Search

Abstract Background Malaria control remains a challenge in sub-Saharan Africa. In 2006, the World Health Organization (WHO) reinforced the recommendation of indoor residual spraying (IRS) with dichlorodiphenyltrichloroethane (DDT) to reduce malaria transmission. The National Malaria Control Programme has been reporting high coverage rates of IRS in Mozambique. It is important to establish to what extent these rates are a reflection of community acceptability, and to explore the factors associated with adherence, in order to recommend suitable approaches for interventions of this nature. Objective To understand the implementation process, reception and acceptability of the IRS program in Manhiça district, Southern Mozambique. Methods Qualitative data was collected through in-depth interviews, participant observation of IRS activities, informal interviews, and focus group discussions. Study participants comprised householders, community leaders, health care providers, sprayers, and community members. Qualitative data analysis was based on grounded theory. Secondary data from the Manhiça Demographic Surveillance System was used to complement the qualitative data. Results IRS was well received in most neighbourhoods. The overall coverage rates varied between 29% and 41% throughout the study period. The factors related to adherence to IRS were: immediate impact on insects in general, trust and obedience in the health authority, community leaders' influence, and acquaintance with the sprayers. Fighting malaria was not an important motivation for IRS adherence. There was a perception of limited efficacy of IRS against mosquitoes, but this did not affect adherence. Non-adherence to the intervention was mainly due to the unavailability of key householders, disagreement with the procedures, and the perception that spraying increased the burden of insects. Most respondents strongly favoured bed nets over IRS. Conclusion The study suggests that the contribution of IRS to malaria and mosquito control is not entirely perceived by the beneficiaries, and that other as cost effective interventions such as insecticide-treated nets are favoured over IRS. Adherence to IRS was found to be influenced by socio-political factors. There is a need to redefine the community sensitization approaches in order to make IRS a genuinely participative, acceptable, and sustainable programme.

Abstract Background Intermittent preventive treatment of malaria in infants (IPTi) reduces the incidence of clinical malaria. However, before making decisions about implementation, it is essential to ensure that IPTi is acceptable, that it does not adversely affect attitudes to immunization or existing health seeking behaviour. This paper reports on the reception of IPTi during the first implementation study of IPTi in southern Tanzania. Methods Data were collected through in-depth interviews, focus group discussions and participant observation carried out by a central team of social scientists and a network of key informants/interviewers who resided permanently in the study sites. Results IPTi was generally acceptable. This was related to routinization of immunization and resonance with traditional practices. Promoting "health" was considered more important than preventing specific diseases. Many women thought that immunization was obligatory and that health staff might be unwilling to assist in the future if they were non-adherent. Weighing and socialising were important reasons for clinic attendance. Non-adherence was due largely to practical, social and structural factors, many of which could be overcome. Reasons for non-adherence were sometimes interlinked. Health staff and "road to child health" cards were the main source of information on the intervention, rather than the specially designed posters. Women did not generally discuss child health matters outside the clinic, and information about the intervention percolated slowly through the community. Although there were some rumours about sulphadoxine pyrimethamine (SP), it was generally acceptable as a drug for IPTi, although mothers did not like the way tablets were administered. There is no evidence that IPTi had a negative effect on attitudes or adherence to the expanded programme on immunisation (EPI) or treatment seeking or existing malaria prevention. Conclusion In order to improve adherence to both EPI and IPTi local priorities should be taken into account. For example, local women are often more interested in weighing than in immunization, and they view vaccination and IPTi as vaguely "healthy" rather preventing specific diseases. There should be more emphasis on these factors and more critical consideration by policy makers of how much local knowledge and understanding is minimally necessary in order to make interventions successful.

Halogen bonding is commonly found with iodine-containing molecules, and it arises when Lewis bases interact with iodine's σ-holes. Halogen bonding and σ-holes have been encountered in numerous monovalent and hypervalent iodine-containing compounds, and in 2022 σ-holes were computationally confirmed and quantified in the iodonium ylide subset of hypervalent iodine compounds. In light of this new discovery, this article provides an overview of the reactions of iodonium ylides in which halogen bonding has been invoked. Herein, we summarize key discoveries and mechanistic proposals from the early iodonium ylide literature that invoked halogen bonding-type mechanisms, as well as recent reports of reactions between iodonium ylides and Lewis basic nucleophiles in which halogen bonding has been specifically invoked. The reactions discussed herein are organized to enable the reader to build an understanding of how halogen bonding might impact yield and chemoselectivity outcomes in reactions of iodonium ylides. Areas of focus include nucleophile σ-hole selectivity, and how ylide structural modifications and intramolecular halogen bonding (e.g., the ortho -effect) can improve ylide stability or solubility, and alter reaction outcomes., (Copyright © 2023, Montgomery and Murphy.)

The first systematic evaluation of the electrostatic potential energy maps of iodonium ylides was conducted. We determined that they possess two σ-holes of differing electron deficiencies, with the more electropositive σ-hole located opposite the dative I-C bond to the β-dicarbonyl motif, and the lesser electropositive σ-hole located opposite the iodoarene C-I bond. We also conducted the first systematic evaluation of carboxylic acids, phenols and thiophenols in the O/S-alkylation reaction of iodonium ylides. While carboxylic acids and thiophenols were found to be generally viable, only phenols possessing electron-withdrawing substituents were effective. This high-yielding and highly chemoselective reaction is believed to involve halogen-bond activation of heteroatoms, and nicely complements existing diazo-based methods for alkylation of acidic functional groups., (© 2022 Wiley-VCH GmbH.)

Older adults typically perform more poorly than younger adults in free recall memory tests. This age-related deficit has been linked to decline of brain activation and brain prefrontal lateralization, which may be the result of compensatory mechanisms. In the present pilot study, we investigated the effect of age on prefrontal cortex (PFC) activation during performance of a task that requires memory associations (temporal vs. spatial clustering), using functional Near-Infrared Spectroscopy (fNIRS). Ten younger adults, ten cognitively high-performing older individuals, and ten low-performing older individuals completed a free recall task, where either a temporal or spatial strategy (but not both simultaneously) could be employed to retrieve groups of same-category stimuli, whilst changes in PFC hemodynamics were recorded by means of a 12-channel fNIRS system. The results suggest PFC activation, and right lateralization specific to younger adults. Moreover, age did not affect use of memory organization, given that temporal clustering was preferred over spatial clustering in all groups. These findings are in line with previous literature on the aging brain and on temporal organization of memory. Our results also suggest that the PFC may be specifically involved in memory for temporal associations. Future research may consider whether age-related deficits in temporal organization may be an early sign of PFC pathology and possible neurodegeneration., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier Inc.)

