Biomedical subjects
Publications and source records attributed to R Hanna.
Gaucher disease (GD) is a lysosomal storage disorder with a broad, overlapping clinical spectrum. The presented two case reports highlight the clinical evaluation required in neuronopathic GD to assist with medical management and genetic counselling.
Explore the source record for details and available documents.
The current BacT/ALERT SA (BTA SA) aerobic blood culture bottle is made from glass, does not require venting, and contains a liquid emulsion sensor (LES). Its performance has been shown to be equivalent to that of the vented standard aerobic culture bottle. A further-improved version of the BTA SA bottle, designated the BacT/ALERT plastic SA (BTA PSA) culture bottle, is made from clear plastic to prevent breakage, does not require venting, and contains a modified LES (LES 2) to reduce the possibility of false positives. The BTA PSA provides a practical alternative to the current glass version of this bottle. The plastic bottle is also comparable to the current glass bottle in transparency and growth performance and additionally minimizes the exposure to infectious agents due to glass bottle breakage.
Explore the source record for details and available documents.
Current research is reshaping basic theories regarding the roles of metal ions in ribozyme function. No longer viewed as strict metalloenzymes, some ribozymes can access alternative catalytic mechanisms depending on the identity and availability of metal ions. Similarly, reaction conditions can allow different folding pathways to predominate, with divalent cations sometimes playing opposing roles.
The current BacT/Alert standard aerobic (VA) blood culture bottle was redesigned and designated a nonvented aerobic (NVA) culture bottle; this bottle does not require venting. A total of 3,873 sets of blood samples for culture were obtained from adult patients with suspected bacteremia or fungemia. The NVA bottle showed performance equivalent to that of the VA bottle for recovery and speed of detection of microorganisms from blood without the need for venting the bottle.
PURPOSE: The recombinant human interleukin-1 receptor (rhu IL-1R) is a soluble truncated form of the type 1 full-length membrane-bound receptor that binds IL-1 with identical affinity to that of the membrane form. As such, it may have clinical potential by sequestering IL-1, thereby preventing it from binding to its membrane-bound receptor and eliciting a biological effect. As IL-1 has been shown to regulate leukemic cell proliferation in an autocrine fashion, a phase I trial of rhu IL-1R was conducted in patients with relapsed and refractory acute myeloid leukemia (AML). METHODS: The study group comprised 11 patients who were sequentially treated on one of three dose levels, receiving a single intravenous (i.v.) bolus dose on day 1 followed by 13 days of daily subcutaneous (s.c.) injections with the option of an additional 14 days of treatment if a response of stable disease or better was achieved. Dose level 1 i.v. bolus 500 microg/m2, s.c. dose 250 microg/m2 per day (five patients); dose level 2 i.v. bolus 1000 microg/m2, s.c. dose 500 microg/m2 per day (three patients); dose level 3 i.v. bolus 2000 microg/m2, s.c. dose 1000 microg/m2 per day (three patients). Owing to limited drug availability, the study was designed to only examine these three dose levels. RESULTS: rhu IL-IR was well tolerated. There was no grade 3 or 4 non-hematological toxicity related to the study drug and the maximum tolerated dose was not reached. No IL-1R-blocking antibodies developed during the course of the study. Serum levels of IL-1beta, IL-6 and TNF were undetectable before, during and after rhu IL-IR administration. The terminal half-life after i.v. dosing was at least 7-12 h, and after s.c. dosing 2-4 days. Serum levels of rhu IL-1R up to 360- and 25-fold those of pretreatment levels were achieved after i.v. and s.c. dosing respectively. No patient had a complete, partial or minor response to treatment; four had stable disease and seven had progressive disease. CONCLUSIONS: rhu IL-1R therapy was safe but did not have any apparent antileukemic effect at the doses administered.
We compared two MR imaging sequences, fast inversion recovery for myelin suppression (FIRMS) and echo-planar FIRMS (EP-FIRMS), for depicting gray/white matter contrast. In 18 patients, the frequency bandwidth (BW) was optimized for each sequence; in nine patients, the BW was held constant. In the BW-optimized group, the mean contrast-to-noise ratio (C/N) was three times higher with the FIRMS sequence. In the BW-constant group, the mean C/N was 27% higher with the EP-FIRMS sequence; however, geometric distortion degraded the EP-FIRMS images excessively. For optimal gray/white contrast, FIRMS appears to be the superior pulse sequence.
