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At least 1,153 records · Page 64Linked to original sources
PubMed2003

The dorsal raphe nucleus exerts opposed control on generalized anxiety and panic-related defensive responses in rats.

It has been proposed that the ascending dorsal raphe (DR)-serotonergic (5-HT) pathway facilitates conditioned avoidance responses to potential or distal threat, while the DR-periventricular 5-HT pathway inhibits unconditioned flight reactions to proximal danger. Dysfunction on these pathways would be, respectively, related to generalized anxiety (GAD) and panic disorder (PD). To investigate this hypothesis, we microinjected into the rat DR the benzodiazepine inverse receptor agonist FG 7142, the 5-HT(1A) receptor agonist 8-OH-DPAT or the GABA(A) receptor agonist muscimol. Animals were evaluated in the elevated T-maze (ETM) and light/dark transition test. These models generate defensive responses that have been related to GAD and PD. Experiments were also conducted in the ETM 14 days after the selective lesion of DR serotonergic neurons by 5,7-dihydroxytriptamine (DHT). In all cases, rats were pre-exposed to one of the open arms of the ETM 1 day before testing. The results showed that FG 7142 facilitated inhibitory avoidance, an anxiogenic effect, while impairing one-way escape, an anxiolytic effect. 8-OH-DPAT, muscimol, and 5,7-DHT-induced lesions acted in the opposite direction, impairing inhibitory avoidance while facilitating one-way escape from the open arm. In the light/dark transition, 8-OH-DPAT and muscimol increased the time spent in the lighted compartment, an anxiolytic effect. The data supports the view that distinct DR-5-HT pathways regulate neural mechanisms underlying GAD and PD.

5,7-Dihydroxytryptamine↗
PubMed2003

The structural evolution of a P2Y-like G-protein-coupled receptor.

Based on the now available crystallographic data of the G-protein-coupled receptor (GPCR) prototype rhodopsin, many studies have been undertaken to build or verify models of other GPCRs. Here, we mined evolution as an additional source of structural information that may guide GPCR model generation as well as mutagenesis studies. The sequence information of 61 cloned orthologs of a P2Y-like receptor (GPR34) enabled us to identify motifs and residues that are important for maintaining the receptor function. The sequence data were compared with available sequences of 77 rhodopsin orthologs. Under a negative selection mode, only 17% of amino acid residues were preserved during 450 million years of GPR34 evolution. On the contrary, in rhodopsin evolution approximately 43% residues were absolutely conserved between fish and mammals. Despite major differences in their structural conservation, a comparison of structural data suggests that the global arrangement of the transmembrane core of GPR34 orthologs is similar to rhodopsin. The evolutionary approach was further applied to functionally analyze the relevance of common scaffold residues and motifs found in most of the rhodopsin-like GPCRs. Our analysis indicates that, in contrast to other GPCRs, maintaining the unique function of rhodopsin requires a more stringent network of relevant intramolecular constrains.

Amino Acid Sequence↗
PubMed1995

Seven-helix bundles: molecular modeling via restrained molecular dynamics.

Simulated annealing via restrained molecular dynamics (SA/MD) has been used to model compact bundles of seven approximately (anti)parallel alpha-helices. Seven such helix bundles occur, e.g., in bacteriorhodopsin, in rhodopsin, and in the channel-forming N-terminal domain of Bacillus thuringiensis delta-endotoxin. Two classes of model are considered: (a) those consisting of seven Ala20 peptide chains; and (b) those containing a single polypeptide chain, made up of seven Ala20 helices linked by GlyN interhelix loops (where N = 5 or 10). Three different starting C alpha templates for SA/MD are used, in which the seven helices are arranged (a) on a left-handed circular template, (b) on a bacteriorhodopsin-like template, or (c) on a zig-zag template. The ensembles of models generated by SA/MD are analyzed in terms of their geometry and energetics, and the most stable structures from each ensemble are examined in greater detail. Structures resembling bacteriorhodopsin and structures resembling delta-endotoxin are both represented among the most stable structures. delta-Endotoxin-like structures arise from both circular and bacteriorhodopsin-like C alpha templates. A third helix-packing mode occurs several times among the stable structures, regardless of the C alpha template and of the presence or absence of interhelix loops. It is characterized by a "4 + 1" core, in which four helices form a distorted left-handed supercoil around a central, buried helix. The remaining two helices pack onto the outside of the core. This packing mode is comparable with that proposed for rhodopsin on the basis of two-dimensional electron crystallographic and sequence analysis studies.

