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PubMed2000

Predictive accuracy and explained variation in Cox regression.

We suggest a new measure of the proportion of the variation of possibly censored survival times explained by a given proportional hazards model. The proposed measure, termed V, shares several favorable properties with an earlier V1 but also improves the handling of censoring. The statistic contrasts distance measures between individual 1/0 survival processes and fitted survival curves with and without covariate information. These distance measures, Dx and D, respectively, are themselves informative as summaries of absolute rather than relative predictive accuracy. We recommend graphical comparisons of survival curves for prognostic index groups to improve the understanding of obtained values for V, Dx, and D. Their use and interpretation is exemplified for a Yorkshire lung cancer study on survival. From this and an overview for several well-known clinical data sets, we show that the likely amount of relative or absolute predictive accuracy is often low even if there are highly significant and relatively strong prognostic factors.

Adult↗

PubMed2004

Explaining public resistance to genetically modified corn: an analysis of the distribution of benefits and risks.

Genetically modified (GM) crops have met with widespread approval among scientists and policy makers in the United States, but public approval of GM crops, both domestically and abroad, is progressing much more slowly. An underlying cause of public wariness may be that both nations and individual consumers do not perceive significant benefits to themselves from GM crops, while fearing the risks they may incur. In this study, an economic analysis is conducted to determine whether the benefits of one type of GM corn, Bt corn (genetically modified to resist damage from the ECB and Southwestern corn borer), outweigh the potential risks; and who the "winners" and "losers" are among stakeholder groups that may be affected by Bt corn. It is found that Bt corn growers, consumers, and industry all benefit from Bt corn adoption, though the purported health and environmental benefits of reducing chemical pesticide usage through Bt corn are negligible. Though the aggregated public benefit is large, the welfare gain to individual consumers is small and may not make up for perceived risks. While environmental and health risks of Bt corn are unlikely, the potential market risks-impacting both the organic corn market and total U.S. corn exports-are found to be significant. Currently, distributional analysis is not a part of regulatory decision making of Bt corn in the United States; yet it may help to explain why decision makers at both the government and individual-consumer levels have failed to embrace Bt corn and other GM crops.

Food, Genetically Modified↗

PubMed1997

A case of recessive X-linked ichthyosis: scale-specific abnormalities of lipid composition may explain the pathogenesis of the skin manifestation.

We analyzed the lipid content of the scales, red blood cells, and plasma from a recessive X-linked icthyosis patient. The patient's scales accumulated cholesterol sulfate, had decreased levels of free sterols, sterol esters and sphingolipids, and lacked phospholipids. Although the accumulation of cholesterol sulfate was found in the patient's red blood cells and plasma as well as in the scales, other lipid composition abnormalities were specific for scales. Such scale-specific abnormal lipid composition may explain the pathogenesis of generalized hyperkeratosis and abnormal scaling of the disease.

Adult↗

PubMed1994

Hypertrichosis and algodystrophy: an hypothesis to explain this uncommon association.

Various skin changes have been described in algodystrophy, but the association of hypertrichosis with this condition is poorly documented. We describe a patient who developed algodystrophy after a mild inflammatory arthritis, in association with a number of skin manifestations, including hypertrichosis. We suggest a mechanism to explain this particular association.

Adult↗

PubMed1979

A cell kinetic model to explain the time of appearance of skin reaction after X-rays or ultraviolet light irradiation.

Skin reactions to various doses of X-rays (300 and 10 kV) and ultraviolet light (u.v.) have been compared using hairless mice. Two regions of epidermis with widely differing cell kinetics and gross structure have been compared. Little evidence could be found to support the idea that the early phases of the reaction are dependent on cell cycle time. The data can be explained by a model based on the assumption that epidermis contains only a small fraction of clonogenic (stem) cells and this fraction may vary in different epidermal regions. X-rays appear to exert their greatest destructive action on these clonogenic cells while u.v. is more indiscriminate in its action, killing both clonogenic and non-clonogenic cells.

Animals↗

PubMed1994

Confounding by severity does not explain the association between fenoterol and asthma death.

