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W Vogel

Publications and source records attributed to W Vogel.

At least 145 records · Page 8Linked to original sources
PubMed1998

Antitumor effect of the nucleoside analogs 2-chlorodeoxyadenosine and 2',2'-difluorodeoxycytidine on human hepatoma HepG2 cells.

BACKGROUND/AIMS: Hepatocellular carcinoma is one of the most malignant tumors in the world. Although a wide range of therapeutic options is available, the efficacy of these methods and the prognosis of hepatocellular carcinoma are still very poor. The nucleoside analogs 2-chlorodeoxyadenosine (Cladribine, 2-CdA) and 2',2'-difluorodeoxycytidine (Gemcitabine, dFdC) have shown potent cytotoxic effects on various human tumor cell lines in vitro and marked therapeutic efficacy in the treatment of lymphoproliferative disorders and several solid tumors in vivo. In the present study we evaluated the antitumor effect of 2-CdA and dFdC on human hepatoma HepG2 cells. METHODS: HepG2 cells were grown in the absence and presence of increasing concentrations of 2-CdA and dFdC. Antitumor activity was assessed by inhibition of cell growth, evaluated by counting cell numbers in a hemocytometer and by 3H-thymidine uptake, and by reduction of cell viability as determined by exclusion of 0.1% trypan blue. For rescue experiments, the natural pyrimidine deoxycytidine (dCyd) was added simultaneously or delayed. RESULTS: A strong antitumor activity was observed for both compounds. dFdC showed a more pronounced effect with an inhibition constant (IC50) of 3.98+/-0.03 nM in comparison to 2-CdA with an IC50 of 16.66+/-0.40 nM. Both drugs achieved their half-maximal antitumor activity after 31 h. With respect to dFdC, fractionated daily administrations showed a distinctly greater antitumor activity than a single transient administration. The cytotoxic effects of 2-CdA and dFdC were completely reversed by simultaneous addition of dCyd. CONCLUSION: In this paper we show strong antitumor effects of the nucleoside analogs 2-CdA and dFdC on the human hepatoma cell line HepG2. These findings suggest that both compounds, but in particular dFdC, are promising substances for further evaluations in the treatment of hepatocellular carcinoma.

Antimetabolites, Antineoplastic↗
PubMed1998

Reinforced intradermal hepatitis B vaccination in hemodialysis patients is superior in antibody response to intramuscular or subcutaneous vaccination.

Since 1960, hepatitis B virus-associated chronic liver disease has been considered an important problem in dialysis units in both Europe and North America. Separate dialysis facilities for hepatitis B-infected patients, the implementation of universal precautions for the prevention of transmission, and the active immunization against hepatitis B have now reduced the yearly incidence to less than 0.05% in Western countries. However, only 50% to 60% of patients with renal insufficiency develop sufficient immune response after intramuscular hepatitis B vaccination. The aim of the current study was to determine whether the mode of vaccine application plays a role in vaccination response and whether increasing the vaccine dose of primary intradermal hepatitis B vaccination can reduce the number of vaccine injections in hemodialysis patients. We designed a prospective, randomized study of antibody responses to hepatitis B vaccine given intradermally, subcutaneously, or intramuscularly in 81 hemodialysis patients. Outcome measures were rates of seroconversion, mean levels of anti-Hbs antibodies, and antibody levels 8 years after vaccination. The results show that intradermal hepatitis B vaccination response with a higher vaccination dose than previously used in hemodialysis patients is superior to conventional intramuscular and subcutaneous vaccination and is also well tolerated. Five intradermal injections of 20 microg each induced the development of sufficient anti-Hbs antibody titer, which persisted in 70% of the patients over 3 years.

Adult↗
PubMed1998

The DMPK gene of severely affected myotonic dystrophy patients is hypermethylated proximal to the largely expanded CTG repeat.