Amino Acid Sequence↗
PubMed2002

Noninvasive three-dimensional activation time imaging of ventricular excitation by means of a heart-excitation model.

We propose a new method for imaging activation time within three-dimensional (3D) myocardium by means of a heart-excitation model. The activation time is estimated from body surface electrocardiograms by minimizing multiple objective functions of the measured body surface potential maps (BSPMs) and the heart-model-generated BSPMs. Computer simulation studies have been conducted to evaluate the proposed 3D myocardial activation time imaging approach. Single-site pacing at 24 sites throughout the ventricles, as well as dual-site pacing at 12 pairs of sites in the vicinity of atrioventricular ring, was performed. The present simulation results show that the average correlation coefficient (CC) and relative error (RE) for single-site pacing were 0.9992+/-0.0008/0.9989+/-0.0008 and 0.05+/-0.02/0.07+/-0.03, respectively, when 5 microV/10 microV Gaussian white noise (GWN) was added to the body surface potentials. The average CC and RE for dual-site pacing were 0.9975+/-0.0037 and 0.08+/-0.04, respectively, when 10 microV GWN was added to the body surface potentials. The present simulation results suggest the feasibility of noninvasive estimation of activation time throughout the ventricles from body surface potential measurement, and suggest that the proposed method may become an important alternative in imaging cardiac electrical activity noninvasively.

Algorithms↗
PubMed1998

Calculation of fecal kinetics in horses fed hay or hay and concentrate.

Marker methods are needed for estimating fecal output by grazing animals in studies of nutrition and environmental impact. In addition, estimates of prefecal mass and turnover time are relevant to exercise performance and certain digestive disorders. As a first step in developing marker methods for field use, a chromic oxide model of fecal kinetics was developed and tested in the context of a digestion balance experiment with stall-fed horses. The model consists of removal of feces at a constant rate from a single compartment, the prefecal mass. Four horses were fed hay, and another four were fed hay and concentrate. Balance-marker experiments were conducted for 10 d, following 7 d of adaptation. A dose of chromic oxide mixed in chopped hay and molasses was administered from a nose bag at 0700 daily for 10 d. Dry matter and Cr were measured in feeds and feces. Fecal Cr concentration (C, mg/kg DM) varied during the day, so data from total daily collections were used for model development. These fecal Cr data (Ct) at time t (days) were fitted to a single exponential, with one rate constant (k), rising to an asymptote (Ca): Ct = Ca - Ca x e(-kt). Superior fits were obtained when a delay (d) was introduced between the pulse oral dose and the entry of marker into the prefecal pool: Ct = Ca - Ca x e(-k(t-d)). Using pooled data, delays of 2.7 and 2.0 h gave best fits (highest estimates of R2) for pooled data from horses fed hay or hay plus concentrate, respectively. The model generated estimates of 3.4 and 3.8 kg/d of DM for fecal outputs (dose/Ca) of horses fed hay or hay and concentrate, respectively. The rate constants yielded turnover times (1/k) of 33 and 18 h, and prefecal masses [(dose/Ca)/k] of 4.6 and 2.9 kg of DM for hay or hay and concentrate groups, respectively. Using data from individual horses, mean estimates for each diet were similar to corresponding values for the pooled data. In balance experiments, feces collected were 3.7 and 4.4 kg/d, and Cr recoveries were 108 and 115% dose for the hay and hay plus concentrate diets, respectively. Marker estimates (M) were correlated with total collection estimates (T) of fecal output [M = T(.890 +/- .045); r = .70, P = .041]. Adjusting for recovery improved the regression coefficient to 1.009 +/- .028 (r = .87, P = .002). The findings suggest that if Cr doses are more frequent than daily and if Cr inputs other than dose can be eliminated this method should give accurate and precise estimates of fecal output.

