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Biomedical subjects

W Becker

Publications and source records attributed to W Becker.

At least 127 records · Page 7Linked to original sources
PubMed2000

Cure of metastatic human colonic cancer in mice with radiolabeled monoclonal antibody fragments.

There is currently no method to cure patients with disseminated colorectal cancer, which is the third leading cancer killer in the Western World. This report shows that the GW-39 intrapulmonary micrometastatic human colonic cancer model in nude mice can be cured with radiolabeled antibodies against carcinoembryonic antigen, and that this approach of radioimmunotherapy is superior to conventional chemotherapy with 5-fluorouracil and leucovorin (5-FU/LV). Monovalent Fab fragments labeled with 131I are superior to intact IgG when survival was evaluated 3, 7, and 14 days after implantation, leading to cures in up to 90% of the mice. Histological results provide support for the differences in therapeutic efficacy observed. Microautoradiography was used to evaluate the intratumoral distribution of each form of antibody. The enhanced tumor control by Fab compared with IgG could be explained in part by the homogeneity of radioantibody distribution of Fab. Biodistribution analysis and initial dose rate calculations for all three forms of antibody also help explain the ability of 131I-labeled Fab to provide better tumor growth control than seen with 131I-labeled IgG. Thus, radioimmunotherapy may be a new modality to treat metastatic disease, particularly when using small antibody fragments.

Animals↗
PubMed2000

Retrospective case series analysis of the factors determining immediate implant placement.

Implant placement at the time of extraction has become an acceptable treatment option. The formation of a restorative treatment plan frequently requires the removal of questionable and hopeless teeth. This retrospective case series analysis reports the reasons for tooth removal before immediate implant placement and provides a rationale for removing questionable and hopeless teeth. Root length is also analyzed as related to tooth loss. Between September 1986 and December 1998, 460 teeth were removed from 282 patients. Reasons for removal were advanced periodontal disease, endodontic complications, nonrestorable caries, roots fractures, short roots (< 14 mm in length), root resorption, and loosened posts. Implants were placed at the time of extraction. Tallies, frequency distributions, and percentages were used to determine individual and multiple reasons for extraction. For teeth with short roots, computerized measurements were made from periapical x-rays. Advanced periodontal disease and restored endodontically treated teeth with posts were the primary reasons for tooth extraction. Dental implants replaced 305 maxillary and 155 mandibular teeth.

Adolescent↗
PubMed1999

High-linear energy transfer (LET) alpha versus low-LET beta emitters in radioimmunotherapy of solid tumors: therapeutic efficacy and dose-limiting toxicity of 213Bi- versus 90Y-labeled CO17-1A Fab' fragments in a human colonic cancer model.

