Expression of mouse CD43 in the B cell lineage of transgenic mice causes impaired immune responses to T-independent antigens

CD43 (leukosialin), a sialylated glycoprotein expressed on the surface of most hematopoietic cells, has been implicated in cell adhesion and signaling. However, its precise physiological function remains unclear. We used mouse CD43 (mCD43)-immunoglobulin enhancer-transgenic (TG) mice to study the role of mCD43 in vivo. Previous work revealed that mCD43 expression on mature B cells in these mice resulted in immunodeficiency to T-dependent (TD) antigens (Ag), possibly by impairing B-T cell interactions. In the present study we have immunized the TG mice with the T-independent (TI) Ag fluorescein-(Fl) lipopolysaccharide (LPS) (TI type 1 Ag) and Fl-Ficoll (TI type 2 Ag). Surprisingly, the mCD43-Ig enhancer expressing mice were impaired in their ability to mount humoral responses to both Fl-LPS and Fl-Ficoll, and had decreased numbers of cells responding to Ag in vivo. Flow cytometric analysis was performed on peritoneal B-1 cells, a population which often plays a major role in humoral responses to TI Ag such as bacterial Ag. This analysis revealed similar B220, IgM and CD5 expression patterns for the TG and nontransgenic (NTG) B-1 cells. In addition, purified peritoneal B-1 cells from TG and NTG mice were able to respond to LPS. Stimulation of splenic B cells in vitro with Fl-LPS and Fl-Ficoll revealed that, in contrast to NTG B cell responses, TG B cell responses could not be enhanced by co-culture with T cells. However, soluble T cell factor enhancement of the TG B cell responses was normal. These data suggest that the mCD43 expression on B cells may inhibit cell interactions that are important for enhanced TI Ag responses. The anti-adhesive forces of mucins in general may thus be critical in regulating both TD and TI humoral responses.     

The 2.35 A crystal structure of the inactivated form of chicken Src: a dynamic molecule with multiple regulatory interactions

The Src protein tyrosine kinase plays a critical role in a variety of signal transduction pathways. Strict regulation of its activity is necessary for proper signalling. We present here the crystal structure of chicken Src which is phosphorylated at Tyr527 and represents its least active form. Our structure, similar to the recently reported human Hck and Src structures, contains the SH3, SH2 and the kinase domains and the C-terminal regulatory tail but not the N-terminal unique domain. The SH3 domain uses its hydrophobic surface to coordinate the SH2-kinase linker such that residues Gln251 and Leu255 specifically interact with side chains in the beta2-beta3 and the alphaC-beta4 loops of the N-terminal lobe opposite of the kinase active site. This position of the SH3 domain and the coordination of the SH2-kinase linker also optimally places the SH2 domain such that the phosphorylated Tyr527 in the C-terminal tail interacts with the SH2 binding pocket. Analogous to Cdk2 kinase, the position of the Src alphaC-helix in the N-terminal lobe is swung out disrupting the position of the active site residues. Superposition of other protein kinases including human Hck and Src onto chicken Src indicate that the alphaC-helix position is affected by the relative position of the N-terminal lobe with respect to the C-terminal lobe of the kinase and that the presence of the SH3/SH2-kinase linker/N-terminal lobe interactions restricts the kinase lobes and alphaC-helix access to the active conformation. These superpositions also suggest that the highly conserved alphaC-beta4 loop restricts the conformational freedom of the N-terminal lobe by anchoring it to the C-terminal lobe. Finally, based on sequence alignments and conservation of hydrophobic residues in the Src SH2-kinase linker as well as in the alphaC-beta4 and beta2-beta3 loops, we propose that the Src-related kinases, Abl, Btk and Csk, share the same quaternary structure.     

Extracellular cellulase system of a thermotolerant streptomycete: Streptomyces albaduncus

In this study we compared viewer-centered (VC) with object-centered (OC) mental exploration of an imagined clock drawn on the ground. An upper case F portrayed on a computer screen was to be imagined standing up in the center of the clock. In Expt. 1, an adjustment task was used to verify that the discrimination of clock directions rendered by this perspective drawing was quite accurate. Precision was not affected by the imaginary size of the clock. In Expt. 2, subjects either (1) indicated the clock location pointed by the F given their viewing position (VC condition), or (2) their location at the periphery of the clock given the location pointed by the F (OC condition). Response latencies were proportional to the explored imaginary distance and increased with the size of the imagined environment. We found an additional mean processing time of at least 2 s in the OC condition with respect to the VC condition. Results are interpreted within Kosslyn's (Kosslyn, S.M., A cognitive neuroscience of visual cognition: further developments. In: R.H. Logie and M. Denis (Eds.), Mental Images in Human Cognition, Elsevier Science Publishers, Amsterdam, 1991, pp. 351-381 [17]) framework of cognitive neuroscience.     

