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PubMed2000

Apolipoprotein E is a genetic risk factor for fetal iodine deficiency disorder in China.

Fetal iodine deficiency disorder (FIDD) is the principal form of endemic cretinism, and the most common cause of preventable mental deficiency in the world. However not everyone at risk develops FIDD and familial aggregation is common. This suggests that genetic factors may also be involved. The Apolipoprotein E (APOE) gene encodes for a lipoprotein that possesses a thyroid hormone binding domain, and APOE genotype may affect the efficiency with which thyroid hormone influences neuronal cell growth during the first and second trimesters of fetal development. We have compared ApoE genotypes in 91 FIDD cases with 154 local control subjects, recruited from three iodine deficiency areas in central China. We have also genotyped 42 FIDD family cases and 158 normal individuals from the families of local controls, and 375 population controls from Shanghai. APOE epsilon4 genotypes were significantly enriched in FIDD probands from each of the three iodine deficiency areas; the epsilon4 allele frequency was 16% vs 6% in controls. The same effect was also observed when we compared FIDD family cases with controls and control families. Our data suggest that in iodine-deficient areas, the APOE epsilon4 allele is a genetic risk factor for FIDD. The phenomenon may affect population selection and contribute to the low frequency of the epsilon4 allele in Chinese compared to Caucasian populations.

Adolescent↗
PubMed1977

Leukaemia in benzene workers.

Workers occupationally exposed to benzene in 1940-49 were followed for vital status up to 1975. In comparison with two control populations, a significant (P less than 0-002) excess of leukaemia was observed. A five-old excessive risk of all leukaemias and a ten-fold excess of deaths from myeloid and monocytic leukaemias combined are demonstrated in the study population compared with controls. These figures under-estimate the true leukaemia risk to benzene-exposed workers, because follow-up is only 75% complete and the untraced 25% of the study population were all regarded, in the statistical analysis, as being alive at the end of the study period. The environment of the workers in the study population was not contaminated with solvents other than benzene, and existing records indicate that the benzene levels themselves were generally below the limits recommended at the time of their measurement.

Adult↗
PubMedDate not supplied

Cell line and schedule-dependent cytotoxicity of paclitaxel (Taxol): role of the solvent Cremophor EL/ethanol.

BACKGROUND: Paclitaxel's optimal dosage and scheduling is currently not determined. To compare paclitaxel (PTX) cytotoxicity in vitro, three cell lines were chosen for investigation by single versus fractionated exposure to Taxol and the diluent Cremophor EL/ethanol (CEL/eth). METHODS: An exponentially growing human lung-carcinoma (SK-LU-1), human glioblastoma (U-138 MG) and mammalian fibroblast cell line (HyB14FAF28) were used for colony forming assay examining cell survival, and flow cytometric DNA analysis by measuring cell cycle development. Tested concentrations varied from 2-50 microM and were incubated for 3 and 15 hours. Single (2-50 microM/d, especially 10 microM/d), versus fractionated (2 microM/d, day 1-5) exposure of Taxol and CEL/eth was investigated. As the control population, cells were exposed to a phosphate buffered solution (PBS). RESULTS: Control populations demonstrated an average survival of 90, 99 and 93% for SK-LU-1, U-138 MG, B14, respectively. Single Taxol exposure at 10 microM showed average survival of 54, 50 and 84% after 3 hours and 9, 48 and 82% after 15 hours for the above cell lines. Fractionated Taxol exposure with 2 microM/d, days 1-5 led to average survival of 55, 86 and 63%, respectively. Single CEL/eth exposure showed a cytotoxic effect with average survival of 94, 126 and 91% after 3 hours and 47, 63 and 88% after 15 hours respectively. Fractionated CEL/eth exposure showed an average survival of 67, 94 and 65% respectively. Flow cytometric analysis detected cell cycle shift concerning S- and G2/M-phase after Taxol exposure only in the two tumour cell lines, and not in the fibroblastic cells. CEL/eth was without significant effect on cell cycle distribution in all three cell lines. CONCLUSIONS: In the two human tumour cell lines cytotoxicity was more pronounced after prolonged Taxol exposure. The fibroblast cell line was not sensitive to single treatment, and was without cell cycle changes. Comparable to Taxol the diluent CEL/eth had a significant but less pronounced cytotoxic effect. Therefore, the cytotoxic mechanisms of paclitaxel's and CEL/eth's are worthy of further investigation.

