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Biomedical subjects

C Otto

Publications and source records attributed to C Otto.

At least 73 records · Page 4Linked to original sources
PubMed2000

Long-term small bowel allograft function induced by short-term FK 506 application is associated with split tolerance.

Functional long-term allograft survival after experimental small bowel transplantation (SBT) is limited by chronic rejection. Initial application of high-dose FK 506 has been shown to induce stable long-term graft function. In order to examine whether this long-term function is associated with donor-specific tolerance, we analyzed the functional status of recipient T cells in vivo and in vitro. One-step orthotopic SBT was performed in the allogeneic Brown Norway (BN)-to-Lewis rat strain combination. FK 506 was given daily at a dose of 2 mg/kg from days 0-5 in the rejection model and from days 0-9 in the long-term functional model. Mean survival time in the rejection model was 98 +/- 2.8 days. Histological examination of these small bowel allografts disclosed signs of chronic rejection. In contrast, all animals of the long-term functional model survived long term (> 250 days) without clinical signs of chronic rejection. The latter model, furthermore, produced evidence of donor-specific tolerance. Whereas heterotopic Dark Agouti (DA) hearts were rejected regularly within 7 days, BN hearts survived indefinitely (> 70 days). In vitro, mixed leukocyte reactivity of CD4+ T cells was similarly strong against donor (BN) antigens as against third-party (DA) antigens. The split tolerance revealed by our in vivo and in vitro results enabled acceptance of both the small bowel allograft without signs of chronic rejection and of donor-specific heart allografts.

Animals↗
PubMed2000

Intracellular reactions in single human granulocytes upon phorbol myristate acetate activation using confocal Raman microspectroscopy.

We have obtained new evidence for the occurrence of intracellular NADPH-oxidase activity in neutrophilic and eosinophilic granulocytes upon stimulation with phorbol myristate acetate (PMA). PMA activation leads to a partial translocation of cytochrome b(558) from the membranes of the specific granules to the plasma membrane. It was suggested that NADPH-oxidase activity only takes place in the plasma membrane, leading to an extracellular release of oxygen metabolites because cellular self-destruction can be avoided in this way. The effects of PMA activation were indirectly studied in recent experiments employing scavengers of extracellular superoxide anion and hydrogen peroxide, and support for intracellular NADPH-oxidase activity was obtained. In this paper we use Raman microspectroscopy as a direct method to study intracellular molecular reactions that result from cellular triggering by PMA. The molecular specificity of this microscopic method enables us to show that intracellular reduction of both myeloperoxidase (MPO) and cytochrome b(558) occurs in neutrophilic granulocytes. Control measurements with cytochrome b(558)-deficient neutrophilic granulocytes did not show a reduction of intracellular MPO. This is direct support for the occurrence of intracellular NADPH-oxidase activity in organelles that must be in close contact with the azurophilic granules that contain MPO. Furthermore, a comparison was made with chemical reactions occurring in eosinophilic granulocytes after activation with PMA. Moreover, in these cells an intracellular reduction of eosinophil peroxidase was observed.

Biophysical Phenomena↗
PubMed2000

Dissecting GHRH- and pituitary adenylate cyclase activating polypeptide-mediated signalling in Xenopus.

The highly conserved neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) has been implicated in a broad variety of physiological processes. The PACAP precursor protein gives rise to three different peptides, the cryptic peptide, GHRH, and PACAP, respectively, and here we dissect their functional properties using Xenopus as model system. PACAP and GHRH but not the cryptic peptide directly neuralize animal caps. In contrast to GHRH, the neuralizing effect mediated by PACAP is independent of the PKA pathway. Moreover, PACAP but not GHRH behaves like a BMP-4 antagonist. Blastocoel injection of PACAP-38 but not of the closely related peptides PACAP-27 and VIP leads to strong anteriorization of the injected embryos suggesting the possible involvement of a novel PACAP-preferring receptor.

