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PubMed1998

Can behavioral risk factors explain the difference in body mass index between African-American and European-American women?

African-American women are heavier than European-American women; the reasons are unknown. The purpose of this study was to examine potentially modifiable reasons for the weight difference among 86,326 female nurses. The determinants of body mass index (BMI) were modelled using the method of linear regression. The findings included the following: mean BMI (kg/m2) was 9.0% (95% CI, 7.8-10.1%) higher among African American (27.3) than among European-American women (25.1) (P<0.0001). However, recalled BMI at age 18 was equal in the two groups (21.4, P=0.98). Multivariate determinants of BMI include age, age 18 BMI, alcohol and calorie intake, exercise, marital status, parity, race, recent intentional weight loss, smoking, and television watching. Even after controlling for these factors, African-American women still had an 8.6% (95% CI, 7.7-9.5%) higher BMI than European-American women. Correction for error in measurement of physical activity attenuated this difference to 6.4% (95% CI, 5.0-7.8%). In conclusion, in this single occupation group, African-American women had a significantly higher BMI than European-American women. Age and measured behavioral factors did not explain this difference. However, imprecision in the measurement of diet and activity may explain this difference in part. Better measurement may help quantify the differences that are as yet unexplained.

Adolescent↗

PubMed2026

Comprehensive Evaluation and Explainable Interpretation of Peptide-HLA Binding Prediction Tools.

Accurate prediction of peptide binding to human leukocyte antigen class I (HLA-I) molecules is critical for advancing immunological research, particularly in vaccine design and immunotherapy. However, limitations in model performance, interpretability, and dataset quality impede the widespread adoption of existing predictive tools. Here, we present a comprehensive evaluation of 17 HLA-I peptide binding prediction models, utilizing a meticulously curated dataset comprising over 290,000 peptides spanning 44 HLA-I alleles. We assessed model accuracy, robustness, and interpretability, employing explainability techniques such as SHAP (SHapley Additive exPlanations) and LIME (Local Interpretable Model-agnostic Explanations) to elucidate underlying prediction mechanisms. Our results reveal substantial performance disparities, with self-attention-based models, including STMHCpan and BigMHC, exhibiting superior accuracy. Notably, the capsule network model CapsNet-MHC_AN demonstrated robust performance. Models trained on eluted ligand datasets outperformed those relying on binding affinity data, underscoring the critical role of high-quality training data. Ensemble and multi-algorithm approaches further improved prediction reliability. These findings highlight the need for ongoing innovation in model architecture, integration of diverse and high-quality datasets, and incorporation of structural predictors to develop more accurate, interpretable, and clinically applicable HLA-I peptide binding prediction tools.

HLA-I binding↗

PubMedDate not supplied

Better psychological functioning and higher social status may largely explain the apparent health benefits of wine: a study of wine and beer drinking in young Danish adults.

BACKGROUND: Findings from a recent series of Danish studies suggest that moderate wine drinkers are healthier than those who drink other alcoholic beverages or those who abstain. OBJECTIVE: To identify possible explanatory factors associated with the health benefits of wine consumption through the examination of a wide spectrum of social, cognitive, and personality characteristics related to both beverage choice and health in young Danish adults. SUBJECTS AND METHODS: Descriptive cross-sectional study of characteristics associated with beverage choice in a sample of 363 men and 330 women between the ages of 29 and 34 years, selected from the Copenhagen Perinatal Cohort on the basis of perinatal records. MAIN OUTCOME MEASURES: Socioeconomic status, education, IQ, personality, psychiatric symptoms, and health-related behaviors, including alcohol consumption, were analyzed. The outcome variables were subjected to linear and logistic regression analyses with 2 factors (beer and wine), each with 2 levels (drinking or not drinking a certain beverage type). RESULTS: Wine drinking was significantly associated with higher IQ, higher parental educational level, and higher socioeconomic status. Beer drinking was significantly associated with lower scores on the same variables. On scales concerning personality, psychiatric symptoms, and health-related behaviors, wine drinking was associated with optimal functioning and beer drinking with suboptimal functioning. CONCLUSIONS: Our data demonstrate that wine drinking is a general indicator of optimal social, cognitive, and personality development in Denmark. Similar social, cognitive, and personality factors have also been associated with better health in many populations. Consequently, the association between drinking habits and social and psychological characteristics, in large part, may explain the apparent health benefits of wine.