Animals↗
PubMed1995

trans isomers of oleic and linoleic acids in adipose tissue and sudden cardiac death.

trans isomers of unsaturated fatty acids are formed by biological or industrial hydrogenation. A population case-control study of sudden cardiac death in mean was done to test the hypothesis that trans isomers of oleic acid and linoleic acid increase the risk of sudden cardiac death due to coronary artery disease. In adipose tissue obtained at necropsy from 66 cases of sudden cardiac death and taken from 286 healthy age and sex matched controls, the proportions of trans isomers of oleic and linoleic acid were measured by gas-liquid chromatography. In cases, the mean (SE) percentage of total trans fatty acids (C18:1 plus C18:2), expressed as a proportion of all fatty acids, was significantly lower (2.68 [0.08]%) than in healthy controls (2.86 [0.04]%; p < 0.05). trans C18:1 was 2.1 (0.7)% in cases compared with 2.27 (0.04)% (p < 0.05) in controls. The proportion of all trans isomers of linoleic acid was 0.58 (0.02)% in cases compared with 0.59 (0.01)% in controls (p = 0.98). The estimated relative risk for sudden cardiac death of trans C18:1 and C18:2 fatty acids combined did not differ significantly from 1.0 in relation to the distribution of these trans isomers by quintile in the control population. The relative risk (95% CI) of sudden cardiac death in the top quintile was 0.40 (0.15-1.02) for C18:1 and 1.08 (0.48-2.74) for C18:2 compared with the bottom quintiles of their respective control distributions. When these univariate relations for trans fatty acids were adjusted for coronary risk factors, smoking was the only factor that remained independently associated with risk of sudden cardiac death (2.27 [1.23-4.17]). Overall, there was no evidence of a relation between trans isomers of oleic and linoleic acids combined and sudden cardiac death. However, trans oleic acid was negatively associated with risk of sudden cardiac death, whereas no association with trans forms of linoleic acid was seen. This study does not support the hypothesis that trans isomers increase the risk of sudden cardiac death.

Adipose Tissue↗
PubMed1980

The pathology of breast cancer in women irradiated for acute postpartum mastitis.

The gross and microscopic pathology of breast cancers in women irradiated for acute postpartum mastitis was compared to the breast cancers found in the sisters of the irradiated women. Fifty-one cancers in 50 irradiated women and 25 cancers in 24 nonirradiated women were examined. In considering the lesions in the two populations, the size, location, histologic type, histologic grade, inflammatory response, lymphatic and blood vascular invasion, nipple involvement, axillary lymph node metastases, and menopausal status at the time of diagnosis were statistically indistinguishable. The only parameter that was different in the two populations was the desmoplastic response to the malignant lesion (P = 0.04). The control population had more marked fibrosis within the cancers compared with the irradiated women. With the exception of stromal response, this study shows that breast cancer in irradiated women is similar in the parameters evaluated to breast cancer in a control population.

Acute Disease↗
PubMed2005

Bayesian models for population-based case-control studies when the population is in Hardy-Weinberg equilibrium.

Association analysis of genetic polymorphisms has been mostly performed in a case-control setting with unrelated affected subjects compared with unrelated unaffected subjects. In this paper, we present a Bayesian method for analyzing such case-control data when the population is in Hardy-Weinberg equilibrium. Our Bayesian method depends on the informative prior which is the retrospective likelihood based on historical data, raised to a power a. By modeling the retrospective likelihood properly, different prior information about the studied population can be incorporated into the specification of the prior. The scalar a is a precision parameter quantifying the heterogeneity between current and historical data. A guide value for a is discussed in this paper. The informative prior and posterior distributions are proper under very general conditions. Therefore, our method can be applied in most case-control studies. Further, for assessing gene-environment interactions, our approach will naturally lead to a Bayesian model depending only on the case data, when genotype and environmental factors are independent in the population. Thus our approach can be applied to case-only studies. A real example is used to show the applications of our method.

Bayes Theorem↗
PubMed1993

Linoleic acid and risk of sudden cardiac death.

