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Development of the musculoskeletal system occurs throughout childhood. This article provides an overview of normal musculoskeletal growth and development and describes some of the common variations seen in children. Knowledge of the normal patterns of growth and common problems can help nurses identify children who require further evaluation and treatment.
Two recent publications reported association of common polymorphisms in the P2 promoter of hepatocyte nuclear factor 4alpha (HNF4alpha) (the MODY1 gene) with risk for type 2 diabetes. We attempted to reproduce this putative association by genotyping 11 single nucleotide polymorphism (SNPs) spanning the HNF4alpha coding region and the P2 promoter in >3,400 patients and control subjects from Sweden, Finland, and Canada. One SNP that was consistently associated in the two previous reports (rs1884613, in the P2 promoter region) also trended in the same direction in our sample, albeit with a lower estimated odds ratio (OR) of 1.11 (P = 0.05, one-tailed). We genotyped this SNP (rs1884613) in an additional 4,400 subjects from North America and Poland. In this sample, the association was not confirmed and trended in the opposite direction (OR 0.88). Meta-analysis of our combined sample of 7,883 people (three times larger than the two initial reports combined) yielded an OR of 0.97 (P = 0.27). Finally, we provide an updated analysis of haplotype structure in the region to guide any further investigation of common variation in HNF4alpha. Although our combined results fail to replicate the previously reported association of common variants in HNF4alpha with risk for type 2 diabetes, we cannot exclude an effect smaller than that originally proposed, heterogeneity among samples, variation in as-yet-unmeasured genotypic or environmental modifiers, or true association secondary to linkage disequilibrium (LD) with as-yet-undiscovered variant(s) in the region.
MOTIVATION: Microarray technology enables the monitoring of expression levels for thousands of genes simultaneously. When the magnitude of the experiment increases, it becomes common to use the same type of microarrays from different laboratories or hospitals. Thus, it is important to analyze microarray data together to derive a combined conclusion after accounting for the differences. One of the main objectives of the microarray experiment is to identify differentially expressed genes among the different experimental groups. The analysis of variance (ANOVA) model has been commonly used to detect differentially expressed genes after accounting for the sources of variation commonly observed in the microarray experiment. RESULTS: We extended the usual ANOVA model to account for an additional variability resulting from many confounding variables such as the effect of different hospitals. The proposed model is a two-stage ANOVA model. The first stage is the adjustment for the effects of no interests. The second stage is the detection of differentially expressed genes among the experimental groups using the residuals obtained from the first stage. Based on these residuals, we propose a permutation test to detect the differentially expressed genes. The proposed model is illustrated using the data from 133 microarrays collected at three different hospitals. The proposed approach is more flexible to use, and it is easier to accommodate the individual covariates in this model than using the meta-analysis approach. AVAILABILITY: A set of programs written in R will be electronically sent upon request.
A procedure to study variations of the common human centre of gravity (stabilometry) permits using a principle of a biological feedback. It is achieved by application of a device to study the nervous system. A procedure is recommended to be widely used in applied physiology.
One of the most promising directions in the study of phenotypic plasticity is its detailed analysis in organisms that are also well-studied in other aspects. Also, conclusions based on plasticity studies in environmental gradients that closely mimic natural variation are shown to be the most relevant. Following those directions, we conducted this study of phenotypic plasticity on the currently best available model system in flowering plants--Arabidopsis thaliana, and utilized one of the most common variations experienced in the wild--variation in density. Four Arabidopsis thaliana commonly used inbred lines (ecotypes) were grown in densities from one to seven plants per pot. Both phenotypic plasticity and its genetic variability were detected for almost all of 11 analyzed traits, with analyzed ecotypes responding strongly to density of just two plants per pot. Density had small effect on life history and moderate effect on size traits, while vegetative and reproductive traits responded strongly. Mortality of plants during the experiment was almost absent, showing that all densities corresponded to the medium density phase in which "carrying capacity" is not yet reached. Genetic variability for phenotypic plasticity was in most cases the result of profound deviation of only one ecotype from the response of others. In the case of reproductive output, however, G x E interaction was the result of greater between-ecotype variability at lower densities. If we reasonably assume that dense stands are more common in the wild, this difference between ecotypes (populations) closely resembles the cases of so-called potential variability within populations.
