bluuebunny/crossref_metadata_2025 huggingface dataset:
Status of Computerized Cognitive Behavioural Therapy for Adults
Authors: Titov Nickolai
Published: March 2007

A growing body of evidence supports the efficacy of computerized cognitive behavioural therapy (CCBT). This technology has the potential to increase the capacity of mental health services, and to overcome some of the barriers to accessing mental health services, including stigma, traveling time for rural patients, treatment delays, and the low availability of skilled clinicians. This review discusses key issues around the implementation of CCBT in current mental health services, and summarizes recent evidence for the efficacy of CCBT in anxiety and depression. Many CCBT systems exist, and the evidence for each varies in quality and quantity. It is concluded that CCBT, particularly guided by a therapist, represents a promising resource. However, considerable work needs to be done to develop CCBT techniques that are appropriate to Australasian populations, acceptable to patients and clinicians, easy to use, and are clinically and cost effective. Suggestions are made for further research and useful website addresses are provided to assist clinicians in familiarizing themselves with CCBT.
Neuropsychological Impairment in Major Depression: Its Nature, Origin and Clinical Significance
Authors: Porter Richard J. , Bourke Cecilia , Gallagher Peter
Published: March 2007

Neuropsychological impairment is well established as a feature of major depressive disorder (MDD) but studies have shown a variable pattern of impairment. This paper seeks first to clarify this by examining methodological and clinical factors that give rise to variability in study findings. Second, it examines theories of the origin of these neuropsychological abnormalities. Third, it reviews evidence regarding the clinical significance of different patterns of deficit. A selective review was undertaken of the literature with a particular emphasis on methodological factors, the influence of clinical subtypes and prevalent theories of neuropsychological abnormality. Methodological issues and the heterogeneity of MDD account for considerable variability in results. Specific investigation of the subtypes of psychotic MDD, melancholic MDD and bipolar depression reduces this heterogeneity and results are more consistent in the elderly. Hypothalamic–pituitary–adrenal axis dysfunction is associated with neuropsychological dysfunction in MDD although evidence of direct causation is not definitive at present. Impairment of executive and psychomotor function is a consistent finding, particularly in the elderly, and may reflect frontostriatal–limbic dysfunction. There is growing evidence that this may have clinical significance. It is suggested that future research take very careful account of the exact phenotype of MDD. Classification based on neuropsychological profile may, in fact, be useful. Further research should examine further the clinical importance of patterns of neuropsychological impairment.
Better Outcomes in Mental Health Care: Impact of Different Models of Psychological Service Provision on Patient Outcomes
Authors: Morley Belinda , Pirkis Jane , Sanderson Kristy , Burgess Philip , Kohn Fay , Naccarella Lucio , Blashki Grant
Published: March 2007

Objective: One hundred and eight Access to Allied Psychological Services projects have been funded under Australia's Better Outcomes in Mental Health Care programme since July 2001. All projects are run by Divisions of General Practice and enable general practitioners (GPs) to refer patients to allied health professionals for evidence-based care. They differ in the models they use to retain, locate and direct referrals to their allied health professionals. This paper examines the extent to which the projects are achieving positive patient outcomes, and explores the association between different models of service delivery and varying levels of patient outcomes.

Method: The paper draws on two data sources (a purpose-designed minimum dataset and a survey of models of service delivery) to examine the level of patient outcomes within and across projects, and variations in the level of patient outcomes by models of service delivery.

Results: The projects are achieving positive effects and these are mostly of large or medium magnitude. The projects do not differ markedly in terms of the patient outcomes they are achieving, despite differences in the models of service delivery they are using. However, those projects implementing a direct referral model, where the GP refers the patient directly to the allied health professional, have significantly greater effect sizes, indicating that they are achieving greater improvements in patient outcomes. In addition, there are non-significant trends toward direct employment of allied health professionals by Divisions being predictive of greater improvements in patient outcomes, and delivery of services from allied health professionals’ own rooms being predictive of weaker patient outcomes.

Conclusions: Overwhelmingly, the Access to Allied Psychological Services projects are having a positive impact for patients in terms of their level of functioning, severity of symptoms and/or quality of life. Preliminary indications suggest that a service delivery model incorporating the use of a direct referral system may be associated with superior outcomes. The findings are discussed in the light of the imminent listing of psychologists’ services on the Medicare Benefits Schedule.
Reliability and Validity of the Kessler 10 and Patient Health Questionnaire among Injecting Drug Users
Authors: Hides Leanne , Lubman Dan I. , Devlin Harriet , Cotton Sue , Aitken Campbell , Gibbie Tania , Hellard Margaret
Published: March 2007

Objective: To examine the reliability and validity of the Kessler 10 (K10) and the Patient Health Questionnaire (PHQ) in a sample of injecting drug users (IDUs).

Method: Participants were 103 IDUs with a current substance use disorder accessing a needle and syringe programme. Presence of mental health disorders was assessed using the Mini International Neuropsychiatric Interview (MINI).

