Massive gastric dilatation after a bulimic excess.
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Abdomen, Acute↗
Biomedical subjects
A Schwarz
Publications and source records attributed to A Schwarz.
Regulatory roles for sphingolipids in the growth of polarized neurons.
Over the past few years, our laboratory has focused on defining the regulatory roles of sphingolipids at various stages of neuronal development. These studies have been performed using primary cultures of hippocampal neurons, which are unique among neuronal cultures inasmuch as they develop by a well-characterized and stereotypic sequence of events that gives rise to fully differentiated axons and dendrites. The data demonstrate that sphingolipids play at least three distinct roles in regulating neuronal development, namely (1) that ceramide enhances the formation of minor neuronal processes from lamellipodia, (2) that glucosylceramide synthesis is required for both normal and accelerated axon growth, and (3) that at both of these stages of development, ceramide induces apoptotic cell death at high concentrations. These observations are consistent with the possibility that minor process formation and apoptosis are regulated by ceramide-dependent signaling pathways, whereas axonal growth may require GlcCer synthesis to support an intracellular transport pathway.
Animals↗
Inhibition of sphingolipid synthesis, but not degradation, alters the rate of dendrite growth in cultured hippocampal neurons.
Axonal growth can be disrupted by various treatments that inhibit the synthesis of membrane components or their delivery by microtubule-based transport. In cultured hippocampal neurons, a direct correlation exists between the synthesis of sphingolipids, and particularly the simplest glycosphingolipid, glucosylceramide, and the ability of growth factors to stimulate axonal growth [S. Boldin, A.H. Futerman, J. Neurochem. 68 (1997) 882-885]. We now demonstrate that dendritic growth in hippocampal neurons also requires ongoing sphingolipid synthesis. Upon incubation with fumonisin B1 (FB1), an inhibitor of acylation of sphingoid long-chain bases, dendritic growth rates are approximately 25% slower than those of control cells, resulting in neurons with shorter dendritic arbors and less dendritic branch points per cell, and readily apparent differences in morphology compared to control cells after 10-14 days in culture. In contrast, FB1 had no effect on the initial growth of the minor processes, which are destined to become dendrites, even in cells in which FB1 affected the rate of axon growth. Inhibition of sphingolipid degradation, by incubation with conduritol-B-epoxide (an inhibitor of glucosylceramide degradation) had no effect on dendrite or minor process growth at any stage of development, and no aberrant neurite or ectopic dendrite formation was observed. Together, these data demonstrate that normal dendrite growth in hippocampal neurons requires sphingolipid synthesis, although the molecular requirements for sphingolipid synthesis may differ from those in axons.
Animals↗
Ultraviolet light-induced immune tolerance is mediated via the Fas/Fas-ligand system.
Hapten sensitization through UV-exposed skin induces tolerance that is mediated via the induction of hapten-specific T suppressor cells. However, the detailed mechanisms underlying tolerance induction remain unclear to date. We show here that the apoptosis-related surface Ag Fas (APO-1, CD95) and its ligand, Fas ligand (FasL) are critically involved, since Fas-deficient lpr mice and FasL-deficient gld mice do not develop UV-induced tolerance. Adoptive transfer experiments revealed that the mediation of tolerance does not require the expression of Fas or FasL by the T suppressor cells but does require the expression of both molecules by the cells of mice receiving the T suppressor cells. To identify the mechanisms involved, the effect of suppressor cells on Ag-presenting dendritic cells (DC) was studied. Coincubation of hapten-pulsed DC with T cells that were obtained from UV-tolerized mice resulted in an enhanced death rate of DC, and this cell death was dependent upon Fas expression. The addition of IL-12, which recently was found to break established tolerance in vivo, prevented DC death. Moreover, IL-12 did not only rescue DC from T suppressor cell-induced death but also from apoptosis induced by rFasL, suggesting that IL-12 may interfere with the Fas/FasL system. Together, these data indicate a crucial role for the Fas/FasL system in UV-induced tolerance, and suggest that UV-induced T suppressor cells may act by inducing the cell death of APCs via the Fas pathway. The ability of IL-12 to break established tolerance may be due to the prevention of DC death induced by T suppressor cells.
