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Biomedical subjects

P B Mullan

Publications and source records attributed to P B Mullan.

At least 19 recordsLinked to original sources
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗
PubMed2001

BRCA1 and GADD45 mediated G2/M cell cycle arrest in response to antimicrotubule agents.

BRCA1 is a tumour suppressor gene implicated in the predisposition to early onset breast and ovarian cancer. We have generated cell lines with inducible expression of BRCA1 to evaluate its role in mediating the cellular response to various chemotherapeutic drugs commonly used in the treatment of breast and ovarian cancer. Induction of BRCA1 in the presence of Taxol and Vincristine resulted in a dramatic increase in cell death; an effect that was preceded by an acute arrest at the G2/M phase of the cell cycle and which correlated with BRCA1 mediated induction of GADD45. A proportion of the arrested cells were blocked in mitosis suggesting activation of both a G2 and a mitotic spindle checkpoint. In contrast, no specific interaction was observed between BRCA1 induction and treatment of cells with a range of DNA damaging agents including Cisplatin and Adriamycin. Inducible expression of GADD45 in the presence of Taxol induced both G2 and mitotic arrest in these cells consistent with a role for GADD45 in contributing to these effects. Our results support a role for both BRCA1 and GADD45 in selectively regulating a G2/M checkpoint in response to antimicrotubule agents and raise the possibility that their expression levels in cells may contribute to the toxicity observed with these compounds.

Antineoplastic Agents↗
PubMed2001

Uncovering BRCA1-regulated signalling pathways by microarray-based expression profiling.

The introduction of microarray technology to the scientific and medical communities has dramatically changed the way in which we now address basic biomedical questions. Expression profiling using microarrays facilitates an experimental approach where alterations in the transcript level of entire transcriptomes can be simultaneously assayed in response to defined stimuli. We have used microarray analysis to identify downstream transcriptional targets of the BRCA1 (Breast Cancer 1) tumour-suppressor gene as a means of defining its function. BRCA1 has been implicated in the predisposition to early onset breast and ovarian cancer and while its exact function remains to be defined, roles in DNA repair, cell-cycle control and transcriptional regulation have been implied. In the current study we have generated cell lines with tetracycline-regulated, inducible expression of BRCA1 as a tool to identify genes, which might represent important effectors of BRCA1 function. Oligonucleotide array-based expression profiling identified a number of genes that were upregulated at various times following inducible expression of BRCA1 including the DNA damage-responsive gene GADD45 (Growth Arrest after DNA Damage). Identified targets were confirmed by Northern blot analysis and their functional significance as BRCA1 targets examined.

BRCA1 Protein↗
PubMed1999

Diagnosis of attention-deficit/hyperactivity disorder and use of psychotropic medication in very young children.

CONTEXT: Increases in diagnosis and treatment of attention-deficit/hyperactivity disorder (ADHD) have elicited public and professional concern. Research suggests that this trend warrants the inclusion of previously underdiagnosed children and adults. It is not clear whether this trend includes young children. OBJECTIVE: To identify patterns of diagnosis and treatment of ADHD in very young children over time. DESIGN: Descriptive study of Michigan Medicaid claims data. PATIENTS: Inclusion criteria included recorded ADHD diagnosis, continuous Medicaid eligibility during a 15-month period, and age 3 years or younger at the first date of service. MAIN OUTCOME MEASURES: Diagnoses of ADHD, conditions commonly comorbid with ADHD, other chronic health conditions, and injuries; treatments such as psychological services and psychotropic medication; and the number of ambulatory visits. RESULTS: We identified 223 children aged 3 years or younger diagnosed with ADHD. Many had conditions commonly comorbid with ADHD (44%), other chronic health conditions (41%), and injuries (40%). More than half received psychotropic medication (57%); fewer received psychological services (27%). Twenty-two different psychotropic medications were used. Patterns included more than 1 psychotropic medication (46%) in 30 combinations of simultaneous use and 44 combinations of sequential use. The mean number of ambulatory visits was 18. CONCLUSIONS: Children aged 3 years or younger had ADHD diagnosed and received markedly variable psychotropic medication regimens. Little information is available to guide these practices. The presence of comorbid conditions and injuries attests to these children's vulnerability. Resources must be identified that will enable physicians to better respond to the compelling needs of these children and their families.

Age Factors↗
PubMed1999

Practice guidelines and late-life depression assessment in long-term care.