Mycobacterial infections are of primary health concern in NHP colonies in biomedical research. NHP are constantly monitored and screened for Mycobacterium spp. We report 6 Chinese-origin rhesus macaques infected with Mycobacterium kansasii that exhibited positive tuberculin skin tests in the absence of disease. Two of these macaques were being used for research purposes; the remaining 4 macaques were residing at the contract quarantine company. Histopathology and acid-fast staining of fixed tissues from all macaques showed that all were free of disease. Thoracic radiographs were negative for any signs of disease or infection. Samples from bronchial lavage and tissues including lung, spleen, hilar and mesenteric lymph nodes tested negative by PCR assay for Mycobacterium spp. One of the research macaques tested culture-positive for M. kansasii and a poorly characterized M. avium complex organism. One macaque from the contract quarantine facility tested culture positive for M. kansasii. Genomic testing and target gene RNA expression analysis of the 2 M. kansasii isolates were performed to evaluate possible kinship and affected genes that might contribute to susceptibility to mycobacterial infection. Genotyping of the 2 isolates revealed 2 genetically distinct strains (strains 1 and 4). The presence of positive tuberculin skin tests in the absence of disease raises serious concerns regarding diagnostic methods used for infected NHP.

Objectives: Our aim was to explore the experiences of engaging in a community-based exercise programme (CBEP) from the perspective of people living with HIV (PLWH)., Design: We conducted a descriptive qualitative study using semistructured interviews., Setting: We recruited adults living with HIV who participated in a 16-week CBEP in Toronto, Canada., Participants: 11 participants, the majority men (64%), with a median age of 52 years, and living with a median of 5 concurrent health conditions in addition to HIV participated in the study., Outcome Measures: We asked participants about their overall experiences: strengths, limitations and perceived benefits of the CBEP; factors influencing participation and current level of exercise after completion of the CBEP. We administered a self-reported demographic questionnaire followed by the Rapid Assessment of Physical Activity (RAPA) questionnaire. We analysed interview data using thematic analysis., Results: We developed a framework that describes the experiences before, during and after the CBEP; and the perceived impact of the CBEP on health, which influenced the intent to, engagement in and sustainability of exercise among PLWH. Participants described the positive impact of the CBEP on their physical, mental and social health. Interviews were completed at a median of 6 months after the CBEP, when 9 participants reported ongoing engagement in exercise, but to a lesser extent than during the CBEP. Intrinsic and extrinsic factors facilitated or hindered engagement in exercise throughout all phases of the CBEP. The episodic nature of HIV and multimorbidity influenced engagement in exercise and posed challenges to re-engagement after periods of inactivity., Conclusions: CBEPs provide an opportunity to enhance physical activity, perceived health outcomes and knowledge about exercise for PLWH. Community-based exercise is a strategy that may be used by health providers to promote engagement in sustained physical activity for PLWH., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Conservation biologists recognize that a system of isolated protected areas will be necessary but insufficient to meet biodiversity objectives. Current approaches to connecting core conservation areas through corridors consider optimal corridor placement based on a single optimization goal: commonly, maximizing the movement for a target species across a network of protected areas. We show that designing corridors for single species based on purely ecological criteria leads to extremely expensive linkages that are suboptimal for multispecies connectivity objectives. Similarly, acquiring the least-expensive linkages leads to ecologically poor solutions. We developed algorithms for optimizing corridors for multispecies use given a specific budget. We applied our approach in western Montana to demonstrate how the solutions may be used to evaluate trade-offs in connectivity for 2 species with different habitat requirements, different core areas, and different conservation values under different budgets. We evaluated corridors that were optimal for each species individually and for both species jointly. Incorporating a budget constraint and jointly optimizing for both species resulted in corridors that were close to the individual species movement-potential optima but with substantial cost savings. Our approach produced corridors that were within 14% and 11% of the best possible corridor connectivity for grizzly bears (Ursus arctos) and wolverines (Gulo gulo), respectively, and saved 75% of the cost. Similarly, joint optimization under a combined budget resulted in improved connectivity for both species relative to splitting the budget in 2 to optimize for each species individually. Our results demonstrate economies of scale and complementarities conservation planners can achieve by optimizing corridor designs for financial costs and for multiple species connectivity jointly. We believe that our approach will facilitate corridor conservation by reducing acquisition costs and by allowing derived corridors to more closely reflect conservation priorities., (© 2016 Society for Conservation Biology.)

Purpose: The study was to understand the facilitators and barriers to exercise using exergames among assisted living residents, particularly in the area of cognitive, physical, and psychosocial effects., Design: Self-efficacy theory was incorporated into the design of the Wii Fit exergaming program., Method: Fifteen participants (mean age: 87.07 ± 3.92) received the program twice a week for 4 weeks. Semi-structural individual interview was conducted after the program. Interview responses were analyzed using basic content analysis methods., Findings: Five themes emerged that facilitated participants? desire to exercise: (1) health and mobility; (2) increased alertness; (3) elevated mindset; (4) social interaction; and (5) structured program. Barriers to engage in exercise included: (1) age- or health-related impairments to exercise; and (2) unpleasant experiences related to exercise., Conclusions: An intervention incorporating self-efficacy and Wii exergames did result in the identification of cognitive, physical, and psychosocial benefits and barriers to exercise., (© 2015 Association of Rehabilitation Nurses.)

The purpose of this study was to investigate the physical and psychosocial effects of the Wii Fit exergames incorporating self-efficacy theory on assisted living residents. The study was a quasi-experimental pre/post-test design. Thirty-two participants were recruited from two assisted living facilities. Sixteen participants received the Wii Fit exergames incorporating self-efficacy theory twice a week for 4 weeks. The other participants received a health education program. Physical function, fear of falling, depression, and quality of life were evaluated. T tests were used for data analysis. After the 4-week intervention, the Wii Fit group showed significant improvements in balance (p < .01), mobility (p < .01), and depression (p < .05). The education group showed no significant improvement in any of the outcomes. Integrating concepts of self-efficacy theory with the exergames show promise as a potential tool to improve and maintain physical and psychosocial health for older adults., (© The Author(s) 2014.)

Objective: The purpose of this review is to summarize and synthesize the impact of using the Nintendo Wii™ exergames in older adults., Method: A database search was conducted to identify relevant studies. The search was limited to empirical studies, with particular attention paid to the effects of Wii exergames intervention on cognition, physical function, and psychosocial outcomes in older adults., Results: A total of 22 empirical studies met inclusion criteria and were included in this review. Positive effects included improving physical function, decreasing depression, and increasing cognition and quality of life in older adults. Improved socialization and motivation to exercise were also reported., Discussion: Using Wii exergames does show promise as an intervention to improve physical function, cognition, and psychosocial outcomes in older adults. Evidence supports that Wii exergames is a safe and feasible tool to encourage older adults to engage in exercise., (© The Author(s) 2014.)

