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PubMed2006

Using the Delphi technique in economic evaluation: time to revisit the oracle?

BACKGROUND AND OBJECTIVE: Although the Delphi technique has been commonly used as a data source in medical and health services research, its application in economic evaluation of medicines has been more limited. The aim of this study was to describe the methodology of the Delphi technique, to present a case for using the technique in economic evaluation, and to provide recommendations to improve such use. METHODS: The literature was accessed through MEDLINE focusing on studies discussing the methodology of the Delphi technique and economic evaluations of medicines using the Delphi technique. RESULTS AND DISCUSSION: The Delphi technique can be used to provide estimates of health care resources required and to modify such estimates when making inter-country comparisons. The Delphi technique can also contribute to mapping the treatment process under investigation, to identifying the appropriate comparator to be used, and to ensuring that the economic evaluation estimates cost-effectiveness rather than cost-efficacy. CONCLUSION: Ideally, economic evaluations of medicines should be based on real-patient data. In the absence of such data, evaluations need to incorporate the best evidence available by employing approaches such as the Delphi technique. Evaluations based on this approach should state the limitations, and explore the impact of the associated uncertainty in the results.

Delphi Technique↗
PubMed2006

Cold stress induces metabolic activation of thyrotrophin-releasing hormone-synthesising neurones in the magnocellular division of the hypothalamic paraventricular nucleus and concomitantly changes ovarian sympathetic activity parameters.

Recent studies suggest thyrotrophin-releasing hormone (TRH) serves as a neurotransmitter and thereby provides a functional vegetative connection between the brain and the ovary. In the present study, magnocellular neurones of the paraventricular nucleus (PVN) in animals subjected to cold exposure were studied to determine the hypothalamic origin of the TRH involved in this pathway. In situ hybridisation analysis of hypothalamic tissue showed that cold exposure causes a two-fold increase in the total number of neurones expressing TRH mRNA in the PVN. Immunohistochemical studies showed that TRH peptide is localised to the magnocellular PVN and that the number of TRH immunoreactive cells increases two-fold following 64 h of cold exposure. Double-immunostaining for MAP-2 and TRH revealed that TRH peptide is localised in the perikarya of the magnocellular neurones. TRH release was measured in vivo from the magnocellular portion of the PVN using push-pull perfusion. Although controls exhibited a very low level of TRH release, animals subjected to cold showed a pulsatile-like TRH release profile with two different patterns of release: (i) low basal level with small bursts of TRH release and (ii) a profile with an up to seven-fold increase in TRH release compared to controls. The colocalisation of TRH with the specific somato-dendritic marker MAP-2 in processes of the magnocellular neurones suggested a local release of TRH. Additional studies demonstrated a reduction in ovarian noradrenaline content after 48 h of cold exposure, a feature indicative of nerve activation at the terminal organ. After 64 h of cold exposure, the ovarian noradrenaline returned to control values but the noradrenaline content of the coeliac ganglia was increased, suggesting a compensatory effect originating in the cell bodies of the sympathetic neurones that innervate the ovary. The correlation between the local release of TRH from dendrites within the magnocellular PVN in conditions of cold and the activation of the sympathetic nerves supplying the ovary raises the possibility that TRH contributes to the processing regulating sympathetic outflow and may thereby impact on the functional activity of the ovary.

Acclimatization↗
PubMed2004

Intestinal barrier dysfunction by enteropathogenic Escherichia coli is mediated by two effector molecules and a bacterial surface protein.

