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Biomedical subjects

C Mah

Publications and source records attributed to C Mah.

12 recordsLinked to original sources
PubMed2000

Coverage by the news media of the benefits and risks of medications.

BACKGROUND: The news media are an important source of information about new medical treatments, but there is concern that some coverage may be inaccurate and overly enthusiastic. METHODS: We studied coverage by U.S. news media of the benefits and risks of three medications that are used to prevent major diseases. The medications were pravastatin, a cholesterol-lowering drug for the prevention of cardiovascular disease; alendronate, a bisphosphonate for the treatment and prevention of osteoporosis; and aspirin, which is used for the prevention of cardiovascular disease. We analyzed a systematic probability sample of 180 newspaper articles (60 for each drug) and 27 television reports that appeared between 1994 and 1998. RESULTS: Of the 207 stories, 83 (40 percent) did not report benefits quantitatively. Of the 124 that did, 103 (83 percent) reported relative benefits only, 3 (2 percent) absolute benefits only, and 18 (15 percent) both absolute and relative benefits. Of the 207 stories, 98 (47 percent) mentioned potential harm to patients, and only 63 (30 percent) mentioned costs. Of the 170 stories citing an expert or a scientific study, 85 (50 percent) cited at least one expert or study with a financial tie to a manufacturer of the drug that had been disclosed in the scientific literature. These ties were disclosed in only 33 (39 percent) of the 85 stories. CONCLUSIONS: News-media stories about medications may include inadequate or incomplete information about the benefits, risks, and costs of the drugs as well as the financial ties between study groups or experts and pharmaceutical manufacturers.

Alendronate↗
PubMed2000

Impaired intracellular trafficking of adeno-associated virus type 2 vectors limits efficient transduction of murine fibroblasts.

Although adeno-associated virus type 2 (AAV) has gained attention as a potentially useful alternative to the more commonly used retrovirus- and adenovirus-based vectors for human gene therapy, efficient gene transfer and transgene expression by AAV vectors require that the following two obstacles be overcome. First, the target cell must express the receptor and the coreceptor for AAV infection, and second, the cell must allow for viral second-strand DNA synthesis. We now describe a third obstacle, impaired intracellular trafficking of AAV to the nucleus, which results in the lack of transgene expression in murine fibroblasts which do express the AAV receptor and the coreceptor and which are permissive for viral second-strand DNA synthesis. We document that AAV vectors bind efficiently and gain entry successfully into NIH 3T3 cells, but trafficking into the nucleus is significantly impaired in these cells. In contrast, viral trafficking to the nucleus in cells known to be efficiently transduced by AAV vectors is both rapid and efficient. The demonstration of yet another obstacle in AAV-mediated gene transfer has implications for the optimal use of these vectors in human gene therapy.

3T3 Cells↗
PubMed1999

Discussion

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Journal Article↗
PubMed1999

Human fibroblast growth factor receptor 1 is a co-receptor for infection by adeno-associated virus 2.

Adeno-associated virus 2 (AAV)-based vectors have gained attention as a potentially useful alternative to the more commonly used retroviral and adenoviral vectors for human gene therapy. Although AAV uses the ubiquitously expressed cell surface heparan sulfate proteoglycan (HSPG) as a receptor, the transduction efficiency of AAV vectors varies greatly in different cells and tissues in vitro and in vivo. We demonstrate here that cell surface expression of HSPG alone is insufficient for AAV infection, and that AAV also requires human fibroblast growth factor receptor 1 (FGFR1) as a co-receptor for successful viral entry into the host cell. We document that cells that do not express either HSPG or FGFR1 fail to bind AAV and, consequently, are resistant to infection by AAV. These non-permissive cells are successfully transduced by AAV vectors after stable transfections with cDNAs encoding the murine HSPG and the human FGFR1. Furthermore, AAV infection of permissive cells, known to express both FGFR1 and the epidermal growth factor receptor, is abrogated by treatment of cells with basic fibroblast growth factor, but not with epidermal growth factor. The identification of FGFR1 as a co-receptor for AAV should provide new insights not only into its role in the life cycle of AAV, but also in the optimal use of AAV vectors in human gene therapy.