Using methylation-sensitive restriction enzymes, we characterized the methylation pattern on the 5' side of the CTG repeat in the DMPK gene of normal individuals and of patients affected with myotonic dystrophy, showing expansions of the repetitive sequence. The gene segment analyzed corresponds to the genomic SacI-HindIII fragment carrying exons 11-15. There is constitutive methylation in intron 12 at restriction sites of SacII and HhaI, localized 1,159-1,232 bp upstream of the CTG repeat, whereas most, if not all, of the other sites of SacII, HhaI, and HpaII in this region are unmethylated, in normal individuals and most of the patients. In a number of young and severely affected patients, however, complete methylation of these restriction sites was found in the mutated allele. In most of these patients, the onset of the disease was congenital. Preliminary in vivo footprinting data gave evidence for protein-DNA contact in normal genes at an Sp1 consensus binding site upstream of the CTG repeat and for a significant reduction of this interaction in cells with a hypermethylated DMPK gene.

Adolescent↗
PubMed1998

Predisposing gene for early-onset prostate cancer, localized on chromosome 1q42.2-43.

There is genetic predisposition associated with >=10% of all cancer of the prostate (CaP). By means of a genomewide search on a selection of 47 French and German families, parametric and nonparametric linkage (NPL) analysis allowed identification of a locus, on chromosome 1q42.2-43, carrying a putative predisposing gene for CaP (PCaP). The primary localization was confirmed with several markers, by use of three different genetic models. We obtained a maximum two-point LOD score of 2.7 with marker D1S2785. Multipoint parametric and NPL analysis yielded maximum HLOD and NPL scores of 2.2 and 3.1, respectively, with an associated P value of . 001. Homogeneity analysis with multipoint LOD scores gave an estimate of the proportion of families with linkage to this locus of 50%, with a likelihood ratio of 157/1 in favor of heterogeneity. Furthermore, the 9/47 families with early-onset CaP at age <60 years gave multipoint LOD and NPL scores of 3.31 and 3.32, respectively, with P = .001.

Age of Onset↗
PubMed1998

Fundamental properties of local anesthetics: half-maximal blocking concentrations for tonic block of Na+ and K+ channels in peripheral nerve.

UNLABELLED: Local anesthetics suppress excitability by interfering with ion channel function. Ensheathment of peripheral nerve fibers, however, impedes diffusion of drugs to the ion channels and may influence the evaluation of local anesthetic potencies. Investigating ion channels in excised membrane patches avoids these diffusion barriers. We investigated the effect of local anesthetics with voltage-dependent Na+ and K+ channels in enzymatically dissociated sciatic nerve fibers of Xenopus laevis using the patch clamp method. The outside-out configuration was chosen to apply drugs to the external face of the membrane. Local anesthetics reversibly blocked the transient Na+ inward current, as well as the steady-state K+ outward current. Half-maximal tonic inhibiting concentrations (IC50), as obtained from concentration-effect curves for Na+ current block were: tetracaine 0.7 microM, etidocaine 18 microM, bupivacaine 27 microM, procaine 60 microM, mepivacaine 149 microM, and lidocaine 204 microM. The values for voltage-dependent K+ current block were: bupivacaine 92 microM, etidocaine 176 microM, tetracaine 946 microM, lidocaine 1118 microM, mepivacaine 2305 microM, and procaine 6302 microM. Correlation of potencies with octanol:buffer partition coefficients (logP0) revealed that ester-bound local anesthetics were more potent in blocking Na+ channels than amide drugs. Within these groups, lipophilicity governed local anesthetic potency. We conclude that local anesthetic action on peripheral nerve ion channels is mediated via lipophilic drug-channel interactions. IMPLICATIONS: Half-maximal blocking concentrations of commonly used local anesthetics for Na+ and K+ channel block were determined on small membrane patches of peripheral nerve fibers. Because drugs can directly diffuse to the ion channel in this model, these data result from direct interactions of the drugs with ion channels.

Anesthetics, Local↗
PubMed1998

Blockade of Na+ and K+ currents by local anesthetics in the dorsal horn neurons of the spinal cord.

