bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reproductive toxicity testing of pharmaceutical compounds to support the inclusion of women in clinical trials
Authors: Parkinson Chris , Thomas Kate E , Lumley Cyndy E 
Published: December 2008

1 The potential for toxicity to reproduction and the developing fetus is an important concern requiring attention during the development of new medicines. However, there are differences in the opinions of the regulatory authorities in Europe, Japan and the USA regarding the nature and amount of data from reproductive toxicity tests that should be available at the various stages of clinical development. 2 Forty-one companies or their subsidiaries from Eur ope, Japan and the USA provided data for a ques tionnaire-based study, carried out in 1994, to ascertain the practices of pharmaceutical companies and their views on an ideal approach to the timing of reproduc tion and development toxicity studies in relation to clinical investigation. 3 Differences were identified in the stage of drug development at which animal studies were completed, the sequence of completion of specific studies, and the extent of reproduction testing completed to support the inclusion of women in clinical trials. 4 A harmonised, but flexible, guideline, encompassing the timing of reproductive toxicity studies in relation to clinical trials, would permit better integration between clinical and non-clinical studies in an international drug development programme.
Ocular injury with xylene - a report of two cases
Authors: Ansari Ejaz A 
Published: December 2008

1 Xylene is a hydrocarbon solvent found in various industrial preparations such as paint and is widely used in pathology laboratories. 2 When inadvertently instilled into the eye significant ocular injury can occur with the potential for blindness. 3 Such injuries to the ocular surface resemble those due to alkali. 4 Ocular surface injury due to xylene has not been reported previously in the literature. We strongly recommend that these injuries be treated as emergen cies in a similar way to alkali burns in the Eye department since the chemical mixture of which xylene forms a part may be alkaline. Such an approach is vital in order to save sight.
Reappraisal of indications and limitations of oxime therapy in organophosphate poisoning
Authors: Worek F. , Bäcker M. , Thiermann H. , Szinicz L. , Mast U. , Klimmek R. , Eyer P. 
Published: December 2008

1 In vitro studies with human erythrocyte acetylcholin esterase (AChE) and the mouse diaphragm model were performed to unravel the various microscopic reaction parameters that contribute to the dynamic equilibrium of AChE inhibition, ageing and reactivation. These data may help to define more precisely the indications and limitations of oxime therapy in organophosphate (OP) poisoning. 2 Diethylphosphoryl-AChE resulting from intoxications with parathion, chlorpyrifos, chlorfenvinphos, diazi non and other OPs is characterized by slow sponta neous reactivation and low propensity for ageing. This kind of phosphorylated enzyme is particularly sus ceptible to reactivation by oximes. 3 None of the oximes tested (pralidoxime, obidoxime, HI 6 and HLö 7) can be regarded as a universally suitable reactivator. Obidoxime turned out to be the most potent and most efficacious oxime in reactivating AChE inhibited by various classes of OP insecticides and tabun. Obidoxime, however, was inferior to HI 6 against soman, sarin, cyclosarin and VX. Pralidoxime was generally less potent. 4 The kinetic data of reactivation established for diethylphosphoryl-AChE of human red cells indicate that the usually recommended dosage to attain a plasma concentration of 4 μg/ml does not permit exploitation of the full therapeutic potential of the oximes, in particular of pralidoxime. However, in suicidal mega-dose poisoning, oximes, even at optimal plasma concentrations, may be unable to cope with the fast re-inhibition of reactivated AChE in the first days following intoxication. 5 It is suggested that oximes be administered by continuous infusion following an initial bolus dose as long as reactivation can be expected and until permanent clinical improvement is achieved.
Abnormal apoptosis and cell cycle progression in humans exposed to methyl tertiary-butyl ether and benzene contaminating water
Authors: Vojdani Aristo , Mordechai Eli , Brautbar Nachman 
Published: December 2008

