Initial Case Reports of Cancer in Naked Mole-rats (Heterocephalus glaber).

Naked mole-rats (NMRs;Heterocephalus glaber) are highly adapted, eusocial rodents renowned for their extreme longevity and resistance to cancer. Because cancer has not been formally described in this species, NMRs have been increasingly utilized as an animal model in aging and cancer research. We previously reported the occurrence of several age-related diseases, including putative pre-neoplastic lesions, in zoo-housed NMR colonies. Here, we report for the first time 2 cases of cancer in zoo-housed NMRs. In Case No. 1, we observed a subcutaneous mass in the axillary region of a 22-year-old male NMR, with histologic, immunohistochemical (pancytokeratin positive, rare p63 immunolabeling, and smooth muscle actin negative), and ultrastructural characteristics of an adenocarcinoma possibly of mammary or salivary origin. In Case No. 2, we observed a densely cellular, poorly demarcated gastric mass of polygonal cells arranged in nests with positive immunolabeling for synaptophysin and chromogranin indicative of a neuroendocrine carcinoma in an approximately 20-year-old male NMR. We also include a brief discussion of other proliferative growths and pre-cancerous lesions diagnosed in 1 zoo colony. Although these case reports do not alter the longstanding observation of cancer resistance, they do raise questions about the scope of cancer resistance and the interpretation of biomedical studies in this model. These reports also highlight the benefit of long-term disease investigations in zoo-housed populations to better understand naturally occurring disease processes in species used as models in biomedical research.

Ti8C12+-Metallo-Carbohedrenes: A New Class of Molecular Clusters?

During the course of studying the dehydrogenation reactions of hydrocarbons by titanium atoms, ions, and clusters, an exceptionally stable and abundant cluster which contains 8 titaniums and 12 carbons was discovered. "Titration" reactions with ND(3) reveal the uptake of eight molecules, pointing to the fact that the titanium atoms are at exposed positions of similar coordination. A dodecahedral structure of T(h) point group symmetry is proposed to account for the unusual stability of this molecular cluster. The Ti(8)C(12)(+) dodecahedron has 12 pentagonal rings and each of the rings is formed by two titanium and three carbon atoms, where each titanium is bound to three carbons. Based on the model, it is expected that neutral Ti(8)C(12) would be a stable metallo-carbododecahedral molecule and may comprise one member of a new class of molecules, namely metallo-carbohedrenes.

Genetic analysis of liver tumorigenesis in SV40 T antigen transgenic mice implies a role for imprinted genes.

Liver tumors from interspecific hybrid, transgenic mice containing the SV40 early region linked to a mouse major urinary protein enhancer/promoter were analyzed for loss of heterozygosity to identify chromosomal regions which potentially contain genetic loci involved in multistep tumorigenesis. A broad pattern of complete and partial loss of heterozygosity or allelic imbalance was observed with frequent loss of heterozygosity/partial loss of heterozygosity of loci on chromosomes 1, 5, 7, 8, and 12. In tumors from Mus domesticus x Mus spretus F1 mice a strong preference for loss of the domesticus allele of H19 on chromosome 7 was observed, whereas loss of heterozygosity/partial loss of heterozygosity on chromosome 8 involved preferential loss of spretus alleles. In tumors from reciprocal crosses with Mus castaneus, the maternal chromosome 7 H19 allele was preferentially lost irrespective of whether it was domesticus or castaneus, strongly suggesting the involvement of an imprinted gene(s) in tumor progression.

Chromosome 8 alterations accompany tumorigenesis in renin-SV40 T antigen transgenic mice.

s.c. and abdominal tumors from interspecific hybrid, transgenic mice containing the SV40 early region linked to a renin enhancer/promoter were analyzed for loss of heterozygosity to identify chromosomal regions involved in tumorigenesis. A very high frequency of loss of heterozygosity/partial loss of heterozygosity or allelic imbalance involving the distal regions of chromosome 8 was observed in the s.c. tumors (76%) with frequent amplification (3-6 times) of the corresponding proximal regions including Junb, suggesting that chromosome 8 breakage and amplification promotes tumorigenesis in these mice.

In vivo endochondral bone formation using a bone morphogenetic protein 2 adenoviral vector.

