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Biomedical subjects

C Huber

Publications and source records attributed to C Huber.

At least 19 recordsLinked to original sources
PubMed2007

A gene responsible for Ghosal hemato-diaphyseal dysplasia maps to chromosome 7q33-34.

Ghosal hemato-diaphyseal dysplasia is a rare autosomal recessive disorder characterized by a progressive sclerosing diaphyseal dysplasia and refractory anemia. The pathogenesis and genetic bases of this syndrome remain hitherto unknown. We have performed a genome wide search in two inbred families originating from Algeria and Tunisia. Here, we report on the mapping of a disease gene to chromosome 7q33-34 (Zmax = 4.21 at theta = 0 at locus D7S2513) in a 3.4 Mb defined by loci D7S2560 and AC091742. Ongoing studies will hopefully lead to identification of the disease-causing gene.

Adult↗
PubMed2006

Initial chemotherapy with mitoxantrone, chlorambucil, prednisone impairs the collection of stem cells in patients with indolent lymphomas--results of a randomized comparison by the German Low-Grade Lymphoma Study Group.

Myeloablative radio-chemotherapy with subsequent autologous stem cell transplantation (ASCT) significantly prolongs progression free and probably overall survival in follicular lymphoma (FL) in first remission. The current trial explored prospectively the rate of successful stem cell mobilization in patients with advanced stage FL after initial therapy with either Mitoxantrone, Chlorambucil, Prednisone (MCP) or Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP) as part of a prospective randomized comparison of both regimens. ASCT patients received Dexa-BEAM (Dexamethasone, BCNU, Melphalan, Etoposide, Cytarabine) for mobilization of stem cells. Stem cells were collected and a minimum of 2x2.0x106/kg bw CD34+ was required for ASCT. Of 79 evaluable patients, 58 (73%) had follicular lymphoma, 13 (16%) mantle cell lymphoma and 8 (10%) lymphoplasmacytic lymphoma. In the 45 patients assigned to CHOP, stem cell collection was successful in 42 cases (93%, 95% CI 82% to 99%). This high mobilization rate after CHOP could be confirmed in 61 subsequent patients (87%). In contrast, after MCP therapy stem cell collection was successful in only 15 of 34 patients (44%, 95% CI 27% to 62%; P=0.0003). In conclusion, initial therapy with MCP significantly impairs the ability to collect stem cells and should be avoided for first line therapy of younger patients potentially qualifying for high dose consolidation and ASCT in first remission.

Adult↗
PubMed2006

The chronology of third molar mineralization in the Austrian population--a contribution to forensic age estimation.

The aim of the present study was to determine the chronology of third molar mineralization and to establish Austrian reference data. Therefore, a cross-sectional study was undertaken by evaluating 610 panoramic radiographs in order to assess the mineralization status of the mandibular third molars of Austrian male and female individuals (275 males and 335 females) between the ages of 12 and 24. The evaluation was carried out using the eight grade scheme of Demirjian et al. (1973). Mean ages, standard deviations, standard errors and percentile distributions are presented for each stage of development. Significant differences between the left and right mandibular third molars were not found. Males reach the developmental stages earlier than females, statistically significant differences were noted in stages E and F. Both mandibular third molars were observed in the majority of the individuals of the Austrian sample (477 individuals, 78.2%). For medicolegal purposes the likelihood of whether an Austrian individual is older than 18 years or not was determined.

Adolescent↗
PubMed2006

High incidence of SHOX anomalies in individuals with short stature.

OBJECTIVE: To study the SHOX gene and the PAR1 region in individuals with short stature. METHODS: The study involved 56 cases of dyschondrosteosis and 84 cases of idiopathic short stature (ISS). The study was designed to determine the following: the prevalence of SHOX anomalies in ISS; the frequency of Madelung deformity in individuals with SHOX anomalies; and the value of a family history of short stature in deciding whether to test for the SHOX gene. RESULTS: 54 SHOX anomalies were observed, including 42 (68%) in the dyschondrosteosis group and 12 (15%) in the ISS group. The high frequency of SHOX anomalies in the ISS group can be explained by the large proportion of boys in this group, reflecting the difficulty in diagnosing dyschondrosteosis in young boys. Clinical evidence of Madelung deformity in six parents of ISS individuals emphasised the importance of family evaluation. Among the 54 SHOX anomalies, 33 PAR1 deletions were identified encompassing the SHOX gene (62%), one partial intragenic deletion (2%), nine deletions located downstream of the SHOX gene (16%), and 11 point mutations (20%). CONCLUSIONS: These data emphasise the value of using microsatellite markers located within and downstream of the SHOX gene.

