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PubMed2006

The distribution of fitness effects of new deleterious amino acid mutations in humans.

The distribution of fitness effects of new mutations is a fundamental parameter in genetics. Here we present a new method by which the distribution can be estimated. The method is fairly robust to changes in population size and admixture, and it can be corrected for any residual effects if a model of the demography is available. We apply the method to extensively sampled single-nucleotide polymorphism data from humans and estimate the distribution of fitness effects for amino acid changing mutations. We show that a gamma distribution with a shape parameter of 0.23 provides a good fit to the data and we estimate that >50% of mutations are likely to have mild effects, such that they reduce fitness by between one one-thousandth and one-tenth. We also infer that <15% of new mutations are likely to have strongly deleterious effects. We estimate that on average a nonsynonymous mutation reduces fitness by a few percent and that the average strength of selection acting against a nonsynonymous polymorphism is approximately 9 x 10(-5). We argue that the relaxation of natural selection due to modern medicine and reduced variance in family size is not likely to lead to a rapid decline in genetic quality, but that it will be very difficult to locate most of the genes involved in complex genetic diseases.

Alleles↗

PubMed2006

Fitness benefits of systemic acquired resistance during Hyaloperonospora parasitica infection in Arabidopsis thaliana.

We investigated the fitness benefits of systemic acquired resistance (SAR) in Arabidopsis thaliana using a mutational and transformational genetic approach. Genetic lines were designed to differ in the genes determining resistance signaling in a common genetic background. Two mutant lines (cpr1 and cpr5) constitutively activate SAR at different points in SAR signaling, and one mutant line (npr1) has impaired SAR. The transgenic line (NPR1-H) has enhanced resistance when SAR is activated, but SAR is still inducible similarly to wild type. The fitness benefits were also investigated under two nutrient levels to test theories that preventing pathogen damage and realized resistance benefits may be affected by nutrient availability. Under low-nutrient conditions and treatment with the pathogenic oomycete, Hyaloperonospora parasitica, wild type had a higher fitness than the mutant that could not activate SAR, demonstrating that normal inducible SAR is beneficial in these conditions; this result, however, was not found under high-nutrient conditions. The mutants with constitutive SAR all failed to show a fitness benefit in comparison to wild type under a H. parasitica pathogen treatment, suggesting that SAR is induced to prevent an excessive fitness cost.

Arabidopsis↗

PubMed2004

Fitness of anopheline mosquitoes expressing transgenes that inhibit Plasmodium development.

One potential strategy for the control of malaria and other vector-borne diseases is the introduction into wild vector populations of genetic constructs that reduce vectorial capacity. An important caveat of this approach is that the genetic construct should have minimal fitness cost to the transformed vector. Previously, we produced transgenic Anopheles stephensi expressing either of two effector genes, a tetramer of the SM1 dodecapeptide or the phospholipase A2 gene (PLA2) from honeybee venom. Mosquitoes carrying either of these transgenes were impaired for Plasmodium berghei transmission. We have investigated the role of two effector genes for malaria parasite blockage in terms of the fitness imposed to the mosquito vector that expresses either molecule. By measuring mosquito survival, fecundity, fertility, and by running population cage experiments, we found that mosquitoes transformed with the SM1 construct showed no significant reduction in these fitness parameters relative to nontransgenic controls. The PLA2 transgenics, however, had reduced fitness that seemed to be independent of the insertion site of the transgene. We conclude that the fitness load imposed by refractory gene(s)-expressing mosquitoes depends on the effect of the transgenic protein produced in that mosquito. These results have important implications for implementation of malaria control via genetic modification of mosquitoes.

Animals↗

PubMed2004

Technique for achieving a passive framework fit: a clinical case report.

The clinical application of a 4-step technique for achieving the passive fit of an implant-supported cast bar or framework is reported. Implant-level transfers were attached, splinted intraorally with pattern resin, picked up in an open-tray elastomeric impression, and used to fabricate a working cast containing implant analogs. A light-cured template was used to verify master cast accuracy. A ceramometal fixed partial denture restoration was fabricated on the working cast with a preliminary try-in of the cast metal framework. A passive prosthesis fit was achieved. Failure to create an accurate working cast can distort the intended fit of a cast framework on the abutments in the patient's mouth. Optimal positioning of the implant analog in the master cast depends on (1) the transfer technique and (2) the ability of the system to maintain precise rotational orientation of the transfer components. The splinted transfer technique developed 20 years ago has sometimes been effective in improving the accuracy of framework fit with external hexagon implant-abutment connections, but it has not been documented with newer implant-abutment connections. Techniques for reestablishing master cast accuracy and correcting the superstructure are presented. The use of the presented technique resulted in a passive-fitting framework.