Three recent case-control studies from New Zealand, and one from Saskatchewan, Canada, have found that fenoterol increases the risk of death in patients with severe asthma. It has been suggested that these findings may be due to confounding by severity, if fenoterol was selectively prescribed to more severe asthmatics. This 'confounding by severity' hypothesis has now been investigated in further analyses of data from the New Zealand case-control studies. This analysis found that among patients whose asthma was severe enough to require hospital admission (the population in whom the case-control studies were conducted), fenoterol was not preferentially prescribed to the more severe asthmatics. There was greater co-prescribing of other drugs with fenoterol (compared with salbutamol) during the later years of the epidemic, but these differences did not explain the excess risk associated with fenoterol, and there was little evidence of greater co-prescribing during the earlier years of the New Zealand epidemic of asthma deaths. There was no association between the prescription of fenoterol and markers of acute asthma severity or psychosocial problems. Patients were not selectively changed to fenoterol as a result of a severe attack resulting in a hospital admission. Most importantly, in the case-control studies of asthma deaths, the inhaled fenoterol relative risk increased when the analysis was restricted to sub-groups defined by markers of chronic asthma severity; whereas the relative risk would have decreased towards 1.0 in these sub-group analyses if the overall elevated risk for fenoterol was due to confounding by severity.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗

PubMed2006

Lyme borreliosis reinfection: might it be explained by a gender difference in immune response?

Lyme borreliosis is a tick-borne disease often manifesting as a circular skin lesion. This cutaneous form of the disease is known as erythema migrans. In a 5-year follow-up study in southern Sweden, 31 of 708 individuals initially diagnosed with erythema migrans and treated with antibiotics were found to be reinfected with Borrelia burgdorferi. Although men and women were tick-bitten to the same extent, 27 of the 31 reinfected individuals were women, all of whom were over 44 years of age. The aim of this study was to determine whether this discrepancy in gender distribution could be a result of differences in immunological response. Twenty single-infected and 21 reinfected women and 18 single-infected and three reinfected men were included in the study. None of the participants showed any sign of an ongoing B. burgdorferi infection, and thus the habitual response was captured. Lymphocytes were separated from blood and stimulated with antigens. The secretion of interleukin (IL)-4, IL-6, IL-10, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha was measured by enzyme-linked immunosorbent assay (ELISA), enzyme-linked immunosorbent spot-forming cell assay (ELISPOT) or Immulite. No difference was detected in cytokine secretion between single-infected and reinfected individuals. We also compared the immunological response in men and women, regardless of the number of B. burgdorferi infections. Women displayed a significantly higher spontaneous secretion of all cytokines measured. The ratios of IL-4:IFN-gamma and IL-10:TNF-alpha were significantly higher in women. Gender differences in immune reactivity might in part explain the higher incidence of reinfection in women. The higher IL-4:IFN-gamma and IL-10:TNF-alpha ratios seen in women indicate that postmenopausal women have T helper type 2 (Th2)-directed reactivity with impaired inflammatory responses which might inhibit the elimination of spirochetes.

Case-Control Studies↗

PubMed2006

Behavioural trade-offs between growth and mortality explain evolution of submaximal growth rates.

1. The importance of body size and growth rate in ecological interactions is widely recognized, and both are frequently used as surrogates for fitness. However, if there are significant costs associated with rapid growth rates then its fitness benefits may be questioned. 2. In replicated whole-lake experiments, we show that a domestic strain of rainbow trout (artificially selected for maximum intrinsic growth rate) use productive but risky habitats more than wild trout. Consequently, domestic trout grow faster in all situations, experience greater survival in the absence of predators, but have lower survival in the presence of predators. Therefore, rapid growth rates are selected against due to increased foraging effort (or conversely, lower antipredator behaviour) that increases vulnerability to predators. In other words, there is a behaviourally mediated trade-off between growth and mortality rates. 3. Whereas rapid growth is beneficial in many ecological interactions, our results show the mortality costs of achieving it are large in the presence of predators, which can help explain the absence of an average phenotype with maximized growth rates in nature.

Animals↗

PubMed2006

Explaining inequalities in access to treatment in lung cancer.

BACKGROUND: Geographical inequalities in lung cancer treatment and patient survival have been described. We hypothesized that lung cancer patients' access to treatment may be influenced by deprivation and the pathway to care. METHODS: Case notes were reviewed for patients resident in south-east London who were registered with lung cancer at the Thames Cancer Registry in 1998. Use of surgery, chemotherapy, radiotherapy or any specific treatment and one-year survival were examined. Analyses were adjusted for age, sex, histology, stage and basis of diagnosis. RESULTS: Data for 695 out of 958 (73%) patients were analysed. Subjects who were initially referred to a specialist in thoracic medicine, surgery or oncology were more likely to receive active treatment (71%) than subjects who were referred to other consultants (51%) or who were admitted as emergencies (42%) (P < 0.0001). CONCLUSION: Socio-economic deprivation was associated with lower rates of treatment and this partly explained variations in survival. Subjects who were referred to specialists were more likely to receive active treatment and treatment patterns varied between first trust attended.