Animals↗
1-Methylthiodihydroceramide, a novel analog of dihydroceramide, stimulates sphinganine degradation resulting in decreased de novo sphingolipid biosynthesis.
1-Methylthiodihydroceramide (10 microM) decreased de novo ceramide biosynthesis by about 90% in primary cultured cerebellar neurons. Accordingly, de novo formation of sphingomyelin and of glycosphingolipids, all of which contain ceramide in their backbone, was reduced in a time- and concentration-dependent manner by up to 80%. Complex sphingolipid synthesis was restored upon addition of dihydroceramide or ceramide, in micromolar concentrations, to the culture medium, suggesting that none of the glycosyltransferases involved in glycosphingolipid biosynthesis is inhibited by this analog. Assays of the enzymes catalyzing sphinganine biosynthesis, as well as its N-acylation to form dihydroceramide, revealed that they were also not affected. In contrast, there was a 2.5-fold increase in the activity of sphinganine kinase. Reduction of de novo sphingolipid biosynthesis by 1-methylthiodihydroceramide is therefore due to its ability to deplete cells of newly formed free sphinganine. As a consequence of depletion of sphinganine levels, 1-methylthiodihydroceramide disrupted axonal growth in cultured hippocampal neurons in a manner similar to that reported for direct inhibitors of sphingolipid synthesis; thus, there was essentially no axon growth after incubation with 1-methylthiodihydroceramide between days 2 and 3, and co-incubation with short acyl chain analogs of ceramide (5 microM) antagonized the inhibition of growth. Interestingly, the D-erythro and the L-threo isomere were equally effective, but the corresponding free base as well as other structurally related compounds did not affect either sphingolipid biosynthesis or neuronal growth.
Animals↗
IRIS 97: an innovative protein A-peptidomimetic solid phase medium for antibody purification.
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Animals↗
Clinical research in surgery: questions but few answers.
BACKGROUND: Surgeons must be prepared to be questioned about their understanding, activities, and achievements in basic and clinical research in terms of structural, organizational, and financial support of surgical research. RESULTS: Clinical research today comprises basic research related to accumulation of knowledge about biological systems, disease-related research including experimental research with animals, and in vitro research with biological material and clinical studies with the strongest empirical basis in data derived from controlled clinical trials. Most clinical methods related to diagnosis and treatment have been introduced into the practice of everyday medicine even in university hospitals without passing a prospective evaluation protocol. To test the efficacy of a new drug or a newly developed surgical technique, the controlled prospective clinical trial is the best method; however, fewer than 50% of clinical questions can be answered by controlled clinical studies. In Germany the frequency of controlled clinical trials for answering clinical questions is presently low; this is particularly true for surgery, in comparison with other countries. The concept of evidence-based medicine is based on the principles of data generation from controlled trials and meta-analyses of those studies. Best-evidence synthesis means a reasonable synthesis of evident knowledge, experience and intuition. The challenge of professionalization of clinical research in surgery is linked to the establishment of full time positions for basic scientists and clinical researchers and the establishment of clinical research teams and of research professorships including basic scientists in surgical departments. CONCLUSION: Clinical research can be effective only if there is good cooperation between clinicians and basic scientists, if high grade scientific methods are established in clinical research institutions, if there is sufficient financial and personal supply, and if there are enough laboratories and animal operating facilities. There is an urgent need for structures integrating basic scientists in clinical research groups, for more interdisciplinary research projects and more multidisciplinary research, independent of clinical care in terms of manpower.
Clinical Medicine↗
Gastric substitute after total gastrectomy--clinical relevance for reconstruction techniques.