Dental Abutments↗

PubMedDate not supplied

[Keratoconus special soft contact lens fitting].

PURPOSE: To evaluate the fitting and use of a soft contact lens in keratoconic patients. METHODS: Retrospective study on 80 eyes of 66 patients, fitted with a special soft contact lens for keratoconus, at the Contact Lens Section of UNIFESP and private clinics. Keratoconus was classified according to degrees of disease severity by keratometric pattern. Age, gender, diagnosis, keratometry, visual acuity, spherical equivalent (SE), base curve and clinical indication were recorded. RESULTS: Of 66 patients (80 eyes) with keratoconus the mean age was 29 years, 51.5% were men and 48.5% women. According to the groups: 15.0% were incipient, 53.7% moderate, 26.3% advanced and 5.0% were severe. The majority of the eyes of patients using contact lenses (91.25%) achieved visual acuity better than 20/40. To 88 eyes 58% were tihed with lens with spherical power (mean -5.45 diopters) and 41% with spherocylinder power (from -0.5 to -5.00 cylindrical diopters). The most frequent base curve was 7.6 in 61% of the eyes. The main reasons for this special lens fitting were due to reduced tolerance and poor fitting pattern achieved with other lenses. CONCLUSION: The special soft contact lens is useful in fitting difficult keratoconic patients by offering comfort and improving visual rehabilitation that may allow more patients to postpone the need for corneal transplant.

Adolescent↗

PubMed2003

Humeral fixation by press-fitting of a tapered metaphyseal stem: a prospective radiographic study.

BACKGROUND: The technique of shoulder arthroplasty requires a method for securely and durably fixing the humeral component in the medullary canal of the proximal part of the humerus. As an alternative to fixation by cementing or tissue ingrowth, we explored the effectiveness of using a prosthesis with a metaphyseal taper from the anatomic neck to the diaphysis. This component is designed to obtain press-fit fixation in the cancellous bone of the metaphysis rather than in the cortical bone of the diaphysis. We tested the hypothesis that this press-fit humeral stem, designed to respect the taper of the proximal part of the humeral canal, would be associated with a low rate of loosening in patients managed with primary shoulder arthroplasty for osteoarthritis. METHODS: A prospective study was conducted to evaluate the prevalence of radiolucent lines around press-fit humeral prostheses. One hundred and thirty-one patients with glenohumeral osteoarthritis were followed for a minimum of two years. A zonal method of evaluating radiolucent lines was established. Shift in position and subsidence were judged qualitatively. RESULTS: No component showed subsidence or a shift in position. Fifty shoulders (39%) had no radiolucency. Two shoulders had radiolucency around the proximal part of the prosthesis, and seventy-five had radiolucency at the distal tip. Eleven radiolucencies were > or =1 mm in width. A neutral stem orientation was significantly less likely to be associated with radiolucency (p = 0.026). The prevalence of radiolucent lines did not differ between patients managed with hemiarthroplasty and those managed with total shoulder arthroplasty, and it did not increase with longer periods of follow-up. CONCLUSIONS: In patients managed with shoulder arthroplasty, the fixation of a press-fit humeral component that has a tapered metaphyseal segment is comparable with that reported for cemented components and superior to that reported for press-fit cylindrical components. CLINICAL RELEVANCE: This type of fixation may provide an alternative to cementing of the humeral stem in individuals with glenohumeral osteoarthritis.

Adult↗

PubMed2003

Established and recently identified coronary heart disease risk factors in young people: the influence of physical activity and physical fitness.

