Showing papers by "University of Utah published in 1989"

Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas

Abstract: Previous studies have demonstrated that allelic deletions of the short arm of chromosome 17 occur in over 75% of colorectal carcinomas. Twenty chromosome 17p markers were used to localize the common region of deletion in these tumors to a region contained within bands 17p12 to 17p13.3. This region contains the gene for the transformation-associated protein p53. Southern and Northern blot hybridization experiments provided no evidence for gross alterations of the p53 gene or surrounding sequences. As a more rigorous test of the possibility that p53 was a target of the deletions, the p53 coding regions from two tumors were analyzed; these two tumors, like most colorectal carcinomas, had allelic deletions of chromosome 17p and expressed considerable amounts of p53 messenger RNA from the remaining allele. The remaining p53 allele was mutated in both tumors, with an alanine substituted for valine at codon 143 of one tumor and a histidine substituted for arginine at codon 175 of the second tumor. Both mutations occurred in a highly conserved region of the p53 gene that was previously found to be mutated in murine p53 oncogenes. The data suggest that p53 gene mutations may be involved in colorectal neoplasia, perhaps through inactivation of a tumor suppressor function of the wild-type p53 gene.

Allelotype of colorectal carcinomas

Abstract: To examine the extent and variation of allelic loss in a common adult tumor, polymorphic DNA markers were studied from every nonacrocentric autosomal arm in 56 paired colorectal carcinoma and adjacent normal colonic mucosa specimens. This analysis was termed an allelotype, in analogy with a karyotype. Three major conclusions were drawn from this analysis: (i) Allelic deletions were remarkably common; one of the alleles of each polymorphic marker tested was lost in at least some tumors, and some tumors lost more than half of their parental alleles. (ii) In addition to allelic deletions, new DNA fragments not present in normal tissue were identified in five carcinomas; these new fragments contained repeated sequences of the variable number of tandem repeat type. (iii) Patients with more than the median percentage of allelic deletions had a considerably worse prognosis than did the other patients, although the size and stage of the primary tumors were very similar in the two groups. In addition to its implications concerning the genetic events underlying tumorigenesis, tumor allelotype may provide a molecular tool for improved estimation of prognosis in patients with colorectal cancer.

Development of Asian monsoon revealed by marked ecological shift during the latest Miocene in northern Pakistan

Abstract: CARBON isotopes from soil carbonate1–4 and soil organic matter5,6 yield palaeoecological information because the carbon in the soil carbonate forms in isotopic equilibrium with local soil CO2 (refs 1, 7), the isotopic composition of which is in turn determined by local plant cover. Siwalik Group sediments in northern Pakistan contain a well exposed palaeosol record spanning the past 18 Myr. Here we report on stable-carbon-isotope results from associated pedogenic carbonate which indicate a dramatic ecological shift from to dominated floodplain biomass beginning ∼7.4–7.0 Myr ago. The earlier C3 floodplain biomasses were probably mainly composed of trees and shrubs, whereas C4 grasslands dominated in the Plio-Pleistocene. Oxygen isotopes also exhibit a shift in the latest Miocene, probably corresponding to a major climate change which may have induced the forest-to-grassland transition. This dramatic ecological shift in the latest Miocene may mark the inception or a marked strengthening of the Asian monsoon system.

Hedging one's evolutionary bets, revisited

Abstract: Evolutionary bet-hedging involves a trade-off between the mean and variance of fitness, such that phenotypes with reduced mean fitness may be at a selective advantage under certain conditions. The theory of bet-hedging was first formulated in the 1970s, and recent empirical studies suggest that the process may operate in a wide range of plant and animal species.

The barrier to recombination between Escherichia coli and Salmonella typhimurium is disrupted in mismatch-repair mutants.

Abstract: The requirement for DNA sequence homology in generalized genetic recombination is greatly relaxed in bacterial mutL,mutS and mutH mutants deficient in mismatch repair. In such mutants, inter-generic recombination occurs efficiently between Escherichia coli and Salmonella typhimurium, which are ∼20% divergent in DNA sequence. This finding has implications for speciation, for regulating recombination between diverged repeated sequences, and for hitherto difficult interspecies hybridizations.