OBJECTIVE: To test the hypothesis that the essential fatty acid, linoleic acid, measured in adipose tissue as an indicator of long term dietary intake, is inversely related to the risk of sudden cardiac death. DESIGN: A population case-control study. SETTING: A regional health district. SUBJECTS: 84 men (age 25-64 years) who died instantaneously or within 24 hours of the onset of symptoms with no history of coronary heart disease or medically treated hyperlipidaemia, and in whom coronary artery disease was diagnosed at postmortem examination as the primary cause of death, were compared with 292 age (to within two years) and sex matched healthy controls and their partners drawn from the general practitioners' records with whom the cases were registered. MAIN OUTCOME MEASURES: Fatty acid composition of adipose tissue and the risk of sudden cardiac death. RESULTS: Linoleic acid in adipose tissue was inversely related to the risk of sudden cardiac death. The estimated relative risk (95% CI) of sudden cardiac death was 5.7 (1.8 to 17.9) for the lowest quintile and 4.0 (1.2 to 12.9) for the next quintile of adipose linoleic acid in the control population when compared with the highest quintile. This inverse relation was independent of age, reported smoking habits, history of hypertension, and diabetes, although there was a close association with cigarette smoking. The estimated adjusted proportionate increase in risk (95% CI) of sudden cardiac death was 1.14 (1.03 to 1.23) for every 1% reduction of linoleic acid in adipose tissue. CONCLUSIONS: The percentage content of linoleic acid in adipose tissue was inversely related to the risk of sudden cardiac death. Populations with a high risk of sudden cardiac death may benefit from increasing their dietary intake of polyunsaturated fatty acid oils, principally from cereals and vegetables.

Adipose Tissue↗
PubMed2003

Genetic analysis of a polymorphism in the human apoA-V gene: effect on plasma lipids.

Recent discovery and characterization of APOAV suggests a role in metabolism of triglyceride (TG)-rich lipoproteins. Previously, variation at the APOAV locus was shown to modestly influence plasma TGs in normolipidemic samples. The aims of this study were to assess the effects of a polymorphism in APOAV (T-1131C) in terms of its frequency among three dyslipidemic populations and a control population, differences of allele frequency across available ethnic groups, and associations with specific lipoprotein TG and cholesterol compartments. We found a striking elevation in the frequency of the rare allele in a Chinese population (P = 0.0002) compared with Hispanic and European populations. The rare allele of the polymorphism was associated with elevated plasma TG (P = 0.012), VLDL cholesterol (P = 0.0007), and VLDL TG (P = 0.012), LDL TG (P = 0.003), and HDL TG (P = 0.016). Linear regression models predict that possession of the rare allele elevates plasma TG by 21 mg/dl (P = 0.009) and VLDL cholesterol by 8 mg/dl (P = 0.0001), and reduces HDL cholesterol by 2 mg/dl (P = 0.017). The association of the polymorphism with altered lipoprotein profiles was observed in combined hyperlipidemia, hypoalphalipoproteinemia, and hyperalphalipoproteinemia, and in controls. These findings indicate that APOAV is an important determinant of plasma TG and lipoprotein cholesterol, and is potentially a risk factor for cardiovascular disease.

Adult↗
PubMed1997

High prevalence of antiphospholipid antibodies in patients taking procainamide.

OBJECTIVE: To determine whether antiphospholipid antibodies (aPL) are more prevalent in cardiac patients taking procainamide than in a control population of similar elderly cardiac patients and to determine whether these antibodies react in an ELISA in which the primary antigen is beta 2-glycoprotein I (beta 2-GPI). METHODS: aPL and antibodies to beta 2-GPI were measured in 66 patients taking procainamide from a Veterans Administration Medical Center population and a control group of 30 similar cardiac patients not taking procainamide. RESULTS: 21% of the patients taking procainamide and no control patients were found to have moderate to high aPL. There were similar results in an assay that measured anti-beta 2-GPI in the absence of exogenous phospholipids. aPL were associated with antinuclear antibodies and antihistone antibodies but not with diabetes or clinical manifestations of drug related lupus. There was no increase in cholesterol or past thrombotic history associated with aPL, but there was a frequent history of noncardiac thrombosis in patients taking procainamide (25.7%). CONCLUSION: The predictive significance of procainamide induced aPL remains unknown but beta 2-GPI dependent aPL may be of some concern in this elderly population already at high risk for thrombosis.

Adult↗
PubMed1996

Effect of density on age-specific mortality in Drosophila: a density supplementation experiment.