Recent studies suggest that radioimmunotherapy (RIT) with high-linear energy transfer (LET) radiation may have therapeutic advantages over conventional low-LET (e.g., beta-) emissions. Furthermore, fragments may be more effective in controlling tumor growth than complete IgG. However, to the best of our knowledge, no investigators have attempted a direct comparison of the therapeutic efficacy and toxicity of a systemic targeted therapeutic strategy, using high-LET alpha versus low-LET beta emitters in vivo. The aim of this study was, therefore, to assess the toxicity and antitumor efficacy of RIT with the alpha emitter 213Bi/213Po, as compared to the beta emitter 90Y, linked to a monovalent Fab' fragment in a human colonic cancer xenograft model in nude mice. Biodistribution studies of 213Bi- or 88Y-labeled benzyl-diethylene-triamine-pentaacetate-conjugated Fab' fragments of the murine monoclonal antibody CO17-1A were performed in nude mice bearing s.c. human colon cancer xenografts. 213Bi was readily obtained from an "in-house" 225Ac/213Bi generator. It decays by beta- and 440-keV gamma emission, with a t(1/2) of 45.6 min, as compared to the ultra-short-lived alpha emitter, 213Po (t(1/2) = 4.2 micros). For therapy, the mice were injected either with 213Bi- or 90Y-labeled CO17-1A Fab', whereas control groups were left untreated or were given a radiolabeled irrelevant control antibody. The maximum tolerated dose (MTD) of each agent was determined. The mice were treated with or without inhibition of the renal accretion of antibody fragments by D-lysine (T. M. Behr et al., Cancer Res., 55: 3825-3834, 1995), bone marrow transplantation, or combinations thereof. Myelotoxicity and potential second-organ toxicities, as well as tumor growth, were monitored at weekly intervals. Additionally, the therapeutic efficacy of both 213Bi- and 90Y-labeled CO17-1A Fab' was compared in a GW-39 model metastatic to the liver of nude mice. In accordance with kidney uptake values of as high as > or = 80% of the injected dose per gram, the kidney was the first dose-limiting organ using both 90Y- and 213Bi-labeled Fab' fragments. Application of D-lysine decreased the renal dose by >3-fold. Accordingly, myelotoxicity became dose limiting with both conjugates. By using lysine protection, the MTD of 90Y-Fab' was 250 microCi and the MTD of 213Bi-Fab' was 700 microCi, corresponding to blood doses of 5-8 Gy. Additional bone marrow transplantation allowed for an increase of the MTD of 90Y-Fab' to 400 microCi and for 213Bi-Fab' to 1100 microCi, respectively. At these very dose levels, no biochemical or histological evidence of renal damage was observed (kidney doses of <35 Gy). At equitoxic dosing, 213Bi-labeled Fab' fragments were significantly more effective than the respective 90Y-labeled conjugates. In the metastatic model, all untreated controls died from rapidly progressing hepatic metastases at 6-8 weeks after tumor inoculation, whereas a histologically confirmed cure was observed in 95% of those animals treated with 700 microCi of 213Bi-Fab' 10 days after model induction, which is in contrast to an only 20% cure rate in mice treated with 250 microCi of 90Y-Fab'. These data show that RIT with alpha emitters may be therapeutically more effective than conventional beta emitters. Surprisingly, maximum tolerated blood doses were, at 5-8 Gy, very similar between high-LET alpha and low-LET beta emitters. Due to its short physical half-life, 213Bi appears to be especially suitable for use in conjunction with fast-clearing fragments.

Animals↗
PubMed1999

Cloning and characterization of DYRK1B, a novel member of the DYRK family of protein kinases.

The DYRK1A gene on human chromosome 21 encodes a protein kinase presumed to be involved in the pathogenesis of mental retardation in Down's syndrome. Here we describe a highly similar homolog, DYRK1B, which is, in contrast to DYRK1A, predominately expressed in muscle and testis. The human DYRK1B gene was mapped to chromosome 19 (19q12-13.11) by radiation hybrid analysis. The amino acid sequences of DYRK1A and DYRK1B are 84% identical in the N-terminus and the catalytic domain but show no extended sequence similarity in the C-terminal region. DYRK1B contains all motifs characteristic for the DYRK family of protein kinases. In addition, the sequence comprises a bipartite nuclear localization motif. A green fluorescent protein (GFP) fusion protein of DYRK1B was found mainly in the nucleus of transfected COS-7 cells. These data suggest that DYRK1B is a muscle- and testis-specific isoform of DYRK1A and is involved in the regulation of nuclear functions.

Amino Acid Sequence↗
PubMed1999

Estimation of self-turning in the dark: comparison between active and passive rotation.