Adult↗

PubMed1990

Racial differences in the anterior circulation in cerebrovascular disease. How much can be explained by risk factors?

The entry characteristics of 1367 patients enrolled into the Extracranial/Intracranial Bypass Study were examined to determine if site differences in intracranial and extracranial arterial lesions among racial groups could be explained by differences in risk factors. Blacks were more often hypertensive, diabetic, or cigarette smokers, while whites had higher systolic blood pressure and hemoglobin values. Orientals had the lowest prevalence of vascular risk factors. Despite these differences in risk factors, multivariate analysis showed race to be an independent and strong predictor of the location of cerebrovascular lesions. To our knowledge, this study is unique in documenting risk factors prospectively and systematically in three racial groups simultaneously. Although generalization is limited by possible biases related to patient selection, the results affirm previous tentative conclusions about the role of race in determining the location of cerebrovascular disease.

Asian People↗

PubMed2006

Role of genes and environments for explaining Alzheimer disease.

CONTEXT: Twin studies using selected samples have shown high heritability for Alzheimer disease (AD). OBJECTIVE: To evaluate genetic and environmental influences on AD in a fully ascertained population of older twins, including like- and unlike-sex pairs. DESIGN: Five-group quantitative genetic model: male monozygotic twins, female monozygotic twins, male dizygotic twins, female dizygotic twins, and unlike-sex twins. SETTING AND PARTICIPANTS: All twins in the Swedish Twin Registry aged 65 years and older. The study included 11,884 twin pairs, among whom were 392 pairs in which 1 or both members had AD. MAIN OUTCOME MEASURES: All individuals were screened for cognitive dysfunction. Suspected cases of dementia and their co-twins received complete clinical diagnostic evaluations for AD. Estimates of heritability, shared environmental influences, and nonshared environmental influences, adjusting for age, were derived from the twin data. RESULTS: Heritability for AD was estimated to be 58% in the full model and 79% in the best-fitting model, with the balance of variation explained by nonshared environmental influences. There were no significant differences between men and women in prevalence or heritability after controlling for age. Within pairs concordant for AD, intrapair difference in age at onset was significantly greater in dizygotic than in monozygotic pairs, suggesting genetic influences on timing of the disease. CONCLUSIONS: In the largest twin study to date, we confirmed that heritability for AD is high and that the same genetic factors are influential for both men and women. However, nongenetic risk factors also play an important role and might be the focus for interventions to reduce disease risk or delay disease onset.

Age of Onset↗

PubMed1991

Tumor necrosis factor alone does not explain the lethal effect of lipopolysaccharide.

Lethality and tumor necrosis factor production induced by different types of lipopolysaccharide were studied in naive (non-primed) rats during the late phase of endotoxin tolerance. The correlation with antilipopolysaccharide antibodies was also analyzed. No correlation was found between tumor necrosis factor levels and lipopolysaccharide-induced mortality in naive animals. Low-toxicity lipopolysaccharide preparations induced levels of tumor necrosis factor similar to those induced with more toxic types of lipopolysaccharide. Late tolerance was associated with progressively lower levels of lipopolysaccharide-induced tumor necrosis factor and increasing titers of antilipopolysaccharide antibodies after repeated injections of homologous lipopolysaccharide. During late endotonxin tolerance, a direct correlation between the lipopolysaccharide dose and peak tumor necrosis factor serum levels was found. We conclude that since tumor necrosis factor serum levels do not correlate with mortality, tumor necrosis factor alone cannot explain the lethal effect of lipopolysaccharide.

Animals↗

PubMed1996

Racial factors cannot explain superior Japanese outcomes in stomach cancer.