Animals↗
PubMed2000

Pituitary adenylate cyclase-activating polypeptide promotes the survival of basal forebrain cholinergic neurons in vitro and in vivo: comparison with effects of nerve growth factor.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a member of the vasointestinal polypeptide gene family for which neurotrophic activity has been postulated. PACAP mRNA is expressed in the developing and adult hippocampus, which is the principal target region of septal cholinergic neurons. We therefore studied the effects of PACAP on septal cholinergic neurons. In primary cultures from septum of embryonic and postnatal rats, PACAP increased the number of neurons immunohistochemically stained for the low-affinity nerve growth factor (NGF) receptor p75 and for the enzyme choline acetyltransferase (ChAT). PACAP also caused a corresponding increase in ChAT activity. In comparison, NGF had a greater effect than PACAP on the number of p75- and ChAT-positive neurons in these cultures. In vivo, following fimbria fornix transection, the number of immunohistochemically stained septal cholinergic neurons fell significantly to 18% in rats given continuous intracerebroventricular infusion of vehicle, whereas in rats given NGF the number of these neurons did not differ significantly from unoperated controls. In PACAP-treated rats the number was 48% of unoperated values, which represented a significant increase compared with vehicle-treated rats and a significant decrease compared with NGF-treated rats or unoperated controls. Double-staining experiments revealed that most ChAT-positive neurons in rat medial septum also express PACAP receptor 1. Together the results show that PACAP promotes the survival of septal cholinergic neurons in vitro, and after injury in vivo, suggesting that PACAP acts as a neurotrophic factor influencing the development and maintenance of these neurons.

Acetylcholine↗
PubMed2000

Influence of atorvastatin versus simvastatin on fibrinogen and other hemorheological parameters in patients with severe hypercholesterolemia treated with regular low-density lipoprotein immunoadsorption apheresis.

Low-density lipoprotein (LDL) apheresis is a treatment option in patients with coronary artery disease and elevated LDL cholesterol concentrations if maximal drug therapy fails to achieve adequate LDL cholesterol reduction. This therapy is more effective when combined with strong lipid-lowering drugs, such as atorvastatin. However, conflicting data have been published concerning the effect of atorvastatin on fibrinogen concentration. Therefore, we investigated the effect of atorvastatin compared to simvastatin on fibrinogen concentration and other hemorheological parameters in patients treated by weekly LDL apheresis. Hemorheological parameters were, studied twice in 9 patients (4 female, 5 male, 54.0+/-8.9 years) with coronary artery disease treated by weekly LDL immunoadsorption, once during concomitant simvastatin therapy (40 mg daily) and once during atorvastatin therapy (40 mg daily). Fibrinogen concentration, plasma and blood viscosity at different shear rates, parameters of red cell aggregation at stasis and shear rate 3/s, and erythrocyte filterability were determined 7 days after the last LDL apheresis after each drug had been given for a minimum for 8 weeks. Fibrinogen concentration did not show any statistically significant difference during therapy with atorvastatin (3.09+/-0.36 g/L) compared to simvastatin (3.13+/-0.77 g/L). Plasma and blood viscosity as well as erythrocyte filterability were also unchanged. The increase in red cell aggregation at stasis during atorvastatin treatment (5.82+/-1.00 U versus 4.89+/-0.48 U during simvastatin; p < 0.05) was inversely correlated with a lower high-density liprotein (HDL) cholesterol concentration (1.17+/-0.21 mmol/L versus 1.31+/-0.30 mmol/L during simvastatin; p < 0.05). LDL cholesterol showed a strong trend to lower concentrations during atorvastatin (4.14+/-0.61 mmol/L versus 4.56+/-0.66 mmol/L during simvastatin; p = 0.07), despite a reduced plasma volume treated (3,547+/-1,239 ml during atorvastatin versus 3,888+/-1,206 mL during simvastatin; p < 0.05). In conclusion, fibrinogen concentration and other hemorheological parameters were unchanged during atorvastatin compared to simvastatin therapy with the exception of a higher red cell aggregation at stasis. Therefore, with respect to hemorheology, we conclude that atorvastatin should not be withheld from hypercholesterolemic patients regularly treated with LDL immunoadsorption.

Anticholesteremic Agents↗
PubMed2000

Contribution of fibrinogen and lipoproteins to plasma viscosity in hypercholesterolemia and hypertriglyceridemia: evaluation by selective depletion of low-density lipoproteins or fibrinogen.