The present work compares passive and active rotations in darkness with the aim of characterizing the contribution of efferent and proprioceptive information to the perception of angular displacement. The perception of angular displacements was measured in 12 naive subjects (Ss), who either stood on a rotating platform (passive mode, P) or actively turned about their vertical axis by stepping around "on the spot" on a stationary platform (active mode, A). Rotations consisted of short acceleration epochs followed by constant velocity periods of 18.5, 37, and 55 degrees /s, with angular displacements ranging from 30 degrees to 810 degrees (presented in a randomized order); in the case of active turning, Ss had learned to approximately produce any of these three velocity levels on command. Ss indicated perceived displacement either verbally (verbal estimation mode, E), or by stopping their rotation when self-displacement appeared to match the magnitude specified by the experimenter (targeting, T). The resulting four conditions (PE, PT, AE, AT) were administered blockwise. In none of the four conditions was there a systematic dependence of perception on turning velocity. Therefore, the results were pooled across velocities, and the Ss' performance was summarized in the form of estimation curves showing median estimates as a function of physical displacement. There were several differences between the passive and active modes: AE- and AT-estimation curves were linear, close to veracity, and fairly similar to each other. In contrast, the PE-curve was curved rightwardly ("saturation"), with small displacements being overestimated and large ones underestimated, whereas the PT-curve was linear and indicated a pronounced overestimation of large displacements. Moreover, both the random and the systematic errors (measures of individual consistency and correctness of individual calibration, respectively) were significantly smaller in the active than in the passive modes. The observed independence of Ss' perception from turning velocity also during passive rotation suggests that the perceptual time constant was significantly longer than 16 s (a value cited as typical for vestibular perception), being possibly "enhanced" by contextual implications and by expectations of the Ss. The clear improvement of perceptual performance in the active mode testifies to the importance of the efferent and proprioceptive signals arising during active motion. On the assumption that these signals are about as "noisy" as the vestibular ones, the smaller errors during active turning could result from their combination with the vestibular signal. Alternatively, they could also be intrinsically less noisy than the vestibular signal and simply replace the latter during active motion. In the context of these alternatives (which are not exhaustive), the general problem of sensory fusion is discussed, that is, by which mechanisms are signals from different sensory sources combined to obtain a unified representation of the self's orientation.

Adult↗
PubMed1999

Podokinetic after-rotation does not depend on sensory conflict.

Humans who have been stepping for 10 min or more about their vertical axis on a counterrotating platform while fixating on a stationary visual scene continue to circle in the same direction when they attempt, thereafter, to step on firm ground in darkness without turning ("podokinetic after-rotation": PKAR). In the present report, we investigate whether PKAR is due to: (1) a sensory reinterpretation triggered by the conflict between the visual signal of stationarity and the somatosensory message of feet-on-platform rotation, or (2) an adaptation of the somatosensory afferents to prolonged unilateral stimulation irrespective of visual stimulation. Subjects (Ss) circled for 10 min about their vertical axis on an either stationary or counterrotating platform while they were either in darkness, or exposed to an optokinetic stimulus, or to a "head-fixed" stationary pattern. Thereafter, Ss first stood motionless in darkness for 30 s, allowing vestibular after-effects to decay, and then tried (still without vision) to step in place on the stationary platform without turning while their body rotation was recorded by a potentiometer coupled to the head. All conditions involving podomotor activity without concomitant optokinetic stimulation evoked similar PKAR. With optokinetic stimulation, PKAR became larger, apparently because it was summed with an optokinetically induced after-rotation (oPKAR). This oPKAR could be demonstrated in isolation when Ss were passively rotated in front of the OKN-pattern instead of actively circling. PKAR could not be "dumped"; it reappeared after 30 s of straight stepping under visual control. We suggest that PKAR is caused by adaptation of the somatosensory channel and not by a sensory conflict.

Afferent Pathways↗
PubMed1999

Structural and functional characteristics of Dyrk, a novel subfamily of protein kinases with dual specificity.

Dyrk-related kinases represent a novel subfamily of protein kinases with unique structural and enzymatic features. Its members have been identified in distantly related organisms. The yeast kinase, Yak1, has been characterized as a negative regulator of growth. Mnb from Drosophila is encoded by the minibrain gene, whose mutation results in specific defects in neurogenesis. Its mammalian homolog, Dyrk1A, is activated by tyrosine phosphorylation in the activation loop between subdomains VII and VIII of the catalytic domain. The human gene for Dyrk1A is located in the "Down syndrome critical region" of chromosome 21 and is therefore a candidate gene for mental retardation in Down syndrome. More recently, six additional mammalian Dyrk-related kinases have been identified (Dyrk1B, Dyrk1C, Dyrk2, Dyrk3, Dyrk4A, and Dyrk4B). All members of the Dyrk family contain in the activation loop the tyrosines that are essential for the full activity of Dyrk1A. Outside their catalytic domains, Dyrk kinases exhibit little sequence similarity except for a small segment immediately preceding the catalytic domain (DH-box, Dyrk homology box). An unusual enzymatic property of Dyrk-related kinases is their ability to catalyze tyrosine-directed autophosphorylation as well as phosphorylation of serine/threonine residues in exogenous substrates. The exact cellular function of the Dyrk kinases is yet unknown. However, it appears reasonable to assume that they are involved in the regulation of cellular growth and/or development.

