Biomedical subjects
Publications and source records attributed to G Lee.
A case of vesicouterine fistula in a young woman following caesarean section is presented. The diagnosis was established successfully using heavily T2-weighted MRI which clearly demonstrated fluid within the fistula, obviating the need for conventional radiographic contrast examination.
The movement of powder/granules within the reaction chambers of two continuously-operating granulators (Niro/Aeromatic-Fielder Contipharm and the Glatt Continuous Fluidized-Bed Granulator) was examined by adding dyestuffs to the powder-inlet. Comparison of the dye mass-fraction in the product with the appropriate transport equation indicated random mixing and transport within the product-chamber. Photographs of powder movement on the gill-plate of the Contipharm showed, however, air-driven transport of powder from inlet to outlet, which evidently does not prevent overall random mixing. The output half-life is > 20 min, showing substantial residence time within each machine. A simplex granule was also prepared using the two machines. With the Niro it was shown that an increase in binder solution spraying rate during the continuous process produced an increase in particle size distribution and moisture content. Reduction of air volumetric flow rate on the Glatt machine during continuous operation produced higher moisture content of the product. It was thus demonstrated that changes in process conditions during continuous operation produce predictable alterations in product properties,
The annual meeting of the American Society for Cell Biology (ASCB) is a large and diverse gathering. At last year's meeting**The American Society for Cell Biology 38th Annual Meeting, San Francisco, USA; 12-16 December, 1998. Program chair: Jennifer Lippincott-Schwartz., there were over 8000 attendees, and the topics discussed covered many areas of cell biology. It would be impossible to cover the entire meeting within a trends in CELL BIOLOGY report, so instead we are focusing on an aspect of it that provided some of the most interesting and fruitful discussions. On Saturday afternoon, before the main symposia began, there were 11 special-interest subgroup meetings. The atmosphere at these meetings was informal, and they encouraged open and frank discussion of data and issues. This report provides a brief summary of the discussions at seven of the special-interest subgroup meetings.
The stability of the model protein lactate dehydrogenase (LDH) during spray-drying and also on subsequent dry storage was examined. Trehalose was used as a carrier. The spray-drying temperatures Tinlet and Toutlet have a measurable effect on LDH inactivation. Low Tinlet produced the least process inactivation, but gave a high residual moisture content making the protein's storage stability poor. High Tinlet reduced residual moisture and improved storage stability, but at the cost of high process inactivation. As already found for other systems, addition of a surfactant (in this case polysorbate 80) could ameliorate process inactivation of LDH at Tinlet = 150 degreesC. Surfactant had, however, a deleterious effect on storage stability of LDH, the vital factor being the molar ratio of surfactant/protein in the dried product. By using electron spectroscopy it was shown that LDH has a 10 times higher surface concentration in the dried trehalose particles than expected for a homogeneous distribution. Surface tension measurements at the water/air interface proved that LDH is surface active, although the Gibbs equation appeared to be inapplicable. Calculations of spray-droplet formation time and drying time indicate than the extent of diffusion-driven LDH adsorption to the liquid/air interface is sufficient to account for the measured amount of LDH inactivation during spray-drying. The presence of 0.1% polysorbate 80 to the spray solution prevents LDH from appearing at the surface of the dried particles. As a negative control, the phosphatide Lipoid E 80 does not prevent the appearance of LDH in the surface according to electron spectroscopy and does not therefore prevent LDH inactivation during spray-drying at Tinlet = 150 degreesC.
Forty-eight primary oral squamous cell carcinomas (SCC) were screened for allelic imbalance (AI) at 3p24-26, 3p21, 3p13, 8p21-23, 9p21, 9q22 and within the Rb, p53 and DCC tumour suppressor genes. AI was detected at all TNM stages with stage 4 tumours showing significantly more aberrations than stage 1-3. A factional allelic loss (FAL) score was calculated for all tumours and a high score was associated with development of local recurrence (P = 0.033) and reduced survival (P = 0.0006). AI at one or more loci within the 3p24-26, 3p21, 3p13 and 9p21 regions or within the THRB and DCC genes was associated with reduced survival. The hazard ratios for survival analysis revealed that patients with AI at 3p24-26, 3p13 and 9p21 have an approximately 25 times increase in their mortality rate relative to a patient retaining heterozygosity at these loci. AI at specific pairs of loci, D3S686 and D9S171 and involving at least two of D3S1296, DCC and D9S43, was a better predictor of prognosis than the FAL score or TNM stage. These data suggest that it will be possible to develop a molecular staging system which will be a better predict of outcome than conventional clinicopathological features as the molecular events represent fundamental biological characteristics of each tumour.