The human intestinal pathogen, enteropathogenic Escherichia coli (EPEC), causes diarrhoeal disease by a mechanism that is dependent on the injection of effector proteins into the host cell. One effector, EspF, is reported to be required for EPEC to disrupt tight junction integrity of intestinal cells and increase the paracellular movement of molecules, which is likely to contribute to diarrhoea. Here, we show that not one but three EPEC-encoded factors play important roles in this process. Thus, the Map (Mitochondria-associated protein) effector is shown to: (i) be as essential as EspF for disrupting intestinal barrier function, (ii) be able to function independently of EspF, (iii) alter tight junction structure and (iv) mediate these effects in the absence of mitochondrial targeting. Additionally, the outer membrane protein Intimin is shown to be crucial for EspF and Map to disrupt the intestinal barrier function. This function of Intimin is completely independent of its interaction with its known receptor Tir, revealing a physiologically relevant requirement for Intimin interaction with alternative receptor(s). This work demonstrates that EPEC uses multiple multifunctional proteins to elicit specific responses in intestinal cells and that EPEC can control the activity of its injected effector molecules from its extracellular location.

Adhesins, Bacterial↗
PubMed2005

UMODL1/Olfactorin is an extracellular membrane-bound molecule with a restricted spatial expression in olfactory and vomeronasal neurons.

The olfactory system provides a unique model for developmental neurobiology. Precise targeting of axonal projections from sensory neurons located in the olfactory epithelium to specific neurons in the olfactory bulb establishes a highly refined spatial sensory map. Distinctively, this process is not restricted to embryonic stages, but continues during the entire life of mammals. A number of secreted and membrane molecules have been implicated in guidance and targeting of olfactory sensory neurons. Here we describe olfactorin, the protein product of the mouse Umodl1 gene, as a potential new element in this process. Olfactorin is a secreted modular protein containing several domains typically present in extracellular matrix proteins (EMI, WAP, FNIII, Ca2+ -binding EGF-like, SEA and ZP domains). By in situ hybridization we find that during embryonic development expression of the Umodl1 gene is detectable only in the olfactory epithelium and vomeronasal organ starting at embryonic day 16.5. At this stage, Umodl1 expression within the olfactory epithelium is punctate, and is restricted to only some of the sensory neurons. At birth and postnatally, expression in these organs continues and involves more neurons. Kallmann syndrome is a genetic disease in which olfactory axons fail to connect to target neurons in the bulb. We tested whether olfactorin might be responsible for an autosomal form of this disease and show that this is not the case. However, based on its domain composition and on the expression in olfactory neurons we suggest that olfactorin may play a role in correct olfactory axon navigation to the brain.

Amino Acid Sequence↗
PubMed2004

One hundred fifty-four genetic markers for the turkey (Meleagris gallopavo).

Identifying and selectively breeding for improved traits is one of the ultimate goals of genetic research in agriculturally important species. Genome characterization and analysis are important first steps in this process. Genetic linkage maps based on the linear order of polymorphic DNA markers are typically developed through statistical analysis of inheritance patterns in pedigreed families. To develop microsatellite markers for further improvement of the turkey genetic linkage map, small-insert genomic libraries were screened for tandem repeats. Oligonuclotide primers were designed to amplify 164 microsatellite-containing fragments from genomic DNA. Genetic polymorphisms at 154 markers were determined by genotyping the F(1) individuals of two resource populations. Markers determined as segregating in the University of Minnesota/Nicholas Turkey Breeding Farms (UMN/NTBF) reference population were used to genotype F(2) individuals and a two-point linkage analysis was performed.

Alleles↗
PubMed2002

Developmental genomic approaches in model organisms.

Functional genomics technologies can help decipher how information encoded in the genome is translated into morphology, physiology, and behavior during the development of complex organisms. A number of researchers have begun to apply DNA microarrays and other functional genomics approaches to study development. Here we review recent studies that take the first steps toward relating genome-wide information to developmental events, we discuss recent genomics approaches taken in animal model systems used to study human disease, and we outline methods that may be useful for constructing genome-wide maps of developmental processes.

Animals↗
PubMed2006

A functional variant in the transcriptional regulatory region of gene LOC344967 cosegregates with disease phenotype in familial nasopharyngeal carcinoma.