The physical and psychosocial benefits of exergames have been reported in various literature. A pre-posttest, single-group design was used to test the effects of an exergames-based intervention on cognition, depression, and health-related quality of life (QOL) in assisted living residents. Bandura's self-efficacy theory was applied. Seven residents (mean age = 86, SD = 5 years) participated in the program two times per week for 8 weeks. Outcome measures included cognition, depression, and health-related QOL. No statistically significant differences were found in any of the outcomes after the intervention. A tendency toward improved cognition occurred, but the outcomes of depression and health-related QOL did not follow a similar trend. However, improved socialization and motivation to exercise were reported. Continued research is needed to investigate the cognitive and psychosocial effects of exergames on this population. Nurses can collaborate with other health care professionals to engage residents in exercise and thus improve residents' QOL., (Copyright 2014, SLACK Incorporated.)

The purpose of this study was to examine the feasibility of a self-efficacy based intervention using Wii exergames in assisted living residents. The study was a single-group pre- and post-test design. Seven older adults (aged 80-94 years) were instructed to engage in exergames twice a week for 8 weeks. Physical function (balance, mobility, and walking distance), fear of falling, self-efficacy for exercise, and outcome expectations for exercise were evaluated. All participants had enjoyable experiences and no serious adverse events were reported. Participants had significant improvement on balance. Although not significant, there were trends indicating that participants improved mobility, walking endurance, and decreased fear of falling. The use of Wii exergames was an acceptable, safe, and potentially effective approach to promote physical activity in older adults. Findings provide support for the applications of integrating self-efficacy theory into exergames as a mechanism to encourage older adults to engage in exercise., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Single-nucleotide changes are the most common cause of natural genetic variation among members of the same species, but there is remarkably little information bearing on how they alter bacterial virulence. We recently discovered a single-nucleotide mutation in the group A Streptococcus genome that is epidemiologically associated with decreased human necrotizing fasciitis ("flesh-eating disease"). Working from this clinical observation, we find that wild-type mtsR function is required for group A Streptococcus to cause necrotizing fasciitis in mice and nonhuman primates. Expression microarray analysis revealed that mtsR inactivation results in overexpression of PrsA, a chaperonin involved in posttranslational maturation of SpeB, an extracellular cysteine protease. Isogenic mutant strains that overexpress prsA or lack speB had decreased secreted protease activity in vivo and recapitulated the necrotizing fasciitis-negative phenotype of the DeltamtsR mutant strain in mice and monkeys. mtsR inactivation results in increased PrsA expression, which in turn causes decreased SpeB secreted protease activity and reduced necrotizing fasciitis capacity. Thus, a naturally occurring single-nucleotide mutation dramatically alters virulence by dysregulating a multiple gene virulence axis. Our discovery has broad implications for the confluence of population genomics and molecular pathogenesis research.

Purpose: The purposes of this study were to survey nurse practitioners (NPs) to determine their comfort level with knowledge about caring for individuals aged 65 years and older and to obtain their input on enhancing geriatric content in the educational preparation of advanced practice nurses who provide care to older adults but are not specialists in gerontology., Data Sources: The sample consisted of 500 randomly selected NPs who were certified to practice in New York State. The Geriatric Curriculum Survey designed by the researchers was based on the 47 "Older Adult Care" competencies developed by the American Association of Colleges of Nursing. The survey was mailed to the subjects along with a stamped self-addressed envelope to facilitate its return. Two hundred and twenty-two surveys (44%) were returned., Conclusions: A majority of the respondents were comfortable with their assessment skill knowledge of individuals aged 65 years and older in all areas except those related to cultural/ethnic items. Over half of the respondents were only "somewhat comfortable" with knowledge of management of Alzheimer's disease, delirium, dementia, neurological problems, polypharmacy, and sleep issues. Finally, respondents were asked to rate their knowledge comfort level on topics relevant to physical and psychosocial issues of individuals aged 65 years and older. The majority of respondents only felt "somewhat comfortable" with their knowledge on all but one of the nine items in this category. Health promotion and disease prevention was the only item that over 50% of the respondents felt "very knowledgeable" about. Ninety-five percent indicated they would be better prepared to care for individuals aged 65 years and older if a didactic course in geriatrics was required in their program of study. Seventy percent indicated they would consider taking an online course in geriatrics., Implications for Practice: Based on the results of this study, an online, four-credit geriatric-focused course "Issues in Geriatric Management" was developed. The course is required in the acute care and adult NP programs. Eventually, this course will be offered as continuing education credit for practicing NPs. The offering of a course focused on geriatrics will help to better prepare NPs to care for the growing number of elderly in this country.

In recent decades an infusion of economics has lent the study of strategy much needed theory and empirical evidence. Strategy consultants, armed with frameworks and techniques, have stepped forward to help managers analyze their industries and position their companies for strategic advantage. Strategy has come to be seen as an analytical problem to be solved. But, says Montgomery, the Timken Professor of Business Administration at Harvard Business School, the benefits of this rigorous approach have attendant costs: Strategy has become a competitive game plan, separate from the company's larger sense of purpose. The CEO's unique role as arbiter and steward of strategy has been eclipsed. And an overemphasis on sustainable competitive advantage has obscured the importance of making strategy a dynamic tool for guiding the company's development over time. For any company, intelligent guidance requires a clear sense of purpose, of what makes the organization truly distinctive. Purpose, Montgomery says, serves as both a constraint on activity and a guide to behavior. Creativity and insight are key to forging a compelling organizational purpose; analysis alone will never suffice. As the CEO--properly a company's chief strategist--translates purpose into practice, he or she must remain open to the possibility that the purpose itself may need to change. Lou Gerstner did this in the 1990s, when he decided that IBM would evolve to focus on applying technology rather than on inventing it. So did Steve Jobs, when he rescued Apple from a poorly performing strategy and expanded the company into attractive new businesses. Watching over strategy day in and day out is the CEO's greatest opportunity to shape the firm as well as outwit the competition.

Salmon are perhaps the quintessential icon of the Pacific Northwest, affecting the region's culture, politics, and economy. The importance Oregonians place on salmon recovery and their willingness to pay for salmon recovery efforts was assessed biennially between 1996 and 2002 through the Oregon Population Survey. Based on these data, we found that Oregonians appear to have become less supportive toward salmon recovery and salmon recovery efforts over that time period; they were less likely to say salmon recovery is important and chose lower willingness to pay responses in 2002 than in 1996. Attitudes do appear to be related to the economic conditions and demographic composition of residents of the state. In particular, we found that local unemployment rates, age of respondent, and rural county residence are significantly negatively correlated with the respondent's expressed support for salmon recovery efforts. Attributes positively correlated with expressions of support for salmon include male gender, graduate-level education, and American Indian identity. We found that a significant portion of the decline in support is unexplained by the variables included in the analysis.

