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Biomedical subjects

C Nelson

Publications and source records attributed to C Nelson.

At least 19 recordsLinked to original sources
PubMed2001

Streptococcus pneumoniae nasopharyngeal carriage prevalence, serotype distribution, and resistance patterns among children on Lombok Island, Indonesia.

Few data exist on childhood pneumococcal carriage prevalence, serotype distribution, and resistance patterns for Indonesia, the world's fourth most populous country. During August 1997, nasopharyngeal samples were collected from a population-based, island-wide sample of 484 healthy children (age, 0-25 months) from Lombok Island, Indonesia. Two hundred twenty-one pneumococcal isolates were identified, for a carriage prevalence of 48%; 66% of isolates were of serogroup or serotype 6, 23, 15, 33, or 12. All isolates were susceptible to penicillin and cefotaxime. Twelve percent of the isolates were nonsusceptible to sulfamethoxazole or chloramphenicol and 4% were nonsusceptible to both of these drugs. Nonsusceptible organisms were most frequently serogroup or serotype 6, 12, and 33. Lombok has a moderate pneumococcal carriage prevalence and a relatively low proportion of resistant isolates. At least 3 of the 5 most common serogroups and serotypes and 2 of the 3 most common nonsusceptible serogroups and serotypes are not included in the current 7-valent pneumococcal conjugate vaccine.

Anti-Bacterial Agents↗
PubMed2001

The sequence of the human genome.

A 2.91-billion base pair (bp) consensus sequence of the euchromatic portion of the human genome was generated by the whole-genome shotgun sequencing method. The 14.8-billion bp DNA sequence was generated over 9 months from 27,271,853 high-quality sequence reads (5.11-fold coverage of the genome) from both ends of plasmid clones made from the DNA of five individuals. Two assembly strategies-a whole-genome assembly and a regional chromosome assembly-were used, each combining sequence data from Celera and the publicly funded genome effort. The public data were shredded into 550-bp segments to create a 2.9-fold coverage of those genome regions that had been sequenced, without including biases inherent in the cloning and assembly procedure used by the publicly funded group. This brought the effective coverage in the assemblies to eightfold, reducing the number and size of gaps in the final assembly over what would be obtained with 5.11-fold coverage. The two assembly strategies yielded very similar results that largely agree with independent mapping data. The assemblies effectively cover the euchromatic regions of the human chromosomes. More than 90% of the genome is in scaffold assemblies of 100,000 bp or more, and 25% of the genome is in scaffolds of 10 million bp or larger. Analysis of the genome sequence revealed 26,588 protein-encoding transcripts for which there was strong corroborating evidence and an additional approximately 12,000 computationally derived genes with mouse matches or other weak supporting evidence. Although gene-dense clusters are obvious, almost half the genes are dispersed in low G+C sequence separated by large tracts of apparently noncoding sequence. Only 1.1% of the genome is spanned by exons, whereas 24% is in introns, with 75% of the genome being intergenic DNA. Duplications of segmental blocks, ranging in size up to chromosomal lengths, are abundant throughout the genome and reveal a complex evolutionary history. Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems. DNA sequence comparisons between the consensus sequence and publicly funded genome data provided locations of 2.1 million single-nucleotide polymorphisms (SNPs). A random pair of human haploid genomes differed at a rate of 1 bp per 1250 on average, but there was marked heterogeneity in the level of polymorphism across the genome. Less than 1% of all SNPs resulted in variation in proteins, but the task of determining which SNPs have functional consequences remains an open challenge.

Algorithms↗
PubMed2001

Use of antisense oligonucleotides targeting the antiapoptotic gene, clusterin/testosterone-repressed prostate message 2, to enhance androgen sensitivity and chemosensitivity in prostate cancer.

