Clinical aspects of hereditary nonpolyposis colorectal cancer.
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Colorectal Neoplasms, Hereditary Nonpolyposis↗
Biomedical subjects
T Vogel
Publications and source records attributed to T Vogel.
Case 3--1999. Severe fetal bradycardia in a pregnant woman undergoing hypothermic cardiopulmonary bypass.
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Adult↗
Virus-specific cytotoxic T-lymphocyte responses select for amino-acid variation in simian immunodeficiency virus Env and Nef.
Cytotoxic T-lymphocyte (CTL) responses to human immunodeficiency virus arise early after infection, but ultimately fail to prevent progression to AIDS. Human immunodeficiency virus may evade the CTL response by accumulating amino-acid replacements within CTL epitopes. We studied 10 CTL epitopes during the course of simian immunodeficiency virus disease progression in three related macaques. All 10 of these CTL epitopes accumulated amino-acid replacements and showed evidence of positive selection by the time the macaques died. Many of the amino-acid replacements in these epitopes reduced or eliminated major histocompatibility complex class I binding and/or CTL recognition. These findings strongly support the CTL 'escape' hypothesis.
Amino Acid Sequence↗
Mice with Y chromosome deletion and reduced Rbm genes on a heterozygous Dazl1 null background mimic a human azoospermic factor phenotype.
A subset of azoospermia or oligozoospermia patients have microdeletions in defined regions of their Y chromosome, namely the AZFa, b, and c regions. Candidate genes in humans that may cause the azoospermia factor (AZF) phenotype have been assigned to these regions and can include the DAZ and RBM genes. Part of the variability in the AZFc phenotype might be due to interaction between the effects of deleting the DAZ and RBM genes. We mimicked human deletions of RBM and DAZ in the mouse by crossing male mice with a deleted Y chromosome with a reduced number of Rbm genes (Y(d1)) to heterozygote Dazl1 null female mice to study the interaction of the Dazl1 and Rbm or other genes located in the Y(d1) deletion interval. Dazl-/+ Y(d1) animals showed a significant reduction in the sperm count (P < 0.001), an increase of abnormal sperm heads and prominent mid-piece defects of the tails compared to either mutation alone (P < 0.001). Hence, Dazl1 and the genes removed on the Y(d1) chromosome are active in different pathways contributing to different stages of spermatogenesis. Reduction of Dazl1 and Rbm genes as well as/or deletion of the Y chromosome in mice gives rise to a phenotype similar to the heterogeneous AZFc phenotype observed in humans.
Animals↗
Reduced coronary NO production in conscious dogs after the development of alloxan-induced diabetes.
The role of nitric oxide (NO) in the control of coronary blood flow (CBF) during the development of diabetes is unknown. To study this, mongrel dogs were chronically instrumented using sterile techniques for measurements of systemic hemodynamics and CBF. With heart rate controlled (150 beats/min), veratrine (1-10 micrograms/kg) caused dose-dependent increases in CBF; e.g., 5 mirograms/kg of veratrine increased CBF by 57 +/- 7% from 41 +/- 1.3 ml/min (P < 0.05). The dogs developed diabetes 4-5 wk after injection of alloxan (40-60 mg/kg iv, blood glucose levels were 384 +/- 18 mg/dl). After diabetes the same doses of veratrine caused smaller increases in CBF; i.e., 5 micrograms/kg of veratrine increased CBF by 32 +/- 2% (P < 0.05 compared with control) from 28 +/- 4 ml/min. ACh- and adenosine-induced coronary vasodilation were reduced after diabetes as well. In anesthetized dogs after diabetes, vagal stimulation caused smaller increases in CBF. ACh and bradykinin caused smaller increases in NO(-)(2) production in coronary microvessels from diabetic dogs. Furthermore, despite the fact that mRNA for endothelial cell NO synthase from the aorta was increased twofold with the use of Northern blotting, the protein for aortic endothelial constitutive NO synthase was reduced by 66% after diabetes, as determined by Western blotting. Our results indicate that the NO-dependent coronary vasodilation by the Bezold-Jarisch reflex is impaired in conscious dogs after diabetes. The mechanism responsible for the impaired endothelium-dependent coronary vasodilation is most likely the decreased release of NO from the endothelium.