Results: Both the K10 and PHQ had high levels of internal consistency and concurrent validity. Individuals with a positive screen on the K10 were ten lines more likely to have a current affective disorder, while those with a positive PHQ screen had nearly 14 times the risk.

Conclusions: The K10 and PHQ are recommended as brief screening and diagnostic tools for current affective disorders among IDUs.
Changes in Brain-Derived Neurotrophic Factor Following Treatment with Mifepristone in Bipolar Disorder and Schizophrenia
Authors: Mackin Paul , Gallagher Peter , Watson Stuart , Young Allan H. , Nicol Ferrier I.
Published: March 2007

Objective: Brain-derived neurotrophic factor (BDNF) is stress-responsive and has been implicated in a number of disparate neuropsychiatric disorders. Glucocorticoid antagonists have been shown to have beneficial effects on mood and cognitive function in bipolar disorder but not in schizophrenia. The aim of the present study was to investigate BDNF levels in patients with bipolar disorder and schizophrenia before and after treatment with the glucocorticoid receptor antagonist mifepristone.

Methods: Peripheral BDNF levels were measured in patients with bipolar disorder (n=20), schizophrenia (n=20) and 14 matched healthy controls following 7 days of adjunctive mifepristone (600 mg day−1) treatment in a double-blind, placebo-controlled crossover design study.

Results: Baseline BDNF values were similar in both patient groups and in healthy controls. Following treatment with mifepristone, cortisol levels were significantly increased and BDNF levels decreased in both schizophrenia and bipolar disorder. A significant correlation existed between change in cortisol level and change in BDNF levels following mifepristone treatment in schizophrenia, but not in bipolar disorder.

Conclusion: Differing BDNF responses to increasing cortisol levels between patients with schizophrenia and with bipolar disorder may reflect underlying pathophysiological mechanisms.
Gene Expression Profiling in Brodmann's Area 46 from Subjects with Schizophrenia
Authors: Dean Brian , Keriakous Dahlia , Scarr Elizabeth , Thomas Elizabeth A.
Published: March 2007

Objective: To identify altered gene expression in the dorsolateral prefrontal cortex obtained after death from subjects with schizophrenia.

Method: Restriction fragment differential display (RFDD) was used to measure levels of mRNA in Brodmann area (BA) 46 from schizophrenia and control subjects. Findings on specific mRNA identified with RFDD were further investigated using real-time polymerase chain reaction (real-time PCR), PCR and western blotting.

Results: Levels of mRNA for 63 of approximately 12 500 genes differed in BA 46 in schizophrenia. Subsequent real-time PCR has shown that mRNA for muscleblind protein 1 ( MBNL1) and protocadherin 17 ( PCDH17) are increased in BA 46 from subjects with schizophrenia of short, but not long, duration. Altered levels of mRNA for neither gene were present in BA 9 from subjects with schizophrenia or in either cortical area from subjects with bipolar 1 disorder. By contrast, both RFDD and real-time PCR failed to show altered expression of the schizophrenia candidate gene disrupted in schizophrenia 1 ( DISC1) BA46 from any diagnostic cohort.

Conclusion: The present study has identified genes that are differentially expressed in BA 46 in schizophrenia. Initial studies have shown that there is a need for a careful validation of genes shown to be affected in schizophrenia using high-throughput technologies. In addition the present study has shown that gene expression may vary considerably depending on the duration of schizophrenia. This raises the hypothesis that changing gene expression may be underlying the change in symptom profile that occurs with disease progression in some subjects with schizophrenia.
Did Geographical Inequalities in Suicide Among Men Aged 15–44 in New Zealand Increase During the Period 1980–2001?
Authors: Pearce Jamie , Barnett Ross , Collings Sunny , Jones Irfon
Published: March 2007

Objective: It has previously been reported that rates of suicide among men aged 15–44 increased rapidly during the 1980s and 1990s. The present study examines whether geographical inequalities in suicide rates among men in this age group rose during the period 1980–2001 in New Zealand.

Methods: Age-standardized rates of suicide for men aged 15–44 were calculated for District Health Boards (DHBs) and in deprivation quintiles (using the 2001 New Zealand deprivation score) for the periods 1980–1982, 1985–1987, 1990–1992, 1995–1997 and 1999–2001. Geographical inequality was measured by calculating the ratio of the suicide rate deprivation quintile 5 to quintile 1.

Results: Age-standardized rates of suicide among men aged 15–44 increased in all but two DHBs between 1980 and 2001. The ratio of inequality in suicide between the least deprived and most deprived areas of New Zealand rose from 1.68 in 1980–1982 to a high of 1.94 in 1990–1992, followed by a small reduction to 1.86 by the end of the study period.

Conclusions: Geographical inequalities in suicide among men aged 15–44 grew during the period 1980–2001 and remain at high levels. The greatest increase in inequality was during the late 1980s and early 1990s, a period of rapid social and economic change to New Zealand society.
Antidepressants: Prevalence of Duplicate Therapy and Avoidable Drug Interactions in Australian Veterans
Authors: Roughead Elizabeth E. , McDermott Brian , Gilbert Andrew L.
Published: March 2007

Objective: This study assessed the prevalence of duplicate antidepressant prescribing and avoidable potential antidepressant drug interactions in the Australian war veteran population.

