Dysmorphism, variable overgrowth, normal bone age, and severe developmental delay: a "Sotos-like" syndrome?
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Acromegaly↗
Biomedical subjects
L Wilson
Publications and source records attributed to L Wilson.
Expression in UVW glioma cells of the noradrenaline transporter gene, driven by the telomerase RNA promoter, induces active uptake of [131I]MIBG and clonogenic cell kill.
One of the most effective ways to kill cancer cells is by treatment of tumours with radiation. However, the administered dose of radiation to the tumour is limited by normal tissue toxicity. Strategies which decrease normal tissue exposure relative to tumour dose are urgently sought. One such promising scheme involves gene transfer, leading to the introduction of transporters specific for pharmaceuticals which can be labelled with radionuclides. We have previously demonstrated in vitro, that transfer of the noradrenaline transporter (NAT) gene, under viral promoter control, induces in host cells the active accumulation of the radiopharmaceutical [131I]meta-iodobenzylguanidine ([131I]MIBG) which results in kill of clonogens. We now report 17-fold enhancement of [131I]MIBG uptake by UVW glioma cells transfected with the NAT gene whose expression is driven by the human telomerase RNA (hTR) promoter (70% the uptake achieved by the strong viral promoter). Multicellular spheroids composed of hTR-NAT-transfected UVW cells exhibited dose-dependent susceptibility to treatment with [131I]MIBG. This was demonstrated by decreased survival of clonogens and complete sterilization of clonogens derived from spheroids and also failure of spheroids to regrow after administration of 7 MBq/ml [131I]MIBG. These data suggest hTR regulated expression of NAT may be an effective gene therapy strategy.
3-Iodobenzylguanidine↗
Resistance to Taxol in lung cancer cells associated with increased microtubule dynamics.
Microtubule dynamics are crucial for mitotic spindle assembly and chromosome movement. Suppression of dynamics by Taxol appears responsible for the drug's potent ability to inhibit mitosis and cell proliferation. Although Taxol is an important chemotherapeutic agent, development of resistance limits its efficacy. To examine the role of microtubule dynamics in Taxol resistance, we measured the dynamic instability of individual rhodamine-labeled microtubules in Taxol-sensitive and -resistant living human cancer cells. Taxol-resistant A549-T12 and -T24 cell lines were selected from a human lung carcinoma cell line, A549. They are, respectively, 9- and 17-fold resistant to Taxol and require low concentrations of Taxol for proliferation. We found that microtubule dynamic instability was significantly increased in the Taxol-resistant cells. For example, with A549-T12 cells in the absence of added Taxol, microtubule dynamicity increased 57% as compared with A549 cells. The length and rate of shortening excursions increased 75 and 59%, respectively. These parameters were further increased in A549-T24 cells, with overall dynamicity increasing by 167% compared with parental cells. Thus, the decreased Taxol-sensitivity of these cells can be explained by their increased microtubule dynamics. When grown without Taxol, A549-T12 cells were blocked at the metaphase/anaphase transition and displayed abnormal mitotic spindles with uncongressed chromosomes. In the presence of 2-12 nM Taxol, the cells grew normally, suggesting that mitotic block resulted from excessive microtubule dynamics. These results indicate that microtubule dynamics play an important role in Taxol resistance, and that both excessively rapid dynamics and suppressed dynamics impair mitotic spindle function and inhibit proliferation.
Antineoplastic Agents, Phytogenic↗
15-lipoxygenase-1 metabolites down-regulate peroxisome proliferator-activated receptor gamma via the MAPK signaling pathway.