Animal Feed↗
PubMed1996

Femoral deformity in adults with developmental hip dysplasia.

Quantitative computed tomography and 3 dimensional modeling were used to portray the deformity of the proximal femur in 24 Japanese adults with low subluxations to high dislocations secondary to developmental dysplasia of the hip. Periosteal and canal bony contours were extracted, 3 dimensional models generated, and morphologic parameters were calculated for each femur. Three dimensional illustrations of the average deformity and variability were created. Morphologic parameters were not found to be statistically correlated with the degree of the disease. Interestingly, the major axis of the canal contours of the proximal femur was found to be aligned with the plane of the femoral neck (anteversion), regardless of the degree of anteversion. Thus, the amount of version correctable in an uncemented prosthesis is limited, and at times may require a special prosthesis, overreaming, undersizing and cementing, or an osteotomy. Additionally, the proximal medial curvature of the dysplastic femurs was straighter than that of normal femurs. This necessitated a corresponding reduction in the proximal medial curvature of a conventional uncemented prosthesis to match the medial curvature of the individual femur and the average developmentally dysplastic femur. This objective description of the developmentally dysplastic femur corroborates clinical observations, highlights some unrecognized findings, provides a rationale for planning reconstructions, and aids in the design of prostheses for adult patients with this deformity.

Adult↗
PubMed2003

Peroxides and macrophages in the toxicity of fine particulate matter in rats.

Epidemiologists have observed a positive association between human morbidity and mortality and the atmospheric concentrations of fine particulate matter (PM), but the mechanisms underlying the toxic effects of PM have not been elucidated. Various components of ambient PM have been implicated in toxicity (including ultrafine particles, transition metals, organics and oxidants). Our research focused on hydrogen peroxide (H2O2). We speculated that fine PM transports H2O2 into the lower lung, leading to tissue injury and to accumulation and activation of macrophages in these regions. The macrophages release cytotoxic mediators and proinflammatory cytokines that contribute to the pathogenesis of tissue injury. To test this hypothesis, we conducted studies to determine (1) whether tissue injury induced by aerosols is mediated by cytotoxic H2O2 carried into the lower lung by fine particles and (2) whether exposure of rats to fine PM leads to accumulation of activated macrophages in the lung. For our studies, systems were designed to generate model atmospheric fine PM and atmospheric peroxides consisting of an ammonium sulfate [(NH4)2SO4] aerosol (mass median diameter, 0.46 +/- 0.14 microm) and H2O2. We also constructed a 6-port nose-only exposure chamber. Female Sprague Dawley rats were exposed for 2 hours to aerosols consisting of (NH4)2SO4 (430 microg/m3), (NH4)2SO4 + 10, 20 or 100 ppb H2O2, vapor-phase H2O2 (10, 20 or 100 ppb), or particle-free air. Studies using oxygen-18 (18O)-labeled H2O2 were conducted to validate the transport of H2O2 into the lower lung with (NH4)2SO4. Rats were killed immediately (0 hours) or 24 hours after exposure. Compared with control animals, inhalation of (NH4)2SO4 and H2O2, alone or in combination, had no major effect on cell number or viability, protein content, or lactate dehydrogenase (LDH) levels in bronchoalveolar lavage (BAL) fluid collected either immediately or 24 hours after exposure. However, electron microscopy revealed that a larger number of neutrophils in pulmonary capillaries adhered to the vascular endothelium, especially in lungs of rats exposed to (NH4)2SO4 + H2O2. Inhalation of (NH4)2SO4 + H2O2 was also found to be associated with altered macrophage functional activity. Thus, exposing rats to (NH4)2SO4 + 20 ppb H2O2 or 20 ppb H2O2 alone caused a level of tumor necrosis factor alpha (TNF-alpha) production by lung macrophages that was higher than in controls. This higher level was observed immediately after exposure and persisted for at least 24 hours. Greater TNF-alpha production was also detected 24 hours after exposure to (NH4)2SO4 + 10 ppb H2O2. Immediately after rats inhaled (NH4)2SO4 + 10 ppb H2O2 or 20 ppb H2O2 alone, we also observed a transiently higher production of superoxide anion (O2-) by alveolar macrophages. Macrophages isolated 24 hours after exposure to 20 ppb H2O2 also produced larger quantities of superoxide anion. In contrast, immediately after exposure, macrophages from rats exposed to (NH4)2SO4 + 10 ppb H2O2 or to 20 ppb H2O2 alone generated less nitric oxide (NO). Reduced nitric oxide production was also observed 24 hours after exposure to (NH4)2SO4 + 10 ppb H2O2 or to 10 or 20 ppb H2O2 alone. Reduced nitric oxide production may have been due to superoxide anion-driven formation of peroxynitrite (ONOO-) anions. In this regard, nitrotyrosine, an in vivo marker of peroxynitrite, was detected in lung tissue immediately after rats were exposed to (NH4)2SO4 + H2O2 or to H2O2 alone (10 or 20 ppb). We also found that alveolar macrophages from rats exposed to (NH4)2SO4 + H2O2 showed a greater expression of the antioxidant enzyme heme oxygenase-1 (HO-1) when stimulated with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). Similar results were observed after exposure of rats to an organic peroxide aerosol (cumene hydroperoxide). Taken together, the results of our studies demonstrate that biological effects of inhaled H2O2 are augmented by fine PM. Moreover, tissue injury induced by (NH4)2SO4 + H2O2 may be related to altered production of cytotoxic mediators by alveolar macrophages. Determining the relevance of these toxicologic results to human health will be important in future studies for evaluating the risk of exposure.