Biosynthesis of cadmium sulphide quantum semiconductor crystallites

Abstract: NANOMETRE-SCALE semiconductor quantum crystallites exhibit size-dependent and discrete excited electronic states which occur at energies higher than the band gap of the corresponding bulk solid1–4. These crystallites are too small to have continuous energy bands, even though a bulk crystal structure is present. The onset of such quantum properties sets a fundamental limit to device miniaturization in microelectronics5. Structures with either one, two or all three dimensions on the nanometer scale are of particular interest in solid state physics6. We report here our discovery of the biosynthesis of quantum crystallites in yeasts Candida glabrata and Schizosaccharomyces pombe, cultured in the presence of cad-mium salts. Short chelating peptides of general structure (γ-Glu-Cys)n-Gly control the nucleation and growth of CdS crystallites to peptide-capped intracellular particles of diameter 20 A. These quantum CdS crystallites are more monodisperse than CdS par-ticles synthesized chemically. X-ray data indicate that, at this small size, the CdS structure differs from that of bulk CdS and tends towards a six-coordinate rock-salt structure.

Carbon isotopes in soils and palaeosols as ecology and palaeoecology indicators

Abstract: THERE are few quantitative techniques in use today for palaeoecological reconstruction in terrestrial depositional systems. One approach to such reconstructions is to estimate the proportion of C3 to C4 plants once present at a site using carbon isotopes from palaeosol carbonates1–3. Until now, this has been hampered by an inadequate understanding of the relationship between the carbon isotopic composition of modern soil carbonate and coexisting organic matter. Here we have found that the two systematically differ by 14–16% in undisturbed modern soils. This difference is compatible with isotopic equilibrium between gaseous CO2, and aqueous and solid carbonate species in a soil system controlled by diffusive mass transfer of soil CO2 derived from irreversible oxidation of soil organic matter. Organic matter and pedogenic carbonate from palaeosols of Pleistocene to late Miocene age in Pakistan also differ by 14–16%,. This indicates that diagenesis has not altered the original isotopic composition of either phase, thus confirming their use in palaeoecological reconstruction.

Solar radiative transfer in cirrus clouds. I - Single-scattering and optical properties of hexagonal ice crystals. II - Theory and computations of multiple scattering in an anisotropic medium

Abstract: The light scattering and absorption programs of Cai and Liou (1982) and Takano and Jaweera (1985) are extended to include hexagonal ice crystals randomly and horizontally oriented in space. The scattering and polarization results for the ice crystals are calculated. The results are compared with measurement data. The single-scattering properties for horizontally oriented columns and plates are presented and used to explain halos and arcs observed in the atmopshere. In the second section, the theory and computations for multiple scattering in cirrus clouds containing oriented ice crystals are presented. The radiative transfer in clouds composed of horizontally oriented ice crystals is formulated. Also, reflected and transmitted intensities, planetary albedo, and polarization in multiple scattering by ice crystals are discussed.

Systematic variations in the carbon and oxygen isotopic composition of pedogenic carbonate along elevation transects in the southern Great Basin, United States