Late displacement of a fracture dislocation at the lumbosacral junction. A case study

STUDY DESIGN: This is a retrospective single-patient case report with a literature review. OBJECTIVE: To report on an uncommon injury: traumatic fracture-dislocation of the lumbosacral junction with delayed displacement. SUMMARY OF BACKGROUND DATA: Only 31 cases of traumatic fracture-dislocation of the lumbosacral junction were found in the English literature. Only three previous reports refer to this injury occurring with a posterior displacement. This is the first report of this type of injury displacing in a delayed manner. METHODS: Chart review. RESULTS: Open reduction, Arbeitsgemeinschaft fur Osteosynthesefargen instrumentation, and interbody fusion resulted in a satisfactory clinical result with no neurologic impairment. CONCLUSIONS: The present study reports a very rare injury consisting of traumatic dislocation of the lumbosacral joint, presenting with displacement 2 months after injury. The patient was treated successfully with surgery even though the injury displaced in a delayed fashion.     

Hereditary cancer risk notification and testing: how interested is the general population?

PURPOSE: Great interest in predictive testing for hereditary cancer syndromes has been reported. Prior research has focused on testing for specific hereditary syndromes and/or among individuals at high risk for positive carrier status. Given anticipated expansion of both the range of hereditary syndromes for which testing will be available, as well as the clinical settings in which testing will occur, assessment of interest in hereditary cancer risk testing and notification in the general public is warranted. METHODS: As part of an annual statewide telephone survey, adults' (N = 654) interest in hereditary cancer risk testing and notification was assessed. RESULTS: Interest in both risk testing (82%) and risk notification (87%) was high. Logistic regression analyses indicated that disinterest in risk notification was associated with female sex, performance of fewer health protective behaviors, and better perceptions of personal health. Disinterest in risk testing was associated with these same variables as well as older age, less concern over developing cancer, and a more extensive history of cancer in first degree relatives. CONCLUSION: In the absence of risk-reducing behaviors with demonstrable efficacy, hereditary risk testing programs may have difficulty attracting the interest of those at greatest risk for carrier status. In contrast, many individuals at low risk for positive carrier status might seek testing, perhaps as a means of seeking reassurance regarding their low hereditary risk.     

Parenteral iron therapy: indications and safety

Bone marrow necrosis (BMN) is a relatively rare entity and has been associated with a poor prognosis. It is most commonly found in patients with neoplastic disorders, severe infections and sickle cell anemia. An unusual case of antiphospholipid syndrome (APS) with extensive bone marrow necrosis is described in a 27 year old woman. The patient presented with severe pancytopenia, some cognitive impairment resulting from a previous cerebrovascular accident, fever, hypertension, dyspnoea, tachycardia, hepatosplenomegaly, and vaginal bleeding. Her laboratory findings included a strongly positive Coombs' test (anti-IgG and anti-C3d), a prothrombin time of 23 seconds and an activated partial thromboplastin time of 45 seconds. Anticardiolipin antibody tests were positive. Antinuclear and anti-DNA antibodies were negative but the anti-SM test was positive. A bone marrow biopsy specimen was reported as showing extensive necrosis. The patient was treated with steroids, transfusion, and plasma exchange with some clinical improvement but her pancytopenia did not respond and necessitated frequent transfusions. This case lends further support to the association between APS and BMN.     

Altered ionic effects of insulin in hypertension: role of basal ion levels in determining cellular responsiveness