UNLABELLED: A hemopoietin with the ability to accelerate both platelet and granulocyte recovery after intensive chemotherapy would have great clinical utility. The recombinant fusion protein composed of human granulocyte-macrophage colony-stimulating factor and interleukin-3 (PIXY321), showed some promise in early adult trials. However, studies for pediatric patients are limited, and there are no systematic data on the pharmacokinetics of PIXY321 given over prolonged periods at current dosage levels. PURPOSE: To determine the safety, clinical effects and plasma concentrations of increasing doses of PIXY321 in children treated with myelosuppressive chemotherapy. METHODS: A total of 39 children with relapsed or high-risk solid tumors were enrolled in this phase I/II study. PIXY321 was administered once or twice daily by subcutaneous injection in total doses of 500 to 1000 microg/m2 per day for 14 days after each course of chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). Pharmacokinetic studies were performed on day 1 of the first course in 33 patients and repeated on day 14 in 13 patients (once-daily schedule only). RESULTS: Although mild local skin reactions and fever were frequent, no dose-limiting toxicity was identified at the maximum dose studied (1000 microg/m2 per day). There were no statistically significant differences in chemotherapy-induced hematologic toxicity with increasing doses of PIXY321 or with twice-daily vs once-daily dosing. On day 1, the median PIXY321 clearance was 657 ml/min per m2 (range 77 1804 ml/min per m2) and the median half-life was 3.7 h (range 2.1-20.8 h). On day 14, clearance increased in all patients studied (median increase 63%), with a corresponding decrease in the median 12-h concentration (from 1.2 to 0.25 ng/ml). Maximum concentrations were < 1 ng/ml in 81% of patients, and only two patients had maximum plasma concentrations equivalent to those required for consistent activity in vitro. CONCLUSIONS: The recombinant fusion protein PIXY321 proved safe in children treated with myelosuppressive ICE chemotherapy but had no demonstrable clinical benefits. The pharmacokinetic studies suggest that the observed lack of hematologic benefit may be explained by low plasma concentrations resulting from increased clearance with prolonged administration. Moreover, the significant increase in PIXY321 systemic clearance in the absence of increased circulating myeloid cells suggests that the upregulation of either extravascular compartment hematopoietic progenitor cells or nonhematopoietic cells may play an important role in controlling circulating concentrations of this unique cytokine. These findings highlight the importance of a thorough assessment of the systemic disposition of cytokines when determining the dose and schedule necessary to achieve clinical activity in patients.
In an attempt to recognize general patterns in the processing of Abs (antibodies) bound to the surface of tumor cells, eight monoclonal antibodies were tested on 10 hematological malignancies of various histological types. The results were compared with previous findings obtained with carcinomas, melanomas, and gliomas, using some of the same antibodies. The data demonstrated that some B-cell lymphomas appear to be unusual in that Abs were unable to bind to them irreversibly; except for those Abs that were rapidly internalized, none of the Abs tested was able to bind irreversibly to the B-cell lymphomas Raji or RL. In contrast, most Abs bound irreversibly to the tumors of other histological types, including other hematological tumors. Irreversible Ab binding to B-cell lymphomas was achieved by cross-linking the Abs on the cell surface. Such differences between cell lines may be due to differences in the supramolecular structure of the surface membrane, which affect the frequency or stability of bivalent Ab binding. The Ab binding interaction could not be described in terms of "functional affinity." These results may lead to improvements in the use of Abs for tumor immunotherapy and for other purposes.