BACKGROUND: The dorsal horn of the spinal cord is a pivotal point for transmission of neuronal pain. During spinal and epidural anesthesia, the neurons of the dorsal horn are exposed to local anesthetics. Unfortunately, little is known about the action of local anesthetics on the major ionic conductances in dorsal horn neurons. In this article, the authors describe the effects of bupivacaine, lidocaine, and mepivacaine on voltage-gated Na+ and K+ currents in the membranes of these neurons. METHODS: The patch-clamp technique was applied to intact dorsal horn neurons from laminae I-III identified in 200-microm slices of spinal cord from newborn rats. Under voltage-clamp conditions, the whole-cell Na+ and K+ currents activated by depolarization were recorded in the presence of different concentrations of local anesthetics. RESULTS: Externally applied bupivacaine, lidocaine, and mepivacaine produced tonic block of Na+ currents with different potencies. Half-maximum inhibiting concentrations (IC50) were 26, 112, and 324 microM, respectively. All local anesthetics investigated also showed a phasic, that is, a use-dependent, block of Na+ channels. Rapidly inactivating K+ currents (KA currents) also were sensitive to the blockers with IC50 values for tonic blocks of 109, 163, and 236 microM, respectively. The block of KA currents was not use dependent. In contrast to Na+ and KA currents, delayed-rectifier K+ currents were almost insensitive to the local anesthetics applied. CONCLUSIONS: In clinically relevant concentrations, local anesthetics block Na+ and KA currents but not delayed-rectifier K+ currents in spinal dorsal horn neurons. The molecular mechanisms of Na+ and K+ channel block by local anesthetics seem to be different. Characterization of these mechanisms could be an important step in understanding the complexity of local anesthetic action during spinal and epidural anesthesia.

Anesthetics, Local↗
PubMed1998

The acute phase protein alpha-1-antitrypsin inhibits transferrin uptake in PLC/PRF/5 cells and increases release of hepatitis B virus surface antigen and alpha-fetoprotein.

BACKGROUND/AIMS: The present study was designed to investigate whether the acute phase protein alpha-1-antitrypsin (alpha1-AT), which has an inhibitory effect on transferrin (tf) receptor-mediated iron uptake in K562 and THP1 cells, has a similar effect in PLC/PRF/5 cells. This hepatic cell line is of specific interest because it is infected with hepatitis B virus (HBV). Therefore, we addressed the additional question whether alpha1-AT has any effect on cellular protein synthesis and replication of HBV in PLC/PRF/5 cells. METHODS: Cells were incubated with various concentrations of alpha1-AT, dexamethasone, IL-6 and desferrioxamine. HBs-AG, alpha-fetoprotein and albumin concentrations in culture media were measured using commercially available methods. For equilibrium inhibition binding experiments, cells were incubated with 85-182 pmol/l [125I]tf. To study the potential effect of alpha1-AT on DNA synthesis we measured the incorporation of [3H]thymidine into DNA. RESULTS: In equilibrium saturation binding experiments, [125I]tf bound to PLC/PRF/5 cells with K(D) 17.45 +/- 4.57 nM and a maximum density of binding sites of 267,285 +/- 39,915 sites/cell. In inhibition studies alpha1-AT demonstrated an apparently monophasic inhibition of [125I]tf to its receptor. At concentrations > 30 micromol/l alpha1-AT inhibited the growth of PLC/PRF/5 cells up to approximately 50%. The inhibitory effect of alpha1-AT on DNA synthesis was not as potent as that on growth. At the highest concentration of 100 micromol/l, alpha1-AT produced a 35% maximum inhibition of [3H]thymidine incorporation. Incubating PLC/PRF/5 cells with corticosteroids enhanced HBs-AG release significantly. Interestingly, alpha1-AT showed the same pattern of effects on cell metabolism and HBs-AG release as the corticosteroids. When we incubated the cells with 50 micromol/l alpha1-AT, alpha-fetoprotein production increased significantly and HBs-AG release almost doubled. CONCLUSION: We have to assume that there is a specific mechanism inducing HBs-AG release by alpha1-AT, as has been shown to be the case with steroids.

Cell Line↗
PubMed1998

Unusual mutations in high functioning fragile X males: apparent instability of expanded unmethylated CGG repeats.