Objective: To describe the incidence of maternal syphilis and the corresponding rate of infection in exposed neonates in British Columbia before and after a serious outbreak of infectious syphilis in the heterosexual population., Methods: We conducted a retrospective chart review of pregnant women with positive syphilis serology and reported cases of congenital syphilis in British Columbia from 1994 to 2003. Clinical charts were reviewed for demographic information, staging of maternal syphilis, and stage of pregnancy when treatment was received. The primary outcome measure was the number of cases of congenital syphilis. We conducted a 2-sided z-test and Fisher's exact test to determine differences in the proportion of infectious syphilis in mothers and the number of cases of congenital syphilis before and during the major outbreak., Results: In 389 478 live births in British Columbia between 1994 and 2003, 77% of mothers had prenatal syphilis serology. A diagnosis of syphilis was made in 183 mothers, resulting in 5 cases of congenital syphilis. Four of these were in infants whose mothers did not undergo prenatal syphilis testing. The proportion of pregnant women with infectious syphilis was significantly higher after the onset of a major outbreak of syphilis in the community than it was before (P = 0.001), but there was no significant difference in the number of cases of congenital syphilis (3 before and 2 after the outbreak, P = 0.36)., Conclusion: Although syphilis rates in British Columbia during the study period rose steadily, the prevalence of congenital syphilis remained low. Our findings suggest that, in the context of a major outbreak, universal screening and prenatal syphilis testing may contribute to controlling rates of congenital syphilis.

If a dam springs several leaks, there are various ways to respond. One could assiduously plug the holes, for instance. Or one could correct the underlying weaknesses, a more sensible approach. When it comes to corporate governance, for too long we have relied on the first approach. But the causes of many governance problems lie well below the surface--specifically, in critical relationships that are not structured to support the players involved. In other words, the very foundation of the system is flawed. And unless we correct the structural problems, surface changes are unlikely to have a lasting impact. When shareholders, management, and the board of directors work together as a system, they provide a powerful set of checks and balances. But the relationship between shareholders and directors is fraught with weaknesses, undermining the entire system's equilibrium. As the authors explain, the exchange of information between these two players is poor. Directors, though elected by shareholders to serve as their agents, aren't individually accountable to the investors. And shareholders--for a variety of reasons--have failed to exert much influence over boards. In the end, directors are left with the Herculean task of faithfully representing shareholders whose preferences are unclear, and shareholders have little say about who represents them and few mechanisms through which to create change. The authors suggest several ways to improve the relationship between shareholders and directors: Increase board accountability by recording individual directors' votes on key corporate resolutions; separate the positions of chairman and CEO; reinvigorate shareholders; and give boards funding to pay for outside experts who can provide perspective on crucial issues.

Public concern about the alarmingly high rate of biodiversity loss has not been matched by public willingness to bear boundless costs to stem the tide of extinction. Because resources for conservation are limited, setting conservation priorities to use those resources effectively is crucial. To do so in a way that addresses people's most pressing concerns about biodiversity loss, managers and policy makers must understand those concerns. This study investigates preferences for an array of benefits associated with biodiversity and wildlife and the relative importance to people of each. A survey was administered to a sample of the US population to explore public preferences for types of benefits often associated with biodiversity: utilitarian (commodity and recreation), ecological (certain and uncertain), aesthetic, symbolic, and humanistic. Respondents were asked to rank hypothetical species presented in choice sets of three species, each described simply in terms of one type of benefit. A rank-ordered multinomial logit model was estimated to establish a ranking of the benefits and evaluate the sensitivity of the ranking to socio-demographic variables. The means of the sample predictions indicated the relative importance of each type of benefit. Confidence intervals were constructed to evaluate the extent to which the ranks could be distinguished from one another. Ecological functions were most important to survey respondents; commodity-based benefits and human attributes were of moderate importance; and recreation, aesthetics, and symbolic references in literature and art appeared to be least important.

NAD(P)H:quinone oxidoreductase1 (NQO1) is a cytosolic protein that reduces and detoxifies quinones and their derivatives, thus protecting cells against redox cycling and oxidative stress. Disruption of the NQO1 gene in mice caused myeloid hyperplasia of bone marrow and highly significant increases in blood neutrophils, eosinophils, and basophils. NQO1-null mice also showed a decrease in lymphocytes and WBCs as compared with wild-type mice. Various techniques also demonstrated an increase in megakaryocytes without an increase in blood platelets. Histological analysis of liver, kidney, spleen, and thymus did not demonstrate a difference between wild-type and NQO1-null mice or a sign of infection. Blood cultures and urine analysis also did not demonstrate any sign of infection in NQO1-null and wild-type mice. Additional analysis of the bone marrow from NQO1-null mice revealed that loss of NQO1 alters the intracellular redox status because of accumulation of NAD(P)H, cofactors for NQO1. This causes a reduction in the levels of pyridine nucleotides and tumor suppressor proteins p53 and p73, and a decrease in apoptosis. The decrease in apoptosis causes myelogenous hyperplasia in NQO1-null mice. These results demonstrate that NQO1 acts as an endogenous factor in the protection against myelogenous hyperplasia. This is significant because 2-4% of human individuals without known abnormalities, and >25% of individuals with benzene poisoning and acute myelogenic leukemia are homozygous for a mutant allele (P187S) of NQO1 and lack NQO1 protein/activity.

A high-throughput, retrovirus-mediated mutagenesis method based on gene trapping in embryonic stem cells was used to identify a novel mouse gene. The human ortholog encodes a transmembrane protein containing five extracellular immunoglobulin-like domains that is structurally related to human NEPHRIN, a protein associated with congenital nephrotic syndrome. Northern analysis revealed wide expression in humans and mice, with highest expression in kidney. Based on similarity to NEPHRIN and abundant expression in kidney, this protein was designated NEPH1 and embryonic stem cells containing the retroviral insertion in the Neph1 locus were used to generate mutant mice. Analysis of kidney RNA from Neph1(-/-) mice showed that the retroviral insertion disrupted expression of Neph1 transcripts. Neph1(-/-) pups were represented at the expected normal Mendelian ratios at 1 to 3 days of age but at only 10% of the expected frequency at 10 to 12 days after birth, suggesting an early postnatal lethality. The Neph1(-/-) animals that survived beyond the first week of life were sickly and small but without edema, and all died between 3 and 8 weeks of age. Proteinuria ranging from 300 to 2,000 mg/dl was present in all Neph1(-/-) mice. Electron microscopy demonstrated NEPH1 expression in glomerular podocytes and revealed effacement of podocyte foot processes in Neph1(-/-) mice. These findings suggest that NEPH1, like NEPHRIN, may play an important role in maintaining the structure of the filtration barrier that prevents proteins from freely entering the glomerular urinary space.