Acetylcholine↗
Role of nitric oxide in the control of renal oxygen consumption and the regulation of chemical work in the kidney.
Inhibition of NO synthesis has recently been shown to increase oxygen extraction in vivo, and NO has been proposed to play a significant role in the regulation of oxygen consumption by both skeletal and cardiac muscle in vivo and in vitro. It was our aim to determine whether NO also has such a role in the kidney, a tissue with a relatively low basal oxygen extraction. In chronically instrumented conscious dogs, administration of an inhibitor of NO synthase, nitro-L-arginine (NLA, 30 mg/kg i.v.), caused a maintained increase in mean arterial pressure and renal vascular resistance and a decrease in heart rate (all P<0.05). At 60 minutes, urine flow rate and glomerular flow rate decreased by 44+/-12% and 45+/-7%, respectively; moreover, the amount of sodium reabsorbed fell from 16+/-1.7 to 8.5+/-1.1 mmol/min (all P<0.05). At this time, oxygen uptake and extraction increased markedly by 115+/-37% and 102+/-34%, respectively (P<0.05). Oxygen consumption also significantly increased from 4.5+/-0.6 to 7.1+/-0.9 mL O2/min. Most important, the ratio of oxygen consumption to sodium reabsorbed increased dramatically from 0.33+/-0.07 to 0.75+/-0.11 mL O2/mmol Na+ (P<0.05), suggesting a reduction in renal efficiency for transporting sodium. In vitro, both a NO-donating agent and the NO synthase-stimulating agonist bradykinin significantly decreased both cortical and medullary renal oxygen consumption. In conclusion, NO plays a role in maintaining a balance between oxygen consumption and sodium reabsorption, the major ATP-consuming process in the kidney, in conscious dogs, and NO can inhibit mitochondrial oxygen consumption in canine renal slices in vitro.
Animals↗
Effective therapy for hepatic M. Osler with systemic hypercirculation by ligation of the hepatic artery and subsequent liver transplantation.
Hereditary hemorrhagic teleangiectasia, or M. Osler (Osler-Weber-Rendu disease), is an autosomal dominant, systemic fibrovascular dysplasia. This may lead to increased liver blood flow from arteriovenous fistulas. A 45-year-old woman with a known M. Osler was admitted for liver transplantation. On admission, exertional dyspnea was the predominant symptom. Radiological investigations revealed multiple intrahepatic arteriovenous fistulas and consecutive high-output heart failure. Laboratory findings revealed remarkably elevated bilirubin and alkaline phosphatase. To alleviate the high-output cardiac failure, the hepatic artery was ligated. Fourteen months later, the patient presented again with increased levels of bilirubin and recurrent bleeding episodes from esophageal varices grade IV. The patient underwent liver transplantation and post-transplant recovery was excellent. A hyperdynamic circulatory state due to a hepatic M. Osler has been treated in several cases by ligation or embolization of the hepatic artery. This procedure, however, is recommended only for patients with normal liver function and carries a considerably risk of bile duct necrosis.
Cardiac Output↗
A murine TSPY.
Sequences homologous to human and bovine TSPY were isolated from M. musculus testicular cDNA, and a nearly full-length gene was polymerase chain reaction (PCR) amplified from mouse genomic DNA. This gene is apparently non-functional. Contrary to the situation encountered in species along the primate and artiodactyl lineages, in which TSPY is moderately repetitive, murine Tspy appears to be single copy. Murine Tspy is located on Yp, i.e. in the same syntenic group as in man. Sequence comparisons of murine, human and bovine TSPY exons suggest that TSPY became non-functional during rodent evolution.
Animals↗
Adenosine and extracellular volume in radiocontrast media-induced nephropathy.
