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Biomedical subjects

B Weber

Publications and source records attributed to B Weber.

At least 73 records · Page 4Linked to original sources
PubMed2001

Radiometric assessment of hexose monophosphate shunt capacity in erythrocytes of rhinoceroses.

OBJECTIVES: To measure metabolic rates of the hexose monophosphate shunt (HMPS) in erythrocytes of rhinoceroses, and to test the hypothesis that low concentrations of endogenous ATP in erythrocytes impair HMPS capacity, thereby increasing susceptibility to oxidant-induced hemolysis. ANIMALS: 13 black and 3 white rhinoceroses, free-ranging in several regions of southern Africa, and 1 Sumatran rhinoceros in US captivity. PROCEDURE: HMPS fluxes were measured in rhinoceros erythrocytes with carbon-labeled glucose in the presence and absence of known HMPS activators. RESULTS: Compared with values for human erythrocytes, mean basal state HMPS fluxes were appreciably lower (22 to 46%) in all 3 rhinoceros species studied. Shunt activators increased HMPS rates approximately 5-fold over basal rates in rhinoceros erythrocytes, compared with increases in humans of 10-fold with ascorbate and 15-fold with methylene blue. Stimulated HMPS rates in human erythrocytes were quantitatively 5- to 10-times greater than those observed in rhinoceros erythrocytes. Overall HMPS catabolic rates were completely independent of intracellular ATP concentrations. CONCLUSIONS AND CLINICAL RELEVANCE: HMPS glycolytic and recycling rates and responses to activators are inherently low in erythrocytes from 3 species of rhinoceros, likely contributing to (but not solely responsible for) the high susceptibility of black rhinoceroses to oxidant-induced hemolysis. Slow erythrocyte HMPS capacities were independent of intracellular ATP concentrations, invalidating a current hypothesis regarding the pathogenesis of hemolytic anemia in captive black rhinoceroses. Limitations in HMPS capacities emphasize the importance of protecting rhinoceroses from exposure to drugs, chemicals, toxins, foodstuffs, and other conditions known to increase production of oxidizing metabolites, reactive oxygen species, and free radicals.

Adenosine Triphosphate↗
PubMed2001

The integration of anthracyclines in the treatment of advanced ovarian cancer.

Since the publication of the Gynecologic Oncology Group (GOG) protocol 111 in 1996, and the results of the Arbeitgemeinschaft Gyna kologische Onkologie (AGO) trial Ovar-3 and the GOG protocol 158, the combination of platinum and paclitaxel has been adopted as the standard therapy in advanced ovarian cancer. One option for achieving further progress in the first-line treatment of advanced ovarian cancer might be the addition of noncross-resistant drugs to the two-drug regimen. Meta-analysis showed a survival benefit for platinum-anthracycline based combinations as compared to platinum-based combinations without anthracyclines. An AGO phase I/II trial compared epirubicin in combination with carboplatin and paclitaxel in untreated patients with gynecological malignancies. Based on the results of this study a randomized phase III trial together with the French GINECO group was conducted. The trial started 11/97 and was closed 11/99. All 1281 patients were randomized. Currently, 1132 end-of-therapy reports have been issued. Nine hundred eighty nine (87%) patients completed six cycles of treatment. Treatment and toxicity data are available for these patients. Three hundred thirty five patients had a measurable residual tumor after initial debulking surgery. Response data of 228 patients (111 ET-Carbo, 117 Carbo-T) are available.

Antibiotics, Antineoplastic↗
PubMed2001

Avoiding HIPAA hype: preparing for HIPAA affordably.

In the scramble to prepare their organizations for HIPAA compliance, healthcare financial managers may believe they must commit significant funds to overhauling information systems and hiring consulting firms. But security and confidentiality policies required by HIPAA cannot be implemented solely by upgrading computer systems. HIPAA compliance requires a wholesale change in staff attitudes and behavior regarding patient security and confidentiality. Healthcare organizations can prepare to comply with HIPAA regulations practically and affordably by combining in-house expertise with limited assistance from outside consulting firms. An added benefit of emphasizing the use of in-house resources to prepare the organization for HIPAA compliance is that the organization can develop and retain its own experts on HIPAA.