OBJECTIVE: To determine the safety and pharmacokinetics of recombinant human tumor necrosis factor receptor (p80) fusion protein (rhTNFR:Fc) administered as a single intravenous (iv) loading dose followed by subcutaneous (sc) maintenance injections twice weekly for one month in patients with refractory rheumatoid arthritis (RA). METHODS: Four dose groups were evaluated with 4 patients with RA per group: 3 received active drug and one received placebo injection. After each dose group completed 4 weeks of treatment, the patient who received placebo was allowed to receive the active drug for one month. After these 16 patients completed the study, 3 additional patients received the highest dose and 3 additional patients received the lowest dose in an open label study to obtain more safety data (total of 22 patients treated). RESULTS: There were no serious adverse effects. Drug related events include mild injection site reactions in 4 patients that did not necessitate discontinuation of the drug. There was no clearcut dose response among the treatment groups. At Week 4, there was 45% mean improvement in total pain and total joint scores in patients receiving active drug (n = 12), compared to 22% mean improvement in patients receiving placebo (n = 4). C-reactive protein (CRP) levels decreased substantially in patients treated with drug compared to placebo, 30 vs 13%, respectively. The decrease in CRP was most pronounced in the highest dose group. CONCLUSION: This initial experience with rhTNFR:Fc fusion protein in RA justifies further evaluation of this agent in a larger placebo controlled trial.
The flt3 ligand is a growth factor that stimulates the proliferation of hematopoietic progenitor and stem cells. We established a sensitive enzyme-linked immunosorbent assay (ELISA) to measure the concentration of flt3 ligand in plasma or serum from normal individuals, as well as in patients with hematopoietic disorders. Concentrations of flt3 ligand in plasma or serum from normal individuals were quite low: only 12% (7 of 60) of normal individuals had flt3 ligand levels above 100 pg/mL (the limit of detection). In contrast, 86% (19 of 22) of samples from patients with Fanconi anemia and 100% (eight of eight) of samples from patients with acquired aplastic anemia had plasma or serum levels above 100 pg/mL. Mean plasma or serum concentrations (calculated by assigning a value of 0 pg/mL to any sample reading below the level of detection) were as follows: normal volunteers, 14 pg/mL; patients with Fanconi anemia, 1,331 pg/mL; and patients with acquired aplastic anemia, 460 pg/mL. Concentrations of flt3 ligand in blood are, therefore, specifically elevated to a level that may be physiologically relevant in hematopoietic disorders with a suspected stem cell component. The elevated flt3 ligand concentrations in these individuals may be part of a compensatory hematopoietic response to boost the level of progenitor cells.
BACKGROUND: Direct laryngoscopy requires movement of the head, neck, and cervical spine. Spine movement may be limited for anatomic reasons or because of cervical spine injury. The Bullard laryngoscope, a rigid fiberoptic laryngoscope, may cause less neck flexion and head extension than conventional laryngoscopes. The purpose of this study was to compare head extension (measured externally), cervical spine extension (measured radiographically), and laryngeal view obtained with the Bullard, Macintosh, and Miller laryngoscopes. METHODS: Anesthesia was induced in 35 ASA 1-3 elective surgery patients. Patients lay on a rigid board with head in neutral position. Laryngoscopy was performed three times, changing between the Bullard, Macintosh, and Miller laryngoscopes. Head extension was measured with an angle finder attached to goggles worn by the patient. The best laryngeal view with each laryngoscope was assessed by the laryngoscopist. In eight patients, lateral cervical spine radiographs were taken before and during laryngoscopy with the Bullard and Macintosh blades. RESULTS: Median values for external head extension were 11 degrees, 10 degrees, and 2 degrees with the Macintosh, Miller, and Bullard laryngoscopy (P < 0.01), respectively. Significant reductions in radiographic cervical spine extension were found for the Bullard compared to the Macintosh blade at the atlantooccipital joint, atlantoaxial joint, and C3-C4. Median atlantooccipital extension angles were 6 degrees and 12 degrees for the Bullard and Macintosh laryngoscopes, respectively. The larynx could be exposed in all patients with the Bullard but only in 90% with conventional laryngoscope (P < 0.01). CONCLUSIONS: The Bullard laryngoscope caused less head extension and cervical spine extension than conventional laryngoscopes and resulted in a better view. It may be useful in care of patients in whom cervical spine movement is limited or undesirable.
Histiocytosis X (HX) is a rare disorder of Langerhans cells and most commonly occurs in children. We report a case of HX of the vulva in a 76-year-old woman that clinically simulated a yeast infection of the vulva but histologically resembled an amelanotic melanoma. We briefly report the clinical and pathologic features of this case, which responded to vincristine followed by vinblastine and was in complete remission after nine months.