Bone morphogenetic proteins (BMPs) are polypeptides that induce ectopic bone formation in standard rat in vivo assay systems. Previous studies have demonstrated the clinical utility of these proteins in spinal fusion, fracture healing, and prosthetic joint stabilization. Gene therapy is also a theoretically attractive technique to express BMPs clinically, since long-term, regulatable gene expression and systemic delivery with tissue-specific expression may be possible in future. This study was performed to determine whether an adenoviral vector containing the BMP-2 gene can be used to express BMP-2 in vitro and promote endochondral bone formation in vivo. In vitro, U87 MG cells transduced per cell with 20 MOI of an adenoviral construct containing the BMP-2 gene under the control of the universal CMV promoter (Ad-BMP-2) showed positive antibody staining for the BMP-2 protein at posttransfection day 2. The synthesis and secretion of active BMP-2 into the conditioned medium of Ad-BMP-2-transduced 293 cells were confirmed by Western blot analysis and the induction of alkaline phosphatase activity in a W-20 stromal cell assay. In vivo, Sprague-Dawley rats and athymic nude rats were injected with Ad-BMP-2 in the thigh musculature and were sacrificed on day 3, 6, 9, 12, 16, 21, 60, and 110 for histological analysis. The Sprague-Dawley rats showed evidence of acute inflammation, without ectopic bone formation, at the injection sites. In the athymic nude rats, BMP-2 gene therapy induced mesenchymal stem cell chemotaxis and proliferation, with subsequent differentiation to chondrocytes. The chondrocytes secreted a cartilaginous matrix, which then mineralized and was replaced by mature bone. This study demonstrates that a BMP-2 adenoviral vector can be utilized to produce BMP-2 by striated muscle cells in athymic nude rats, leading to endochondral bone formation. However, in immunocompetent animals the endochondral response is attenuated, secondary to the massive immune response elicited by the first-generation adenoviral construct.

Morphologic analysis of BMP-9 gene therapy-induced osteogenesis.

The present study was performed to determine the histological, ultrastructural, and radiographic changes that occur over time at intramuscular BMP-9 gene therapy treatment sites. Several members of the bone morphogenetic protein (BMP) family have the potential to induce osteochondrogenesis when the protein is delivered to rodents, canines, rabbits, and nonhuman primates. Previous studies have also demonstrated that BMP gene therapy utilizing adenoviral vectors can also stimulate orthotopic and heterotopic bone formation in rodents and rabbits. Athymic nude and Sprague-Dawley rats were injected with Ad-BMP-9 or Ad-beta-Gal (3.75 x 10(9) particles) in their thigh musculature and light microscopic, electron microscopic, and computerized tomography analysis was performed 3, 6, 9, 12, 15, 18, 21, and 100 days later. To assess early mesenchymal cell proliferation, a bromodeoxyuridine (BrdU) immunohistochemical analysis was also performed 48, 60, and 72 hr postinjection in athymic nude rats. All animals demonstrated extensive endochondral bone formation at the Ad-BMP-9 treatment sites within 3 weeks. The Sprague-Dawley rats also exhibited a massive, acute inflammatory infiltrate during the first week. Proliferating mesenchymal stem cells were clearly evident as early as 2 days after treatment, which differentiated into small or hypertrophied chondrocytes during the next week. During the third week, the cartilaginous matrix mineralized and formed woven bone, which converted to lamellar bone by 3 months. No evidence of bone formation was demonstrated at the Ad-beta-Gal injection sites in the athymic nude or Sprague-Dawley rats. In addition, no cellular proliferation was seen at the Ad-beta-Gal treatment sites in the athymic nude animals as assessed by light microscopy and BrdU immunohistochemistry. The extensive bone formation induced by Ad-BMP-9 suggests that BMP gene therapy may have potential utility in the treatment of degenerative, rheumatic, or traumatic bone pathology.

The effects of two types of cognitive tasks on postural stability in older adults with and without a history of falls.

