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PubMed2006

Oxidation-resistant membrane phospholipids can explain longevity differences among the longest-living rodents and similarly-sized mice.

Underlying causes of species differences in maximum life span (MLS) are unknown, although differential vulnerability of membrane phospholipids to peroxidation is implicated. Membrane composition and longevity correlate with body size; membranes of longer-living, larger mammals have less polyunsaturated fatty acid (PUFA). We determined membrane phospholipid composition of naked mole-rats (MLS > 28.3 years) and similar-sized mice (MLS = 3-4 years) by gas-liquid chromatography to assess if the approximately 9x MLS difference could be explained. Mole-rat membrane composition was unchanged with age. Both species had similar amounts of membrane total unsaturated fatty acids; however, mice had 9 times more docosahexaenoic acid (DHA). Because this n-3PUFA is most susceptible to lipid peroxidation, mole-rat membranes are substantially more resistant to oxidative stress than are mice membranes. Naked mole-rat peroxidation indices, calculated from muscle and liver mitochondrial membranes, concur with those predicted by MLS rather than by body size, suggesting that membrane phospholipid composition is an important determinant of longevity.

Animals↗

PubMed2004

Can culture help explain the physical health effects of caregiving over time among African American caregivers?

OBJECTIVES: The purposes of this study were to longitudinally examine the health outcomes of 107 African American caregivers who provided care to their elderly dependent family members and to determine the role of culture in predicting health outcomes. METHODS: With use of the stress and coping model of Pearlin and colleagues (1990) as a guide, the direct effects of background characteristics and stressors and the direct and mediating effects of resources (including culture) on two caregiver health outcomes (i.e., psychosocial health and physical functioning) were analyzed with hierarchical multiple regression analyses. RESULTS: Similar to other studies, we found that combinations of caregiver background characteristics, stressors, and resources at wave 1 had direct effects on African American caregivers' health outcomes at wave 3. Unlike previous studies, where culture was not measured, we found that cultural beliefs and values did help to explain health outcomes for African American caregivers. Specifically, culture justifications for caregiving, baseline psychosocial health, and caregiving mastery predicted wave 3 psychosocial health. Caregiver education, number of morbidities, and physical functioning at wave 1 were associated with physical functioning at wave 3. DISCUSSION: The findings from this study have implications for future studies, particularly in regard to cultural beliefs and values among African American caregivers.

Black or African American↗

PubMed2001

Explaining discrepancies in reproductive health indicators from population-based surveys and exit surveys: a case from Rwanda.

OBJECTIVES: Reproductive health programmes often need exit surveys and population-based surveys for monitoring and evaluation. This study investigates why such studies produce discrepant estimates of condom use, sexual behaviour and condom brand knowledge, and discusses the implications for future use of exit surveys for programme monitoring. METHODS: Logistic regression is used to explain differences between a household survey of 1295 persons and an exit survey among a random sample of 2550 consumers at retail outlets in RWANDA: RESULTS: Discrepancies in ever use of condoms and risky sexual behaviours are due to differences in socioeconomic status of the two samples. After controls, exit surveys at most outlet types have the same results as the household survey. Only exit surveys at bars, nightclubs and hotels yield significantly different estimates. However, the above-average knowledge of Prudence Plus condoms in the exit interviews is not attributable to socioeconomic or demographic variables, most likely because respondents have seen the product at the outlets. CONCLUSIONS: Information about condom use and sexual behaviour obtained from exit surveys appears as accurate as that obtained through household surveys. Nevertheless, exit surveys must be used cautiously. Because exit surveys may include wealthier and better-educated respondents, they are not representative of the general population. The composition of exit survey samples should be validated through existing household surveys. Comparisons across survey types are generally unadvisable, unless they control for sample differences. When generalizing to the population at large is not needed (e.g. for studies aimed at identifying the characteristics and behaviour of users of particular products or services), exit surveys can provide an appropriate alternative to household surveys.

Adolescent↗

PubMed2002

Heteroligomerization of an Aquaporin-2 mutant with wild-type Aquaporin-2 and their misrouting to late endosomes/lysosomes explains dominant nephrogenic diabetes insipidus.