Human colon tumors have elevated levels of 15-lipoxygenase-1 (15-LO-1), suggesting that 15-LO-1 may play a role in the development of colorectal cancer. Also, 15-LO-1 metabolites can up-regulate epidermal growth factor signaling pathways, which results in an increase in mitogenesis. However, metabolites of 15-LO-1 can serve as ligands for peroxisome proliferator-activated receptor gamma (PPARgamma), and activation of this receptor causes most colon cancer cell lines to undergo a differentiative response and reverse their malignant phenotype. Hence, the role 15-LO-1 plays in colon cancer is not clear. To clarify the role of 15-LO-1 in carcinogenesis, the effect of 15-LO-1 and its metabolites on epidermal growth factor signaling and PPARgamma was investigated. In HCT-116 cells, exogenously added 15-LO-1 metabolites, 13-(S)-hydroxyoctadecadienoic acid, 13-(R)-hydroxyoctadecadienoic acid, and 13-(S)-hydroperoxyoctadecadienoic acid, up-regulated the MAPK signaling pathway, and an increase in PPARgamma phosphorylation was observed. Furthermore, in stable overexpressing 15-LO-1 HCT-116 cells, which produce endogenous 15-LO-1 metabolites, an up-regulation in mitogen-activated protein kinase and PPARgamma phosphorylation was observed. Incubation with a MAPK inhibitor ablated MAPK and PPARgamma phosphorylation. The 15-LO-1 up-regulates MAPK activity and increases PPARgamma phosphorylation, resulting in a down-regulation of PPARgamma activity. Thus, 15-LO-1 metabolites may not only serve as ligands for PPARgamma but can down-regulate PPARgamma activity via the MAPK signaling pathway.
Arachidonate 15-Lipoxygenase↗
Mitochondrial contributions to cancer cell physiology: potential for drug development.
Mitochondria make an integral contribution to the regulation of several aspects of cell biology such as energy production, molecular metabolism, redox status, calcium signalling and programmed cell death. In accordance with an endosymbiotic origin, mitochondria rely upon the nucleus for synthesis and function. In addition, these organelles can respond to intra- and extracellular cues independently, and there exists a highly coordinated "cross talk" between mitochondrial and nuclear signals that can greatly influence cell behaviour. This review focuses upon the putative roles of altered mitochondrial physiology in the process of cellular transformation. Discussed are: mitochondria as targets of drug-induced cytotoxicity or cancer promotion, as regulators of apoptosis, as sources of cell signalling through reactive oxygen species, and mitochondrial control of specific nuclear responses.
Animals↗
Purification and characterization of native conventional kinesin, HSET, and CENP-E from mitotic hela cells.
We have developed a strategy for the purification of native microtubule motor proteins from mitotic HeLa cells and describe here the purification and characterization of human conventional kinesin and two human kinesin-related proteins, HSET and CENP-E. We found that the 120-kDa HeLa cell conventional kinesin is an active motor that induces microtubule gliding at approximately 30 microm/min at room temperature. This active form of HeLa cell kinesin does not contain light chains, although light chains were detected in other fractions. HSET, a member of the C-terminal kinesin subfamily, was also purified in native form for the first time, and the protein migrates as a single band at approximately 75 kDa. The purified HSET is an active motor that induces microtubule gliding at a rate of approximately 5 microm/min, and microtubules glide for an average of 3 microm before ceasing movement. Finally, we purified native CENP-E, a kinesin-related protein that has been implicated in chromosome congression during mitosis, and we found that this form of CENP-E does not induce microtubule gliding but is able to bind to microtubules.
Centrifugation, Density Gradient↗
Assessment of knowledge of melanoma risk factors, prevention, and detection principles in Texas teenagers.
INTRODUCTION: The incidence of melanoma has increased in the past 10 years more rapidly than any other cancer. Exposure to intense solar radiation in youth significantly increases the lifetime risk of developing melanoma. We postulate that teenagers have little awareness of melanoma prevention or detection principles. The purpose of this study was to assess the knowledge of teenagers about melanoma and to identify which age groups are most receptive to altering their sun exposure behaviors. METHODS: Two hundred and ten examinations testing general knowledge of sun exposure and melanoma were completed and returned by junior high and high school students ages 12 to 18 in Dallas and Houston, Texas. All students completing and returning the examination were provided with the correct answers to the test and a detailed explanation of each of the test items as part of an educational exercise. A second questionnaire was then administered to determine the effect of the educational exercise on future sun exposure practices. Students were divided into two age groups (12 to 15 and >or=16 years old) for comparison of scores on the knowledge examination and responses to behavioral items. Comparison of response rates between age groups was performed using chi(2) analysis. RESULTS: The return rate was 100%, with 109 students age 12-15 years, and 101 students >or=16 years. Seventy-six percent of all respondents sunbathed outdoors, and 18% had used a tanning bed in the past 6 months. Thirty-three percent of students admitted to at least three blistering sunburns in the past. The average score on the knowledge assessment examination was 65% correct for students >or=16 years old and 54% correct for those 12-15 years old. Students 12 to 15 years old were significantly more likely to indicate they planned to change future behaviors regarding performance of skin self-examinations and limiting sun exposure as compared to the older students. CONCLUSION: A significant number of teenagers have already enhanced their risk for future melanoma by suffering severe sunburns. Students younger than 16 years of age were significantly more likely to indicate they planned to change future behaviors after receiving information about melanoma. The data from this pilot study support education aimed at younger age groups to most effectively achieve risk reduction and prevent future melanomas.
