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Biomedical subjects

C Winkler

Publications and source records attributed to C Winkler.

At least 73 records · Page 4Linked to original sources
PubMed1998

Plasma leptin levels: interaction of obesity with a common variant of insulin receptor substrate-1.

Obesity is associated with insulin resistance and other major cardiovascular risk factors. A common amino acid polymorphism at codon 972 of the insulin receptor substrate-1 (IRS-1) has been shown to interact with obesity in the expression of insulin resistance. The plasma concentration of the adipocyte-specific hormone leptin is increased in obesity and is correlated with adipose tissue mass. Because in vitro studies demonstrated inhibitory effects of leptin on insulin signaling, leptin may be involved in obesity-associated insulin resistance. To gain insight into the relationship between insulin and leptin in obesity, we studied plasma leptin levels and several cardiovascular risk factors, as well as their modification by the IRS-1 codon 972 genotype, in 156 obese individuals and 131 lean control subjects. In both groups, 10% of the subjects were heterozygous for the IRS-1 codon 972 variant. Obese individuals harboring the IRS-1 variant displayed significantly lower plasma concentrations of leptin than obese subjects without the polymorphism (means, 26.7 versus 37.8 ng/mL, P<0.0293). In a subgroup of obese patients, leptin mRNA abundance was measured in the adipose tissue and was significantly lower in carriers of the IRS-1 variant than in subjects with the wild-type variant (P<0.0291). Our data suggest that insulin signaling influences plasma leptin concentrations at the mRNA expression level and argue against leptin as a major causative factor of insulin resistance.

Adult↗
PubMed1997

Grafts of EGF-responsive neural stem cells derived from GFAP-hNGF transgenic mice: trophic and tropic effects in a rodent model of Huntington's disease.

The present study examined whether implants of epidermal growth factor (EGF)-responsive stems cells derived from transgenic mice in which the glial fibrillary acid protein (GFAP) promoter directs the expression of human nerve growth factor (hNGF) could prevent the degeneration of striatal neurons in a rodent model of Huntington's disease (HD). Rats received intrastriatal transplants of GFAP-hNGF stem cells or control stem cells followed 9 days later by an intrastriatal injection of quinolinic acid (QA). Nissl stains revealed large striatal lesions in rats receiving control grafts, which, on average, encompassed 12.78 mm3. The size of the lesion was significantly reduced (1.92 mm3) in rats receiving lesions and GFAP-hNGF transplants. Rats receiving QA lesions and GFAP-hNGF-secreting grafts stem cell grafts displayed a sparing of striatal neurons immunoreactive (ir) for glutamic acid decarboxylase, choline acetyltransferase, and neurons histochemically positive for nicotinamide adenosine diphosphate. Intrastriatal GFAP-hNGF-secreting implants also induced a robust sprouting of cholinergic fibers from subjacent basal forebrain neurons. The lesioned striatum in control-grafted animals displayed numerous p75 neurotrophin-ir (p75NTR) astrocytes, which enveloped host vasculature. In rats receiving GFAP-hNGF-secreting stem cell grafts, the astroglial staining pattern was absent. By using a mouse-specific probe, stem cells were identified in all animals. These data indicate that cellular delivery of hNGF by genetic modification of stem cells can prevent the degeneration of vulnerable striatal neural populations, including those destined to die in a rodent model of HD, and supports the emerging concept that this technology may be a valuable therapeutic strategy for patients suffering from this disease.

Animals↗
PubMed1997

Radiotherapy in stage IIA and IIB testicular seminoma with reduced portals: a prospective multicenter study.