Aged↗

PubMed2006

Black patients with chronic hepatitis C have a lower sustained viral response rate than non-Blacks with genotype 1, but the same with genotypes 2/3, and this is not explained by more frequent dose reductions of interferon and ribavirin*.

In previous hepatitis C virus (HCV) treatment studies, Black patients not only had a lower sustained viral response (SVR) rate to interferon and ribavirin (RBV) than non-Black patients but also a higher frequency of HCV genotype 1 (GT-1) infection. The aim of this community-based study was to determine whether Black patients have a lower SVR rate independent of genotype. We prospectively enrolled 785 patients (24.8% Black, 71.5% White, 3.7% others) who received interferon alpha-2b 3 MU three times weekly + RBV 1000-1200 mg/day for 24 weeks (GT-2/3) or 48 weeks (GT-1). Black patients were more commonly infected with GT-1 (86.8%vs 64.8%, P < 0.001) and less frequently had an SVR compared with non-Black patients (8.4%vs 21.6%, P < 0.001). Within GT-1, Black patients had a lower SVR rate than non-Black patients (6.1%vs 14.1%, P = 0.004) but not within GT-2/3 (50.0%vs 36.5%, P = 0.47). Black patients had lower baseline haemoglobin levels (14.8 vs 15.3 g/dL, P < 0.001) and neutrophil counts (2900 vs 4100/mm(3), P < 0.001) and required more frequent dose reductions of RBV (29.8%vs 18.5%, P < 0.001) and interferon (4.7%vs 1.6%, P = 0.012). However, dose reductions were not associated with lower SVR rates while early treatment discontinuations were (2.9%vs 25.7%, P < 0.001). Independent predictors of SVR were GT-1 [odds ratio (OR) 0.33; 95% confidence interval (CI) 0.20-0.55; P < 0.001], Black race (OR 0.45; 95% CI 0.22-0.93; P = 0.030), and advanced fibrosis, stages 3 + 4 (OR 0.53; 95% CI 0.31-0.92; P = 0.023). In conclusion, Black patients infected with HCV GT-1 (but not GT-2/3) have a lower SVR rate than non-Black patients. This is not explained by their lower baseline haemoglobin levels and neutrophil counts that lead to higher rates of ribavirin and interferon dose reductions.

Alanine Transaminase↗

PubMed2005

Genetic population structure of Natterer's bats explained by mating at swarming sites and philopatry.

During autumn 'swarming', large numbers of temperate bats chase each other in and around underground sites. Swarming has been proposed to be a mating event, allowing interbreeding between bats from otherwise isolated summer colonies. We studied the population structure of the Natterer's bat (Myotis nattereri), a swarming species in northern England, by sampling bats at seven sites in two swarming areas and at 11 summer colonies. Analysis of molecular variance (amova) and genetic assignment analyses showed that the swarming areas (60 km apart) support significantly different populations. A negative correlation was found between the distance of a summer colony from a swarming area and the assignment of bats to that area. High gene diversity was found at all sites (HE = 0.79) suggesting high gene flow. This was supported by a low FST (0.017) among summer colonies and the absence of isolation by distance or substructure among colonies which visit one swarming area. The FST, although low, was significantly different from zero, which could be explained by a combination of female philopatry and male-mediated gene flow through mating at swarming sites with bats from other colonies. Modelling suggested that if effective size of the summer colonies (Ne) was low to moderate (10-30), all mating must occur at the swarming sites to account for the observed FST. If the Ne was higher (50), in addition to random mating during swarming, there may be nonrandom mating at swarming sites or some within-colony mating. Conservation of swarming sites that support potentially large populations is discussed.

Animals↗

PubMed2004

Delayed-relaxed response explained by hyperactivation of RelE.

Escherichia coli encodes two rel loci, both of which contribute to the control of synthesis of macromolecules during amino acid starvation. The product of relA (ppGpp synthetase I) is responsible for the synthesis of guanosine tetraphosphate, ppGpp, the signal molecule that exerts stringent control of stable RNA synthesis. The second rel locus, relBE, was identified by mutations in relB that confer a so-called 'delayed-relaxed response' characterized by continued RNA synthesis after a lag period of approximately 10 min after the onset of amino acid starvation. We show here that the delayed-relaxed response is a consequence of hyperactivation of RelE. As in wild-type cells, [ppGpp] increased sharply in relB101 relE cells after the onset of starvation, but returned rapidly to the prestarvation level. RelE is a global inhibitor of translation that is neutralized by RelB by direct protein-protein interaction. Lon protease activates RelE during amino acid starvation by degradation of RelB. We found that mutations in relB that conferred the delayed-relaxed phenotype destabilized RelB. Such mutations confer severe RelE-dependent inhibition of translation during amino acid starvation, indicating hyperactivation of RelE. Hyperactivation of RelE during amino acid starvation was shown directly by measurement of RelE-mediated cleavage of tmRNA. The RelE-mediated shutdown of translation terminated amino acid consumption and explains the rapid restoration of the ppGpp level observed in relB mutant cells. Restoration of the prestarvation level of ppGpp, in turn, allows for the resumption of stable RNA synthesis seen during the delayed-relaxed response.