To determine how well nursing home physicians believe they can detect and treat depression, we conducted a national survey, eliciting a 63% response rate. More than 75% of respondents believed they detected and treated depression well. Excellent depression training (vs "good," "fair," "poor/none") was associated with better self-reported recognition (odds ratio [OR] 14.25; 95% confidence interval [CI] 1.81, 111.93) and treatment skills (OR 6.72; 95% CI 1. 91, 23.64). Screening tool use predicted greater self-assessed detection (OR 1.89; 95% CI 0.92, 3.87) and treatment competency (OR 2.00; 95% CI 1.14, 3.50). Practice guideline awareness was associated with greater self-reported treatment competency (OR 2.47; 95% CI 1.56, 3.91).

Chi-Square Distribution↗
PubMed1998

Pasteurella multocida toxin stimulates bone resorption by osteoclasts via interaction with osteoblasts.

In this study we used an in vitro assay system with osteoblast and osteoclast co-cultures to assess the effect of purified recombinant Pasteurella multocida toxin on bone resorption. Resorption was measured by the release of a telopeptide breakdown product of type I collagen. It was found that P. multocida did not stimulate bone resorption by osteoclasts directly and also did not stimulate bone breakdown via the release of collagenase or other proteases from osteoblasts. During co-culture of osteoblasts and osteoclasts, with cell-cell contact prevented, P. multocida toxin produced no significant effect. Osteoblast-conditioned media gave a biphasic effect; low concentrations of P. multocida toxin stimulated bone resorption, whereas 100 ng/ml inhibited resorption by osteoclasts. However, when both cell types were co-cultured with cell-cell contact permitted, P. multocida toxin induced a large concentration-dependent increase in bone resorption over a 7-day period. This suggested that P. multocida toxin causes bone breakdown via an osteoblast-dependent mechanism and that a membrane-bound receptor may be involved.

Animals↗
PubMed1998

Secreted effector proteins of Salmonella dublin act in concert to induce enteritis.

The ability of enteropathogenic salmonellae to recruit inflammatory cells and induce secretory responses in the infected ileum is considered to be a main feature in Salmonella-induced enteritis. Interactions between the pathogen and intestinal epithelial cells result in a variety of cellular responses mediating inflammation and fluid secretion. It is becoming apparent that proteins secreted by the Inv-Spa type III secretion system of Salmonella spp. play a key role in the induction of these responses. We have recently demonstrated that the SopB effector protein is translocated into eukaryotic cells via a Sip-dependent pathway and mediates inflammation and fluid secretion in infected ileal mucosa. However, SopB did not appear to be the only effector involved, as inactivation of the sopB gene only partially impaired enteropathogenicity. We suggested that at least some of such protein effectors are likely to be proteins of the same class as SopB, i.e., secreted effector proteins translocated into eukaroyotic cells via a Sip-dependent pathway. In this work, we identify SopD, another secreted protein belonging to the family of Sop effectors of Salmonella dublin. Using the cya reporter system we showed that SopD is translocated into eukaroyotic cells. We assessed the potential involvement of SopD in enteropathogenicity and found that inactivation of sopD has an additive effect in relation to the sopB mutation.

Amino Acid Sequence↗
PubMed1997

A secreted effector protein of Salmonella dublin is translocated into eukaryotic cells and mediates inflammation and fluid secretion in infected ileal mucosa.

Enteritis induced by non-typhoid pathogenic Salmonella is characterized by fluid secretion and inflammatory responses in the infected ileum. The inflammatory response provoked by Salmonella initially consists largely of a neutrophil (PMN) migration into the intestinal mucosa and the gut lumen. The interactions between Salmonella and intestinal epithelial cells are known to play an essential role in inducing the inflammatory response. Upon interaction with epithelial cells salmonellae are able to elicit transepithelial signalling to neutrophils. This signalling is recognized as a key virulence feature underlying Salmonella-induced enteritis. However, the nature and mechanism of such signalling has not been clarified to date. Here, we characterize SopB, a novel secreted effector protein of Salmonella dublin, and present data implying that SopB is translocated into eukaryotic cells via a sip-dependent pathway to promote fluid secretion and inflammatory responses in the infected ileum.

Amino Acid Sequence↗
PubMed1997

Activities of potential tumour marker enzymes during induced differentiation in HL-60 and U-937 cells.

HL-60 and U-937 cells were used as models to assess the involvement of the enzymes of thymidine metabolism in differentiation. Both cell types showed decreased thymidine kinase and thymidylate synthase but increased thymidine phosphorylase activities in response to the induction of differentiation by dimethylsulfoxide and 12-O-tetradecanoylphorbol 13-acetate. This was accompanied by a greater than three-fold increase in the stimulation of superoxide production in both cell lines. Thymidylate synthase and thymidine kinase activities were noted as potential markers of leukaemic cell proliferation while thymidine phosphorylase and superoxide production correlated well with differentiated phenotypes. Prolonged treatment of U-937 by 12-O-tetradecanoylphorbol 13-acetate resulted in a marked de-differentiation, indicating overstimulation of one or more of the isoforms of protein kinase C.