Autosomal nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin, is caused by mutations in the Aquaporin-2 (AQP2) gene. Analysis of a new family with dominant NDI revealed a single nucleotide deletion (727deltaG) in one AQP2 allele, which encoded an AQP2 mutant with an altered and extended C-terminal tail. When expressed in oocytes, the tetrameric AQP2-727deltaG was retained within the cell. When co-expressed, AQP2-727deltaG, but not a mutant in recessive NDI (AQP2-R187C), formed hetero-oligomers with wild-type (wt) AQP2 and reduced the water permeability of these oocytes, because of a reduced plasma membrane expression of wt-AQP2. Expressed in renal epithelial cells, AQP2-727deltaG predominantly localized to the basolateral membrane and late endosomes/lysosomes, whereas wt-AQP2 was expressed in the apical membrane. Upon co-expressing in these cells, wt-AQP2 and AQP2-727deltaG mainly co-localized to late endosomes/lysosomes. In conclusion, hetero-oligomerization of AQP2-727deltaG with wt-AQP2 and consequent mistargeting of this complex to late endosomes/lysosomes results in absence of AQP2 in the apical membrane, which can explain dominant NDI in this family. Together with other mutants in dominant NDI, our data reveal that a misrouting, instead of a lack of function, is a general mechanism for the 'loss of function' phenotype in dominant NDI and visualizes for the first time a mislocalization of a wild-type protein to late endosomes/lysosomes in polarized cells after oligomerization with a mutant protein.

Amino Acid Sequence↗

PubMed2003

Identification of SLURP-1 as an epidermal neuromodulator explains the clinical phenotype of Mal de Meleda.

Mal de Meleda is an autosomal recessive inflammatory and keratotic palmoplantar skin disorder due to mutations in the ARS B gene, encoding for SLURP-1 (secreted mammalian Ly-6/uPAR-related protein 1). SLURP-1 belongs to the Ly-6/uPAR superfamily of receptor and secreted proteins, which participate in signal transduction, immune cell activation or cellular adhesion. The high degree of structural similarity between SLURP-1 and the three fingers motif of snake neurotoxins and Lynx1 suggests that this protein interacts with the neuronal acetylcholine receptors. We found that SLURP-1 potentiates the human alpha 7 nicotinic acetylcholine receptors that are present in keratinocytes. These results identify SLURP-1 as a secreted epidermal neuromodulator which is likely to be essential for both epidermal homeostasis and inhibition of TNF-alpha release by macrophages during wound healing. This explains both the hyperproliferative as well as the inflammatory clinical phenotype of Mal de Meleda.

Acetylcholine↗

PubMed1985

Major colorectal cancer aetiological hypotheses do not explain mortality trends among Maori and non-Maori New Zealanders.

New Zealand colorectal cancer mortality rates are presented for the period 1947-1980. Mortality has been increasing and is now the highest in the world for both males and females in the age range 35-64; indeed New Zealand mortality rates for those aged 35-44 are approximately twice those of other countries with high mortality. By contrast, colorectal cancer mortality rates among Maoris, the indigenous New Zealanders of Polynesian descent, have been decreasing so that they are now less than half the non-Maori mortality rates. These findings cannot be explained by ethnic differences in consumption of the major proposed dietary risk factors: total fat, cholesterol, meat, fibre and beer. Possible differences in the prevalence of lactose malabsorption, in faecal mutagen activity, and in the prevalence of colorectal polyps warrant further investigation.

Adult↗

PubMed1992

Are race differences in the prevalence of hypertension explained by body mass and fat distribution? A survey in a biracial population.