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OBJECTIVE: To investigate the pharmacological effects of ethanol and its metabolite acetaldehyde on isolated rat bladder muscle, and thus assess the potential influence of ethanol ingestion on the risk of urinary retention in patients with benign prostatic hyperplasia. MATERIALS AND METHODS: Isometric tension changes of isolated rat bladder muscle strips were recorded in an organ bath using a pressure transducer. The acute or prolonged effects of ethanol (1-4%) or acetaldehyde (0.01, 0.1 or 1 mmol/L) were assessed on resting tension, electrical field stimulation (EFS), and bethanechol- (0.5 mmol/L), ATP- (2 mmol/L) or KCl- (127 mmol/L) induced contraction. To determine the mechanism of acetaldehyde-induced stimulation, an antihistamine, diphenhydramine was used after bethanechol stimulation. RESULTS: At the concentrations used, ethanol and acetaldehyde did not change the pH of the bathing medium. The resting tension of the muscle was not changed by ethanol, and acetaldehyde caused only a small increase in baseline tone at 1 mmol/L. Incubation with ethanol or acetaldehyde significantly suppressed contractility induced by EFS, bethanechol, ATP or KCl at each concentration (P<0.05). Contractions induced by all drugs were not changed significantly by the acute application of ethanol and the acute application of acetaldehyde did not affect contractions induced by ATP or KCl. However, EFS- or bethanechol-induced contractions were significantly enhanced (P<0. 05). The acetaldehyde-induced effects were completely blocked by the H1 antagonist, diphenhydramine (10 micromol/L). CONCLUSIONS: Ethanol did not affect resting tension but acetaldehyde and ethanol suppressed bladder muscle contractions. However, direct acetaldehyde-stimulation may release histamine and enhance contractility. This suggests that chronic alcoholism rather than acute intoxication is more likely to provoke urinary retention.
The purpose of this research was to investigate the freeze- and vacuum-drying behavior of L-amino acids of current/potential use as adjuvants for formulating proteins. The analytical methods used were wide-angle x-ray diffraction, differential scanning calorimetry, and scanning electron microscopy. Protein analysis was performed either as an activity assay (lactate dehydrogenase [LDH]) or by size-exclusion chromatography (granulocyte colony-stimulating factor [rhG-CSF]). After samples were freeze-dried, only the four basic amino acids (arginine, lysine, histidine, and citrulline) formed amorphous solids, which, however, were partially crystalline. The remaining amino acids all formed fully crystalline solids. After samples were vacuum-dried, (20 degrees C, 0.1 mbar, 1 ml fill volume in 2-ml vials) fully crystalline solids were formed by all of the amino acids. For arginine, the addition of either HCl, H3PO4, or H2SO4 sufficient to form the respective salt produced amorphous solids after vacuum-drying, but they had high residual water contents and low glass transition temperatures (Tg). Addition of phenylalanine to arginine base inhibited crystallization of the latter at low concentrations during vacuum-drying procedure, leading to formation of a pure rubbery solid. At higher concentrations the phenylalanine crystallized, producing dry products with glass transition temperatures of > 60 degrees C. The process and storage stability of LDH and rhG-CSF in the vacuum-dried phenylalanine/arginine glasses was greatly improved at temperatures up to 40 degrees C compared with the unprotected proteins. Uptake of moisture during storage was, however, a complicating factor, reducing Tg, promoting crystallization, and leading to decreased protein stability. The PO4 salt of arginine produced especially high glass transition temperatures after it was vacuum-dried. These sugar-free amino acid formulations thus are potential stabilizes for proteins.
We attempted to determine whether treatment using intramuscular methylprednisolone plus intravitreal vancomycin decreased ocular inflammation and preserved retinal function better in experimental Staphylococcus aureus (S. aureus) endophthalmitis than treatment with intravitreal vancomycin alone. Sixteen rabbits received intravitreal inoculations in both eyes with S. aureus and the rabbits were divided into two groups (group I and group II) of eight rabbits each. Group I rabbits were treated with one injection of intravitreal vancomycin in each eye at either 24, 36, 48 or 72 hours after bacterial inoculation followed by seven consecutive days of high dose intramuscular methylprednisolone (30 mg/kg per day). Group II rabbits were treated with only one intravitreal injection of vancomycin in each eye at equivalent time intervals as in Group I. Clinical evaluations of ocular inflammation were performed by slit-lamp biomicroscopy and indirect ophthalmoscopy. Electroretinography (ERG) was performed eight days after bacterial inoculation to assess retinal function in all eyes. The combination of intramuscular methylprednisolone and intravitreal vancomycin resulted in a degree of ocular inflammation equal to eyes treated with intravitreal vancomycin alone at all treatment intervals. ERG responses were not significantly different in either group. A single intravitreal injection of vancomycin plus daily intramuscular methylprednisolone for seven days were found neither to decrease ocular inflammation nor preserve retinal function better than a single intravitreal injection of vancomycin in our experimental model of S. aureus endophthalmitis.