We have previously reported a common variation in the liver promoter of the human glucokinase, which is regulated by insulin, in the patients with non-insulin-dependent diabetes mellitus (NIDDM). The variation occurred within a 10-bp region completely conserved between human and rat. Its basic motif was almost identical to the insulin regulatory element of the phosphoenolpyruvate carboxykinase gene. In vitro transfection experiment showed that the G-to-A variation causes a 58% reduction in the promoter activity. After oral glucose challenge, the homozygous A/A subjects had the highest stimulated insulin levels at 60 and 90 minutes and the highest insulin area under the curve as compared to the subjects with other genotypes, which suggested the homozygous A/A subjects were more insulin resistant. As insulin resistance is a risk factor of NIDDM, we concluded that this promoter variation is a risk factor for NIDDM.
INTRODUCTION: Atherosclerosis, the underlying disorder of coronary artery disease (CAD), is an inflammatory process involving multiple molecular pathways. Chemokine-mediated mechanisms are potent regulators of atherosclerosis. Genetic variations that alter such signaling pathways could affect susceptibility to CAD. We investigated the effect of 5 common variations of chemokine and chemokine receptor genes (SDF1-3'A, CCR5-delta32, CCR2-64I, CX3CR1-V249I and CX3CR1-T280M) on predisposition to CAD. MATERIALS AND METHODS: The hypothesis was tested by screening the prevalence of the above polymorphisms in 210 angiographically diagnosed CAD patients (152 with history of acute coronary syndromes, 58 with stable disease) in comparison to 165 selected controls with negative coronary angiography. Genotyping was performed by PCR/RFLP analysis. RESULTS: There were no significant differences among cases and controls concerning allelic and genotypic frequencies of SDF1-3'A, CCR5-delta32, CCR2-64I and CX3CR1-V249I variations. A borderline higher allelic frequency of the M280 variant was observed in controls compared to CAD group (adjusted OR=0.65, 95% CI: 0.35-0.99, p=0.05). Subjects carrying at least one copy of the M280 allele were significantly more common in the control group, suggesting an atheroprotective effect of this variant (adjusted OR=0.58, 95% CI: 0.35-0.97, p=0.04). CONCLUSIONS: The study confers additional data in the field of genetic predisposition to CAD: it confirms the atheroprotective effect of the M280 variant in a completely different population and supports the role of the fractalkine-CX3CR1 pathway in atherosclerosis.
Malpositioning of iliosacral screws happens more often when common variations in the morphology of the upper sacral segments are unrecognized. Radiological-anatomic correlations of sacral anatomy were studied in 10 fresh-frozen cadaveric pelvises without evidence of skeletal disease, obtained from six male and four female donors. Eighty consecutive patients with complicated pelvic fractures treated operatively by the same surgeon using percutaneously placed iliosacral screws were evaluated. Variations in the sacral alar anatomy and slope found in upper sacral segmentation anomalies are common. Surgically important and predictable abnormal morphological patterns can be easily identified using pelvic outlet and lateral sacral plain radiographs along with computed tomographic scans. On the true lateral projections, the iliac cortical density adjacent to the sacroiliac joint parallels the sacral alar slope and is almost always caudal and posterior to it; it delineates the anterior extent of the "safe zone" for iliosacral screw insertion. Thus, the lateral sacral image provides the surgeon with a better understanding of the sacral alar slope and can help prevent iliosacral screw placement errors. The lateral sacral image should always be used intraoperatively with the inlet and outlet images to guide iliosacral screw placement.
Structural variations from agonists to their selective antagonists seemed to follow certain patterns. To analyze the variation patterns in the structural modification processes in past examples as well as to utilize the "common" variation patterns as possible principles to design new selective antagonistic drugs, the structures of agonists and their antagonists were superimposed on a two-dimensional grid template composed of regular hexagons and the topological similarities and dissimilarities of substructural elements between agonists and antagonists were examined. Between several pairs of neurotransmitter amines and their "selective" antagonists, similar patterns were disclosed in their structural modification processes. The generalized structural modification patterns were successfully applied as guiding principles to design and identify a new prototype structure of the 5-HT3 antagonist. The prototype structure was optimized by use of QSAR procedures leading to a compound which shows a potent antiemetic activity as well as a powerful gastrointestinal-motility modulation.