Age-specific mortality rates were studied at two adult density levels in four inbred lines of Drosophila melanogaster. In experimental populations, adult densities were maintained at constant levels throughout the experiment by replacing dead flies with live, marked mutants. In control populations, densities declined naturally as the cohorts aged. For all experimental populations the best mortality model is the two-stage Gompertz model, with slower mortality acceleration at older ages. Flies in the experimental populations generally lived longer than flies in control populations, regardless of sex, genotype, or initial density level. The data demonstrate that deceleration of age-specific mortality rates at older ages is not caused by declining cohort densities. Mortality deceleration is a real phenomenon that raises serious questions about the evolution of senescence.

Age Factors↗
PubMed1992

Epidemiological and biological study of acquired immunodeficiency syndrome-related lymphoma in the County of Los Angeles: preliminary results.

A population-based case control study of intermediate- and high-grade lymphoma in the County of Los Angeles, CA, was initiated in 1989. Human immunodeficiency virus (HIV)-positive lymphoma patients are compared to HIV-negative lymphoma patients, to HIV-positive controls with acquired immunodeficiency syndrome but without lymphoma, and to HIV-positive asymptomatic individuals. The HIV-negative lymphoma cases are compared to neighborhood controls, who are matched in terms of age, sex, race/ethnicity, and socioeconomic status. All cases are reviewed for pathology by a single group of pathologists. All cases and controls are studied for HIV, Epstein-Barr virus (EBV), and human herpesvirus 6 antigens and antibodies. Tissues from HIV-positive and -negative cases are studied for immunoglobulin gene rearrangement, presence of EBV and HIV, c-myc oncogene rearrangements, and karyotypic analysis. To date, with 294 lymphoma cases and 181 control cases interviewed, high-grade lymphoma has been diagnosed in 82% of the HIV-positive cases versus 40% of the HIV-negative cases (P = 0.001). Although elevated titers of EBV-viral capsid antigen were demonstrated in 82% of HIV-positive versus 50% of HIV-negative lymphoma cases, the geometric mean titer of EBV-viral capsid antigen is similar among HIV-positive lymphoma cases and HIV-positive controls. The geometric mean titer of human herpesvirus 6 antibodies was similar in HIV-positive and HIV-negative lymphoma cases and in the control populations. Monoclonality was demonstrated in all cases of lymphoma. EBV genome was demonstrated within lymphoma DNA in 68% of HIV-positive and 15% of HIV-negative lymphoma cases. Further study will be required to elucidate the full mechanisms of pathogenesis of the acquired immunodeficiency syndrome-related lymphomas.

Adolescent↗
PubMed2004

A study of environmental and behavioural factors that may be associated with feline idiopathic cystitis.

The cause of cystitis in many cats remains unknown. The aim of this study was to determine whether or not any environmental or behavioural factors, particularly those that could be considered potentially stressful, were associated with feline idiopathic cystitis (FIC). The questionnaire-based study involved comparing 31 cats with FIC to 24 cats in the same households that did not have cystitis. They were also compared with a control population of 125 clinically healthy cats. Compared with the live-in controls and the control population, the cats with FIC were significantly more likely to be male, overweight and pedigree. Several stress factors were found to be associated with FIC. The factor that stood out most prominently was living with another cat with which there was conflict. The findings support the hypothesis that stress may be implicated in some cases of FIC.

Animal Husbandry↗
PubMed2002

Prognostic value of the Duke treadmill score in the elderly.