The erythroid membrane cytoskeletal protein 4.1 is the prototypical member of a genetically and topologically complex family that is generated by combinatorial alternative splicing pathways and is localized at diverse intracellular sites including the nucleus. To explore the molecular determinants for nuclear localization, we transfected COS-7 cells with epitope-tagged versions of natural red cell protein 4.1 (4.1R) isoforms as well as mutagenized and truncated derivatives. Two distant topological sorting signals were required for efficient nuclear import of the 4.1R80 isoform: a basic peptide, KKKRER, encoded by alternative exon 16 and acting as a weak core nuclear localization signal (4.1R NLS), and an acidic peptide, EED, encoded by alternative exon 5. 4.1R80 isoforms lacking either of these two exons showed decreased nuclear import. Fusion of various 4.1R80 constructs to the cytoplasmic reporter protein pyruvate kinase confirmed a requirement for both motifs for full NLS function. 4.1R80 was efficiently imported in the nuclei of digitonin-permeabilized COS-7 cells in the presence of recombinant Rch1 (human importin alpha2), importin beta, and GTPase Ran. Quantitative analysis of protein-protein interactions using a resonant mirror detection technique showed that 4.1R80 bound to Rch1 in vitro with high affinity (KD = 30 nM). The affinity decreased at least 7- and 20-fold, respectively, if the EED motif in exon 5 or if 4.1R NLS in exon 16 was lacking or mutated, confirming that both motifs were required for efficient importin-mediated nuclear import of 4.1R80.
Kaposi's sarcoma-associated herpesvirus (KSHV), which was originally detected in Kaposi's sarcoma, also has been found in primary effusion lymphomas (PELs) and some cases of multicentric Castleman's disease. We describe two transplant recipients who developed Kaposi's sarcoma and a spectrum of non-neoplastic lymphoproliferative disorders that show pronounced plasmacytic and plasmacytoid features. The first patient had recurrent pleural effusions and Castleman's disease-like changes in lymph nodes. The second patient had systemic lymphadenopathy and hepatosplenomegaly secondary to diffuse infiltration by polyclonal plasma cells and plasmacytoid B lymphocytes that clinically mimicked Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease. In both cases, KSHV DNA was detected by polymerase chain reaction and Southern blotting, and KSHV vIL-6 protein expression was identified in affected tissues by immunohistochemical localization. In contrast, no evidence of KSHV coinfection was detected in any of 31 EBV-related posttransplant lymphoproliferative disorders or 112 non-PEL lymphomas tested. The pathologic findings in these two patients were not representative of malignancy by morphologic, immunophenotypic, or molecular criteria. This study underscores the marked propensity for hematolymphoid proliferations associated with KSHV infections to show plasmacytic features. Additionally, this study describes use of an antibody reactive against KSHV vIL-6 that can readily detect a subpopulation of KSHV-infected hematopoietic cells.
A diverse family of protein 4.1R isoforms is encoded by a complex gene on human chromosome 1. Although the prototypical 80-kDa 4.1R in mature erythrocytes is a key component of the erythroid membrane skeleton that regulates erythrocyte morphology and mechanical stability, little is known about 4.1R function in nucleated cells. Using gene knockout technology, we have generated mice with complete deficiency of all 4.1R protein isoforms. These 4.1R-null mice were viable, with moderate hemolytic anemia but no gross abnormalities. Erythrocytes from these mice exhibited abnormal morphology, lowered membrane stability, and reduced expression of other skeletal proteins including spectrin and ankyrin, suggesting that loss of 4. 1R compromises membrane skeleton assembly in erythroid progenitors. Platelet morphology and function were essentially normal, indicating that 4.1R deficiency may have less impact on other hematopoietic lineages. Nonerythroid 4.1R expression patterns, viewed using histochemical staining for lacZ reporter activity incorporated into the targeted gene, revealed focal expression in specific neurons in the brain and in select cells of other major organs, challenging the view that 4.1R expression is widespread among nonerythroid cells. The 4.1R knockout mice represent a valuable animal model for exploring 4.1R function in nonerythroid cells and for determining pathophysiological sequelae to 4.1R deficiency.