Nasopharyngeal carcinoma is a common malignancy in Southeast Asian countries, and genetic background is a well-known component of the complexity underlying its tumorigenic process. We have mapped a nasopharyngeal carcinoma susceptibility locus to chromosome 4p15.1-q12 in a previous linkage study on nasopharyngeal carcinoma pedigrees. In this study provided in this communication, we screened all the genes in this region, with a focus on exons, promoters, and the exon-intron boundary to identify nasopharyngeal carcinoma-associated mutations or functional variants. Importantly, we found a novel gene (LOC344967) with a single nucleotide polymorphism -32G/A in the promoter region. This gene is a member of the acyl CoA thioesterase family that plays an important role in fatty acid metabolism and is involved in the progression of various types of tumors. The -32A variant was found cosegregated with the disease phenotype in the nasopharyngeal carcinoma pedigrees that we previously used for the linkage study. Moreover, this -32A variant creates an activator protein (AP-1)-binding site in the transcriptional regulatory region of LOC344967, which significantly enhanced the binding of AP-1 to the promoter region and the transcription activity of the promoter in vivo. Furthermore, the expression of LOC344967 was significantly up-regulated at both mRNA and protein levels in nasopharyngeal carcinoma cells sharing the -32G/A genotype compared with nasopharyngeal carcinoma cells with the -32G/G genotype. Collectively, these results provide evidence that the -32A variant is a functional sequence change and may be related to nasopharyngeal carcinoma susceptibility in the families studied.

Carcinoma↗
PubMed2004

Development of a cervical cancer educational program for Chinese women using intervention mapping.

This article describes the development of a program to increase Pap screening behavior among women in Taiwan. Intervention mapping, an innovative process of intervention design, guided the development of this program. The development process included a needs assessment identifying factors influencing Pap screening behavior relevant to Chinese women. The program used methods such as information transmission, modeling, persuasion, and facilitation. Strategies included direct mail communication, role-model stories and testimonials, and a telephone-counseling component. The delineation of specific plans for implementation and evaluation are also described.

China↗
PubMed2006

Genomewide identification of pheromone-targeted transcription in fission yeast.

BACKGROUND: Fission yeast cells undergo sexual differentiation in response to nitrogen starvation. In this process haploid M and P cells first mate to form diploid zygotes, which then enter meiosis and sporulate. Prior to mating, M and P cells communicate with diffusible mating pheromones that activate a signal transduction pathway in the opposite cell type. The pheromone signalling orchestrates mating and is also required for entry into meiosis. RESULTS: Here we use DNA microarrays to identify genes that are induced by M-factor in P cells and by P-factor in M-cells. The use of a cyr1 genetic background allowed us to study pheromone signalling independently of nitrogen starvation. We identified a total of 163 genes that were consistently induced more than two-fold by pheromone stimulation. Gene disruption experiments demonstrated the involvement of newly discovered pheromone-induced genes in the differentiation process. We have mapped Gene Ontology (GO) categories specifically associated with pheromone induction. A direct comparison of the M- and P-factor induced expression pattern allowed us to identify cell-type specific transcripts, including three new M-specific genes and one new P-specific gene. CONCLUSION: We found that the pheromone response was very similar in M and P cells. Surprisingly, pheromone control extended to genes fulfilling their function well beyond the point of entry into meiosis, including numerous genes required for meiotic recombination. Our results suggest that the Ste11 transcription factor is responsible for the majority of pheromone-induced transcription. Finally, most cell-type specific genes now appear to be identified in fission yeast.

Gene Expression Regulation, Fungal↗
PubMed2006

Development and validation of an Opioid Attractiveness Scale: a novel measure of the attractiveness of opioid products to potential abusers.