Aerosols↗
PubMed1988

Approximate surface development of the left side half-trunk by a free-formed model.

The approximate surface development, skin length, and surface area of the left side of the trunk of 51 female students were compared with regard to static and stretched postures. The data for each subject were obtained from geometrical models generated by moiré topography with a computer. When the chest was stretched, the anterior surface, the shoulder line, and the arm-base line were transformed from concave to convex, and a gap oriented toward the nipple widened out. The skin elongated vertically and transversely, except at the side of the waistline, where the skin contracted. The area at the top of the trunk decreased about 25%, while the other parts of the trunk increased 8-15%. The total anterior area was 1.20 m2 for the static posture and 1.29 m2 for the stretched posture. When the posterior surface was stretched, the shoulder line changed from convex to concave, the side line from quasi-straight to concave, and gaps oriented toward the chest line disappeared. The skin elongated most at the infrascapular region (20-35%), while the neck base line contracted (-11%). The center of the back and the lower arm base areas enlarged the most (25%) and the lumbar area enlarged the least (12%). The total posterior area was 1.26 m2 in the static posture and 1.37 m2 in the back-stretched posture. In conclusion, the back skin elongated and enlarged more when stretched than the frontal skin.

Adult↗
PubMed2001

Mutational analysis of the K+-competitive inhibitor site of gastric H,K-ATPase.