3T3 Cells↗
PubMed1998

Identification of a novel genetic locus for familial cardiac myxomas and Carney complex.

BACKGROUND: Intracardiac myxomas are significant causes of cardiovascular morbidity and mortality through embolic stroke and heart failure. In the autosomal dominant syndrome Carney complex, intracardiac myxomas arise in the setting of lentiginosis and other lesions associated with cutaneous hyperpigmentation, extracardiac myxomas, and nonmyxomatous tumors. Genetic factors that regulate cardiac tumor growth remain unknown. METHODS AND RESULTS: We used the molecular genetic techniques of linkage analysis to study 4 kindreds affected by Carney complex to determine the genetic basis of this syndrome. Our investigation confirmed genetic heterogeneity of Carney complex. Moreover, genetic linkage analysis with polymorphic short tandem repeats on the long arm of chromosome 17 revealed maximal pairwise LOD scores of 5.9, 1.5, 1.8, and 2.9 for families YA, YB, YC01, and YC11, respectively. Haplotype analysis excluded a founder effect at this locus. These data identify a major 17 cM locus on chromosome 17q2 that contains the Carney complex disease gene. CONCLUSIONS: The ultimate identification and analysis of the Carney complex disease gene at this human chromosome 17q2 locus will facilitate diagnosis and treatment of cardiac myxomas and will foster new concepts in regulation of cardiac cell growth and differentiation.

Chromosomes, Human, Pair 17↗
PubMed1998

Adeno-associated virus type 2-mediated gene transfer: role of epidermal growth factor receptor protein tyrosine kinase in transgene expression.

Adeno-associated virus type 2 (AAV), a single-stranded, DNA-containing, nonpathogenic human parvovirus, has gained attention as a potentially useful vector for human gene therapy. However, the transduction efficiency of AAV vectors varies greatly in different cells and tissues in vitro and in vivo. We have recently documented that a cellular tyrosine phosphoprotein, designated the single-stranded D-sequence-binding protein (ssD-BP), plays an important role in AAV-mediated transgene expression (K. Y. Qing et al., Proc. Natl. Acad. Sci. USA 94:10879-10884, 1997) and that a strong correlation exists between the phosphorylation state of the ssD-BP and AAV transduction efficiency in vitro as well as in vivo (K. Y. Qing et al., J. Virol. 72:1593-1599, 1998). In this report, we document that treatment of cells with specific inhibitors of the epidermal growth factor receptor protein tyrosine kinase (EGF-R PTK) activity, such as tyrphostin, leads to significant augmentation of AAV transduction efficiency, and phosphorylation of the ssD-BP is mediated by the EGF-R PTK. Treatment of cells with EGF results in phosphorylation of the ssD-BP, whereas treatment with tyrphostin causes dephosphorylation of the ssD-BP and consequently leads to increased expression of the transgene. Furthermore, AAV transduction efficiency inversely correlates with expression of the EGF-R in different cell types, and stable transfection of the EGF-R cDNA causes phosphorylation of the ssD-BP, leading to significant inhibition in AAV-mediated transgene expression which can be overcome by the tyrphostin treatment. These data suggest that the PTK activity of the EGF-R is a crucial determinant in the life cycle of AAV and that further studies on the interaction between the EGF-R and the ssD-BP may yield new insights not only into its role in the host cell but also in the successful use of AAV vectors in human gene therapy.

Cell Line↗
PubMed1998

Adeno-associated virus type 2-mediated gene transfer: correlation of tyrosine phosphorylation of the cellular single-stranded D sequence-binding protein with transgene expression in human cells in vitro and murine tissues in vivo.