Amino Acid Sequence↗
PubMed1999

Anterior cruciate ligament and intercondylar notch in the coronal oblique plane: anatomy complemented by magnetic resonance imaging in cruciate ligament-intact knees.

We assessed the anatomy of the anterior cruciate ligament (ACL) and femoral intercondylar notch on cryosections from one cadaveric knee specimen in the coronal oblique plane oriented parallel to the intercondylar roof. We determined the course of the ACL, the widths of the cruciate ligaments at intersection, and the intercondylar notch configuration on coronal oblique plane magnetic resonance images in 51 adult cruciate ligament-intact knees (25 women, 26 men; age range, 16 to 47 years). The intercondylar notch widths were measured at the notch entrance, at the intersection of the ACL and posterior cruciate ligament (PCL), and at the notch outlet. In the coronal oblique plane, the ACL exhibited a diagonal course from the central and medial part of the anterior intercondylar area of the tibia distally, across the lateral third of the intercondylar notch, to the intercondylar surface of the lateral femoral condyle proximally. At the cruciate ligament intersection, the absolute widths of the ACLs measured on average 6.1+/-1.1 mm in men and 5.2+/-1.0 mm in women representing 31.9% and 31.1% of the ACL/central intercondylar notch width ratios. The absolute widths of the PCLs measured on average 9.6+/-1.3 mm in men and 8.5+/-1.3 mm in women representing 50.4% and 51.4% of PCL/central intercondylar notch width ratios. On average for both groups, men and women, the absolute widths of the PCLs were significantly larger than the absolute widths of the ACLs. However, the relative widths of the cruciate ligaments with respect to corresponding intercondylar notch widths were not significantly different. In the coronal oblique plane, the intercondylar notch widths showed on average a significant decrease from posterior to intersection and from intersection to anterior. At notch outlet, the mean notch width measured 21.4 mm in men and 18.5 mm in women. At intersection, the mean notch width measured 19.1 mm in men and 16.6 mm in women. At notch entrance, the notch width measured 14.6+/-1.8 mm in men and 12.7+/-2.1 mm in women. We recommend magnetic resonance tomography of the knee in the coronal oblique plane oriented parallel to the intercondylar roof as the imaging modality of choice to visualize accurately the anatomic diagonal course of the ACL and its relation to the intercondylar notch and posterior cruciate ligament complex.

Adolescent↗
PubMed1999

Dietary guidelines and patterns of food and nutrient intake in Sweden.

The Nordic and Swedish Nutrition Recommendations emphasize the balance between macronutrients in the diet. The amount of saturated and total fat should be limited to c. 10 %energy and 30 %energy, respectively, and the amount of total carbohydrates should be 55-60 %energy. Data from the first Swedish national dietary survey in 1989 show that the average diet is too high in fat, especially saturated fat (36-37 %energy and 16 %energy, respectively) while the content of total carbohydrates and dietary fibre is too low. However, parts of the population consume a diet that meets the recommendation for a particular macronutrient. A comparison of subjects with a low or high intake of total fat and saturated fat, dietary fibre or fruit and vegetables show some common trends with respect to the characteristics of a dietary pattern equal or close to the recommendations, e.g. more frequent consumption of fruit and vegetables and a lower consumption of some fat-rich foods, such as spreads, cheese and sausages.

Adolescent↗
PubMed1999

Energy under-reporting in Swedish and Irish dietary surveys: implications for food-based dietary guidelines.