Epidemiological studies have identified several risk factors for coronary heart disease (CHD), many of which are present in young people. [For the purpose of this review, the phrase "young people" embraces both children and adolescents.] One such risk factor is hypertension. In adults, exercise is thought to have a positive effect on blood pressure levels; however, findings are inconclusive for young people. Despite its association with CHD, obesity is on the increase in Western society's young population; prevention and intervention during early years is needed. An active lifestyle is considered to have a beneficial effect on body fatness. Lipoprotein profiles are directly associated with CHD status. In adults, there is some evidence that physical activity and/or fitness have a favourable effect on lipoprotein levels. Although information regarding the younger population is more ambiguous, it tends to concur with these findings. High levels of lipoprotein(a), are considered an independent risk factor for CHD. Relatively little has been written on young people, although some studies have postulated a favourable relationship with physical activity. An inverse relationship between aerobic fitness and CHD has been confirmed in adults; an association is not as easily verified for young people. Physical activity is similarly deemed to have a beneficial effect on health status. A high-fat diet has been linked to CHD in adults, and evidence to date reports similar findings for young people. Smoking increases the risk of CHD and even moderate smoking during youth could have damaging long-term consequences. There is some evidence that smoking is related to physical activity and fitness levels in young people. In adults, high levels of homocyst(e)ine have been associated with CHD. As yet, little has been written on the relationship between physical activity or physical fitness and homocysteine status in young people. High levels of plasma fibrinogen have been linked to CHD. Several studies have explored the relationship between plasma fibrinogen and physical activity and/or fitness in adults, but findings are inconclusive; for young people, the ambiguity is even greater. C-reactive protein is a molecular marker for CHD but, to date, little attention has been given to this aspect, especially amongst young people. The link between high levels of plasminogen activator inhibitor-1 and CHD has been confirmed, although the essence of this relationship is not established. There is a paucity of data on the younger population and the relevance of collating such information is questionable. For the younger population, most research is limited to the established CHD risk factors and further investigations of recently identified CHD risk factors are needed.

Adolescent↗

PubMed2003

Fitness variations and their impact on the evolution of antiretroviral drug resistance.

The human immunodeficiency virus (HIV) exhibits extensive heterogeneity due to its rapid turnover, high mutation rate, and high frequency of recombination. Its remarkable genetic diversity plays a key role in virus adaptation, including development of drug resistance. The increasing complexity of antiretroviral regimens has favored selection of HIV variants harboring multiple drug resistance mutations. Evolution of drug resistance is characterized by severe fitness losses, which can be partially overcome by compensatory mutations or other adaptive changes that restore virus replication capacity. Recent reports have addressed the impact of drug-resistance mutations on viral fitness. Methods include in vitro estimates based on the determination of viral replication kinetics, viral infectivity in single-cycle assays and growth competition experiments; as well as estimates of the relative fitness of viral populations in vivo calculated from standard population genetics theory. This review focuses on the effects in viral fitness of mutations arising during treatment with reverse transcriptase and protease inhibitors, and the molecular mechanisms (including compensatory mutations) that improve the viral fitness of drug-resistant variants.

Anti-HIV Agents↗

PubMed2003

Facial anthropometric dimensions of Koreans and their associations with fit of quarter-mask respirators.

Past studies on respirator fit or performance have mostly been done for Whites or male subjects, and little attention has been paid to minorities and Asians. To fill this gap, this study was designed to provide facial anthropometric data for Koreans and to analyze the association between facial dimensions and respirator fit factors for three brands of quarter-mask respirators, two domestic and one imported brand, using a Portacount 8020. A total of 110 university student subjects, 70 males and 40 females volunteered for participation in the study. The results of this study showed that Korean males and females have different facial dimensions as compared with those of White males and females. Unexpectedly, the imported respirator performed better than the domestic respirators. Males were found to achieve better respirator fit than females regardless of respirator brands tested. The regression analysis found no common prognostic variables with the three respirator brands studied. A stepwise logistic regression analysis was conducted to find predictive facial dimensions with respirator fits. Some facial dimensions were found to be statistically significant, but these dimensions are different from the traditionally recommended facial dimensions of face length and lip width for quarter mask. To improve respirator fit for Koreans, these different facial characteristics need to be considered in the design of quarter mask respirators.

Adult↗

PubMed1995

Marginal and internal fit of four different types of ceramic inlays after luting. An in vitro study.