We report on further cases of high functioning fragile X males showing decreased expression of FMR1 protein, absence of detectable methylation at the EagI site in the FMR1 gene promoter, and highly unusual patterns of fragile X mutations defined as smear of expansions extending from premutation to full mutation range. Very diffuse and therefore not easily detectable patterns of full mutations were also observed on prenatal testing using DNA from chorionic villi sampled at a time of development when full mutations were still unmethylated in this particular tissue. In the search for possible determinants of such unusual patterns, repeat expansions in the premutation and in the lower full mutation range were identified on genomic PstI blots previously prepared for fragile X DNA testing. Cases with 130 or more triplets, and a number of shorter repeats, were reinvestigated on EcoRI plus EagI digests. Among the 119 expansions, there were 22 in our sample showing either blurred bands or smears on PstI blots. This particular characteristic was strongly associated with the coincidence of a repeat size of more than 130 triplets and absence of EagI site methylation. Our data set also includes cases of mosaic patterns consisting of smears of unmethylated expansions to more than 130 CGGs and of clear bands of methylated expansions. We therefore suggest that in fragile X syndrome unusual smeared patterns of mutations result from somatic instability of larger repeats under circumstantial absence of repeat methylation.

Blotting, Southern↗
PubMed1998

Complex blockade of TTX-resistant Na+ currents by lidocaine and bupivacaine reduce firing frequency in DRG neurons.

Mechanisms of blockade of tetrodotoxin-resistant (TTXr) Na+ channels by local anesthetics in comparison with the sensitivity of tetrodotoxin-sensitive (TTXs) Na+ channels were studied by means of the patch-clamp technique in neurons of dorsal root ganglions (DRG) of rat. Half-maximum inhibitory concentration (IC50) for the tonic block of TTXr Na+ currents by lidocaine was 210 micromol/l, whereas TTXs Na+ currents showed five times lower IC50 of 42 micromol/l. Bupivacaine blocked TTXr and TTXs Na+ currents more potently with IC50 of 32 and 13 micromol/l, respectively. In the inactivated state, TTXr Na+ channel block by lidocaine showed higher sensitivities (IC50 = 60 micromol/l) than in the resting state underlying tonic blockade. The time constant tau1 of recovery of TTXr Na+ channels from inactivation at -80 mV was slowed from 2 to 5 ms after addition of 10 micromol/l bupivacaine, whereas the tau2 value of approximately 500 ms remained unchanged. The use-dependent block of TTXr Na+ channels led to a progressive reduction of current amplitudes with increasing frequency of stimulation, which was </=53% block at 20 Hz in 10 micromol/l bupivacaine and 81% in 100 micromol lidocaine. The functional importance of the use-dependent block was confirmed in current-clamp experiments where 30 micromol/l of lidocaine or bupivacaine did not suppress the single action potential but clearly reduced the firing frequency of action potentials again with stronger potency of bupivacaine. Because it was found that TTXr Na+ channels predominantly occur in smaller sensory neurons, their blockade might underlie the suppression of the sensation of pain. Different sensitivities and varying proportions of TTXr and TTXs Na+ channels could explain the known differential block in spinal anesthesia. We suggest that the frequency reduction at low local anesthetic concentrations may explain the phenomenon of paresthesia where sensory information are suppressed gradually during spinal anesthesia.

Action Potentials↗
PubMed1998

ZOO-FISH analysis in insectivores: "Evolution extols the virtue of the status quo".

In evolutionary terms, insectivores are thought to be close to primates. Through ZOO-FISH analysis using human chromosome-specific painting probes, the syntenic relationship between the human and common shrew, Sorex araneus, karyotypes was studied. The human karyotype was found to be conserved in the shrew, with 32 autosomal segments of common synteny. Special arrangements, already known from similar studies on other species, were noted: fusions of HSA 16 and 19, HSA 3 and 21, and HSA 14 and 15. Only 10 breaks are necessary to transform the human karyotype into the karyotype of the common shrew. Together with known ZOO-FISH data from species belonging to other orders, this puts the human karyotype arrangement near the basis of all mammalian karyotypes. Human chromosome 2 was found to be conserved in its entirety as a single chromosome arm in the shrew. Evidence is presented that the same fusion of two original chromosomal segments formed the shrew chromosome ortholog of HSA 2 as the fusion that occurred during primate evolution to form human chromosome 2. This is a remarkable example of chromosomal coevolution.