An analysis of dietary survey data from Sweden and Ireland revealed that with a declining ratio of energy intake to estimated basal metabolic rate (EI:BMR), %energy from fat, saturated fat and carbohydrate fell while that of protein increased. However, where the definition of under-reporting is less strict, as in the Irish database (EI:BMR) < 1.27), the quantitative effect on macronutrient balance, while statistically significant, is not of such magnitude as to be of nutritional significance. However, with respect to foods, under-reporting was found to be of considerable significance in using such data to formulate food-based dietary guidelines. The Swedish data show that under-reporting of foods is associated with a decreasing percentage of consumers, decreasing intake per eating occasion and decreasing frequency of eating. The development of food-based dietary guidelines will involve comparisons of patterns of food intake among people with contrasting high or low intakes of target nutrients. The Swedish data compared food intakes for those with low or high intakes of saturated fatty acids (SFA) among under-reporters and acceptable reporters of energy intake. Whereas absolute values were always lower with the lower EI:BMR group (< 1.1) compared to the higher EI:BMR group (> 1.35) the ratio of intakes for the low vs. high SFA groups were broadly significant at either EI:BMR ratio. This paper highlights the difficulties that under-reporting will pose for food-based dietary guidelines.

Adolescent↗
PubMed1999

Intake of fatty acids in western Europe with emphasis on trans fatty acids: the TRANSFAIR Study.

OBJECTIVE: To assess the intake of trans fatty acids (TFA) and other fatty acids in 14 Western European countries. DESIGN AND SUBJECTS: A maximum of 100 foods per country were sampled and centrally analysed. Each country calculated the intake of individual trans and other fatty acids, clusters of fatty acids and total fat in adults and/or the total population using the best available national food consumption data set. RESULTS: A wide variation was observed in the intake of total fat and (clusters) of fatty acids in absolute amounts. The variation in proportion of energy derived from total fat and from clusters of fatty acids was less. Only in Finland, Italy, Norway and Portugal total fat did provide on average less than 35% of energy intake. Saturated fatty acids (SFA) provided on average between 10% and 19% of total energy intake, with the lowest contribution in most Mediterranean countries. TFA intake ranged from 0.5% (Greece, Italy) to 2.1% (Iceland) of energy intake among men and from 0.8% (Greece) to 1.9% among women (Iceland) (1.2-6.7 g/d and 1.7-4.1 g/d, respectively). The TFA intake was lowest in Mediterranean countries (0.5-0.8 en%) but was also below 1% of energy in Finland and Germany. Moderate intakes were seen in Belgium, The Netherlands, Norway and UK and highest intake in Iceland. Trans isomers of C18:1 were the most TFA in the diet. Monounsaturated fatty acids contributed 9-12% of mean daily energy intake (except for Greece, nearly 18%) and polyunsaturated fatty acids 3-7%. CONCLUSION: The current intake of TFA in most Western European countries does not appear to be a reason for major concern. In several countries a considerable proportion of energy was derived from SFA. It would therefore be prudent to reduce intake of all cholesterol-raising fatty acids, TFA included.

Adult↗
PubMed1999

Monitoring allergen immunotherapy of pollen-allergic patients: the ratio of allergen-specific IgG4 to IgG1 correlates with clinical outcome.

BACKGROUND: Although allergen immunotherapy has been established as a treatment of type I allergy back in 1911, until now the underlying mechanisms have not been fully understood, nor are there any parameters which would allow one to monitor an ongoing treatment or to assess therapeutic success in the meantime. OBJECTIVE: We wanted to define allergen-specific parameters that change due to treatment in correlation with the clinical outcome. METHODS: We conducted a controlled study with grass pollen-allergic children and compared allergen-specific antibody titres before and 1 year after the onset of immunotherapy in contrast with untreated allergic and healthy children. Two recombinant forms of the major allergen group V of Phleum pratense (Phl p 5) served as model allergens. RESULTS: No change in IgE levels and no significant reduction of skin prick test (SPT) reactivity were seen. On the other hand, a significant reduction of symptom scores in the treated group and a significant rise in allergen-specific IgG1, IgG2 and IgG4 due to the treatment could be observed, but in neither case could we establish a correlation between the increasing amounts of the single antibody classes and the reduction of symptom scores. But most interestingly, when comparing the ratio of IgG4 to IgG1 with the symptom scores, we found significant correlations. Nevertheless, treated allergic patients still differ considerably from healthy controls as nonatopics have hardly any measurable allergen-specific IgG antibodies and no IgE antibodies at all. CONCLUSION: The ratio of IgG4 to IgG1 can serve as a valuable parameter that allows us to assess the success of immunotherapy already 1 year after the onset. The increase of specific IgG1 in relation to IgG4 during treatment reflects a possible influence of this subclass on the induction of tolerance towards allergens.

