supporting the assignment of SEN6 to this region. Since human tumors including non-Hodgkins lymphoma, mammary carcinoma and ovarian carcinoma show LOH in 6q26-27, inactivation of SEN6 may be responsible for immortalization of these tumors as well.

Food selectivity, mealtime behavior problems, spousal stress, and family food choices in children with and without autism spectrum disorder.

Mealtime behavior problems and family stress occur frequently among families of children with autism spectrum disorder (ASD). However, it is unknown whether food selectivity is an associated factor. The associations of high food selectivity with mealtime behavior problems, spousal stress, and influence on family members were assessed among 53 children with ASD and 58 typically developing (TD) children ages 3-11 years. Compared to TD children, children with ASD were more likely to have high food selectivity, and their parents reported more mealtime behavior problems, higher spousal stress, and influence on what other family members ate. High food selectivity was associated with mealtime behavior problems in both groups. Interventions to reduce food selectivity may lead to decreases in mealtime behavior problems.

The Karyote physico-chemical genomic, proteomic, metabolic cell modeling system.

Modeling approaches to the dynamics of a living cell are presented that are strongly based on its underlying physical and chemical processes and its hierarchical spatio-temporal organization. Through the inclusion of a broad spectrum of processes and a rigorous analysis of the multiple scale nature of cellular dynamics, we are attempting to advance cell modeling and its applications. The presentation focuses on our cell modeling system, which integrates data archiving and quantitative physico-chemical modeling and information theory to provide a seamless approach to the modeling/data analysis endeavor. Thereby the rapidly growing mess of genomic, proteomic, metabolic, and cell physiological data can be automatically used to develop and calibrate a predictive cell model. The discussion focuses on the Karyote cell modeling system and an introduction to the CellX and VirusX models. The Karyote software system integrates three elements: (1) a model-building and data archiving module that allows one to define a cell type to be modeled through its reaction network, structure, and transport processes as well as to choose the surrounding medium and other parameters of the phenomenon to be modeled; (2) a genomic, proteomic, metabolic cell simulator that solves the equations of metabolic reaction, transcription/translation polymerization and the exchange of molecules between parts of the cell and with the surrounding medium; and (3) an information theory module (ITM) that automates model calibration and development, and integrates a variety of data types with the cell dynamic computations. In Karyote, reactions may be fast (equilibrated) or slow (finite rate), and the special effects of enzymes and other minority species yielding steady-state cycles of arbitrary complexities are accounted for. These features of the dynamics are handled via rigorous multiple scale analysis. A user interface allows for an automated generation and solution of the equations of multiple timescale, compartmented dynamics. Karyote is based on a fixed intracellular structure. However, cell response to changes in the host medium, damage, development or transformation to abnormality can involve dramatic changes in intracellular structure. As this changes the nature of the cellular dynamics, a new model, CellX, is being developed based on the spatial distribution of concentration and other variables. This allows CellX to capture the self-organizing character of cellular behavior. The self-assembly of organelles, viruses, and other subcellular bodies is being addressed in a second new model, VirusX, that integrates molecular mechanics and continuum theory. VirusX is designed to study the influence of a host medium on viral self-assembly, structural stability, infection of a single cell, and transmission of disease.

SV40-mediated immortalization of human fibroblasts.

We have identified a multistep mechanism by which the DNA virus SV40 overcomes cellular senescence. Expression of SV40 T antigen is required for both transient extension of life span and unlimited life span or immortalization. These effects are mediated through inactivation of function of growth suppressors pRB and p53 via complex formation with T antigen. However, immortalization additionally requires inactivation of a novel growth suppressor gene, which has recently been identified to be on the distal portion of the long arm of chromosome 6, designated SEN6. We propose that SEN6 is responsible for cellular senescence in fibroblasts and other cells.

Immunochemical quantitation of thymine glycol in oxidized and X-irradiated DNA.

The present study demonstrates the usefulness of immunochemical assays for quantitating modified bases in oxidized and X-irradiated DNA. Escherichia coli, phi X174 RF I, PM2, and M13 DNA containing thymine glycols introduced by OsO4 oxidation were used as antigens in a direct enzyme-linked immunosorbent assay (ELISA). The number of thymine glycols per DNA molecule was determined by reactivity with antithymine glycol antibody standardized either to the acetol fragment assay or to the number of Escherichia coli endonuclease III-sensitive sites. The number of thymine glycols was also determined in phi X174 RF I DNA X-irradiated in either phosphate or Tris buffer under air. Using a direct ELISA with phi X174 RF I DNA irradiated in a phosphate buffer solution, the anti-thymine glycol antibody detected damage at the level of 40 Gy. The immunochemical assay was sensitive, specific, quantitative, and independent of DNA structure.

Characterization of a monoclonal antibody to thymidine glycol monophosphate.