Method: The Department of Veterans’ Affairs Pharmacy Claims database was interrogated, using specific criteria, to identify antidepressant duplication. In addition, potential drug interactions where safer alternative therapies were available were assessed. These included anticholinergic agents with tricyclic antidepressants and tramadol with antidepressants. Episodic tramadol dispensings with antidepressants were also assessed.

Results: A total of 46 859 veterans had antidepressants regularly dispensed to them in the period 1 April–31 July 2005. Overall, 4037 potential interactions were identified in 3818 veterans (8.1%) to whom were dispensed antidepressants regularly. Antidepressant and tramadol co-prescribing was the most common potential interaction identified among 3.6% of veterans. Two or more interactions were identified in 212 veterans (0.5%). Analysis of episodic tramadol dispensings with antidepressants suggested a much higher prevalence of 7.7%.

Conclusion: The increasing use of antidepressants and the high level of potentially avoidable interactions detected in the present study, highlight the necessity of ongoing vigilance concerning the use of potentially inappropriate drug combinations, particularly in the elderly.
Motivational beliefs, cognitive engagement, and achievement in language and mathematics in elementary school children
Authors: Metallidou Panagiota , Vlachou Anastasia
Published: March 2007

The contextual differences in the patterns of relations among various motivational, cognitive, and metacognitive components of self‐regulated learning and performance in two key curriculum subject areas, language and mathematics, were examined in a sample of 263 Greek primary school children of fifth‐ and sixth‐grade classrooms. Age and gender differences were also investigated. Students were asked to complete the Motivated Strategies for Learning Questionnaire (Pintrich & De Groot, 1990), which comprised five factors: (a) Self‐efficacy, (b) Intrinsic Value, (c) Test Anxiety, (d) Cognitive Strategy Use, and (e) Self‐regulation Strategies. They responded to the statements of the questionnaire on a 7‐point Likert scale in terms of their behaviour in mathematics and language classes, respectively. Moreover, their teachers were asked to evaluate each of their students' academic achievement in Greek language and mathematics on a 1‐ to 20‐point comparative scale in relation to the rest of the class. The results of the study indicated very few differences in the pattern of relations among self‐regulated components within and across the two subject areas and at the same time revealed a context‐specific character of self‐regulated components at a mean level differences. Further, the current study (a) confirmed the mediatory role of strategies in the motivation‐performance relation, (b) stressed the differential role of cognitive and regulatory strategies in predicting performance in subject areas that differ in their structural characteristics of the content, and (c) pointed out the key motivational role of self‐efficacy. In fact, self‐efficacy proved the most significant predictor not only of performance but of cognitive and regulatory strategy use as well. Gender differences in motivation and strategy use were not reported, while motivation was found to vary mainly with age. The usefulness of these findings for promoting greater clarity among motivational and metacognitive frameworks and ideas for future research are discussed.
Sex and culture differences in perceptions of estimated multiple intelligence for self and family: A Macanese1Portuguese comparison
Authors: Neto Félix , Furnham Adrian , Paz Regina
Published: March 2007

Differences in sex and culture between Macanese and Portuguese university students in self and parental estimations of IQ were examined using Gardner's (1999) list of 10 multiple intelligences. A total of 197 Macanese (90 male and 107 female) and 331 Portuguese (139 male and 192 female) students participated in the investigation. The following hypotheses were tested: it was anticipated that there would be sex differences in self‐rated mathematical and spatial intelligence, with men giving higher self‐estimates than women; it was predicted that there would be cultural differences between Macanese and Portuguese, with the former awarding themselves and their parents significantly lower scores than the latter; participants would rate their fathers as more intelligent overall than their mothers; the best predictors of overall (g) IQ would be logical/mathematical, spatial, and verbal intelligence. In contrast to previous results (Furnham, 2001), when examined separately, gender differences in both self‐estimates and parents estimates did not occur in the Macanese sample. There were, however, consistent and clear culture differences. Portuguese gave higher self and family ratings than Macanese, as expected. Portuguese rated their verbal, body kinetic, interpersonal, intrapersonal, and naturalistic intelligence higher than did Macanese. Portuguese rated verbal, mathematical, spatial, interpersonal, intrapersonal, existential, and naturalistic father's intelligence higher than did Macanese. Portuguese rated verbal, mathematical, spatial, musical, interpersonal, intrapersonal, existential, spiritual, and naturalistic mother's intelligence higher than did Macanese. Participants of both cultures rated overall intelligence of their father higher than that of their mother. This was also to be expected as previous studies have shown this to be the case in terms of gender stereotyping. In both cultures verbal and interpersonal intelligences predict overall intelligence. However, in Macao, body‐kinetic and intrapersonal intelligences, and in Portugal logical and naturalistic intelligences, also predict overall intelligence. Implications of these results for education and self‐presentations are considered.
Adaptations to changing times: Agency in context
Authors: Schoon Ingrid
Published: March 2007