Adolescent↗
PubMed2006

Risk factors for neuropsychiatric symptoms in dementia: the Cache County Study.

OBJECTIVE: To investigate the probability of individual neuropsychiatric symptoms in dementia patients as a function of eight risk factors. METHODS: In the Cache County Study, we administered the Neuropsychiatric Inventory (NPI) to 328 dementia patients at baseline. Approximately 18 months later, we re-administered the NPI to 184 participants available for follow-up. Generalized estimating equation methods were used to model the probability of individual neuropsychiatric symptoms as a function of: gender, age, education, dementia type and severity, APOE status, time of observation, and general medical health. RESULTS: Women showed increased tendency toward anxiety, [odds ratio (OR) 2.22, 95% confidence interval (CI) 1.31-3.76] and delusions (OR 2.15, CI 1.22-3.78), but older persons of both sexes showed less tendency toward anxiety. Dementia severity increased the tendency toward hallucinations and agitation (OR 2.42, CI 1.81-3.23) and decreased risk of depression. Positive APOE epsilon4 status increased the tendency toward aberrant motor behavior (OR 1.84, CI 1.05-3.22). Among dementia diagnoses, those with Alzheimer's disease showed decreased tendency toward agitation (OR 0.58, CI 0.35-0.95), depression (OR 0.56, CI 0.33-0.96) and disinhibition (OR 0.46, CI 0.24-0.88). Later time of observation increased risk of aberrant motor behavior and delusions, and more serious medical comorbidity increased risk of, agitation, irritability, disinhibition, and aberrant motor behavior. CONCLUSIONS: Gender, age, dementia severity, APOE epsilon4, dementia diagnosis, time of observation, and general medical health appear to influence the occurrence of individual neuropsychiatric symptoms.

Age Factors↗
PubMed2006

Depletion of alloreactive T cells via CD69: implications on antiviral, antileukemic and immunoregulatory T lymphocytes.

Selective depletion of alloreactive T cells from stem-cell allografts should abrogate graft-versus-host disease while preserving beneficial T cell specificities to facilitate engraftment and immune reconstitution. We therefore explored a refined immunomagnetic separation strategy to effectively deplete alloreactive donor lymphocytes expressing the activation antigen CD69 upon stimulation, and examined the retainment of antiviral, antileukemic, and immunoregulatory T cells. In addition to the CD69high T cell fraction, our studies retrieved two T cell subsets based on residual CD69 expression. Whereas, truly CD69(neg) cells were devoid of detectable alloresponses to original stimulators, CD69-low (CD69low)-expressing T cells elicited significant residual alloreactivity upon restimulation. In interferon-gamma enzyme linked immunospot assays, anti-cytomegalovirus and anti-Epstein-Barr virus responses were preserved at significant numbers among CD69neg T lymphocytes. Accordingly, T cells recognizing the leukemia-associated Wilm's tumor-1 antigen were still detectable in the CD69neg subset. However, antiviral and antileukemic specificities were also consistently found within CD69low T cells, suggesting that memory-type donor T cells were partially captured due to residual CD69 expression. Finally, CD4+CD25+ Foxp3+ immunoregulatory T cells did not upregulate CD69 upon allogeneic stimulation. Our data suggest that CD69-mediated removal of alloreactivity can result in efficient allodepletion, but may partially affect the persistence of antiviral and antileukemic donor memory specificities captured among CD69low-expressing lymphocytes.

Antigens, CD↗
PubMed2006

Oestrogen synthesis in the hippocampus: role in axon outgrowth.