Abstract: Stable carbon- and oxygen-isotope variations in Holocene soil carbonates that formed in the unsaturated zone were examined along several elevation transects in the southern Great Basin, United States, a region with a semi-arid climate. Our intent was to study the relationship between the stable isotopic composition of pedogenic carbonates and climate, ecological variations, differences in parent material, and soil depth. δ 13 C of pedogenic carbonate in three different soil profiles from different elevations decreases with soil depth, indicating a decrease in the ratio of atmospheric to plantderived CO 2 downprofile. Pedogenic carbonate at the soil-air interface approaches a δ 13 C value in equilibrium with atmospheric CO 2 in all three soils. Observed δ 13 C profiles for pedogenic carbonate can be described using a one-dimensional model for 12 CO 2 and 13 CO 2 , assuming isotopic equilibrium between soil CO 2 and soil carbonate. The modeled best fit to observed isotopic profiles suggests that the profile differences in part result from differing soil-respiration rates at each site. δ 13 C in deep pedogenic carbonate (>50 cm) varies by about 12 per mil over a 2,440-m elevation range, being enriched in 13 C at the lowest elevations. The slope of δ 13 C for these carbonates versus elevation is very similar for soils developed on carbonate and on noncarbonate parent materials: depletion by 4.6 to 4.7 per mil per 1,000 m increase in altitude between 300 to 2,740 m above mean sea level for the localities studied. This concordance makes it likely that there has been complete isotopic exchange between HCO 3 - in solution and soil CO 2 prior to carbonate precipitation. Soil CO 2 and soil-respiration rates increase systematically with elevation. The plantderived component of soil CO 2 indicates that C 3 plants dominate the biomass at most measured sites, in agreement with plant surveys. Calculated equilibrium fractionation factors between soil CO 2 and soil carbonate are very similar to those observed, again indicating complete isotopic exchange between carbon species. In all, the soil CO 2 and soil-carbonate data suggest that the δ 13 C variation with elevation observed in the soil carbonates results from differing soil-respiration rates at each site, as well as from variations in the proportion of C 3 to C 4 and CAM plants in each site9s surface biomass. δ 18 O values in pedogenic carbonates are higher at lower elevations, due in part to the more positive δ 18 O values for meteoric waters at lower elevations. The average δ 18 O value of deep (>50 cm) pedogenic carbonate at all sites, however, is enriched 2.4 to 3.7 per mil with respect to values we predict should be in equilibrium with the isotopic composition of local meteoric waters. This suggests that evaporative isotopic enrichment of soil waters may have occurred at all elevations prior to precipitation of carbonate, or that seasonal differences in the isotopic composition of meteoric waters coupled with differential infiltration may be taking place. One or both of these processes also may explain the δ 18 O decrease in soil carbonate with depth observed in two of three soil profiles.

Protein-resistant surfaces prepared by PEO-containing block copolymer surfactants.

Abstract: Polyethylene oxide(PEO)-containing non-ionic polymeric surfactants were studied as a possible means to produce PEO-rich surfaces by a simple coating treatment of a common hydrophobic medical material—polyethylene Surface tension and adsorption properties of PEO/polypropylene oxide(PPO) and PEO/polybutylene oxide(PBO) block copolymer surfactants on a hydrophobic surface (low density polyethylene, LDPE) were investigated, using the Wilhelmy plate surface tension technique and x-ray photoelectron spectroscopy(XPS) The protein resistance of the surfactant-treated surfaces was evaluated by XPS and 125I-labeled proteins The data presented indicate that adsorption of the surfactants on LDPE is dependent on the molecular geometry of the surfactants Adsorption of human albumin was significantly decreased on the surfactant-treated LDPE surfaces, as compared with the untreated surface Surfactants suitable for the preparation of PEO-rich surfaces and possible mechanisms for their protein resistance are discussed

Stratigraphic context of fossil hominids from the Omo group deposits: northern Turkana Basin, Kenya and Ethiopia.

Abstract: The chronometric framework developed for Plio-Pleistocene deposits of the northern Turkana Basin is reviewed in light of recent advances in lithostratigraphy, geochemical correlation, paleomagnetic stratigraphy, and isotopic dating. The sequence is tightly controlled by 20 precise ages on volcanic materials. These ages are internally consistent but are at variance with estimates for the boundaries of the magnetic polarity time scale by about 0.07 my. This discrepancy can be only partially resolved at present. Based on the established chronometric framework and stratigraphic sequences, depositional ages can be estimated for significant marker beds. These ages can in turn be used to constrain the 449 hominid specimens thus far reported from the basin. Ages for most hominid specimens can be estimated with a precision of +/- 0.05 my. In addition, the chronometric framework will be applicable to other paleontological collections, archeological excavations, and future discoveries in the basin.

Optimism, Neuroticism, Coping, and Symptom Reports: An Alternative Interpretation of the Life Orientation Test

Abstract: Found in two studies that the Life Orientation Test (LOT) had limited discriminant validity relative to measures of neuroticism. Furthermore, although previous correlations of the LOT with measures of symptom reports and coping behaviors were replicated, these correlations were eliminated when neuroticism was controlled. In contrast, the correlations of symptoms and coping with neuroticism remained significant when LOT scores were controlled. Thus, the LOT is virtually indistinguishable from measures of neuroticism, and previously reported findings using this scale are perhaps more parsimoniously interpreted as reflecting neuroticism rather than optimism. These findings are discussed in terms of existing support for models of optimism and self-control and general methodological issues in studies of personality and health.