British society has changed greatly over the past half century. Increasing uncertainty about economic and social developments is becoming a distinctive feature of modern industrialized countries, affecting the life chances and opportunities of young people making the transition from dependent childhood into independent adulthood. Summarizing recent findings from data collected from about 30,000 individuals born 12 years apart, in 1958 and 1970 respectively, this paper examines the role of individual agency in shaping educational and occupational transitions as well as the assumption of family‐related roles in times of social change. The data suggest that societal change and the associated increasing uncertainty does not impact on all individuals in the same way, and that there has been an increasing polarization between those who are able to benefit from the economic and social transformations and the ones who are excluded, largely because of their relatively disadvantaged socioeconomic circumstances and lack of access to opportunities in education and employment. It is concluded that human agency processes cannot be studied in isolation from the sociohistorical context in which they are embedded.
Adolescent agency and adult economic success in a transitional society
Authors: Titma Mikk , Tuma Nancy Brandon , Roots Ave
Published: March 2007

Following our previous research, we argue that weak societal institutions allow human agency factors to influence human behaviour strongly and, in particular, to affect how people coped with the collapse of Soviet institutions and responded to new opportunities that arose in the transition from communism. We chose Estonia as our study site because it had a “bottom‐up” transition that encouraged individual initiative and mass participation. Further, its state rapidly developed efficient, democratic institutions and legalized private ownership, which reorganized economic activity. Human agency factors include pre‐conditions (e.g., skills, education, goals), processes (e.g., making choices and factors affecting choices, such as self‐efficacy and locus of control), and previous agentic actions. We examined the impacts of adolescent abilities and goals, completed education, and economic activities in the first stage of the transition on economic success in the second stage using longitudinal data from the Paths of a Generation study. Respondents were interviewed around age 18 (in 1983) and again around ages 23 (in 1988), 28 (in 1993), 32 (in 1997), and 39 (in 2004). As hypothesized, we found evidence that adolescents' abilities affected both income in 2004 and income mobility between 1997 and 2004. Additional education completed after adolescence and economic activities reflecting individual initiative in the first stage of the transition also promoted economic success. Surprisingly, adolescent agency had noteworthy effects on the economic success of adults who were almost 40 years old and who had been reared and educated in a communist society with strikingly different institutions, norms, and values than those in Estonia in 2004.
The Undiladze Feudal House in the Sixteenth to Seventeenth-Century Iran According to the Georgian Sources
Authors: Gabashvili Valerian N.
Published: March 2007

In this article by one of the founders of the Georgian school of Oriental Studies, the role of the gholams in Safavid service is highlighted by focusing on the career of Allahverdi Khan and his children. First, it is shown that Allahverdi Khan was not an Armenian, but a Georgian of the noble Undiladze family. Second, the rise of the Georgian slave in the Safavid administration and that of his children is discussed, both their political and cultural roles within the Safavid kingdom as well as their continued relations with Georgia. Finally, the cause of the family's downfall, due to too much success, its continued involvement in the affairs of Georgia, and its rivalry with fellow-Georgian Rostam Khan, is analyzed with emphasis on the use of Georgian sources.
Regional Polarisation and National Development in the European Union
Authors: Ezcurra Roberto , Pascual Pedro
Published: March 2007

This paper examines spatial polarisation in the regional distribution of per capita income in a set of European Union countries over the period 1980-2001. The analysis reveals marked differences in the level and evolution of regional polarisation within the various countries considered. In addition, the empirical evidence presented clearly supports the key role played by national development processes in this context. The estimations show that, beyond a certain level of per capita income, regional polarisation decreases as the process of economic development advances. However, there are signs to suggest that regional polarisation increases once a relatively high level of per capita income is attained, although this rise is less marked than the decrease experienced previously. In fact, these findings are robust to the inclusion of additional variables in the analysis and to the choice of the measure used to quantify regional polarisation.
The role and effects of teaching assistants in English primary schools (Years 4 to 6) 2000–2003. Results from the Class Size and Pupil—Adult Ratios (CSPAR) KS2 Project
Authors: Blatchford Peter , Russell Anthony , Bassett Paul , Brown Penelope , Martin Clare
Published: March 2007