We describe a case of an unusual tongue hamartoma associated with ectrodactyly-ectodermal dysplasia-clefting syndrome in a 3-month-old white female infant. The lesion was composed of a mixture of salivary glands, adipose tissue, smooth muscle and skeletal muscle in a haphazard fashion. Lingual hamartomas are rare and can present a clinical differential diagnostic problem. We review the literature on this unique combination of malformations.
Oligosaccharide subunits were prepared from xyloglucan (XG) by partial hydrolysis with cellulase and added back at micro- to millimolar concentrations to XG in the presence of nasturtium seed xyloglucanase (XG-ase). The oligosaccharides (0.2 mM) stimulated the capacity of this XG-ase to reduce the viscosity of XG solutions by 10- to 20-fold. Purification and fractionation of seed XG-ase activity by gel permeation fast protein liquid chromatography produced a single peak that was much more active in the presence than absence of added XG oligosaccharide. [14C]Fucose-labeled XG nonasaccharide was synthesized by pea fucosyltransferase and shown to be incorporated into polymeric XG in the presence of seed XG-ase without the net production of new reducing chain ends, even while the loss of XG viscosity and XG depolymerization were enhanced. It is concluded that in vitro seed XG-ase can transfer cleavage products of XG to XG oligosaccharides via endotransglycosylation reactions, thereby reducing XG M(r) without hydrolysis. Since this is the only XG-cleaving enzyme that develops in nasturtium seeds during germination, it may be that its transglycosylase and hydrolase capacities are both necessary to account for the rapid and complete depolymerization of XG that takes place.
GDP-fucose:xyloglucan 1,2-alpha-L-fucosyltransferase from pea (Pisum sativum) epicotyl microsomal membranes was readily solubilized by extraction with the zwitterionic detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (Chaps). When using GDP-[14C]fucose as fucosyl donor and tamarind xyloglucan (XG) as acceptor, maximum activation was observed at 0.3% (w/v) Chaps and the highest yield of solubilized activity at 0.4%. The reaction product was hydrolyzed by Trichoderma cellulase to yield labeled oligosaccharides that peaked on gel permeation chromatography at the same elution volume as pea XG nona- and decasaccharide subunits. The apparent Km for fucosyl transfer to tamarind XG by the membrane-bound or solubilized enzyme was about 80 microM GDP-fucose. This was 10 times the apparent Km for fucosyl transfer to endogenous pea nascent XG. Optimum activity was between pH 6 and 7, and the isoelectric point was close to pH 4.8. The solubilized enzyme showed no requirement for, or stimulation by, added cations or phospholipids, and was stable for several months at -70 degrees C. Solubilization and gel permeation chromatography on columns of Sepharose CL-6B enriched the specific activity of the enzyme by about 20-fold relative to microsomes. Activity fractionated on columns of CL-6B with an apparent molecular weight of 150 kDa. The solubilized fucosyltransferase was electrophoresed on nondenaturing polyacrylamide slab gels containing 0.02% (w/v) tamarind XG, and its activity located by incubation in GDP-[14C]fucose, washing, and autoradiographing the gel. A single band of labeled reaction product appeared with an apparent molecular weight of 150 kDa.
[14C]Fucose-labelled xyloglucan (XG) was synthesized from tamarind seed XG by incubating it with GDP-[14C]fucose plus solubilized pea fucosyltransferase, and [14C]fucose-labelled XG nonasaccharide was prepared from the parent hemicellulose by partial hydrolysis with fungal cellulase. alpha-L-Fucosidase activity was readily detected in crude enzyme extracts of growing regions of etiolated pea stems (Pisum sativum) and in cotyledons of germinating nasturtium seedlings (Tropaeolum majus) using the fucosylated XG-nonasaccharide as substrate. Both enzymes showed little activity against intact fucosylated XG and they were totally inactive against p-nitrophenyl-alpha-L-fucoside. Auxin treatment of pea stems, which greatly increased the activity of endo-1,4-beta-glucanases that hydrolyse XG in apical growing regions, failed to result in a similar increase in XG-nonasaccharide alpha-fucosidase activity. However, germination of nasturtium seed, which resulted in a large increase in endo-1,4-beta-glucanase (XG-ase) activity in the cotyledons, was accompanied by comparable increases in XG-alpha-fucosidase activity.