As the human and mouse genome projects approach their goals, initiatives in functional genomics are advancing. When the nucleotide sequences are available, identification of gene functions will assume even greater importance. Determination of gene products and their proximal biochemical functions provide a part of the picture, but determination of their functions in the context of the whole organism is the ultimate goal. The manipulated mouse genome has become accepted as a model for understanding the genetic basis of human conditions and diseases. Consequently, biomedical research institutions have seen significant increases in the use of mice since the early 1980s, and these increases are largely attributable to the use of genetically modified mice. The role of comparative pathology in research on mutant mouse models of disease is increasing in response to these trends. Evaluation and phenotypic characterization of mutant mice, via clinical and anatomic pathology techniques, will be an important component of functional genomics initiatives.

The role of an extracellular cysteine protease encoded by the speB gene in group A Streptococcus (GAS) skin infection was studied with a mouse model. Mice were injected subcutaneously with a wild-type GAS serotype M3 strain or a cysteine protease-inactivated isogenic derivative grown to stationary phase. The mortality rate of mice injected with the M3 speB mutant strain was significantly decreased (P < 0.0008) compared to that of animals injected with the wild-type parental organism. The abscesses formed in animals infected with the cysteine protease mutant strain were significantly smaller (P < 0.0001) than those caused by the wild-type organism and slowly regressed over 3 to 4 weeks. In striking contrast, infection with the wild-type GAS isolate generated necrotic lesions, and in some animals the GAS disseminated widely from the injection site and produced extensive cutaneous damage. All of these animals developed bacteremia and died. GAS dissemination was accompanied by severe tissue and blood vessel necrosis. Cysteine protease expression in the infected tissue was identified by immunogold electron microscopy. These data demonstrate that cysteine protease expression contributes to soft tissue pathology, including necrosis, and is required for efficient systemic dissemination of the organism from the initial site of skin inoculation.

During the last half-century pathologists have explored the biologic mechanisms associated with inherited human and veterinary diseases by using inbred and inbred mutant (spontaneous) strains of mice. The first successful gene transfer to mice by pronuclear injection of the herpes simplex virus thymidine kinase gene and rabbit and human beta-globulin genes was achieved in the early 1980s. This accomplishment was followed a few years later with the creation of a mouse bearing a disrupted hypoxanthine phosphoribosyl transferase (hrpt) gene (targeted mutation based on ES cell blastocyst injection). Since then, hundreds of genetically engineered models of biomedical importance have been created. The unprecedented scale and scope of development of engineered models present great opportunities as well as experimental challenges to the investigator. The aim of the present review is to provide a framework of information on engineered mouse models from the perspective of experimental and comparative pathology research. Sections include: 1) a brief historical account of the development of mouse models of disease, with increasing progression of genetic refinement as represented by inbred (spontaneous) and congenic (targeted) mutant strains of mice; 2) a synopsis of spontaneous and targeted mutations, with anecdotal examples of expression of individual genes and interactions between multiple mutant genes; 3) selected examples of targeted mutations of interest to developmental and cancer biologists and immunologists; 4) an overview of the technology of development of transgenic mice; and 5) an introduction to on-line database resources of current multi-species genomic information.

The incidence of primary renal neoplasia in animals is quite low. Carcinomas are the most common primary renal tumors of dogs, cattle, and sheep. Among rabbit tumors, only uterine adenocarcinomas occur more frequently than do embryonal nephromas. However, spontaneous renal cell carcinomas in laboratory rabbits have only been reported once previously. We here report a second occurrence of a renal cell carcinoma in the laboratory rabbit.

Adenoviral vectors were inoculated via intracardiac injection into 5- to 1O-week-old cotton rats (Sigmodon hispidus) to evaluate the effects of systemic delivery. Cotton rats were chosen as a model because they are semipermissive to the replication of human adenoviruses. The vector used was AdV.RSV-tk, a replication-deficient adenovirus with a herpes simplex virus thymidine kinase gene inserted in the E1 region. Vector doses were 3 x 10(8), 3 x 10(9), and 3 x 10(10) viral particles per animal with and without ganciclovir at 10 mg/kg twice a day. Animals were sacrificed and necropsied at 24 hours, 7 days, and 14 days postinoculation. Gross and microscopic pathologic observations in dosed groups were compared with an unmanipulated control group. From each animal, 10 different organ systems were analyzed for histopathology and vector distribution. The only significant microscopic lesions observed were epicardial inflammation and splenic hemosiderosis. Vector sequences persisted throughout the 14-day assay with preponderance in the heart, lung, and lymphoid organs. Infectious virions were detected for 24 hours, and these virions were only detected at the site of injection of two animals in the highest dose group. No viral replication was detected. Therefore, systemic delivery of up to 3 x 10(11) viral particles/kg was well tolerated in this semipermissive host model and did not result in any significant pathology.

Infants and adults on oxygen often are treated with glucocorticoids in an attempt to reduce lung inflammatory injury. However, glucocorticoids hasten the development of hyperoxic lung injury in some animal models. The purpose of this study was to test the hypothesis that dexamethasone alters the lung inflammatory responses to hyperoxia exposure. We studied male Sprague-Dawley rats, placing them in >95% oxygen immediately after administration of 0, 0.1, 1, or 10 mg/kg of dexamethasone. At 0, 24, or 48 hr of exposure to hyperoxia, extravascular lung water contents were measured, and lung inflammatory responses were assessed by lung myeloperoxidase activities, lung neutrophil counts, and lung expression of E-Selectin and intercellular adhesions molecule-1 (ICAM-1). Dexamethasone, independent of exposure to hyperoxia, led to marked increases in lung neutrophil counts, without increases in lung myeloperoxidase activities or increases in the expression of the adhesion molecules. Hyperoxia exposure also enhanced lung neutrophil accumulation, and extravascular lung water increased earlier in animals exposed to hyperoxia and dexamethasone than in those exposed to hyperoxia alone. In conclusion, the increase in lung neutrophils in dexamethasone-treated rats without enhanced expression of E-Selectin or intracellular adhesions molecule-1 suggests that dexamethasone leads to lung neutrophil accumulation by its effect on neutrophils. The more rapid development of hyperoxic lung injury associated with earlier lung neutrophil accumulation suggests that dexamethasone-induced lung neutrophil sequestration primes the lung for the development of hyperoxic lung injury and supports further the conclusion that lung inflammation contributes significantly to the development of hyperoxic lung injury.