The gastric H,K-ATPase is inhibited selectively and K(+)-competitively from its luminal surface by protonated imidazo[1,2alpha]pyridines (e.g., SCH28080). Identification of the amino acids in the membrane domain that affect SCH28080 inhibition should provide a template for modeling a luminally directed vestibule in this enzyme, based on the crystal structure of the sr Ca-ATPase. Five conserved carboxylic residues, Glu343, Glu795, Glu820, Asp824, Glu936, and unique Lys791 in the H,K-ATPase were mutated, and the effects of mutations on the K(i) for SCH28080, V(max), and K(m,app)[NH(4)(+)] were measured. A kinetic analysis of the ATP hydrolysis data indicated that all of these residues significantly affect the interaction of NH(4)(+) ions with the protein but only three of them, Glu795, Glu936, and Lys791, greatly affected SCH28080 inhibition. A Glu795Asp mutation increased the K(i) from 64 +/- 11 to 700 +/- 110 nM. Since, however, the mutation Glu795Gln did not change the K(i) (86 +/- 31 nM), this site has a significant spatial effect on inhibitor kinetics. A Glu936Asp mutation resulted in noncompetitive kinetics while Gln substitution had no effect either on inhibitor affinity or on the nature of the kinetics, suggesting that the length of the Glu936 side chain is critical for the exclusive binding of the ion and SCH28080. Mutation of Lys791 to Ser, the residue present in the SCH28080-insensitive Na,K-ATPase, resulted in a 20-fold decrease in SCH28080 affinity, suggesting an important role of this residue in SCH28080 selectivity of the H,K-ATPase versus Na,K-ATPase. Mutations of Asp824, Glu343, and Glu820 increased the K(i) 2-3-fold, implying a relatively minor role for these residues in SCH28080 inhibition. It appears that the imidazopyridine moiety of SCH28080 in the protonated state interacts with residues near the negatively charged residues of the empty ion site from the luminal side (TM4, -5, -6, and -8) while the hydrophobic phenyl ring interacts with TM1 or TM2 (the latter conclusion based on previous data from photoaffinity labeling). The integrity of the SCH28080 binding site depends on the presence of Lys791, Glu936, and Glu795 in H,K-ATPase. A computer-generated model of this region illustrates the possible involvement of the residues previously shown to affect SCH28080 inhibition (Cys813, Ile816, Thr823, Met334, Val337) and may predict other residues that line the SCH28080 binding vestibule in the E(2) conformation of the pump.

Amino Acid Sequence↗
PubMed1987

A model of the generation of the cochlear microphonic with nonlinear hair cell transduction and nonlinear basilar membrane mechanics.

A phenomenological model of the generation of the cochlear microphonic of the guinea pig is presented which incorporates sharp tuning and nonlinear growth of the vibration of the cochlear partition, and nonlinear transduction of this response by a single linear array of hair cells (assumed to be the outer hair cells). The contribution to the microphonic potential from each hair cell generator is also assumed to decay exponentially with distance from the hair cell. Using experimentally obtained estimates for the parameters a good agreement between the theoretical microphonic tuning curves and growth functions was obtained without recourse to complex micromechanical motion of the cochlear partition, electrical tuning of the hair cells or a contribution from the inner hair cells of the cochlea.

Acoustic Stimulation↗
PubMed2003

Noninvasive imaging of cardiac transmembrane potentials within three-dimensional myocardium by means of a realistic geometry anisotropic heart model.

We have developed a new approach for imaging cardiac transmembrane potentials (TMPs) within the three-dimensional (3-D) myocardium by means of an anisotropic heart model. The cardiac TMP distribution is estimated from body surface electrocardiograms by minimizing objective functions of the "measured" body surface potential maps (BSPMs) and the heart-model-generated BSPMs. Computer simulation studies have been conducted to evaluate the present 3-D TMP imaging approach using pacing protocols. Simulations of single-site pacing at 24 sites throughout the ventricles, as well as dual-site pacing at 12 pairs of sites in the vicinity of atrio-ventricular ring were performed. The present simulation results show that the correlation coefficient (CC) and relative error (RE) between the "true" and inversely estimated TMP distributions were 0.9915 +/- 0.0041 and 0.1266 +/- 0.0326, for single-site pacing, and 0.9889 +/- 0.0034 and 0.1473 +/- 0.0237 for dual-site pacing, respectively, when 10 microV Gaussian white noise (GWN) was added to the BSPMs. The effects of heart and torso geometry uncertainty were also evaluated by shifting the heart position by 10 mm and altering the torso size by 10%. The CC between the "true" and inversely estimated TMP distributions was above 0.97 when these geometry uncertainties were considered. The present simulation results demonstrate the feasibility of noninvasive estimation of TMP distribution throughout the ventricles from body surface electrocardiographic measurements, and suggest that the present method may become a useful alternative in noninvasive imaging of distributed cardiac electrophysiological processes within the 3-D myocardium.

