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At least 883 records · Page 49Linked to original sources
PubMed2001

Influence of preassay and sequence variations on viral load determination by a multiplex real-time reverse transcriptase-polymerase chain reaction for feline immunodeficiency virus.

Determination of retroviral load is an important tool in the investigation of the success of therapeutic or vaccination trials in patients infected with lentiviruses such as HIV, or with their simian (SIV) or feline (FIV) counterparts. We have developed an one-tube quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay based on the ABI Prism 7700 Sequence Detection System (TaqMan) to quantify the viral load of FIV-infected cats. Two different primer/probe systems were designed to detect a broad range of clade A FIV isolates. Both systems are characterized by excellent reproducibility, high sensitivity, and a wide range of quantification. As a consequence of this improved precision in the quantitative RT-PCR, preassay variations have greater impact on the accuracy of the viral load estimation. To compensate for these variations, we improved the assay and developed a multiplex real-time RT-PCR, which allows simultaneous calculation of the viral copy number and the individual recovery rate in an one-tube reaction. This enables the rapid and accurate calculation of copy number independent of preassay variations. In further studies, two additional real-time RT-PCR assays were designed and used to investigate the influence of sequence variations in the binding regions for either the primers or probe. Sequence mismatches in this region had a significant effect (up to 4 logarithmic decades) on reaction efficiency. In view of the inherent variability of retroviral sequences, these results underline the necessity to check reaction efficiencies before determining viral load.

Animals↗
PubMed2004

Risk factors for osteoarthritis: understanding joint vulnerability.

Joint damage occurs when structures protecting the joint fail. Because osteoarthritis consists of end-stage joint damage, I propose that risk factors for disease can be best understood as either impairments of joint protectors, increasing joint vulnerability, or as factors that excessively load the joint, leading to injury. I review current knowledge using this paradigm, separating factors into those increasing joint vulnerability (malalignment, muscle weakness, genetic and ethnic predispositions, aging) and those that cause excessive loading (obesity; certain physical activities). Osteoarthritis and cartilage loss can occur without pain. This review focuses separately on factors associated with pain in those with osteoarthritis. To identify sources of pain in osteoarthritis, recent studies have compared magnetic resonance imaging findings of people with osteoarthritis with and without pain, focusing on structures known to have nociceptive innervations. Those with pain are more likely to have effusions, bone marrow lesions, synovial hypertrophy, and tendinitis and bursitis around the joint. This review creates a new paradigm for understanding risk factors for osteoarthritis, using joint vulnerability and loading as a framework and focuses separately on the emerging investigative area of sources of pain.

Humans↗
PubMed2004

The opportunity for canalization and the evolution of genetic networks.

There has been a recent revival of interest in how genetic interactions evolve, spurred on by an increase in our knowledge of genetic interactions at the molecular level. Empirical work on genetic networks has revealed a surprising amount of robustness to perturbations, suggesting that robustness is an evolved feature of genetic networks. Here, we derive a general model for the evolution of canalization that can incorporate any form of perturbation. We establish an upper bound to the strength of selection on canalization that is approximately equal to the fitness load in the system. This method makes it possible to compare different forms of perturbation, including genetic, developmental, and environmental effects. In general, load that arises from mutational processes is low because the mutation rate is itself low. Mutation load can create selection for canalization in a small network that can be achieved through dominance evolution or gene duplication, and in each case selection for canalization is weak at best. In larger genetic networks, selection on genetic canalization can be reasonably strong because larger networks have higher mutational load. Because load induced through migration, segregation, developmental noise, and environmental variance is not mutation limited, each can cause strong selection for canalization.

Evolution, Molecular↗
PubMed1997

Clinical and family studies in genetic hemochromatosis: microsatellite and HFE studies in five atypical families.