1 In this study we hypothesized that in individuals with certain genetic makeup, MTBE, benzene or their metabolites act as adducts and may induce pro grammed cell death. 2 Our study involved a group of 60 male and female subjects who were exposed to MTBE and benzene- 5 contaminated water concentrations up to 76 PPB for MTBE and 14 PPB for benzene, for a period of 5 to 8 years. For comparison, we recruited a control group consisting of 32 healthy males and females with similar age distribution and without a history of exposure to MTBE or benzene. 3 Peripheral blood lymphocytes (PBL) of both groups were tested for the percentage of apoptotic cells and cell cycle progression using flow cytometry. 4 When apoptotic lymphocytes from exposed indivi duals were compared to apoptotic lymphocytes from the control group, statistically-significant differences between each mean group were detected (26.4 ± 1.8 and 12.1 ± 1.3, respectively), indicating an increased rate of apoptosis in 80.5% of exposed individuals ( P<0.0001, Mann-Whitney U-Test). MTBE and ben- a zene-induced apoptosis is attributed to a discrete block within the cell cycle progression. Because cell cycle analysis showed that in PBL from chemically-exposed individuals, between 20-50% of cells were accumu lated at the S-G2/M boundaries. One of the signaling molecules which mediates programmed cell death is nuclear factor Kappa-B (NF-kB). NF-kB was examined as one of the many molecular mechanisms for mediating cell death by MTBE and benzene. Indeed, addition of inhibitors of NF-kB activation pyrrolidine dithiocarbamate (PDTC), to the lymphocytes of the chemically-exposed group was capable of inhibiting programmed cell death by 40%. This reversal of apoptosis almost to the control level by inhibitor of NF-kB activation may indicate involvement of this signaling molecule in MTBE and benzene induction of programmed cell death.
Ganciclovir induces reproductive hazards in male rats after short-term exposure
Authors: Faqi AS , Klug A. , Merker H-J. , Chahoud I. 
Published: December 2008

1 The effect of short-term treatment of ganciclovir on male reproduction in adult rats was studied. The animals were treated subcutaneously with either a single dose of 60 mg/kg daily for 5 days (Gan5day) or with 100 mg/kg administered three times at 4 h- intervals (Gan1day). The effects were investigated every 2 weeks up to 8 weeks, followed by investigations 16 and 24 weeks after treatment to detect the potential of recovery. 2 Time to mating was significantly increased in Gan1day group. The pregnancy index and outcome were only decreased 8 weeks (Gan5day and Gan1day) or 16 weeks (Gan1day) after treatment. 3 The lowest values of sperm variables studied were registered 8 weeks after treatment: The number of spermatid was reduced up to 4% (Gan5day) or 2% (Gan1day) of control; the sperm number was 5% and 8% of control in Gan5day and Gan1day, respectively. Over 80% of sperm were abnormal in Gan5day group, and only few normal sperm was detected in Gan1day group. 4 Morphological investigation of testes revealed a clear- cut time-dependency effect. Four weeks after treat ment distinct alterations were located exclusively in the peripheral part of the tubuli which included fat inclusions, cell and pyknotic nuclear debris and swellings of Sertoli cells. The effect was reversible 24 weeks after treatment. 5 Ganciclovir induces testicular damage and affects sperm variables after short-term exposure. The in tensity and degree of the hazards varied in between the time of investigation after treatment.
The myelotoxicity of chloramphenicol: in vitro and in vivo studies: I. In vitro effects on cells in culture
Authors: Holt DE , Ryder TA , Fairbairn A. , Hurley R. , Harvey D. 
Published: December 2008

