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PubMed1994

Unstable pre-mutation may explain mosaic disease expression of incontinentia pigmenti in males.

Mosaic skin lesions following the lines of Blaschko are found in boys affected by incontinentia pigmenti (IP). For an X-linked gene defect, this is rather surprising. To explain the mosaic disease expression of IP in males, we propose that the disease is caused by an unstable pre-mutation, which normally remains silent in males during early embryogenesis. Occasionally "silencing" is incomplete and gives rise to clinical manifest IP reflecting a mosaic state of alleles with the full and the pre-mutation in the same patient. This model can account for mother-to-son transmission of IP and for disparate phenotypes in monozygotic female twins.

Child↗

PubMed2004

Variation in the urokinase-plasminogen activator gene does not explain the chromosome 10 linkage signal for late onset AD.

Linkage studies indicate that the same region of chromosome 10 contains a risk locus for late onset Alzheimer disease (LOAD) and a QTL for plasma Abeta42 levels suggesting that a single locus may influence risk for AD by elevating plasma Abeta42 [Ertekin-Taner et al., 2000; Myers et al., 2000]. A strong positional and biological candidate is the urokinase-plasminogen activator (PLAU) gene. Eight polymorphisms spanning the entire gene were examined using case control (CC) and family-based association methods. No association was observed by any method making it unlikely that variation in PLAU explains our linkage data.

Aged↗

PubMed2006

Presence of significant synovitis in rheumatoid arthritis patients with disease-modifying antirheumatic drug-induced clinical remission: evidence from an imaging study may explain structural progression.

OBJECTIVE: More timely and effective therapy for rheumatoid arthritis (RA) has contributed to increasing rates of clinical remission. However, progression of structural damage may still occur in patients who have satisfied remission criteria, which suggests that there is ongoing disease activity. This questions the validity of current methods of assessing remission in RA. The purpose of this study was to test the hypothesis that modern joint imaging improves the accuracy of remission measurement in RA. METHODS: We studied 107 RA patients receiving disease-modifying antirheumatic drug therapy who were judged by their consultant rheumatologist to be in remission and 17 normal control subjects. Patients underwent clinical, laboratory, functional, and quality of life assessments. The Disease Activity Score 28-joint assessment and the American College of Rheumatology remission criteria, together with strict clinical definitions of remission, were applied. Imaging of the hands and wrists using standardized acquisition and scoring techniques with conventional 1.5T magnetic resonance imaging (MRI) and ultrasonography (US) were performed. RESULTS: Irrespective of which clinical criteria were applied to determine remission, the majority of patients continued to have evidence of active inflammation, as shown by findings on the imaging assessments. Even in asymptomatic patients with clinically normal joints, MRI showed that 96% had synovitis and 46% had bone marrow edema, and US showed that 73% had gray-scale synovial hypertrophy and 43% had increased power Doppler signal. Only mild synovial thickening was seen in 3 of the control subjects (18%), but no bone marrow edema. CONCLUSION: Most RA patients who satisfied the remission criteria with normal findings on clinical and laboratory studies had imaging-detected synovitis. This subclinical inflammation may explain the observed discrepancy between disease activity and outcome in RA. Imaging assessment may be necessary for the accurate evaluation of disease status and, in particular, for the definition of true remission.

Adult↗

PubMed2004

A cluster translocation model may explain the collinearity of Hox gene expressions.