A monoclonal antibody specific for thymine glycol (TG) in irradiated or OsO4-treated DNA was obtained by immunizing with thymidine glycol monophosphate (TMP-glycol) conjugated to bovine serum albumin by a carbodiimide procedure. Screening by dot-immunobinding and enzyme-linked immunosorbant assay (ELISA) procedures gave eight clones that bound OsO4- treated DNA. One of them, 2.6F.6B.6C, an IgG2a kappa, was characterized further. Hapten inhibition studies with OsO4-treated DNA showed that the antibody was specific for TMP-glycol. Among the various inhibitors tested, inhibition was in the order TMP-glycol greater than 5,6-dihydrothymidine phosphate greater than TMP greater than thymidine glycol greater than TG. Inhibition by 5,6-dihydrothymidine, thymidine, thymine, AMP, and CMP was negligible. In OsO4-treated DNA, as few as 0.5 TG per 10,000 bp were detectable by direct ELISA. Inhibition assays could detect as few as 1.5 TG per 10,000 bp. The antibody was equally reactive with native or denatured DNA containing TG. Among the X-irradiated homopolymers dC, dA, dG, and dT, only dT reacted with the antibody. Using an ELISA, the antibody could detect damage in irradiated DNA at the level of 20 Gy. Thus the antibody is of potential use in assays for DNA damage caused by X rays or other agents that damage DNA by free radical interactions.

The Bird's Nest Filter. An alternative to long-term oral anticoagulation in patients with advanced malignancies.

Thromboembolic complications are common in patients with advanced malignancies. For these patients anticoagulation with warfarin is often complicated by severe bleeding. For this reason we evaluated the safety and efficacy of the Bird's Nest Filter, a new device capable of preventing migration of thromboemboli to the pulmonary arteries through interruption of the inferior vena cava. We report a series of 31 unselected patients with advanced malignancies and thromboembolic disease in whom the filter was used in lieu of chronic full-dose warfarin anticoagulation. No documented cases of pulmonary emboli occurred after insertion of the filter. Placement of the filter was uncomplicated. Eight patients (25.8%) developed lower-extremity edema. Venous thrombosis distal to the filter was documented in six (19.4%) patients but did not require institution of heparin or warfarin. Two patients (6.5%) required treatment with aspirin for painful lower-extremity thrombophlebitis. No filter migration was documented. We conclude that the use of the Bird's Nest Filter is an option for patients with cancer-related lower-extremity thrombosis who are at risk for pulmonary emboli and are poor candidates for full-dose systemic anticoagulation with warfarin. A prospective randomized trial comparing the filter and the new strategy of low-dose anticoagulation with warfarin will be needed to completely validate this approach.

Phase II evaluation of iproplatin in patients with advanced gastric and pancreatic cancer.

A total of 48 patients with measurable advanced gastric adenocarcinoma (n = 16) or adenocarcinoma of the exocrine pancreas (n = 32) were prospectively treated with iproplatin at a starting dose of 270 mg/m2 intravenously over 2 hours. The dose was repeated every 28 days, and dose escalations or reductions were made on the basis of toxicity in the preceding course. No patient with gastric carcinoma achieved either a complete or partial response. One partial response and two complete responses were seen with pancreatic adenocarcinoma for an overall response rate of 10%. One patient has remained free of disease for more than 2 years. The major toxicities were granulocytopenia, thrombocytopenia, nausea, vomiting, and diarrhea. All toxicities were reversible upon discontinuation of the drug. On the basis of this trial, we conclude that iproplatin has no substantive activity in advanced gastric or pancreatic carcinomas.

Comparison of the pathogenicity for pregnant sheep of Rift Valley fever virus and a live attenuated vaccine.

A live attenuated mutant of Rift Valley fever virus, MV P12, was previously shown to be non-pathogenic in young lambs, but capable of producing protective immunity. The studies reported here show that the abortion in sheep caused by an infection with virulent virus is the result of necrosis of the maternal villi and cotyledons arising from an acute inflammation of the maternal caruncles. Pregnant ewes infected with the attenuated mutant virus MV P12 showed none of these lesions in the placenta and gave birth to healthy lambs. Colostrum from ewes infected with MV P12 virus was able to induce protective immunity in the offspring. These data along with previously published results suggest that the mutant virus MV P12 is an excellent candidate for use as a live attenuated veterinary vaccine.

Ability of a mutagenized virus variant to protect young lambs from Rift Valley fever.

A live attenuated vaccine virus variant of Rift Valley fever (RVF) virus was developed by passaging a human isolate in tissue culture under the influence of the mutagen 5-fluorouracil. This virus variant (MV P12) has been assessed in this study as to its suitability as a vaccine, by testing its pathogenicity in young lambs and measuring its ability to induce a protective immune response. Even high doses of the vaccine virus failed to induce any of the clinical or histopathologic changes associated with classical RVF virus infection. Although the vaccine induced mild pyrexia when given in high doses, viremia was not induced. Neutralizing antibody and a protective immune response was elicited with even low doses of vaccine virus. These data, along with data of other workers on the lack of abortigenicity of this virus variant, indicate that the MV P12 variant of RVF virus is an excellent candidate for a safe and effective vaccine against RVF.

Efficacy of a suicide detection scale in determining lethality of ideation among hospitalized veterans: a case study.

Active suicidal ideation, its underlying psychopathology, concomitant stressors, and ultimate self-destructive behaviors can compromise the combat readiness of the military. An investigation into the clinical utility of a pre-suicidal detection scale (Suicide Probability Scale (SPS] was recently undertaken at the Veterans Administration Medical Center, Hampton, Virginia. A record review of 1,397 patients who were administered the SPS was conducted. Data indicate that 100% of a sample of patients were accurately identified as either imminently or chronically suicidal. The incidence of false negatives was 50%. Results suggest that while the SPS appears to accurately identify patients who have potentially dangerous levels of suicidal ideation, it does not adequately determine lethality or chronicity of suicidal ideation without intent. Potential uses of the SPS are discussed, military health care environments in which its use may be warranted are considered, and future directions are examined.