1 Chloramphenicol is used extensively in non-industria lized countries for the treatment of life-threatening infections because it is cheap and effective, despite its known hemotoxicity and linkage to fatal aplastic anaemia. It is important to define the mechanism of toxicity so that means can be devised to ameliorate the toxic effects in order to produce safer usage. 2 Chloramphenicol, at concentrations from 5 mM to 2 mM initiated apoptosis in dividing cells from a monkey kidney-derived cell line and in haematopoie tic progenitor cells from human neonatal cord blood. 3 Growth of progenitor cells was suppressed at concen trations of chloramphenicol which would be consid ered less than therapeutic during patient treatment. 4 These effects could be ameliorated in progenitor cells by co-culture with the antioxidant mercaptoethyla mine and in monkey kidney cells by co-culture with vitamin C. 5 This is the first report of apoptosis in chloramphenicol toxicity and suggests a possible link between a metabolic event i.e. the production of free radicals; a morphological effect, apoptosis; and a clinical effect, bone marrow suppression and aplastic anaemia.
The role of mouse intestinal microflora in the metabolism of trichloroethylene, an in vivo study
Authors: Moghaddam AP , Abbas R. , Fisher JW , Lipscomb JC 
Published: December 2008

1 Both trichloroethylene and its metabolite, dichloroa cetic acid, produce liver tumors peroxisome prolifera tion and other adverse cellular alterations in rodents.2 The hepatic mechanism by which dichloroacetic acid is formed is not conclusively demonstrated, but pharmacokinetic models have successfully associated its formation with trichloroacetic acid as immediate precursor.3 Previous investigations have shown that dichloroace tic acid is formed from trichloroacetic acid by gut microflora isolated in vitro.4 To determine the impact of gut microflora on dichlor oacetic acid formation from a trichloroethylene dose in vivo, we developed a procedure which reduced gut microflora some 3 orders of magnitude below pub lished levels.5 The administration of trichloroethylene to control mice and to mice whose gut was practically sterile resulted in equivalent concentrations of dichloroace tic acid and other metabolites in blood and liver, but significantly different content of these metabolites in cecum contents.6 These data indicate that gut microflora contribute minimally, if at all, to the formation of circulating dichloroacetic acid under these conditions.
The percutaneous absorption and skin distribution of lindane in man
Authors: Dick Ian P , Blain Peter G , Williams Faith M 
Published: December 2008

1 The absorption of lindane through human skin was assessed in vitro using static diffusion cells with 50% aqueous ethanol as the receptor fluid. Four formula tions of lindane were applied, three of which were commercial preparations. The dermal distribution of lindane within the skin was also examined, focusing particularly on any association of lindane to the stratum corneum. The results were then compared with a parellel in vivo study. 2 Two of the formulations contained white spirit as the predominant solvent, and lindane absorption was greatest from these preparations in terms of the percentage of the applied dose (15-25% by 24 h). Absorption was less from an aqueous spray dilution (3% by 24 h), with absorption from acetone being the least ( < 1% by 24 h). Similar amounts of lindane penetrated by 24 h for the acetone and white spirit- based applications (approx. 8 ?g). This supported the in vivo observation that similar plasma lindane levels were recorded following exposure to the acetone solution and the white spirit-based formulation A, although the lindane concentration in acetone was 40- fold higher. 3 For the acetone and water-based preparations, a soap/ water swab of the skin surface at 6 h contained the majority of the applied dose (around 75%). Substantial amounts of lindane were recovered in tape-strippings taken at 6 h (representative of stratum corneum content) which were significantly greater than lindane in the remainder of the skin, for the acetone solution and formulation A. This provided a strong indication that lindane had accumulated in the stratum corneum, a property that has been linked with other lipophilic chemicals.
Inhibitory effects of antibiotics on platelet aggregation in vitro
Authors: Kariyazono Hiroko , Nakamura Kazuo , Shinkawa Terutoshi , Moriyama Yukinori , Toyohira Hitoshi , Taira Akira , Yamada Katsushi 
Published: December 2008