A null mutation was prepared in the mouse for CD18, the beta2 subunit of leukocyte integrins. Homozygous CD18 null mice develop chronic dermatitis with extensive facial and submandibular erosions. The phenotype includes elevated neutrophil counts, increased immunoglobulin levels, lymphadenopathy, splenomegaly, and abundant plasma cells in skin, lymph nodes, gut, and kidney. Very few neutrophils were found in spontaneously occurring skin lesions or with an induced toxic dermatitis. Intravital microscopy in CD18 null mice revealed a lack of firm neutrophil attachment to venules in the cremaster muscle in response to N-formyl- methionyl-leucyl-phenylalanine. A severe defect in T cell proliferation was found in the CD18 null mice when T cell receptors were stimulated either by staphylococcal enterotoxin A or by major histocompatibility complex alloantigens demonstrating a greater role of CD11/CD18 integrins in T cell responses than previously documented. The null mice are useful for delineating the functions of CD18 in vivo.

What differentiates truly great corporate strategies from the merely adequate? How can executives at the corporate level create tangible advantage for their businesses that makes the whole more than the sum of the parts? This article presents a comprehensive framework for value creation in the multibusiness company. It addresses the most fundamental questions of corporate strategy: What businesses should a company be in? How should it coordinate activities across businesses? What role should the corporate office play? How should the corporation measure and control performance? Through detailed case studies of Tyco International, Sharp, the Newell Company, and Saatchi and Saatchi, the authors demonstrate that the answers to all those questions are driven largely by the nature of a company's special resources--its assets, skills, and capabilities. These range along a continuum from the highly specialized at one end to the very general at the other. A corporation's location on the continuum constrains the set of businesses it should compete in and limits its choices about the design of its organization. Applying the framework, the authors point out the common mistakes that result from misaligned corporate strategies. Companies mistakenly enter businesses based on similarities in products rather than the resources that contribute to competitive advantage in each business. Instead of tailoring organizational structures and systems to the needs of a particular strategy, they create plain-vanilla corporate offices and infrastructures. The company examples demonstrate that one size does not fit all. One can find great corporate strategies all along the continuum.

The pulmonary damage caused by prolonged exposure to high oxygen concentrations is accompanied by lung inflammation, which may contribute to the expression of hyperoxic lung injury. In turn, adhesion molecules are crucial for initiating inflammatory responses. The goal of the present study was to investigate the association of contents of soluble adhesion molecules in plasma or alveolar fluids of hyperoxic rats with lung expression of adhesion molecules, lung inflammation and lung injury. We exposed adult Sprague-Dawley rats to > 95% oxygen for up to 60 h and measured the contents of intercellular adhesion molecule-I (ICAM-I) and E-Selectin in plasma and lung tissue expression of the same molecules, and we assessed lung myeloperoxidase (MPO) activties and lung water contents as indices of lung inflammation and injury, respectively. We also assessed ICAM-I content in lavage samples, because ICAM-I may be shed from the alveolar epithelium. Lung water was elevated at 60 h of hyperoxia-exposure, and this effect was preceded by increases in lung MPO activities. Lung ICAM-I expression was more than doubled at 48 h, although soluble ICAM-I contents were not elevated in plasma or lavage. Soluble E-Selectin was increased by more than 50% at 24 h of hyperoxia-exposure, while lung expressions of E-Selectin were not increased until 48 h. The sequence of the events observed in the present studies suggests that E-Selectin contributes to lung inflammation in hyperoxia and the acceleration of lung injury immediately following the inflammatory response suggests a pivotal role for inflammation in this injury.

Previously, a hypomorphic mutation in CD18 was generated by gene targeting, with homozygous mice displaying increased circulating neutrophil counts, defects in the response to chemically induced peritonitis, and delays in transplantation rejection. When this mutation was backcrossed onto the PL/J inbred strain, virtually all homozygous mice developed a chronic inflammatory skin disease with a mean age of onset of 11 weeks after birth. The disease was characterized by erythema, hair loss, and the development of scales and crusts. The histopathology revealed hyperplasia of the epidermis, subcorneal microabscesses, orthohyperkeratosis, parakeratosis, and lymphocyte exocytosis, which are features in common with human psoriasis and other hyperproliferative inflammatory skin disorders. Repetitive cultures failed to demonstrate bacterial or fungal organisms potentially involved in the pathogenesis of this disease, and the dermatitis resolved rapidly after subcutaneous administration of dexamethasone. Homozygous mutant mice on a (PL/J x C57BL/6J)F1 background did not develop the disease and backcross experiments suggest that a small number of genes (perhaps as few as one), in addition to CD18, determine susceptibility to the disorder. This phenotype provides a model for inflammatory skin disorders, may have general relevance to polygenic human inflammatory diseases, and should help to identify genes that interact with the beta2 integrins in inflammatory processes.

Although progesterone has been recognized as essential for the establishment and maintenance of pregnancy, this steroid hormone has been recently implicated to have a functional role in a number of other reproductive events. The physiological effects of progesterone are mediated by the progesterone receptor (PR), a member of the nuclear receptor superfamily of transcription factors. In most cases the PR is induced by estrogen, implying that many of the in vivo effects attributed to progesterone could also be the result of concomitantly administered estrogen. Therefore, to clearly define those physiological events that are specifically attributable to progesterone in vivo, we have generated a mouse model carrying a null mutation of the PR gene using embryonic stem cell/gene targeting techniques. Male and female embryos homozygous for the PR mutation developed normally to adulthood. However, the adult female PR mutant displayed significant defects in all reproductive tissues. These included an inability to ovulate, uterine hyperplasia and inflammation, severely limited mammary gland development, and an inability to exhibit sexual behavior. Collectively, these results provide direct support for progesterone's role as a pleiotropic coordinator of diverse reproductive events that together ensure species survival.