OBJECTIVE: To compare the stage-stratified survival of Japanese patients treated in Honolulu according to Western techniques with that of Japanese patients treated in Tokyo according to Japanese techniques, thus eliminating race as a potentially confounding variable. DESIGN AND PATIENTS: Of 312 Honolulu Japanese patients surviving Western-type gastric resection for neoplasm between 1974 and 1985, 279 were identified with invasive gastric adenocarcinoma unassociated with any second malignancy. This Honolulu cohort, treated by Western methods, was retrospectively compared with a similar, previously described cohort of 3176 Tokyo Japanese patients treated according to Japanese methods. MAIN OUTCOME MEASURES: American Joint Committee on Cancer/Union Internationale Contre le Cancer criteria for stage-stratified survival. RESULTS: Despite non-TNM prognostic factors favoring higher survival for the Honolulu Japanese patients, for every TNM stage, we observed higher survival for the Tokyo Japanese patients who were treated according to Japanese techniques. For stage I disease, the survival rates were 86% vs 96%, respectively (P < .001); for state II, 69% vas 77% (P = .15); for stage III, 21% vs 49% (P < .001); and for stage IV, 4% vs 14% (P < .001). CONCLUSIONS: Because all patients in this study are Japanese, race-related factors or the "different-disease" hypothesis cannot explain these results. Lymphadenectomy-related stage-migration and/or differing therapeutic efficacy seem more likely explanations.

Adenocarcinoma↗

PubMed1996

"Shifted" threshold may explain diversity of cardiovascular malformations in multiple congenital abnormalities syndromes: 3C (Ritscher-Schinzel) syndrome as an example.

The analysis of cardiovascular malformations (CVM) in 3C (Ritscher-Schinzel) syndrome showed at least 9 types of CVM in 24 cases, including 4 cases from the Baltimore-Washington Infant Study. The proportion of different CVM forms was similar to that of the general population. The same is also true for many other syndromes of multiple congenital abnormalities (MCA), due either to aneuploidy or to Mendelian mutation. Such a wide spectrum of very different CVM in patients with the same entity has yet to be explained. According to the hypothesis proposed, the basic mutation (or chromosome imbalance) affects cellular homeostasis and leads to the "shifting" of a threshold to the left. This allows the expression of some genes silent under normal conditions. The principle of the shifted threshold is applicable to the explanation of the origin of many other defects in MCA syndromes.

Abnormalities, Multiple↗

PubMed1999

Paradominant inheritance, a hypothesis explaining occasional familial occurrence of sporadic syndromes.

Heterozygous individuals carrying a "paradominant" mutation, as a rule, are phenotypically normal. Therefore, the mutation can be transmitted unperceived through many generations. The trait becomes manifest when a somatic mutation occurs during embryogenesis giving rise to loss of heterozygosity and forming a mutant cell population, being either homozygous or hemizygous for the mutation. This concept explains the occasional familial occurrence of usually sporadic traits like the Klippel-Trenaunay syndrome and others.

Genes, Dominant↗

PubMed1997

A disulfide bridge near the active site of carbapenem-hydrolyzing class A beta-lactamases might explain their unusual substrate profile.

Bacterial resistance to beta-lactam antibiotics, a clinically worrying and recurrent problem, is often due to the production of beta-lactamases, enzymes that efficiently hydrolyze the amide bond of the beta-lactam nucleus. Imipenem and other carbapenems escape the activity of most active site serine beta-lactamases and have therefore become very popular drugs for antibacterial chemotherapy in the hospital environment. Their usefulness is, however, threatened by the appearance of new beta-lactamases that efficiently hydrolyze them. This study is focused on the structure and properties of two recently described class A carbapenemases, produced by Serratia marcescens and Enterobacter cloacae strains and leads to a better understanding of the specificity of beta-lactamases. In turn, this will contribute to the design of better antibacterial drugs. Three-dimensional models of the two class A carbapenemases were constructed by homology modeling. They suggested the presence, near the active site of the enzymes, of a disulfide bridge (C69-C238) whose existence was experimentally confirmed. Kinetic parameters were measured with the purified Sme-1 carbapenemase, and an attempt was made to explain its specific substrate profile by analyzing the structures of minimized Henri-Michaelis complexes and comparing them to those obtained for the "classical" TEM-1 beta-lactamase. The peculiar substrate profile of the carbapenemases appears to be strongly correlated with the presence of the disulfide bridge between C69 and C238.

Amino Acid Sequence↗

PubMed1999

Macroscopic growth of filamentous fungi on solid substrate explained by a microscopic approach.