Body Surface Potential Mapping↗
PubMed1994

The role of cytokines in the formation of the schistosome egg granuloma.

Schistosomiasis mansoni is a helminth-induced disease infecting over 120 million people in the tropics. Morbidity and mortality are caused by parasite eggs that evoke in the liver and intestines of infected persons, T cell-mediated granulomatous inflammation and irreversible fibrosis. In the murine model granulomatous inflammation is induced by CD4+ T helper lymphocytes. This short review summarizes recent observations that implicate a variety of lymphokines and cytokines as mediators of the granulomatous inflammatory response. Mediator production was examined in splenocyte as well as granuloma cell cultures of infected or egg granuloma-bearing mice. In the synchronous pulmonary granuloma model generated around i.v. injected eggs in naive mice IL-1 mRNA expression and IL-1 production were detectable within the first 4 days of granuloma growth. After 4-6 days TNF-alpha mRNA message appeared and cytokine production was observed. With the aging of the granuloma, production of both cytokines diminished. Thus, these cytokines are considered to be the primary recruiters of cellular aggregation in granuloma growth. The role of TNF-alpha in granuloma formation was also confirmed in infected mice. Whereas treatment of animals with anti-TNF-alpha antiserum diminished hepatic granuloma size, repeated injection of murine rTNF-alpha into chronically-infected mice enhanced the downmodulated granuloma response. With the administration of specific anti-lymphokine mAbs and recombinant murine lymphokines, as well as serial assays of lymphokine production by splenic, granuloma lymphocytes of infected mice, the role of INF-gamma, IL-2 and IL-4 was delineated. Interferon-gamma was found to be produced very early at the inception of the liver granulomatous response. By the time granulomas reached maximal size (8 wks post infection) production declined. Concurrently IL-2, IL-4 production peaked with maximal granuloma growth and declined with the onset of the immune modulation of the inflammation. Whereas these latter lymphokines appear to play a proinflammatory role, IFN-gamma when administered in large doses diminished granulomatous inflammation, plays a regulatory role in the maintenance of the granulomatous response. The T helper cell population of the granulomas may also influence the lymphokine profile of the developing granuloma. So far precursor type TH0, and TH2 subset of helper cells have been cloned from liver granulomas. The former secreted both IL-2, IL-4 and IFN-gamma lymphokines and adoptively transferred the granulomatous response.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2026

A trainable language model with potential to modulate translation rates in non-model organisms by generating upstream untranslated region sequence libraries.

Tuning protein expression in non-model organisms is often constrained by the lack of validated genetic parts and predictive design tools. Translational tuning through the modulation of upstream untranslated regions (5'-UTRs) offers a potentially organism-agnostic route, but existing methods typically rely on mechanistic assumptions, prior knowledge that may not be available in non-model contexts, or the screening of sequence libraries. Here, we present a simple generative approach for creating synthetic 5'-UTR libraries based solely on the genomic sequence statistics of any desired organism. The method uses a sliding-window n-gram language model applied to native 5'-UTR sequences to produce novel sequences that preserve organism-specific base distributions and motifs without hard-coding specific motifs or mechanistic rules into inflexible statistical templates. We have applied this approach to the model bacterium Escherichia coli and the non-model probiotic Limosilactobacillus reuteri. Libraries of approximately 1,000 sequences were generated for each organism, from which about 100 unique sequences were experimentally tested for translation of a fluorescent reporter protein. In both organisms, the synthetic libraries yielded a broad range of translation levels from this relatively small number of tested variants. Sequences derived from an organism's own genomic statistics provided a more uniformly distributed range of translation rates in that organism than sequences derived from the other species. Correlations of individual sequence performance across the two species were weak, and thermodynamic predictions of ribosome binding strength showed very little predictive power, especially in the non-model L. reuteri. The results demonstrate that simple statistical language model approaches applied to genomic data can generate functional translational regulatory sequence libraries without detailed mechanistic knowledge or explicit reference to consensus motifs. The approach requires minimal computational resources, avoids reproducing native sequences, and can be readily applied to any organism with a sequenced genome. This strategy may lower technical barriers to expression tuning in non-model organisms.