Epidemiological studies suggest that the plasma fibrinogen concentration is the main determinant of plasma viscosity (PV), but the concentration of other macromolecules (eg, immunoglobulins) and low-density lipoprotein (LDL) cholesterol and triglycerides are also correlated with PV. However, only a few data exist concerning the in vitro effects of these plasma constituents on PV. Therefore, we investigated PV before and after the specific elimination of fibrinogen and LDL in hypercholesterolemic and hypertriglyceridemic plasma. First, hypercholesterolemic samples (n = 7) were pumped simultaneously through 2 columns: a fibrinogen-depleting column containing the pentapeptide Gly-Pro-Arg-Pro-Lys (GPRPK) and a LDL-depleting column containing specific antibodies against apolipoprotein B-100. In the plasma and in each fraction from the column, the cholesterol level was measured enzymatically, fibrinogen was determined by immunonephelometry, and PV was analyzed using a low-shear rotation viscosimeter. After the fibrinogen-depleting column, the fibrinogen concentration decreased from 3.21 +/- 0.20 to 0.94 +/- 0.16 g/L (P < .005), inducing a decrease in PV from 1.27 +/- 0.02 to 1.17 +/- 0.01 mPas (milliPascal seconds) (P < .005). Despite a marked reduction of the LDL cholesterol after the LDL-depleting column (from 6.40 +/- 0.23 to 4.08 +/- 0.32 mmol/L, P < .005), PV remained unchanged. Second, hypertriglyceridemic samples (n = 7) were pumped through the fibrinogen-depleting column, which reduced the fibrinogen concentration from 4.29 +/- 0.79 to 1.62 +/- 0.69 g/L (P < .001) and PV from 1.42 +/- 0.06 to 1.03 +/- 0.05 mPas (P < .01) while the triglyceride concentration remained unchanged. Our results confirm the epidemiological correlation between the fibrinogen concentration and PV in patients with hypercholesterolemia and hypertriglyceridemia. The influence of fibrinogen on PV seems much more pronounced than the direct effect of lipoprotein concentrations. Therefore, the elevated PV in patients with hypercholesterolemia and especially with hypertriglyceridemia seems mainly due to elevated fibrinogen levels.

Antibodies↗
PubMed2000

Effects of a 21-day expedition to 6,194 m on human skeletal muscle SR Ca2+-ATPase.

We investigated the effects of a 21-day expedition to the summit of Mount Denali, Alaska (6,194 m) on selected Ca2+ sequestration properties of sarcoplasmic reticulum (SR) calcium pump in vastus lateralis muscle. Muscle samples were obtained by biopsy from 5 male climbers (peak oxygen consumption, VO2peak = 52.3 +/- 2.1 mL.kg(-1).min(-1)) approximately 7 days prior to (PRE) and 4 days following (POST) the expedition. A comparison of PRE versus POST measures of maximal Ca2+-ATPase activities (117 +/- 8.5 vs. 97.6 +/- 5.6 nmol.mg protein(-1).min(-1)) and Ca2+-uptake (204 +/- 15 vs. 161 +/- 11 nmol.mg protein(-1).min(-1)) measured in crude homogenates obtained from pre-exercised muscle, indicated only an effect (p < 0.05) of the expedition on Ca2+-uptake. The reduction in Ca2+-ATPase activity, representing 16.6%, was not significant (p = 0.089). The sarco endoplasmic reticulum calcium (SERCA)-ATPase isoforms, measured using Western blotting techniques, revealed a small reduction (p < 0.05) in SERCA 1 (-4.6 +/- 1.9%), but not in SERCA 2a (+2.0 +/- 1.4%). Prior to the expedition, both Ca2+-ATPase activity and Ca2+-uptake were reduced (p < 0.05) by approximately 34 and 18%, respectively, following 40 min of a two-step continuous cycling task (20 min at 59% VO2peak and 20 min at 74% VO2peak). The exercise-induced reduction in Ca2+-ATPase activity was independent of fiber type. Only in the case of Ca2+-uptake was a lower exercise response (p < 0.05) observed following the expedition, an effect that was due to the lower resting value. It is concluded that acclimatization as experienced during a mountaineering expedition induces changes in the properties of the SR Ca2+-pump, and particularly to Ca2+-sequestering function.

