Malignant uveal schwannoma with peripheral nerve extension in a 12-week-old color-dilute Labrador Retriever.

The formalin-fixed, amber-colored right globe from a 12-week-old female silver Labrador Retriever dog was submitted to the Comparative Ocular Pathology Laboratory of Wisconsin for light microscopic evaluation. The clinical history described a collapsed anterior chamber and multifocal nodular lesions in the peripheral iris. Histologically, immunohistochemically, and ultrastructurally, the uveal mass was consistent with a malignant schwannoma; there was extension along peripheral nerves within the sclera. The signalment and behavior of the neoplasm distinguish it from the uveal schwannoma of blue-eyed dogs and bear some resemblance to the ocular lesions in human neurofibromatosis. The dilute color mutation may contribute to the cause. Six weeks later, the dog did not develop any additional masses.

Oncogenic RIT1 mutations in lung adenocarcinoma.

Lung adenocarcinoma is comprised of distinct mutational subtypes characterized by mutually exclusive oncogenic mutations in RTK/RAS pathway members KRAS, EGFR, BRAF and ERBB2, and translocations involving ALK, RET and ROS1. Identification of these oncogenic events has transformed the treatment of lung adenocarcinoma via application of therapies targeted toward specific genetic lesions in stratified patient populations. However, such mutations have been reported in only ∼55% of lung adenocarcinoma cases in the United States, suggesting other mechanisms of malignancy are involved in the remaining cases. Here we report somatic mutations in the small GTPase gene RIT1 in ∼2% of lung adenocarcinoma cases that cluster in a hotspot near the switch II domain of the protein. RIT1 switch II domain mutations are mutually exclusive with all other known lung adenocarcinoma driver mutations. Ectopic expression of mutated RIT1 induces cellular transformation in vitro and in vivo, which can be reversed by combined PI3K and MEK inhibition. These data identify RIT1 as a driver oncogene in a specific subset of lung adenocarcinomas and suggest PI3K and MEK inhibition as a potential therapeutic strategy in RIT1-mutated tumors.

Risedronate pharmacokinetics and intra- and inter-subject variability upon single-dose intravenous and oral administration.

PURPOSE: To determine the pharmacokinetics and absolute bioavailability of risedronate after single-dose oral administration of 30 mg risedronate as a tablet and an aqueous solution, and 0.3 mg risedronate as an intravenous infusion. METHODS: This study was a randomized, three-treatment, four-period, partial replicate crossover study involving 33 healthy volunteers. Treatments were administered 7 weeks apart, and the third treatment was repeated during the fourth period. Serum and urine were collected over 72 hours and 672 hours, respectively. RESULTS: Following intravenous administration, renal clearance accounted for 87% of total clearance, with 65% of the dose excreted within 24 hours and 85% of the dose excreted within four weeks. The absolute bioavailability was approximately 0.62% after both oral formulations, and the relative bioavailability of the tablet compared with the oral solution was 104%. The rate and extent of absorption from the two formulations were bioequivalent based on the range proposed for highly variable drugs. Intrasubject variability following oral administration was 50-80%, and was primarily associated with absorption. CONCLUSION: The majority of the total clearance after intravenous administration of risedronate was renal clearance, indicating that only a small percentage of a systemic dose is potentially incorporated, or "cleared," into bone. The absolute bioavailability of orally administered risedronate is approximately 0.6%, and is independent of formulation. Variability in the pharmacokinetics following oral administration is primarily associated with intrasubject variability in absorption.

Radiation exposure during air travel: guidance provided by the Federal Aviation Administration for air carrier crews.

Air carrier crews are occupationally exposed to ionizing radiation, principally from galactic cosmic radiation. To promote radiation safety in aviation the Federal Aviation Administration has: issued educational material on the nature of the radiation received during air travel; recommended radiation exposure limits for pregnant and nonpregnant aircrew members; developed computer programs that estimate for a given flight profile the amount of galactic radiation received on a current flight or on one flown at any time back to January 1958; published tables that enable aircrew members to estimate possible health risks associated with their occupational exposure to radiation; and conducted research on effects of radiation during pregnancy. References for this material are given in the article. In addition, graphic and tabular data in the article show how galactic radiation levels and the composition of the galactic radiation has changed between 1958 and 1999. Also given are estimates of effective doses received by air travelers on a wide variety of air carrier flights.

Galactic cosmic radiation exposure of pregnant flight crewmembers.

BACKGROUND: In recommending the occupational dose limit of ionizing radiation for pregnant women, the International Commission on Radiological Protection apparently assumes that the dose to the conceptus from ionizing radiation exposure is about half the dose at the surface of the mother's abdomen. METHODS: To test this assumption with respect to galactic cosmic radiation, calculations were made using FAA computer program CARI-LF2, which calculates equivalent doses from galactic cosmic rays at selected depths in soft tissue at any specified location in the atmosphere or on user-entered flight profiles. RESULTS: The calculations showed that the equivalent dose of galactic radiation was almost the same at all depths. CONCLUSIONS: Thus the assumption of considerable shielding of the conceptus being provided by the woman's body is not correct with respect to galactic cosmic radiation, the principal type of radiation to which aircrews are exposed. The effective dose as calculated with FAA computer program CARI-5E, which calculates effective dose in an anthropomorphic phantom at any specified location in the atmosphere or on user-entered flight profiles, was found to be a good estimate of the equivalent dose at the depth of the conceptus.