Body mass and body fat distribution are important considerations in the study of hypertension. However, few studies have investigated the relationships with regards to race differences in elevated arterial pressure. A population-based sample of black and white adults was assessed by interview and physical measurement. The prevalence of hypertension (defined as 140/90 mmHg and/or medically treated) was disproportionately higher among blacks than whites. In addition, blacks had a higher prevalence of the more severe hypertension (160/95 mmHg) and hypertension with higher prevalence at earlier ages than whites. Black females had a significantly higher distribution of body mass index (BMI) than white females, while no difference was found in the distributions of males. White males had a higher distribution of waist to hip ratio (WHR) than black males, while black females had the higher values compared to white females. The prevalence of hypertension increased with BMI and WHR. Blacks maintained higher rates of hypertension after controlling for BMI and WHR, however, the margin of difference diminished when BMI and WHR was considered together. The black-white difference in hypertension was not completely explained by BMI and WHR. In addition, the strength of the association of hypertension and body size was different for blacks and whites which suggests possible differences in the mechanisms regulating blood pressure.

Adipose Tissue↗

PubMed1999

Increased risk of fatal prostate cancer may explain the rise in mortality in The Netherlands.

BACKGROUND: Several lines of evidence suggest that, as a result of improved diagnostic techniques, the increase in incidence of prostate cancer is due largely to increased detection of subclinical cases. Between 1971 and 1989, a considerable increase in incidence was found in Southeastern Netherlands among men aged under 60 years without an improvement in prognosis. We hypothesized that in addition to the increase due to increased detection, a genuine increase in incidence has occurred in the last two decades and that this should be reflected in national mortality rates. METHODS: Age-specific and age-adjusted mortality rates were calculated to determine whether mortality due to prostate cancer continued to increase after 1990. Using log-linear Poisson modelling according to Clayton and Schifflers, we estimated the contribution of period and cohort effects to prostate cancer mortality between 1955 and 1994. RESULTS: The age-adjusted mortality increased from 22 in 1955-1959 to 33 per 10(5) in 1990-1994 (European standardized rate). For men under 65, the rates stabilized after 1989. The age-cohort model fitted the data better than the age-period model. Therefore, the increase in mortality can be explained largely by the increasing risk for successive birth cohorts for men born until 1930. However, more frequent reporting of prostate cancer as the underlying cause of death (partly attributable to a decline in competing causes of death) may have occurred as well. CONCLUSIONS: Our findings suggest an increased risk of fatal prostate cancer in The Netherlands between 1955 and 1994.

Aged↗

PubMed2001

Can inaccuracy of reported parental history of diabetes explain the maternal transmission hypothesis for diabetes?

BACKGROUND: The mode of inheritance of type 2 diabetes mellitus is still under discussion. Several studies have suggested an excess maternal transmission, however, more recent studies could not always confirm these findings. METHODS: We investigated the frequency of a maternal and paternal history of diabetes among diabetic and non-diabetic subjects and assessed the association between diabetes and a parental history of diabetes among participants of the MONICA Augsburg study. As an extension to previous studies, unknown parental status was taken into account. RESULTS: Of the 542 diabetic probands, 25.3% reported a positive maternal history of diabetes and 10.9% reported a positive paternal history of diabetes. Among the 12,209 non-diabetic participants a positive maternal history was also more common than a positive paternal history (12.5% versus 7.1%). Conversely, an unknown paternal status was more common than an unknown maternal status in both groups (diabetic subjects: 27.9% versus 16.8%, non-diabetic subjects: 16.8% versus 8.4%). Adjusted odds ratios (OR) for the association between a parental history of diabetes and diabetes status were similar for a positive maternal (OR = 2.9, 95% CI : 2.3-3.6) and paternal history (OR = 2.8, 95% CI : 2.1-3.8) and for an unknown maternal (OR = 1.3, 95% CI : 1.0-1.8) and paternal history (OR = 1.5, 95% CI : 1.2-1.9). CONCLUSION: Our findings do not support a strong excess maternal transmission of diabetes. Epidemiological biases and failure to account for 'don't know' responses may in part explain the previously observed predominance of a maternal history of diabetes.

Bias↗

PubMed1999

Demographic, dietary and lifestyle factors differentially explain variability in serum carotenoids and fat-soluble vitamins: baseline results from the sentinel site of the Olestra Post-Marketing Surveillance Study.

