Biomedical subjects

D A Weber

Publications and source records attributed to D A Weber.

At least 19 recordsLinked to original sources

PubMed2001

Transmembrane domain-mediated colocalization of HLA-DM and HLA-DR is required for optimal HLA-DM catalytic activity.

HLA-DM catalyzes peptide loading and exchange reactions by MHC class II molecules. Soluble recombinant DM, lacking transmembrane and cytoplasmic domains, was observed to have 200- to 400-fold less activity compared with the full-length protein in assays measuring DM-catalyzed peptide dissociation from purified HLA-DR1 in detergent solutions. Additional studies with truncated soluble DR1 demonstrated that transmembrane domains in DR1 molecules are also required for optimal activity. The potential requirement for specific interaction between the transmembrane domains of DM and DR was ruled out in experiments with chimeric DR1 molecules containing transmembrane domains from either DM or the unrelated protein CD80. These results suggested that the major role of the transmembrane domains is to facilitate colocalization of DM and DR in detergent micelles. The latter conclusion was further supported by the observation that HLA-DM-catalyzed peptide binding to certain murine class II proteins is increased by reducing the volume of detergent micelles. The importance of membrane colocalization was directly demonstrated in experiments in which DM and DR were reconstituted separately or together into membrane bilayers in unilamellar liposomes. Our findings demonstrate the importance of membrane anchoring in DM activity and underscore the potential importance of membrane localization in regulating peptide exchange by class II molecules.

Amino Acid Sequence↗

PubMed2000

Adult-onset recalcitrant eczema: a marker of noncutaneous lymphoma or leukemia.

BACKGROUND: Generalized eczema or erythroderma may be the presenting sign of cutaneous T-cell lymphoma. Additionally, intractable pruritus has been associated with Hodgkin's lymphoma. However, reports of adult-onset eczematous dermatitis has rarely been linked to noncutaneous lymphoproliferative disorders. OBSERVATIONS: We observed one patient in 1993 who had the onset of intractable dermatitis characterized by prurigo nodularis-like lesions and widespread erythematous plaques. After 18 months of cutaneous symptoms he experienced dyspnea. At this time Hodgkin's disease was diagnosed. This observation prompted us to evaluate subsequent patients with adult-onset eczema who were poorly responsive to therapy and in whom an obvious cause could not be determined. Over the next 24 months we identified an additional 2 patients with lymphoma who met this criteria. CONCLUSION: Unexplained eczema of adult onset may be associated with an underlying lymphoproliferative malignancy. When a readily identifiable cause (eg, contactants, drugs, or atopy) is not found, a systematic evaluation should be pursued. Patients should be evaluated with a careful physical examination, complete blood cell counts, peripheral blood smears, chest roentgenography, computed tomography of the chest and abdomen, and serum protein electrophoresis.

Adult↗

PubMed2000

An advanced toothbrush with improved plaque removal efficacy.

PURPOSE: To compare the plaque removal efficacy and safety of a new advanced manual toothbrush, the Oral-B CrossAction, with seven other toothbrushes. MATERIALS AND METHODS: Seven independent, cross-over design clinical studies were conducted using the same examiner who was blind to the identity of the test products and treatment assignments. In each study, approximately 75 healthy adult subjects from a general population brushed with their randomly assigned toothbrush (CrossAction or comparison brush) at Visit 1 for 1 min without supervision or instruction in brushing technique. Subjects returned after a 1-week washout period and brushed with the alternate toothbrush (Visit 2). Plaque was evaluated before and after brushing using the Rustogi Modified Navy Plaque Index. Statistical analyses were conducted by an independent statistician who remained blind to the identity of all test products. RESULTS: Each of the toothbrushes tested provided significant (P < or = 0.0001) reductions in plaque scores after a single brushing. In each of the studies, the CrossAction toothbrush removed significantly (P < or = 0.0001) greater amounts of whole mouth, gingival margin, and approximal plaque than the compared toothbrush. All toothbrushes were found to be safe, with no changes in oral tissues or restorations observed over the course of each study. The results from these studies were consistent, demonstrating that the CrossAction toothbrush significantly enhances the ability of subjects to remove more plaque during normal brushing compared to seven other toothbrushes.

Adult↗

PubMed2000

A comparative clinical investigation of a novel toothbrush designed to enhance plaque removal efficacy.