Collaboration with government leaders to promote sustainability, Cross River State, Nigeria. The Calabar PMM Team.

PRELIMINARY STUDIES: Focus group studies and facility reviews revealed poorly equipped and under-utilized emergency obstetric facilities in two rural communities in Cross River State, Nigeria. INTERUENTIONS: Beginning in late 1992, state and local government leaders were contacted to sensitize them to the problem of maternal mortality and enlist their cooperation in activities to upgrade obstetric services. RESULTS: A maternal health unit was created in the State Ministry of Health. Government officials were instrumental in upgrading hospital and polyclinic facilities, correcting staff shortages, repairing an ambulance, establishing a blood bank, granting leave to midwives for participation in skills workshops and facilitating dissemination of information. COSTS: Nineteen visits to government officials required approximately 33 person-days of the team's time. Transportation, communication and per diems were also paid. Government contributed a considerable amount in staff time and provided venues for workshops. CONCLUSIONS: A great deal can be achieved to improve emergency obstetric services through collaboration with government. Support and cooperation of government leaders can also enhance sustainability of interventions.

Community mobilization for blood donation, Cross River State, Nigeria. The Calabar PMM Team.

PRELIMINARY STUDIES: A study of institutions in Cross River State, Nigeria, revealed poor storage facilities and inadequate availability of blood. Focus group discussions highlighted people's fears and misconceptions about blood donations as important factors contributing to the problem. INTERVENTIONS: Blood facilities were upgraded in the teaching hospital and a secondary institution. Fifteen community mobilization sessions to improve attitudes and stimulate voluntary blood donation were conducted over three months in 1994. Non-cash incentives were offered, including certificates of honor, free blood screening and assurance of priority if a family member needed blood. RESULTS: Blood donations to the teaching hospital maternity increased from 40 pints per month in 1991 to 81 in 1994. However, national strikes interrupted service and the increase was not sustained. At the secondary facility, blood transfusions increased from 14 in 1991 to 35 in 1995, with 100% of donations from volunteers. COSTS: The cost of community mobilization for blood donation was US $17,531. CONCLUSIONS: Increasing voluntary blood donations through non-cash incentives and community mobilization is possible. No conclusions may be drawn regarding sustainability, however.

Mobilizing the community to utilize obstetric services, Cross River State, Nigeria. The Calabar PMM Team.

PRELIMINARY STUDIES: Twenty-one focus groups and a survey in two rural communities revealed socioeconomic and cultural barriers to utilization of emergency obstetric services. INTERVENTIONS: To facilitate the use of services, 20 community educators were trained and an education campaign was conducted beginning in 1994. Educational activities emphasized the need for women with obstetric complications to use obstetric services at two local health facilities and one teaching hospital. Communities were also mobilized to set up loan and transport programs. RESULTS: Awareness of obstetric complications increased in both communities and for all complications: increases ranged from 5% (for obstructed labor) to 63% (for hemorrhage). Fourteen of 39 project communities established new loan programs (six communities already had them). Loans were granted in only nine communities. Transport systems were established in nine communities. Referrals to the teaching hospital of women with major obstetric complications from two health facilities in the study area increased from three in 1990 to 11 in 1995 in one community and from four to eight in the other. COSTS: The cost of the mobilization activities was approximately US $6500. CONCLUSION: Community education and mobilization can help increase awareness of obstetric complications.

Evidence for a schizophrenia vulnerability locus on chromosome 8p in the Irish Study of High-Density Schizophrenia Families.

OBJECTIVE: This study was an attempt to replicate evidence for a vulnerability locus for schizophrenia and associated disorders in the 8p22-21 region reported by Pulver and colleagues. METHOD: The linkage sample of the Irish Study of High-Density Schizophrenia Families consists of 265 multiplex families containing 1,408 individuals. Fifteen markers covering 30 centimorgans on chromosome 8p were tested. Three statistical methods were used: two-point and multipoint heterogeneity lod scores and a multipoint nonparametric test. RESULTS: According to two-point heterogeneity lod scores, the strongest evidence for linkage was found for markers D8S1731 (maximum lod score = 2.00), D8S1715 (maximum lod score = 2.52), and D8S133 (maximum lod score = 2.08) by assuming a phenotypic definition of all psychiatric illness and a range of genetic models. According to multipoint heterogeneity lod scores, the strongest evidence for linkage (maximum lod score = 2.34), found by using a dominant genetic model and a broad definition of the schizophrenia spectrum, extended over a 10-cM region between markers D8S1715 and D8S1739. Multipoint nonparametric linkage found the strongest evidence (maximum z = 2.51) over a broader region when either a diagnosis of core schizophrenia or a narrow definition of the schizophrenia spectrum was used. This putative vulnerability locus was segregating in 10%-25% of the families studied. CONCLUSIONS: This study supports the existence of a vulnerability locus for schizophrenia on chromosome 8p. In this sample, this locus appears to influence the risk of illness in only a modest proportion of families and predisposes to a range of schizophrenia spectrum and possibly nonspectrum disorders.