The Strain Energy Release Rate of Composite Microcracking: A Variational Approach

Abstract: A variational analysis approach has been used to determine the two- dimensional thermoelastic stress state in cross-ply laminates of type [0m/90n] s and [90m/ 0n]s. The stress analysis was used to calculate the energy release rate due to formation of a new microcrack. The analysis accurately includes the effect of residual thermal stresses. When compared with experiments, the new energy release rate expressions are found to predict typical data using a single value for the critical energy release rate for microcrack ing. This critical energy release rate has a physical interpretation as a microcracking fracture toughness or as an intralaminar fracture toughness. We also used the variational solution to get an analytical expression for the longitudinal expansion coefficient of the microcracked cross-ply laminate as a function of microcrack density. Finally, variational theorems are used to show that this new microcracking fracture analysis is rigorously more accurate than previous attempts at the same problem.

Beta 1- and beta 2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium.

Abstract: Prenalterol (beta 1-agonist), denopamine (beta 1-agonist), and zinterol (beta 2-agonist) were partial agonists of adenylate cyclase (AC) stimulation in human ventricular myocardium obtained from nonfailing chambers whose beta 1/beta 2 receptor subtype ratio was approximately 80/20. At a concentration less than its low affinity (beta 2) Kl, betaxolol, a highly selective beta 1-antagonist, inhibited isoproterenol (non-selective agonist), denopamine, and prenalterol stimulation of AC, indicating that isoproterenol, denopamine, and prenalterol are all capable of stimulating AC through beta 1-receptor activation. At a concentration less than its low affinity (beta 1) Kl, ICI 118,551, a highly selective beta 2-agonist, inhibited both isoproterenol and zinterol stimulation of AC, indicating that isoproterenol and zinterol stimulate AC through beta 2-receptors. Zinterol stimulation of AC was mediated entirely by beta 2-receptors, inasmuch as 10(-7) M betaxolol had no effect on the zinterol dose-response curve and ICI 118,551 produced a degree of blockade (KB = 5.2 +/- 1.6 X 10(-9) M), consistent with the beta 2-receptor Kl of the latter (2.0 +/- .4 X 10(-9) M, p, not significant). In nonfailing myocardium, analysis of beta 1 versus beta 2 stimulation by the nonselective agonist isoproterenol revealed that the numerically small (19% of the total) beta 2 fraction accounted for the majority of the total adenylate cyclase stimulation. In failing ventricular chambers with a beta 1/beta 2 receptor subtype ratio reduced from 82/19 (nonfailing) to 64/36 (p less than 0.001) and a beta 1-receptor density reduced by 61% (p less than 0.001), maximal denopamine stimulation was reduced by 49% (p less than 0.001). Moreover, in preparations from failing heart, the component of denopamine stimulation that was inhibited by 10(-7) M betaxolol (beta 1 component) was reduced by 77% (p less than 0.05). Finally, in preparations derived from failing ventricular myocardium, beta 2-receptor density was not significantly decreased, but zinterol stimulation of AC was reduced by 32% (p less than 0.05). We conclude that heart failure results in subsensitivity to both selective beta 1 and beta 2 stimulation of adenylate cyclase, with beta 1 subsensitivity due to selective beta 1 receptor down-regulation and beta 2 subsensitivity due to partial uncoupling of beta 2 receptors from subsequent events in the beta 2-adrenergic pathway.

Three-dimensional electrode device

Abstract: A three-dimensional electrode device is disclosed The device is useful as a neuron interface or as a cortical implant A plurality of spire-shaped electrodes, formed of semiconductor material, are associated with a rigid base The electrodes are electrically isolated from each other at the base Multiplexing circuitry allows the electrodes to be addressed individually

Isolation and characterization of a membrane protein from normal human erythrocytes that inhibits reactive lysis of the erythrocytes of paroxysmal nocturnal hemoglobinuria.