PURPOSE: To investigate the safety and efficacy of a new toothbrush with a novel brush head design (Oral-B CrossAction) in comparison with seven leading manual brushes. MATERIALS AND METHODS: Seven independent clinical studies, each involving approximately 100 healthy subjects from a general population, were carried out using a crossover design. In each study, the Oral-B CrossAction toothbrush was compared with an alternative brush for plaque removal efficacy. Plaque was evaluated before and after brushing for 60 s using the Proximal/Marginal Plaque Index. Subjects were randomly assigned to the two brushes in each study and after brushing at visit 1 they returned after a further 2 weeks to repeat the procedure with the second brush. RESULTS: All toothbrushes in the seven studies significantly reduced levels of plaque from their pre-brushing values and were found to be safe with no evidence of oral soft tissue trauma. In each of the studies, the CrossAction was found to be significantly (P < 0.05) more effective than the comparison brush for whole mouth plaque scores, as well as for plaque scores at the gingival margin and proximal surfaces. Advantages in favor of the CrossAction ranged from 9.8% to 23.2% for whole mouth plaque, from 5.3% to 20.6% for the gingival margin and from 12.8% to 24.5% for proximal surfaces. It was concluded that the novel brush head design of the CrossAction toothbrush provides enhanced plaque removal, especially from proximal surfaces, and that this toothbrush is significantly more effective than all seven toothbrushes tested.

Adolescent↗

PubMed2000

A 3-month comparative investigation of the safety and efficacy of a new toothbrush: results from two independent clinical studies.

PURPOSE: To compare the efficacy of a new toothbrush featuring a novel brush head design with those of two established toothbrushes by measuring plaque and gingivitis over a period of 12 weeks. MATERIALS AND METHODS: The Oral-B CrossAction toothbrush was compared with the Dr. Best InterDent and Crest DeepSweep toothbrushes in two independent, parallel-group, examiner-blind clinical studies. Each study involved approximately 100 healthy individuals from a general population. At baseline, after 23-25 hrs of no oral hygiene, oral hard and soft tissues were examined and whole mouth, marginal and approximal plaque scores and whole mouth gingivitis scores were recorded. Subjects in the two studies were asked to use their assigned toothbrush twice a day. No instruction in brushing technique or brushing time was given. After a period of 6 weeks and finally after 12 weeks, subjects in the studies were reassessed for oral tissue status, and their plaque and gingival indices were rescored. RESULTS: In each of the two studies, the tested toothbrushes significantly reduced levels of plaque and gingivitis. The CrossAction toothbrush was, however, more effective in reducing both plaque and gingivitis over 12 weeks, the differences in favor of the CrossAction being statistically significant. All the toothbrushes tested in this investigation were found to be safe with no evidence of hard or soft tissue trauma.

Adolescent↗

PubMed2000

Development and laboratory evaluation of a new toothbrush with a novel brush head design.

Despite many developments in manual toothbrush design, plaque removal at the back of the mouth and at approximal surfaces remains inadequate, yet it is at these sites in particular that plaque accumulates and leads to the development of gingival disease. Improved oral hygiene can be achieved by better brushing technique and by increasing brushing time, but a change in behavior patterns is almost impossible to achieve for the majority of individuals. What is required is a brush head design that maximizes plaque removal, regardless of how the user brushes. As a result of a detailed investigation into the action of bistles during brushing, the Oral-B CrossAction toothbrush has been developed. It incorporates bristles angled at 16 degrees in a unique CrissCross design arranged along the horizontal axis of the toothbrush. Laboratory studies have demonstrated that this development significantly enhances interproximal penetration and cleaning effectiveness when compared with an identical brush head with vertical rather than angled bristles. Laboratory comparisons with more than 80 leading manual toothbrushes from around the world demonstrate a consistent, significant advantage for the new CrossAction toothbrush, both with respect to interproximal penetration and cleaning effectiveness. These results suggest that the CrossAction toothbrush has the potential to remove greater amounts of plaque, especially from the approximal surfaces, than conventional toothbrushes incorporating vertical bristles or more traditional tuft designs.

Adult↗

PubMed1999

Class II-associated invariant chain peptide-independent binding of invariant chain to class II MHC molecules.

The class II-associated invariant chain peptide (CLIP) region of invariant chain (Ii) is believed to play a critical role in the assembly and transport of MHC class II alphabetaIi complexes through its interaction with the class II peptide-binding site. The role of the CLIP sequence was investigated by using mutant Ii molecules with altered affinity for the DR1 peptide-binding site. Both high- and low-affinity mutants were observed to efficiently assemble with DR1 and mediate transport to endosomal compartments in COS cell transfectants. Using N- and C-terminal truncations, a region adjacent to CLIP within Ii(103-118) was identified that can complement loss of affinity for the peptide-binding site in mediating efficient assembly of alphabetaIi. A C-terminal fragment completely lacking the CLIP region, Ii(103-216), was observed binding stably to class II molecules in immunoprecipitation studies and experiments with purified proteins. The Ii(103-118) region was required for this binding, which occurs through interactions outside of the alphabeta peptide-binding groove. We conclude that strong interactions involving Ii(103-118) and other regions of Ii cooperate in the assembly of functional alphabetaIi under conditions where CLIP has little or no affinity for the class II peptide-binding site. Our results support the hypothesis that the CLIP sequence has evolved to avoid high-stability interactions with the peptide-binding sites of MHC class II molecules rather than as a promiscuous binder with moderate affinity for all class II molecules.