BACKGROUND: This study used a dual task design to investigate the effects of two different types of cognitive tasks on stability (as measured by center of pressure displacement) in young vs older adults with and without a history of falls. METHODS: Two secondary cognitive tasks, a sentence completion and a visual perceptual matching task, were used to produce changes in attention during quiet stance under flat vs compliant surface conditions in 20 healthy young adults, 20 healthy older adults, and 20 older adults with a history of imbalance and falls. Postural stability was quantified using forceplate measures of center of pressure (COP). Speed and accuracy of verbal response on the cognitive tasks were also quantified. RESULTS: During the simultaneous performance of a cognitive and postural task, decrements in performance were found in the postural stability measures rather than the cognitive measures for all three groups. While no differences were found between the young adults and the older healthy adults on the firm surface, no task condition, when task complexity was increased (either through the introduction of a secondary cognitive task, or a more challenging postural condition such as standing on the compliant surface), significant differences in postural stability between the two groups became apparent. In contrast to the young and healthy older adults, postural stability in older adults with a history of falls was significantly affected by both cognitive tasks. CONCLUSION: Results suggest that when postural stability is impaired, even relatively simple cognitive tasks can further impact balance. Results further suggest that the allocation of attention during the performance of concurrent tasks is complex; depending on many factors including the nature of both the cognitive and postural task, the goal of the subject and the instructions.

Percutaneous spinal fusion using bone morphogenetic protein-2 gene therapy.

OBJECT: Gene therapy has many potential applications in neurosurgery. One application involves bone morphogenetic protein-2 (BMP-2), a low-molecular-weight glycoprotein that induces bone formation in vivo. Numerous studies have demonstrated that the BMP-2 protein can enhance spinal fusion. This study was undertaken to determine whether direct injection of an adenoviral construct containing the BMP-2 gene can be used for spinal fusion. METHODS: Twelve athymic nude rats were used in this study. Recombinant, replication-defective type 5 adenovirus with the cytomegalovirus (CMV) promoter and BMP-2 gene (Ad-BMP-2) was used. A second adenovirus constructed with the CMV promoter and beta-galactosidase (beta-gal) gene (Ad-beta-gal) was used as a control. In three groups (four rats each) 7.5 microl of virus (5x10(8) particles/microl) was injected percutaneously and paraspinally at the lumbosacral junction: Group 1 received Ad-BMP-2 bilaterally; Group 2 received Ad-BMP-2 on the right, Ad-beta-gal on the left; and Group 3 received Ad-beta-gal bilaterally. Computerized tomography (CT) scans of the lumbosacral spine were obtained at 3, 5, 8, and 12 weeks. At 12 weeks, the animals were killed and underwent histological inspection. Ectopic bone formation was observed both on three-dimensionally reconstructed CT scans and histological examination in all rats at sites treated with Ad-BMP-2. Histological analysis demonstrated bone at different stages of maturity adjacent to the spinous processes, laminae, and transverse processes. CONCLUSIONS: Results of this study clearly demonstrated that it is possible to produce in vivo endochondral bone formation by using direct adenoviral construct injection into the paraspinal musculature, which suggests that gene therapy may be useful for spinal fusion in the future.

Use of bone morphogenetic protein-9 gene therapy to induce spinal arthrodesis in the rodent.

OBJECT: Bone morphogenetic proteins (BMPs) have been shown to have significant osteoinductive activity in numerous in vitro and in vivo assay systems, and BMP-2 and BMP-7 are currently being evaluated in human clinical studies. In the spinal region, BMPs have been shown to promote spinal arthrodesis at a higher rate than autologous bone alone. The delivery of BMPs via direct or ex vivo gene therapy techniques is also currently being evaluated and has shown promise in several mammalian models. The present study was designed to evaluate the efficacy of the use of direct, percutaneous BMP-9 adenoviral gene therapy to promote spinal fusion in the rodent. METHODS: Each animal was injected with 7.5x10(8) pfu of a BMP-9 adenoviral vector in the lumbar paraspinal musculature and allowed to survive 16 weeks. Computerized tomography studies and histological analysis demonstrated massive bone induction at the injection sites, clearly leading to solid spinal arthrodesis, without evidence of pseudarthroses, nerve root compression, or systemic side effects. CONCLUSIONS: The results of this study strongly support the advancement of BMP gene therapy techniques toward clinical use.

A light and electron microscopic study of ectopic tendon and ligament formation induced by bone morphogenetic protein-13 adenoviral gene therapy.