The parental origin of mitochondria in hydatidiform moles has been investigated by analysis of genetic variants of mtDNA restriction enzyme patterns. In six complete moles the mtDNA was found to be maternal in origin, with no contribution from the sperm mitochondria, while the nuclear genome was shown to be exclusively paternal in five cases. The occurrence of mtDNA variation in the healthy population was investigated using white blood cells and placentae, and the most common variation occurred at the Ava II restriction sites. The variants exhibited by molar mtDNA were the same as those found in material from healthy individuals.
BACKGROUND: Patients with Alzheimer's disease show a wide variation in clinical phenotype. Genetic research has been largely concerned with the role of mutations or common variants as risk factors for the disease. Do genetic factors also influence clinical phenotype? AIMS: To examine the evidence that genetic factors influence the clinical expression of the disease in addition to influencing risk. METHOD: A selective review was made of the key literature. RESULTS: Mutations in three genes, coding for amyloid precursor protein, presenilin-1 and presenilin-2, and a common variation (epsilon4) in another gene, APOE, have been shown to lead to an earlier development of the disease. More recently, genetic association and twin studies have suggested a role for genetic factors in the development of other aspects of clinical phenotype, notably the appearance of non-cognitive symptoms. CONCLUSIONS: In Alzheimer's disease genetic variation influences a number of aspects of clinical phenotype.
OBJECTIVES: Because there is interindividual variation in the metabolic response to diet, it important to find and evaluate candidate genes, which have common functional variants in the general population, and which may be determinants of interindividual differences in the response to components of the diet, such as dietary fat and fiber. One such candidate gene is FABP2, which encodes the intestinal fatty acid binding protein. This gene has a common variation in the coding sequence, which results in either alanine or threonine to be translated at residue 54. This amino acid variation has an in vitro functional impact. In addition, there have been several published associations with metabolic phenotypes, such as impaired glucose tolerance, obesity, altered plasma lipids and lipoproteins. RESULTS: It is the FABP2 T54 variant that is almost always associated with the more deleterious phenotypic expression. Recent experiments have found that most of the inter-individual variation in the plasma lipoprotein response to dietary fiber could be attributed to the FABP2 A54T polymorphism. However, it is likely that differences in environment, such as the type of fatty acid or fiber consumed, might interact with functional differences in the gene product to produce phenotypic differences. CONCLUSIONS: This means that more experimental work, using a variety of study samples and complementary approaches, is necessary before advocating routine testing of FABP2 genotype in people in order to determine their potential responsiveness to various dietary interventions, such as increased dietary soluble fiber.
Widespread species that are morphologically uniform may be likely to harbour cryptic genetic variation. Common ravens (Corvus corax) have an extensive range covering nearly the entire Northern Hemisphere, but show little discrete phenotypic variation. We obtained tissue samples from throughout much of this range and collected mitochondrial sequence and nuclear microsatellite data. Our study revealed a deep genetic break between ravens from the western United States and ravens from throughout the rest of the world. These two groups, the 'California clade' and the 'Holarctic clade' are well supported and over 4% divergent in mitochondrial coding sequence. Microsatellites also reveal significant differentiation between these two groups. Ravens from Minnesota, Maine and Alaska are more similar to ravens from Asia and Europe than they are to ravens from California. The two clades come in contact over a huge area of the western United States, with mixtures of the two mitochondrial groups present in Washington, Idaho and California. In addition, the restricted range Chihuahuan raven (Corvus cryptoleucus) of the south-west United States and Mexico is genetically nested within the paraphyletic common raven. Our findings suggest that the common raven may have formerly consisted of two allopatric groups that may be in the process of remerging.