Amino Acid Sequence↗

PubMed1999

HLA-DM and the MHC class II antigen presentation pathway.

The MHC class II antigen processing pathway provides a mechanism to selectively present peptides generated in the endosomal compartments of antigen presenting cells to CD4+ T cells. Transport of newly synthesized class II molecules to the endosomal pathway requires the function of an accessory protein, invariant chain, which contains a region that interacts directly with the class II peptide binding site. Release of invariant chain and peptide loading by class II molecules are facilitated by a second accessory protein, HLA-DM. This MHC-encoded membrane protein catalyzes peptide exchange reactions, influencing the repertoire of peptides that are available for recognition by T cells.

Animals↗

PubMed1999

Peptide exchange in MHC molecules.

Major histocompatibility complex (MHC)-encoded glycoproteins bind peptide antigens through non-covalent interactions to generate complexes that are displayed on the surface of antigen-presenting cells (APC) for recognition by T cells. Peptide-binding site occupancy is necessary for stable assembly of newly synthesized MHC proteins and export from the endoplasmic reticulum (ER). The MHC class II antigen-processing pathway provides a mechanism for presentation of peptides generated in the endosomal pathway of APC. The chaperone protein, invariant chain, includes a surrogate peptide that stabilizes newly synthesized class II molecules during transport to endosomal compartments. The invariant chain-derived peptide must be replaced through a peptide exchange reaction that is promoted by acidic pH and the MHC-encoded co-factor HLA-DM. Peptide exchange reactions are not required for presentation of antigens by MHC class I molecules because they bind antigens during initial assembly in the ER. However, exchange reactions may play an important role in editing the repertoire of peptides presented by both class II and class I molecules, thus influencing the specificity of immunity and tolerance.

Animals↗

PubMed1999

MIRD pamphlet no. 16: Techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates.

This report describes recommended techniques for radiopharmaceutical biodistribution data acquisition and analysis in human subjects to estimate radiation absorbed dose using the Medical Internal Radiation Dose (MIRD) schema. The document has been prepared in a format to address two audiences: individuals with a primary interest in designing clinical trials who are not experts in dosimetry and individuals with extensive experience with dosimetry-based protocols and calculational methodology. For the first group, the general concepts involved in biodistribution data acquisition are presented, with guidance provided for the number of measurements (data points) required. For those with expertise in dosimetry, highlighted sections, examples and appendices have been included to provide calculational details, as well as references, for the techniques involved. This document is intended also to serve as a guide for the investigator in choosing the appropriate methodologies when acquiring and preparing product data for review by national regulatory agencies. The emphasis is on planar imaging techniques commonly available in most nuclear medicine departments and laboratories. The measurement of the biodistribution of radiopharmaceuticals is an important aspect in calculating absorbed dose from internally deposited radionuclides. Three phases are presented: data collection, data analysis and data processing. In the first phase, data collection, the identification of source regions, the determination of their appropriate temporal sampling and the acquisition of data are discussed. In the second phase, quantitative measurement techniques involving imaging by planar scintillation camera, SPECT and PET for the calculation of activity in source regions as a function of time are discussed. In addition, nonimaging measurement techniques, including external radiation monitoring, tissue-sample counting (blood and biopsy) and excreta counting are also considered. The third phase, data processing, involves curve-fitting techniques to integrate the source time-activity curves (determining the area under these curves). For some applications, compartmental modeling procedures may be used. Last, appendices are included that provide a table of symbols and definitions, a checklist for study protocol design, example formats for quantitative imaging protocols, temporal sampling error analysis techniques and selected calculational examples. The utilization of the presented approach should aid in the standardization of protocol design for collecting kinetic data and in the calculation of absorbed dose estimates.

Humans↗

PubMed1999

MIRD Pamphlet No. 15: Radionuclide S values in a revised dosimetric model of the adult head and brain. Medical Internal Radiation Dose.