A candidate gene (HFE) has been described for hereditary hemochromatosis on chromosome 6. The study of well-defined atypical hemochromatosis families using genetic markers may increase our understanding of the sensitivity and the specificity of genotyping in hemochromatosis. One hundred and thirteen Canadian families with genetic hemochromatosis were surveyed to find atypical families as possible examples of people with genetic recombinations. All families underwent clinical investigations including iron studies and HLA typing. Each individual was typed at three polymorphic microsatellite loci (D6S105, D6S1260, and D6S299) on chromosome 6. Sixteen subjects were studied for the two missense mutations described for the candidate gene for hemochromatosis (C282Y, H63D). There were eight HLA-identical siblings found in four different families (five men, three women; age range 30-72) with normal transferrin saturation and ferritin levels. There were two patients identified who were homozygous for the C282Y mutation without biochemical evidence of iron overload, and two patients with no evidence of the mutation with significant iron overload. Our conclusions are as follows: 1) finding HLA-identical siblings without iron overload does not confirm a genetic recombination, 2) difficulties in phenotypic definition of disease and the description of new iron overload syndromes that may differ from classical genetic HC cause complicated genetic studies, and 3) finding iron-loaded patients without a C282Y mutation and patients that are homozygous for the C282Y mutation without evidence of iron overload may limit the use of genotyping in population screening for hemochromatosis.

Adult↗
PubMed1994

Expression of the Menkes gene homologue in mouse tissues lack of effect of copper on the mRNA levels.

The expression of the homologue of the Menkes disease gene (Mnk) in mice was studied using RNA blots. The highest level of expression of the 8.0 kb mRNA was found in placenta, substantial expression was noted in lung, heart, brain, testis and kidney and gut mucosa, but very low levels were found in spleen and adult liver. In fetal liver, the amount of Mnk mRNA is similar to that found in kidney, however, it declines soon after birth. Results with copper-loaded normal mice and mutant mice with genetic defects in copper transport suggested that Mnk mRNA levels are not regulated by tissue copper concentrations.

Animals↗
PubMed2005

Backward bifurcation in a model for HTLV-I infection of CD4+ T cells.

Human T-cell Lymphotropic Virus Type I (HTLV-I) primarily infects CD4+ helper T cells. HTLV-I infection is clinically linked to the development of Adult T-cell Leukemia/Lymphoma and of HTLV-I Associated Myelopathy/Tropical Spastic Paraparesis, among other illnesses. HTLV-I transmission can be either horizontal through cell-to-cell contact, or vertical through mitotic division of infected CD4+ T cells. It has been observed that HTLV-I infection has a high proviral load but a low rate of proviral genetic variation. This suggests that vertical transmission through mitotic division of infected cells may play an important role. We consider and analyze a mathematical model for HTLV-I infection of CD4+ T cells that incorporates both horizontal and vertical transmission. Among interesting dynamical behaviors of the model is a backward bifurcation which raises many new challenges to effective infection control.

Algorithms↗
PubMed1996

Urinary kallikrein: a marker of blood pressure sensitivity to salt.

We evaluated if a rat strain inbred for low urinary kallikrein excretion differs from normal-kallikrein Wistar rats regarding blood pressure levels in basal conditions and during alterations in sodium balance. Blood pressure was measured in unanesthetized rats on normal sodium intake. Then, blood pressure sensitivity to salt was evaluated over a period of 20 days of high sodium diet (0.84 mmol per g chow). Low-kallikrein rats showed greater systolic blood pressure levels (125 +/- 3 vs. 114 +/- 2 mm Hg in controls, P < 0.01) at nine weeks of age. Systolic blood pressure was increased after sodium loading in the low-kallikrein group and remained unchanged in controls (150 +/- 6 vs. 112 +/- 2 mm Hg, P < 0.01). This effect was associated with a reduced cumulative urinary excretion of sodium in the low-kallikrein rats. No group difference was found in the clearance of endogenous creatinine in basal conditions. Urinary creatinine excretion decreased during sodium loading, particularly in the low-kallikrein group. The group-difference in urinary kallikrein excretion found in basal conditions (6.85 +/- 0.31 vs. 20.74 +/- 1.71 nkat/24 hr in controls, P < 0.01) was enhanced by high salt diet (2.96 +/- 0.67 vs. 22.07 +/- 2.47 nkat/24 hr in controls, P < 0.01). In addition, renal kallikrein activity and content were reduced in low-kallikrein rats. The latter group showed a greater ratio of heart weight to body wt both in basal conditions and after sodium loading. The ratio of kidney weight to body wt was reduced after sodium loading. These results indicate that a genetically-determined defect in urinary kallikrein excretion is associated with a greater blood pressure sensitivity to salt, possibly due to altered renal sodium handling.

Animals↗
PubMed2003

The relationship between multiple mating by queens, within-colony genetic variability and fitness in the ant Lasius niger.