PURPOSE: A prospective multicenter study was carried out to estimate the treatment outcome of radiotherapy in Stage II seminoma after the application of modern staging and radiotherapy techniques. The lower margin of the iliac field was positioned on the upper rim of the acetabulum to reduce the amount of scattered irradiation to the remaining testicle. METHODS AND MATERIALS: The study was carried out in 25 centers in Germany. Patients with pure seminoma, negative AFP-values, and retroperitoneal lymph node metastases of less than 5 cm in diameter were entered into the study. All patients received a ventrodorsal opposed field irradiation of the para-aortic and the ipsilateral iliac lymph nodes. The fields extended from the top of the 11th thoracic vertebra to the top of the acetabulum. Patients in Stage IIA (lymph nodes <2 cm ) received 30 Gy, and patients with Stage IIB (lymph nodes between 2 and 5 cm) 36 Gy total dose. RESULTS: 39 patients in Stage IIA and 19 patients in Stage IIB were evaluated. After a median observation time of 37 months all patients are alive and disease free. Recurrence free survival in stage IIA was 100%. Two patients in Stage IIB experienced a recurrence 10 and 17 months after the end of radiotherapy. The actuarial recurrence free survival estimate in Stage IIB was 94.1% for 1 year and 87.4% for 2 years. One recurrence in Stage IIB occurred in the mediastinum, one in the mediastinum, and one the lung. Both patients could be salvaged by chemotherapy. There were no pelvic recurrences. The treatment was well tolerated, with nausea being the most common side effect (56.9% Grade 1, 15.5% Grade 2, and 8.6% Grade 3). Diarrhea occurred in 15.5% (Grade 1), 15.5% (Grade 2), and 5.2% (Grade 3) of the patients. CONCLUSIONS: The outcome of para-aortic and ipsilateral iliac irradiation in Stage IIA/B testicular seminoma is excellent with the currently available staging methods and treatment facilities. The treatment is well tolerated. The lower margin of the iliacal field can be placed at the acetabulum.

Adult↗
PubMed1997

Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC), ALIVE Study.

The critical role of chemokine receptors (CCR5 and CXCR4) in human immunodeficiency virus-type 1 (HIV-1) infection and pathogenesis prompted a search for polymorphisms in other chemokine receptor genes that mediate HIV-1 disease progression. A mutation (CCR2-64I) within the first transmembrane region of the CCR2 chemokine and HIV-1 receptor gene is described that occurred at an allele frequency of 10 to 15 percent among Caucasians and African Americans. Genetic association analysis of five acquired immunodeficiency syndrome (AIDS) cohorts (3003 patients) revealed that although CCR2-64I exerts no influence on the incidence of HIV-1 infection, HIV-1-infected individuals carrying the CCR2-64I allele progressed to AIDS 2 to 4 years later than individuals homozygous for the common allele. Because CCR2-64I occurs invariably on a CCR5-+-bearing chromosomal haplotype, the independent effects of CCR5-Delta32 (which also delays AIDS onset) and CCR2-64I were determined. An estimated 38 to 45 percent of AIDS patients whose disease progresses rapidly (less than 3 years until onset of AIDS symptoms after HIV-1 exposure) can be attributed to their CCR2-+/+ or CCR5-+/+ genotype, whereas the survival of 28 to 29 percent of long-term survivors, who avoid AIDS for 16 years or more, can be explained by a mutant genotype for CCR2 or CCR5.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Activation of transcription of the melanoma inducing Xmrk oncogene by a GC box element.

Melanoma formation in Xiphophorus is caused by overexpression of the Xmrk gene. The promoter region of the Xmrk oncogene differs strikingly from the corresponding proto-oncogenic sequences and was acquired in the course of a nonhomologous recombination with another gene locus, D. In order to identify regulatory elements leading to the strong transcriptional activation of Xmrk in melanoma tissue and to contribute to an understanding of the role the regulatory locus R might play in suppressing the tumor phenotype in wild-type Xiphophorus, we performed functional analysis of the Xmrk oncogene promoter. Transient transfections in melanoma and nonmelanoma cells revealed the existence of a potent positive regulatory element positioned close to the transcriptional start site. Contained within this promoter segment is a GC-rich sequence identical to the binding site described for human Sp1. In vitro binding studies and biochemical characterizations demonstrated the existence of GC-binding proteins in fish that share immunological properties with members of the human Sp family of transcription factors and appear to be involved in the high transcriptional activation of the Xmrk oncogene. Since the identified cis element is functional in both melanoma and nonmelanoma cells, additional silencer elements suppressing Xmrk expression in nonpigment cells must exist, thereby suggesting a negative regulatory function for the genetically defined R locus.