Renal hemodynamic changes could play a key role in radiocontrast media-induced nephropathy (RCIN), although the pathophysiological mechanisms are unclear. We investigated the role of adenosine in RCIN caused by sodium diatrizoate (Urografin, 3 ml/kg) in nitro-L-Arg methyl ester (L-NAME)-hypertensive rats in different hydration states [eight weeks of L-NAME (50 mg/liter) in drinking water; high or low sodium intake for the last two weeks]. In clearance experiments under thiobutabarbital anesthesia in these previously mentioned animals, glomerular filtration rate (GFR), renal blood flow (RBF), and mean arterial pressure (MAP) were measured in the presence or absence of the adenosine A1-receptor antagonist 8-cyclopropyl-1,3-dipropylxanthine (DPCPX, 100 microg/kg bolus plus 10 microg/kg/hr). DPCPX or pretreatment did not change control hemodynamics. Contrast medium caused GFR and RBF to fall significantly in volume-depleted rats (from 0.29 +/- 0.02 to 0.21 +/- 0.02 ml/min/100 g and 5.4 +/- 0.3 to 4.0 +/- 0.4 ml/min, respectively) without change in MAP. In volume-expanded rats, changes were not significant (0.25 +/- 0.01 to 0.24 +/- 0.02 ml/min/100 g and 5.6 +/- 0.3 to 5.3 +/- 0.4 ml/min, respectively). In the volume-depleted rats, changes were prevented by DPCPX (0.27 +/- 0.02 to 0.24 +/- 0.02 ml/min/100 g and 4.8 +/- 0.1 to 5.0 +/- 0.1 ml/min, respectively). The acute hemodynamic effects elicited by contrast medium in L-NAME hypertensive rats thus can be prevented by volume expansion. Adenosine, via A1-receptors, contributes to the adverse effects of contrast media.
Acute Kidney Injury↗
Molecular cloning and characterization of P47, a novel boar sperm-associated zona pellucida-binding protein homologous to a family of mammalian secretory proteins.
P47, a peripherally associated 47-kDa protein of porcine spermatozoa, was identified by affinity chromatography in the fraction of solubilized plasma membrane proteins bound to immobilized porcine zona pellucida glycoproteins. N-terminal and internal amino acid sequences revealed structural similarity between P47 and rat O-acetyl ganglioside synthase, bovine mammary gland protein (MGP)57/53 and mouse milk fat globule protein E8-polypeptides of unknown function secreted by mammary gland epithelial cells in both species. A polyclonal antibody directed against bovine MGP57/53 displayed cross-reactivity with P47. Indirect immunofluorescence analysis located porcine P47 on the acrosomal cap of testicular sperm and on sperm recovered along different sections of the ductus epididymidis, as well as on swim-up and in vitro-capacitated sperm. Porcine P47 was demonstrated on sperm bound to the zona pellucida of a homologous oocyte. Western blot analysis identified P47 (or MGP57/53) homologous proteins in porcine and human milk. Like the sperm-associated protein, porcine milk P47 possesses affinity for isolated, biotinylated sow oocyte zona pellucida glycoproteins. Reverse transcription-polymerase chain reaction was used to isolate P47 homologous cDNAs from porcine testis and mammary gland tissues as well as from bovine, mouse, and human testis. P47 proteins deduced from these cDNA sequences showed 60-100% amino acid sequence identity. These proteins display a mosaic structure organized into two N-terminal, tandemly arranged epidermal growth factor (EGF)-like domains followed by a region with similarity to C1 and C2 domains found in blood clotting factors V and VII. The second EGF-like domain contains an arginine-glycine-aspartic acid sequence, a motif often found in integrin receptor ligands. P47-like proteins are not expressed solely in testicular and mammary gland tissues. Northern blot analysis showed that P47 mRNA is transcribed in several porcine and bovine tissues. These data indicate a potential role for boar sperm-associated P47 in membrane remodeling and/or as a zona pellucida binding protein.
Amino Acid Sequence↗
Structure and function of TSPY, the Y-chromosome gene coding for the "testis-specific protein".
The TSPY genes are arranged in clusters on the Y chromosome of many mammalian species. TSPY is believed to function in early spermatogenesis and is a candidate for GBY, the putative gonadoblastoma-inducing gene on the Y. The TSPY family forms part of a superfamily, TTSN, with autosomal representatives, highly conserved in mammals and beyond.
Animals↗
Murine and human TSPYL genes: novel members of the TSPY-SET-NAP1L1 family.