Mice with disrupted germline p53 alleles have been engineered by us and others and have been shown to have enhanced susceptibility to spontaneous tumors of various types. We monitored a large number of p53-deficient mice (p53+/- and p53-/-) and their wild-type littermates (p53+/+) of two different genetic backgrounds (129/Sv and mixed C57BL/6 x 129/Sv) up to 2 yr of age. p53+/- and p53-/- 129/Sv mice show accelerated tumorigenesis rates compared with their p53-deficient counterparts of mixed C57BL/6 x 129/Sv genetic background. The tumor spectra of the two strains of mice are similar except that almost half of 129/Sv p53-/- males develop malignant teratomas, whereas these tumors are rarely observed in C57BL/6 x 129/Sv mice and never in 129/Sv p53+/- males. In the study reported here, we further characterized the lymphomas that arose in the p53-nullizygous mice and found that over three-quarters of the lymphomas were of thymic origin and contained primarily immature (CD4+/CD8+) T-cells, whereas the remainder originated in the spleen and peripheral lymph nodes and were of B-cell type. The high incidence of early-onset lymphomas in the nullizygous mice makes these animals a good lymphoma model, whereas the heterozygous mice may be a useful model for Li-Fraumeni syndrome, a human inherited cancer predisposition.

Glutathione reductase catalyzes the NADPH-dependent conversion of glutathione disulfide to glutathione and helps protect the lung from injury by reactive oxygen. In animals allowed to breathe nearly 100% oxygen, the activities of other antioxidants in the lung can be induced by treatment with endotoxin, and this induction is associated with increased tolerance to hyperoxia. The purpose of this study was to see whether glutathione reductase activity in the lungs of mice increased with endotoxin treatment alone. We studied 60 FVB mice (20 males and 40 females). Half received endotoxin (500 micrograms/kg) intraperitoneally at time 0 and 24 h, and the controls received an equal volume of saline. At 48 h we killed the mice and removed their lungs. Treatment of mice with endotoxin increased glutathione reductase activity in the lung 55% (0.035 +/- 0.005 to 0.054 +/- 0.010 mumol NADPH reduced/min/mg protein; mean +/- SD; endotoxin different from control, p < 0.001). The increase in activity was the same for male and female mice. We measured the specific protein for glutathione reductase by Western analysis and mRNA for glutathione reductase using a slot-blot analysis and found that both increased roughly 2-fold with endotoxin treatment. This suggests that endotoxin treatment resulted in either increased rate of transcription of glutathione reductase mRNA or increased mRNA stability. We conclude that endotoxin treatment increases glutathione reductase activity in the lung and that this increase in activity may play a role in subsequent protection from hyperoxia.

Using gene targeting techniques, mice that have been generated with two germ-line p53 null alleles (homozygotes) develop normally but are highly susceptible to early onset spontaneous tumours. Here, we show that mice with a single null p53 allele (heterozygotes) produced in the same way are also susceptible to spontaneous tumours, but with a delayed onset compared to homozygotes. The most frequent tumour type in homozygotes was malignant lymphoma; in heterozygotes, osteosarcomas and soft tissue sarcomas predominated. Heterozygous mice treated with a liver carcinogen, dimethylnitrosamine, showed a decreased survival time in comparison to treated wild type mice, suggesting that the p53-deficient mice may be useful for some in vivo carcinogenesis assays.

Lung injury caused by breathing enriched oxygen continues to be a major problem in clinical medicine. Experimentally, hyperoxic lung injury is characterized by pulmonary edema and associated neutrophil accumulation. Although extensively investigated, the mechanisms for neutrophil accumulation and the role of this accumulation in hyperoxic lung injury remain controversial. Intercellular adhesion molecule-1 (ICAM-1) is an adhesion molecule that when increased on endothelium by inflammatory cytokines leads to increased adhesion of neutrophils to the inflamed endothelium and transendothelial migration. The purpose of this study was to examine the role of inflammation in hyperoxia-induced lung injury by investigating ICAM-1 expression in the lungs of mice exposed to > 95% oxygen continuously. Lung tissue from mice exposed to > 95% oxygen was analyzed for ICAM-1 mRNA by slot blot analysis and for ICAM-1 protein expression. We also examined lungs from mice exposed to hyperoxia for up to 96 h by light microscopy to correlate pulmonary inflammation with ICAM-1 expression. We found that mRNA for ICAM-1 increased 56% over baseline after 48 h of exposure to hyperoxia, that ICAM-1 protein increased by more than 5-fold over baseline after 96 h of exposure to hyperoxia, and that lung inflammation and injury were not evident until 96 h of exposure. Our data demonstrate that exposure to hyperoxia causes an increase in ICAM-1 gene transcription and/or mRNA stability in mouse lungs, and that this increase is followed by an increase in ICAM-1 protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Using gene targeting in embryonic stem cells, we have generated mice with one or two null p53 germ line alleles. Mice with both p53 alleles inactivated are developmentally normal but highly susceptible to the early development of spontaneous tumors. Initial studies were performed in mice with a mixed inbred genetic background (75% C57BL/6 and 25% 129/Sv) (Donehower et al., Nature (London) 356, 215-221, 1992). To study the effect of genetic background on tumorigenesis in p53-deficient mice, we have put the p53 null allele into a pure 129/Sv background and monitored tumor development. 129/Sv mice with two p53 null alleles developed tumors sooner than the mixed genetic background p53-deficient animals. The most frequently observed tumor in p53 null mice of both genetic backgrounds was a malignant lymphoma. Because the 129/Sv strain has a low incidence of lymphoma, the frequent occurrence of lymphomas in all p53 null mice suggests that this particular tumor type may be a direct result of p53 loss and not a result of a particular genetic background. In addition to malignant lymphomas, the 129/Sv p53-deficient mice showed an increased incidence of aggressive teratocarcinomas (8 of 18 tumor-bearing males), a tumor type rare in virtually all inbred mice except for 129 strains. Thus, it appears that loss of p53 may accelerate a prior tumor predisposition and that genetic background can play a role in mediating both the rate and spectrum of tumor development in these mice.

A recessive mutation was identified in a family of transgenic mice that resulted in a reversal of left-right polarity (situs inversus) in 100 percent of the homozygous transgenic mice tested. Sequences that flanked the transgenic integration site were cloned and mapped to mouse chromosome 4, between the Tsha and Hxb loci. During early embryonic development, the direction of postimplantation turning, one of the earliest manifestations of left-right asymmetry, was reversed in homozygous transgenic embryos. This insertional mutation identifies a gene that controls embryonic turning and visceral left-right polarity.