BACKGROUND: More than 60 different methods of reconstruction after total gastrectomy have been described. The different surgical procedures can be reduced essentially to pouch reconstruction, pouch size and maintenance of duodenal passage. METHODS: To clarify the importance of pouch reconstruction and maintenance of duodenal passage, we reviewed all controlled prospectively randomized clinical studies reporting on the various methods of reconstruction after gastrectomy. RESULTS: After reconstruction with a pouch, 6-month postoperative patients have a better food intake, a slower food passage (t50% 12 vs 25 min), fewer postprandial symptoms (4-10% vs 20-60%), less weight loss (7 vs 14 kg), and in tendency, they have a better quality of life. With maintenance of duodenal passage, disturbance of blood sugar regulation (stimulated glucose level 22% lower) and iron deficiency anemia (hemoglobin: 13.9 vs 12.5 g/dl; iron: 18.4 vs 10.2 micromol/l) are prevented. In addition, the patients lose less body weight (8% higher) and they tend to have a better quality of life (life quality score: 84 vs 76 points). Nevertheless, in several studies the number of patients is too small to demonstrate significant differences. CONCLUSIONS: After total gastrectomy, curatively operated patients might benefit from a reconstruction with pouch and maintenance of duodenal passage. Nevertheless, the present study results are partially divergent. For definitive demonstration of the superiority of this technique, further controlled longitudinal studies should be conducted with a larger number of cases and suitable instruments for assessing the quality of life.
Anastomosis, Roux-en-Y↗
Interleukin 12 breaks ultraviolet light induced immunosuppression by affecting CD8+ rather than CD4+ T cells.
Recent studies showed that injection of interleukin (IL)-12 prevents ultraviolet (UV) light mediated suppression of contact hypersensitivity and breaks UV-induced hapten specific tolerance. UV-mediated suppression can be adoptively transferred by injecting splenocytes from UV-irradiated mice; however, suppression is not transferable when donor mice are treated with IL-12 after UV-irradiation. This study was performed to elucidate the mechanisms by which IL-12 counteracts this immunosuppression. To characterize the cells transferring suppression, depletion studies were performed revealing that UV-induced suppression is transferred via CD8+ T cells. To investigate whether IL-12 counteracts UV-induced suppression by either inhibiting the development of CD8+ suppressor T cells or inducing CD4+ effector T cells, splenocytes from mice, which were IL-12 treated and sensitized through UV-exposed skin, were depleted from CD4+ T cells and transferred into naive mice that were subsequently sensitized. Whereas transfer of splenocytes from UV-irradiated mice inhibited sensitization of recipients, no inhibition was observed after transfer of splenocytes from UV-exposed and IL-12 treated mice. Recipients that received CD4 depleted spleen cells from UV-exposed and IL-12 treated donors, were still fully sensitizable. IL-12 also blocked transfer of UV-induced suppression when it was injected into UV-exposed donor animals at a time point when suppressor cells had already developed. CD4 depletion of such splenocytes did not result in a loss of the reconstitutive effect of IL-12. This suggests that IL-12 may break UV-induced tolerance not by inducing CD4+ effector T cells, but rather by inhibiting or inactivating suppressor T cells belonging to the CD8 subtype.
Adoptive Transfer↗
[Quantitative assessment of brain morphology with CT in agoraphobia].
This CT study was designed to assess brain morphology in agoraphobia. 21 patients and 21 normal control subjects matched in age and sex were investigated. Frontal and parietooccipital cortex, temporal cortex, lateral ventricles and third ventricle were evaluated by qualitative assessment on a 3-point scale (normal, questionable, abnormal). Patients showed significant bilateral enlargement of prefrontal cortical cerebrospinal fluid (CSF) spaces (p < .05). The rating "abnormal" was given to none (0%) of the normal controls, but to 6 (28.6%) of the patients in the left hemisphere, and to 4 patients (19%) in the right hemisphere, respectively. No qualitative differences were seen in the temporal cortex, lateral ventricles and third ventricle. These findings support the hypothesis that alterations in brain morphology are involved in the etiology of agoraphobia. The lack of a correlation between CSF enlargement and duration of illness suggests that prefrontal CSF enlargement is a neurobiological vulnerability marker in agoraphobia.