Animals↗
PubMed1997

Eating disorders in adolescence in a Swiss epidemiological study.

OBJECTIVE: This is a study of prevalence rates for anorexia nervosa (AN) and bulimia nervosa (BN) in an epidemiological sample of Swiss adolescents. METHOD: A two-stage approach was used which involved the screening of a large sample of adolescents aged 14-17 and subsequent interviews of screen-positive and control subjects. RESULTS: The prevalence rates for adolescent girls were 0.7% for AN and 0.5% for BN. DISCUSSION: Full clinical syndromes of AN and BN in adolescents are by far less frequent than individual symptoms of eating disorders. There is more cross-cultural variation for prevalence rates in BN than in AN.

Adolescent↗
PubMed1997

Generation and transplantation of EGF-responsive neural stem cells derived from GFAP-hNGF transgenic mice.

EGF-responsive neural stem cells isolated from murine striatum have the capacity to differentiate into both neurons and glia in vitro. Genetic modification of these cells is hindered by a number of problems such as gene stability and transfection efficiency. To circumvent these problems we generated transgenic mice in which the human GFAP promoter directs the expression of human NGF. Neural stem cells isolated from the forebrain of these transgenic animals proliferate and form clusters, which appear identical to stem cells generated from control animals. Upon differentiation in vitro, the transgenic stem cell-derived astrocytes express and secrete bioactive hNGF. Undifferentiated GFAP-hNGF or control stem cells were transplanted into the striatum of adult rats. One and 3 weeks after transplantation, hNGF was detected immunocytochemically in an halo around the transplant sites. In GFAP-hNGF-grafted animals, intrinsic striatal neurons proximal to the graft appear to have taken up hNGF secreted by the grafted cells. Ipsilateral to implants of GFAP-hNGF-secreting cells, choline acetyltransferase-immunoreactive neurons within the striatum were hypertrophied relative to the contralateral side or control-grafted animals. Further, GFAP-hNGF-grafted rats displayed a robust sprouting of p75 neurotrophin receptor-positive fibers emanating from the underlying basal forebrain. These studies indicate that EGF-responsive stem cells which secrete hNGF under the direction of the GFAP promoter display in vitro and in vivo properties similar to that seen following other methods of NGF delivery and this source of cells may provide an excellent avenue for delivery of neurotrophins such as NGF to the central nervous system.

Animals↗
PubMed1997

Studies on neuroprotective and regenerative effects of GDNF in a partial lesion model of Parkinson's disease.

Intrastriatal 6-hydroxydopamine injections in rats induce partial lesions of the nigrostriatal dopamine (DA) system which are accompanied by a delayed and protracted degeneration of DA neurons within the substantia nigra. By careful selection of the dose and placement of the toxin it is possible to obtain reproducible and regionally defined partial lesions which are well correlated with stable functional deficits, not only in drug-induced behaviors but also in spontaneous motoric and sensorimotoric function, which are analogous to the symptoms seen in patients during early stages of Parkinson's disease. The intrastriatal partial lesion model has proved to be particularly useful for studies on the mechanisms of action of neurotrophic factors since it offers opportunities to investigate both protection of degenerating DA neurons during the acute phases after the lesion and stimulation of regeneration and functional recovery during the chronic phase of the postlesion period when a subset of the spared nigral DA neurons persist in an atrophic and dysfunctional state. In the in vivo experiments performed in this model glial cell line-derived neurotrophic factor (GDNF) has been shown to exert neurotrophic effects both at the level of the cell bodies in the substantia nigra and at the level of the axon terminals in the striatum. Intrastriatal administration of GDNF appears to be a particularly effective site for induction of axonal sprouting and regeneration accompanied by recovery of spontaneous sensorimotor behaviors in the chronically lesioned nigrostriatal dopamine system.