Acclimatization↗
PubMed2000

Different kinetics of donor cell populations after isolated liver and combined liver/small bowel transplantation.

Spontaneous tolerance induction after liver transplantation also supports additional transplants, e.g. a small bowel graft, from the same donor (tolerogenic effect). Chimerism serves as a possible explanation of this phenomenon. Isolated liver (LTx) and combined liver/small bowel transplantation (LSBTx) are compared. LSBTx and LTx were performed in the BN --> LEW rat strain combination without immunosuppression. Parenchymal damage during rejection was monitored by sequential standard histology. Donor/recipient populations were identified and further differentiated for immunohistochemical single and double staining. A small number of donor specific leukocytes can be detected on all days in host organs (microchimerism). A significantly larger donor leukocyte population survives long-term in the sinusoids of liver (graft chimerism). Sinusoidal donor leukocytes survive rejection and recover in number after tolerance induction. Rejection of liver allografts and infiltration by host leukocytes are more pronounced after LSBTx than after LTx. Accordingly, during rejection a steeper decline of sinusoidal donor leukocytes is observed after LSBTx and recovery after tolerance induction is not as marked. Microchimerism apparently plays no significant role in either transplantation model. The number of sinusoidal donor leukocytes, however, mirrors closely host immune responses.

Animals↗
PubMed2000

Human skeletal muscle exercise metabolism following an expedition to mount denali.

Chronic exposure to high altitude is known to result in changes in the mechanisms regulating O(2) delivery to the contracting muscle. However, the effects of acclimatization on metabolism in the contracting muscle cell remain unclear. In this study, we have investigated the hypothesis that acclimatization would result in a closer coupling between ATP utilization and ATP production and that the improved energy state would be accompanied by a reorganization of the metabolic pathways consisting of an increased oxidative and decreased glycolytic potential. Five men, mean age of 28 +/- 2 (SE) yr, performed a standardized, two-stage submaximal cycling task in normoxia for 20 min at each of 59 and 74% peak O(2) consumption before and 3-4 days after returning from a 21-day expedition to Mount Denali (6,194 m). Acclimatization was without effect in altering the resting values of the adenine nucleotides (ATP, ADP, AMP), inosine monophosphate (IMP), or phosphocreatine (PCr) in the vastus lateralis. During exercise (40 min) after acclimatization compared with preacclimatization, PCr was not as depressed (33.2 +/- 7.1 vs. 40.6 +/- 5.4 mmol/kg dry wt) and IMP (0.289 +/- 0.11 vs. 0. 131 +/- 0.03 mmol/kg dry wt) and lactate (26.1 +/- 6.2 vs. 18.6 +/- 8.8 mmol/kg dry wt) in contracting muscle were not as elevated (P < 0.05). Although no effect of acclimatization was observed for the maximal activity (mol. kg protein(-1). h(-1)) of citrate synthase (4. 76 +/- 0.44 vs. 4.94 +/- 0.45), lactate dehydrogenase was increased by 13% (36.5 +/- 2.6 vs. 41.2 +/- 3.1, P < 0.05). It is concluded that acclimatization results in an improved energy state in the contracting muscle when tested under normoxic conditions; however, these effects are not associated with a higher oxidative potential or a lower glycolytic potential as hypothesized.

Acclimatization↗
PubMed2000

Downregulation in muscle Na(+)-K(+)-ATPase following a 21-day expedition to 6,194 m.