Multiple mating has been suggested to benefit social insect queens because high genetic variation within colonies might decrease the load imposed by sterile diploid males, enhance resistance to parasites and pathogens, and lead to a more effective division of labour and/or a wider range of tolerable environmental conditions. We tested these hypotheses in the ant Lasius niger with three population samples from Switzerland and Sweden. We found no diploid males in young or mature colonies suggesting a lack of diploid male load. Colonies with multiply-mated queens were not larger nor did they produce more sexuals than colonies with singly-mated queens. We did find a significantly lower frequency of multiple mating among newly mated queens than among the queens heading mature colonies in one population sample (Switzerland 1997). However, this result was not repeated in the other study population, or in the following year in the Swiss population.

Animals↗
PubMed2005

A 6-year survey of HFE gene test for hemochromatosis diagnosis.

PURPOSE: A 6-year survey of HFE gene test was conducted to evaluate its helpfulness for hereditary hemochromatosis diagnosis. METHODS: We analyzed C282Y, H63D, and S65C mutations on 3525 individuals. RESULTS: The test produced 89.7% and 30% of positive results for individuals clinically diagnosed hemochromatosis before HFE gene-test availability and those prospectively tested because of elevated serum iron parameter and/or family history, respectively; among them there were 90.4% and 48.7% of C282Y homozygotes. CONCLUSIONS: The HFE gene test confirmed a genetic defect that may lead to iron loading in individuals when iron parameter values, especially for the C282Y/C282Y, were still low as well as for genotypes usually associated with low expressivity and penetrance (C282Y/H63D, H63D/H63D). This gene-test should allow a biochemical follow-up of patients carrying a disease-related genotype.

Amino Acid Substitution↗
PubMed1983

Photosynthetic rate control in cotton : photorespiration.

The purpose of this research was to determine the magnitude of photorespiration in field-grown cotton (Gossypium hirsutum L.) as a function of environmental and plant-related factors. Photorespiration rates were estimated as the difference between measured gross and net photosynthetic rates.A linear increase in photorespiration was observed as air temperature increased from 22 to 40 degrees C at saturating photon flux density. At 22 degrees C, photorespiration was less than 15 per cent of net photosynthesis and very comparable to the dark respiration rate. At 40 degrees C, photorespiration represented about 50 per cent of net photosynthesis. Gross photosynthesis had a temperature optimum of 32 to 34 degrees C. Water stress, as indicated by Psi(L), did not alter the ratio of gross photosynthesis to net photosynthesis when the confounding effects of leaf temperature differences were accounted for in the data analyses. A reduction in both gross and net photosynthesis was apparent as Psi(L) declined from -2.0 megapascals indicating direct effects of water stress on the photosynthetic process. Photorespiration expressed as a proportion of net photosynthesis increased as water stress intensified.Cotton cultivars possessing a fruit load had significantly higher gross and net photosynthetic rates and lower photorespiration rates than did photoperiod-sensitive cotton strains without a fruit load. Within the fruiting types, which were genetically very similar, only minor differences were observed in the photorespiration:net photosynthesis ratios. However, in the photoperiod-sensitive strains, considerable genetic variability existed when photorespiration was expressed as a proportion of net photosynthesis. These results suggest that the kinetics of ribulose-1,5-bisphosphate carboxylase:oxygenase may be different and, thus, the possibility of genetically reducing photorespiration exists.

Journal Article↗
PubMed2006

Mild dehydrated hereditary stomatocytosis revealed by marked hepatosiderosis.

We report a patient in whom hepatosiderosis was diagnosed at the age of 55 years and who has since been treated by regular bleeding. The H63D mutation was found in the heterozygous state in the HFE gene. No mutation was recorded in the SLC11A3 gene (ferroportin). Hepatosiderosis did not seem primary, nevertheless its cause long remained elusive. Only 2 years ago did we find the responsible condition, a very mildly expressed form of dehydrated hereditary stomatocytosis (DHS). This genetic disease is a strongly iron-loading condition. Haemolysis was fully compensated. Kalaemia was slightly elevated, suggesting a pseudohyperkalaemia that may be associated with DHS. Osmotic gradient ektacytometry allowed to assess the diagnosis of DHS. The red cell monovalent Na+ and K+ concentrations were moderately elevated and reduced respectively. The temperature dependence of the ouabain + bumetanide-resistant K+ influx produced a shallow slope, above and parallel to the control curve. These features were consistent with the diagnosis of DHS. The pronounced hepatosiderosis contrasted with the mildly expressed DHS, and with the ferritinaemia that was slightly elevated, if at all, prior to bleeding. Bleeding caused ferritinaemia to decrease and hepatosiderosis to recede. The whole picture accounts for a misleading presentation of DHS, in which the primary condition long remained hidden behind one of its remotest complications, hepatosiderosis.