Ovarian oestrogens have been postulated to be neuroprotective. It has also been shown that considerable amounts of oestrogens are synthesised in hippocampal neurones. In the present study, we focused on a potential role of hippocampus-derived oestradiol compared to gonad-derived oestradiol on axon outgrowth of hippocampal neurones. To address the role of hippocampus-derived oestradiol, we inhibited oestrogen synthesis by treatment of neonatal hippocampal cell cultures with letrozole, a specific aromatase inhibitor. As an alternative, we used siRNA against steroidogenic acute regulatory protein (StAR). Axon outgrowth and GAP-43 expression were significantly down-regulated in response to letrozole and in siRNA-StAR transfected cells. The effects after inhibition of oestrogen synthesis in response to letrozole and in siRNA-StAR transfected cells were reversed by oestrogen supplementation. No difference was found between ovariectomised animals, cycling animals at pro-oestrus and ovariectomised and subsequently oestradiol-treated animals. However, high pharmacological doses of oestradiol promoted axon outgrowth, which was possible to abolish by the oestrogen receptor antagonist ICI 182,780. Our results show that oestradiol-induced neurite outgrowth is very likely mediated by genomic oestrogen receptors and requires higher doses of oestradiol than physiological serum concentrations derived from the gonads.

Animals↗
PubMed2005

TLR-4 surface display on human monocytes is increased in septic patients.

BACKGROUND: Sepsis is a serious condition, most often occurring as a complication of bacterial infections. The Toll-like receptors (TLR)-2 and TLR-4 have been identified as key molecules in response to Gram-positive and Gram-negative bacteria. This study aimed to assess possible alterations of the surface display of TLR-2 and TLR-4 on monocytes and granulocytes derived from patients with sepsis in comparison with healthy controls. - METHODS: We have utilized flow-cytometry to determine the presence of TLR-2 and TLR-4 on the cell surface at baseline and in response to LPS (40 ng/ml) in vitro. - RESULTS: We found no significant differences of TLR-2 display on monocytes and granulocytes from septic patients compared to controls. Surface display of TLR-4 on monocytes from septic patients at baseline was significantly higher than in healthy controls but there was no further response to LPS, whereas controls showed a significant increase of TLR-4 display on the cell surface after LPS stimulation. In contrast, TLR-4 baseline cell surface display on granulocytes was significantly lower in septic patients than in controls and there was no response to LPS in both groups. - CONCLUSION: Our data suggest a complex relationship between TLR-4 display and bacterial challenge in vivo and in vitro.

Adult↗
PubMed2005

Antithymocyte globulin for the prevention of graft-versus-host disease after unrelated hematopoietic stem cell transplantation for acute myeloid leukemia: results from the multicenter German cooperative study group.

A total of 155 patients with acute myeloid leukemia (AML) received hematopoietic stem cell transplants from unrelated donors after standard conditioning. Clinical outcome after the use of two different antithymocyte globulins for the prevention of graft-versus-host disease (GvHD) was analyzed in a retrospective study as follows: rabbit ATG (Thymoglobulin Sangstat/Genzyme, n=49, median age 42 years, 53% in CR, further ATG-S); rabbit ATG (ATG-Fresenius, n=38, median age 42 years, 58% in CR, further ATG-F) or no ATG (n=68, median age 36 years, 55% in CR). The groups were comparable regarding disease status at transplant, age, CMV status and cytogenetics. Grade III-IV acute GvHD was found in 15% in the ATG and 27% in the no ATG group (P=0.44). The most important independent risk factors for chronic GvHD (cGvHD) were the use of ATG, disease status at transplant and conditioning. cGvHD developed significantly more frequently in no ATG group. With the median follow-up of 34 months, the 5-year survival is 42% for those transplanted in CR. To conclude, these data demonstrate that the transplants performed in CR, with ATG, are associated with a good outcome, low incidence of cGvHD and no increase of relapse.

Adolescent↗
PubMed2005

Inhibitors of apoptosis confer resistance to tumour suppression by adoptively transplanted cytotoxic T-lymphocytes in vitro and in vivo.

Deregulation of apoptosis signalling is commonly found in cancer and results in resistance to cytotoxic therapies. Immunotherapy is a promising strategy to eliminate resistant cancer cells. The transfer of T-lymphocytes during allogeneic stem cell transplantation is clinically explored to induce a 'graft-versus-tumor' effect (GvT). Cytotoxic T-lymphocytes (CTL), which are major effectors of GvT, eliminate cancer cells by inducing apoptosis via multiple parallel pathways. Here, we study in vitro and in vivo the susceptibility of murine cancer cells engineered to express single antiapoptotic genes to CTL-mediated cytotoxicity. Interestingly, we find that single inhibitors of caspase activation, such as BCL-XL or dominant-negative mutants of FADD and caspase-9, protect cancer cells against antigen-specific CTL in vitro. Moreover, expression of BCL-XL impairs the growth suppression by adoptively transplanted CTL of established tumours in vivo. Hence, apoptosis defects that provide protection to cytotoxic cancer therapies can confer crossresistance to immunotherapy by tumour-reactive CTL.