Animals↗
PubMed1998

Sex determination in Ellobius lutescens: the story of an enigma.

The unusual karyotype of Ellobius lutescens (2n = 17,X in males and females) has attracted permanent interest and prompted a series of hypotheses on sex determination in this species since its first description by Matthey (1953). The developing knowledge about the sex chromosomes and sex determination as well as the availability of new cytogenetic and molecular genetic techniques prompted studies to test the compatibility between current hypotheses and new findings and rendered modifications of the hypotheses necessary. After a long period dominated by the question what the sex chromosome constitution of this species might be and where the testis determining factor could be located, the presence of Sry had been eventually excluded and sex determination attributed to a hypothetical mutated gene acting downstream of Sry. An X-chromosomal or autosomal location of this gene can be assessed by cosegregation of sex with X-chromosome markers. Some preliminary results concerning X-chromosome dinucleotide repeat markers are reported. However, these markers were homomorphic in Ellobius lutescens. We now report evidence that Zfy is also missing in Ellobius lutescens and E. tancrei (males and females XX), a finding from which we conclude that the entire Y chromosome has been lost from these species. Perspectives concerning future studies are discussed.

Animals↗
PubMed1998

Modulation of iron metabolism in monocytic THP-1 cells and cultured human monocytes by the acute-phase protein alpha1-antitrypsin.

The reticuloendothelial (RE) system plays an important role in the changes in iron metabolism associated with the anemia of chronic disease (ACD). We previously reported that the acute-phase protein alpha1-antitrypsin (alpha1-AT) reduced growth and proliferation in cells of the erythroid cell system by interfering with transferrin (Tf)-mediated iron uptake. The regulation of iron metabolism in cells of the RE system is distinctly different from that in other cell systems; moreover, monocytes and macrophages play an essential part in the regulation of the production and clearance of alpha1-AT. In the present study we examined the effect of alpha1-AT on cells of the monocyte-macrophage lineage. Alpha1-AT completely inhibited the binding of Tf to its receptor (TfR) on THP-1 human myelomonocytic cells and cultured human monocytes. Results of equilibrium saturation and kinetic studies indicated that this inhibition was competitive. No other acute-phase protein demonstrated the same inhibitory potency. Furthermore, alpha1-AT almost completely prevented internalization of the Tf-TfR complex in a dose-dependent manner. Interestingly, and in sharp contrast to the results of our studies with erythroid cells, this inhibition did not reduce the growth and proliferation of THP-1 cells. Furthermore, alpha1-AT significantly increased the concentration of intracellular ferritin in THP-1 cells and monocytes, whereas the number of TfR remained unchanged. Because alpha1-AT showed no enhancing effect on ferritin transcription and translation, we believe that an as-yet unidentified posttranslational mechanism may be responsible for this phenomenon. In addition, our results indicate that the increase in ferritin concentration caused by alpha1-AT is mediated independently of iron supply, as has previously been shown for several proinflammatory cytokines. These data provide further evidence that alpha1-AT is a mediator of the alterations in iron metabolism characteristic of ACD.

Cell Division↗
PubMed1998

Two types of TTX-resistant and one TTX-sensitive Na+ channel in rat dorsal root ganglion neurons and their blockade by halothane.