Adult↗
Apolipoprotein E4 promotes incipient Alzheimer pathology in the elderly.
To evaluate the influence of the apolipoprotein E (ApoE) epsilon4 allele on the age at which Alzheimer-like lesions appear in the brain, we analyzed the degree of cerebral beta-amyloidosis and neurofibrillary tangle formation in the hippocampal formation and adjacent cortical areas 28, 27, and 36 of persons who had died between the ages of 50 and 93 years and who had shown no signs of clinical dementia. The occurrence of the three common polymorphisms of the ApoE gene in this sample of 147 routine autopsy cases from eastern Germany was comparable to previously reported values in European and North American populations: ApoEepsilon2/2, 0.7%; ApoEepsilon2/3, 14.3%; ApoEepsilon2/4, 4.1%; ApoEepsilon3/3, 56.5%; ApoEepsilon3/4, 22.4%; and ApoEepsilon4/4, 2.0%. Nondemented persons carrying the ApoEepsilon4 allele were significantly more likely to have senile plaques, diffuse amyloid deposits, cerebrovascular amyloid, and neurofibrillary tangles than were those lacking E4. Comparing the two largest ApoE subgroups, ApoEepsilon3/3 and ApoEepsilon3/4, the relative increase in the occurrence of beta-amyloid in the epsilon3/4 group was evident by the mid-60s, with the relative increase in neurofibrillary tangles in this group emerging slightly earlier. The ApoEepsilon2 allele appears to delay the appearance of the lesions somewhat. We conclude that ApoEepsilon4 promotes the early appearance of beta-amyloid and neurofibrillary tangles in the elderly and that the increased frequency of these lesions is related to the higher risk of Alzheimer disease in persons bearing the ApoEepsilon4 allele.
Aged↗
The Endothelin system in polycystic kidneys of Han:SPRD rats.
Polycystic kidney disease (PKD) is characterized by structural alterations such as thickening of the tubule basement membrane, interstitial fibrosis, and formation of cysts. Han:SPRD rats are a well-known rat model of human PKD. Interestingly, interstitial fibrosis, glomerulosclerosis, and cyst formation were also seen in human endothelin-1 (ET-1) transgenic mice. We therefore analyzed the tissue concentrations of ET-1 and the expression of ET receptor subtypes in the kidneys of young homozygous (cy/cy), heterozygous (cy/+) 6 week-old male Han:SPRD, and corresponding control rats. The kidneys of affected rats showed significantly elevated tissue levels of ET-1 compared to age-matched controls. Scatchard analysis, on the other hand, revealed markedly decreased ETA and ETB receptor density in all groups of affected rats. The binding affinity of both ET receptor subtypes was slightly decreased in Han:SPRD rats. These data show that the renal paracrine ET system is activated in PKD and might contribute to renal cyst formation and development of end-stage kidney disease.
Animals↗
Apoptosis in kidneys of endothelin-1 transgenic mice.
Endothelin-1 (ET-1) transgenic mice are characterized by age-dependent development of renal cysts and renal fibrosis (interstitial fibrosis and glomerulosclerosis), leading to a progressive decrease in glomerular filtration rate. The mechanism causing the loss of functionally and morphologically normal renal tissue is unknown. An imbalance between cell proliferation and apoptosis in the kidneys of ET-1 transgenic mice might contribute to this process. We identified apoptotic cells in kidney sections by in situ end-labeling and by the typical nuclear chromatin morphology after propidium iodide (PI) staining. Cell proliferation was measured by estimating the proliferating cell nuclear antigen (PCNA)-positive cells. The numbers of apoptotic cells were significantly increased (p < 0.001) in the kidneys of 14-month-old ET-1 transgenic mice, whereas cell proliferation was not enhanced. Apoptotic cells were detected in the glomeruli, tubular cells, and renal interstitial cells in ET-1 transgenic mice. In conclusion, apoptotic loss of functional renal tissue appears to be associated with the progression of cyst formation and renal fibrosis. Therefore, an imbalance between cell proliferation and apoptosis could be an important cellular mechanism in ET-1 transgenic mice leading to end-stage kidney disease.