The 17beta-hydroxysteroid dehydrogenase 1 gene (HSD17B1) encodes 17HSD1, which catalyzes the final step of estradiol biosynthesis. Despite the important role of HSD17B1 in hormone metabolism, few epidemiologic studies of HSD17B1 and breast cancer have been conducted. This study includes 5,370 breast cancer cases and 7,480 matched controls from five large cohorts in the Breast and Prostate Cancer Cohort Consortium. We characterized variation in HSD17B1 by resequencing and dense genotyping a multiethnic sample and identified haplotype-tagging single nucleotide polymorphisms (htSNP) that capture common variation within a 33.3-kb region around HSD17B1. Four htSNPs, including the previously studied SNP rs605059 (S312G), were genotyped to tag five common haplotypes in all cases and controls. Conditional logistic regression was used to estimate odds ratios (OR) for disease. We found no evidence of association between common HSD17B1 haplotypes or htSNPs and overall risk of breast cancer. The OR for each haplotype relative to the most common haplotype ranged from 0.98 to 1.07 (omnibus test for association: X2 = 3.77, P = 0.58, 5 degrees of freedom). When cases were subdivided by estrogen receptor (ER) status, two common haplotypes were associated with ER-negative tumors (test for trend, Ps = 0.0009 and 0.0076; n = 353 cases). HSD17B1 variants that are common in Caucasians are not associated with overall risk of breast cancer; however, there was an association among the subset of ER-negative tumors. Although the probability that these ER-negative findings are false-positive results is high, these findings were consistent across each cohort examined and warrant further study.
BACKGROUND: Aromatase catalyses the conversion of androgens to estrogens and thus variation in the aromatase gene could contribute to female syndromes of androgen excess, such as precocious pubarche (PP) and polycystic ovarian syndrome (PCOS). METHODS: Two groups, one case-control containing girls from Barcelona, Spain with PP (n = 186) or healthy controls (n = 71), and the other a population study of young women from Oxford, UK, who volunteered for a study of normal women's health (n = 109), were genotyped at four aromatase gene haplotype-tag single nucleotide polymorphisms (SNP). Clinical features and hormone concentrations relevant to hyperandrogenism were compared across haplotypes or genotypes. RESULTS: Distributions of aromatase haplotypes (P < 0.0001) and aromatase SNP_50 genotype (P = 0.001) were significantly different between PP girls and Spanish controls. The AGGG haplotype was associated with an odds ratio (95% confidence interval) of 0.5 (0.3-0.9) (P = 0.005) for the presence of PP compared to GAGG. In 84 post-pubertal PP girls, aromatase haplotype was associated with functional ovarian hyperandrogenism (P < 0.05), independently of insulin sensitivity. In the Oxford population, SNP_50 was associated with variation in PCOS symptom score (P = 0.008) and circulating testosterone concentrations (P = 0.02). CONCLUSIONS: This study suggests that common variation at the aromatase gene (and not just rare loss-of-function mutations) is associated with androgen excess in girls and young women.
BACKGROUND: Chromosome 22q13 has shown linkage with schizophrenia (SCZ) and bipolar affective disorder (BPAD). A missense mutation in MLC1 (putative cation-channel gene on 22q13) co-segregating with periodic catatonic schizophrenia has been reported. We have investigated the relationship of MLC1 with SCZ and BPAD in Southern India. METHODS: All exons and flanking intronic sequences of MLC1 were screened for novel variations. Case-control (216 BPAD, 193 SCZ, 116 control subjects) and family-based analyses (113 BPAD, 107 SCZ families) were performed to evaluate association of MLC1 with these disorders. RESULTS: We found 33 MLC1 sequence variations, including three novel mutations: Val210Ile, Leu308Gln, and Arg328His in six BPAD cases and Val210Ile in one control individual. Minor allele of a common variation, ss16339182 (in approximately 6 Kb Linkage-Disequilibrium [LD]-block) was associated with BPAD in case-control (p = .03) and family-based analyses (transmitted/nontransmitted [T/NT]-44/20; p = .003). Association was observed for rs2235349 and rs2076137 with SCZ and ss16339163 with BPAD in case-control study. Using Block 2 haplotype tagging single nucleotide polymorphisms (htSNPs), GC haplotype revealed association (p = .02) and excess transmission (p = .002) with BPAD. CONCLUSIONS: Association of MLC1 with SCZ and BPAD suggests involvement of a common pathway. Rare missense mutations and common variants associated with BPAD favors hypothesis about likely involvement of both rare and common polymorphisms in etiology of this complex disorder.