OBJECT: Bone morphogenetic proteins (BMPs) are involved in the growth and development of many tissues, but it is their role in skeletal development and their unique ability to induce ectopic and orthotopic osteogenesis that have attracted the greatest interest. Expression of the BMP-13 gene is predominantly localized to hypertrophic chondrocytes in regions of endochondral bone formation during development, as well as in mature articular cartilage in the adult. In addition, the application of BMP-13 on a collagen carrier induces neotendon/neoligament formation when delivered subcutaneously or intramuscularly in rodents. The aim of the present study was to determine the histological and ultrastructural changes that occur after the intramuscular injection of a first-generation BMP-13 adenoviral vector. METHODS: Athymic nude rats were injected with 3.75 x 10(10) plaque-forming units of adenovirus (Ad)-BMP-13 or Ad-beta-galactosidase in the thigh musculature, and the region was examined using light and electron microscopy at various time points between 2 days and 100 days postinjection. As early as 2 days after injection of Ad-BMP-13, progenitor cells were observed infiltrating between the transduced muscle fibers. These cells subsequently proliferated, differentiated, and secreted large amounts of collagenous extracellular matrix. By 100 days postinjection, the treated tissue displayed the histological and ultrastructural appearance of neotendon/neoligament, which was clearly demarcated from the surrounding muscle. Small foci of bone and fibrocartilage were also seen within the treated tissue. A short-term bromodeoxyuridine study also demonstrated rapid mesenchymal cell proliferation at the Ad-BMP-13 injection site as early as 48 hours postinjection. At all time points, the control AD-beta-gal injection sites were found to contain only normal muscle, without evidence of inflammation or mesenchymal cell proliferation. CONCLUSIONS: The results of this study indicate that in the future the use of the BMP-13 gene may have therapeutic utility for the healing of tendon and ligament tears and avulsion injuries.

An investigation of prospective memory in children with ADHD.

Prospective memory, defined as the ability to follow through on intended behavior, is believed to be subserved by a number of neuroanatomical substrates, but particularly dependent, at least in part, on the frontal lobes. Children with Attention-Deficit Hyperactivity Disorder (ADHD) traditionally have difficulty on tasks dependent on frontal lobe structures. The present study attempted to determine whether children with ADHD are impaired in prospective memory function. Two studies are described that use a new measure of time-based prospective memory, the CyberCruiser (Kerns, 2000), to compare children with ADHD to a control group consisting of participants who were matched in respect to age, gender, and IQ. The results document prospective memory deficits in ADHD. Prospective memory performance correlated significantly with clinical measures of ADHD as assessed by the Conners' Parent Rating Scale (Conners, 1990) Hyperactivity Index, but was unrelated to intellectual ability. Though psychometric measures of attention correlated with prospective memory performance, they did not account for the differences in prospective memory that were observed between the ADHD and control groups.

Time reproduction, working memory, and behavioral inhibition in children with ADHD.

Barkley (1997a) proposed that the central deficit in Attention Deficit Hyperactivity Disorder (ADHD) is in behavioral inhibition, resulting in deficits both in working memory and sense of time. To test this theory, 21 children with ADHD and a matched sample (ages 6-13) completed a variety of tasks that measured behavioral inhibition, working memory, attention, and time reproduction. Children with ADHD performed significantly below controls on measures of inhibition, attention, and time reproduction. They did not differ significantly from controls, however, on tasks of working memory. In addition, performance on the working memory tasks was not correlated with the time reproduction task. We discuss the relevance of these results in the context of current theories of ADHD.

Emotion regulation as a mediator of associations between mother-child attachment and peer relationships in middle childhood.

Although a link between attachment and peer relationships has been established, the mechanisms that account for this link have not been identified. The 1st goal of this study was to test emotion regulation as a mediator of this link in middle childhood. The 2nd goal was to examine how different aspects of emotion regulation relate to peer competence. Fifth graders completed self-report and semiprojective measures to index mother-child attachment, mothers reported on children's emotionality and coping strategies, and teachers reported on children's peer competence. Constructive coping was related to both attachment and peer competence, and mediated the association between attachment and peer competence, suggesting that emotion regulation is one of the mechanisms accounting for attachment-peer links. Constructive coping was more strongly associated with peer competence for children high on negative emotionality than for children low on negative emotionality.

Parent-child attachment and monitoring in middle childhood.