It is widely assumed that increasing the number of teaching assistants (TAs) in the classroom will be beneficial to children, and this is one important aim of the recently implemented Workforce Agreement. But there are still significant gaps in knowledge about many aspects of their deployment and impact. The Class Size and Pupil—Adult Ratios (CSPAR) KS2 study built on earlier findings when the pupils were in reception and Key Stage (KS) 1, and investigated: (1) the deployment of TAs in classrooms and how key parties involved perceived this; and (2) the effect of TAs on interactions involving pupils and teachers in the same classrooms, and on pupil attainments. The study had a longitudinal, mixed method and multi‐informant design. Methods of data collection included: (for the whole sample) questionnaires completed by TAs, teachers and head teachers, assessments of pupil attainments in mathematics, English and science, data on pupil background, and (for a sub‐sample) case studies and a systematic observation study. This study found that the TA's role in KS2 is predominantly a direct one, in the sense of face‐to‐face interactions supporting certain pupils. There was no evidence that the presence of TAs, or any characteristic of TAs, had a measurable effect on pupil attainment. However, results were clear in showing that TAs had an indirect effect on teaching, e.g. pupils had a more active form of interaction with the teacher and there was more individualised teacher attention. This supported teachers' views that TAs are effective in supporting them in this way. The authors conclude that more attention needs to be paid to what they call the pedagogical role of TAs so that they can be used effectively to help teachers and pupils, particularly in the context of the enhanced roles for TAs being introduced as part of the Government's remodelling agenda.
Secondary school pupils' satisfaction with their ability grouping placements
Authors: Hallam Susan , Ireson Judith
Published: March 2007

There has been little research exploring pupils' satisfaction with their ability group placement. This article explores the extent to which pupils are happy with their placement, and the reasons they give for wanting to move to another class or set. The sample comprised over 5000 Year 9 pupils (aged 13–14 years) in 45 mixed secondary comprehensive schools in England. The schools represented three levels of ability grouping in the lower school (Years 7 to 9). Pupils responded to a questionnaire which explored their current set placement, their satisfaction with it, and their reasons for wanting to change. A substantial proportion of pupils expressed a wish to change set, most, but not all, in an upward direction, mainly because the level of work was inappropriate. The implications for ability grouping practices in schools are discussed.
British South Asians and pathways into selective schooling: social class, culture and ethnicity
Authors: Abbas Tahir
Published: March 2007

This article is a theoretical and empirical study of the ways in which different South Asian groups, Bangladeshi, Indian, and Pakistani, achieve entry into the selective education system, taking into consideration the factors of social class, ethnicity and culture. In‐depth interviews with 42 South Asian school pupils from three single‐sex selective schools (one independent and two grammar), 47 South Asian school pupils from three secondary modern schools, and 25 South Asian parents are used to interpret perceptions, attitudes towards, and experiences of selective school entry. It is found that that certain working‐class South Asian parents possess strong middle‐class attitudes towards selective education, irrespective of their ability to facilitate it as a function of their financial, cultural, or social capital. Middle‐class South Asians were not only highly motivated but also possessed the economic, social and cultural capital to ensure successful selective school entry. In general, social class status was the strongest factor in the likelihood of gaining entry into selective schools. This research contributes to the literature on selective education as well as on the intricacies of the British South Asian educational experience.
Critical realism and statistical methods—a response to Nash
Authors: Scott David
Published: March 2007

This article offers a defence of critical realism in the face of objections Nash (2005) makes to it in a recent edition of this journal. It is argued that critical and scientific realisms are closely related and that both are opposed to statistical positivism. However, the suggestion is made that scientific realism retains (from statistical positivism) a number of elements that result in misleading accounts of social processes and events: indicators are used which do not reflect the close relationship between structure and agency; indicators refer to reified and not real properties of both structures and agents; and indicators do not refer to causal properties of objects and entities. In order to develop a narrative of causal processes, as Nash argues researchers should, then some adjustments need to be made to the principles that underpin scientific realism.
Acknowledging the affective in higher education
Authors: Beard Colin , Clegg Sue , Smith Karen
Published: March 2007

This article argues that we need richer conceptions of students as affective and embodied selves and a clearer theorisation of the role of emotion in educational encounters. These areas are currently under‐researched and under‐theorised in higher education. The first part of the article explores the literature on emotion. The second reports on a case study which aimed to map students' emotional journeys over their first year at university. These data highlight the importance of relationships, students' changing emotions over the year, their perceptions of their academic studies and understandings of life at university. The article concludes that it is important to understand the affective dimension in pedagogic encounters and the lifeworld of students, and that it is possible to do so without a collapse into therapeutic discourses.
Upper Respiratory Tract Lesions in Inhalation Toxicology
Authors: Renne Roger A. , Gideon Kathy M. , Harbo Sam J. , Staska Laurie M. , Grumbein Sondra L.
Published: March 2007

This paper describes some important differences in normal histology of the upper respiratory tract of laboratory animals. It also provides examples of lesions observed or reported in the upper respiratory tract of laboratory animals, predominantly rodents, exposed via inhalation. The anatomy and physiology of upper respiratory tract tissues play a major role in the response to an insult, given that different epithelial types vary in susceptibility to injury and toxicant exposure concentrations throughout the airway vary due to airflow dynamics. Although dogs and nonhuman primates are utilized for inhalation toxicology studies, less information is available regarding sites of upper respiratory injury and types of responses in these species. Awareness of interspecies differences in normal histology and zones of transition from squamous to respiratory to olfactory epithelium in different areas of the upper respiratory tract is critical to detection and description of lesions. Repeated inhalation of chemicals, drugs, or environmental contaminants induces a wide range of responses, depending on the physical properties of the toxicant and concentration and duration of exposure. Accurate and consistent fixation, trimming, and microtomy of tissue sections using anatomic landmarks are critical steps in providing the pathologist the tools needed to compare the morphology of upper respiratory tract tissues from exposed and control animals and detect and interpret subtle differences.
Respiratory Tract Lesions in Noninhalation Studies
Authors: Sells Donald M. , Brix Amy E. , Nyska Abraham , Jokinen Micheal P. , Orzech Denise P. , Walker Nigel J.
Published: March 2007