OBJECTIVES: The purpose of this study was to test the hypothesis that the Duke treadmill score works less well for risk stratification in patients age 75 years or above. BACKGROUND: Although the Duke treadmill score is generally effective for risk stratification, its prognostic value in the elderly may be limited because they have a higher prevalence of coronary artery disease (CAD), more severe CAD and a lower exercise tolerance. METHODS: The study population consisted of 247 patients age 75 years or above, and the control population consisted of 2,304 patients below 75 years of age. All patients were symptomatic, had undergone exercise thallium testing between 1989 and 1991 and were followed for a median of >6.5 years. The Cox regression model was used to test the association of the Duke score (utilized both as a continuous variable and using previously published risk group cutoffs) with outcomes (cardiac death, nonfatal myocardial infarction [MI], late revascularization). RESULTS: Using the Duke score to risk-stratify the elderly, 26% were in the low risk group, 68% were in the intermediate risk group and 6% were in the high risk groups; seven-year cardiac survival was 86%, 85% and 69%, respectively (p = 0.45). There was also no significant association between these Duke score risk groups and all other outcome end points in the elderly. The Duke score as a continuous variable did not predict cardiac death (p = 0.43) or cardiac death or MI (p = 0.42), but did predict total cardiac events (which included late revascularization) (p = 0.0027). For the control population, more patients (55%) were in the low risk group, and the Duke score (as a continuous variable or in risk groups) was highly predictive of all end points (p = 0.0001). CONCLUSIONS: The Duke score predicted cardiac survival in younger patients but not in patients age 75 years or above. The majority of the elderly were classified as intermediate risk by the Duke score. Only a minority of the elderly were classified as low risk, but this group still had an annual cardiac mortality of 2%/year.

Age Factors↗
PubMed2000

Paraoxonase gene polymorphisms are associated with carotid arterial wall thickness in subjects with familial hypercholesterolemia.

Human serum paraoxonase (PON) is a high density lipoprotein (HDL) associated enzyme capable of hydrolyzing lipid peroxides in vitro. PON has recently attracted attention as a protective factor against oxidative modification of LDL and may therefore play an important role in the prevention of the atherosclerotic process. Two frequent mutations at the paraoxonase gene locus (PON1) are the leucine (L allele)-->methionine (M allele) and the glutamine (Q allele)-->arginine (R allele) substitutions at residues 55 and 192, respectively. We have examined the influence of these two polymorphisms on carotid atherosclerosis in familial hypercholesterolemia (FH) patients. The allele frequencies of these two polymorphisms were determined by PCR and restriction fragment analysis, for both the FH population and healthy controls. High resolution B-mode ultrasound was used to assess intima-media wall thickness (IMT) of the carotid artery. No differences were found in allele frequencies between the FH and the control population. In FH patients, the LL, LM and MM genotypes at position 55 occurred in 86 (46.0%), 78 (41.7%) and 23 (12.3%) subjects, respectively, whereas the QQ, QR and RR genotypes at position 192 were found in 90 (48.1%), 79 (42.2%) and 18 (9.6%) individuals. When both polymorphisms were considered separately, no different carotid IMTs were found between the genotype groups. However, our data did show a significant association between the various genotypes of the combined polymorphisms at position 55 and 192 of PON1 and the carotid artery IMT in FH subjects. Subjects with the homozygous wildtype LL/QQ for paraoxonase had the highest mean carotid IMTs when compared to other genotypes, combined. Multiple regression analysis demonstrated age (beta=0.34, P<0.0001), total plasma cholesterol (beta=0.17, P=0. 0109) and the LL/QQ genotype of the PON1 gene (beta=0.22, P=0.0018) to be significant risk factors for carotid atherosclerosis in subjects with FH. The LL/QQ genotype could explain 5.3% of total variance of carotid IMT. In conclusion, this is the first study to report an independent association between the combined PON1 polymorphism genotypes and carotid wall thickness. The homozygous wildtype LL/QQ for PON1 may represent an additional risk factor for carotid atherosclerosis in subjects with FH.

Adult↗
PubMed1992

Cereal fiber, calcium, and colorectal cancer.

Food intake during the preceding 15 years was evaluated in detail in 41 patients treated for colorectal cancer and an equal number of matched control subjects by means of a dietary history technique that permitted quantitation of nutrients. Dietary habits of the control group could be compared against two larger groups of 371 hospital control and 430 population control subjects. Patients with cancer, who were interviewed after complete recovery from surgery, consumed more fat, protein, and carbohydrates, and thus more energy, than control subjects although these differences were not statistically significant. Per unit energy, the habitual diet of patients with cancer contained less cereal fiber (P less than 0.001), less riboflavin (P less than 0.05), less calcium (P less than 0.05), and less phosphorus (P less than 0.05) than the diet of the control subjects. A high intake of either cereal fiber, total fiber, calcium, and phosphorus in relation to energy intake was found to be associated with a reduced risk ratio of colorectal cancer. For colon cancer separately, a high intake of calcium and cereal fiber was associated with a reduced risk ratio. For rectal cancer, a high intake of total fiber and cereal fiber was associated with a reduced risk ratio. High alcohol consumption correlated with an increased risk ratio. These data are compatible with previous Scandinavian studies relating food consumption to the incidence and mortality of colorectal cancer.