To investigate the hypothesis that acclimatization to altitude would result in a downregulation in muscle Na(+)-K(+)-ATPase pump concentration, tissue samples were obtained from the vastus lateralis muscle of six volunteers (5 males and 1 female), ranging in age from 24 to 35 yr, both before and within 3 days after a 21-day expedition to the summit of Mount Denali, Alaska (6,194 m). Na(+)-K(+)-ATPase, measured by the [(3)H]ouabain-binding technique, decreased by 13.8% [348 +/- 12 vs. 300 +/- 7.6 (SE) pmol/g wet wt; P < 0.05]. No changes were found in the maximal activities (mol. kg protein(-1). h(-1)) of the mitochondrial enzymes, succinic dehydrogenase (3.63 +/- 0.20 vs. 3.25 +/- 0.23), citrate synthase (4. 76 +/- 0.44 vs. 4.94 +/- 0.44), and malate dehydrogenase (12.6 +/- 1. 8 vs. 12.7 +/- 1.2). Similarly, the expedition had no effect on any of the histochemical properties examined, namely fiber-type distribution (types I, IIA, IIB, IC, IIC, IIAB), area, capillarization, and succinic dehydrogenase activity. Peak aerobic power (52.3 +/- 2.1 vs. 50.6 +/- 1.9 ml. kg(-1). min(-1)) and body mass (76.9 +/- 3.7 vs. 75.5 +/- 2.9 kg) were also unaffected. We concluded that acclimatization to altitude results in a downregulation in muscle Na(+)-K(+)-ATPase pump concentration, which occurs without changes in oxidative potential and other fiber-type histochemical properties.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2000

Increases in submaximal cycling efficiency mediated by altitude acclimatization.

To investigate the hypothesis that respiratory gas exchange and, in particular, the O(2) consumption (VO(2)) response to exercise is altered after a 21-day expedition to 6,194 m, five male climbers (age 28.2 +/- 2 yr; weight 76.9 +/- 4.3 kg; means +/- SE) performed a progressive and prolonged two-step cycle test both before and 3-4 days after return to sea level. During both exercise tests, a depression (P < 0.05) in VO(2) (l/min) and an increase (P < 0.05) in minute ventilation (VE BTPS; l/min) and respiratory exchange ratio were observed after the expedition. These changes occurred in the absence of changes in CO(2) production (l/min). During steady-state submaximal exercise, net efficiency, calculated from the rates of the mechanical power output to the energy expended (VO(2)) above that measured at rest, increased (P < 0.05) from 25.9 +/- 1.6 to 31. 3 +/- 1.3% at the lighter power output and from 24.4 +/- 1.3 to 29.5 +/- 1.5% at the heavy power output. These changes were accompanied by a 4.5% reduction (P < 0.05) in peak VO(2) (3.99 +/- 0.17 vs. 3.81 +/- 0.18 l/min). After the expedition, an increase (P < 0.05) in hemoglobin concentration (15.0 +/- 0.49 vs. 15.8 +/- 0.41 g/100 ml) was found. It is concluded that, because resting VO(2) was unchanged, net efficiency is enhanced during submaximal exercise after a mountaineering expedition when the exercise is performed soon after return to sea level conditions.

Acclimatization↗
PubMed2000

Effects of chewing betel nut (Areca catechu) on the symptoms of people with schizophrenia in Palau, Micronesia.

BACKGROUND: Although millions of people with schizophrenia live in betel chewing regions, the effects of betel chewing on their symptoms are unknown. Betel nut alkaloids include potent muscarinic cholinomimetics: recent research suggests that these agents may be therapeutic in schizophrenia. AIMS: To compare the primary and extrapyramidal symptom profiles and substance-using habits of betel chewing v. non-chewing people with schizophrenia. METHOD: A cross-sectional study of 70 people with schizophrenia. Symptom ratings measured by the Positive and Negative Syndrome Scale (PANSS) and Extrapyramidal Symptom Rating Scale (ESRS), and demographic and substance-use data, were compared for 40 chewers and 30 non-chewers of betel nut. RESULTS: Betel chewers with schizophrenia scored significantly lower on the positive (P = 0.001) and negative (P = 0.002) sub-scales of the PANSS than did non-chewers. There were no significant differences in extrapyramidal symptoms or tardive dyskinesia. CONCLUSIONS: Betel chewing is associated with milder symptomatology and avoidance of more harmful recreational drugs. These initial results indicate that longitudinal research is merited.

Adult↗
PubMed1999

Human and mouse XAP-5 and XAP-5-like (X5L) genes: identification of an ancient functional retroposon differentially expressed in testis.