1 We evaluated in vitro inhibitory effects of six types of antibiotic, aztreonam (AZT), cefamandole (CMD), cefmetazole (CMZ), cefotiam (CTM), flomoxef (FMOX) and latamoxef (LMOX), on platelet aggregation, using healthy volunteers' blood. Four types-FMOX, LMOX, CTM and CMD-inhibited, in concentration of 2500 ?g/ml, the secondary aggregation induced by 3.0 ?M adenosine diphosphate (ADP), and also inhibited the aggregation induced by 0.5 ?g/ml collagen. AZT in the same concentration, did not inhibit the aggregation induced by collagen, and it inhibited only ADP induced aggregation. CMZ, in the same concentration, inhibited neither of the two aggregations. 2 The inhibitory effects of the antibiotics on collagen- induced aggregation were dependent on the concen tration of respective antibiotics. When classified by the strength of inhibitory action, LMOX and FMOX were strong, followed by CTM and CMD. The action of AZT and CMZ was weak. In particular, LMOX showed a 32% inhibitory effect at concentration of 50 ?g/ml, a level near the blood concentration obtained with clinical usual dose. 3 No relationship was observed between inhibitory effects of antibiotics on ADP- or collagen-induced aggregation and the presence or absence of carboxyl group and/or N-methyltetrazolethiol group in the chemical structure.
Access to Vocational Rehabilitation Services for Persons With Severe Disabilities
Authors: Salkever David S. 
Published: December 2008

It is widely recognized that the number of persons eligible to receive the services of state vocational rehabilitation (VR) agencies far exceeds the capacity of these agencies. The U.S. General Accounting Office (GAO) notes that in 1989 "program funding for VR was sufficient to serve only ... 7 per cent of the estimated 13.4 million persons with disabilities who were potentially eligible" for services (1991, p. 2). Under such tight resource constraints, the problem of rationing services becomes a critical concern. This paper presents the results of a population-based study of the receipt of VR services using a recent survey data base of youth and adults with developmental disabilities. The paper describes relationships between disability-related factors, demographic factors, and receipt of services. It also examines how state VR agency resources and reported client selection practices relate to the probability of receiving services.
SAFE:
Authors: Hylton Judith 
Published: December 2008

A multimedia approach for adolescents and adults who have serious learning problems New Products is a regular department that describes recently published teaching materials or tests. It is usually written by the staff of the publisher or by the author of the material or test. Suggestions for this column should be sent to Ann Grasso Ryan, Column Editor, University of St. Thomas, 2115 Summit Ave., St. Paul, MN 55105.–-AGR
Allergies and Learning/Behavioral Disorders
Authors: McLoughlin James A. , Nall Michael 
Published: December 2008

How allergies affect school learning and behavior---and how to help Every fall and spring many teachers notice an outburst of coughmg, sneezing, wheezing, and nose blowing in their classrooms. Afflicted students E are rubbing itchy and bloodshot eyes, scratchmg rashes, and complaining of stomachaches and headaches. They are listless and generally miserable. Yes, you guessed it; it is allergy season! Besides the additional noise and movement in the classroom, teachers are concerned about other things. They question whether this is a temporary condition, and whether they should call parents about it. They sometimes wonder if the sleepy or hyperactive child is taking too much medication. Allergy outbreaks could not come at a worse time than the beginning of the school year, when the student's full attention is particularly crucial, or the end of the school year, when the student's best performance is required on final examinations.
Comprehensive Planning for Hearing Impaired Children: A Summary of State Planning
Authors: Murphy Lee C. , Hargis Charles , Kretschmer Robert 
Published: December 2008

This document is a summary of a study of state level comprehensive planning for the hearing impaired. The project was undertaken in January, 1975. Requests for information were sent to state directors of special education and state directors of vocational rehabilitation. The first request for information was mailed in late March of 1975, and follow-up requests were mailed early in July. The last materials were received in November. Some response was received from all but six states. A wide variety of documents and correspondence was received. Each piece of material was reviewed and summary items were prepared. The variety of laws or rules and policies varied greatly from state to state.
The Speech-Language Pathologist's Changing Role
Authors: Dohan Margaret , Schulz Henry 
Published: December 2008