Abstract: The observation that type III erythrocytes of paroxysmal nocturnal hemoglobinuria (PNH) are susceptible to hemolysis initiated by activated cobra venom factor complexes (CoFBb), whereas normal erythrocytes are resistant, implies that the PNH III cells are deficient in a membrane constituent that regulates this process. To isolate the inhibitory factor from normal erythrocytes, membrane proteins were first extracted with butanol and then subjected to sequential anion exchange, hydroxylapatite, and hydrophobic chromatography. Analysis by SDS-PAGE and silver stain of the inhibitory fractions showed a single band corresponding to a protein with an apparent Mr of 18 kD. PNH erythrocytes were incubated with incremental concentrations of the radiolabeled protein and then washed. In a dose-dependent fashion, the protein incorporated into the cell membrane and inhibited CoFBb-initiated lysis. This protein inhibitor functioned by restricting the assembly of the membrane attack complex at the level of C7 and C8 incorporation. By using a monospecific antibody to block the function of the inhibitor, it was shown that normal erythrocytes are rendered susceptible to CoFBb-initiated hemolysis. Analysis by Western blot of membrane proteins revealed that PNH III erythrocytes are deficient in the 18-kD protein. By virtue of its molecular weight and inhibitory activity, the 18-kD protein appears to be discrete from other previously described erythrocyte membrane proteins that regulate complement. These studies also indicate that the susceptibility of PNH III erythrocytes to reactive lysis is causally related to a deficiency of the 18-kD membrane inhibitor.

Contrasting effects of glucocorticoids on the capacity of T cells to produce the growth factors interleukin 2 and interleukin 4.

Abstract: The molecular mechanisms which govern the biosynthesis and secretion of the various T cell-derived lymphokines are poorly understood at this time, in spite of their tremendous importance to the control of the mammalian immune system. Here we provide compelling evidence that production of the murine T cell growth factors interleukin (IL)2 and IL 4 are differentially regulated by glucocorticoid (GCS) hormones. Under conditions where IL 2 production is reduced by GCS hormones, IL 4 production is increased. In vivo, this effect on T cell production of growth factors is manifest at low GCS concentrations that are well within physiologic ranges. In vitro, splenocytes isolated from antigen-stimulated donors, as well as antigen-specific cloned T cell lines, undergo alterations in their capacity to secrete T cell growth factors when stimulated with antigens in the presence of GCS. Responses normally dominated by IL 2 are dramatically shifted to a condition where IL 4 represents the major species of T cell growth factor produced. Similar changes in the pattern of T cell growth factor production are observed following short pulses with low-dose GCS in vitro, and the steroid-induced depression in IL 2 production can be reversed and/or inhibited by treatment with the potent steroid antagonist RU486. Our results imply that GCS hormones, presumably through their capacity to activate a specified family of ligand-dependent transcriptional regulatory proteins (steroid hormone receptors), function to control the pattern of lymphokines produced by activated T cells. Steroid-mediated regulation of lymphokine gene expression could serve to dictate the types of immune effector mechanisms which can be initiated subsequent to antigen exposure.

Identification, characterization, and mapping of the Escherichia coli htrA gene, whose product is essential for bacterial growth only at elevated temperatures.

Abstract: We identified and cloned an Escherichia coli gene called htrA (high temperature requirement). The htrA gene was originally discovered because mini-Tn10 transposon insertions in it allowed E. coli growth at 30 degrees C but prevented growth at elevated temperatures (above 42 degrees C). The htrA insertion mutants underwent a block in macromolecular synthesis and eventually lysed at the nonpermissive temperature. The htrA gene was located at approximately 3.7 min (between the fhuA and dapD loci) on the genetic map of E. coli and between 180 and 187.5 kilobases on the physical map. It coded for an unstable, 51-kilodalton protein which was processed by removal of an amino-terminal fragment, resulting in a stable, 48-kilodalton protein. Images

Allelic Loss in Colorectal Carcinoma

Abstract: Clinical and pathological associations with molecular genetic alterations were studied in colorectal carcinomas from 83 patients. Fractional allelic loss, a measure of allelic deletions throughout the genome, and allelic deletions of specific chromosomal arms (the short arm of 17 and long arm of 18) each provided independent prognostic information by multivariate analysis when considered individually with Dukes'classification. Distant metastasis was significantly associated with high fractional allelic loss and with deletions of 17p and 18q. Mutations of ras proto-oncogenes and deletions of 5q had no prognostic importance. Statistically significant associations were also found between allelic losses and a family history of cancer, left-sided tumor location, and absence of extracellular tumor mucin. Allelic deletion analysis thus identified subsets of colorectal carcinoma with increased predilection for distant metastasis and cancer-related death. Further studies may define a subset of genetic alterations that can be used clinically to help assess prognosis. (JAMA. 1989;261:3099-3103)

Vascular (humoral) rejection in heart transplantation: pathologic observations and clinical implications.