Aged↗
PubMed2004

Oesophageal and gastric bile exposure after gastroduodenal surgery with Henley's interposition or a Roux-en-Y loop.

BACKGROUND: The degree which the various reconstruction techniques prevent bile reflux after gastroduodenal surgery has been poorly studied. METHODS: Bile exposure in the intestinal tract just proximal to the jejunal loop was measured with the Bilitec 2000 device for 24 h after gastroduodenal surgery in three groups of patients. Group 1 comprised 24 patients with a 60-cm Henley's loop after total gastrectomy. Group 2 included 31 patients with a 60-cm Roux-en-Y loop after total (22 patients) or subtotal (nine) gastrectomy. Group 3 contained 21 patients with a 60-cm Roux-en-Y loop anastomosed to the proximal duodenum as part of a duodenal switch operation for pathological transpyloric duodenogastric reflux. Bile exposure, measured as the percentage time with bile absorbance greater than 0.25, was classified as nil, within the range of a control population of healthy subjects, or pathological (above the 95th percentile for the control population). Reflux symptoms were scored and all patients had upper gastrointestinal endoscopy. RESULTS: Bile was detected in the intestine proximal to the loop in none of 24 patients in group 1, eight of 31 in group 2 and 12 of 21 in group 3 (P < 0.001). The mean reflux symptom score increased with the degree of bile exposure, and the proportion of patients with oesophagitis or gastritis correlated well with the extent of bile exposure (P < 0.001). CONCLUSION: A long Henley's loop was more effective in preventing bile reflux than a long Roux-en-Y loop. Bilitec data correlated well with the severity of reflux symptoms and the presence of mucosal lesions.

Adolescent↗
PubMed1989

Patterns of familial transmission of HBV and the risk of developing liver cancer: a case-control study in the Philippines.

The present case-control study was carried out in the Philippines to determine the risk of developing hepatocellular carcinoma (HCC) in relation to different HBV serological profiles of parents and sibs of HCC cases and controls. The HBV serological profiles of parents and sibs of 33 patients with HCC were compared with those of 2 types of community control: 33 general population controls matched for sex and age (C1 controls) and 33 asymptomatic HBsAg carriers also matched for sex and age (C2 controls). When cases were compared with C1 controls, increased risks were associated with the fact of having an HBsAg-positive mother (RR = 2.5, 95% C1 = 0.4-26.3) and older sibs positive for HBsAg (RR = 2.0, 95% C1 = 0.5-9.1), but the increased risk was not statistically significant. However, a significantly increased risk was associated with the fact of having a mother (95% C1 = 3.5-infinity) or father (RR = 11, 95% C1 = 1.6-473) who had been exposed to HBV. On the other hand, when cases were compared with C2 controls, a non-significant 2-fold increase was associated with the fact of having an HBsAg-positive mother, but no differences were observed in the HBV serological profiles of their fathers and older sibs. These results suggest that, in the Philippines, the fact of having a mother or father who has been infected in the past with HBV increases the risk of developing HCC but that the contribution of the mother to this increase in risk is not as important as hitherto believed.

Female↗
PubMed2001

Evolution of faster development does not lead to greater fluctuating asymmetry of sternopleural bristle number in Drosophila.

Both strong directional selection and faster development are thought to destabilize development, giving rise to greater fluctuating asymmetry (FA), although there is no strong empirical evidence supporting this assertion. We compared FA in sternopleural bristle number in four populations of Drosophila melanogaster successfully selected for faster development from egg to adult, and in four control populations. The fraction of perfectly symmetric individuals was higher in the selected populations, whereas the FA levels did not differ significantly between selected and control populations, clearly indicating that directional selection for faster development has not led to increased FA in sternopleural bristle number in these populations. This may be because: (i) development time and FA are uncorrelated, (ii) faster development does result in FA, but selection has favoured developmentally stable individuals that can develop fast and still be symmetrical, or (iii) the increased fraction of symmetric individuals in the selected populations is an artifact of reduced body size. Although we cannot discriminate among these explanations, our results suggest that the relationship between development time, FA and fitness may be far more subtle than often thought.

Animals↗