Animals↗
Effects of red and white wine on endothelium-dependent vasorelaxation of rat aorta and human coronary arteries.
Beneficial effects of wine on myocardial infarction mortality may be because of its vasodilatory properties. This study investigated whether the vasodilatory activity involves the endothelium and is specific for certain wines. Effects of different red and white wines and phenolic grape ingredients on vascular tension and cGMP content were studied in human coronary arteries and rat aortic rings in vitro. Only French and Italian red wines produced "en barrique" (Bordeaux, Châteauneuf du Pape, Barolo) (1:1,000, vol/vol), quercetin (1-100 microM), and tannic acid (1-100 microgram/ml) decreased tension of precontracted vascular rings and increased vascular cGMP content (both P < 0.001). The effects were abolished after endothelial denudation and reversible by nitric oxide synthase inhibition. Red wines not produced en barrique (Valpolicella, Ahr Spätburgunder), white wines (en barrique-produced Rioja, Chardonnay, Mosel-Riesling), and ethanol did not affect vascular tension or cGMP content. Thus endothelium-dependent vasodilatory effects appear to be specific for red barrique wines, possibly because of their high content of phenolic substances. Divergent effects of wines indicate that a general view on the effects of wine and alcoholic beverages is not warranted.
Animals↗
Renal endothelin system in polycystic kidney disease.
Polycystic kidney disease (PKD) is characterized by interstitial fibrosis and formation of renal cysts. Interestingly, interstitial fibrosis and renal cyst formation were also seen in human endothelin-1 (ET-1) transgenic mice. This study, therefore, analyzes the tissue distribution of ET-1, the tissue concentrations of ET-1, as well as the expression of ET receptor subtypes in the kidneys of a rat model of PKD: Han:SPRD rats. Six-week-old heterozygous (cy/+) and homozygous (cy/cy), as well as 6-mo-old heterozygous (cy/+) Han:SPRD rats and the corresponding age-matched Sprague Dawley littermates (SD) (+/+) were analyzed. Furthermore, the acute effects of the mixed (A/B) endothelin receptor antagonist bosentan on hemodynamic and renal function were investigated in 6-mo-old, conscious, chronically instrumented (cy/+) rats. The kidneys of affected rats showed significantly elevated tissue levels of ET-1 compared with age-matched controls (3.5 +/- 0.3-fold in young cy/cy rats, P < 0.01; 1.4 +/- 0.2-fold in young cy/+ rats, P < 0.01; 6.2 +/- 0.4-fold in old cy/+ rats, P < 0.001) due to a highly increased ET-1 synthesis within the epithelial cells of the cysts. Analyzing tissue sections from patients with typical autosomal dominant PKD demonstrated a high ET-1 expression within the epithelial cells of the cysts as well. Scatchard analysis revealed a markedly decreased ETA and ETB receptor density in all groups of affected rats. The acute blockade of both endothelin receptor subtypes using bosentan in 6-mo-old heterozygous PKD rats led to a significant decrease in mean arterial BP (MAP) (-19.7 +/- 2.1 mmHg, P < 0.05) and GFR (-41 +/- 5%, P < 0.005). Renal blood flow (RBF) was significantly increased (+2.1 +/- 0.5 ml/min, P < 0.05) after bosentan, whereas bosentan had no effect on MAP, GFR, and RBF in age-matched controls. These data show that the paracrine renal endothelin system is activated in PKD and participates in the regulation of MAP, GFR, RBF, and possibly contributes to renal cyst formation and fibrosis.
Analysis of Variance↗
Nephrotoxicity of antiinfective drugs.