A model is proposed that deals with the observed collinearities (spatial, temporal and quantitative) of Hox gene expression during pattern formation along the primary and secondary axes of vertebrates. In particular, in the proximodistal axis of the developing limb, it is assumed that a morphogen gradient is laid down with its source at the distal tip of the bud. The extracellular signals in every cell of the morphogenetic field are transduced and uniformly amplified so that molecules are produced in the nucleus with appropriate physicochemical properties. These molecules can exert a concentration-dependent force on the Hox cluster. It is assumed that, before activation, the Hox cluster is packaged as an elongated rigid body inside the chromatin and is covered by a coat that prevents the transcription factors reaching the genes of the cluster. The transcription factors are confined to the interchromatin domain and their density decreases with their distance from the chromatin surface. A gradual increase in the extracellular morphogen concentration causes a corresponding increase in the number of the nuclear molecules and the resulting bigger force pushes the Hox cluster toward the interchromatin domain. The step-by-step translocations of the Hox cluster initiate the consecutive exposure of genes to their transcription factors. The model explains how gene activation is triggered and it describes spatial, temporal and quantitative collinearities at the initial stages of gene expression. Some recent experiments of Hox deletions and duplications are accounted for by the model.

Animals↗

PubMed2006

A kinetic model to explain the maximum in alpha-amylase activity measurements in the presence of small carbohydrates.

The effect of the presence of several small carbohydrates on the measurement of the alpha-amylase activity was determined over a broad concentration range. At low carbohydrate concentrations, a distinct maximum in the alpha-amylase activity versus concentration curves was observed in several cases. At higher concentrations, all carbohydrates show a decreasing alpha-amylase activity at increasing carbohydrate concentrations. A general kinetic model has been developed that can be used to describe and explain these phenomena. This model is based on the formation of a carbohydrate-enzyme complex that remains active. It is assumed that this complex is formed when a carbohydrate binds to alpha-amylase without blocking the catalytic site and its surrounding subsites. Furthermore, the kinetic model incorporates substrate inhibition and substrate competition. Depending on the carbohydrate type and concentration, the measured alpha-amylase activity can be 75% lower than the actual alpha-amylase activity. The model that has been developed can be used to correct for these effects in order to obtain the actual amount of active enzyme.

Binding Sites↗

PubMed2006

Progressive rise in gut hormone levels after Roux-en-Y gastric bypass suggests gut adaptation and explains altered satiety.

BACKGROUND: Bariatric surgery is the most effective treatment for achieving long-term weight loss in morbidly obese patients. This study investigated prospective changes in gut hormones and metabolic indices after Roux-en-Y gastric bypass (RYGB). METHODS: Six patients were seen before, and at 1, 3 and 6 months after operation. Blood was collected after a 12-h fast and at regular intervals after a mixed 420-kcal meal. Hormonal responses were determined, and comparisons between basal levels and areas under the curve were made. Visual analogue scores were used to assess satiety, hunger and nausea. RESULTS: Mean body mass index decreased from 48.3 kg/m(2) before surgery to 36.4 kg/m(2) 6 months after RYGB. This was accompanied by a decrease in fasting leptin (P < 0.001) and insulin (P = 0.021) levels. At 1, 3 and 6 months after operation, progressively increasing peptide YY (P < 0.001), enteroglucagon (P = 0.045) and glucagon-like peptide 1 (P = 0.042) responses were observed. There was no change in fasting ghrelin levels (P = 0.144). Postprandial satiety was significantly increased by 1 month after surgery and this was maintained until the end of the study (P < 0.001). CONCLUSION: RYGB resulted in substantial weight loss with enhanced postprandial satiety, a sustained weight plateau, and proportionate reduction in fasting insulin and leptin levels. Lack of the expected increase in appetite and food intake as components of a counter-regulatory response may be explained by gut adaptation and the consequent graded rise in the levels of gut hormones that promote satiety.

Adaptation, Physiological↗

PubMed2005

The imbalance between coronary reserve and wall stress explains the severity of ventricular dysfunction in hypertension.