Facility Regulation and Control↗
PubMed2000

Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Hereditary Breast Cancer Clinical Study Group.

BACKGROUND: Women with a mutation in BRCA1 or BRCA2 have a high risk of developing breast cancer and of contralateral cancer after the initial diagnosis of breast cancer. Tamoxifen protects against contralateral breast cancer in the general population, but whether it protects against contralateral breast cancer in BRCA1 or BRCA2 mutation carriers is not known. METHODS: We compared 209 women with bilateral breast cancer and BRCA1 or BRCA2 mutation (bilateral-disease cases), with 384 women with unilateral disease and BRCA1 or BRCA2 mutation (controls) in a matched case-control study. Age and age at diagnosis of breast cancer (range 24-74 years) were much the same in bilateral-disease cases and controls, and both groups had been followed up for the same time for a second primary breast cancer. History of tamoxifen use for first breast cancer was obtained by interview, or by self-administered questionnaire. FINDINGS: The multivariate odds ratio for contralateral breast cancer associated with tamoxifen use was 0.50 (95% CI 0.28-0.89). Tamoxifen protected against contralateral breast cancer for carriers of BRCA1 mutations (odds ratio 0.38, 95% CI 0.19-0.74) and for those with BRCA2 mutations (0.63, 0.20-1.50). In women who used tamoxifen for 2-4 years, the risk of contralateral breast cancer was reduced by 75%. A reduction in risk of contralateral cancer was also seen with oophorectomy (0.42, 0.22-0.83) and with chemotherapy (0-40, 0.26-0.60). INTERPRETATION: Tamoxifen use reduces the risk of contralateral breast cancer in women with pathogenic mutations in the BRCA1 or BRCA2 gene. The protective effect of tamoxifen seems independent of that of oophorectomy.

Adult↗
PubMed2000

Mucopolysaccharidosis type IIIB: characterisation and expression of wild-type and mutant recombinant alpha-N-acetylglucosaminidase and relationship with sanfilippo phenotype in an attenuated patient.

Mucopolysaccharidosis type IIIB (MPS-IIB) is a lysosomal storage disorder characterised by the defective degradation of heparan sulfate due to a deficiency of alpha-N-acetylglucosaminidase (NAG). The clinical severity of MPS-IIIB ranges from an attenuated to severely affected Sanfilippo phenotype. This paper describes the expression and characterisation of wild-type recombinant NAG and the molecular characterisation of a previously identified R297X/F48L compound heterozygous MPS-IIIB patient with attenuated Sanfilippo syndrome. We have previously shown R297X to be the most common mutation in a cohort of Dutch and Australian patients, occurring at a frequency of approximately 12.5%. To date F48L has only been described in the proband. To determine the contribution of each mutation to the overall clinical phenotype of the patient, both mutant alleles were engineered into the wild-type NAG cDNA and expressed in Chinese hamster ovary cells. The wild-type NAG and F48L mutant alleles were also retrovirally expressed in MPS-IIIB skin fibroblasts. Residual NAG activity and the stability and maturation of immunoprecipitated NAG were determined for wild-type NAG and mutant NAG. The combined biochemical phenotypes of the two NAG mutant alleles demonstrated a good correspondence with the observed attenuated Sanfilippo phenotype of the patient.

Acetylglucosaminidase↗
PubMed2000

Tamoxifen adjuvant treatment duration in early breast cancer: initial results of a randomized study comparing short-term treatment with long-term treatment. Fédération Nationale des Centres de Lutte Contre le Cancer Breast Group.