BACKGROUND: The growing trends in opioid abuse, assessment of the abuse liability of prescription opioid products, and growing efforts by the pharmaceutical industry to develop 'abuse-resistant' formulations highlight a need to understand the features that make one product more 'attractive' than another to potential abusers. We developed a scale to measure the 'attractiveness' of prescription opioids to potential abusers, and used the scale to measure the relative attractiveness of 14 opioid analgesic products. METHODS: First, the concept of attractiveness was empirically defined with a group of prescription opioid abusers and experts in opioid abuse using a process called Concept Mapping. Abuse liability consisted of two components: factors intrinsic to the drug formulation (e.g., speed of onset, duration) and factors extrinsic to drug formulation (e.g., availability, availability of alternatives, cost). A 17-item Opioid Attractiveness Scale (OAS) was constructed, focusing on factors intrinsic to the drug product. RESULTS: A total of 144 individuals participated in tests of validity and reliability. Internal consistency was excellent (Cronbach's alpha = 0.85-0.94). Drug rankings based on OAS scores achieved good inter-rater agreement (Kendall's W 0.37, p < 0.001). Agreement on drug OAS scores between the developmental sample and a confirmation sample was good (IntraClass Correlations [ICC] of 0.65-0.69). Global ratings of overall attractiveness of the 14 selected opioid products by substance abuse counselors corresponded with the rankings based on OAS ratings of the abuser group. Finally, substance abuse counselors completed the OAS, yielding a high level of correspondence with ratings by the abuser group (ICC = 0.83, p = 0.002). The OAS differentiated attractiveness among 14 selected pharmaceutical opioid products. OxyContin, Dilaudid, and Percocet were ranked highest (most attractive); Talwin NX and Duragesic were ranked lowest (least attractive). CONCLUSION: An initial examination of the psychometric properties of the OAS suggests that it is a valid and reliable scale. The OAS may be useful in providing important guidance on product features that are attractive to potential abusers.

Journal Article↗
PubMed2006

Invisible barriers to clinical trials: the impact of structural, infrastructural, and procedural barriers to opening oncology clinical trials.

PURPOSE: To investigate the administrative barriers that impact the opening of clinical trials at the Vanderbilt-Ingram Cancer Center (VICC) and at VICC Affiliate Network (VICCAN) sites. METHODS: VICC, a National Cancer Institute-designated comprehensive cancer center, and three VICCAN community practice sites were studied. Methodology used was identification and mapping of existing processes and analysis of historical timing data. RESULTS: At course granularity, the process steps required at VICC and VICCAN main office plus local sites are 20 v 17 to 30 steps, respectively; this gap widens with finer granularity, with more than 110 v less than 60 steps, respectively. Approximately 50% of the steps are nonvalue added. For example, in the institutional review board (IRB) process, less than one third of the steps add value to the final protocol. The numbers of groups involved in the approval processes are 27 (VICC) and 6 to 14 (VICCAN home office and local sites). The median times to open a trial are 171 days (95% CI, 158 to 182 days) for VICC and 191 days (95% CI, 119 to 269 days) for the VICCAN sites. Contrary to expectations, the time for IRB review and approval (median, 47 days) is the fastest process compared with the scientific review committee review and approval (median, 70 days) and contracts and grants review (median, 78.5 days). Opening a cooperative group clinical trial is significantly (P = .05) more rapid because they require fewer review steps. CONCLUSION: There are numerous opportunities to remove nonvalue-added steps and save time in opening clinical trials. With increasing numbers of new agents, fewer domestic principal investigators, and more companies off-shoring clinical trials, overcoming such barriers is of critical importance for maintenance of core oncology research capabilities in the United States.

Clinical Trials as Topic↗
PubMed2003

A zone of frontonasal ectoderm regulates patterning and growth in the face.

A fundamental set of patterning genes may define the global organization of the craniofacial region. One of our goals has been to identify these basic patterning genes and understand how they regulate outgrowth of the frontonasal process, which gives rise to the mid and upper face. We identified a molecular boundary in the frontonasal process ectoderm, defined by the juxtaposed domains of Fibroblast growth factor 8 and Sonic hedgehog, which presaged the initial site of frontonasal process outgrowth. Fate maps confirmed that this boundary region later demarcated the dorsoventral axis of the upper beak. Ectopic transplantation of the ectodermal boundary region activated a cascade of molecular events that reprogrammed the developmental fate of neural crest-derived mesenchyme, which resulted in duplications of upper and lower beak structures. We discuss these data in the context of boundary/morphogen models of patterning, and in view of the recent controversy regarding neural crest pre-patterning versus neural crest plasticity.