Although the adeno-associated virus type 2 (AAV)-based vector system has gained attention as a potentially useful alternative to the more commonly used retroviral and adenoviral vectors for human gene therapy, the single-stranded nature of the viral genome, and consequently the rate-limiting second-strand viral DNA synthesis, significantly affect its transduction efficiency. We have identified a cellular tyrosine phosphoprotein, designated the single-stranded D sequence-binding protein (ssD-BP), which interacts specifically with the D sequence at the 3' end of the AAV genome and may prevent viral second-strand DNA synthesis in HeLa cells (K. Y. Qing et al., Proc. Natl. Acad. Sci. USA 94:10879-10884, 1997). In the present studies, we examined whether the phosphorylation state of the ssD-BP correlates with the ability of AAV to transduce various established and primary cells in vitro and murine tissues in vivo. The efficiencies of transduction of established human cells by a recombinant AAV vector containing the beta-galactosidase reporter gene were 293 > KB > HeLa, which did not correlate with the levels of AAV infectivity. However, the amounts of dephosphorylated ssD-BP which interacted with the minus-strand D probe were also as follows: 293 > KB > HeLa. Predominantly the phosphorylated form of the ssD-BP was detected in cells of the K562 line, a human erythroleukemia cell line, and in CD34+ primary human hematopoietic progenitor cells; consequently, the efficiencies of AAV-mediated transgene expression were significantly lower in these cells. Murine Sca-1+ lin- primary hematopoietic stem/progenitor cells contained predominantly the dephosphorylated form of the ssD-BP, and these cells could be efficiently transduced by AAV vectors. Dephosphorylation of the ssD-BP also correlated with expression of the adenovirus E4orf6 protein, known to induce AAV gene expression. A deletion mutation in the E4orf6 gene resulted in a failure to catalyze dephosphorylation of the ssD-BP. Extracts prepared from mouse brain, heart, liver, lung, and skeletal-muscle tissues, all of which are known to be highly permissive for AAV-mediated transgene expression, contained predominantly the dephosphorylated form of the ssD-BP. Thus, the efficiency of transduction by AAV vectors correlates well with the extent of the dephosphorylation state of the ssD-BP in vitro as well as in vivo. These data suggest that further studies on the cellular gene that encodes the ssD-BP may promote the successful use of AAV vectors in human gene therapy.

Animals↗
PubMed1997

Adeno-associated virus type 2-mediated transduction in primary human bone marrow-derived CD34+ hematopoietic progenitor cells: donor variation and correlation of transgene expression with cellular differentiation.

Although the adeno-associated virus type 2 (AAV) is known to possess a broad host range that transcends the species barrier, we suggested in an earlier study that AAV infection of human cells is receptor mediated (S. Ponnazhagan et al., J. Gen. Virol. 77:1111-1122, 1996). In the present studies, we investigated the ability of AAV to infect primary human hematopoietic progenitor cells capable of multilineage differentiation. Bone marrow-derived CD34+ cells from 12 hematologically normal volunteer donors were infected with a recombinant AAV containing the beta-galactosidase gene under the control of the cytomegalovirus immediate-early promoter (vCMVp-lacZ). Whereas 15 to 80% of the cells from approximately 50% of the donors showed various levels of lacZ gene expression, the expression was undetectable in cells from the remaining donors. However, if cells from both sets of donors were stimulated with various combinations of cytokines to induce differentiation into myeloid and lymphoid lineages following AAV infection, then the level of expression of the transduced gene increased up to 20-fold over a period of 14 days. The results of virus-binding assays suggested that the observed difference between the two groups was due to the differential susceptibility of CD34+ cells to AAV infection rather than to differences in transcription and translation of the transduced gene. To corroborate these results, CD34+ cells from the two donor groups, KB (human nasopharyngeal carcinoma) cells, and M07e (human megakaryocytic leukemia) cells were infected with vCMVp-lacZ. KB cells served as a positive control for AAV infection, and M07e cells served as a negative control. Whereas abundant hybridization to the single-stranded viral DNA on Southern blots was detected in KB and CD34+ cells that were positive for lacZ gene expression, little activity was detected in M07e and CD34+ cells that did not show expression of the lacZ gene. These results suggest that the levels of expression of the putative cellular receptor for AAV vary widely in CD34+ cells from different donors. These studies have implications for the potential use of AAV vectors in human gene therapy involving primary human primitive hematopoietic stem and progenitor cells.