Biochemical measures of nutrients or other dietary constituents can be an important component of nutritional assessment and monitoring. However, accurate interpretation of the nutrient concentration is dependent on knowledge of the determinants of the body pool measured. The purpose of this study was to identify the determinants of serum carotenoid and fat-soluble vitamin concentrations in a large, community-based sample (n = 1042). Multiple linear regression analysis was used to examine effects of demographic characteristics (age, sex, race/ethnicity, education), health-related behavior (exercise, sun exposure, smoking, alcohol consumption), and intake (diet, supplements) on serum retinol, 25-hydroxyvitamin D, alpha-tocopherol, phylloquinone, and carotenoid concentrations. Age, sex, race/ethnicity, vitamin A intake, and alcohol consumption were found to be determinants of serum retinol concentration. Race/ethnicity, vitamin D intake, body mass index, smoking status, and sun exposure were determinants of serum 25-hydroxyvitamin D concentration. Determinants of serum alpha-tocopherol were age, sex, race/ethnicity, alpha-tocopherol intake, serum cholesterol, percentage of energy from fat (inversely related), supplement use, and body mass index. Age, sex, phylloquinone intake, serum triglycerides, and supplement use were determinants of serum phylloquinone concentration. Primary determinants of serum carotenoids were age, sex, race/ethnicity, carotenoid intake, serum cholesterol, alcohol consumption, body mass index, and smoking status. Overall, the demographic, dietary, and other lifestyle factors explained little of the variability in serum concentrations of retinol (R2 = 0.20), 25-hydroxyvitamin D (R2 = 0.24), and the carotenoids (R2 = 0.15-0.26); only modest amounts of the variability in serum phylloquinone concentration (R2 = 0.40); and more substantial amounts of the variability in serum alpha-tocopherol concentration (R2 = 0.62).

Adult↗

PubMed2004

Asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, explains the "L-arginine paradox" and acts as a novel cardiovascular risk factor.

There is abundant evidence that the endothelium plays a crucial role in the maintenance of vascular tone and structure. One of the major endothelium-derived vasoactive mediators is nitric oxide (NO). Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of NO synthase. ADMA inhibits vascular NO production in concentrations found in pathophysiological conditions; ADMA also causes local vasoconstriction when it is infused intraarterially. Thus, elevated ADMA levels may explain the "L-arginine paradox," i.e., the observation that supplementation with exogenous L-arginine improves NO-mediated vascular functions in vivo, although its baseline plasma concentration is about 25-fold higher than the Michaelis-Menten constant K(m) of the isolated, purified endothelial NO synthase in vitro. The biochemical and physiological pathways related to ADMA are well understood: Dimethylarginines are the result of degradation of methylated proteins; the methyl group is derived from S-adenosylmethionine. Both ADMA and its regioisomer, symmetric dimethylarginine, are eliminated from the body by renal excretion, whereas only ADMA is metabolized via hydrolytic degradation to citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). DDAH activity and/or expression may therefore contribute to the pathogenesis of endothelial dysfunction in various diseases. Plasma ADMA levels are increased in humans with hypercholesterolemia, atherosclerosis, hypertension, chronic renal failure, and chronic heart failure. Increased ADMA levels are associated with reduced NO synthesis as assessed by impaired endothelium-dependent vasodilation. In several prospective and cross-sectional studies, ADMA evolved as a marker of cardiovascular risk. With increasing knowledge of the role of ADMA in the pathogenesis of cardiovascular disease, ADMA is becoming a goal for pharmacotherapeutic interventions. Among other potential strategies that are currently being tested, administration of L-arginine has been shown to improve endothelium-dependent vascular functions in subjects with high ADMA levels. Finally, ADMA has gained clinical importance recently because several studies have shown that ADMA is an independent cardiovascular risk factor.

Animals↗

PubMed2006

The reduced energy intake of rats fed a high-protein low-carbohydrate diet explains the lower fat deposition, but macronutrient substitution accounts for the improved glycemic control.