A quantitative model predicting biomass growth on solid media has been developed. The model takes into account steric interactions between hyphae and tips at the microscopic level (competition for substrate and tip-hypha collisions). These interactions effect a slowing down of the hyphal, population-averaged extension rate and are responsible, at the microscopic level, for the distribution of tip orientations observed at the colony border. At the macroscopic level, a limiting value of the colony radial extension rate is attained. A mathematical model that combines hyphal branching, tip diffusion, and biomass growth was proposed to explain such behavior. Experiments using Gibberella fujikuroi were performed to validate the model; good agreement between experiments and simulations was achieved. Most parameters can be measured by simple image analysis on the peripheral growth zone, and they have clear physical meaning; that is, they correspond to properties of single, leading hyphae. The model can be used to describe two-dimensional (2D) solid media fermentation experiments under varying culture conditions; the model can also be extended to consider growth in three-dimensional (3D), complex geometry substrates.

Biomass↗

PubMed1996

Could preferential prescribing and referral behaviour of physicians explain the elevated thrombosis risk found to be associated with third generation oral contraceptives?

BACKGROUND: Recently published case-control studies on third versus second generation oral contraceptives showed a slightly increased risk for venous thromboembolism (VTE) and led to a discussion about biases or confounders external to the study such as, preferential prescribing of third generation pills to women at higher risk and differential diagnostic behaviour. METHODS: An interview survey with 102 physicians was performed in 2 weeks of December 1995 in Germany and 1209 of their patients were included in a retrospective cohort analysis of drug utilization and risk markers. RESULTS: German physicians previously preferred to prescribe third generation pills whenever an increased risk was perceived, i.e. risk for VTE and for arterial thrombosis (risk factors, personal or family history of cardiovascular diseases). Almost all predefined risk scenarios were associated with an increased attention to non-specific venous symptoms and patients were more frequently sent for intensive diagnostic search for venous thromboses. The behaviour was not directly dependent on the type of OC; however the third generation pills were indirectly associated with higher risk in the pill-taking women. The physicians' view was confirmed by the analysis of the cohorts of patients: preferential prescribing was also found in this data set, although it was not as impressive as in the physicians responses. CONCLUSION: The possibility cannot be excluded that preferential prescribing and differential diagnostic behaviour alone could have explained the roughly two-fold increased odds ratios from case-control studies recently published, had this information been available among the study variables.

Journal Article↗

PubMed2000

Anti-SSA/Ro52 autoantibodies blocking the cardiac 5-HT4 serotoninergic receptor could explain neonatal lupus congenital heart block.

The 52-kDa SSA/Ro (Ro52) ribonucleoprotein is an antigenic target strongly associated with the autoimmune response in mothers whose children develop neonatal lupus and congenital heart block. When sera from patients with systemic lupus erythematosus were used as autoimmune controls in an enzyme immunoassay to screen for antibodies against the human serotoninergic 5-HT4-receptor, a high correlation was found between the presence of anti-Ro52 protein antibodies in such sera and antibodies reacting with a synthetic peptide, corresponding to the second extracellular loop of the human 5-HT4 receptor (amino acid residues 165-185). Homology scanning between the 5-HT4 peptide and the sequence of the Ro52 protein indicated two potential common epitopes located between residues 365 and 396 of the Ro52 protein. Cross-reactivity was found between the peptide derived from the 5-HT4 receptor, and a peptide corresponding to residues 365-382 of the Ro52 protein. Autoantibodies, affinity-purified on the 5-HT4 receptor peptide, specifically recognized both the Ro52 protein and the 5-HT4 receptor protein in immunoblots. The affinity-purified antibodies antagonized the serotonin-induced L-type Ca channel activation on human atrial cells. This effect could explain the electrophysiological abnormalities in neonatal lupus.

Adult↗

PubMed2000

The disease process and utilization of health services in rheumatoid arthritis: the relative contributions of various markers of disease severity in explaining consumption patterns.

OBJECTIVE: To examine the predictive ability of a wide array of measures of disease severity in explaining Dutch and German patterns of health services utilization during a 2-year period. METHODS: Slightly over 200 rheumatoid arthritis (RA) patients, 136 from a Dutch and 98 from a German outpatient clinic, supplied information on symptom and functional status, global health, and emotional and social functioning at baseline. The patients' rheumatologists provided clinical assessments of functional grade and disease activity. A questionnaire mailed twice at 12-month intervals was the source of retrospective information on physician consultations, hospitalization, and referrals for surgery and physical therapy during the previous period. Major determinants of use were studied with multivariate analyses. RESULTS: German patients reported more frequent physician contacts than Dutch patients, but the volume of surgery, hospital admissions, and referrals for physical therapy did not differ between the two countries. In a hierarchical regression, the consultation rate was directly associated with pain quality and global health. Markers of RA progression were related to surgery, and the latter to volume of in-hospital care. Fatigue severity and physical disability predicted referrals for physical therapy. Patient self-management activities were only weakly associated with disease severity variables. CONCLUSION: The activity and damage components of RA were related to the separate components of total health service utilization. Disease activity was the prime determinant of physician services used, and RA progression the determinant of surgical interventions and hospitalization.