Adaptation, Physiological↗

PubMed2006

Mutations in Mycobacterium tuberculosis Rv0444c, the gene encoding anti-SigK, explain high level expression of MPB70 and MPB83 in Mycobacterium bovis.

It has recently been advanced that Mycobacterium tuberculosis sigma factor K (SigK) positively regulates expression of the antigenic proteins MPB70 and MPB83. As expression of these proteins differs between M. tuberculosis (low) and Mycobacterium bovis (high), this study set out to determine whether M. bovis lacks a functional SigK repressor (anti-SigK). By comparing genes near sigK in M. tuberculosis H37Rv and M. bovis AF2122/97, we observed that Rv0444c, annotated as unknown function, had variable sequence in M. bovis. Analysis of in vitro mpt70/mpt83 expression and Rv0444c sequencing across M. tuberculosis complex (MTC) members revealed that high-level expression was associated with a mutated Rv0444c. Complementation of M. bovis bacillus Calmette-Guerin Russia, a high producer of MPB70/MPB83, with wild-type Rv0444c resulted in a significant decrease in mpb70/mpb83 expression. Conversely, a M. tuberculosis H37Rv mutant which expressed sigK but not Rv0444c manifested the M. bovis phenotype of high-level MPB70/MPB83 expression. Further support that Rv0444c encodes the anti-SigK was obtained by yeast two-hybrid studies, where the N-terminal region of Rv0444c-encoded protein interacted with SigK. Together these findings indicate that Rv0444c encodes the regulator of SigK (RskA) and mutations in this gene explain high-level MPT70/MPT83 expression by certain MTC members.

Antigens, Bacterial↗

PubMed1994

A molecular and cellular model to explain the differences in reactivation from latency by herpes simplex and varicella-zoster viruses.

There are marked similarities in the biological properties of the human neurotropic herpesviruses herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV), including their ability to establish lifelong latent infections in human peripheral sensory ganglia (PSG). Despite this, their patterns of reactivation are quite different: HSV-1 reactivations occur many times during a lifetime, they are localized to the cutaneous distribution of a single sensory nerve, they are not associated with sensory symptomatology and their frequency decreases with age. VZV recurrence on the other hand is usually a single event which tends to appear with advancing age, its cutaneous eruption involves an entire dermatome and is usually extremely painful. To help explain these differences, we have formulated a model based on current knowledge of the molecular and cellular basis of latent infection in the nervous system. We suggest that the amount of latent viral DNA and RNA in the latently infected tissue (higher with HSV-1), the cellular location of latent virus (neuronal in HSV-1, probably non-neuronal in VZV), the presence or absence of viral replication in the PSG during reactivation together with the host immune response, are all key determinants of the clinical expression of viral reactivation.

DNA, Viral↗

PubMed2007

Anisohydric but isohydrodynamic: seasonally constant plant water potential gradient explained by a stomatal control mechanism incorporating variable plant hydraulic conductance.

Isohydric and anisohydric regulations of plant water status have been observed over several decades of field, glasshouse and laboratory studies, yet the functional significance and mechanism of both remain obscure. We studied the seasonal trends in plant water status and hydraulic properties in a natural stand of Eucalyptus gomphocephala through cycles of varying environmental moisture (rainfall, groundwater depth, evaporative demand) in order to test for isohydry and to provide physiological information for the mechanistic interpretation of seasonal trends in plant water status. Over a 16 month period of monitoring, spanning two summers, midday leaf water potential (psi(leaf)) correlated with predawn psi(leaf), which was correlated with water table depth below ground level, which in turn was correlated with total monthly rainfall. Eucalyptus gomphocephala was therefore not seasonally isohydric. Despite strong stomatal down-regulation of transpiration rate in response to increasing evaporative demand, this was insufficient to prevent midday psi(leaf) from falling to levels below -2 MPa in the driest month, well into the region likely to induce xylem air embolisms, based on xylem vulnerability curves obtained in the study. However, even though midday psi(leaf) varied by over 1.2 MPa across seasons, the hydrodynamic (transpiration-induced) water potential gradient from roots to shoots (delta psi(plant)), measured as the difference between predawn and midday psi(leaf), was relatively constant across seasons, averaging 0.67 MPa. This unusual pattern of hydraulic regulation, referred to here as isohydrodynamic, is explained by a hydromechanical stomatal control model where plant hydraulic conductance is dependent on transpiration rate.