Biomarkers, Tumor↗
PubMed1996

SopE, a secreted protein of Salmonella dublin, is translocated into the target eukaryotic cell via a sip-dependent mechanism and promotes bacterial entry.

The entry of Salmonella into cultured epithelial cells is dependent on genes located in several adjacent chromosomal loci. One of these loci encodes the recently identified secretory proteins, denoted Sips (Salmonella invasion proteins). SipB, C,D proteins are essential for the ability of the pathogen to invade epithelial cells. To examine if additional invasion-associated proteins were secreted by Salmonella dublin, the genes encoding already characterized secretory proteins were inactivated to facilitate this analysis. The proteins produced and secreted by a double fIIM/polar sipB mutant of S. dublin were analysed; this revealed a set of novel secreted proteins. These proteins, which we denoted Sops (Salmonella outer proteins), formed large filamentous aggregates in the medium of bacterial culture growing at 37 degrees C. These aggregates contained five predominant proteins. Here we report the identification and characterization of one of these proteins, SopE, which is a novel invasion-associated secretory protein of S. dublin. A specific sopE mutant of S. dublin was found to be defective for invasion into epithelial cells. Upon interaction of Salmonella with HeLa cells, SopE was found to be translocated into the cytoplasm of the target cell by extracellular bacteria. The translocation of SopE was shown to be dependent on the Sip proteins because a polar sipB mutant did not translocate SopE across the HeLa cell membrane.

Amino Acid Sequence↗
PubMed1996

Exploratory factor analysis of students' ratings of a problem-based learning curriculum.

PURPOSE: To identify the factor structure underlying medical students' initial experience with a problem-based learning (PBL) curriculum and to examine the stability of this structure as students acquire further experience with PBL. METHOD: The PBL curriculum at the Michigan State University College of Human Medicine begins in the students' second year and is divided into 11 domains. In 1992-93 students were asked to evaluate their learning experiences in the first and last domains of their first PBL semester, by using a five-point Likert scale to rate 19 items. Principal-components analysis and varimax rotation were used to identify the factors underlying the students' ratings. RESULTS: Ratings of the first and last domains were available from 101 and 71 students, respectively. Analysis yielded four meaningful factors: learning materials, small-group process, tutor effectiveness, and academic support. These four factors shifted in relative importance as the students progressed through the curriculum: for the first domain, tutor effectiveness accounted for the highest percentage of variance in the data; for the last domain, this factor ranked third, after learning materials and small group process. Internal reliabilities for the ratings of the last domain of the semester were higher and more consistent, ranging from .92 to .97. CONCLUSION: The students' initial dependence on the tutor progressed to an emphasis on learning resources. This shift is congruent with the theoretical model of the dynamics of PBL. The results suggest that the survey instrument provides a reliable measure of the multidimensional constructs underlying students' experience with PBL.

Curriculum↗
PubMed1996

Skin cancer prevention and detection practices in a Michigan farm population following an educational intervention.

Farmers face an increased risk of skin cancer, presumed to be secondary to their increased occupational exposure to sunlight. This study examines skin cancer prevention and detection beliefs and practices among adult farmers in defined control and comparison farming communities in four contiguous counties of Michigan, before and after a community-based educational intervention. The educational intervention included mailing packets containing information on skin cancer risks and community sources for screening, disseminating articles in local newspapers on skin cancer prevention and control measures, and providing information and screening at local county fairs and agricultural community fairs. The responses of 2,999 survey participants were analyzed to identify the interrelationships among their beliefs and their descriptions of their (primary preventive) self-care and professional medical care seeking (for detection and treatment) practices. Factors associated with the likelihood of skin cancer screening and with measures of knowledge and practices associated with medical care of skin cancer were examined. The intervention appeared to improve the practice of preventive behaviors and seeking medical care.

Agriculture↗
PubMed1996

Cloning, expression, and molecular characterization of the dermonecrotic toxin gene of Bordetella spp.