Aged↗
PubMed1997

Hormones as regulators of brain development: life-long effects related to health and disease.

The life-long interplay between genes and the environment is instrumental in shaping the structure and function of the body, and these interactions apply to the brain as a plastic and ever-changing organ of the body. Hormones are key regulators of gene expression throughout the body, and the actions of hormones on the brain are instrumental in shaping sex differences and in determining the effects of stress on brain function, including the rate of brain aging. This article also introduces a new term, allostatic load, to describe the cost of adaptation to stressors. Allostasis (stability through change) refers to the output of hormones and autonomic regulators that help to maintain homeostasis, and allostatic load is the consequence of the overactivity of these systems when they are not shut off properly or are forced to be hyperactive by stressors. Key brain areas like the hippocampus are vital to the processing of information that affects how each individual adapts to and responds to potentially stressful life events, and the response of the brain through its control of endocrine and autonomic function in turn determines the degree of allostatic load that an individual will experience. This allostatic load in turn works with the intrinsic genetic susceptibility to determine the progression toward declining health.

Adaptation, Psychological↗
PubMed2005

Design and application of compliant mechanisms for surgical tools.

This paper introduces the benefits of exploiting elasticity in the engineering design of surgical tools, in general, and of minimally invasive procedures, in particular. Compliant mechanisms are jointless mechanisms that rely on elastic deformation to transmit forces and motion. The lack of traditional joints in these single-piece flexible structures offers many benefits, including the absence of wear debris, pinch points, crevices, and lubrication. Such systems are particularly amenable to embedded sensing for haptic feedback and embedded actuation with active-material actuators. The paper provides an overview of design synthesis methods developed at the Compliant Systems Design Laboratory and focuses specifically on surgical applications. Compliant systems have potential to integrate. well within the constraints of laparoscopic procedures and telerobotic surgery. A load-path representation is used within a genetic algorithm to solve two gripper example problems. In addition, the paper illustrates the design and construction of an organ (kidney) manipulator for use in minimally invasive procedures.

Computer Simulation↗
PubMed2003

Duodenal mucosal reductase in wild-type and Hfe knockout mice on iron adequate, iron deficient, and iron rich feeding.

BACKGROUND: Genetic haemochromatosis is a common hereditary iron loading disorder in humans. The disease is associated with loss of function mutations in the HFE gene. This is thought to change iron stores via increased iron absorption. AIMS: In this study we investigated how adaptation of mucosal reductase activity is engaged in this process and how the changes compare with adaptation seen when an iron deficient diet is fed. METHODS: Duodenal mucosal surface reductase was measured with nitroblue tetrazolium in age matched groups of male Hfe knockout mice (Hfe) and wild- type mice fed a purified diet containing normal (iron adequate), high (iron rich), or low (iron deficient) iron concentrations. RESULTS: Reductase activity increased when mice were fed an iron deficient diet and decreased when they were fed an iron rich diet. Total villus activity, as measured by the average area under the activity curve along the crypt-villus axis, was increased 2.8-2.9-fold by iron deficiency in both genotypes. Approximately half of this difference was attributable to the significantly increased length of the villi in mice on an iron deficient diet (p<0.05). Hfe knockout did not affect villus length but increased mucosal reductase activity near the villus tips. Similar increases (1.3-1.6-fold) were seen on all diets but the increase was significant for iron deficient and iron loaded diets only (p<0.05). CONCLUSION: Hfe gene product and dietary iron downregulate villus reductase activity in mice.

Animals↗
PubMed1999

Storage of iron in bone marrow plasma cells. Ultrastructural characterization, mobilization, and diagnostic significance.