Plants↗

PubMed1995

Linkage disequilibrium in HLA cannot be explained by selective recombination.

Some combinations of HLA-A, -B and -DR antigens occur more frequently than would be expected from their gene frequencies in the population. This phenomenon, referred to as Linkage Disequilibrium (LD) has been the origin of many speculations. One hypothesis to explain LD is that some haplotypes are protected from recombination. A second hypothesis is that these HLA antigens preferentially recombine after cross-over to create an LD haplotype. We tested these 2 hypotheses: from a pool of over 10,000 families typed in our department, we analyzed 126 families in which HLA-A:B or B:DR recombinant offspring was documented. To overcome a possible bias in our material, we used the non-recombined haplotypes from the same 126 families as a control group. Our results show that the number of cross-overs through LD haplotypes is not significantly lower then would be expected if recombination occurred randomly. Also the number of LD haplotypes created upon recombination was not significantly increased.

Family↗

PubMed1980

Isomeric incorporation of the Haem into monomeric haemoglobins of Chironomus thummi thummi. 2. The Bohr effect of the component III explained on a molecular basis and functional differences between the two isomeric structures.

The Bohr effect in the monomeric haemoglobin component III of Chironomus thummi thummi is described on a molecular basis using various pH-dependent proton resonances. One of the three titratable histidines changes its pK from 7.9 in the unligated state to 7.7 upon ligation with CO and up to 7.0 upon ligation with O2. It can be concluded from an analysis of the C-2 proton resonance intensities that these shifts in pK occur in only one of the two conformational isomers of the component III, whereas in the second isomer these pK shifts are not observed. The differences between these functional properties are also derived from pH-dependent changes of the mesoproton resonances as well as of the methyl resonances of Ile-E11. The conformational change of the component III, which is connected with the Bohr effect, influences a variety of other resonances which could not be assigned. The pK values derived from the pH dependence of these changes agree exactly with the pK value of the Bohr proton donating group, which is supposed to be His-G2. Also the corresponding signal intensities indicate the presence of two conformational isomers in the haemoglobin component III. Although the change in chemical shift of the His-G2 C-2 proton resonance is only small upon deprotonation of the imidazole ring, it has been shown with potentiometric and calorimetric methods that this histidine is deprotonated in this pH range. Considering the tertiary structure obtained from an X-ray study of Steigemann and Weber we can readily explain the conformational changes in the Bohr active isomer of the component III. With binding of ligands dislocations of side chains at the proximal site produce a change in the interactions of His-G2 with the carboxyl group of the C-terminal methionine-H22.

Allosteric Regulation↗

PubMedDate not supplied

Increases in the myocardial concentration of vasoactive intestinal peptide may explain the positive inotropic effect of angiotensin converting enzyme inhibitors.

1. In patients with congestive cardiac failure, treatment with angiotensin converting enzyme (ACE) inhibitors results in peripheral vasodilatation and an increase in cardiac output without an increase in heart rate, which suggests a positive inotropic effect. This cannot be explained by changes in angiotensin II and bradykinin concentrations that occur. ACE has been suggested to also metabolise vasoactive intestinal peptide (VIP), which is a positive inotrope. As VIP is synthesized by the heart and acts locally to increase cardiac output, we postulated that ACE inhibition would increase the myocardial concentration of VIP. 2. Male Sprague-Dawley rats received enalapril (2 mg/kg per day) in their drinking water or no therapy for 7 days. On day 7 the rats were anaesthetized and blood was sampled. Hearts and kidneys were then harvested and snap frozen by immersion in liquid nitrogen. Concentrations of VIP in plasma and tissue extracts were measured by radioimmunoassay. 3. Plasma and renal concentrations of VIP did not change in enalapril-treated rats. However, the myocardial concentration of VIP increased significantly in rats receiving enalapril compared with control animals (P < 0.0005). 4. We conclude that treatment with ACE inhibitors results in increased myocardial VIP concentrations and suggest that this may contribute to the improvement in cardiac function that occurs with these agents.

Angiotensin-Converting Enzyme Inhibitors↗