Animals↗
PubMed1997

Phenotypic rescue of the albino mutation in the medakafish (Oryzias latipes) by a mouse tyrosinase transgene.

Mutations of the tyrosinase gene are one common cause of a similar phenotype in all vertebrates, known as albinism. In an attempt to contribute to an understanding of the genetic hierarchy governing the development of pigmentation, we have used a mouse tyrosinase minigene under the control of its 5.2 kb upstream promoter region to rescue two different albino mutations in the medakafish, Oryzias latipes. Around hatching stages an almost perfect phenocopy of the wildtype pigmentation was obtained. Subsequent ectopic melanin overproduction indicated a possible incompatibility of the heterologous mouse promoter for stable expression during the entire ontogenesis. Like in some tyrosinase transgenic mouse lines a strong variegation effect was observed. The transgene-mediated pigmentation phenotype was obtained up to the eighth offspring generation. The phenotypic effects of the tyrosinase transgene in different albino mutant strains places the i3-locus upstream and the b-locus downstream of the tyrosinase locus i1 in the genetic hierarchy leading to wildtype pigmentation.

Albinism↗
PubMed1997

Evolutionary analysis of the 5'-terminal region of hepatitis G virus isolated from different regions in China.

We have determined the nucleotide sequence of the 5'-terminal region of the hepatitis G virus (HGV) genome in 11 hepatitis patients from three cities in China. Phylogenetic analyses revealed that the Chinese isolates were genetically distinct from previously described West African isolates (type 1) and American, European and East African isolates (type 2), with a mean sequence divergence of approximately 10%. The mean divergence between isolates from Lanzhou, in the northwest of China, and those from Shanghai and Nanjing, on the east coast of China, was 5% (range 3-7%). The isolates from Shanghai and Nanjing were closely related to a common strain in Japan, while some of those from Lanzhou were closely related to a southeast Asian type 3 isolate. Thus, the Chinese isolates belong to the type 3 variant of HGV.

Base Sequence↗
PubMed1997

[Frozen section diagnosis using telepathology].

DEFINITION: Since 1992 we transfer digitalized frozen section images by means of videomicroscope and a personal computer through the public telephone network (ISDN) to the Institut of Pathology at the University Hospital in Basel. The aim of this study is to determine whether the quality of frozen section diagnosis obtained by telepathology is comparable to the conventional one. METHOD: The frozen section diagnoses by telepathology from Oct. 1992 to May 1996 (n = 94) are compared to the paraffin sections performed in each case after the primary examination. The result is then compared to the well documented data of conventional frozen section diagnosis in the literature. RESULTS: From Oct. 1992 to May 1996 we performed 94 frozen sections. In 84 cases the diagnosis was correct compared to the paraffin section (89%). The sensitivity to detect a malignant tumor was 92%, the specifity 100%. Four examinations were not conclusive and one examination had to be canceled because of technical problems. DISCUSSION: In the literature, 92% of malignancy is diagnosed by conventional frozen section [1]. Telepathology gives the same result.

Frozen Sections↗
PubMed1996

Short-term GDNF treatment provides long-term rescue of lesioned nigral dopaminergic neurons in a rat model of Parkinson's disease.

Glial cell line-derived neurotrophic factor (GDNF) has been shown to exert neuroprotective effects on dopamine (DA) neurons in vivo. Here we report long-term rescue of nigral DA neurons after delayed short-term GDNF administration in a rat lesion model that reproduces the slowly progressing degenerative process seen in Parkinson's disease. GDNF injected close to the substantia nigra provided near-complete protection and persistent survival of the lesioned nigral neurons for at least 4 months after discontinuation of GDNF treatment. Long-term rescue of the nigral cells, however, was not accompanied by any significant reinnervation of the lesioned striatal target or any signs of functional recovery in either drug-induced or spontaneous motor behaviors. We conclude that not only preservation of the nigral DA neurons but also restoration of striatal DA function is necessary for functional recovery in the rat Parkinson model.