Using expressed sequence tag (EST) sequence information, novel genes related to the Y chromosome gene family TSPY were isolated and characterized. Because of a significant homology to TSPY, the novel genes were designated TSPY-Like (TSPYL) and were assigned as new members of the TSPY-SET-NAP1L1 family. A human TSPYL gene was localized on chromosome 6 and a murine Tspyl gene was localized on chromosome 10. Expression of TSPYL was observed in all tissues investigated, as well as early onset during development. Both the human and murine Tspyl homologs lack introns over the entire region so far investigated and are thought to have arisen by an ancient retroposition event. Retroposition of Tspyl genes is supported by the isolation of a murine Tspyl pseudogene on chromosome 12 which also lacks intronic sequences, and by its observed proximity to an R element, a family of dispersed repetitive DNA.
Animals↗
Organization and expression of rat Tspy.
We have isolated both a full-length rat Tspy cDNA from testicular mRNA by rapid amplification of cDNA ends (RACE) and RT-PCR and a full-length rat Tspy gene from genomic DNA by PCR. In contrast to the mouse, where Tspy is present in a single copy and is apparently functionless, and to man and cattle, where TSPY is organized in a moderately repetitive cluster, the rat Tspy locus apparently consists of one complete functional and one truncated, probably nonfunctional, copy, coherently localized on Yp, as revealed by FISH analysis.
Animals↗
[Pelvic exenteration from the surgical viewpoint].
Pelvic exenteration (PE) is associated with specific problems in the indication of excision and reconstructive surgery. Indication are colorectal cancer or cervical cancer recurrence. In each case intensive and early cooperation of gynecologist, surgeon and urologist is warranted. Thus, PE is indicated in some T3 N1 and T4 rectal carcinoma patients without distant metastases and may be superior to chemotherapy. In cervix carcinoma recurrence, PE with or without intestinal reconstruction is of specific importance. While intestinal reconstruction may improve the quality of life in R0 resected patients we reluctantly perform this in noncurative treated patients, since their expected survival time is limited and reconstructive surgery in these pretreated patients (radiation and surgery) increases the risk of morbidity.
Adult↗
Heparan sulfate proteoglycan-mediated uptake of apolipoprotein E-triglyceride-rich lipoprotein particles: a major pathway at physiological particle concentrations.
We explored potential mechanisms of non-low-density lipoprotein (LDL) receptor-mediated uptake of triglyceride-rich particles (TGRP) in the presence of apolipoprotein E (apo E). Human fibroblasts were incubated with model intermediate-density lipoprotein- (IDL-) sized TGRP (10-1000 microg of neutral lipid/mL) containing apo E. The extent of receptor-mediated uptake of TGRP was assessed with (a) an anti-apo E monoclonal antibody, which blocks receptor interaction; (b) incubation with heparin; (c) normal vs LDL receptor-negative fibroblasts; and (d) receptor-associated protein (RAP) to determine the potential contribution of LDL receptor-related protein (LRP). Cell surface heparan sulfate proteoglycan- (HSPG-) mediated uptake was examined with or without the addition of heparinase and heparitinase to cell incubation mixtures. At low particle concentrations (</=100 microg of neutral lipid/mL), almost all apo E-TGRP uptake was via the LDL receptor. At higher particle concentrations, within the physiologic range (>250 microg of neutral lipid/mL), most (>/=60%) particle uptake and internalization was via HSPG-mediated pathways. This HSPG pathway did not involve classical lipoprotein receptors, such as LRP or the LDL receptor. These data suggest that in peripheral tissues, such as the arterial wall, apo E may act in TGRP as a ligand for uptake not only via the LDL receptor and LRP pathways but also via HSPG pathways that are receptor-independent. Thus, at physiologic particle concentrations apo E-TGRP can be bound and internalized in certain cells by relatively low affinity but high capacity HSPG-mediated pathways.
Antibodies, Monoclonal↗
Selective modification at the N-terminal region of human growth hormone that shows antagonistic activity.
