Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Venous malformations (VMs), the most common errors of vascular morphogenesis in humans, are composed of dilated, serpiginous channels. The walls of the channels have a variable thickness of smooth muscle; some mural regions lack smooth muscle altogether. A missense mutation resulting in an arginine-to-tryptophan substitution at position 849 in the kinase domain of the receptor tyrosine kinase TIE2 segregates with dominantly inherited VM in two unrelated families. Using proteins expressed in insect cells, we demonstrate that the mutation results in increased activity of TIE2. We conclude that an activating mutation in TIE2 causes inherited VMs in the two families and that the TIE2 signaling pathway is critical for endothelial cell-smooth muscle cell communication in venous morphogenesis.
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PMID:Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. 898 Feb 21

This study investigates firstly how far cellular edema correlates with parameters of the anaerobic energy turnover independent of the method used for cardiac arrest, and secondly to what extent cellular edema developing during reversible global ischemia is reduced after reperfusion. Canine hearts were arrested 1. by aortic cross clamping (ACC), 2. by coronary perfusion with St. Thomas solution, or 3. HTK (histidine tryptophan ketoglutarate) solution (Custodiol). Samples for biochemical and structural analysis were taken at different times during ischemia and after reperfusion with Tyrode solution. Cellular edema determined morphometrically and given as volume ratio of sarcoplasm and mitochondria to myofibrils (Vvsp + V vmi/Vvmf) varies significantly in the differently arrested hearts. Reperfusion after a decrease in ATP to 4 mumol/gww (revival time) leads to a nearly complete structural recovery. The relationship between cellular edema and defined over-all metabolite tissue concentrations and extracellular pHe values shows: 1. during the decrease of creatine phosphate to 3 mumol/gww, cellular edema does not change; it is, however, significantly higher after ACC and St. Thomas than after HTK perfusion; 2. at each lactate concentration, cellular edema differs significantly depending on the form of cardiac arrest; 3. during the decrease of ATP and pHe cellular edema increases and is comparable at concentrations < 4 mumol/gww and at pHe values < 6.5 independent of the form of cardiac arrest; 4. beyond 10 mumol/gww of inorganic phosphate (Pi), increasing values for cellular edema correspond to defined Pi values in the differently arrested hearts. Thus, the ratio VVSp+ VVMi/VVMf is a powerful parameter for the determination of cellular edema during ischemia, as well as for correlations with metabolic parameters.
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PMID:Cellular edema and alterations in metabolite content in the ischemic and reperfused canine heart following different forms of cardiac arrest. 912 37

Pfeiffer syndrome is a skeletal disorder characterized by craniosynostosis associated with foot and hand anomalies. Mutations in the genes encoding fibroblast growth factor receptors 1 and 2 (FGFR1 and FGFR2) have recently been implicated in the aetiology of such a syndrome, as well as of other craniosynostotic conditions. We now report a novel missense mutation, a G to C transversion at position 1049 (exon IIIa) of FGFR2, detected in a patient with severe Pfeiffer clinical features. The mutation results in the substitution of a cysteine for tryptophan-290 in the third immunoglobulin-like domain and affects both spliceoforms of FGFR2. Mutations causing replacement of tryptophan-290 have also been reported previously in Crouzon syndrome, a similar but clinically distinct craniosynostotic disorder. This finding confirms the involvement of mutations of FGFR2 exon IIIa in Pfeiffer syndrome, and emphasizes both the extensive heterogeneity of the FGFR2 mutations that result in the Pfeiffer phenotype and the perturbations caused by unpaired cysteine residues in receptor dimerization and transduction of the FGFs signal.
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PMID:Trp290Cys mutation in exon IIIa of the fibroblast growth factor receptor 2 (FGFR2) gene is associated with Pfeiffer syndrome. 915 Jul 25