This paper reviews respiratory tract lesions observed in rodents administered various chemicals by noninhalation routes. Chemicals administered by inhalation caused lesions in the respiratory tract and were well described; however, when chemicals were administered by noninhalation routes the effort to evaluate tissues for lesions may have been less or not considered, especially in the upper respiratory tract, and some lesions may have gone undetected. Lesions described in this review mostly occurred in rodent chronic noninhalation studies conducted by the National Toxicology Program; however, some were noted in studies of shorter duration. The nasal cavity was vulnerable to damage when chemicals were administered by noninhalation routes. Changes included respiratory epithelial hyperplasia, degeneration and necrosis of olfactory epithelium, olfactory epithelial metaplasia, adenoma, adenocarcinoma, squamous cell carcinoma, and neuroblastoma. In the lung, compound-related lesions included alveolar histiocytosis, alveolar epithelial hyperplasia, bronchiolar metaplasia of the alveolar epithelium, squamous metaplasia, alveolar/bronchial adenoma and carcinoma, and squamous tumors. Pathogenesis of these lesions included regurgitation of volatiles, metabolites arriving from the blood stream, and additional metabolism by olfactory epithelium or Clara cells. The presence of respiratory tract lesions in noninhalation studies emphasizes the need for a thorough examination of the respiratory tract including nasal passages, regardless of the route of administration.
K-ras Mutations in Lung Tumors and Tumors from Other Organs are Consistent with a Common Mechanism of Ethylene Oxide Tumorigenesis in the B6C3F1 Mouse
Authors: Hong Hue-Hua L. , Houle Christopher D. , Ton Thai-Vu T. , Sills Robert C.
Published: March 2007

Ethylene oxide is a multisite carcinogen in rodents and classified as a human carcinogen by the National Toxicology Program. In 2-year mouse studies, ethylene oxide (EO) induced lung, Harderian gland (HG), and uterine neoplasms. We evaluated representative EO-induced and equivalent spontaneous neoplasms for K- ras mutations in codons 12, 13, and 61. K- ras mutations were identified in 100% (23/23) of the EO-induced lung neoplasms and 25% (27/108) of the spontaneous lung neoplasms. Codon 12 G to T transversions were common in EO-induced lung neoplasms (21/23) but infrequent in spontaneous lung neoplasms (1/108). K -ras mutations were found in 86% (18/21) of the EO-induced HG neoplasms and 7% (2/27) of the spontaneous HG neoplasms. Codon 13 G to C and codon 12 G to T transversions were predominant in the EO-induced HG neoplasms but absent in spontaneous HG neoplasms (0/27). K- ras mutations occurred in 83% (5/6) of the EO-induced uterine carcinomas and all were codon 13 C to T transitions. These data show a strong predilection for development of K- ras mutations in EO-induced lung, Harderian gland, and uterine neoplasms. This suggests that EO specifically targets the K- ras gene in multiple tissue types and that this event is a critical component of EO-induced tumorigenesis.
Environmental, Inhaled and Ingested Causes of Pulmonary Fibrosis
Authors: Khalil Nasreen , Churg Andrew , Muller Nestor , O’Connor Robert
Published: March 2007

Pulmonary fibrosis is a general term that refers to a collection of connective tissue around alveolar structures. There are over 200 disorders where the lungs may be involved in a fibrotic response. To determine the cause of pulmonary fibrosis requires an in depth understanding of the pathogenesis of pulmonary fibrosis and breadth of knowledge of the causative agents and associated disorders that may lead to pulmonary fibrosis. A comprehensive evaluation of the patient is absolutely essential, starting with detailed history that includes an occupational and environmental history because fibrogenic exposures can occur in many settings. Equally important is a history of ingestion of pharmaceutical or nonpharmaceutical substances. A physical examination and judicious investigations are always a part of any comprehensive clinical assessment but they are not commonly helpful in elucidating the cause of most pulmonary fibrotic disorders. Although, a chest film is invariably done, a logical and strongly recommended next step is a high-resolution computed tomography (HRCT). HRCT provides a better assessment of the radiological pattern, may suggest a diagnosis as well as direct the site, and type of lung biopsy. If the history and investigations do not lead to a diagnosis then a lung biopsy is required. Prevention or removal of the inciting agent is critical to the treatment of these disorders and in some instances corticosteroids may be of help.
Inhalation Aspects of Therapeutic Aerosols
Authors: Leach Chet L.
Published: March 2007