A new analogue of recombinant human growth hormone (hGH), hGH des(1-6,14) was expressed in Escherichia coli, refolded and purified to homogeneity. The mutation decreased the hormone's ability to bind lactogenic and somatogenic receptors through its site 1, and almost completely abolished its ability to bind these receptors through site 2, as evidenced by both binding and gel-filtration experiments. More specifically, the binding to prolactin receptors (PRLRs) from various species or their soluble recombinant extracellular domains (ECDs) was decreased 1.5-4-fold, whereas the binding to hGH receptor (hGHR) was decreased 10-85-fold. These changes caused an almost total loss of hormone agonistic activity in several in vitro bioassays and subsequently, the hGH des(1-6,14) analogue acquired antagonistic properties. This antagonistic activity was dependent upon modification of site 1. In those cases in which the binding was reduced only slightly, e.g. binding to rabbit PRLRs, hGH des(1-6,14) acted as a strong antagonist, whereas in others in which the binding of site 1 was reduced to a higher degree, such as other PRLRs and, in particular, hGHR, the antagonistic activity was correspondingly weaker. Circular dichroism spectra of the analogue suggested that these changes do not result from a decrease in overall alpha-helix content, but rather from minor local structural modifications at the N-terminus.
Animals↗
Mechanisms of nitrate accumulation in plasma during pacing-induced heart failure in conscious dogs.
The goal of this study was to understand the mechanisms behind the changes in plasma NOx during heart failure. Heart failure is associated with an increase in plasma nitrate levels, and yet most experimental evidence demonstrates a reduction in endothelial nitric oxide production during heart failure. Dogs were chronically instrumented for measurement of systemic hemodynamics and left ventricular (LV) dimensions. Hearts were paced at 210 bpm for 3 weeks (n = 14) and then 240 bpm for 1 week (n = 7). Hemodynamics, arterial blood gases, plasma NOx, and creatinine levels were monitored weekly. Heart failure was evidenced by cachexia, ascites, and hemodynamic alterations. Resting heart rate rose (94 +/- 6 to 135 +/- 9 bpm), and LV dP/dt fell (2810 +/- 82 to 1471 +/- 99 mm Hg/s), while LV end diastolic pressure quadrupled (5.8 +/- 0.7 to 25 +/- 0.8 mm Hg), and diastolic wall stress quadrupled (11 +/- 1.3 to 43 +/- 6.0 g/cm2, all P < 0.05). These changes occurred during a doubling in plasma NOx (5.5 +/- 1.5 to 10 +/- 1.6 microM, P < 0.05). There were no changes in plasma NOx through 3 weeks of pacing. Plasma creatinine levels increased 450% (from 0.27 +/- 0.32 to 1.21 +/- 0.63 mg%). Stimulated nitrite production by agonists in sieved coronary microvessels was unchanged after 3 weeks of pacing but was reduced after heart failure. Plasma NOx did not correlate with LV dP/dt or systolic wall stress but correlated directly with LV EDP or diastolic wall stress and inversely with cardiac work. Plasma NOx rose in direct relation to plasma creatinine levels (Y = 4.8X + 2.8, r2 = 0.84), suggesting that the rise in plasma NOx during heart failure is due to decreased renal function not increased NO production.
Acetylcholine↗
Organization and expression of bovine TSPY.
We have isolated genomic sequences as well as transcripts from the bovine homolog of the human testis-specific protein, Y-encoded, TSPY which-in both species-is located on the Y Chromosome (Chr), organized as a gene family with a variable number of members, and expressed exclusively in the testis. 1266 bp of bovine TSPY specific sequence have been isolated from a testis cDNA library, by RT-PCR analyses and by Rapid Amplification of cDNA Ends (RACE). A bovine TSPY gene 4 is organized in seven exons, and transcripts are polyadenylated at various 3' ends. Consensus polyadenylation signals AAUUAAA are missing. Microheterogeneous sequence variation is found between TSPY family members. In addition, homologies to other Y-located repeated sequence families, BRY, have been discovered; these sequences are presumably derived from ancient members of the TSPY cluster, now forming a separate, probably nonfunctional subfamily. Bovine TSPY is subject to differential splicing. In the adult, it is expressed in early germ-cell stages, and expression could also be detected in fetal testis. Comparison with the human homolog shows the highest degree of similarity in the coding regions of exons 2, 3, and 4, which are also precisely conserved regarding their length.
Age Factors↗