PURPOSE: In 1986, The Fédération Nationale desCentres de Lutte Contre le Cancer Breast Group initiated a multicenter randomized trial to assess the usefulness of long-term adjuvant tamoxifen treatment. Short-term adjuvant tamoxifen treatment was to be compared with life long adjuvant tamoxifen treatment. PATIENTS AND METHODS: Patients who were disease-free after 2 to 3 years of adjuvant tamoxifen treatment were eligible for the trial. From September 1986 to May 1995, 3,793 patients were randomized from France, Belgium, and Argentina. A total of 1,882 patients stopped tamoxifen (short-term group), and 1,911 patients were to continue tamoxifen for life (long-term group) at the same dose as previously prescribed. The protocol was modified in February 1997, limiting tamoxifen treatment to 10 years after randomization, thus giving a comparison between a 2- to 3-year treatment and a 12- to 13-year treatment. To date, the median duration of tamoxifen treatment is 30 months in the short-term group, and 70 months in the long-term group. RESULTS: Overall, longer tamoxifen treatment induced a 23% reduction in relapse rates, leading to a 7-year disease-free survival rate of 78%, compared with 72% in the shorter-treatment group. In contrast, overall survival did not differ between the two groups, with a 79% overall survival rate in both groups. This improvement in disease-free survival could be observed in node-positive patients (P: =.001); however, it was not found in node-negative patients. Prolonged tamoxifen treatment corresponded to a significant increase in disease-free survival in estrogen receptor-positive patients (P: =.03) as well as in estrogen receptor-negative patients (P: =.05). Furthermore, longer treatment reduced contralateral breast cancers and did not increase the number of endometrial cancers. CONCLUSION: Although no survival advantage was noted, patients did benefit from longer tamoxifen treatment over 3 years and had significantly better disease-free survival compared with patients who stopped hormonal treatment. Long-term follow-up is needed to assess these results. Most patients in the long-term group are still receiving treatment. Comparison of results as time passes will enable conclusions to be made on the value of long-term treatment over 5 years compared with 2 to 3 years.

Antineoplastic Agents, Hormonal↗
PubMed2000

Absence of evidence for a familial breast cancer susceptibility gene at chromosome 8p12-p22.

Several recent studies indicate that the majority of families with five or fewer cases of breast cancer and no cases of ovarian cancer are not due to BRCA1 or BRCA2. It has been proposed that a further breast cancer susceptibility gene that may account for some of these families is located on chromosome 8p12-p22. We have identified 31 site-specific breast cancer families that have a greater than 80% posterior probability of being due to genes other than BRCA1 or BRCA2. These families have been examined for linkage to 8p12-p22 using markers flanking the putative location of the gene. The overall multi-point LOD score is strongly negative across the whole 44 cM. The individual multi-point LOD score is negative in 23 families and only exceeds 0.5 in a single family (with a multi-point LOD score of 1.22). The maximum heterogeneity LOD score was 0.03 at marker D8S136 with estimated proportion linked (alpha) of 3% (95% CI 0 - 30%). These data do not lend support to the hypothesis that chromosome 8p12-p22 harbours a familial breast cancer susceptibility gene. Oncogene (2000) 19, 4170 - 4173

BRCA2 Protein↗
PubMed2000

The fib locus in Streptococcus pneumoniae is required for peptidoglycan crosslinking and PBP-mediated beta-lactam resistance.

Penicillin resistance in pneumococci is mediated by modified penicillin-binding proteins (PBPs) that have decreased affinity to beta-lactams. In high-level penicillin-resistant transformants of the laboratory strain Streptococcus pneumoniae R6 containing various combinations of low-affinity PBPs, disruption of the fib locus results in a collapse of PBP-mediated resistance. In addition, crosslinked muropeptides are highly reduced. The fib operon consists of two genes, fibA and fibB, homologous to Staphylococcus aureus femA/B which are also required for expression of methicillin resistance in this organism. FibA and FibB belong to a family of proteins of Gram-positive bacteria involved in the formation of interpeptide bridges, thus representing interesting new targets for antimicrobial compounds for this group of pathogens.

Amino Acid Sequence↗
PubMed2000

Role for ATM in DNA damage-induced phosphorylation of BRCA1.