A comparison of the major cerebral arteries between humans and rats shows many similarities, including anomalies in their general organization, the structure of these vessels at the light and electron microscope levels and their morphological changes associated with cerebral vascular diseases. The general organization of the major cerebral arteries shows the following main differences between humans and rats. In rats, the internal carotid arteries have become an integral part of the circle of Willis. In the anterior cerebral arteries, a common variation in humans is the underdevelopment of one of the two arteries, whereas in rats, buttonhole-like structures are common in one or both arteries. The anterior communicating artery present in humans is absent in rats. The olfactory artery is prominent in rats, but absent in humans. The posterior communicating artery in humans is the most variable component of the circle of Willis, being asymmetric in its origin, diameters and branches. Similarly, the posterior cerebral arteries in rats often exhibit asymmetrical origin from the basilar artery. There was some confusion in the literature regarding the name of the posterior cerebral arteries in rats, but this was caused mainly by misquotations and incorrect interpretations of the papers. In humans, most aneurysms occur in the anterior half of the circle of Willis, and the incidence is higher in females than males; the middle cerebral artery is most often the one to become occluded, and the vertebral arteries are common sites for thrombosis. The various channels that constitute collateral circulation in humans provide a margin of safety, so that in case of cerebral occlusion due to thrombosis, atherosclerosis, or vasospasm related to hemorrhage, blood supply to the affected area can be maintained through these collaterals. Collateral circulation is also present in rats. However, in rats, information on the presence of various types of aneurysms, their location and frequency in normal and experimental models of hypertension and stroke is still lacking. Cerebral arteries from humans and rats are characterized by the absence of external elastic lamina, as compared with systemic arteries. A type of multipolar cell resembling the interstitial cell of Cajal is present in the cerebral arteries of humans. Its function is unknown. Earlier reports of cerebral valves have been shown to represent intimal cushions near the branching points of the cerebral arteries. Intravascular bridges present in human cerebral arteries, have not been reported in rats. Finally, the presence of vascular remodeling, as found in the cerebral arterioles of hypertensive rats, remains to be established in the cerebral arterioles of human hypertensives.(ABSTRACT TRUNCATED AT 400 WORDS)
BACKGROUND: Factor (F)XIII B-subunit, which plays a carrier role for zymogen FXIIIA, is highly polymorphic, but the molecular basis for these polymorphisms and their relationship to disease remains unknown. OBJECTIVES: To screen the FXIIIB gene coding region for common variation and analyze possible functional effects. METHODS AND RESULTS: We examined the FXIIIB gene by PCR-SSCP and identified three common single nucleotide polymorphisms: A8259G, C29470T and A30899G. A8259G results in substitution of His95Arg in the second Sushi domain. An FXIII tetramer ELISA was developed to analyze B-subunit dissociation from A-subunit (leading to access to the catalytic site of FXIII). Increased subunit dissociation, 0.51 vs. 0.45 (fraction of total tetramer), was found in plasma from subjects possessing the Arg-allele. However, when the variants were purified to homogeneity and binding was analyzed by steady-state kinetics, no difference was observed. The relationship between His95Arg and venous thrombosis was investigated in 214 patients and 291 controls from Leeds. His/Arg + Arg/Arg genotypes were more frequent in patients than controls (22.4% vs. 15.1%). His95Arg was also investigated in the Leiden Thrombophilia Study, in which a similar difference was observed for 471 patients vs. 472 controls (18.5% vs. 14.0%), for a pooled odds ratio (OR) of 1.5 (CI95 1.1-2.0). CONCLUSIONS: We have identified three FXIIIB polymorphisms, one of which codes for substitution of His95Arg. The Arg95 variant associates with a moderately increased risk for venous thrombosis, and with increased dissociation of the FXIII subunits in plasma, although in vitro steady-state binding between purified subunits was not affected.