Amphetamine↗
PubMed1996

Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study.

The chemokine receptor 5 (CKR5) protein serves as a secondary receptor on CD4(+) T lymphocytes for certain strains of human immunodeficiency virus-type 1 (HIV-1). The CKR5 structural gene was mapped to human chromosome 3p21, and a 32-base pair deletion allele (CKR5Delta32) was identified that is present at a frequency of approximately0.10 in the Caucasian population of the United States. An examination of 1955 patients included among six well-characterized acquired immunodeficiency syndrome (AIDS) cohort studies revealed that 17 deletion homozygotes occurred exclusively among 612 exposed HIV-1 antibody-negative individuals (2.8 percent) and not at all in 1343 HIV-1-infected individuals. The frequency of CKR5 deletion heterozygotes was significantly elevated in groups of individuals that had survived HIV-1 infection for more than 10 years, and, in some risk groups, twice as frequent as their occurrence in rapid progressors to AIDS. Survival analysis clearly shows that disease progression is slower in CKR5 deletion heterozygotes than in individuals homozygous for the normal CKR5 gene. The CKR5Delta32 deletion may act as a recessive restriction gene against HIV-1 infection and may exert a dominant phenotype of delaying progression to AIDS among infected individuals.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Conditionally immortalized neural progenitor cells grafted to the striatum exhibit site-specific neuronal differentiation and establish connections with the host globus pallidus.

The cell line RN33B has been reported to differentiate into neurons in a site-specific manner when grafted to the cortex and hippocampus of adult rats. To investigate the fate of RN33B cells in a subcortical structure, we grafted RN33B cells into the intact or excitoxically lesioned striatum of adult or neonatal rats. The total number and phenotypic characteristics of the [3H]thymidine-labeled grafted cells were analyzed at different time points after transplantation. Transplanted RN33B cells were found to survive, integrate, and differentiate into both neurons and astrocytes, and a significant proportion of the cells (approx. 10%) were found to differentiate into cells with morphological and phenotypic characteristics of medium-sized striatal projection neurons. Retrograde tracing showed that at least some of the graft-derived neurons were capable of establishing connections with one of the primary striatal targets, the globus pallidus. These findings demonstrate a remarkable capacity of the RN33B cells for site-specific neuronal differentiation in both the adult and the developing striatum and suggest that the same differentiating factors that are operating during normal neurogenesis in brain development are retained, at least to some extent, also in the adult CNS.

Adult↗
PubMed1996

Intraoperative autotransfusion in aortic surgery: comparison of whole blood autotransfusion versus cell separation.

OBJECTIVE: Differences concerning alteration of hemostatic, hemolysis, and hematologic parameters after transfusion of blood from a cell-separation (CS) device or whole blood autotransfusion (WBA) were prospectively evaluated during major aortic surgery. METHOD: Thirty-two patients were randomly selected to receive autologous retransfusion by using either WBA or a CS device. Coagulation and hematologic parameters and levels of hemolytic degradation products (HDP) were assessed in the retransfused blood and in the patients' plasma preoperatively and until 24 hours after autologous retransfusion, respectively. RESULTS: Mean volume of retransfused blood was 1072 +/- 473 ml in the WBA group and 556 +/- 504 in the CS group. Level of HDP (bilirubin, free hemoglobin [free HB], and lactic dehydrogenase [LDH] and hemostatic disturbances (d-dimer value, fibrin degradation products) were significantly higher in the WBA device compared with the CS blood. Blood samples taken from the WBA group revealed significantly higher level of HDP (free HB, LDH) and of d-dimer values after autotransfusion compared with the CS group. CONCLUSION: Levels of HDP and the degree of hemostatic disturbances were significantly higher in retransfused whole blood compared with CS blood. Hemostatic disturbances and levels of HDP were significantly pronounced in the patients' plasma after WBA compared with CS. CS retransfused blood seems to be of superior quality compared with WBA and the degree of hemolysis and hemostatic disturbances is minor after CS retransfusion.

Aged↗