A cosmid library of random fragments of Bordetella bronchiseptica genomic DNA was prepared and screened with oligonucleotides designed from the sequence of the B. pertussis dermonecrotic toxin (DNT) gene. Two cosmid clones which apparently contained the complete B. bronchiseptica DNT gene were identified, but they did not express the toxin. A 5-kb fragment containing the DNT gene was subcloned from one of the cosmid clones onto a high-copy-number plasmid, and this resulted in low-level expression of the toxin. The expression level was increased by deletion of a small region upstream of the coding sequence. Assays for biological activity, including the infant mouse dermonecrosis assay, confirmed that the product of the cloned gene was DNT. The complete sequence of the B. bronchiseptica DNT gene was determined and was more than 99% homologous to the DNT gene of B. pertussis. A putative purine nucleotide-binding motif was shown to be important for toxic activity. Extracts containing the recombinant or the native toxin induced DNA synthesis in Swiss 3T3 cells but inhibited cell division leading to binucleation.

3T3 Cells↗
PubMed1996

Pasteurella multocida toxin is a mitogen for bone cells in primary culture.

The effect of recombinant Pasteurella multocida toxin (PMT) on primary cultures of embryonic chick bone-derived osteoblastic cells was investigated. It was found that PMT was a potent mitogen for primary derived chicken osteoblasts. The toxin stimulated DNA synthesis and cell proliferation in quiescent osteoblasts at the first passage and accelerated cell growth in subconfluent cultures. Cell viability was not affected by PMT, even at relatively high concentrations. Osteoblast numbers increased in a dose-dependent manner in response to PMT. Intracellular inositol phosphates were elevated in response to PMT, but no elevation in cyclic AMP (cAMP) levels was evident. Indeed, PMT inhibited cAMP elevation in osteoblasts in response to cholera toxin at a stage before other PMT-mediated events take place. In addition to increased cell turnover, PMT down-regulated the expression of several markers of osteoblast differentiation. Both alkaline phosphatase and type I collagen were reduced, but osteonectin was not affected. The in vitro deposition of mineral in cultures of primary osteoblasts and osteoblast-like osteosarcoma cells was also inhibited by the presence of PMT. This suggests that PMT interferes with differentiation at a preosteoblastic stage.

Animals↗
PubMed1995

Mammography usage and knowledge about breast cancer in a Michigan farm population before and after an educational intervention.

The purpose of this study was to identify factors associated with the use of mammography screening in a farm population, before and after a community-based educational intervention. The educational intervention included sending individual mailings containing information about breast cancer risk and community sources for screening, and providing information and screening at local county fairs and agricultural community fairs. The authors used multivariate analytic methods to analyze the responses, reported by 1,545 women, to discern the roles of sociodemographic, attitudinal, and knowledge variables in this population's breast cancer screening practices. Results showed that the rural participants in both the intervention and the control communities demonstrated significant changes in knowledge and attitudes about breast cancer. Mammography usage was significantly higher among women who had higher scores on the knowledge and awareness assessments. Education--rather than income, insurance coverage, or family history of breast cancer--emerged in multivariate analyses as the most significant predictor of knowledge and awareness score levels associated with greater use of mammography. Implications of this study include support for education that emphasizes the benefits of early detection of breast cancer for all women.

Adult↗
PubMed1994

Mutation of a putative ADP-ribosylation motif in the Pasteurella multocida toxin does not affect mitogenic activity.

Pasteurella multocida toxin (PMT) is a potent mitogen for Swiss 3T3 fibroblasts and cytotoxic to embryonic bovine lung cells. Site-directed mutagenesis was used to investigate the functional significance of a three amino acid motif in PMT that is present in five other bacterial protein toxins which exhibit ADP-ribosyl transferase activity. Crude lysates of mutant clones were fully cytotoxic for embryonic bovine lung cells. Purified mutant toxin was also as effective at stimulating inositol phosphate turnover and nucleic acid synthesis as wild type toxin. We conclude that this motif has no functional significance in Pasteurella multocida toxin.

3T3 Cells↗
PubMed1992

Faculty expectations and primary care residents' perceptions concerning residents' growth in competence at one medical school.

The authors studied at one school both the developing confidence of primary care residents and the expectations of both internal medicine and specialty faculty members regarding the abilities of the residents. From 1980 to 1988, residents in the study institution's program in internal medicine primary care completed self-assessments concerning their diagnostic and management skills in primary care and several specialties at the start of their training and at the ends of their first, second, and third years. In 1988, the authors elicited the expectations of the primary care and specialty faculties regarding the levels of competence that residents should achieve in the specialties by the end of their third year. When the faculty assessments were compared, the specialists were found to ascribe greater levels of autonomy to residents. The authors conclude that involving residents and faculty members from various disciplines in developing expectations and evaluation criteria can enhance faculty members' perceptions of residents' clinical competence and residents' achievement of it.

Analysis of Variance↗