This study investigated the pathways to many monoamines and their metabolites in the central nervous system of the frog Rana nigromaculata and the toad Bufo bufo japonicus during embryonic development and metamorphosis. Metabolites were analyzed by three-dimensional HPLC. The two species provided evidence of similar pathways, with slightly different timetables for the development of their monoamine systems. During embryonic development, the main metabolic pathways in entire embryos were tyrosine (TYR)-->[3,4-dihydroxyphenylalanine in Bufo]-->3-hydroxytyramine-->norepinephrine or epinine (EPIN)-->epinephrine, TYR-->tyramine--> (octopamine in Rana) and TYR-->3-O-methyldopa for catecholamines, and tryptophan-->kynurenine and 5-hydroxytryptamine (5-HT)-->[5-hydroxyindoleacetic acid and N-methyl-5-hydroxytryptamine (N-MET) in Bufo]. The monoamine system in the brain was similar during metamorphosis to that during embryogenesis with a few exceptions. The most striking change was the development of the bufotenine (5-hydroxy-N, N-dimethyltryptamine) pathway from 5-HT via N-MET. EPIN and norepinephrine in Rana and octopamine in both species disappeared during metamorphosis. These results are discussed in relation to the roles of the various pathways in development.
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PMID:The metabolism of biogenic monoamines during embryogenesis and metamorphosis in two anuran species. 920 70

Warm ischemia is known to induce substantial damage to the liver parenchyma. With respect to clinical liver transplantation, the tolerance of the liver to warm ischemia and the preservation of these organs have not been studied in detail. In isolated reperfused pig livers we proceeded according to the following concept: Livers were subjected to 1 or 3 h of warm ischemia. Subsequently, these organs were preserved by either normothermic perfusion or cold storage (histidine-tryptophan-alpha-ketoglutarate, HTK) for 3 h each. After storage, liver function was assessed in a reperfusion circuit for another 3 h. Parameters under evaluation were bile flow, perfusion flow, oxygen consumption, enzyme release into the perfusate (creatine kinase, glutamic oxaloacetic transaminase (GOT), lactic dehydrogenase, and glutamic pyruvic transaminase), and histomorphology. Damage to the liver was lowest after warm ischemia of 1 h. The results after cold storage were superior to those after normothermic perfusion (GOT: 3.2 +/- 0.3 and 2.6 +/- 0.2 U/g liver; cumulative bile production: 14.7 +/- 2.1 and 9.4 +/- 1 ml, respectively; P < 0.05). In contrast, we found substantial damage at the end of reperfusion in livers undergoing 3 h of warm ischemia under both preservation techniques with severe hepatocellular pyknoses and essentially altered nonparenchymal cells. The results suggest that pig livers undergoing 1 h of warm ischemia and cold storage for 3 h with HTK solution may lead to functioning after transplantation.
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PMID:Preservation of pig liver allografts after warm ischemia: normothermic perfusion versus cold storage. 939 99

The quality of organ preservation is of major importance in minimizing the incidence of primary graft nonfunction and organ rejection. For this study a new semiquantitative score was developed that grades morphologic tissue alterations in the liver according to their frequency and severity. It was applied to assess commonly used perfusion solutions for their efficacy in preventing early and late tissue damage after rat liver transplantation. For transplantation the livers were stored in Euro-Collins (EC, group I; n = 11), histidine-tryptophan-alpha-ketoglutarate (HTK, group II; n = 11), or University of Wisconsin solution (UW, group III; n = 11). Rat liver transplantation was performed with graft arterialization by the method of Engemann. Biopsies were taken for morphological examination and semiquantitative scoring during the donor operation, after 4 h of cold storage, 1 h after reperfusion, and 4 weeks postoperatively. An immunohistological bromodeoxyuridine (BrdU) assay was also performed on the day of dissection to assess the rate of hepatic proliferation. Semiquantitative morphological analysis gave widely differing results in all experimental groups after 4 h of ischemia. There was less intracellular and interstitial edema, fatty degeneration, intralobular necrosis, and hepatocellular proliferation in the HTK group than in the other groups. Neither after cold ischemia nor 1 h after reperfusion did Kupffer-cell activation occur; this is known to play a major role in the development ofischemia and reperfusion injury. Furthermore, late changes such as bile-duct proliferation and vascular and sinusoidal alterations appeared less frequently in this group. The hepato-protective powers of HTK solution might therefore be due to decreased Kupffer-cell activation.
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PMID:Organ preservation with EC, HTK, and UW, solution in orthotopic rat liver transplantation. Part II. Morphological study. 1050 Oct 78