BACKGROUND: Androgen resistance develops, in part, from upregulation of antiapoptotic genes after androgen withdrawal. Identification and targeting of genes mediating androgen-independent (AI) progression may lead to development of novel therapies that delay hormone-refractory prostate cancer. Clusterin is a cell survival gene, that increases after androgen ablation. Here, we review clusterin's functional role in apoptosis and the ability of antisense oligonucleotides (ASOs) against clusterin to enhance apoptosis in prostate cancer xenograft models. RESULTS: Immunostaining of radical prostatectomy specimens confirm that clusterin is highly expressed in 80% prostate cancer cells after neoadjuvant hormone therapy, but is low or absent (<20%) in untreated specimens. Clusterin levels increase >10 fold in regressing Shionogi tumors after castration. Pretreatment of mice bearing androgen-dependent Shionogi tumors with calcium antagonists inhibited castration-induced apoptosis, tumor regression, and clusterin gene upregulation, illustrating that clusterin is an apoptosis-associated gene and not an androgen-repressed gene. Clusterin ASOs reduced clusterin levels in a dose-dependent and sequence-specific manner. Adjuvant treatment with murine clusterin ASOs after castration of mice bearing Shionogi tumors decreased clusterin levels by 70% and resulted in earlier onset and more rapid apoptotic tumor regression, with significant delay in recurrence of AI tumors. Species-specific clusterin ASOs also increased the cytotoxic effects of paclitaxel, reducing the 50% inhibitory concentration (IC(50)) of PC-3 and Shionogi cells by 75% to 90%. Although clusterin ASOs had no effect on the growth of established AI Shionogi or PC-3 tumors, clusterin ASOs synergistically enhanced paclitaxel-induced tumor regression in both Shionogi and PC-3 models. CONCLUSIONS: Collectively, these data identify clusterin as an antiapoptosis protein, upregulated in an adaptive cell-survival manner by androgen ablation and chemotherapy, which confers resistance to various cell-death triggers. Inhibition of clusterin upregulation using clusterin ASOs can enhance cell death after treatment with androgen ablation and chemotherapy.

Androgen Antagonists↗
PubMed2001

Evaluating a prevention program for teenagers on sexual coercion: a differential effectiveness approach.

The authors evaluated a coeducational program for teenagers on preventing sexual coercion in dating situations. Students examined individual and social attitudes underlying coercive sexual behavior and learned communication skills aimed at preventing or dealing with unwanted sexual advances. Instruction was enhanced by video and an interactive video "virtual date." Outcomes were assessed using sexual attitude scales with a sample of 458 high school students. Student health education classes were randomly assigned to either a treatment or a control condition. Findings, based on a latent variable model of differential effectiveness, showed that students in the treatment group with initial coercive attitude scores at or above the mean benefited significantly more than students with the same range of scores in the control group.

Adolescent↗
PubMed2000

FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family.

Bronchoalveolar lavage fluid from mice with experimentally induced allergic pulmonary inflammation contains a novel 9.4 kDa cysteine-rich secreted protein, FIZZ1 (found in inflammatory zone). Murine (m) FIZZ1 is the founding member of a new gene family including two other murine genes expressed, respectively, in intestinal crypt epithelium and white adipose tissue, and two related human genes. In control mice, FIZZ1 mRNA and protein expression occur at low levels in a subset of bronchial epithelial cells and in non-neuronal cells adjacent to neurovascular bundles in the peribronchial stroma, and in the wall of the large and small bowel. During allergic pulmonary inflammation, mFIZZ1 expression markedly increases in hypertrophic, hyperplastic bronchial epithelium and appears in type II alveolar pneumocytes. In vitro, recombinant mFIZZ1 inhibits the nerve growth factor (NGF)-mediated survival of rat embryonic day 14 dorsal root ganglion (DRG) neurons and NGF-induced CGRP gene expression in adult rat DRG neurons. In vivo, FIZZ1 may modulate the function of neurons innervating the bronchial tree, thereby altering the local tissue response to allergic pulmonary inflammation.

Amino Acid Sequence↗
PubMed2000

Acquisition of chemoresistant phenotype by overexpression of the antiapoptotic gene testosterone-repressed prostate message-2 in prostate cancer xenograft models.