OBJECT: Glioblastoma multiforme (GBM) is a malignant tumor of the central nervous system that directly suppresses immunological defenses in vitro and in vivo. The authors used the peripheral delivery of continuously infused granulocyte-macrophage colony-stimulating factor (GM-CSF) in the presence of irradiated tumor antigens as a tumor-specific stimulant to dendritic cells to initiate an immune response to GBM in rats. METHODS: The 9L gliosarcoma tumors were established in the flanks of syngeneic Fischer 344 rats. Osmotic minipumps implanted in the animals' contralateral flanks continuously delivered recombinant GM-CSF (0, 0.1, 1, or 10 ng/day) for 28 days. Irradiated gliosarcoma cells were intermittently injected at the site of the GM-CSF infusion. Animals in the saline control group (0 ng/day GM-CSF) died on Day 59 with average tumor volumes greater than 30,000 mm3. This control group was significantly different from the GM-CSF-treated animals, which all survived with average tumor volumes that peaked on Day 23 and later regressed completely. Tumor growth as well as peak tumor volumes (5833+/-2284 mm3, 3294+/-1632 mm3, and 1979+/-1142 mm3 for 0.1, 1, and 10 ng/day GM-CSF, respectively) in the different treatment groups reflected a significant dose-response relationship with the GM-CSF concentrations. All animals treated with GM-CSF and irradiated cells were resistant to additional challenges of peripheral and intracerebral gliosarcoma, even when they were inoculated 8 months after initial immunotherapy. The colocalization of GM-CSF and inactivated tumor antigens was required to stimulate immunoprotection. To test the efficacy of a peripherally administered immunological therapy on intracerebral brain tumors the authors transplanted 10(6) gliosarcoma cells into the striatum of treated and control animals. Subcutaneous pumps that released GM-CSF (10 ng/day) and irradiated gliosarcoma cells were placed in the treated animals. The control animals all died within 31 days after intracerebral tumor implantation. In contrast, 40% of the animals receiving GM-CSF-irradiated cell vaccinations survived beyond 300 days. These long-term survivors showed no evidence of gliosarcoma at the injection site on evaluation by magnetic resonance imaging. CONCLUSIONS: These results suggest that the continuous localized delivery of subcutaneous GM-CSF in conjunction with inactivated tumor antigens can initiate a systemic response that leads to the regression of distant peripheral and intracerebral tumors. The success of this treatment illustrates the feasibility of tumor-specific peripheral immunological stimulation after tumor resection to prevent the recurrence of malignant brain tumors.
Acute pancreatitis in cancer patients can be secondary to the malignant process itself or a complication of antineoplastic agent administration. However, acute pancreatitis caused by metastatic carcinoma of the pancreas is an uncommon condition with a poor prognosis. We report a case of a 63-year-old man with small cell carcinoma of the lung, who developed acute pancreatitis lately. Thirteen months earlier, he developed small cell carcinoma of the lung and received 6 cycles of chemotherapy. Abdominal CT scan showed swelling of the pancreas with multiple masses. The patient was managed conservatively and pancreatitis subsided. This case indicates that metastasis induced acute pancreatitis can be a manifestation of lung cancer, especially in small cell carcinoma.
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In a population-based study, we examined residential power frequency electromagnetic field exposures for 492 adults newly diagnosed with histologically confirmed glioma between August 1, 1991 and April 30, 1994, in the San Francisco Bay area and 462 controls, obtained through random-digit dialing frequency, matched to cases for age, gender, and race. Residential exposure assessment consisted of spot measures with EMDEX (Enertech Consultants, Campbell, CA) meters and wire codes based on characterization and location of nearby power lines. We considered the index residence at the time of the case's diagnosis or the control's interview and all other California residences of each subject for 7 years before study entry. We obtained wire codes for eligible residences of 76% and for index residences of 99% of subjects. Using the Kaune-Savitz wire code classification, the relative risk for longest held residences coded as "high" compared with "low" was 0.9 [95% confidence interval (CI) = 0.7-1.3], while relative risk and 95% CIs for front door spot measures of 1.01-2 milligauss, 2.01-3 milligauss, and higher than 3 milligauss compared with < or =1 milligauss were 1.0 (0.7-1.4), 0.6 (0.3-1.1), and 1.7 (0.8-3.6). Adjustment for age, gender, race, and whether the subject owned the residence did not meaningfully alter these findings, nor did comparisons using index or highest coded residence. Because of potential exposure misclassification and the unknown pertinent exposure period, these data cannot provide strong support against, but clearly do not support an association between, adult glioma and residential power frequency electromagnetic field exposures.