Pheochromocytomas are rare tumours, with an incidence of 1-2 per million which arise from chromaffin cells of the adrenal medulla. They occur sporadically or as part of dominantly inherited cancer syndromes like multiple endocrine neoplasia 2 (MEN2A and 2B) and others. Continuous cell lines, not available so far, are essential tools for studies in these tumours. A continuous cell line (KNA) was established from a sporadic pheochromocytoma of the right adrenal gland of a 73-year-old woman. The KNA cells grow as suspensions of spheroids and show the morphological and immunocytochemical characteristics of neuronal chromaffin cells, such as neuroendocrine granules, and positive reactions to chromogranin- and related peptide-, neuron specific enolase and vasoactive intestinal peptide antibodies. Neurite-like processes are formed after addition of nerve growth factor. Chromosomal analyses revealed a diploid (46,XX,n = 50) to hypodiploid (43-45,XX,n = 15) karyotype. In hypodiploid metaphases most frequently #19, #17, #21 and #22 were missing. Chromosome arms 1p and 4q showed apparently consistent interstitial deletions: 6q, 8q, 13q and 22q showed clonal interstitial deletions. The cell line shows a heterozygous sequence variant TGC (cysteine) to TGG (tryptophan) in codon 611 in exon 10 of the RET proto-oncogene. So far, PC-12, a rat adrenal pheochromocytoma, has been the only continuous pheochromocytoma cell line available. KNA represents the first report on a human continuous pheochromocytoma cell line, the first report of structural chromosome aberrations in pheochromocytomas and the first report of a RET mutation TGC to TGG in exon 10 of the RET proto-oncogene in a sporadic pheochromocytoma.
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PMID:First continuous human pheochromocytoma cell line: KNA. Biological, cytogenetic and molecular characterization of KNA cells. 1064 Jan 77

Pancreatic segmental autotransplantation in the pig has been considered an attractive model to study several aspects of pancreas transplantation because of the absence of rejections related to the immune system. However, the frequent presence of anatomical variations in the vascular supply of the left pancreatic segment in the pig makes this model difficult, impairing the access for vascular flushing and revascularization in pancreatic autotransplantation. We assessed pancreatic vascular anatomy of 71 Landrace pigs: group I (G1, n = 32) transplanted after direct reconstruction of the hepatic flow; and group II (G2, n = 39) transplanted after hepatic-celiac arterial reconstruction (HECAR) with an iliac vascular graft between the celiac trunk and the hepatic artery. HTK (histidine-tryptophan-ketoglutarate; Custodiol) and UW (University of Wisconsin; Viaspan) solutions were used. In total, 23 technically successfully transplanted animals (HTK = 15; UW = 8) after 24 h of cold storage were studied. Reconstruction time was longer in G2 than in G1 (p = .04). Thrombosis of the reconstructed hepatic artery occurred more in G1 than in G2 (45% vs. 8%, respectively, p = .013). Pancreatic arterial thrombosis was noticed in 10 animals in G1 (32%) and in 2 in G2 (5%) (p = .026). Ninety-four percent of pancreas grafts were suitable for cold storage study in G2 versus 45% for G1 (p < .001). No differences were noticed in K values, weight of transplanted grafts, preoperative and 24 h postoperative glycemia, for both preservation solutions. Segmental pancreatic autotransplantation can be successfully performed for cold preservation studies. A high percentage of pancreas useable for transplantation can be achieved using hepato-celiac arterial reconstruction. HTK solution is suitable for flushing and 24 h of preservation for pancreatic grafts in the porcine model.
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PMID:Segmental porcine pancreatic autotransplantation as model for pancreas preservation studies using two different techniques for vascular reconstruction. 1099