The human genetic disorder ataxia-telangiectasia is characterized by immunodeficiency, progressive cerebellar ataxia, radiosensitivity, cell cycle checkpoint defects, and cancer predisposition. The gene product [ataxia-telangiectasia mutation (ATM)] mutated in this syndrome is a component of the DNA damage detection pathway. Loss of ATM function in human and mouse cells causes defects in DNA repair and cell cycle checkpoint control and, not surprisingly, humans and mice with compromised ATM function are prone to cancers. An excess of breast cancer in the relatives of ataxia-telangiectasia patients has also been reported by epidemiological studies. Predisposition to breast and ovarian cancers is also observed in women with germline mutations in BRCA1, a tumor suppressor gene. BRCA1 is a nuclear protein with a cell cycle-regulated expression pattern and is hyperphosphorylated in response to DNA-damaging agents. Here we show that rapid ionizing radiation-induced in vivo phosphorylation of BRCA1 requires the presence of functional ATM protein. Furthermore, we show that ATM interacts with BRCA1, and this association is enhanced by radiation. We also demonstrate that BRCA1 is a substrate of ATM kinase in vitro and in vivo. Using phospho-specific antibodies against serines 1387, 1423, and 1457 of BRCA1, we demonstrate radiation-induced, ATM-dependent phosphorylation of BRCA1 at these sites. These findings show that BRCA1 is regulated by an ATM-dependent mechanism as a part of the cellular response to DNA damage. This interaction between ATM and BRCA1 argues in favor of the involvement of particular aspects of ATM function in breast cancer predisposition.

Ataxia Telangiectasia↗
PubMed2000

Heparan N-sulfatase gene: two novel mutations and transient expression of 15 defects.

Sanfilippo syndrome type A or mucopolysaccharidosis IIIA (MPS IIIA) results from the deficiency of the enzyme heparan N-sulfatase (NS, EC 3.10.1.1), required for the degradation of heparan sulfate. Molecular defects of 24 Italian MPS IIIA patients were recently reported by our group. We report here two novel mutations: 1040insT and Q365X and the expression studies on 15 of the identified defects. Transient expression of COS cells by cDNA mutagenized to correspond to heparan N-sulfatase mutations Y40N, A44T, 166delG, G122R, P128L, L146P, R150Q, D179N, R182C, R206P, P227R, 1040insT, 1093insG, E369K, R377C did not yield active enzyme, demonstrating the deleterious nature of the mutations. Western blot analysis and metabolic labeling experiments revealed, for cells transfected with wild-type enzyme, a precursor 62-kDa form and a mature 56-kDa form. Western blot resulted, for 11 mutations, in the presence of both forms, indicating a normal maturation of the mutant enzyme. Western blot, metabolic labeling and immunofluorescence experiments suggested, for mutations 166delG, L146P, 1040insT and 1093insG, an increased degradation of the mutant enzymes.

Animals↗
PubMed2000

Hierarchical visual processing is dependent on the oculomotor system.

Using functional MRI and eye movement recordings we studied the processing of hierarchical stimuli. In agreement with others, we found a minor left hemispheric dominance during local and right dominance during global processing. When attention was directed locally, well-known oculomotor cortical areas were activated, and saccades were elicited in 41% of the trials. Their latencies were similar to pro-saccades. During global processing virtually no saccades occurred. These results suggest two different operational modes of attention. Attending to local features induces a shift of attention, which simultaneously computes a saccade on any level above the brainstem with a computational burden equal to reflexive saccades. Conversely, attending to global features induces an expansion of the focus of attention, which reinforces fixation.

Attention↗
PubMed2000

Identification of tumor-associated MHC class I ligands by a novel T cell-independent approach.

Specific immunotherapy of cancer utilizes tumor-directed cytotoxic T lymphocytes (CTL) that lyse tumor cells presenting MHC class I-associated peptides derived from tumor-associated proteins. Many tumor-associated gene products are known, but corresponding T cell epitopes are only known for relatively few of these. The most commonly used approaches to identify such antigens require pre-existing CTL lines or clones. By using a CTL-independent high performance liquid chromatography mass spectrometry (HPLC MS)-based approach we identified HLA-A2-presented peptides from carcinoembryonic antigen and wild-type p53 with a copy number as low as eight molecules per cell. Potential epitopes were predicted from the sequences of known tumor antigens and the corresponding synthetic peptides were analyzed by nanocapillary HPLC MS. In parallel, peptides were extracted from fresh, solid tumor tissue or tumor cell lines and analyzed in the same way. Upon co-elution of a natural peptide with a predicted peptide of the same mass, the peptide sequence was confirmed by on-line tandem MS. This approach allows rapid screening of large numbers of tumor-associated gene products for naturally processed peptides presented by different MHC class I molecules as a prerequisite for efficient epitope identification and rapid transfer to therapeutic vaccine trials.