BACKGROUND: The pathophysiologic role of coronary reserve impairment in hypertensive cardiac dysfunction is still debated. Previously, we demonstrated that satisfactory coronary vasodilatation may coexist with ventricular systolic dysfunction. It is conceivable that coronary reserve might otherwise be inappropriate for enhanced myocardial oxygen demand and may thus affect cardiac performance negatively. HYPOTHESIS: Myocardial supply-demand imbalance contributes to the severity of ventricular dysfunction in hypertension (HTN). METHODS: Fractional shortening (%) and end-systolic stress (10(3) x dyn x cm(-2)) were determined using echocardiography, and coronary reserve was calculated using transesophageal Doppler echocardiography. Coronary reserve/stress (cm2 x dyn(-1)) was utilized as a measure of supply-demand. Groups NL (20 healthy subjects), HTN1 (15 patients, fractional shortening > or = 30), HTN2 (19 patients, 20 < or = fractional shortening < 30), and HTN3 (21 patients, fractional shortening < 20) were constituted. RESULTS: Compared with NL and HTN1, groups HTN2 and HTN3 had significantly (p < 0.05) greater end-systolic stress (NL = 72 +/- 16, HTN1 = 72 +/- 23, HTN2 = 143 +/- 32, HTN3 = 186 +/- 70). Coronary reserve was impaired in HTN3 alone (NL = 3.5 +/- 0.6, HTN1 = 3.4 +/- 1.0, HTN2 = 3.1 +/- 1.0, HTN3 = 2.6 +/- 1.1), but coronary reserve/stress was reduced in both HTN2 and HTN3 (NL = 50 +/- 12, HTN1 = 53 +/- 21, HTN2 = 22 +/- 7, HTN3 = 15 +/- 7). Stepwise regression analysis identified diastolic internal dimension, end-systolic stress, and coronary reserve/stress as independently associated with fractional shortening. CONCLUSION: The imbalance between supply-demand explains the severity of hypertensive cardiac dysfunction and adds information to cardiac enlargement and elevated wall stress.

Adult↗

PubMed2001

The role of perfectionism and excessive commitment to exercise in explaining dietary restraint: replication and extension.

UNLABELLED: The etiological complexity of the eating disorders has incited researchers to examine how personality characteristics and other variables operate jointly in the development of deviant eating patterns. OBJECTIVE: This study investigated the independent, interactive, and indirect prediction of dietary restraint by perfectionism and excessive commitment to exercise. METHOD: Multiple regression analyses designed to test moderating and mediating models were conducted on a sample of female university students (n = 269). RESULTS: Several dimensions of perfectionism, as well as excessive commitment to exercise, significantly and independently predicted dietary restraint in these women. There was no evidence for an interaction effect. Mediation analyses suggested that for selected dimensions of perfectionism, the direct relationship between perfectionism and dietary restraint is partially explained by excessive commitment to exercise. DISCUSSION: Interventions aimed at challenging perfectionistic standards in the context of dieting need to address not only one's self-standards, but one's perceptions of standards held by others. The mediating role of excessive exercise commitment pinpoints this variable as an alternative intervention target in the prevention of excessive dieting.

Adult↗

PubMed1995

Functional discrepancies between tumor necrosis factor and lymphotoxin alpha explained by trimer stability and distinct receptor interactions.

Tumor necrosis factor (TNF) and lymphotoxin alpha (LT alpha) are closely related cytokines which bind with nearly identical affinities to the same pair of cell surface receptors, p55 and p75TNFR. Therefore it is assumed that TNF and LT alpha are redundant cytokines. This study, however, demonstrates that TNF and LT alpha differ significantly with regard to their mitogenic and cytotoxic potentials. LT alpha's superior mitogenic effect could be explained by its formation of a more stable trimer. In contrast to the TNF trimer, which disintegrated under physiological conditions into biologically inactive monomers, the LT alpha trimer remained stable for several days. Accordingly, LT alpha more effectively induced fibroblast growth which demands long-term presence of the cytokine. TNF's superior cytotoxicity, which requires only short-term impact of the cytokine, could be attributed to a distinct interaction with the human p55TNFR. This was demonstrated in NIH 3T3 cells transfected with the human p55TNFR, where cytotoxicity is mediated exclusively by the transfected receptor. Although the p55ATNFR had virtually identical affinities for TNF and LT alpha, as defined by Scatchard analysis, it nevertheless discriminated between binding of each cytokine and showed a 200-fold enhanced cytotoxicity mediated by TNF.