Allergens↗
PubMed1999

Evaluation of procollagen III peptide as a marker of tissue hyperthyroidism in long-term treated women with TSH suppressive doses of thyroxine.

Increased serum concentrations of the aminoterminal propeptide of collagen III (PIIINP) are found in overt hyperthyroidism. Thus, measurement of serum PIIINP might be useful as an early marker of tissue hyperthyroidism in patients with TSH suppressive thyroxine treatment. In a prospective study we evaluated female patients followed in the thyroid outpatient clinic. Serum PIIINP concentrations were analysed in three groups: patients with TSH suppressive thyroxine treatment for more than 6 months (n = 33, TSH < 0.1 mU/l), patients with thyroxine substitution for hypothyroidism for more than 6 months (n = 20, TSH 0.2-4.0 mU/l) and spontaneous hyperthyroid patients (n = 8, TSH < 0.03 mU/l, increased freeT4 and/or T3). Beside TSH, thyroid hormones and serum PIIINP we measured serum SHBG and a clinical score. Hyperthyroid patients had clearly elevated serum PIIINP and SHBG values and a higher clinical score when compared with other study groups (p < 0.001). Patients with TSH suppressive thyroxine treatment had higher fT4 and T3 concentrations than the thyroxine substitution group (fT4 22 +/- 4.8 pmol/l vs. 17 +/- 2.6 pmol/l, T3 2.2 +/- 0.4 nmol/l vs. 1.8 +/- 0.3 nmol/l, p < 0.001) and also elevated serum SHBG values (77.6 +/- 27.5 nmol/l vs. 58.4 +/- 18 nmol/l, p < 0.01). However, serum PIIINP concentrations and the clinical score were very similar in both thyroxine treated groups (PIIINP in TSH suppression group 3.0 +/- 0.67 microg/l vs. 2.8 +/- 0.65 microg/l in the substitution group, clinical score 2 +/- 1.8 pts. vs. 1.7 +/- 1.5 pts. p = n.s.). In conclusion, serum PIIINP is not a reliable early marker for detection of tissue hyperthyroidism in long-term thyroxine treated women with suppressed TSH.

Adult↗
PubMed1999

In vivo stability and metabolism of 99Tcm-labelled anti-CD4 monoclonal antibodies and Fab' fragments.

In a comparative study, the in vivo metabolic profile of 99Tcm-anti-CD4 monoclonal antibodies (MAb) and Fab' fragments (direct thiol-reduction method) was investigated in rats with adjuvant arthritis. Plasma samples were obtained 1, 4 and 15 h following intravenous injection and urine was collected over 15 h. The composition of the radiolabelled molecules was analysed by gel filtration chromatography. The profile of the complete MAb was as follows. (1) Serum: a predominant peak of 150 kDa (complete MAb; approximately 80%); three minor peaks of 125, 100 and 50 kDa (presumably H2L1, H2 and H1 chains; 14%); and two small peaks of approximately 1500 and 300 Da (presumably 99Tcm-glutathione and Cys-99Tcm-Cys; 5%). (2) Urine: minor peaks of 125, 100 and 50 kDa (15%), major peaks of 1500 and 300 Da (50%), and an additional 25-kDa peak (30%). The profile of the Fab' was as follows. (1) Serum: three minor peaks of 150 kDa [conceivably F(ab')2 plus soluble-CD4], 110 kDa [F(ab')2] and 95 kDa (Fab' plus soluble-CD4; together 30%); a predominant peak of 55 kDa (Fab'; 61%); and two minor peaks of 1500 and 300 Da (8%). (2) Urine: predominantly a 55 kDa (16%) and 1500 and 300 Da peaks (74%). Also, the anti-CD4 Fab' showed higher urine excretion and lower plasma levels than the complete anti-CD4 MAb, but still more favourable tissue-to-blood ratios following scintigraphy of the arthritic joints. Thus, the complex metabolic profile of the anti-CD4 Fab' does not appear to interfere with specific targeting of the inflamed synovial membrane.

Animals↗