Adoptive Transfer↗
PubMed2005

Individual assessment of sperm morphology of single spermatozoa used for intracytoplasmic sperm injection.

Intracytoplasmic sperm injection (ICSI) is an integral part of assisted reproduction. Although many papers have shown that global sperm count, sperm motility and sperm morphology of the ejaculate play no role in the fertilization rate after ICSI, embryologists who carry out ICSI, try to use the 'best looking' spermatozoa. The aim of the study was to investigate whether those spermatozoa with the best morphology really achieve the highest fertilization rate. In the present study, a total of 798 spermatozoa used for ICSI were documented by high-resolution photo. After ICSI the oocytes were cultured in single droplets and the formation of pronuclei was assessed 16 h later. The spermatozoa (all normal according to WHO criteria) were classified into four groups of different morphology. Group 1: normal head shape (approximately 5 microm diameter), group 2: like group 1, but with 15-20% smaller diameter, group 3: like group 1, but with 15-20% larger diameter, and group 4: like group 1, but with slight mid-piece cytoplasmic irregularities. Using the Pearson chi-square test, no significant difference in terms of fertilization was found among the different groups, showing that marginal sperm differences do not alter the fertilization process in ICSI.

Humans↗
PubMed2004

High-resolution record of Northern Hemisphere climate extending into the last interglacial period.

Two deep ice cores from central Greenland, drilled in the 1990s, have played a key role in climate reconstructions of the Northern Hemisphere, but the oldest sections of the cores were disturbed in chronology owing to ice folding near the bedrock. Here we present an undisturbed climate record from a North Greenland ice core, which extends back to 123,000 years before the present, within the last interglacial period. The oxygen isotopes in the ice imply that climate was stable during the last interglacial period, with temperatures 5 degrees C warmer than today. We find unexpectedly large temperature differences between our new record from northern Greenland and the undisturbed sections of the cores from central Greenland, suggesting that the extent of ice in the Northern Hemisphere modulated the latitudinal temperature gradients in Greenland. This record shows a slow decline in temperatures that marked the initiation of the last glacial period. Our record reveals a hitherto unrecognized warm period initiated by an abrupt climate warming about 115,000 years ago, before glacial conditions were fully developed. This event does not appear to have an immediate Antarctic counterpart, suggesting that the climate see-saw between the hemispheres (which dominated the last glacial period) was not operating at this time.

Journal Article↗
PubMed2004

[Outcome quality of psychosomatic rehabilitation: goal attainment scaling on the basis of a structured catalogue of therapy goals].

Within the scope of a multicenter study regarding the outcome quality of inpatient psychosomatic rehabilitation a structured catalogue of therapy goals (SZK, strukturierter Therapiezielkatalog) was developed. The catalogue contains 89 predetermined therapy goals as well as the option to formulate further goals in own words. The SZK is available both as a patient and as a therapist version. At the beginning of treatment up to five primary objectives are chosen from the list. At the end of treatment and at the 1-year follow-up the level of achievement of objectives is assessed. Moreover the SZK contains the option to mark goals as not relevant any more and to add goals which came up during the treatment and to evaluate them regarding the level of achievement. The study on hand asks for empirical identification of the target structure. Furthermore, reliability and validity of the calculated measures of goal attainment are analysed. As the most important finding the SZK turns out to be a practical and economical assessment instrument for goal-oriented evaluation.

Adult↗
PubMed2003

Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome p450 3A4 substrate, in patients with chronic myeloid leukaemia.