Vascular congestion and liver swelling have long been recognized as features of the hepatotoxic effects of acetaminophen (AAP) in mice and rats and have been proposed as contributing factors to the eventual extent of necrosis produced. Neutrophil accumulation in the hepatic microcirculation has been proposed as being responsible for the blockage of hepatic blood flow and thereby the expansion of the region of damage. We therefore determined in mice the effects of hepatotoxic doses of AAP on the messenger RNA for intercellular adhesion molecule-1 (ICAM-1), which is a critical determinant of neutrophil adhesion, activation and ultimately of neutrophil-mediated tissue injury. Hepatotoxic doses of AAP did not upregulate ICAM-1 messenger RNA. However, doses of bacterial lipopolysaccharide (LPS) did cause a rapid and dramatic increase in ICAM-1 message, which was accompanied by a much greater hepatic accumulation of neutrophils, but which led to only scattered single cell necrosis. In addition, we investigated the effects of pentoxifylline (PTX) on AAP-induced vascular congestion and on hepatic necrosis as evaluated histologically and by measurement of plasma transaminase activities. Although PTX has been shown to increase blood cell deformability and improve vascular perfusion in a number of animal models of restricted blood flow, and is used in humans for the treatment of intermittent claudication, we found no decrease in AAP-induced hepatic swelling or in AAP-induced necrosis in response to PTX. With some dosing regimens, PTX-treated animals proved to be slightly more susceptible to AAP, which may be related to the reported potentiation of the cytotoxicities of a number of alkylating anti-cancer drugs by PTX and other methylxanthines. We conclude from these studies that upregulation of ICAM-1 and subsequent adhesion and vascular plugging by neutrophils are not significant determinants of AAP-induced liver swelling and necrosis and that whatever hemorheological advantages PTX might offer in AAP-induced hepatic damage appear to be overshadowed by effects that potentiate the toxic responses.

A group B streptococcus (GBS) isolated from human neonates diagnosed with sepsis and respiratory distress ("early-onset disease") produces a polysaccharide exotoxin (GBS toxin) that, when infused in sheep, causes lung pathophysiology similar to that seen in humans. Histological studies have demonstrated that GBS toxin induces a strong inflammatory response in the lung, with pulmonary sequestration of granulocytes and extensive capillary endothelial damage. The susceptibility of humans to GBS toxin is age-dependent and limited to about 4 days after birth. It is rarely evident thereafter. This suggests that the binding of GBS toxin to the target endothelium occurs via specific components in the developing lung endothelial cells of the newborn that are later lost. We report here that GBS toxin can also bind to developing endothelium associated with neoplasia and induce an inflammatory response. GBS toxin was shown by immunohistochemistry to bind to capillary endothelium of human large-cell carcinomas. In nude mice bearing human tumor xenografts, intravenously administered GBS toxin caused tumor necrosis and hemorrhagic lesions, and substantially inhibited the rate of growth of the tumors. In BALB/c mice bearing Madison lung tumors, GBS toxin induced an inflammatory response resulting in marked changes in tumor morphology, including vasodilation, endothelial and tumor cell necrosis, invasion of lymphocytes and macrophages, and capillary thrombosis. In these tumor models, no evidence of toxicity to the vasculature of other tissues was observed. The reported pathophysiology of GBS in human neonates, the lack of disease in non-neonates colonized with GBS, and these results suggest that GBS toxin may have potential as a well tolerated agent in cancer therapy of some human tumors.

Mutations in the p53 tumour-suppressor gene are the most frequently observed genetic lesions in human cancers. To investigate the role of the p53 gene in mammalian development and tumorigenesis, a null mutation was introduced into the gene by homologous recombination in murine embryonic stem cells. Mice homozygous for the null allele appear normal but are prone to the spontaneous development of a variety of neoplasms by 6 months of age. These observations indicate that a normal p53 gene is dispensable for embryonic development, that its absence predisposes the animal to neoplastic disease, and that an oncogenic mutant form of p53 is not obligatory for the genesis of many types of tumours.

Malignant cystosarcoma phylloides (CP) is a relatively rare cancer of the breast. A CP tumor was processed as part of a tumor acquisition, propagation, and preservation program in patient biotherapy. Two tissue culture cell lines were developed from this tumor, one directly from the biopsy, another from a xenograft tumor grown in athymic mice. The two cell lines were similar in character. There was strong immunochemical reactivity with antibodies to vimentin, type I collagen, and type III collagen. There was no reactivity with antibodies to cytokeratin and epithelial membrane antigen. Both cell lines were aneuploid, clonogenic in soft agar, and tumorigenic in nude mice. 5 alpha-dihydrotestosterone and thyroxine added to the culture medium stimulated growth, while testosterone, 17 beta-estradiol, and 4-hydroxytamoxifen were without effect. Dexamethasone and cortisol were inhibitory at high doses (10(-6) M). Dibutyryl cyclic AMP, theophylline, and vitamin C were all inhibitory. The biopsy contained tumor-infiltrating lymphocytes which proliferated in cultures containing interleukin 2. The expanded lymphocytes were activated T cells which had the capacity to lyse tumor cells. These results suggest possibilities in the therapy of cystosarcoma phylloides involving vitamin C, certain hormones, and tumor-infiltrating lymphocytes.

This study was designed to investigate the toxicity of intravenously administered alpha-tocopherol, alpha-tocopheryl acetate, and a polysorbate vehicle similar to that used in a commercial preparation of alpha-tocopheryl acetate intended for intravenous administration. Cesarean-delivered newborn rabbits fed intravenously were administered 100 mg of either alpha-tocopherol or alpha-tocopheryl acetate in a polysorbate vehicle, or the vehicle only, or no treatment for 6 or 7 days. Two intravenous diets were employed which differed in nutritional content and were termed low energy (LE) and high energy (HE). High concentrations of alpha-tocopherol were present in the tissues of all pups that received either treatment with alpha-tocopherol or alpha-tocopheryl acetate in the polysorbate vehicle, irrespective of the nutritional regimen. Pups in all treatment and control groups which received the LE diet had hepatic centrilobular degeneration, necrosis and pigment accumulation, which was attributed to malnutrition. No additional toxicities could be attributed to the vitamin E or polysorbate treatments. Administration of the HE diet eliminated the nutrition-related centrilobular degeneration, and revealed treatment-related liver changes. HE pups treated with alpha-tocopheryl acetate in the polysorbate vehicle had microscopic evidence of mild bile stasis and had elevated serum bilirubin. Minimal lipidosis or fatty change in the liver was observed only in alpha-tocopherol and alpha-tocopheryl acetate-treated pups. Lipidosis in the spleen was moderate in the alpha-tocopherol group and minimal in the alpha-tocopheryl acetate group. Lipidosis also occurred in the adrenal gland primarily in the alpha-tocopheryl acetate group.(ABSTRACT TRUNCATED AT 250 WORDS)

An enlarged nodular mass, assumed to be the prostate gland because of location and consistency, was palpated in the pelvic region of a 10-year-old German Shepherd Dog. Castration was performed as a therapeutic procedure after an estrogenic hormone failed to reduce the size of the mass. A tumor identified histologically as a seminoma was in the right testicle. The dog died 1 month after castration, and generalized metastatic neoplasia was observed at necropsy. The mass that involved the neck of the bladder and the metastases were identified as leiomyosarcoma.