Research on parent-child attachment and parental child rearing practices has been pursued independently. The purpose of the present study was to test whether a secure attachment relationship is related to parental monitoring and child efforts to contribute to the monitoring process. This question was examined in a cross-sectional study of third- and sixth-grade children and their parents. Attachment-based measures were used to tap child and parent perceptions of attachment. Monitoring (i.e., parents' awareness of children's whereabouts and activities) was assessed through phone interviews with children and parents. Child contributions to monitoring were assessed with parent and child questionnaires. A more secure attachment was related to closer monitoring and greater cooperation by the child in monitoring situations, especially at sixth grade. The findings illustrate the importance of embedding attachment within a larger child rearing context.

A community-based dental program for older adults.

The planning and implementation of a community-based outreach program for older adults is described. Objectives of the program were to provide dental health education to older persons at their place of residence, to improve access to dental care for that population, and to increase the number of older adults treated at a dental facility administered by the Department of Community Dentistry, University of Michigan. Data collected during encounters with participants are reported to supplement the description of the program. In the first year, 98 older adults (mean age 71.3 years) participated in the outreach program which was directed by a dental hygienist. Of those persons whose initial encounter was with the outreach program, 47 percent eventually contacted the dental care facility and 36 percent completed treatment. Persons who elected to seek treatment average 3.9 encounters with the hygienist during the program; persons who did not seek treatment averaged 2.2 encounters. Strengths and weaknesses of the program are discussed.

Management of attention and memory disorders following traumatic brain injury.

Disorders of attention, memory, and executive function are common sequelae in children who have sustained traumatic brain injuries. Given the persistent nature of these deficits, there is a need for efficacious remedial approaches. Typically, remediation is approached, through one of three general intervention strategies: externally focused interventions aimed at changing the environment so that the effect of the dysfunction is minimized, internally focused interventions aimed at improving the underlying cognitive ability, and compensatory interventions aimed at teaching children to use alternate strategies that lessen the impact of the dysfunction. This article describes current research involving these approaches for the treatment of attention and memory disorders in children.

Cognitive deficits in nonretarded adults with fetal alcohol syndrome.

Persons with fetal alcohol syndrome (FAS) who are not mentally retarded often have difficulty qualifying for special educational and vocational services. In this pilot study, 16 nonretarded young adults with FAS were divided into two groups--one with average to above-average IQ and one with borderline to low-average IQ. Participants in both groups manifested clear deficits on neuropsychological measures sensitive to complex attention, verbal learning, and executive function. The frequency and severity of cognitive impairment demonstrated in both FAS groups were greater than what would have been predicted on the basis of IQ alone. The implications of these findings for identification and management of cognitive impairment in individuals with FAS are discussed.

Radiation safety instruction for non-radiation workers.

In today's society, neglecting to provide adequate hazard-awareness instruction to workers can be successfully used to file suit against institutions where radioactive material (RAM) or radiation generating devices (RGDs) are used. Because of the lack of instruction, in some cases, just the perceived risk (even where no significant exposure to radiation existed) has proven to be more important than the actual risk. Groups of non-radiation workers such as custodian, maintenance and laboratory personnel, whose duties may require them to work in the vicinity of RAM and RGDs, sometimes do not receive proper hazard-awareness instruction. Misinterpretation of the applicable hazard-awareness regulations is a reason why institutions sometimes fail to instruct their workers. The objectives of this paper are to help radiation safety program managers become more aware of the importance of having well-instructed non-radiological personnel and to develop and provide basic information to help implement an effective hazard-awareness instruction program for workers. Topics discussed in this paper include regulatory aspects regarding the instruction to non-radiation workers, a list of radiological incidents that could have been prevented with proper instruction to workers and recommendations for the development and implementation of an effective instruction program.

Managing a sound portable gauge radiation safety program.

At some construction engineering companies, individuals with no background in radiation safety sometimes are assigned the not always welcome title of Radiation Safety Officer (RSO). With this new title comes the responsibility of ensuring that portable gauges are used safely at their facilities and in tile field. These newly appointed RSOs sometimes lack the knowledge and experience needed to manage a radiation safety program. This article was developed to provide the basic information needed to work confidently and safely around these instruments and to discuss licensing requirements and other information pertaining to the management of a portable gauge radiation safety program.