Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

By the principle of identity by descent, parental consanguinity in individuals with rare recessively transmitted disorders dictates homozygosity not just at the mutated disease-associated locus but also at sequences that flank that locus closely. In 25 of 26 individuals with Bloom syndrome examined whose parents were related, a polymorphic tetranucleotide repeat in an intron of the protooncogene FES was homozygous, far more often than expected (P < 0.0001 by chi 2). Therefore, BLM, the gene that when mutated gives rise to Bloom syndrome, is tightly linked to FES, a gene whose chromosome position is known to be 15q26.1. This successful approach to the assignment of the Bloom syndrome locus to one short segment of the human genome simultaneously (i) demonstrates the power of homozygosity mapping and (ii) becomes the first step in a "reverse" genetics definition of the primary defect in Bloom syndrome.
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PMID:Bloom syndrome: an analysis of consanguineous families assigns the locus mutated to chromosome band 15q26.1. 802 33

Bloom syndrome (BS) is more common in the Ashkenazi Jewish than in any other population. Approximately 1 in 110 Ashkenazi Jews carries blm, the BS mutation. The locus mutated in BS, BLM, maps to chromosome subband 15q26.1, tightly linked to the proto-oncogene FES. We have investigated the basis for the increased frequency of blm in the Ashkenazim by genotyping polymorphic microsatellite loci tightly linked to BLM in affected and unaffected individuals from Ashkenazi Jewish and non-Ashkenazi populations. A striking association of the C3 allele at FES with blm (delta = .422; p = 5.52 x 10(-7)) and of the 145-bp and 147-bp alleles at D15S127 with blm (delta = .392 and delta = .483, respectively; p = 2.8 x 10(-5) and p = 5.4 x 10(-7), respectively) was detected in Ashkenazi Jews with BS. This linkage disequilibrium constitutes strong support for a founder-effect hypothesis: the chromosome in the hypothetical founder who carried blm also carried the C3 allele at FES and either the 145-bp or the 147-bp allele at D15S127.
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PMID:Linkage disequilibrium between the FES, D15S127, and BLM loci in Ashkenazi Jews with Bloom syndrome. 807 89

To identify the novel receptor tyrosine kinases (RTKs) critical to the proliferation of hematopoietic stem cells, we performed polymerase chain reaction-based cloning from highly purified murine hematopoietic stem cells. Lineage marker-negative, c-KIT-positive, and Ly6A/E- or Sca-1-positive (Lin-c-KIT+Sca-1+) cells were sorted by a fluorescence-activated cell sorter. Two sets of degenerate oligonucleotide primers were directed to the conserved sequences of the catalytic domain, and were used to amplify cDNAs that encode protein tyrosine kinases (PTKs). One hundred cDNA clones were sequenced and 8 RTKs were identified, as well as 12 non-RTKs and 2 serine/threonine kinases. Sixteen cDNAs were identical to the known kinase genes (PKC beta, JAK-1, JAK-2, TYK-2, HCK, FGR, FYN, BLK, c-FES, FER, c-ABL, c-KIT, FLK-1, FLK-2, IGF1R, and ECK). Six novel cDNA sequences (stk series) were identified. However, three of them turned out to be BPK, RYK, and TEK. The remaining three showed high homology to S6 kinase II, JAK-2, and v-SEA/c-MET, respectively. Characterization of full-length cDNA sequence of the v-SEA/cMET-related gene showed that this was a novel RTK gene and we named this gene STK (stem cell-derived tyrosine kinase). We identified two distinct forms of STK cDNA; the short one encoded a putative truncated protein that lacked most of the extracellular domain. STK was expressed at various stages of hematopoietic cells, including stem cells, but we could not detect any apparent expression in other adult tissues. The expression of the truncated form of mRNA was more predominant than that of the complete form. STK was assigned by fluorescent in situ hybridization to the R-positive F1 band of chromosome 9, the same region to which hepatic growth factor-like protein has been assigned. Characterization of these PTKs, including STK, will be helpful to elucidate the molecular mechanism of the growth regulation of hematopoietic stem cells.
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PMID:Molecular cloning of a novel receptor tyrosine kinase gene, STK, derived from enriched hematopoietic stem cells. 819 52