The inhibition by imatinib of the cytochrome p450 3A4 isoenzyme may reduce the CYP3A4-mediated metabolic clearance of clinically important coadministered drugs. The main purpose of this study was to evaluate the effect of the coadministration of imatinib on the pharmacokinetics of simvastatin, a probe CYP3A4 substrate. In total, 20 patients with chronic myeloid leukaemia received an oral dose of 40 mg of simvastatin on study day 1. On study days 2-7, each patient received 400 mg of imatinib once daily orally and on study day 8, 400 mg imatinib together with 40 mg of simvastatin was given. Blood levels of simvastatin were measured predose and for 24 h postdose on study days 1 and 8. Two additional blood samples were taken for imatinib pharmacokinetic (PK) assessment on day 8 before, and 24 h after, imatinib administration. Imatinib increased the mean maximum concentration (C(max)) value of simvastatin two-fold and the area under concentration-time curve (AUC ((0-inf))) value 3.5-fold (P<0.001) compared with simvastatin alone. There was a statistically significant decrease in total-body clearance of drug from the plasma (CL/F) with a mean reduction of 70% for simvastatin (P<0.001): the mean half-life of simvastatin was prolonged from 1.4-2.7 h when given together with imatinib. No changes in imatinib PK parameters were found when given concomitantly with simvastatin. In conclusion, the coadministration of imatinib at steady state with 40 mg simvastatin increases the exposure (C(max) and AUCs) of simvastatin significantly (P<0.001) by two-three-fold. Caution is therefore required when administering imatinib with CYP3A4 substrates with a narrow therapeutic window. The coadministration of simvastatin with imatinib (400 mg) was well tolerated and no major safety findings were reported in this study.

Administration, Oral↗
PubMed2003

Fast high-precision on-line determination of hydrogen isotope ratios of water or ice by continuous-flow isotope ratio mass spectrometry.

A new fast high-precision on-line technique is described for the determination of hydrogen isotope ratios of water by continuous-flow mass spectrometry. For the first time H(2)/H(2)O-equilibration using a platinum catalyst has been used in a fully continuous process. A significant reduction in the H(2)/H(2)O-equilibration time is achieved by a complete vaporization of the water and by increasing the exchange temperature to 100 degrees C. The analysis time is only approximately 5 min/sample which includes equilibration and processing. Measurement precision and accuracy are better than 1 per thousand and sample consumption is only approximately 5 microL. This new technique allows the measurement of a wide range of aqueous samples either in a semi-continuous way (discrete samples are injected one after another) or in a fully continuous way. This allows us, for the first time, to make continuous measurements of ice cores.

Calibration↗
PubMed2003

Genomic studies in AIDS: problems and answers. Development of a statistical model integrating both longitudinal cohort studies and transversal observations of extreme cases.

Genomic studies developed to understand HIV-1 infection and pathogenesis have often lead to conflicting results. This is linked to various factors, including differences in cohort design and selection, the numbers of patients involved, the influence of population substructure, the ethnic origins of the participants, and phenotypic definition. These difficulties in the interpretation of results are examined through published studies on the role of polymorphisms in HLA and the chemokine receptors genes in AIDS. Our analysis suggests that the use of haplotypes will strengthen the results obtained in a given cohort, and meta-analysis including multiple cohorts to gather large-enough numbers of patients should also allow clarification of the genetic associations observed. A P-value of 0.001 appears to be a good compromise for significance on candidate genes in a genetic study. Due to the generally limited size of available cohorts, results will have to be validated in other cohorts. We developed a model to fit transversal case studies (extreme case-control studies) with longitudinal cohorts (all-stages patients) for observations on two gene polymorphisms of CCR5 and NQO1. Interestingly, we observe a protective effect for the CCR5-Delta32 mutant allele in 95% of the simulations based on that model when using a population of 600 subjects; however, when using populations of 250 subjects we find a significant protection in only 59% of the simulations. Our model gives thus an explanation for the discrepancies observed in the various genomic studies published in AIDS on CCR5-Delta32 and other gene polymorphisms: they result from statistical fluctuations due to a lack of power. The sizes of most seroconverter cohorts presently available seem thus insufficient since they include less than a few hundred subjects. This result underlines the power and usefulness of the transversal studies involving extreme patients and their complementarity to longitudinal studies involving seroconverter cohorts. The transposition approach of extreme case-control data into longitudinal analysis should prove useful not only in AIDS but also in other diseases induced by chronic exposure to a foreign agent or with chronic clinical manifestations.

Acquired Immunodeficiency Syndrome↗