Testosterone-repressed prostate message-2 (TRPM-2) expression is highly up-regulated in normal and malignant prostate cells after androgen withdrawal. Although recent studies have suggested a protective role of TRPM-2 expression against apoptosis in several experimental models, the functional role of TRPM-2 in chemotherapy-induced apoptosis remains undefined. Here, we demonstrated that overexpression of TRPM-2 in human androgen-dependent LNCaP prostate cancer cells by stable transfection rendered them highly resistant to paclitaxel treatment than control LNCaP cells, with a 20-fold higher IC50 through the inhibition of apoptotic cell death. In mice bearing TRPM-2-overexpressing LNCaP tumors, tumor volume and serum prostate-specific antigen increased two to three times faster after castration and paclitaxel treatment compared with mice bearing control tumors. We then tested the efficacy of combined treatment with antisense TRPM-2 oligodeoxynucleotide (ODN) and paclitaxel in the mouse androgen-dependent Shionogi tumor model. Antisense TRPM-2 ODN treatment significantly enhanced paclitaxel chemosensitivity of Shionogi tumor cells in a dose-dependent manner, reducing the IC50 by 75%. Combined treatment of Shionogi cells with 500 nM antisense TRPM-2 ODN and 10 nM paclitaxel-induced apoptosis, either agent alone did not. Adjuvant administration of antisense TRPM-2 ODN and polymeric micellar paclitaxel after castration resulted in reduced TRPM-2 levels in vivo and a significant delay of emergence of androgen-independent recurrent Shionogi tumors compared with administration of either agent alone. Furthermore, combined treatment of mice bearing androgen-independent recurrent Shionogi tumors with antisense TRPM-2 ODN and micellar paclitaxel inhibited tumor growth compared with treatment with either agent alone. Collectively, these findings demonstrate that TRPM-2 overexpression helps confer a chemoresistant phenotype through inhibition of apoptosis, and that antisense TRPM-2 ODN may be useful in enhancing the effects of cytotoxic chemotherapy in hormone-refractory prostate cancer.

Animals↗
PubMed2000

Nonlinearity in genetic decoding: homologous DNA replicase genes use alternatives of transcriptional slippage or translational frameshifting.

The tau and gamma subunits of DNA polymerase III are both encoded by a single gene in Escherichia coli and Thermus thermophilus. gamma is two-thirds the size of tau and shares virtually all its amino acid sequence with tau. E. coli and T. thermophilus have evolved very different mechanisms for setting the approximate 1:1 ratio between tau and gamma. Both mechanisms put ribosomes into alternate reading frames so that stop codons in the new frame serve to make the smaller gamma protein. In E. coli, approximately 50% of initiating ribosomes translate the dnaX mRNA conventionally to give tau, but the other 50% shift into the -1 reading frame at a specific site (A AAA AAG) in the mRNA to produce gamma. In T. thermophilus ribosomal frameshifting is not required: the dnaX mRNA is a heterogeneous population of molecules with different numbers of A residues arising from transcriptional slippage on a run of nine T residues in the DNA template. Translation of the subpopulation containing nine As (or +/- multiples of three As) yields tau. The rest of the population of mRNAs (containing nine +/- nonmultiples of three As) puts ribosomes into the alternate reading frames to produce the gamma protein(s). It is surprising that two rather similar dnaX sequences in E. coli and T. thermophilus lead to very different mechanisms of expression.

Bacterial Proteins↗
PubMed2000

Testosterone-repressed prostate message-2 is an antiapoptotic gene involved in progression to androgen independence in prostate cancer.

Although initially reported as an androgen-repressed gene in the rat prostate, the functional role of testosterone-repressed prostate message-2 (TRPM-2) in apoptosis remains undefined. Inhibition of castration-induced apoptosis by calcium channel blocker treatment in androgen-dependent Shionogi tumors resulted in the prevention of TRPM-2 gene up-regulation, suggesting that TRPM-2 is not directly androgen-repressed, but is regulated by apoptotic stimuli. The overexpression of the TRPM-2 gene in human androgen-dependent LNCaP prostate cancer cells by stable transfection rendered them highly resistant to androgen ablation in vivo. We then tested the efficacy of antisense TRPM-2 oligodeoxynucleotide (ODN) therapy in the Shionogi tumor model and demonstrated that the systemic administration of antisense TRPM-2 ODNs in mice bearing Shionogi tumors after castration resulted in a more rapid onset of apoptosis and time to complete regression, as well as a significant delay of emergence of androgen-independent recurrent tumors compared to control ODN treatment. Collectively, these findings illustrate that TRPM-2 is an antiapoptotic rather than an androgen-repressed gene that confers resistance to androgen ablation and thereby helps accelerate the progression to androgen independence.