Antigens, Neoplasm↗
PubMed2000

Effect of coadministration of clozapine and fluvoxamine versus clozapine monotherapy on blood cell counts, plasma levels of cytokines and body weight.

RATIONALE: Clozapine treatment is associated with side-effects such as blood cell dyscrasias and weight gain. Increased plasma levels of the cytokines and soluble cytokine receptors leptin, tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors p55 and p75, as well as toxic metabolites of clozapine, have been suggested as the basis for these side-effects, OBJECTIVES: This study examined whether the coadministration of the selective serotonine reuptake inhibitor fluvoxamine, which interferes with clozapine's hepatic metabolism, affects the immunomodulation by clozapine and some of its side-effects. METHODS: The following parameters were measured: circulating levels of the cytokines and soluble receptors, plasma concentrations of clozapine and its metabolite N-desmethylclozapine, body weight and blood cell counts in 11 and 12 schizophrenic inpatients on combined and monotherapy, respectively, before and during the first 6 weeks of medication. RESULTS: On the basis of comparable plasma levels of clozapine and N-desmethylclozapine, the coadministration of fluvoxamine 1) attenuated and delayed the clozapine-induced increase in TNF-alpha plasma levels, 2) enhanced and accelerated the clozapine-induced increase in leptin plasma levels without significant effect on clozapine-induced weight gain, and 3) decreased granulocyte counts. CONCLUSIONS: As clozapine, its metabolite N-desmethylclozapine and fluvoxamine are unlikely to make these differences, other metabolites might be responsible. The coadministration of clozapine and fluvoxamine offers the opportunity to investigate further the putative associations between certain metabolites, immunomodulation and these side-effects.

Adolescent↗
PubMed2000

Minimal incision parathyroidectomy: cure, cosmesis, and cost.

The goals of operative treatment of primary hyperparathyroidism are (1) cure; (2) minimal invasion; and (3) cost-effectiveness. The optimal strategy is controversial. Retrospective review of was undertaken 66 previously unoperated patients having minimal-incision, full-neck exploration by one surgeon over 29 months. A group of 51 women and 15 men had open full neck exploration under general anesthesia through a small (25-40 mm) incision using specifically selected instruments; patients remained hospitalized overnight. Preoperative sestamibi scans were obtained before referral for 17 patients: 11 had localized disease, and 6 did not (65% sensitivity). Four parathyroid glands were identified in 98% of patients; intraoperative frozen section was used selectively on a median of one gland per patient. About 76% of patients had single-gland disease, 6% had two-gland disease, and 18% had four-gland hyperplasia. One patient had four normal cervical parathyroid glands and an aortopulmonary window parathyroid adenoma resected at thoracotomy 1 week later; preoperative sestamibi scans failed to localize his disease. There were no nerve injuries and a 98% cure rate after initial cervical exploration. Excluding the cost of the sestamibi scans, there was no difference between those who had preoperative localization and those who did not; 60% of hospital costs were operating room time-related. Minimal-incision parathyroidectomy is effective for curing hyperparathyroidism and has excellent cosmetic results with negligible scar. Preoperative sestamibi scanning had no impact on cure or treatment costs. Strategies to improve cost-effectiveness must address the substantial costs of anesthesia and operating room services.

Adult↗
PubMed2000

Vitamin D in schizophrenia, major depression and alcoholism.

25-Hydroxyvitamin D3, 1,25-dihydroxyvitamin D3, calcium, phosphate and parathyreoidal hormone levels were assessed in 34 patients with schizophrenia (DSM-III-R, 44% female, mean age 38.9 +/- 2.1 years), 30 patients with alcohol addiction (16% female, mean age 48.7 +/- 2.2 years), 25 patients with major depression (56% female, mean age 57.6+/- years) and 31 healthy controls. Only 25-hydroxyvitamin D3 and 1,25-dihydroxvitamin D3 levels were significantly lower in all groups of psychiatric patients than in normal controls, but not phosphate, calcium and parathyreoidal hormone levels. Significant differences in the vitamin D levels could not be found between the three psychiatric groups. These findings do not support the idea that vitamin D is specifically involved in the pathophysiology of depression. The difference in patients as compared to the healthy controls might be related to a different social background resulting in differing habits e.g. of nutrition.

Adult↗