A large body of data from a number of different laboratories worldwide has demonstrated a general tendency for reduced adrenocortical responsiveness in CFS. It is still not clear if this is secondary to CNS abnormalities leading to decreased activity of CRH- or AVP-producing hypothalamic neurons. Primary hypofunction of the CRH neurons has been described on the basis of genetic and environmental influences. Other pathways could secondarily influence HPA axis activity, however. For example, serotonergic and noradrenergic input acts to stimulate HPA axis activity. Deficient serotonergic activity in CFS has been suggested by some of the studies as reviewed here. In addition, hypofunction of sympathetic nervous system function has been described and could contribute to abnormalities of central components of the HPA axis. One could interpret the clinical trial of glucocorticoid replacement in patients with CFS as confirmation of adrenal insufficiency if one were convinced of a positive therapeutic effect. If patient symptoms were related to impaired activation of central components of the axis, replacing glucocorticoids would merely exacerbate symptoms caused by enhanced negative feedback. Further study of specific components of the HPA axis should ultimately clarify the reproducible abnormalities associated with a clinical picture of CFS. In contrast to CFS, the results of the different hormonal axes in FMS support the assumption that the distortion of the hormonal pattern observed can be attributed to hyperactivity of CRH neurons. This hyperactivity may be driven and sustained by stress exerted by chronic pain originating in the musculoskeletal system or by an alteration of the CNS mechanism of nociception. The elevated activity of CRH neurons also seems to cause alteration of the set point of other hormonal axes. In addition to its control of the adrenal hormones, CRH stimulates somatostatin secretion at the hypothalamic level, which, in turn, causes inhibition of growth hormone and thyroid-stimulating hormone at the pituitary level. The suppression of gonadal function may also be attributed to elevated CRH because of its ability to inhibit hypothalamic luteinizing hormone-releasing hormone release; however, a remote effect on the ovary by the inhibition of follicle-stimulating hormone-stimulated estrogen production must also be considered. Serotonin (5-HT) precursors such as tryptophan (5-HTP), drugs that release 5-HT, or drugs that act directly on 5-HT receptors stimulate the HPA axis, indicating a stimulatory effect of serotonergic input on HPA axis function. Hyperfunction of the HPA axis could also reflect an elevated serotonergic tonus in the CNS of FMS patients. The authors conclude that the observed pattern of hormonal deviations in patients with FMS is a CNS adjustment to chronic pain and stress, constitutes a specific entity of FMS, and is primarily evoked by activated CRH neurons.
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PMID:Neuroendocrine perturbations in fibromyalgia and chronic fatigue syndrome. 1108 55

We have identified and characterized a gene (60% on protein level) and a pseudogene (93% on DNA level) that show high similarity to the Wolf-Hirschhorn syndrome candidate gene-1 (WHSC1). These genes, WHSC1L1 and WHSC1L2P, map to human chromosomes 8p11.2 and 17q21, respectively. WHSC1L1 is ubiquitously expressed and, like WHSC1, generates two major transcripts, a short (s-type) and a long (l-type). The WHSC1L1 l-type transcript encodes a 1437-amino-acid protein containing 2 PWWP (proline-trypto-phan-proline-tryptophan) domains, 5 PHD (plant-home-domain)-type zinc finger motifs, a SAC (SET-associated Cys-rich) domain, and a SET (Suppressor of Variegation, Enhancer of Zeste and Trithorax) domain. The s-type transcript encodes a protein of 645 amino acids containing a PWWP domain only. WHSC1L2P is an unexpressed, intronless pseudogene of a WHSC1L1 s-type transcript. The 8p11.2 region around WHSC1L1 contains a set of genes including TACC1, FGFR1, LETM2, and WHSC1L1, which seems to be derived from a recent duplication involving 4p16.3 where a similar set of genes is located. Rearrangements of 8p are frequently found in human cancer, including breast cancer. These characteristics indicate that WHSC1L1 might have a role in embryonic development and, when disregulated, in cancer development.
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PMID:WHSC1L1, on human chromosome 8p11.2, closely resembles WHSC1 and maps to a duplicated region shared with 4p16.3. 1154 11


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