5' Untranslated Regions↗
PubMed2000

CT-generated 3-dimensional models for complex acetabular reconstruction.

Before undergoing complex acetabular reconstruction, 10 patients who met prospectively established criteria for severe acetabular bone deficiency received plain radiographs, computed tomography (CT) scans, and CT-generated 3-dimensional pelvic models. The radiographs, CT scans, and models each were graded according to the American Academy of Orthopaedic Surgery (AAOS) classification for acetabular deficiency. The classifications for the radiographs, CT scans, and models were then compared with findings at surgery. The models predicted acetabular deformity and AAOS classification significantly better than the other imaging modalities. The models agreed with the surgical findings in 9 of 10 cases, compared with 2 of 10 for the CT scans (P = .016) and 4 of 10 for the plain radiographs (P = .063). The models closely predicted the available space for the hemispheric acetabular shells, based on the size of the last reamer used, for the 6 hips reconstructed with standard components. Four patients required custom acetabular components; in 2 of those 4, the need for custom components was not anticipated by plain radiographs or CT scans. Three-dimensional CT-generated acetabular models were found to be useful in preoperative planning of complex acetabular reconstructions.

Acetabulum↗
PubMed2000

Alzheimer disease: mouse models pave the way for therapeutic opportunities.

Research into the molecular mechanisms of Alzheimer disease (AD) continues to clarify important issues in aberrant protein processing while seeking to identify therapeutic targets. Mutations of genes on chromosomes 1, 14 (presenilins 1 and 2), and 21 (the amyloid-beta [Abeta] amyloid precursor protein [APP]) cause the familial forms of AD that often begin before age 65. An allelic polymorphism on chromosome 19 (apolipoprotein E ) affects the age of onset of the more common forms of sporadic AD. Multiple studies in transgenic mice provide strong evidence to support the view that Abeta amyloid formation is an early and critical pathogenic event: mice expressing pathogenic human APP mutations develop Abeta deposits; coexpression of mutant presenilin genes accelerates the rate of Abeta deposition; and apolipoprotein E plays a role in this process. Thus, the 3 established genetic causes or risk factors for AD affect Abeta deposition. The fact that elevation of the Abeta42/Abeta40 ratio (differing only in 2 amino acids in length) is also linked to amyloid deposition in the APP mice and is temporally linked to cognitive impairment suggests that Abeta42 may be a principal inducing factor of AD. The exact sequence of events is still unknown, but the transgenic models generated so far have shown their usefulness in clarifying this complex part of the pathology. The continuing progress in elucidation of the molecular pathogenesis of AD suggests a range of rational pharmacological interventions for this disorder. The most promising strategy involves the development of approaches to retard, halt, or prevent Abeta-mediated disease progression, and these can now be tested in transgenic animals.

Alzheimer Disease↗
PubMed1983

Multivariate analysis. Some guidelines for physicians.

"Mystified" best characterizes the feeling of many physicians as they read the results of a multivariate analysis. Much of the mystery disappears when two items are shown: (1) explicit tabulations revealing how each factor selected by the analysis relates to outcome, both singly and jointly with other factors; and (2) alternative models generated by repeating the analysis after removing the most important variables one by one from the list of factors that was initially analyzed. In this way, one can determine which variables are good stand-ins or substitutes for the best variables in the initial analysis. Showing these substitutes may expose exaggerations in benefits attributed to a particular therapy (ie, elective regional node dissection for clinical stage I malignant melanoma). We have applied these guidelines to examples in the literature, particularly studies of malignant melanoma.