UNLABELLED: Current dosimetric models of the brain and head lack the anatomic detail needed to provide the physical data necessary for suborgan brain dosimetry. During the last decade, several new radiopharmaceuticals have been introduced for brain imaging. The marked differences of these tracers in tissue specificity within the brain and their increasing use for diagnostic studies support the need for a more anthropomorphic model of the human brain and head for use in estimating regional absorbed dose within the brain and its adjacent structures. METHODS: A new brain model has been developed that includes eight subregions: the caudate nuclei, the cerebellum, the cerebral cortex, the lateral ventricles, the lentiform nuclei, the thalami, the third ventricle and the white matter. This brain model is incorporated within a total revision of the head model presented in MIRD Pamphlet No. 5 Revised. Modifications include the addition of the eyes, the teeth, the mandible, an upper facial region, a neck region and the cerebrospinal fluid within both the cranial and spinal regions. RESULTS: Absorbed fractions of energy for photon and electron sources located in 14 source regions within the new model were calculated using the EGS4 Monte Carlo radiation transport code for particles in the energy range 10 keV-4 MeV. These absorbed fractions were then used along with radionuclide decay data to generate S values for 24 radionuclides that are used in clinical or investigational studies of the brain, 12 radionuclides that localize within the cranium and spinal skeleton and 12 radionuclides that selectively localize in the thyroid gland. CONCLUSION: A substantial revision to the dosimetric model of the adult head and brain originally published in MIRD Pamphlet No. 5 Revised is presented. This revision supports suborgan brain dosimetry for a variety of radiopharmaceuticals used in neuroimaging. Dose calculations for the neuroimaging agent 1231-tropane provide an example of the new model and yield mean brain doses that are consistent with published values. However, the absorbed dose to subregions within the brain such as the caudate and lentiform nuclei may exceed the average brain dose by a factor of up to 5.

Adult↗

PubMed1999

Thalidomide in the treatment of refractory rheumatoid arthritis.

OBJECTIVE: To review outcomes in 10 patients with rheumatoid arthritis (RA) treated with thalidomide. METHODS: We reviewed our experience with 10 patients treated with thalidomide using a standard therapeutic protocol and standard outcome measures. RESULTS: We observed no significant improvement in any outcome measure, likely as a consequence of the limited duration of therapy related to thalidomide toxicity. CONCLUSION: Formal studies of the efficacy of thalidomide in RA are required with alternative doses of the compound used by us, or with compounds derived from other sources.

Antirheumatic Agents↗

PubMed1998

Improvement of the prompt-gamma neutron activation facility at Brookhaven National Laboratory.

The prompt-gamma neutron activation facility at Brookhaven National Laboratory was upgraded to improve both the precision and accuracy of its in vivo determinations of total body nitrogen. The upgrade, guided by Monte Carlo simulations, involved elongating and modifying the source collimator and its shielding, repositioning the system's two NaI(Tl) detectors, and improving the neutron and gamma shielding of these detectors. The new source collimator has a graphite reflector around the 238PuBe neutron source to enhance the low-energy region of the neutron spectrum incident on the patient. The gamma detectors have been relocated from positions close to the upward-emerging collimated neutron beam to positions close to and at the sides of the patient. These modifications substantially reduced spurious counts resulting from the capture of small-angle scattered neutrons in the NaI detectors. The pile-up background under the 10.8 MeV 14N(n, gamma)15N spectral peak has been reduced so that the nitrogen peak-to-background ratio has been increased by a factor of 2.8. The resulting reduction in the coefficient of variation of the total body nitrogen measurements from 3% to 2.2% has improved the statistical significance of the results possible for any given number of patient measurements. The new system also has a more uniform composite sensitivity.

Gamma Rays↗

PubMed1997

Inefficient peptide binding by cell-surface class II MHC molecules.

The efficiency of peptide loading onto surface class II MHC molecules in intact APC was investigated, using a previously defined europium immunoassay as well as a simplified Western blot procedure. Conditions normally employed for peptide loading in T cell stimulation assays were suboptimal for peptide binding, which is enhanced at low pH, in the presence of protease inhibitors, and the absence of competing serum proteins. In contrast to some earlier reports, our results indicate that the rate of peptide loading by class II molecules is not enhanced in the environment of the plasma membrane. Peptide association rates were similar for purified and cell-surface class II molecules. As previously reported, rapid peptide binding can be achieved by reconstituting class II molecules into total cellular membranes. We report that this activity is due solely to HLA-DM (which is not present at the cell surface), since it can be specifically removed by immunodepletion with an anti-DM mAb. Thus, we find no evidence for additional cellular cofactors capable of catalyzing peptide binding to class II molecules.