3T3 Cells↗

PubMed1996

Processing of pro-tumor necrosis factor-alpha by venom metalloproteinases: a hypothesis explaining local tissue damage following snake bite.

Venom-induced necrosis is a common local debilitating sequela of bites by many vipers, frequently resulting in severe permanent scarring and deformity. Antivenoms are not effective under these circumstances unless administered within a few minutes of the bite; this is unlikely to occur in the rural tropics where most victims take a long time to reach medical care. We have shown that two venom zinc metalloproteinases (jararhagin from Bothrops jararaca venom and a metalloproteinase from Echis pyramidum leakeyi venom) successfully cleaved the recombinant glutathione-S-transferase-tumor necrosis factor-alpha fusion protein (GST-TNF-alpha) substrate to form biologically active TNF-alpha which was shown to be neutralized by ovine TNF-alpha Fab antibodies. This resulted in a reduction of venom-induced necrosis in mice when injected intravenously or intradermally both before and after intradermal injections of E.p.leakeyi venom. A peptidomimetic (POL 647) was also found to inhibit the Echis metalloproteinase, thus preventing the processing of the TNF precursor; this was shown using a TNF-alpha-sensitive cell culture assay and electrophoresis. These observations demonstrate the possible importance of TNF-alpha in the development of the resulting necrotic lesion and leads to the hypothesis that increased levels of venom metalloproteinases following snake bite release active TNF-alpha. This cytokine may contribute to the local necrosis and also induce the production of endogenous matrix metalloproteinases, which in turn generate a positive feedback mechanism resulting in continued cleavage of pro-TNF-alpha. The results indicate that inhibition or neutralization of endogenous TNF-alpha appears to result in a significant reduction in venom-induced necrosis. This could help to explain the clinical observations that treatment of local necrosis following snake bite by antivenom is only minimally successful.

Amino Acid Sequence↗

PubMed2007

A FISH comparison of variant derivatives of the recurrent dic(17;20) of myelodysplastic syndromes and acute myeloid leukemia: Obligatory retention of genes on 17p and 20q may explain the formation of dicentric chromosomes.

The dic(17;20) is a recurrent unbalanced translocation occurring rarely in myelodysplastic syndromes and acute myeloid leukemia. We have studied eleven cases with the dic(17;20) or a more complex derivative, all of which showed deletion of 17p and 20q material. The tumor suppressor gene TP53 was not always lost, supporting a more distal gene as the target of these 17p deletions. All derivatives could be interpreted as having initially been formed as a dicentric chromosome, those with a larger amount of material between the centromeres having undergone further rearrangement to stabilize the chromosome while retaining proximal 17p and proximal 20q material. We propose that critical sequences on both 17p and 20q proximal to the sites of deletion must be retained during the critical 17p and 20q deletions. This would explain the excess of dicentric chromosomes resulting from 17;20 translocation, and the apparent stabilization of the unstable derivatives by further rearrangements which preserve 17p and 20q material.

Acute Disease↗

PubMed2004

Genetically heterogeneous selective intestinal malabsorption of vitamin B12: founder effects, consanguinity, and high clinical awareness explain aggregations in Scandinavia and the Middle East.

Selective intestinal malabsorption of vitamin B(12) causing juvenile megaloblastic anemia (MGA; MIM# 261100) is a recessively inherited disorder that is believed to be rare except for notable clusters of cases in Finland, Norway, and the Eastern Mediterranean region. The disease can be caused by mutations in either the cubilin (CUBN; MGA1; MIM# 602997) or the amnionless (AMN; MIM# 605799) gene. To explain the peculiar geographical distribution, we hypothesized that mutations in one of the genes would mainly be responsible for the disease in Scandinavia, and mutations in the other gene in the Mediterranean region. We studied 42 sibships and found all cases in Finland to be due to CUBN (three different mutations) and all cases in Norway to be due to AMN (two different mutations), while in Turkey, Israel, and Saudi Arabia, there were two different AMN mutations and three different CUBN mutations. Haplotype evidence excluded both CUBN and AMN conclusively in five families and tentatively in three families, suggesting the presence of at least one more gene locus that can cause MGA. We conclude that the Scandinavian cases are typical examples of enrichment by founder effects, while in the Mediterranean region high degrees of consanguinity expose rare mutations in both genes. We suggest that in both regions, physician awareness of this disease causes it to be more readily diagnosed than elsewhere; thus, it may well be more common worldwide than previously thought.