Animals↗
PubMed2000

CI-1017, a functionally M1-selective muscarinic agonist: design, synthesis, and preclinical pharmacology.

The five muscarinic receptor subtypes (M1-M5) are characterized by seven helices that define a transmembrane cavity which serves as the binding pocket for agonists and antagonists. The five cavities appear to be topographically different enough to permit subtype selectivity among antagonists but not among classical agonists which tend to be smaller in size than antagonists. It was reasoned that synthesis of muscarinic agonists longer/larger than their classical counterparts might result in subtype selectivity. M1 subtype selectivity was found in a class of 1-azabicyclo[2.2.1]heptan-3-one, O-(3-aryl-2-propynyl) oximes. One of these, CI-1017, improved spatial memory of hippocampally deficient mice and nbM-lesioned rats at doses of 1.0-3.2 and 0.1-0.3 mg/kg, respectively, while producing parasympathetic side effects only at very high doses (100-178 mg/kg). Additionally, CI-1017 inhibited production of amyloidogenic A beta and increased secretion of soluble APP. Thus, CI-1017, besides treating AD symptomatically, may also retard its progression. CI-1017 has recently completed phase I clinical trials.

Animals↗
PubMed2000

Characterization of an androgen-specific response region within the 5' flanking region of the murine epididymal retinoic acid binding protein gene.

The epididymis provides the optimal milieu for sperm maturation and storage. Epididymal secretory proteins are believed to be involved in that process. Androgens are the major endocrine and paracrine regulatory signals that regulate gene expression in the epididymis. We have previously identified an androgen-dependent retinoic acid-binding protein (mE-RABP) that is secreted into the luminal fluid from the mouse mid/distal caput epididymidis. The mE-RABP protein belongs to the lipocalin superfamily and may be involved in the trafficking of retinoic acid within the epididymis. We have recently demonstrated that 5 kilobases of the 5' flanking region of the mE-RABP gene contained all the information for the hormonal regulation and the tissue-, region-, and cell-specific expression of the mE-RABP gene. In this study, we have identified a complex androgen-specific response region (ARR) within the first 600 base pairs of the mE-RABP gene promoter. Androgen (DHT) but not glucocorticoid (DEX) activates the ARR in HeLa and PC-3 cells. Two androgen receptor binding sites have been located at positions -445/-459 and -102/-88 and were named ARBS-1 and ARBS-0, respectively. Point mutations of ARBS-0 resulted in a slight decrease of the androgen response. However, mutations of ARBS-1 led to a total loss of the androgen responsiveness, suggesting that it was a major cis-acting element. When ARBS-1 is isolated from its promoter context, it serves as a weak androgen-responsive element that was activated by both androgens and glucocorticoids. Also, the -543/-88 DNA promoter fragment behaved as a poor androgen-responsive region, suggesting that regulatory elements located within the proximal mE-RABP promoter were required for a full androgen response. In conclusion, the mE-RABP ARR is a good model for the study of molecular mechanisms that lead to an androgen-specific responsiveness in vivo.

Androgens↗
PubMed2000

Porous polyethylene as a spacer graft in the treatment of lower eyelid retraction.

PURPOSE: An experimental study was performed to: 1) assess the tolerance and incorporation of porous polyethylene (Medpor) in the posterior lamella of the rabbit lower eyelid; 2) analyze the effect of implant thickness on incorporation; 3) investigate the ability of conjunctiva to grow over vascularized Medpor and; 4) determine the effects of Medpor surface modification on biocompatibility and fibrovascularization. METHODS: In phase I, 10 rabbit eyelids were operated on to analyze the effects of implant thickness and to develop the surgical technique used in phase II of the study. In phase II, 20 lower eyelids of 10 rabbits received 0.85-mm-thick Medpor grafts, each rabbit receiving both an uncoated implant and one coated with an immobilized collagen. RESULTS: There were no extrusions in phase II. with a postoperative follow-up from 14 to 17 weeks. Fourteen of 20 eyelids had full-thickness conjunctival incisions or excisions placed over the Medpor implant to determine the growth potential of conjunctiva over a vascularized implant. All but one eyelid showed complete defect coverage, occurring in as little as 3 days. Histopathology indicated complete Medpor fibrovascularization as early as 4 weeks after implantation. Because neither coated nor uncoated implants extruded in phase II, no conclusions can be drawn regarding the efficacy of Medpor surface modification. CONCLUSION: Medpor was well tolerated in this soft tissue application, and it offers advantages over other graft materials.