Although most retroposons that arose by reverse transcription of cellular mRNAs and by reintegration into the genome are nonfunctional, several examples exist in which the retroposon acquired a novel function and became fixed in the genome as a functional gene. We identified another such case: the ubiquitously expressed X-linked XAP-5 gene with unknown function gave rise to its retroposed counterpart, XAP-5-like (X5L), which has an intronless open reading frame and is autosomal in human. Phylogenetic analysis of the human and mouse XAP-5 and X5L genes shows that the retroposition most likely took place before the radiation of eutherian mammals. The XAP-5 and X5L genes are expressed in a wide range of tissues but are differentially expressed in testis. The ancient origin and broad expression of the X5L retroposon indicate that the XAP-5 and X5L genes may have assumed different functions in somatic cells. In addition to this, because of its autosomal location and its high level and particular pattern of expression in spermatogenic cells, the X5L expression in testis may compensate for the X-linked XAP-5 gene, which may be silenced during spermatogenesis.

Amino Acid Sequence↗
PubMed1999

The sulfonium ion linkage in myeloperoxidase. Direct spectroscopic detection by isotopic labeling and effect of mutation.

The heme group of myeloperoxidase is covalently linked via two ester bonds to the protein and a unique sulfonium ion linkage involving Met(243). Mutation of Met(243) into Thr, Gln, and Val, which are the corresponding residues of eosinophil peroxidase, lactoperoxidase, and thyroid peroxidase, respectively, and into Cys was performed. The Soret band in the optical absorbance spectrum in the oxidized mutants is now found at approximately 411 nm. Both the pyridine hemochrome spectra and resonance Raman spectra of the mutants are affected by the mutation. In the Met(243) mutants the affinity for chloride has decreased 100-fold. All mutants have lost their chlorination activity, except for the M243T mutant, which still has 15% activity left. By Fourier transform infared difference spectroscopy it was possible to specifically detect the (13)CD(3)-labeled methionyl sulfonium ion linkage. We conclude that the sulfonium ion linkage serves two roles. First, it serves as an electron-withdrawing substituent via its positive charge, and, second, together with its neighboring residue Glu(242), it appears to be responsible for the lower symmetry of the heme group and distortion from the planar conformation normally seen in heme-containing proteins.

Amino Acid Substitution↗
PubMed1999

Videomicroscopic imaging of graft mucosa for monitoring immunosuppressive therapy after small intestinal transplantation in rats.

BACKGROUND: Early diagnosis of rejection and effective immunosuppressive treatment are essential after small intestinal transplantation. To date little is known about microscopic alterations of the intestinal mucosa of the graft during rejection. We attempted to determine whether videomicroscopic imaging of the graft mucosa is a suitable method for monitoring immunosuppressive therapy. METHODS: Real-time videomicroscopic imaging of an ileostoma was performed daily after allogeneic heterotopic small bowel transplantation in the rat (BN to LEW) with and without FK506 immunosuppression. Subsequently, the videomicroscopic findings were compared with the histologically determined grade of rejection. RESULTS: A semiquantitative staging system was established for the intravital mucosal changes during graft rejection. The earliest changes related to rejection appeared on POD 6 in the untreated allogeneic group. The mucosa developed patchy paleness and the mucosal architecture was interrupted in places. The crypts were slightly widened and their color turned dark red (stage I). These alterations spread progressively over the mucosa on POD 7 (stage II). On POD 9 the mucosa appeared pale, the villi were shortened, and the crypts appeared wide and rounded (stage III). In the animals treated with FK506 similar changes were observed, but with a delayed onset. When FK506 was administered as antirejection therapy at the onset of rejection, a temporary improvement of mucosal alterations was observed (stage II --> stage I). The video-microscopic stages correlated with the histological grade of rejection. CONCLUSIONS: The introduction of videomicroscopy has made computer-based high resolution imaging of mucosal microarchitecture possible. With videomi-croscopy beginning rejection can be detected, although it can still be reversed with antirejection therapy. This is a new noninvasive technique that might be of high clinical relevance.

Acute Disease↗