Activities of Daily Living↗

PubMed1992

Diffusion or autocatalysis of retinoic acid cannot explain pattern formation in the chick wing bud.

We have collected several experimental data of pattern duplications due to the ZPA transplantation or application of retinoic acid on the developing chick limb bud. We have compared these data with the predictions of models based on diffusion or autocatalysis of retinoids. It turns out that these models cannot comprehensively explain the data. More specifically, retinoic acid cannot be either diffusing from a ZPA source or participate in an autocatalytic gradient formation.

Animals↗

PubMed1993

Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes.

Investigation of red blood cells from beta-thalassemia patients by means of prothrombinase assay reveals phosphatidylserine in the outer leaflet of the plasma membrane. This might explain their elevated susceptibility to phagocytosis by macrophages and the chronic hypercoagulable state, frequent thrombotic events, and life-long platelet activation that are found in thalassemic patients.

Blood Coagulation Disorders↗

PubMedDate not supplied

Cardiovascular factors explain genetic background differences in VO2max.

The purpose of this study was to further explore factors that may be related to ethnic differences in the maximum rate at which an individual can consume oxygen (VO2max) between 20 African American (AA) and 30 European American (EA) sedentary women who were matched for body weight (kg) and fat-free mass (FFM). VO2max (l/min) was determined during a graded treadmill exercise test. Submaximal steady-state heart rate and submaximal VO2 were determined at a treadmill speed of 1.3 m/sec and a 2.5% grade. Hemoglobin (Hb) was determined by the cyanide method, muscle oxidative capacity by 31P magnetic resonance spectroscopy (ADP time constant), and FFM (kg) by dual-energy x-ray absorptiometry. Genetic classification was self-reported, and in a subset of the sample (N = 32), the determinants of ethnicity were measured by African genetic admixture. AA women had significantly reduced VO2max, Hb levels, and muscle oxidative capacity (longer ADP time constants, P < or = 0.05) than EA women. Submaximal oxygen pulse (O2Psubmax), ADP time constant, Hb, and ethnic background were all significantly related to VO2max (ml/kg/min and ml/kg FFM/min, all P < or = 0.01). By multiple regression modeling, Hb, O2Psubmax, muscle oxidative capacity, and ethnicity were found to explain 61% and 57% of the variance of VO2max in ml/kg/min and ml/kg FFM/min, respectively. Muscle oxidative capacity and O2Psubmax were both significantly and independently related to VO2max in all three models (P < or = 0.05), whereas Hb and ethnicity were not. These results suggest that mitochondrial muscle oxidative capacity and oxygen delivery capabilities, as determined by O2Psubmax, account for most if not all of the ethnic differences in VO2max.

Adenosine Diphosphate↗

PubMed1985

A premutation that generates a defect at crossing over explains the inheritance of fragile X mental retardation.

The view that the Martin-Bell syndrome (X-linked mental retardation with fragile site at Xq27/8) is inherited in a regular X-linked fashion is becoming untenable with the increasing number of reports of transmission through phenotypically normal males. Analysis of the published pedigrees containing such males shows that their heterozygous daughters are never mentally retarded, and have either no fragile site or very few indeed. By contrast, in the next generation, a third of the female heterozygotes are mentally subnormal with an average of 29% fragile sites. These data suggest a premutation that generates the definitive mutation only when transmitted by a female. We propose an inherited sub-microscopic chromosome rearrangement involving the Xq27/8 region that causes no ill effect per se, but generates a significant genetic imbalance when involved in a recombination event with the other X chromosome. This hypothesis explains many of the puzzling genetic aspects of the Martin-Bell syndrome, but it also complicates the interpretation of linkage analysis with genetic markers.

Crossing Over, Genetic↗