Irish study on high-density schizophrenia families: field methods and power to detect linkage.

Large samples of multiplex pedigrees will probably be needed to detect susceptibility loci for schizophrenia by linkage analysis. Standardized ascertainment of such pedigrees from culturally and ethnically homogeneous populations may improve the probability of detection and replication of linkage. The Irish Study of High-Density Schizophrenia Families (ISHDSF) was formed from standardized ascertainment of multiplex schizophrenia families in 39 psychiatric facilities covering over 90% of the population in Ireland and Northern Ireland. We here describe a phenotypic sample and a subset thereof, the linkage sample. Individuals were included in the phenotypic sample if adequate diagnostic information, based on personal interview and/or hospital record, was available. Only individuals with available DNA were included in the linkage sample. Inclusion of a pedigree into the phenotypic sample required at least two first, second, or third degree relatives with non-affective psychosis (NAP), one whom had schizophrenia (S) or poor-outcome schizo-affective disorder (PO-SAD). Entry into the linkage sample required DNA samples on at least two individuals with NAP, of whom at least one had S or PO-SAD. Affection was defined by narrow, intermediate, and broad criteria. The phenotypic sample contained 277 pedigrees and 1,770 individuals and the linkage sample 265 pedigrees and 1,408 individuals. Using the intermediate definition of affection, the phenotypic sample contained 837 affected individuals and 526 affected sibling pairs. Parallel figures for the linkage sample were 700 and 420. Individuals with schizophrenia from these multiplex pedigrees resembled epidemiologically sampled cases with respect to age at onset, gender distribution, and most clinical symptoms, although they were more thought-disordered and had a poorer outcome. Power analyses based on the model of linkage heterogeneity indicated that the ISHDSF should be able to detect a major locus that influences susceptibility to schizophrenia in as few as 20% of families. Compared to first-degree relatives of epidemiologically sampled schizophrenic probands, first-degree relatives of schizophrenic members from the ISHDSF had a similar risk for schizotypal personality disorder, affective illness, alcoholism, and anxiety disorder. With sufficient resources, large-scale ascertainment of multiplex schizophrenia pedigrees is feasible, especially in countries with catchmented psychiatric care and stable populations. Although somewhat more severely ill, schizophrenic members of such pedigrees appear to clinically resemble typical schizophrenic patients. Our ascertainment process for multiplex schizophrenia families did not select for excess familial risk for affective illness or alcoholism. With its large sample ascertained in a standardized manner from a relatively homogeneous population, the ISHDSF provides considerable power to detect susceptibility loci for schizophrenia.

A potential vulnerability locus for schizophrenia on chromosome 6p24-22: evidence for genetic heterogeneity.

In 265 Irish pedigrees, with linkage analysis we find evidence for a vulnerability locus for schizophrenia in region 6p24-22. The greatest lod score, assuming locus heterogeneity, is 3.51 (P = 0.0002) with D6S296. Another test, the C test, also supported linkage, the strongest results being obtained with D6S296 (P = 0.00001), D6S274 (P = 0.004) and D6S285 (P = 0.006). Non-parametric analysis yielded suggestive, but substantially weaker, findings. This locus appears to influence the vulnerability to schizophrenia in roughly 15 to 30% of our pedigrees. Evidence for linkage was maximal using an intermediate phenotypic definition and declined when this definition was narrowed or was broadened to include other psychiatric disorders.

The potassium disulphate-potassium sulphate, silver chloride-potassium chloride electrochemical cell.

The fused salt electrochemical cell: Ag; AgCl, KC1; K(2)S(2),O(7),K(2)SO(4); O(2), Pt has been studied. Exact thermodynamic treatment of the chemical reaction, which occurs when current is drawn from the cell, is possible because K(2)S(2)O(7)(1) and AgCl(1) are immiscible, so that no junction potential occurs. Potentials observed at temperatures ranging from 700-800 degrees K for six different mixtures are reported. The Nernst equation is obeyed if it is assumed that the potassium disulphate-potassium sulphate system behaves ideally and that the silver chloride-potassium chloride system deviates slightly, negatively, from ideality. The thermodynamic functions, DeltaG degrees , DeltaH degrees and DeltaS degrees have been calculated from the corrected values of E degrees obtained. The free energy change follows the equation: DeltaG(700-800 degrees K) degrees = -71,680-29.50 T cal mole .

Flavin enzymes: molecular orbital calculations.

Molecular orbital calculations were obtained for one hundred and forty-four versions of the flavin group contained in oxidase enzymes. Ten different structures were considered and the results indicate that the flavin group changes its identity from a pi electron acceptor to a pi electron donor after reduction occurs, regardless of the inductive effect of the attached protein. Furthermore, the calculations suggest both the site for reduction and the mechanism by which it proceeds.