The clinically employed general anaesthetic halothane was shown to exert action on the peripheral nervous system by suppressing spinal reflexes, but it is still unclear which mechanisms underlie this action. The present study addressed the question whether blockade of tetrodotoxin-sensitive (TTXs) and -resistant (TTXr) Na+-channels in rat dorsal root ganglia (DRG) neurons by halothane could explain its peripheral effects. Two types of TTXr Na+-currents, fast and slow, with distinct activation and inactivation kinetics were found in small (< 25 micrometer) and medium sized (25-40 micrometer) DRG neurons. These currents were blocked by halothane with IC50 values of 5.4 and 7.4 mmol/L, respectively. Additionally, in a concentration-dependent manner halothane accelerated the inactivation kinetics of both currents and shifted the inactivation curves to more hyperpolarized potentials. Neither the activation curves of both TTXr Na+-currents were influenced by halothane nor a voltage-dependent block at test potentials of the currents was seen. In contrast to that of fast current, the time-to-peak for slow current was changed in the presence of halothane. The TTXs Na+-current which prevailed in large neurons (> 40 micrometer) was blocked by halothane with an IC50 of 12.1 mmol/L. Its inactivation curve was also shifted to more hyperpolarized potentials and the inactivation kinetics accelerated with increasing halothane concentration. Similarly to TTXr Na+-currents, the activation curve of TTXs Na+-current and its time-to-peak were not influenced by halothane. It is suggested that two types of TTXr Na+-currents can explain the heterogeneity in kinetic data for TTXr Na+-currents. Furthermore, the incomplete blockade of Na+-currents might underlie the incomplete reduction of spinal reflexes at clinically used concentrations of halothane.

Animals↗
PubMed1998

False-negative findings in chorionic villus sampling. An experimental approach and review of the literature.

61 fetuses/newborns who had an aberrant karyotype in amniocentesis (AC) or percutaneous umbilical blood sampling (PUBS) were followed-up by chorionic villus sampling (CVS) at birth or after interruption. The overall rate of discrepancies is surprisingly high. Among 46 cases with a non-mosaic numerical aberration an AC or PUBS three had a discrepant finding in placental tissue. This was also true in one of seven cases with non-mosaic structural aberrations and in three of five cases with mosaic structural aberrations. All three cases with a mosaic numerical aberration in AC or PUBS were not represented by CVS and/or lymphocytes or fibroblasts, demonstrating the general problem of the unpredictable prognostic value of mosaicism. Our data suggest, that in case of prenatal diagnosis by CVS, using a combined procedure of short-term (STC) and long-term culture (LTC), in our sample we would have missed one case of 45,X (1.6 per cent). When relying only on STC another two cases, one with 47, +21 and one with 46,XX,der(22) would not have been recognized (4.9 per cent, n = 3). All other chromosome aberrations would have been detected by STC alone. On the other hand, one case of 45,X was 'nearly missed' because of low-grade mosaicism in AC (45,X[1]/46,XX[19]), whereas in placental tissues and PUBS only 45,X was represented. This study mimics a false-negative rate of about 1:3000 (STC plus LTC) or about 1:1000 (STC alone) for an a priori risk group of two per cent (e.g., advanced maternal age).

Adult↗
PubMed1997

Functional distribution of three types of Na+ channel on soma and processes of dorsal horn neurones of rat spinal cord.

1. Voltage-gated Na+ channels and their distribution were studied by the patch-clamp technique in intact dorsal horn neurones in slices of newborn rat spinal cord and in neurones isolated from the slice by slow withdrawal of the recording pipette. This new method of neurone isolation was further used to study the roles of soma and axon in generation of action potentials. 2. Tetrodotoxin (TTX)-sensitive Na+ currents in intact neurones consisted of three components. A fast component with an inactivation time constant (tau f) of 0.6-2.0 ms formed the major part (80-90%) of the total Na+ current. The remaining parts consisted of a slowly inactivating component (tau s of 5-20 ms) and a steady-state component. 3. Single fast and slow inactivating Na+ channels with conductances of 11.6 and 15.5 pS, respectively, were identified in the soma of intact neurones in the slice. Steady-state Na+ channels were not found in the soma, suggesting an axonal or dendritic localization of these channels. 4. In the whole-cell recording mode, the entire soma of a dorsal horn neurone could be isolated from the slice by slow withdrawal of the recording pipette, leaving all or nearly all of its processes in the slice. The isolated structure was classified as: (1) 'soma' if it lost all of its processes, (2) 'soma+axon' complex if it preserved one process and at least 85% of its original peak Na+ current or (3) 'soma+dendrite' complex if it preserved one process but the remaining Na+ current did not exceed those observed in the isolated 'somata'. 5. The spatial distribution of Na+ channels in the neurone was studied by comparing Na+ currents recorded before and after isolation. The isolated 'soma' contained 13.8 +/- 1.3% of inactivating Na+ current but no steady-state Na+ current. 'Soma+axon' complexes contained 93.6 +/- 1.4% of inactivating and 46% of steady-state Na+ current. 6. In current-clamp experiments, the intact neurones and isolated 'soma+axon' complexes responded with 'all-or-nothing' action potentials to current injections. In contrast, isolated 'somata' showed only passive or local responses and were unable to generate action potentials. 7. It is concluded that dorsal horn neurones of the spinal cord possess three types of TTX-sensitive voltage-gated Na+ channels. The method of entire soma isolation described here shows that the majority of inactivating Na+ channels are localized in the axon hillock and only a small proportion (ca 1/7) are distributed in the soma. Steady-state Na+ channels are most probably expressed in the axonal and dendritic membranes. The soma itself is not able to generate action potentials. The axon or its initial segment plays a crucial role in the generation of action potentials.

