Decision and Discovery in Defining “Disease”

This version (May 17, 2005) was published in its final form as: Schwartz PH. Decision and discovery in defining 'disease'. In: Kincaid H, McKitrick J, editors. Establishing medical reality: essays in the metaphysics and epistemology of biomedical science. Dordrecht: Springer; 2007. p. 47-63. http://dx.doi.org/10.1007/1-4020-5216-2_5The debate over how to analyze the concept of disease has often centered on the question of whether to include a reference to values, in particular the ‘disvalue’of diseases, or whether to avoid such notions. ‘Normativists,’such as King ([1954], 1981) and Culver and Gert (1982) emphasize the undesirability of diseases, while ‘Naturalists,’ most prominently Christopher Boorse (1977, 1987, 1997), instead require just the presence of biological dysfunction. The debate between normativism and naturalism often deteriorates into stalemate, with each side able to point out significant problems with the other. It starts to look as if neither approach can work. In this paper, I argue that the standoff stems from deeply questionable assumptions that have been used to formulate the opposing positions and guide the debate. In the end, I propose an alternative set of guidelines that offer a more constructive way to devise and compare theories

Medical hypothesis: xenoestrogens as preventable causes of breast cancer.

Changes in documented risk factors for breast cancer and rates of screening cannot completely explain recent increases in incidence or mortality. Established risk factors for breast cancer, including genetics, account for at best 30% of cases. Most of these risk factors can be linked to total lifetime exposure to bioavailable estrogens. Experimental evidence reveals that compounds such as some chlorinated organics, polycyclic aromatic hydrocarbons (PAHs), triazine herbicides, and pharmaceuticals affect estrogen production and metabolism and thus function as xenoestrogens. Many of these xenoestrogenic compounds also experimentally induce mammary carcinogenesis. Recent epidemiologic studies have found that breast fat and serum lipids of women with breast cancer contain significantly elevated levels of some chlorinated organics compared with noncancer controls. As the proportion of inherited breast cancer in the population is small, most breast cancers are due to acquired mutations. Thus, the induction of breast cancer in the majority of cases stems from interactions between host factors, including genetics and environmental carcinogens. We hypothesize that substances such as xenoestrogens increase the risk of breast cancer by mechanisms which include interaction with breast-cancer susceptibility genes. A series of major epidemiologic studies need to be developed to evaluate this hypothesis, including studies of estrogen metabolism, the role of specific xenoestrogenic substances in breast cancer, and relevant genetic-environmental interactions. In addition, experimental studies are needed to evaluate biologic markers of suspect xenoestrogens and biologic markers of host susceptibility and identify pathways of estrogenicity that affect the development of breast cancer. If xenoestrogens do play a role in breast cancer, reductions in exposure will provide an opportunity for primary prevention of this growing disease.(ABSTRACT TRUNCATED AT 250 WORDS

Evolution of protein-coupled RNA dynamics during hierarchical assembly of ribosomal complexes

Assembly of 30S ribosomes involves the hierarchical addition of ribosomal proteins that progressively stabilize the folded 16S rRNA. Here, we use three-color single molecule FRET to show how combinations of ribosomal proteins uS4, uS17 and bS20 in the 16S 5' domain enable the recruitment of protein bS16, the next protein to join the complex. Analysis of real-time bS16 binding events shows that bS16 binds both native and non-native forms of the rRNA. The native rRNA conformation is increasingly favored after bS16 binds, explaining how bS16 drives later steps of 30S assembly. Chemical footprinting and molecular dynamics simulations show that each ribosomal protein switches the 16S conformation and dampens fluctuations at the interface between rRNA subdomains where bS16 binds. The results suggest that specific protein-induced changes in the rRNA dynamics underlie the hierarchy of 30S assembly and simplify the search for the native ribosome structure

Short-Term Visual Deprivation Does Not Enhance Passive Tactile Spatial Acuity

An important unresolved question in sensory neuroscience is whether, and if so with what time course, tactile perception is enhanced by visual deprivation. In three experiments involving 158 normally sighted human participants, we assessed whether tactile spatial acuity improves with short-term visual deprivation over periods ranging from under 10 to over 110 minutes. We used an automated, precisely controlled two-interval forced-choice grating orientation task to assess each participant's ability to discern the orientation of square-wave gratings pressed against the stationary index finger pad of the dominant hand. A two-down one-up staircase (Experiment 1) or a Bayesian adaptive procedure (Experiments 2 and 3) was used to determine the groove width of the grating whose orientation each participant could reliably discriminate. The experiments consistently showed that tactile grating orientation discrimination does not improve with short-term visual deprivation. In fact, we found that tactile performance degraded slightly but significantly upon a brief period of visual deprivation (Experiment 1) and did not improve over periods of up to 110 minutes of deprivation (Experiments 2 and 3). The results additionally showed that grating orientation discrimination tends to improve upon repeated testing, and confirmed that women significantly outperform men on the grating orientation task. We conclude that, contrary to two recent reports but consistent with an earlier literature, passive tactile spatial acuity is not enhanced by short-term visual deprivation. Our findings have important theoretical and practical implications. On the theoretical side, the findings set limits on the time course over which neural mechanisms such as crossmodal plasticity may operate to drive sensory changes; on the practical side, the findings suggest that researchers who compare tactile acuity of blind and sighted participants should not blindfold the sighted participants