Amino Acid Sequence↗

PubMed1997

Intact proteins can bind to class II histocompatibility molecules with high affinity.

The ability of intact protein antigens to bind to purified class II histocompatibility molecules was investigated. Intact bovine ribonuclease (RNase) inhibited peptide binding to DR1 with a potency similar to that of a high affinity peptide or irreversibly denatured RNase. Similarly, horse myoglobin (Mb) was a potent inhibitor of peptide binding to I-E(k). I-E(k)-Mb complexes were directly visualized as a distinct band with reduced mobility on SDS PAGE. Direct binding experiments with biotin-labeled proteins demonstrated that Mb and RNase bind to class II molecules through the peptide-binding groove with high affinity, and that binding occurs in the absence of detergent. The possibility that HLA-DM can catalyse the binding of intact protein antigens was supported by the observation that DM enhances the binding of biotin-RNase to DR1. Our results provide further support for the hypothesis that intact, partially unfolded protein antigens can act as ligands for initial interaction with class II molecules.

Animals↗

PubMed1997

A modified bottle manikin phantom for in vivo neutron activation analysis.

An artificial skeleton was designed and placed inside a bottle manikin absorber phantom to provide a new reference standard for measurements of total body calcium by in vivo neutron activation analysis at Brookhaven National Laboratory. The composition of the epoxy-based calcium and phosphorus mixture used to construct the skeleton, the dimensions and weight of each bone are given for two phantoms representing an adult male and female. Also, the dimensions, composition, and weights of overlays designed to simulate the influence of obesity on in vivo neutron activation analysis are given for each.

Adult↗

PubMed1997

Impaired permeability in radiation-induced lung injury detected by technetium-99m-DTPA lung clearance.

UNLABELLED: This study evaluates the use of the 99mTc-DTPA aerosol lung clearance method to investigate radiation-induced lung changes in eight patients undergoing radiotherapy for lung or breast carcinoma. The sensitivity of the method was compared with chest radiography for detecting radiation-induced changes in the lung, regional alterations within (irradiated region) and outside (shielded region) the treatment ports, effect of irradiated lung volume, and dependence on time after radiotherapy. METHODS: Serial DTPA lung clearance studies were performed before the first radiation treatment (baseline), then weekly during a 5- to 7-wk course, and up to 12 times post-therapy over periods of 56-574 days. The total activity deposited in the lungs for each study was approximately 150 microCi (approximately 5.6 MBq). DTPA clearance, expressed in terms of the biological half-time, t 1/2, was computed from the slopes of the least-squares fit regression lines of the time-activity curves for the first 10 min for irradiated and shielded lung regions. RESULTS: Major findings include: (a) significant and early DTPA t 1/2 changes were observed in all patients during and after radiotherapy; (b) changes in DTPA t 1/2 values were observed in both irradiated and shielded lung regions in all patients suggesting a radiation-induced systemic reaction; (c) changes in DTPA t 1/2 values were correlated (p < 0.05) with the irradiated lung volumes; (d) significantly reduced DTPA t 1/2 values were observed in three patients who subsequently presented with clinical symptoms and/or radiographic changes consistent with radiation pneumonitis (t1/2 felt to 19% +/- 6% of baseline values, compared with 64% +/- 17% in the remaining patients [p < 0.01]); (e) the onset of decreased DTPA t 1/2 values in these three patients occurred 35-84 days before clinical symptoms and/or radiographic changes; and (f) DTPA t 1/2 tended to approach baseline values with time after radiotherapy, suggesting a long-term recovery in lung injury. CONCLUSION: These observations show significant and early alterations in DTPA lung clearance during and after radiotherapy that may provide a sensitive assay to monitor changes in radiation-induced lung injury and may facilitate early therapeutic intervention.

Aerosols↗

PubMed1996

Enhanced dissociation of HLA-DR-bound peptides in the presence of HLA-DM.

Human leukocyte antigen (HLA)-DM is a critical participant in antigen presentation that catalyzes the release of class II-associated invariant chain-derived peptides (CLIP) from newly synthesized class II histocompatibility molecules, freeing the peptide-binding site for acquisition of antigenic peptides. The mechanism for the selective release of CLIP but not other peptides is unknown. DM was found to enhance the rate of peptide dissociation to an extent directly proportional to the intrinsic rate of peptide dissociation from HLA-DR, regardless of peptide sequence. Thus, CLIP is rapidly released in the presence of DM, because its intrinsic rate of dissociation is relatively high. In antigen presentation, DM has the potential to markedly enhance the rate of peptide exchange, favoring the presentation of peptides with slower intrinsic rates of dissociation.

Amino Acid Sequence↗