Abstract: We prospectively studied 551 sequential endomyocardial biopsies from 36 consecutive cardiac allografts. With the use of a combination of light microscopy (including careful evaluation of vascular changes) and immunofluorescence to detect the deposition of immunoglobulin and complement, we identified three patterns of allograft rejection, designated as cellular rejection, vascular (humoral) rejection, and mixed rejection. Cellular rejection was diagnosed with modified Billingham criteria. Vascular rejection was diagnosed by finding the combination of prominent endothelial cell swelling and/or vasculitis on light microscopy and the vascular deposition of immunoglobulin and complement by immunofluorescence. In such patients, cellular lymphoid infiltrates were uniformly absent at the time the vascular changes were detected. Mixed rejection consisted of findings of both cellular and vascular rejection occurring simultaneously. Twenty of 36 allografts exhibited cellular rejection; seven allografts showed vascular rejection, and nine allografts developed mixed rejection. The vascular (humoral) pattern of rejection was important to identify because the patients with this type of rejection had a significantly decreased survival compared with that of patients with cellular rejection (p less than 0.05). Survival in the mixed rejection category was intermediate. Positive donor-specific cross-match and/or panel-reactive antibody greater than or equal to 5% and systolic dysfunction were seen in three of the seven allografts with vascular (humoral) rejection but not in the other types. In the early period after transplant (up to 3 weeks after transplant), the only reliable identifying characteristics of patients with vascular (humoral) rejection were the presence of vascular immunoglobulin and complement assessed by immunofluorescence and endothelial cell swelling and interstitial edema as confirmed by histologic examination. We conclude that immunofluorescence should be routinely done on all heart biopsies for the first month after transplantation. Patients with vascular (humoral) rejection cannot be reliably identified by any other means.

Clonality of Parathyroid Tumors in Familial Multiple Endocrine Neoplasia Type 1

Abstract: Familial multiple endocrine neoplasia type 1 (MEN-1) is characterized by tumors of the parathyroids, endocrine pancreas, and anterior pituitary. Since the gene associated with MEN-1, locat...

Thermodynamic and Kinetic Effects of Oxygen Removal on the Thermal Conductivity of Aluminum Nitride

Abstract: Etude de deux types d'echantillons: echantillons contenant des oxydes de terres rares ou d'alcalinoterreux (Dy 2 O 3 , Yb 2 O 3 , MgO, BaO, CaO) et echantillons contenant differentes quantites de Y 2 O 3

Genetic heritability and common environmental components of resting and stressed blood pressures, lipids, and body mass index in utah pedigrees and twins

Abstract: The relative contributions of genes and shared environment to cardiovascular risk factors were studied in twins and pedigrees in 1983-1985. Sitting, standing, isometric hand grip, bicycling, and mentally stressed (serial subtraction) blood pressures were obtained from 146 male monozygous twins, 162 male dizygous twins, and 1,102 healthy adults in 67 Utah pedigrees. Fasting total plasma cholesterol, triglycerides, high density lipoprotein cholesterol (HDL), and body mass index were also measured. Heritability was estimated before and after adjusting for 12 environmental variables (measures of socioeconomic status; personality types; exercise levels; use of tobacco, alcohol, coffee, etc.) by using age-adjusted twin intraclass correlations. These heritabilities were compared with those obtained from a variance components analysis of the pedigree data separating genetic and common household effects. Sitting and standing blood pressure heritability estimates were much higher from twin than from pedigree data (39-63% in twins vs. 16-22% in pedigrees), as were those for cholesterol and triglycerides (65 and 75% from twins vs. 42 and 37% from pedigrees) and body mass index (51 vs. 21%). Estimates were similar for heritability of HDL cholesterol (51 vs. 45%). Most of the stressed blood pressure heritabilities were similar to sitting blood pressure estimates. No common household effect (except for adjusted HDL cholesterol (24%), p less than 0.01) was statistically significant for the lipids, blood pressures, or body mass index. Environmental variables correlated much better in monozygous twins and spouses than in dizygous twins, brothers, or sisters. Spouse correlations for lipids, blood pressures, and body mass index were low, with a maximum of 0.12 (p less than 0.05) for HDL cholesterol. We conclude that genes contribute much more than shared environment to the well-recognized familial correlation of blood pressures, lipids, and body mass index.