Adolescent↗
Efficient retrovirus-mediated PIG-A gene transfer and stable restoration of GPI-anchored protein expression in cells with the PNH phenotype.
Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic stem cell disorder characterized by complement-mediated hemolysis due to deficiencies of glycosylphosphatidylinositol-anchored proteins (GPI-APs) in subpopulations of blood cells. Acquired mutations in the X-linked phosphatidylinositol glycan-class A (PIG-A) gene appear to be the characteristic and pathogenetic cause of PNH. To develop a gene therapy approach for PNH, a retroviral vector construct, termed MPIN, was made containing the PIG-A complementary DNA along with an internal ribosome entry site and the nerve growth factor receptor (NGFR) as a selectable marker. MPIN transduction led to efficient and stable PIG-A and NGFR gene expression in a PIG-A-deficient B-cell line (JY5), a PIG-A-deficient K562 cell line, an Epstein-Barr virus-transformed B-cell line (TK-14(-)) established from a patient with PNH, as well as peripheral blood (PB) mononuclear cells from a patient with PNH. PIG-A expression in these cell lines stably restored GPI-AP expression. MPIN was transduced into bone marrow mononuclear cells from a patient with PNH, and myeloid/erythroid colonies and erythroid cells were derived. These transduced erythroid cells restored surface expression of GPI-APs and resistance to hemolysis. These results indicate that MPIN is capable of efficient and stable functional restoration of GPI-APs in a variety of PIG-A-deficient hematopoietic cell types. Furthermore, MPIN also transduced into PB CD34(+) cells from a normal donor, indicating that MPIN can transduce primitive human progenitors. These findings set the stage for determining whether MPIN can restore PIG-A function in multipotential stem cells, thereby providing a potential new therapeutic option in PNH.
3T3 Cells↗
Mammalian mad2 and bub1/bubR1 recognize distinct spindle-attachment and kinetochore-tension checkpoints.
Metaphase checkpoint controls sense abnormalities of chromosome alignment during mitosis and prevent progression to anaphase until proper alignment has been attained. A number of proteins, including mad2, bub1, and bubR1, have been implicated in the metaphase checkpoint control in mammalian cells. Metaphase checkpoints have been shown, in various systems, to read loss of either spindle tension or microtubule attachment at the kinetochore. Characteristically, HeLa cells arrest in metaphase in response to low levels of microtubule inhibitors that leave an intact spindle and a metaphase plate. Here we show that the arrest induced by nanomolar vinblastine correlates with loss of tension at the kinetochore, and that in response the checkpoint proteins bub1 and bubR1 are recruited to the kinetochore but mad2 is not. mad2 remains competent to respond and is recruited at higher drug doses that disrupt spindle association with the kinetochores. Further, although mad2 forms a complex with cdc20, it does not associate with bub1 or bubR1. We conclude that mammalian bub1/bubR1 and mad2 operate as elements of distinct pathways sensing tension and attachment, respectively.
Blotting, Western↗
Autoimmunity, self-tolerance and immune homeostasis: from whole animal phenotypes to molecular pathways.
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Animals↗
Detection of antibodies to the nucleocapsid protein of PRRS virus by a competitive ELISA.
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Animals↗
Sedimentation analysis of novel DNA structures formed by homo-oligonucleotides.