Action Potentials↗
PubMed1997

[High dose chemotherapy of solid tumors].

BACKGROUND: The availability of hemopoetic growth factors and the retransfusion of autologous peripheral blood stem cells (PBSC) have enabled high-dose chemotherapy (HDT) options for the treatment of advanced solid tumours, during recent years. Though the transfusion of PBSC can manage the myelosuppression, dose-escalation ist still limited by non-haematological toxicity. METHOD: Usually, HDT has been given after a proceeding dose-intense chemotherapy that allowed the evaluation of chemosensitivity of the disease and resulted in a stem cell mobilization into the peripheral blood. The autologous bone marrow transplantation has almost completely been replaced by retransfusion of PBSC together with hemopoietic growth factors as specific supportive treatment. The PBSC are harvested by apheresis using a blood cell separator. RESULTS: Results on the efficacy of HDT are available for breast, testicular, ovarian, small cell lung cancer as well as melanoma, glioblastoma and soft-tissue sarcoma. The studies showed the feasibility and efficacy of HDT with tolerable toxicity. CONCLUSION: High-dose chemotherapy will be of increasing importance in the treatment strategies of primary solid tumors, in the near future.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Detection of the His1069Gln mutation in Wilson disease by rapid polymerase chain reaction.

BACKGROUND: Most known mutations in the gene associated with Wilson disease are rare. Only the His1069Gln mutation is found often in patients of Northern or Eastern European origin. OBJECTIVE: To examine the frequency of the His1069Gln mutation in Austrian patients with Wilson disease and their families by using a new, rapid polymerase chain reaction (PCR) test. DESIGN: Cross-sectional study. SETTING: University medical center. PATIENTS: 83 patients from 72 families and 98 relatives of 11 homozygous index patients. MEASUREMENTS: Results of a semi-nested PCR-based assay to detect the His1069Gln mutation in Wilson disease, clinical symptoms, and liver histologic findings. RESULTS: 20 patients, including 5 siblings, were homozygous for the His1069Gln mutation. Thirty-three patients, including 4 siblings, were compound heterozygotes. The mutation was not detected in 30 patients, including 2 siblings. Homozygotes were older at onset of symptoms (mean age, 24 +/- 6 years) than compound heterozygotes (17 +/- 6 years [95% CI, 3.3 to 10.7 years]; P = 0.0135) and patients with other mutations (18 +/- 8 years [CI, 1.8 to 10.2 years]; P = 0.117). Homozygotes were more often female (73.3%) than were compound heterozygotes (48% [CI, 0.94% to 2.46%]) and patients with other mutations (50% [CI, 0.91% to 2.37%]) (P = 0.05). Four of 98 asymptomatic relatives of 11 homozygous index patients were also homozygotes. Heterozygosity was confirmed in 46 relatives (19 parents, 11 children, and 16 distant relatives). CONCLUSION: The His1069Gln mutation was detected in 61% of Austrian patients with Wilson disease. Polymerase chain reaction may be useful for diagnosis and screening of family members of homozygous index patients, even if first-degree relatives are not available for examination.

Adolescent↗