The effects of subchronic (30 days) drinking water exposure of rats to ZnSO4 or Pb(CH3COO)2 alone or in combination on the adrenergically-mediated contractile responses of isolated vas deferens were studied. The contractile effects of the alpha 1, alpha 2-adrenoceptor agonist noradrenaline (NA) and to the alpha 1-adrenoceptor agonist 1-phenylephrine (1-PhE) were decreased after zinc exposure, whereas after lead exposure or lead plus zinc exposure they were not changed. The contractile responses to field electrical stimulation (FES, 0.1 Hz, 1 msec, 80 V) were diminished in amplitude in all metal-treated preparations as compared to controls. The yohimbine-induced restoration of the clonidine inhibited contractions in response to FES was decreased in both lead- and zinc-treated preparations, the EC50 for yohimbine being 0.018 +/- 0.001 microM in control preparations, 0.073 +/- 0.019 microM in lead-treated preparations and 0.056 +/- 0.021 microM in zinc-treated preparations. The calcium-channel blocker verapamil was found to inhibit at low concentrations and to increase at higher concentrations the FES-induced contractile responses in preparations from zinc-exposed rats. The inhibitory effect of cumulatively applied nitrendipine on the FES-induced contractions was increased in both lead- and zinc-treated smooth muscles, but was not altered in the preparations from lead plus zinc-treated rats. Therefore, subchronic exposure to subtoxic doses of lead of zinc led to different changes in the adrenergically-mediated contractility of isolated vas deferens. The changes induced by zinc exposure were not observed after lead plus zinc exposure. All these findings might be of pharmacological, toxicological or clinical importance.
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PMID:Effects of subchronic exposure of rats to lead or zinc on alpha-adrenoceptor-mediated contractile responses in isolated vas deferens. 820 81

The status of gait restoration in spinal cord-injured patients by means of FES is reviewed and the main aspects are discussed. This introduction highlights the issues of balance control, stimulation sequence synthesis, and control of enhanced gait modes containing unbalancing. The use of statically unstable dynamic weight-transfer phases is important for enhanced gait modes. To show how this phase can be employed the mode of static balance currently used for FES-assisted four-point gait in paraplegic patients is discussed, and how this mode of gait can be converted to a semi-dynamic gait mode is described. The possibilities and consequences of such an approach are briefly discussed.
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PMID:FES gait restoration and balance control in spinal cord-injured patients. 823 63

In a previous work, we studied the mechanical and the metabolic profiles of fatigue of paralyzed quadriceps muscle under activation by FES. The metabolic state of the muscle during stimulation of paraplegic patients was monitored, simultaneously with the decaying force, by using 31P nuclear magnetic resonance spectroscopy. In the present work, a musculotendon model was developed to enable prediction of the force output during continuous electrical stimulation. The model consisted of five elements, including the tendon, the parallel elastic, contractile and damper muscle elements, as well as the muscle mass. The mechanism of the contractile element was based upon the length-tension and the velocity-tension curves, the activation trajectory, and the experimentally obtained relationship between force and intracellular pH. In the equations obtained, three sets of parameters were used: 1) general muscle parameters, associated with the length-tension curves of tendon, fascia, and muscle and the velocity-tension curve of the contractile element; 2) specific anthropometric parameters of the muscle; and 3) fatigue parameters which were obtained from our previously recorded experimental data. The model was formulated to allow prediction of the quadriceps muscle force under dynamic activation and at various levels of stimulation. The model solution was for isometric contraction in supermaximal stimulation, and it provided the force decaying profiles, which were compared to those obtained experimentally. The parameters yielding the best fit between the model and the experimental results were indicated. Particularly, two muscle nonspecific parameters, namely, the muscle stress parameter and the parameter representing the ratio between the muscle's slack length and its length in vivo at various knee angles, were determined using the model. The muscle stress parameter was found to be between 60 and 64 N/cm2, and the length ratio was 0.952, 0.935, 0.920, and 0.901 for the 0, 30, 60, and 90 degrees knee angle, respectively. Finally, a sensitivity analysis was conducted of the model to perturbations of these two estimated parameters, revealing that the model was sensitive to these parameters.
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PMID:A musculotendon model of the fatigue profiles of paralyzed quadriceps muscle under FES. 824 27