Animals↗
PubMed2000

A single deletion in the membrane-proximal region of the Sindbis virus glycoprotein E2 endodomain blocks virus assembly.

The envelopment of the Sindbis virus nucleocapsid in the modified cell plasma membrane involves a highly specific interaction between the capsid (C) protein and the endodomain of the E2 glycoprotein. We have previously identified a domain of the Sindbis virus C protein involved in binding to the E2 endodomain (H. Lee and D. T. Brown, Virology 202:390-400, 1994). The C-E2 binding domain resides in a hydrophobic cleft with C Y180 and W247 on opposing sides of the cleft. Structural modeling studies indicate that the E2 domain, which is proposed to bind the C protein (E2 398T, 399P, and 400Y), is located at a sufficient distance from the membrane to occupy the C protein binding cleft (S. Lee, K. E. Owen, H. K. Choi, H. Lee, G. Lu, G. Wengler, D. T. Brown, M. G. Rossmann, and R. J. Kuhn, Structure 4:531-541, 1996). To measure the critical spanning length of the E2 endodomain which positions the TPY domain into the putative C binding cleft, we have constructed a deletion mutant, DeltaK391, in which a nonconserved lysine (E2 K391) at the membrane-cytoplasm junction of the E2 tail has been deleted. This mutant was found to produce very low levels of virus from BHK-21 cells due to a defect in an unidentified step in nucleocapsid binding to the E2 endodomain. In contrast, DeltaK391 produced wild-type levels of virus from tissue-cultured mosquito cells. We propose that the phenotypic differences displayed by this mutant in the two diverse host cells arise from fundamental differences in the lipid composition of the insect cell membranes which affect the physical and structural properties of membranes and thereby virus assembly. The data suggest that these viruses have evolved properties adapted specifically for assembly in the diverse hosts in which they grow.

Amino Acid Sequence↗
PubMed2000

Two regulators of Ste12p inhibit pheromone-responsive transcription by separate mechanisms.

The yeast Saccharomyces cerevisiae transcription factor Ste12p is responsible for activating genes in response to MAP kinase cascades controlling mating and filamentous growth. Ste12p is negatively regulated by two inhibitor proteins, Dig1p (also called Rst1p) and Dig2p (also called Rst2p). The expression of a C-terminal Ste12p fragment (residues 216 to 688) [Ste12p(216-688)] from a GAL promoter causes FUS1 induction in a strain expressing wild-type STE12, suggesting that this region can cause the activation of endogenous Ste12p. Residues 262 to 594 are sufficient to cause STE12-dependent FUS1 induction when overexpressed, and this region of Ste12p was found to bind Dig1p but not Dig2p in yeast extracts. In contrast, recombinant glutathione S-transferase-Dig2p binds to the Ste12p DNA-binding domain (DBD). Expression of DIG2, but not DIG1, from a GAL promoter inhibits transcriptional activation by an Ste12p DBD-VP16 fusion. Furthermore, disruption of dig1, but not dig2, causes elevated transcriptional activation by a LexA-Ste12p(216-688) fusion. Ste12p has multiple regions within the C terminus (flanking residue 474) that can promote multimerization in vitro, and we demonstrate that these interactions can contribute to the activation of endogenous Ste12p by overproduced C-terminal fragments. These results demonstrate that Dig1p and Dig2p do not function by redundant mechanisms but rather inhibit pheromone-responsive transcription through interactions with separate regions of Ste12p.

Fungal Proteins↗
PubMed2000

Macmillan Carers Schemes in England: results of a multicentre evaluation.

Maintaining sick and elderly people at home, particularly as they approach the end of life, is a long-established challenge for health and social care services. Over the past 30 years palliative care providers have attempted a variety of innovations in this area. We report on a descriptive study of seven pilot Macmillan Carers Schemes in England. The schemes sought to provide practical and emotional help to cancer patients and families living in their own homes. Data are available on 624 referrals to the schemes over a 1-year period. Emphasizing comparisons between schemes, we report on reasons for and sources of referral, services offered, number and duration of visits and tasks undertaken. We consider the views of informal carers who made use of the service, the perceptions of Macmillan carers themselves, and we compare financial costs of schemes. It is concluded that the schemes have the potential for further development but face problems, which reflect on their borderline position between 'health' and 'social care'. Current policy changes may be beneficial to the schemes in this respect.