Monitoring HSVtk suicide gene therapy: the role of [18F]FHPG membrane transport

Favourable pharmacokinetics of the prodrug are essential for successful HSVtk/ganciclovir (GCV) suicide gene therapy. [F-18] FHPG PET might be a suitable technique to assess the pharmacokinetics of the prodrug GCV noninvasively, provided that [F-18] FHPG mimics the behaviour of GCV. Since membrane transport is an important aspect of the pharmacokinetics of the prodrug, we investigated the cellular uptake mechanism of [F-18] FHPG in an HSVtk expressing C6 rat glioma cell line and in tumour- bearing rats. The nucleoside transport inhibitors dipyridamol, NBMPR and 2- chloroadenosine did not significantly affect the [F-18] FHPG uptake in vitro. Thymidine and uridine significantly decreased [F-18] FHPG uptake by 84 and 58%, respectively, but an enzyme assay revealed that this decline was due to inhibition of the HSVtk enzyme rather than membrane transport. Nucleobase transport inhibitors, thymine and adenine, caused a 58 and 55% decline in tracer uptake, respectively. In vivo, the ratio of [F-18] FHPG uptake in C6tk and C6 tumours decreased from 3.070.5 to 1.070.2 after infusion of adenine. Thus, in our tumour model, [F-18] FHPG transport exclusively occurred via purine nucleobase transport. In this respect, FHPG does not resemble GCV, which is predominantly taken up via the nucleoside transporter, but rather acyclovir, which is also taken up via the purine nucleobase carrier

Genotype determination for polymorphisms in linkage disequilibrium

<p>Abstract</p> <p>Background</p> <p>Genome-wide association studies with single nucleotide polymorphisms (SNPs) show great promise to identify genetic determinants of complex human traits. In current analyses, genotype calling and imputation of missing genotypes are usually considered as two separated tasks. The genotypes of SNPs are first determined one at a time from allele signal intensities. Then the missing genotypes, i.e., no-calls caused by not perfectly separated signal clouds, are imputed based on the linkage disequilibrium (LD) between multiple SNPs. Although many statistical methods have been developed to improve either genotype calling or imputation of missing genotypes, treating the two steps independently can lead to loss of genetic information.</p> <p>Results</p> <p>We propose a novel genotype calling framework. In this framework, we consider the signal intensities and underlying LD structure of SNPs simultaneously by estimating both cluster parameters and haplotype frequencies. As a result, our new method outperforms some existing algorithms in terms of both call rates and genotyping accuracy. Our studies also suggest that jointly analyzing multiple SNPs in LD provides more accurate estimation of haplotypes than haplotype reconstruction methods that only use called genotypes.</p> <p>Conclusion</p> <p>Our study demonstrates that jointly analyzing signal intensities and LD structure of multiple SNPs is a better way to determine genotypes and estimate LD parameters.</p

InVERT molding for scalable control of tissue microarchitecture

Complex tissues contain multiple cell types that are hierarchically organized within morphologically and functionally distinct compartments. Construction of engineered tissues with optimized tissue architecture has been limited by tissue fabrication techniques, which do not enable versatile microscale organization of multiple cell types in tissues of size adequate for physiological studies and tissue therapies. Here we present an ‘Intaglio-Void/Embed-Relief Topographic molding’ method for microscale organization of many cell types, including induced pluripotent stem cell-derived progeny, within a variety of synthetic and natural extracellular matrices and across tissues of sizes appropriate for in vitro, pre-clinical, and clinical studies. We demonstrate that compartmental placement of non-parenchymal cells relative to primary or induced pluripotent stem cell-derived hepatocytes, compartment microstructure, and cellular composition modulate hepatic functions. Configurations found to sustain physiological function in vitro also result in survival and function in mice for at least 4 weeks, demonstrating the importance of architectural optimization before implantation.National Institutes of Health (U.S.) (EB008396)National Institutes of Health (U.S.) (DK56966)National Cancer Institute (U.S.) (Cancer Center Support Core Grant P30-CA14051)National Institutes of Health (U.S.). Ruth L. Kirschstein National Research Service Award (1F32DK091007)National Institutes of Health (U.S.). Ruth L. Kirschstein National Research Service Award (1F32DK095529)National Science Foundation (U.S.). Graduate Research Fellowship Program (1122374

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Light Scalar Meson and Decay Constant in SU(3) Gauge Theory with Eight Dynamical Flavors

The SU(3) gauge theory with $N_f=8$ nearly massless Dirac fermions has long been of theoretical and phenomenological interest due to the near-conformality arising from its proximity to the conformal window. One particularly interesting feature is the emergence of a relatively light, stable flavor-singlet scalar meson $\sigma$ $(J^{PC}=0^{++})$ in contrast to the $N_f=2$ theory QCD. In this work, we study the finite-volume dependence of the $\sigma$ meson correlation function computed in lattice gauge theory and determine the $\sigma$ meson mass and decay constant extrapolated to the infinite-volume limit. We also determine the infinite volume mass and decay constant of the flavor-nonsinglet scalar meson $a_0$