Antigens, CD34↗
PubMed1996

A measure of peripheral nerve stimulation efficacy applicable to H-reflex studies.

BACKGROUND: When H-reflexes are recorded during movement in human subjects, the stimulator current output is not a good indicator of sensory stimulation efficacy because of unavoidable nerve movement relative to the stimulus electrodes. Therefore, the M-wave amplitude has been used by researchers as an indicator of the efficacy of the stimulus. In this study we have examined the general validity of the hypothesis that the M-wave amplitude is directly proportional to the group I sensory afferent volley evoked by the stimulus. METHODS: A nerve recording cuff, stimulating electrodes, and EMG recording electrodes were implanted in cats. Nerve cuff recordings of centrally propagating volleys evoked by electrical stimuli were directly compared to M-waves produced by the same stimuli. Compound action potentials (CAPs) recorded in the sciatic nerve were compared with soleus M-waves during either tibial nerve or soleus muscle nerve stimulation. CAPs in the ulnar nerve were correlated with flexor carpi ulnaris M-waves during ulnar nerve stimulation. RESULTS AND CONCLUSIONS: Our findings indicate that for mixed nerve stimulation (e.g., tibial or ulnar nerve) the M-wave can be a reliable indicator of the centrally propagating sensory volley. Due to the high correlation between CAP and M-wave amplitude in these nerves, a small number of M-waves can give a good estimate of the size of the group I sensory volley. On the other hand, when nerves with only partially overlapping fibre diameter populations are stimulated (e.g., the soleus muscle nerve), the M-wave is not well correlated with the group I sensory volley and thus may not be used as a measure of the size of the input volley for H-reflex studies.

Action Potentials↗
PubMed1990

The evolution of implants over the last fifty years.

In discussing the evolution of implants over the last fifty years, one must consider the objectives of the use of the dental implant, the nature of its design, the biocompatibility of materials with the oral environment, research data, and finally the long-term clinical trials which have influenced the developments of such implants.

Dental Implants↗
PubMed1986

Carcinoid tumors of the lung: cytologic differential diagnosis in fine-needle aspirates.

Pulmonary carcinoid tumors presenting as peripheral or coin lesions are rare and radiologically may resemble other primary or metastatic neoplasms in the lung. This study consisted of the cytologic evaluation of fine-needle aspirates from five peripheral carcinoid tumors of the lung with particular reference to the differences between the cytologic manifestations of this neoplasm and of small-cell carcinoma and well-differentiated adenocarcinoma. Aspirates of typical carcinoid tumors are characterized by isolated cells and loose aggregates of cells; spindle- and oval-shaped cells of uniform size with scanty, pale eosinophilic cytoplasm; and nuclei with evenly dispersed finely granular chromatin and usually prominent single micronucleoli with occasional macronucleoli. In contrast, the cells of small-cell carcinoma are pleomorphic and arranged in noncohesive loose aggregates, their cytoplasm is scanty, and they show nuclear molding. Their nuclei are hyperchromatic with fine to coarsely granular chromatin. The cells of well-differentiated adenocarcinoma are arranged in three-dimensional clusters or loose aggregates of relatively uniform cells with a columnar configuration. The nuclei are uniformly round and hyperchromatic with finely granular chromatin. Macronucleoli are usually prominent. This study demonstrates that cytologic analysis of fine-needle aspirates can play a significant role in the evaluation and management of peripheral lung tumors.

Adenocarcinoma↗