Animals↗
PubMed1992

The fate of medial edge epithelial cells during palatal fusion in vitro: an analysis by DiI labelling and confocal microscopy.

Fusion of bilateral shelves, to form the definitive mammalian secondary palate, is critically dependent on removal of the medial edge cells that constitute the midline epithelial seam. Conflicting views suggest that programmed apoptotic death or epithelial-mesenchymal transformation of these cells is predominantly involved. Due in part to the potentially ambiguous interpretation of static images and the notable absence of fate mapping studies, the process by which this is achieved has, however, remained mechanistically equivocal. Using an in vitro mouse model, we have selectively labelled palatal epithelia with DiI and examined the fate of medial edge epithelial (MEE) cells during palatal fusion by localisation using a combination of conventional histology and confocal laser scanning microscopy (CLSM). In dynamic studies using CLSM, we have made repetitive observations of the same palatal cultures in time-course investigations. Our results concurred with the established morphological criteria of seam degeneration; however, they provided no evidence of MEE cell death or transformation. Instead we report that MEE cells migrate nasally and orally out of the seam and are recruited into, and constitute, epithelial triangles on both the oral and nasal aspects of the palate. Subsequently these cells become incorporated into the oral and nasal epithelia on the surface of the palate. We hypothesize an alternative method of seam degeneration in vivo which largely conserves the MEE population by recruiting it into the nasal and oral epithelia.

Animals↗
PubMed2002

Tracking the merger: the human experience.

Research in two recently merged teaching hospitals has studied the effects of merger on the organizational culture of the hospitals and individual staff. Organizational culture is both a tool for managers introducing change and also an observable indicator of change, and hospitals have particularly strong cultures. After reviewing different approaches to analysing culture, and adopting Hofstede's six-dimensional model, the researchers describe one hospital as an aggressive, entrepreneurial, results-oriented organization, with a loosely controlled, devolved management, high expectations of staff and limited participation in decision making. The other is described as a tightly controlled, centralized and paternalistic organization, concerned for its staff and open to dialogue, with a principled commitment to partnership. The management's vision for the new trust combines elements of both cultures. In studying the effects of the merger on staff, the research documents individuals' journey through the merger experience, using Stuart's 'map' of the processes of change. The principal experiences are categorized as sensing, worry work, positioning, shock, hoping and sharing, holding on, letting go, moving, and moving on or away. Individuals' perceptions of the changing hospital cultures show a slow convergence but with new 'fault lines' opening up in the organization.

Decision Making, Organizational↗
PubMed2006

Regulation of peripheral inflammation by spinal p38 MAP kinase in rats.

BACKGROUND: Somatic afferent input to the spinal cord from a peripheral inflammatory site can modulate the peripheral response. However, the intracellular signaling mechanisms in the spinal cord that regulate this linkage have not been defined. Previous studies suggest spinal cord p38 mitogen-activated protein (MAP) kinase and cytokines participate in nociceptive behavior. We therefore determined whether these pathways also regulate peripheral inflammation in rat adjuvant arthritis, which is a model of rheumatoid arthritis. METHODS AND FINDINGS: Selective blockade of spinal cord p38 MAP kinase by administering the p38 inhibitor SB203580 via intrathecal (IT) catheters in rats with adjuvant arthritis markedly suppressed paw swelling, inhibited synovial inflammation, and decreased radiographic evidence of joint destruction. The same dose of SB203580 delivered systemically had no effect, indicating that the effect was mediated by local concentrations in the neural compartment. Evaluation of articular gene expression by quantitative real-time PCR showed that spinal p38 inhibition markedly decreased synovial interleukin-1 and -6 and matrix metalloproteinase (MMP3) gene expression. Activation of p38 required tumor necrosis factor alpha (TNFalpha) in the nervous system because IT etanercept (a TNF inhibitor) given during adjuvant arthritis blocked spinal p38 phosphorylation and reduced clinical signs of adjuvant arthritis. CONCLUSIONS: These data suggest that peripheral inflammation is sensed by the central nervous system (CNS), which subsequently activates stress-induced kinases in the spinal cord via a TNFalpha-dependent mechanism. Intracellular p38 MAP kinase signaling processes this information and profoundly modulates somatic inflammatory responses. Characterization of this mechanism could have clinical and basic research implications by supporting development of new treatments for arthritis and clarifying how the CNS regulates peripheral immune responses.