Anemia, Megaloblastic↗

PubMedDate not supplied

The presence of a motility inhibitor within spermatozoa may explain the poor sperm motility of some infertile men.

The presence of motility inhibitors in seminal plasma and within spermatozoa from control and infertile men with poor sperm motility was investigated using demembranated reactivated human spermatozoa. No difference was found in the inhibitory capacities in seminal plasma of patients with poor sperm motility (less than 50%) when compared with that of fertile controls with motility above 50%. No correlation was observed between inhibitory capacity and sperm motility. However, when extracts of spermatozoa from these patients were tested for the presence of inhibitor, it was observed that three of nine patients had an inhibitor in their sperm extract. By contrast, all sperm extracts from fertile control subjects were devoid of inhibitor. It was concluded that the presence of a motility inhibitor in seminal plasma does not explain the poor sperm motility observed in patients. The presence of a motility inhibitor within spermatozoa, however, may represent an important factor in the etiology of the poor sperm motility observed in some patients.

Adult↗

PubMed1980

The apparent discrepancy of ouabain inhibition of cation transport and of lymphocyte proliferation is explained by time-dependency of ouabain binding.

Mitogenesis of human blood lymphocytes in culture is inhibited by concentrations of ouabain that are approximately one order of magnitude lower than those that block Na and K transport. For example, the 50% inhibition (ID50) of Na-K transport, 280 nM, is seven-fold greater than the Id50 for RNA synthesis, DNA synthesis, or blastogenesis, approximately 40 nM. Yet, inhibition of transport and consequent reduction in cell K is considered responsible for the effects of ouabain on mitogenesis. Since synthetic processes are assessed at least 24 hours after lymphocyte stimulation, this discrepancy could be explained by either 1) a progressive increase in K leak, or 2) a progressive inhibition of Na-K transport by ouabain during 24 hours of PHA treatment. We found that the lymphocyte membrane leak rate of K increased immediately after PHA treatment but did not increase further from 4 to 24 hours. In contrast, the ouabain sensitivity of 42K uptake was markedly increased with time: ID50 for 42K uptake of 35 nM at 24 hours as compared to 280 nM at 30 minutes. Measurement of ouabain binding revealed a seven-fold increase in the lymphocyte-associated ouabain after 24 hours compared to binding at 1 hour. These data indicate that the dose response of ouabain inhibition of active K transport and lymphocyte proliferation are closely correlated if one considers the slow membrane binding of ouabain at low concentrations.

Biological Transport, Active↗

PubMed1983

Can differences in limb regeneration ability between individuals within certain amphibian species be explained by differences in the quantity of innervation?

In some species of amphibians, the regenerative response to limb amputation is not uniform. For example, regenerative ability varies from one individual to another within the species Xenopus laevis, Ambystoma maculatum, and Amphiuma tridactylum. In many species, limb regenerative ability declines with increasing age. The objective of this investigation was to determine if this variation in regenerative ability can be explained by variation in the quantity of innervation. In each of the above-named species, limbs were amputated and allowed to regenerate. The quantity of innervation (percentage of cross-sectional area of amputated surface occupied by nerves) was measured in the amputated part of the limb as close as possible to the amputation surface. The presence, rate, or extent of limb regeneration in that specific limb was then compared to the quantity of innervation at the amputation surface. The results indicated that there was no correlation between innervation and the rate or extent of regeneration in Xenopus laevis or Ambystoma maculatum. On the other hand, in Amphiuma tridactylum, those limbs that regenerated were the ones that had the highest levels of innervation. In Ambystoma maculatum, the quantity of innervation was measured at five different stages, from early larvae to mature adult. The results showed that the quantity of innervation was highest during the larval period, reaching a maximum at the late larval stage before declining greatly to the adult level. It appears that the decline in regenerative ability in the adult cannot be attributed solely to a reduction in innervation to below the threshold level.