The metabolic effect of high-protein low-carbohydrate (HP) diets on body composition and glucose homeostasis remains incompletely understood. This study assesses the respective roles of the increased protein:carbohydrate ratio (P:C) and the resulting moderate decrease in energy intake in the metabolic effects of HP diets. Rats had free access to normal (NP; 14%) or high (HP; 53%) total milk protein isoenergetic diets, or were fed the NP diet but restricted to the energy intake of HP rats (NPr), which was 89.1 +/- 9.3% that of NP rats. After 8 wk, body weight was lower in HP and NPr rats than in NP rats. In HP rats, the lower body weight was associated with a lower adipose tissue mass and a reduced proportion of large adipocytes. HP rats also had an improved oral glucose tolerance and insulin sensitivity, as assessed by the homeostatic model assessment index, compared with NPr and NP rats, and these effects were related solely to the increased P:C. These data suggest that the reduced energy intake of rats fed a high-protein, low-carbohydrate diet explains the lower fat deposition but an increased P:C per se improves glucose homeostasis.

Animals↗

PubMed1995

Proportion of breast cancer cases in the United States explained by well-established risk factors.

BACKGROUND: Few estimates of the fraction of cases of breast cancer attributable to recognized risk factors have been published. All estimates are based on selected groups, making their generalizability to the U.S. population uncertain. PURPOSE: Our goal was to estimate the fraction of breast cancer cases in the United States attributable to well-established risk factors (i.e., later age at first birth, nulliparity, higher family income, and first-degree family history of breast cancer), using data from the first National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-up Study (NHEFS), the survey and follow-up of a probability sample of the U.S. population. METHODS: From a cohort of 7508 female participants surveyed in the early 1970s, and followed up between 1982 and 1984 and again in 1987, 193 breast cancer cases were accrued for study. We calculated incidence rates, relative risks (RRs), and population attributable risks (PARs) for breast cancer risk factors and extended our results to the U.S. female population by using sample weights from the NHANES I survey. RESULTS: Our PAR estimates suggest that later age at first birth and nulliparity accounted for a large fraction of U.S. breast cancer cases, 29.5% (95% confidence interval [CI] = 5.6%-53.3%); higher income contributed 18.9% (95% CI = -4.3% to 42.1%), and family history of breast cancer accounted for 9.1% (95% CI = 3.0%-15.2%). Taken together, these well-established risk factors accounted for approximately 47% (95% CI = 17%-77%) of breast cancer cases in the NHEFS cohort and about 41% (95% CI = 2%-80%) in the U.S. population. CONCLUSIONS: The RRs for most of these risk factors were modest, but their prevalence as a group was high, leading to estimates that suggest that a substantial proportion of breast cancer cases in the United States are explained by well-established risk factors. IMPLICATIONS: Elucidation of the determinants underlying recognized factors and study of other factors that may confer risk or protection are needed in efforts to advance understanding of breast cancer etiology and to aid in devising strategies for prevention.

Adult↗

PubMed2004

Genetic diversity patterns in the SR-BI/II locus can be explained by a recent selective sweep.

The human scavenger receptor class B type I (SR-BI and splice variant SR-BII) plays a central role in HDL cholesterol metabolism and represents a candidate gene for a number of related diseases. We examined the genetic diversity of its coding and flanking regions in a sample of 178 chromosomes from individuals of European, African, East Asian (including Southeast Asian), Middle-Eastern as well as Amerindian descent. Nine of the 14 polymorphisms observed are new. Four of the five variants causing amino acid replacements, G2S, S229G, R484W, and G499R, are likely to affect protein structure and function. SR-BI/BII diversity is partitioned among 19 haplotypes; all but one interconnected by single mutation or a recombination event. Such tight haplotype network and the unusual geographic partitioning of this diversity, high not only in Africa but in East Asia as well, suggests its recent origin and possible effect of selection. Coalescent analysis infers a relatively short time to the most recent common ancestor and points to population expansion in Africa and East Asia. These two continents differ significantly in pairwise F(ST) values, differing as well from a single cluster formed by Europe, Middle East and America. In the context of findings for similarly analyzed other loci, we propose that a selective sweep at the origin of modern human populations could explain the low level of ancestral SR-BI/II diversity. The unusually deep split between Africa and Asia, well beyond the Upper Paleolithic when inferred under neutrality, is consistent with subsequent geographical and demographic expansion favoring the accumulation of new variants, especially in groups characterized by large effective population sizes, such as Asians and Africans. The relevance of such partitioning of SR-BI/II diversity remains to be investigated in genetic epidemiological studies which can be guided by the present findings.