Sedimentation velocity analysis has been used to examine the base-specific structural conformations and unusual hydrogen bonding patterns of model oligonucleotides. Homo-oligonucleotides composed of 8-28 residues of dA, dT, or dC nucleotides in 100 mM sodium phosphate, pH 7.4, at 20 degrees C behave as extended monomers. Comparison of experimentally determined sedimentation coefficients with theoretical values calculated for assumed helical structures show that dT and dC oligonucleotides are more compact than dA oligonucleotides. For dA oligonucleotides, the average width (1.7 nm), assuming a cylindrical model, is smaller than for control duplex DNA whereas the average rise per base (0.34 nm) is similar to that of B-DNA. For dC and dT oligonucleotides, there is an increase in the average widths (1.8 nm and 2.1 nm, respectively) whereas the average rise per base is smaller (0.28 nm and 0.23 nm, respectively). A significant shape change is observed for oligo dC(28) at lower temperatures (10 degrees C), corresponding to a fourfold decrease in axial ratio. Optical density, circular dichroism, and differential scanning calorimetry data confirm this shape change, attributable from nuclear magnetic resonance analysis to i-motif formation. Sedimentation equilibrium studies of oligo dG(8) and dG(16) reveal extensive self-association and the formation of G-quadruplexes. Continuous distribution analysis of sedimentation velocity data for oligo dG(16) identifies the presence of discrete dimers, tetramers, and dodecamers. These studies distinguish the conformational and colligative properties of the individual bases in DNA and their inherent capacity to promote specific folding pathways.
Calorimetry, Differential Scanning↗
Annual direct cost of urinary incontinence.
OBJECTIVE: To estimate the annual direct cost of urinary incontinence in 1995 US dollars. METHODS: Epidemiologically based models using diagnostic and treatment algorithms from published clinical practice guidelines and current disease prevalence data were used to estimate direct costs of urinary incontinence. Prevalence and event probability estimates were obtained from literature sources, national data sets, small surveys, and expert opinion. Average national Medicare reimbursement was used to estimate costs, which were determined separately by gender, age group, and type of incontinence. Sensitivity analyses were performed on all variables. RESULTS: The annual direct cost of urinary incontinence in the United States (in 1995 dollars) was estimated as $16.3 billion, including $12.4 billion (76%) for women and $3.8 billion (24%) for men. Costs for community-dwelling women ($8.6 billion, 69% of costs for women) were greater than for institutionalized women ($3.8 billion, 31%). Costs for women over 65 years of age were more than twice the costs for those under 65 years ($7.6 and $3.6 billion, respectively). The largest cost category was routine care (70% of costs for women), followed by nursing home admissions (14%), treatment (9%), complications (6%), and diagnosis and evaluations (1%). Costs were most sensitive to changes in incontinence prevalence, routine care costs, and institutionalization rates and costs. CONCLUSION: Urinary incontinence is a very costly condition, with annual expenditures similar to other chronic diseases in women.
Adolescent↗
National practice patterns of sentinel lymph node dissection for breast carcinoma.
BACKGROUND: The sentinel node is the first regional lymph node to receive tumor cells that metastasize through the lymphatic channel from a primary tumor. The tumor status of the sentinel node should reflect the tumor status of the entire regional node basin. Sentinel lymph node dissection (SLND) has recently been investigated for use in patients with early breast carcinoma to avoid the sequelae of complete axillary lymph node dissection (ALND). Published studies of SLND in breast cancer patients identify marked variations in technique, and there are few guidelines for credentialing surgeons to perform SLND. STUDY DESIGN: The purpose of this study was to assess the current practice of SLND for breast cancer in the United States. A 27-item questionnaire was mailed to 1,000 randomly selected Fellows of the American College of Surgeons. Responses were anonymous. Statistical analysis was performed using SAS software (SAS Institute, Cary, NC). RESULTS: Response rate was 41% (n = 410), and 77% of those who responded performed SLND for breast cancer. The majority (60%) of surgeons responding routinely ordered preoperative lymphoscintigraphy. Of those who did lymphoscintigraphy, 28% removed internal mammary lymph nodes when lymphoscintigraphy showed drainage to these nodes. Ninety percent of surgeons used both blue dye and radiocolloid. Eighty percent of centers responding performed routine immunohistochemistry on sentinel lymph nodes, and 15% performed reverse transcription polymerase chain reaction. Ninety-six percent of surgeons performed SLND for primary tumors 5 cm or smaller, and 95% performed SLND for an excisional cavity 6 cm and smaller. Twenty-eight percent performed SLND for high-grade ductal carcinoma in situ, and 28% of respondents performed 10 or fewer SLND procedures with subsequent ALND before performing SLND alone. Surgeons learned SLND through courses (35%), oncology fellowships (26%), observation of other surgeons (31%), or were self-taught (26%). CONCLUSIONS: The majority of surgeons in the United States use similar technique for SLND breast cancer. But, there was marked variation in the number of SLND cases validated by an ALND before performing SLND only.
Academic Medical Centers↗
Psittacine restraint in the examination room.