Antiinfective drugs may show the same mechanisms of nephrotoxicity as other drugs, and these can be subgrouped into vascular, tubulotoxic, tubulo-obstructive, and immunologic effects. While vascular effects of antiinfective drugs are rare, tubulotoxicity is a well known phenomenon, especially in connection with aminoglycosides and amphotericin B as well as cephalosporins, pentamidine, foscarnet, and cidovir. The tubulo-obstructive effect caused by precipitation of the drug and first observed after treatment with sulfonamides in the 1940s, has become a renascent problem now that high doses of sulfonamides are being given to immunocompromised patients (sulfadiazine, cotrimoxazole). Moreover, this effect has also been associated with newer antiviral drugs like acyclovir and indinavir. We describe a transplant patient who received high doses of cotrimoxazole for pneumocystis carinii pneumonia and lost transplant function mainly due to bioptically proven glomerular and tubular crystallization with tubular degeneration caused by sulfamethoxazole. Acute interstitial nephritis is the main immunologic effect of antiinfective drugs (especially rifampicin but also cephalosporins, quinolones, sulfonamides, and penicillins). Immune stimulation by cytokine treatment (mainly interferon-alpha) involves several kinds of autoimmune renal diseases like acute interstitial nephritis or glomerulonephritis as well as interstitial and vascular rejection of renal transplants.
Adult↗
Isolation of gangliosides by cloud-point extraction with a nonionic detergent.
A rapid, simple, and efficient chloroform/methanol-free method of isolating gangliosides is described. The nonionic polyoxyethylene detergent, hexaethyleneglycol mono-n-tetradecyl ether (C14EO6), forms clear micellar solutions in water, but two-phase separation can be achieved by centrifugation in the presence of ammonium sulfate at room temperature. A mixture of pure gangliosides, metabolically labeled gangliosides obtained from cultured hippocampal neurons, and gangliosides from rat cerebellar tissue were quantitatively recovered in the detergent-rich upper (coacervate) phase, with a partition coefficient K > 60. Gangliosides were subsequently separated from the detergent using an Iatrobead column prior to analysis by thin-layer chromatography. The procedure described here is as efficient as other methods of ganglioside extraction, such as that using chloroform/methanol/water/pyridine, but is less time-consuming inasmuch as extraction, purification, and TLC analysis can be completed within 1 day.
Animals↗
Hepatitis G virus RNA and hepatitis G virus antibodies in renal transplant recipients: prevalence and risk factors.
BACKGROUND: Hepatitis G virus (HGV/GBV-C) RNA indicating current infection has been frequently isolated from the sera of transplant recipients and other multitransfused individuals. Lifetime exposure to the virus, however, is unknown. We carried out a study to determine the prevalence and risk factors of HGV antibodies and of HGV RNA among renal transplant recipients, and to investigate possible associations between HGV RNA and immunosuppressive treatment. METHODS: HGV RNA was detected by reverse transcriptase-polymerase chain reaction, and HGV antibodies (anti-E2) by a newly developed immunoassay. To assess risk factors for HGV exposure, univariate and multivariate analysis was performed. RESULTS: Of the 221 patients, 14% were HGV RNA positive and 40% had HGV antibodies. Both HGV RNA and anti-HGV were present in only two individuals. Thus, the overall HGV exposure prevalence was 53%. It increased significantly with the number of blood transfusions. In logistic regression, the adjusted HGV exposure prevalence odds ratio was 5.7 (95% confidence interval [CI]: 2.2-15) among patients with > or =10 transfusions (baseline: no transfusions). Other independent risk factors were a longer duration of hemodialysis and a longer time interval since transplantation. HGV viremia was not associated with the type of immunosuppressive treatment. Alanine aminotransferase levels were not significantly increased among HGV RNA-positive patients. CONCLUSIONS: Much higher proportions of renal transplant recipients were exposed to HGV than is suggested by HGV RNA detection alone. The majority of infected individuals apparently eliminate the virus over time. Contaminated blood transfusions have to be regarded as a main risk factor for HGV infection.
Adolescent↗