This study gathered descriptive information on the status of classroom-based speech and language services in Canada through a questionnaire mailed to school speech-language pathologists (SLPs). Seven service delivery approaches for classroom-based intervention ranging from least collaborative to most collaborative were listed. The approaches were used by the largest percentages of respondents for language disorders, followed in order by those for articulation, fluency, and voice disorders, and for students in Kindergarten to Grade 3, followed in order by those for Grades 4 to 6, Grades 7 to 9, and Grades 10 to 12. The approaches were judged to be successful with all disorder types and all grade level categories by the majority of respondents who used them. The less collaborative approaches were used by larger percentages of SLPs than the more collaborative approaches. Results are consistent with reports in the literature on the use of classroom-based approaches by SLPs. Findings reflect the SLP's current role as a communication and language specialist who collaborates with teachers to meet students' communication needs, often through the use of classroom-based approaches. Conclusions of the study lead to suggestions for facilitating collaboration between SLPs and teachers.
Population-specific genetic variants important in susceptibility to cytarabine arabinoside cytotoxicity
Authors: Hartford Christine M. , Duan Shiwei , Delaney Shannon M. , Mi Shuangli , Kistner Emily O. , Lamba Jatinder K. , Huang R. Stephanie , Dolan M. Eileen 
Published: December 2008

Abstract
Cytarabine arabinoside (ara-C) is an antimetabolite used to treat hematologic malignancies. Resistance is a common reason for treatment failure with adverse side effects contributing to morbidity and mortality. Identification of genetic factors important in susceptibility to ara-C cytotoxicity may allow for individualization of treatment. We used an unbiased whole-genome approach using lymphoblastoid cell lines derived from persons of European (CEU) or African (YRI) ancestry to identify these genetic factors. We interrogated more than 2 million single nucleotide polymorphisms (SNPs) for association with susceptibility to ara-C and narrowed our focus by concentrating on SNPs that affected gene expression. We identified a unique pharmacogenetic signature consisting of 4 SNPs explaining 51% of the variability in sensitivity to ara-C among the CEU and 5 SNPs explaining 58% of the variation among the YRI. Population-specific signatures were secondary to either (1) polymorphic SNPs in one population but monomorphic in the other, or (2) significant associations of SNPs with cytotoxicity or gene expression in one population but not the other. We validated the gene expression-cytotoxicity relationship for a subset of genes in a separate group of lymphoblastoid cell lines. These unique genetic signatures comprise novel genes that can now be studied further in functional studies.
Successful treatment of canine hemophilia by continuous expression of canine FVIIa
Authors: Margaritis Paris , Roy Elise , Aljamali Majed N. , Downey Harre D. , Giger Urs , Zhou Shangzhen , Merricks Elizabeth , Dillow Aaron , Ezban Mirella , Nichols Timothy C. , High Katherine A. 
Published: December 2008

Abstract
Continuous expression of activated factor VII (FVIIa) via gene transfer is a potential therapeutic approach for hemophilia patients with or without inhibitory antibodies to human factor VIII (FVIII) or IX (FIX). Here, we investigate whether gene transfer of an engineered canine FVIIa (cFVIIa) transgene can affect hemostasis in a canine model of hemophilia, a good predictor of efficacy of hemophilia treatments. Purified recombinant cFVIIa exhibited 12-fold higher tissue factor–dependent activity than purified recombinant zymogen cFVII. Subsequently, we generated a serotype 8 recombinant adeno-associated viral vector expressing cFVIIa from a liver-specific promoter. Vector delivery via the portal vein in hemophilia A and B dogs was well tolerated, and long-term expression of cFVIIa resulted in a shortening of the prothrombin time, partial correction of the whole blood clotting time and thromboelastography parameters, and a complete absence of spontaneous bleeding episodes. No evidence of hepatotoxicity, thrombotic complications, or inhibitory immune response was found. These data provide the first evidence for in vivo efficacy and safety of continuously expressed FVIIa as a FVIII/FIX-bypassing agent in a large animal model of hemophilia, avoiding the risk of inhibitor formation associated with bolus FVIII or FIX infusion.