Age Factors↗

PubMed1999

The individual regulation of granule protein mRNA levels during neutrophil maturation explains the heterogeneity of neutrophil granules.

The in vivo mRNA levels for 16 granule proteins during neutrophil differentiation were determined to address the question of whether the synthesis of granule proteins is regulated individually or blockwise. RNA was extracted from peripheral blood granulocytes and three different populations of neutrophil precursors isolated from human bone marrow by Percoll density centrifugation. The mRNA levels in relation to the maturation of the cells were determined by Northern blot for the 12 matrix proteins myeloperoxidase, proteinase-3, elastase, defensin, lactoferrin, NGAL, hCAP-18, transcobalamin-I, SGP28, gelatinase, lysozyme, and serglycin and the 4 membrane proteins CD68, CD11b, N-formyl-methionyl-leucyl-phenylalanine receptor, and CD35. This panel of transcripts ensured that markers for all exocytosable organelles of the neutrophil were included in the study. A highly differentiated distribution of mRNAs for granule proteins was demonstrated that can explain the heterogeneity of the intracellular storage granules and secretory vesicles of the neutrophil. Furthermore, the individual distribution of these transcripts provides the basis for a more detailed assessment of neutrophil maturation than that obtained by morphological studies or the use of a single marker protein for azurophil, specific, and gelatinase granules.

Blood Proteins↗

PubMed2007

Stem-cement porosity may explain early loosening of cemented femoral hip components: experimental-computational in vitro study.

A combination of laboratory experiment and computational simulation was performed to assess the role of interface porosity on stem migration. The early motion of in vitro prepared cemented femoral components was measured during application of cyclic stair climbing loads. Following testing, transverse sections were obtained and the distribution of pores at the stem-cement interface was determined. Finite element models of cemented stem constructs were developed and a scheme was implemented to randomly assign pores to the stem-cement interface. For a series of 14 in vitro prepared components, pore fractions at the stem-cement interface ranged from 23% to 67%. The majority of pores at the stem-cement interface were less than 1 mm in length with a mean length of 1.27 +/- 2.7 mm and thickness of 0.12 +/- 0.11 mm. For stems with large pore fractions, pores tended to coalesce in longer extended gaps over the stem surface. Finite element and experimental models both revealed strong positive correlations (r(2) = 0.55-0.72; p < 0.0001) between stem-cement pore fraction and stem internal rotation, suggesting that the presence and extent of pores could explain the early motion of the stems. There was an increased volume of cement at risk of fatigue failure with increasing stem migration. Pore fractions greater than 30% resulted in large increases in stem internal rotation, suggesting that attempts to maintain surface porosity at or below this level may be desirable to minimize the risk of clinical loosening.

Aged↗

PubMed1975

Kinetics and mechanisms of monolayer interactions. III: models to explain time-dependent effects of injected cetrimonium bromide.

Two kinetic models are derived to explain the time-dependent effects of cetrimonium ions injected beneath an air-aqueous solution interface without any previously adsorbed or spread monolayer at different ionic strengths. The data show excellent fit and consistency with a nulticompartmental kinetic model which postulates a barrier or intermediate compartment between the ionic surfactant in the subphase and the sites on the surface. Such a barrier inhibits free diffusion of the surfactant from the bulk of the solution to these sites. The experimental data are not inconsistent with a model that postulates a time-dependent binding process and the absence of a diffusion-limiting subinterface since, within the limits of the error, the derived rate constants conform to the model prediction that they should be proportional to the surfactant-ion concentration.

Adsorption↗