The physiological site of iron storage in the human bone marrow is the macrophage (orthotopic iron store). Iron-storing plasma cells, as bone marrow indicators of iron overload, and/or chronic alcoholism represent a pathological (heterotopic) iron store. They were demonstrated by light and electron microscopy in 23 iron-overloaded patients: transfusional siderosis (n = 8), genetic haemochromatosis (GH; n = 11), iron-loading anaemias (n = 4) and in patients with bone marrow impairment due to chronic alcoholism (n = 6). The pattern of iron storage in bone marrow plasma cells was monitored during iron loading in patients receiving continuous transfusional therapy (n = 7) and also upon reversal of iron overload by repeated phlebotomies in GH (n = 9) and in iron-loading anaemias (n = 4). The first ultrastructural evidence of iron storage in plasma cells was the appearance of free ferritin molecules in the cytosol, thus indicating endogenous ferritin synthesis. Accumulation of iron proceeded with the additional formation of ferritin- and haemosiderin-containing lysosomes (siderosomes) in these cells. Lysosomal ferritin partially showed a paracrystalline array. The siderosomes originated from autophagocytosis of cytoplasmic areas containing free ferritin molecules. In addition, the formation of ferritin-containing vesicles in the proximity of the Golgi apparatus was observed. The heterotopic iron store of bone marrow plasma cells was less readily mobilizable by blood-letting than the orthotopic store of macrophages.

Adult↗
PubMed1996

Blunted pressure natriuresis in ovariectomized Dahl-Iwai salt-sensitive rats.

Our objective was to determine whether increased salt sensitivity after menopause precedes the development of overt hypertension. We investigated the effect of ovariectomy on pressure natriuresis in Dahl-Iwai salt-sensitive (DS) and salt-resistant (DR) rats by in vivo perfusion studies. Differences in the neural and hormonal backgrounds of the kidney were minimized by renal denervation and by holding plasma vasopressin, aldosterone, corticosterone, and norepinephrine levels constant by intravenous infusion. The pressure-natriuresis relationship was blunted in DS rats compared with DR rats (slope, 0.30 versus 0.63 mumol.min-1.g kidney wt-1.mm Hg-1, P < .01). The impaired pressure-natriuresis response of DS rats was further blunted by ovariectomy (from 0.30 to 0.14 mumol.min-1.g kidney wt-1.mm Hg-1, P < .05), and that of DR rats was not. The ovariectomized DS rats developed hypertension earlier than sham-operated DS rats by salt loading. These results show that ovariectomy enhances genetic salt sensitivity by blunting the pressure-natriuresis relationship, which precedes the development of overt hypertension in female DS rats.

Animals↗
PubMed2001

Aged mother cells of Saccharomyces cerevisiae show markers of oxidative stress and apoptosis.

Recently, we and others have shown that genetic and environmental changes that increase the load of yeast cells with reactive oxygen species (ROS) lead to a shortening of the life span of yeast mother cells. Deletions of yeast genes coding for the superoxide dismutases or the catalases, as well as changes in atmospheric oxygen concentration, considerably shortened the life span. The presence of the physiological antioxidant glutathione, on the other hand, increased the life span of yeast cells. Taken together, these results pointed to a role for oxygen in the yeast ageing process. Here, we show by staining with dihydrorhodamine that old yeast mother cells isolated by elutriation, but not young cells, contain ROS that are localized in the mitochondria. A relatively large proportion of the old mother cells shows phenotypic markers of yeast apoptosis, i.e. TUNEL (TdT-mediated dUTP nick end labelling) and annexin V staining. Although it has been shown previously that apoptosis in yeast can be induced by a cdc48 allele, by expressing pro-apoptotic human cDNAs or by stressing the cells with hydrogen peroxide, we are now showing a physiological role for apoptosis in unstressed but aged wild-type yeast mother cells.

Apoptosis↗
PubMed1975

[A schizophrenia-like variant of phenylketonuria].

In the clinical picture of 121 patients from 1 to 14 years among the group of 250 with phenylketonuria (48.4%), besides symptoms of mild mental retardation, there were also signs of autism, shallow emotional reactions and catatonic disturbances. This group was distinguished as a special schizophreno-like variant of phenylketonuria. A study of the age and therapeutical dynamics of the psychotic symptomatology has demonstrated that the schizophreno-like syndrome in phenylketonuria may be transient (63 cases) and more stable (58 cases) and does not depend upon the content of hyperphenilalaninemia, the genetical variant of the disorder and hereditary loading by schizophrenia. It is concluded that the schizophreno-like symptomatology in phenylketonuria develops due to a pleiotropic effect of the phenylketonuric gene.

Adolescent↗