The pulmonary route of drug delivery can provide an excellent alternative to other routes both for local lung disease as well as systemic delivery. The year 2006 marks the 50th year since the invention of metered dose inhalers, yet inhalation is a very much underutilized route of delivery, possibly because inhalation drug development is perceived as being too difficult and expensive. However with proper knowledge these purported difficulties can be overcome. The process begins with identifying the target tissue and then utilizing technologies such as particle size adjustments through formulation techniques and delivery devices to most efficiently deliver the desired dose. There are a variety of new and existing inhaled excipients available to accomplish this goal. The active molecule can also be modified to increase solubility, decrease immunogenicity, and protect it from unwanted metabolism using PEGylation. Sustained release of an inhaled drug is also possible using biocompatible matrices such as oligolactic acid.
Characterization of Urban Atmospheres during Inhalation Exposure Studies in Detroit and Grand Rapids, Michigan
Authors: Keeler Gerald J. , Morishita Masako , Wagner James G. , Harkema Jack R.
Published: March 2007

An inhalation exposure study for particulate matter (PM) investigates links between exposure and observed changes in respiratory function by evaluating the interactions of chemical and physical properties of the PM with physiological mechanisms. Laboratory studies are useful in this regard, but provide limited information because of the difficulty in reproducing real atmospheric PM compositions and processes. To better understand the types of particles to which people are actually exposed in their daily lives, and the human health risks for source-specific PM, a real world assessment of the source-to-receptor pathways for ambient PM is vital. This was accomplished using a unique mobile air research laboratory (AirCARE1) which enables inhalation exposure studies in real-world settings. The overall goal of this study was to determine the effects of concentrated air particulates (CAPs) from 2 different urban atmospheres in Michigan on the lungs of ovalbumin-sensitized rats concurrently challenged with the allergen. Our work demonstrated that short-term (8 hours) exposure to ambient fine particulate matter (aerodynamic diameter ≤ 2.5 μm; PM2.5) concentrated from 2 different urban atmospheres in Michigan induced distinct allergic responses in the lungs of rats. This paper presents detailed characterization of CAPs and their sources in an effort to define possible associations between the observed health effects and source-specific ambient PM2.5.
Comparative Oncology of Lung Tumors
Authors: Hahn Fletchert F. , Gigliotti Andrew , Hutt Julie A.
Published: March 2007

Toxicologic pathologists need to understand the comparative oncology of lung tumors because lung cancer is a common and serious cancer in the human population. Lung cancer in humans is known to be caused by cigarette smoke and a number of other carcinogens in the environment. Animal studies are needed to elucidate possible interactions with other potential carcinogens in environmental or occupational settings. In addition, knowledge of dose-response relationships and potential synergistic effects are needed to minimize harmful effects. Understanding the pathogenesis of common lung tumors will also aid in the prevention, diagnosis and treatment of the disease. Toxicologic pathologists need to remember several important points about lung tumors. The lung cancer response varies among species. Important factors in this variation are the nature of the administered carcinogen, the tissue dose of the carcinogen, the mode of exposure, the sensitivity of the test animal species and the similarity to the human response. Studies of molecular changes are important new tools to understanding lung carcinogenesis. For example, the molecular changes in lung tumors of mice and humans have a number of similarities that may be important in evaluating the significance of compound-induced lung tumors in mice.
Effects of Cyclosporin A and Cyclophosphamide on Peyer’s Patches in Rat, Exposed in utero and Neonatally or During Adult Age
Authors: Kuper C. Frieke , Van Zijverden Maaike , Klaassen Carlijn , Tegelenbosch-Schouten Mariska , Wolterbeek Andre P.M.
Published: March 2007

The effects of cyclosporin A (CY) and cyclophosphamide (CPS) on Peyer’s patches (PP) were studied in Wistar rats, exposed in utero and neonatally or during adult age. In one study, pregnant dams received 5 or 15 mg/kg bw/day CY from gestation day 6 to day 21 of lactation. In two other studies, animals were exposed at young adult age: female rats received orally 5 or 20 mg/kg/day CY or 5 or 10 mg/kg bw CPS for 4 weeks; males received orally 5 mg/kg bw CPS for 4 weeks, or a single iv injection of 50 mg/kg bw CPS. Upon in utero and neonatal exposure, the numbers of grossly observed PP were increased in male pups from the high-dose CY dams at 70 days of age. Exposure to high-dose CY at adult age only tended to decrease the numbers of PP; germinal center development was reduced in the PP from the middle segment of the small intestines, as examined microscopically. Exposure to both doses CPS at adult age reduced the numbers of PP and reduced germinal centre development and the number of lymphocytes in all compartments of PP. It was concluded that the effects of CPS and CY could be established by counting the number of grossly visible PP and by microscopic observation of PP, provided that regional differences of PP were taken into account. Moreover, the type of effects of an immunotoxic agent may vary with age of exposure.
Inhibition of ALK5 Signaling Induces Physeal Dysplasia in Rats
Authors: Frazier Kendall , Thomas Roberta , Scicchitano Marshall , Mirabile Rosanna , Boyce Rogely , Zimmerman Dawn , Grygielko Eugene , Nold James , DeGouville Anne-Charlotte , Huet Stephane , Laping Nicholas , Gellibert Francoise
Published: March 2007