CD36 Antigens↗

PubMed2006

Observations of amino acid gain and loss during protein evolution are explained by statistical bias.

The authors of a recent manuscript in "Nature" claim to have discovered "universal trends" of amino acid gain and loss in protein evolution. Here, we show that this universal trend can be simply explained by a bias that is unavoidable with the 3-taxon trees used in the original analysis. We demonstrate that a rigorously reversible equilibrium model, when analyzed with the same methods as the "Nature" manuscript, yields identical (and in this case, clearly erroneous) conclusions. A main source of the bias is the division of the sequence data into "informative" and "noninformative" sites, which favors the observation of certain transitions.

Algorithms↗

PubMed1993

Nucleotide, dinucleotide and trinucleotide frequencies explain patterns observed in chaos game representations of DNA sequences.

The chaos game representation (CGR) is a scatter plot derived from a DNA sequence, with each point of the plot corresponding to one base of the sequence. If the DNA sequence were a random collection of bases, the CGR would be a uniformly filled square; conversely, any patterns visible in the CGR represent some pattern (information) in the DNA sequence. In this paper, patterns previously observed in a variety of DNA sequences are explained solely in terms of nucleotide, dinucleotide and trinucleotide frequencies.

Base Sequence↗

PubMed2006

Structures of omega repressors bound to direct and inverted DNA repeats explain modulation of transcription.

Repressor omega regulates transcription of genes required for copy number control, accurate segregation and stable maintenance of inc18 plasmids hosted by Gram-positive bacteria. omega belongs to homodimeric ribbon-helix-helix (RHH2) repressors typified by a central, antiparallel beta-sheet for DNA major groove binding. Homodimeric omega2 binds cooperatively to promotors with 7 to 10 consecutive non-palindromic DNA heptad repeats (5'-(A)/(T)ATCAC(A)/(T)-3', symbolized by -->) in palindromic inverted, converging (--><--) or diverging (<---->) orientation and also, unique to omega2 and contrasting other RHH2 repressors, to non-palindromic direct (-->-->) repeats. Here we investigate with crystal structures how omega2 binds specifically to heptads in minimal operators with (-->-->) and (--><--) repeats. Since the pseudo-2-fold axis relating the monomers in omega(2) passes the central C-G base pair of each heptad with approximately 0.3 A downstream offset, the separation between the pseudo-2-fold axes is exactly 7 bp in (-->-->), approximately 0.6 A shorter in (--><--) but would be approximately 0.6 A longer in (<---->). These variations grade interactions between adjacent omega2 and explain modulations in cooperative binding affinity of omega2 to operators with different heptad orientations.

Bacterial Proteins↗

PubMed2006

The different cleavage DNA sequence specificity explains the camptothecin resistance of the human topoisomerase I Glu418Lys mutant.

Yeast cells expressing the Glu418Lys human topoisomerase I mutant display a camptothecin resistance that slowly decreases as a function of time. Molecular characterization of the single steps of the catalytic cycle of the purified mutant indicates that it has a relaxation activity identical to the wild-type protein but a different DNA sequence specificity for the cleavage sites when compared to the wild-type enzyme, as assayed on several substrates. In particular the mutant has a low specificity for CPT sensitive cleavable sites. In fact, the mutant has, at variance of the wild-type enzyme, a reduced preference for cleavage sites having a thymine base in position -1 of the scissile strand. This preference, together with the strict requirement for a thymine base in position -1 for an efficient camptothecin binding, explains the temporary camptothecin resistance of the yeast cell expressing the mutant and points out the importance of the DNA sequence in the binding of the camptothecin drug.

Amino Acid Substitution↗