The marginal and internal fit of four different types of ceramic inlays--Cerec, Celay, Empress, and Vita In-Ceram Spinell--was determined after they had been luted on extracted premolars. For the Cerec inlays sharp and U-shaped proximal box shapings were also compared. There was no statistically significant difference either in the proximal fit or in the gingivoproximal fit between the four inlay systems studied, with the exception of the Cerec inlays made for preparations with sharp proximal boxes, which had wider marginal gaps. At the occlusal margins a significant-principle order of the gap width was established. The best internal fit was recorded for the Celay inlays, whereas there was no significant difference in the internal fit between the other systems. For the Cerec inlays the U-shaped proximal box shaping improved the marginal accuracy all around the restoration.

Aluminum Oxide↗

PubMed1984

Auditory adaptation: notes on power and parabolic curve fitting across intensity and time. I.

The classic procedure for the study of auditory adaptation has been the method of Simultaneous Dichotic Loudness Balance ( SDLB ). Data from four publications ( Jerger , 1957; Palva and Karja , 1969; Weiler , Loeb and Alluisi , 1972 and Weiler and Hood, 1977) were combined to yield values extending from 20 dB to 80 dB average sensation level. A growth curve was fitted to the data by means of the Gompertz curve-fitting technique. A close fit was obtained, and a somewhat closer fit was found using a parabolic curve. In addition to the average data for SDLB adaptation across test intensities, the Gompertz method was used to fit the course of adaptation over time for one additional study ( Thwing , 1955).

Adaptation, Physiological↗

PubMed1987

Optimum side for fitting a monaural hearing aid. 1. Patients' preference.

The criteria generally used to decide in which ear to fit a monaural hearing aid are based on theory or anecdote and have not been verified by experimental observation. In this study to determine optimum side of fitting, 58 new hearing aid users were fitted with a hearing aid in one ear for 10 weeks, and then fitted in the other ear for a further 10 weeks. Subsequently, the subjects were asked their preference for side of hearing aid use and their reasons for this preference. 30 (52%) subjects reported better hearing with their aid in one ear than in the other; 24 (80%) of these preferred the ear with the poorer half-peak level elevation on a speech audiogram. The remaining 28 (48%) reported no difference in their aided hearing ability between ears, though 20 preferred one ear for practical reasons, unrelated to audiometric parameters. A patient's preference for side of fitting can be predicted from audiometric data but with only modest reliability. It is, therefore, recommended that bilateral ear moulds should be routinely provided for bilateral mild to moderate hearing impairment (speech frequency average less than 75 dB HL). If it is decided that only one ear mould should be provided, this should be made for the poorer hearing ear. The poorer hearing ear is best identified from the half-peak level elevation on a speech audiogram.

Adult↗

PubMed1991

The performance and calibration of TDH39 earphones fitted with Model 51 and MX41/AR cushions.

Coupler measurements were made to compare the performances of new-style Model 51 cushions and old-style MX41/AR cushions fitted to TDH39 earphones. In addition, the calibration, using an artificial ear, of TDH39 earphones fitted with Model 51 cushions was compared with the calibration, using a reference coupler, of the same earphones fitted with MX41/AR cushions. It is concluded that the two cushion types can be taken as identical when fitted to TDH39 earphones, except at 6 kHz where differences in earphone sensitivity of up to 2.8 dB were observed. Likewise, output hearing levels of TDH39 earphones measured using a reference coupler and an artificial ear were found to be similar, except at 6 kHz where differences of up to 6.4 dB were observed. The data support the decision by ISO to declare the Model 51 equivalent to the MX41/AR cushion, thereby requiring TDH39 earphones to be calibrated using a reference coupler whichever cushion is fitted. However, they also highlight once again the ill-defined performance of TDH39 earphones at 6 kHz.

Acoustics↗

PubMed1989

Primary survival and prosthetic fitting of lower limb amputees.