This article suggests that there is a high probability of connections between emotional and physical health in animals. Many avian veterinarians are putting these ideas into practice. Recently, several veterinary schools have invited speakers to address their students about these ideas, suggesting a positive change in attitude (Irene Pepperburg, personal communication, 2000). There has been substantial progress in the avian veterinary community's attitude towards the psychological health of these exceptionally intelligent animals. In fact, over the last 5 years, there has been a substantial increase in avian medicine's interest in the work lay parrot behaviorists are doing regarding the psychology of these fascinating birds. More significant progress in the coming years is expected.
Animals↗
Biting and screaming behavior in parrots.
Biting and excessive screaming in companion parrots are common problems, but they are also correctable. Through clear and unaggressive training and the consistent use of commands, controls, and limits on their behaviour, parrots can learn how to successfully share the human habitat.
Animals↗
Exposure of California quail to organophosphorus insecticides in apple orchards in the Okanagan Valley, British Columbia.
We studied the exposure and effect of the organophosphate insecticides azinphos-methyl and diazinon on adult California quail (Callipepla californica) in an apple orchard in the Okanagan Valley, British Columbia. Cholinesterase activity was measured in plasma samples (n = 65) collected from 54 individuals either prior to spraying, immediately (< 24 hours) or 10 days after three spray events. Mean plasma cholinesterase levels declined significantly (P < 0.05, n = 12) to 61% of pre-spray mean activity (controls) immediately following the first spray event, but by ten days had recovered to 86% of mean control activity. Subsequent spray events caused no significant declines in mean plasma cholinesterase activity. Four of the 26 quail sampled within 24 h of a spray event exhibited plasma-ChE inhibition exceeding 50% inhibition. Radio-tagged quail (n = 25) were monitored throughout the breeding season to determine use of orchards and detect changes in use patterns resulting from the spraying of insecticides. Use of orchards by quail varied over the summer, with the highest use occurring in May, declining to very low use by July. Quail exhibited a diurnal pattern, roosting in sparsely forested uplands at night, travelling to orchard areas to feed early each morning and returning to roosts at dusk. Orchard use by quail differed during spray events compared to non-spray times. During the three hour period immediately after spraying (0530-0800), 14-20% of observed quail were in the orchard, after which use declined to < 4%, and returned to 12% by the next day. During non-spray times, 3-13% of radio-tagged the quail were observed in orchard habitat, with the heaviest use (13%) occurring later in the day (0830-1700 h). Seven radio-tagged quail were predated during the study period. However, no deaths could be attributed to insecticide poisoning as carcasses were not in suitable condition for testing. It was concluded that adult quail using orchard habitat early in the summer may be acutely poisoned by anti-cholinesterase insecticides, but the risk of exposure declined over the summer.
Agriculture↗
Evaluation of ASPAN's preoperative patient teaching videos on general, regional, and minimum alveolar concentration/conscious sedation anesthesia.
This descriptive study was undertaken as part of a clinical improvement effort by the ASPAN Research and Education Committees to evaluate adult patients' perception of and satisfaction with the ASPAN Preoperative Patient Teaching videotape on general, regional, and minimum alveolar concentration (MAC)/conscious sedation anesthesia. Research findings on the use of videotapes for preoperative education are mixed. Some studies have reported that the use of videotapes increases knowledge and decreases anxiety, whereas other studies have shown a minimal effect on knowledge and anxiety. A convenience sample of 96 adult patients was chosen from those who were scheduled for surgeries with the above anesthesia techniques in 11 US hospitals and/or surgical centers within 4 ASPAN regional boundaries. Patients viewed the videotape the day(s) before surgery and then completed ASPAN's Preoperative Anesthesia Patient Teaching Questionnaire to measure patient perception and satisfaction. Sixty percent of the patients were women, and 50% had a college degree or higher. The average age of the patients was 51 (+/-17.2). Overall satisfaction scores had a potential range of 10 to 40, with higher scores indicating greater satisfaction. The mean satisfaction score for this study was 35 (+/-6.6). No significant relationships were found between satisfaction with the videotape and age, gender, or educational level. Patients were asked to rank each of 4 teaching methods. Among the choices of individualized instruction, written materials, Internet-based instruction, and videotape, the videotape method was ranked as most preferred. The information obtained from this study will be used to modify and improve the content of the patient education videotape produced by ASPAN.
Adult↗