Humans↗
PubMed1998

A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see commetns].

BACKGROUND: The National Cancer Data Base (NCDB) represents a national electronic registry system now capturing nearly 60% of incident cancers in the U. S. In combination with other Commission on Cancer programs, the NCDB offers a working example of voluntary, accurate, cost-effective "outcomes management" on a both a local and national scale. In addition, it is of particular value in capturing clinical information concerning rare cancers, such as those of the thyroid. METHODS: For the accession years 1985-1995, NCDB captured demographic, patterns-of-care, stage, treatment, and outcome information for a convenience sample of 53,856 thyroid carcinoma cases (1% of total NCDB cases). This article focuses on overall 10-year relative survival and American Joint Committee on Cancer (AJCC) (3rd/4th edition) stage-stratified 5-year relative survival for each histologic type of thyroid carcinoma. Care patterns also are discussed. RESULTS: The 10-year overall relative survival rates for U. S. patients with papillary, follicular, Hürthle cell, medullary, and undifferentiated/anaplastic carcinoma was 93%, 85%, 76%, 75%, and 14%, respectively. For papillary and follicular neoplasms, current AJCC staging failed to discriminate between patients with Stage I and II disease at 5 years. Total thyroidectomy +/- lymph node sampling/dissection represented the dominant method of surgical treatment rendered to patients with papillary and follicular neoplasms. Approximately 38% of such patients receive adjuvant iodine-131 ablation/therapy. At 5 years, variation in surgical treatment (i.e., lobectomy vs. more extensive surgery) failed to translate into compelling differences in survival for any subgroup with papillary or follicular carcinoma, but longer follow-up is required to evaluate this. NCDB data appeared to validate the AMES prognostic system, as applied to papillary cases. Younger age appeared to influence prognosis favorably for all thyroid neoplasms, including medullary and undifferentiated/anaplastic carcinoma. NCDB data also revealed that unusual patients diagnosed with undifferentiated/anaplastic carcinoma before age of 45 years have better survival. CONCLUSIONS: The NCDB system permits analysis of care patterns and survival for large numbers of contemporaneous U. S. patients with relatively rare neoplasms, such as thyroid carcinoma. In this context, it represents an unsurpassed clinical tool for analyzing care, evaluating prognostic models, generating new hypotheses, and overcoming the volume-related drawbacks inherent in the study of such neoplasms. [See editorial on pages 2434-6, this issue.]

Adenocarcinoma↗
PubMed1999

Assessment of inner dynein arm structure and possible function in ciliary and flagellar axonemes.

The construction and assessment of a three-dimensional computer-generated model of inner dynein arms on a 96-nm repeat unit of an axonemal doublet is described. The model is based on published electron micrographs of axonemes from Tetrahymena cilia and eel sperm, which were prepared using several different techniques: negative stain, freeze etch, and thin section. The inner arm structure is represented as three inner dynein arm complexes containing four inner dynein arms (IDAs), three dyads, and one single-headed arm, each capable of bridging the interdoublet gap. The IDA structures in the model have been correlated with the domains containing dynein heavy-chain isoforms mapped by several authors using genetic analyses of Chlamydomonas mutants. The model is consistent with micrographic evidence from axonemes of cilia and flagella from other organisms that led previously to conflicting structural interpretations. In this reconciling interpretation, the different alignments of the IDAs relative to the corresponding outer dynein arms observed in micrographs of differently prepared samples, result from the IDAs being arrested at different stages of their cycles of activity in each preparation. By interpolating between these positions of arrest, cycles of activity are proposed for each of the IDAs during which the arms attach to the neighbouring doublet microtubule and drive it tipwards.

Animals↗