The relationship between cystic fibrosis (CF) and sinus disease has been appreciated since at least 1959. Unfortunately the standard methods used to treat sinus disease have been very unrewarding in the CF patients. We evaluated the long-term results achieved on 17 patients with CF that underwent FES surgery between July 1988 and January 1991. This group consisted of 16 pediatric and 1 adult patients with previously diagnosed CF, documented chronic sinus disease and nasal polyposis that had failed long-term maximal medical management. The patients, or their parents, were contacted and asked to rate the severity and frequency of their symptoms associated with chronic sinus disease, pre- and postoperatively. The specific symptoms evaluated were nasal obstruction, nasal discharge, postnasal drip, halitosis and cough. In addition, we attempted to measure the number of hospitalizations and the presence and frequency of headaches. We were able to show that, while there was no change in the relative health of patients as measured by the number of hospitalizations, there was a significant improvement in the quality of life. There was a marked decline in the frequency of nasal obstruction, nasal discharge and postnasal drip and a high level of patient satisfaction with the procedure. No changes were seen in the frequency or nature of the cough, halitosis or headache.
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PMID:The results of functional endoscopic sinus (FES) surgery on the symptoms of patients with cystic fibrosis. 830 Mar 11

A system for clinical analysis of sit-to-stand transfer using two force plates is presented. Distinct time-events and phases are estimated. Illustrative parameters are also determined, such as the distribution of the vertical ground reaction forces, displacement of the center of gravity in the sagittal and frontal planes, and a comparison of the displacement of the center of gravity and the center of pressure. These parameters indicate a symmetrical raising while keeping the middle of the body. Future applications include the validation of therapy, biofeedback and the control of closed-loop FES.
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PMID:[A clinically applicable system for analysis of standing up using measurements of floor reaction forces]. 833 19

We have measured in vivo the uptake of 16 alpha-[18F]estradiol (FES) by target tissues in the immature rat at increasing dose levels (obtained by dilution of [18F]FES with unlabeled estradiol). This was done to examine the binding capacity of target tissues in vivo and to determine whether the uptake in receptor-rich tissues was flow limited, as this has implications concerning the appropriateness of using receptor-rich tissues in experimental animals as models for FES uptake by receptor-poor breast tumors in humans. We also wanted to establish the dose level of the anti-estrogen tamoxifen required to block target tissue uptake of FES. We found that in untreated rats, specific uptake in the uterus saturated at c. 180 pmol/g, in the ovary at c. 54 pmol/g and in the muscle at c. 2 pmol/g. At an intermediate dose of tamoxifen (570 micrograms/kg), uptake saturated at somewhat lower levels, and at a high tamoxifen dose (1710 micrograms/kg), yet lower specific uptake was evident. In the FES titrations at low dose levels of FES, both the uterus and the ovaries, but not the muscle, showed characteristics of flow-limited uptake, i.e. the uptake-to-dose ratio reached a maximum level. This flow limitation suggests that only when receptor levels are sufficiently low will the FES uptake be related to receptor concentration. While receptor-rich tissues such as the rat uterus will show this flow limitation, the receptor concentration in most primary and metastatic human breast tumors is sufficiently low, so that the uptake should parallel receptor content. In in vivo distribution studies, target tissues (or tumors) with low receptor content will be more fully saturated and ligand more readily displaced. Also, uptake by secondary target tissues (i.e. those with a lower content of estrogen receptor, such as muscle, thymus and kidney) may be better models for assessing the effectiveness of new breast tumor imaging agents than uptake by receptor-rich tissues.
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PMID:Titration of the in vivo uptake of 16 alpha-[18F]fluoroestradiol by target tissues in the rat: competition by tamoxifen, and implications for quantitating estrogen receptors in vivo and the use of animal models in receptor-binding radiopharmaceutical development. 840 74

Subjects with spinal cord injury are often distressed by pressure sores, which usually appear after prolonged pressure (wheelchair, bed) across the soft tissue which has already lost sensibility and has diminished microcirculation. The healing ability and its dynamics depend on the state of the subject's overall health. Consequently, evaluation of a particular treatment requires careful consideration of as many as possible of the parameters relevant to healing and an adequate criterion for assessing the state of the pressure sore. Bearing in mind these two circumstances, the results of a multicentre clinical study are analysed. The aim of the study was to test two hypotheses: first that healing is faster when sores are also treated by electric currents (ECs) (in addition to conventional treatment); and secondly that there exist differences in the efficiency of the treatment if direct or low-frequency pulsed currents (FES parameters) are applied. The data analysed show that pressure sores are likely to heal twice as fast when treated with low-frequency pulsed currents. EC seems to improve the healing rate in cases where the natural healing mechanisms of the body are not sufficient (chronic wounds, older subjects).
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PMID:Treatment of chronic wounds by means of electric and electromagnetic fields. Part 2. Value of FES parameters for pressure sore treatment. 841 73


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