Animals↗
PubMed2005

A hyperspace model to decipher the genetic architecture of developmental processes: allometry meets ontogeny.

To better utilize limited resources for their survival and reproduction, all organisms undergo developmental changes in both body size and shape during ontogeny. The genetic analysis of size change with increasing age, i.e., growth, has received considerable attention in quantitative developmental genetic studies, but the genetic architecture of ontogenetic changes in body shape and its associated allometry have been poorly understood partly due to the lack of analytical tools. In this article, we attempt to construct a multivariate statistical framework for studying the genetic regulation of ontogenetic growth and shape. We have integrated biologically meaningful mathematical functions of growth curves and developmental allometry into the estimation process of genetic mapping aimed at identifying individual quantitative trait loci (QTL) for phenotypic variation. This model defined with high dimensions can characterize the ontogenetic patterns of genetic effects of QTL over the lifetime of an organism and assess the interplay between genetic actions/interactions and phenotypic integration. The closed forms for the residual covariance matrix and its determinant and inverse were derived to overcome the computational complexity typical of our high-dimensional model. We used a worked example to validate the utility of this model. The implications of this model for genetic research of evo-devo are discussed.

Algorithms↗
PubMed2002

Three-dimensional reconstruction of ryanodine receptors.

Nearly all available information on the three-dimensional structure of the ryanodine receptor (RyR) class of intracellular calcium release channels has come from electron microscopy. This review focuses on results that have been obtained by cryo-electron microscopy of purified, detergent-solubilized receptors in combination with single-particle image processing. This approach has led to the most detailed 3D models of RyRs, which are currently at resolutions of 20-30 . All three of the known genetic isoforms show essentially identical architectures at this resolution: a large, 4-fold symmetric, cytoplasmic assembly that accounts for greater than 80% of the receptor's mass and is composed of at least 10 discrete, loosely packed domains, and a transmembrane region whose dimensions lead us to conclude that very little of RyR's protein mass is present on the lumenal side of the sarco/endoplasmic reticulum. Three-dimensional reconstructions determined for RyRs that have been exposed to conditions that promote either open or closed states show subtle differences, some of which are located in the cytoplasmic assembly, at sites more distant than 100 from the ion channel in the transmembrane region. Several of the ligands (FK506-binding protein, calmodulin, dihydropyridine receptor) that interact in vivo with the skeletal RyR have been, or are in the process of being, mapped to various locations on the cytoplasmic assembly.

Animals↗
PubMed2001

Segregation by color/luminance does not necessarily facilitate motion discrimination in the presence of motion distractors.

Under what circumstances is the common motion of a group of elements more easily perceived when the elements differ in color and/or luminance polarity from their surround? Croner and Albright (1997), using a conventional global motion paradigm, first showed that motion coherence thresholds fell when target and distractor elements were made different in color. However, in their paradigm, there was a cue in the static view of the stimulus as to which elements belonged to the target. Arguably, in order to determine whether the visual system automatically groups, or prefilters, the image into different color maps for motion processing, such static form cues should be eliminated. Using various arrangements of the global motion stimulus in which we eliminated all static form cues, we found that global motion thresholds were no better when target and distractors differed in color than when they were identical, except under certain circumstances in which subjects had prior knowledge of the specific target color. We conclude that, in the absence of either static form cues or the possibility of selective attention to the target color, features with similar colors/luminance-polarities are not automatically grouped for global motion analysis.

Attention↗