Mutational effects on protein stability

Abstract: PERS PECT IVES AND S UMMAR y 765 THE PROB LEM 767 THERMODYNAM ICS OF AM INO AC ID S UBST IT UTIONS 770 GENE TIC S TUD IES O F PRO TEIN S TAB ILITy 774 COO PERA TIVITY 777 S TR UCT URA L ST UD IES OF PROTE IN VAR IAN TS 777 FORCES THAT STAB ILIZE PROTE INS 779 Effects on Conformational Entropy 779 The Hydrophobic Eff ect .. . . . . . . ...... . . ...... . ..... ...... 781 Hydrogen Bonds . . 784 Dispersion Forces 786 Electrostatic Interactions 788 Helix Stabilization 790 CONC LUD ING REMAR KS 793

Prevention of symptomatic recurrences of paroxysmal atrial fibrillation in patients initially tolerating antiarrhythmic therapy. A multicenter, double-blind, crossover study of flecainide and placebo with transtelephonic monitoring. Flecainide Supraventricular Tachycardia Study Group.

Abstract: Paroxysmal atrial fibrillation (PAF) is a problematic clinical arrhythmia that is usually symptomatic. Unfortunately, few adequate trials and trial methods are available for assessment of the value of therapy, and traditional treatment has often been ineffective or associated with unacceptable side effects. Transtelephonic monitoring is a new method that allows evaluation of paroxysmal arrhythmias and arrhythmia-related symptoms in outpatients. We used a patient-initiated transtelephonic monitor system to evaluate the potential of flecainide, a class 1C antiarrhythmic, in prevention of symptomatic recurrences of PAF. Sixty-four patients qualified for the study (two or more PAF attacks documented within a 4-week baseline period) and entered a dose-finding phase to determine drug tolerance. Dose was incremented at weekly intervals from 200-300 and finally to 400 mg/day. The largest dose that was well tolerated was selected for the 4-month, double-blind, randomized, crossover comparison with placebo. Fifty-five patients entered and 53 received both treatments in the double-blind phase; 48 of these patients without protocol violations were evaluable for efficacy comparisons. Evaluable patients had undergone an average of 3.8 previous drug trials (range, 1-8); 30 were men, 18 had hypertension, and 14 had ischemic heart disease. The study demonstrated a highly significant correlation (p less than 0.0001) between perceived symptoms and documented PAF by transtelephonic monitoring. The rate of symptoms and PAF attacks was also significantly reduced by therapy (median dose, 300 mg/day). The first PAF attack occurred after a median of 3 days on placebo versus 14.5 days on flecainide (p less than 0.001) therapy. Similarly, the time interval between attacks was lengthened, from a median of 6.2 days on placebo to 27.0 days on flecainide (p less than 0.001) therapy. PAF was prevented in 15 patients (31%) during flecainide and four (9%) during placebo therapy (p = 0.013). However, during the study, 13 patients dropped out, seven because of adverse effects (five cardiac), five for other reasons, and one because of cardiac arrest/death. Adverse cardiac events occurred in a total of seven patients (11%) during flecainide therapy. Thus, transtelephonic monitoring is a useful method for documentation of the occurrence of paroxysmal arrhythmias such as PAF and its related symptoms during daily living and for assessment of new therapies in an outpatient setting.

On the spatial spread of the grey squirrel in Britain.

Abstract: We present a diffusion-competition model to describe the interaction between the externally introduced grey squirrel and the indigenous red squirrel in Britain. We estimate the model parameters from field data. Solution of the model predicts waves of grey squirrel invasion with speed of invasion typical of that observed in the field. Numerical solution of the model on a two-dimensional domain gives population distributions qualitatively similar to those observed. We suggest that competition alone could account for the observed displacement of the red squirrel by the grey in large regions of Britain. The solutions are qualitatively similar to those for a single species spreading in the absence of competition. The quantitative difference is because competition slows down the speed of advance of the invading species.