Aged↗
PubMed2000

Overexpression of insulin-like growth factor binding protein-5 helps accelerate progression to androgen-independence in the human prostate LNCaP tumor model through activation of phosphatidylinositol 3'-kinase pathway.

Although insulin-like growth factor (IGF) binding protein-5 (IGFBP-5) is highly up-regulated in normal and malignant prostate tissues after androgen withdrawal, its functional role in castration-induced apoptosis and androgen-independent progression remains undefined. To analyze the functional significance of IGFBP-5 overexpression in IGF-I-mediated mitogenesis and progression to androgen-independence, IGFBP-5-overexpressing human androgen-dependent LNCaP prostate cancer cells were generated by stable transfection. The growth rates of IGFBP-5-transfected LNCaP cells were significantly faster, compared with either the parental or vector-only transfected LNCaP cells in both the presence and absence ofdihydrotestosterone. IGFBP-5-induced increases in LNCaP cell proliferation occurs through both IGF-I-dependent and -independent pathways, with corresponding increases in the cyclin D1 messenger RNA expression and the fraction of cells in S + G2/M phases of the cell cycle. Changes in Akt/protein kinase B, a downstream component of phosphatidylinositol 3'-kinase (PI3K) pathway, in the LNCaP sublines also paralleled changes in their growth rates. Although treatment with a PI3K inhibitor induced apoptosis in both control and IGFBP-5-overexpressing LNCaP cells, this PI3K inhibitor-induced apoptosis was prevented by exogenous IGF-I treatment only in IGFBP-5 transfectants, suggesting that IGFBP-5 overexpression can potentiate the antiapoptotic effects of IGF-I. Furthermore, tumor growth and serum prostate-specific antigen levels increased several fold faster in mice bearing IGFBP-5-transfected LNCaP tumors after castration, despite having similar tumor incidence and tumor growth rates with controls when grown in intact mice before castration. Collectively, these data suggest that IGFBP-5 overexpression in prostate cancer cells after castration is an adaptive cell survival mechanism that helps potentiate the antiapoptotic and mitogenic effects of IGF-I, thereby accelerating progression to androgen independence through activation of the PI3K-Akt/ protein kinase B signaling pathway.

Androgens↗
PubMed2000

Clinical versus mechanical prediction: a meta-analysis.

The process of making judgments and decisions requires a method for combining data. To compare the accuracy of clinical and mechanical (formal, statistical) data-combination techniques, we performed a meta-analysis on studies of human health and behavior. On average, mechanical-prediction techniques were about 10% more accurate than clinical predictions. Depending on the specific analysis, mechanical prediction substantially outperformed clinical prediction in 33%-47% of studies examined. Although clinical predictions were often as accurate as mechanical predictions, in only a few studies (6%-16%) were they substantially more accurate. Superiority for mechanical-prediction techniques was consistent, regardless of the judgment task, type of judges, judges' amounts of experience, or the types of data being combined. Clinical predictions performed relatively less well when predictors included clinical interview data. These data indicate that mechanical predictions of human behaviors are equal or superior to clinical prediction methods for a wide range of circumstances.

Decision Making, Computer-Assisted↗
PubMed1999

At-birth immunisation against hepatitis B using a novel pre-filled immunisation device stored outside the cold chain.

We evaluated the immunogenicity of hepatitis B (HB) vaccine in UniJect, a pre-filled, non-reusable injection device, stored at tropical temperatures for up to one month and used to give the first dose of HB vaccine to newborns. Infants in Tabanan district, Bali, Indonesia, were given their first dose of HB vaccine with UniJect stored out of the cold chain, UniJect stored in the cold chain; or standard syringe, needle and multidose vial stored in the cold chain. Subsequent doses were given by usual means and blood samples drawn 4-6 weeks after the third dose. No significant differences were found in seroconversion rates or geometric mean titres of HB surface antibody between the three groups.

Cold Temperature↗