During the period 1984-1985 amputation of the lower limb at a level potentially requiring a prosthesis was performed on 577 patients in 16 operative units. The mean age was 75.7 years for females and 68.1 for males. The most common site of the amputation was above the knee (49.9%). The majority of amputations (93.8%) were performed for vascular diseases and diabetes. Survival figures showed that 25.5% of amputees died within 2 months of amputation, 60.7% were alive after one year and 43.2% after two years. Out of a total of 577 patients, 26.9% were fitted with a prosthesis. Out of below-knee and above-knee amputees surviving over 2 months, 61.5% and 27.2% respectively were fitted with a prosthesis. There were markedly fewer prosthetic fittings in the over-60 age group. Diabetic patients of both sexes were fitted with a prosthesis more often than arterio-sclerotic patients. Among tumour patients 82.4% received a prosthesis. In the study area more emphasis must be put on the concept of preserving the knee joint and preoperative assessment of vascular patients for selection of amputation level. Every effort must be made to avoid delay in the postoperative mobilization and rehabilitation. Prosthetic fitting of amputees could be improved by better liaison between surgical unit and specialized rehabilitation unit and by closer team approach of amputee care.

Aged↗

PubMed1979

Running fits and gamma-aminobutyric acid of the superior colliculus of the mouse.

The present experiment was performed to examine the relationship between the content of gamma-aminobutyric acid of the superior colliculus and running fits induced by injection of semicarbazide (SC), an antivitamin B6, into the superior colliculus of the mouse. (1) The distribution of 4-aminobutyrate: 2-oxoglutarate aminotransferase [EC 2.6.1.19] of the superior colliculus was studied histochemically. A high activity was observed in the superficial and medial gray layers of the superior colliculus. Pretreatment with aminooxyacetic acid at a dose which inhibits running fits induced by intracollicular injection of SC depressed the activity. (2) The contents of gamma-aminobutyric acid in superior colliculi of mice which received an intracollicular injection of SC were 60 per cent of the control, when measured immediately after the first running fit. Administration of pyridoxine together with SC inhibited the fall. (3) Intracollicular injection of thiosemicarbazide and 4-deoxypyridoxine, other antivitamins B6, also induced running fits. These results suggest that the running fits by SC injected intracollicularly are induced by the decrease of gamma-aminobutyrate due to insufficient vitamin B6 in the superior colliculus.

Aminooxyacetic Acid↗

PubMed2005

Risks of drawing inferences about cognitive processes from model fits to individual versus average performance.

With the goal of drawing inferences about underlying processes from fits of theoretical models to cognitive data, we examined the tradeoff of risks of depending on model fits to individual performance versus risks of depending on fits to averaged data with respect to estimation of values of a model's parameters. Comparisons based on several models applied to experiments on recognition and categorization and to artificial, computer-generated data showed that results of using the two types of model fitting are strongly determined by two factors: model complexity and number of subjects. Reasonably accurate information about true parameter values was found only for model fits to individual performance and then only for some of the parameters of a complex model. Suggested guidelines are given for circumventing a variety of obstacles to successful recovery of useful estimates of a model's parameters from applications to cognitive data.

Cognition↗

PubMed1998

The influence of semantic fit on on-line sentence processing.

The interactive influence of verb complement preferences and noun phrase semantic fit on resolution of temporary syntactic ambiguity was investigated in an eye movement experiment. The present semantic fit manipulation included noun phrases that fit well as direct objects of the verbs that they followed and noun phrases that were possible but less likely direct objects of the verbs in question. This contrasted with existing research on the use of verb complement preferences and semantic fit during sentence processing, in which processing of noun phrases that are possible direct objects has been compared with processing of noun phrases that are not possible direct objects of the verbs that they follow. Verb complement preference information and noun phrase semantic fit interacted at early stages of on-line sentence processing. Implications of these results for interactive and structural models of sentence processing are discussed.

Adult↗

PubMed2003

Model fitting in (n+1) dimensions.

Conventionally, fitting a mathematical model to empirically derived data is achieved by varying model parameters to minimize the deviations between expected and observed values in the dependent dimension. However, when functions to be fit are multivalued (e.g., an ellipse), conventional model fitting procedures fail. A novel (n+1)-dimensional [(n+1)-D] model fitting procedure is presented which can solve such problems by transforming the n-D model and data into (n+1)-D space and then minimizing deviations in the constructed dimension. While the (n+1)-D procedure provides model fits identical to those obtained with conventional methods for single-valued functions, it also extends parameter estimation to multivalued functions.

Algorithms↗