TGF-|β|, and its type 1 (ALK5) receptor, are critical to the pathogenesis of fibrosis. In toxicologic studies of 4 or more days in 10-week-old Sprague–Dawley rats, using an ALK5 inhibitor (GW788388), expansion of hypertrophic and proliferation zones of femoral physes were noted. Subphyseal hyperostosis, chondrocyte hypertrophy/hyperplasia, and increased matrix were present. Physeal zones were laser microdissected from ALK5 inhibitor-treated and control rats sacrificed after 3 days of treatment. Transcripts for TGF-|β|1, TGF-|β|2, ALK5, IHH, VEGF, BMP-7, IGF-1, bFGF, and PTHrP were amplified by real-time PCR. IGF and IHH increased in all physis zones with treatment, but were most prominent in prehypertrophic zones. TGF-|β|2, bFGF and BMP7 expression increased in proliferative, pre- and hypertrophic zones. PTHrP expression was elevated in proliferative zones but decreased in hypertrophic zones. VEGF expression was increased after treatment in pre- and hypertrophic zones. ALK5 expression was elevated in prehypertrophic zones. Zymography demonstrated gelatinolytic activity was reduced after treatment. Apoptotic markers (TUNEL and caspase-3) were decreased in hypertrophic zones. Proliferation assessed by Topoisomerase II and Ki67 was increased in multiple zones. Movat stains demonstrated that proteoglycan deposition was altered. Physeal changes occurred at doses well above those resulting in fibrosis. Interactions of factors is important in producing the physeal dysplasia phenotype.
Administration of an Antagonist of Neurokinin Receptors 1, 2, and 3 Results in Reproductive Tract Changes in Beagle Dogs, but Not Rats
Authors: Losco Patricia E. , Leach Michael W. , Sinha Dineshwar , Davis Preston , Schmahai Theodore J. , Nomier Amin , Kakkar Tarundeep , Reyderman Larisa , Lynch Mary Ellen
Published: March 2007

SCH 206272, an antagonist of neurokinin receptors 1, 2, and 3, was administered orally by gavage for 1 month to 8- to 10-month-old dogs at doses of 0, 15, 30, or 60 mg/kg, and to 6-week-old rats at doses of 0, 30, 100, or 300 mg/kg. The most important changes occurred in the reproductive tract of the dogs at all doses. Absolute and relative group mean organ weights for the testes, prostate gland, epididymides, ovaries, and uterus were 33–86% lower than concurrent controls in groups receiving SCH 206272. Organ weight changes were not dose-related. Microscopic changes that correlated with the organ weight changes occurred in all groups receiving SCH 206272. For males, they included minimal to severe atrophy of the testes, epididymides, and prostate gland. In addition, the epididymides exhibited severe oligospermia or aspermia, minimal epithelial apoptosis and mild epithelial vacuolation. In female dogs, the ovaries and uteri appeared immature. Microscopic changes were similar in incidence and severity in dogs receiving 30 or 60 mg/kg, but were slightly less in dogs receiving 15 mg/kg. In contrast, similar findings were not observed in the reproductive tract of male or female rats, despite overlapping systemic, hypothalamic, and pituitary gland concentrations of SCH 206272.
Polychlorinated Biphenyl Exposure Causes Gonadal Atrophy and Oxidative Stress in Corbicula fluminea Clams
Authors: Lehmann Daniel W. , Levine Jay F. , Law J. Mchugh
Published: March 2007

Polychlorinated biphenyls (PCBs) are widespread environmental contaminants that have been linked to oxidative and other toxic effects in both humans and wildlife. Due to recent environmental health concerns at a PCB contaminated Superfund site near Raleigh, NC, we used a common clam species ( Corbicula fluminea) as surrogates to isolate the effects of PCBs on threatened bivalves native to the region. Under controlled laboratory conditions, clams were exposed to 0, 1, 10, or 100 ppb Aroclor 1260 in the ambient water for 21 days. Measured biomarkers spanned a range of effective levels of biological organization including low molecular weight antioxidants, lipid-soluble antioxidants, and whole tissue radical absorption capacity. These data were augmented by use of histological evaluation of whole samples. Aroclor 1260 significantly increased reduced glutathione (GSH) and total protein concentrations at all treatments levels. Significant decreases were measured in all treatments in γ-tocopherol and total oxidant scavenging capacity (TOSC) and α-tocopherol values in the 100 ppb exposure. Histologically, Aroclor 1260 caused significant gonadal atrophy, effacement of gonad architecture with accumulations of Brown cells, and inflammation and necrosis in digestive glands and foot processes. Our results indicate that oxidative mechanisms play a significant role in the decreased health of these clams due to exposure to Aroclor 1260. The changes in the gonads of exposed clams suggest that a serious threat to bivalve reproduction exists due to PCB exposure.