To investigate the ionic actions of insulin in hypertension, 19F- and 31P-nuclear magnetic resonance spectroscopy were used to measure cytosolic free calcium (Ca(i)) and intracellular free magnesium (Mg(i)) levels in red blood cells from normal (n = 9) and hypertensive (n = 9) subjects before and 30, 60, 120, and 180 min after in vitro incubation with insulin. In hypertensive patients, basal Ca(i) levels were significantly higher (30.0 +/- 2.2 vs. 19.8 +/- 2.5 nmol/L; P < 0.05), and basal Mg(i) levels were significantly lower (170 +/- 10.9 vs. 209 +/- 8 micromol/L; P < 0.05) than in normotensive subjects. In normal cells, insulin significantly elevated Ca(i) to 39.8 +/- 8.0, 50.1 +/- 8.2, 69.3 +/- 11.1, and 50.9 +/- 13.4 nmol/L at 30, 60, 120, and 180 min and Mg(i) to 238 +/- 10,264 +/- 14,226 +/- 11, and 216 +/- 10 micromol/L at 30, 60, 120, and 180 min. In hypertensive subjects, the insulin-dependent Ca(i) elevation was blunted, and Mg(i) accumulation was completely suppressed. Continuous relationships were observed between basal values of each ion and insulin responses; the greater the Ca(i), the less the Ca(i) rose (r = -0.574; P = 0.013), and the lower the Mg(i), the less Mg(i) rose (r = 0.524; P = 0.025). Furthermore, a blunting of Mg(i) responses to insulin could be reproduced in normal cells that were magnesium depleted by prior treatment either with A23187 in a calcium-free medium or with high glucose concentrations (15 mmol/L). Once again, insulin responsiveness followed basal Mg(i) levels (r = 0.637; P < 0.001). Together, these data demonstrate ionic aspects of insulin resistance in hypertension and suggest that Ca(i) and Mg(i) levels may regulate cellular responsiveness to insulin. This may help to explain the different vascular actions attributed to insulin in normal compared with insulin-resistant states such as hypertension.     

Suppository administration of chemotherapeutic drugs with concomitant radiation for rectal cancer

PURPOSE: Preoperative radiation with combined chemotherapy is effective in shrinking advanced rectal cancer locally and facilitating subsequent surgery. Suppository delivery of 5-fluorouracil is associated with less toxicity and higher rectal tissue concentrations than intravenous administration. This prompted us to evaluate suppository and intravenous administration of 5-fluorouracil and mitomycin C with concomitant radiation to determine associated toxicity. METHODS: Rectal, liver, lymph node, and lung tissue and systemic and portal blood were collected serially from male Sprague Dawley rats to determine drug concentrations following suppository or intravenous delivery of 5-fluorouracil or mitomycin C. Thirty-six animals were randomly assigned to treatment groups and received 5-fluorouracil suppositories, mitomycin C suppositories, or an equivalent intravenous dose of 5-fluorouracil or mitomycin C 30 minutes before radiation therapy. Before and 3, 6, 10, and 15 days following this treatment, blood was collected, colonoscopy was performed, and rectal tissue was harvested for histologic examination. RESULTS: Mitomycin C suppository was significantly less toxic compared with intravenous delivery, and higher rectal tissue concentrations were observed from 10 to 30 minutes (P < 0.05). Compared with intravenous 5-fluorouracil administration and radiation, 5-fluorouracil suppository and radiation resulted in additive myelosuppression at day 6 (P < 0.05) with rapid recovery. CONCLUSIONS: 5-Fluorouracil and mitomycin C suppository delivery combined with radiation causes less systemic toxicity and is more effective than intravenous administration.     

Patterns of hospitalization in elderly patients with asthma and chronic obstructive pulmonary disease

The purpose of this study was to describe the impact of asthma and chronic obstructive pulmonary disease (COPD) in the elderly on health care utilization. The Health Care Financing Administration (HCFA) file for the year 1984 through 1991 involving beneficiaries < or = 65 yr were searched for the diagnoses of asthma and COPD by ICD-9 codes. The study groups were created by determining the first admission for an exacerbation of either disease during each year from 1984 through 1991. Patients were identified by their social security number. The 1984 cohort consisted of 56,692 patients with asthma exacerbation and 162,899 with COPD exacerbation. The 1991 cohort consisted of 67,758 patients with asthma exacerbation and 131,974 patients with COPD exacerbation. In addition, the 1984 cohort was tracked by social security number for evidence of rehospitalization for either asthma or COPD through 1991. Length of hospitalization increased as patients grew older. The discharge rate to an independent living facility diminished as age increased. The use of convalescent and nursing homes or home health care after discharge more than doubled from 1984 through 1991. The utilization of health care resources by elderly patients with asthma and COPD is immense, both during hospitalization and after discharge.     

MRI of the brain in patients with miliary pulmonary tuberculosis without symptoms or signs of central nervous system involvement

MRI was performed on patients with miliary pulmonary tuberculosis to look for brain involvement and to study the features sequentially, during treatment. We studied seven patients with typical radiographic tuberculosis, and no symptoms or signs of central nervous system involvement. Conventional spin-echo (SE) imaging, including contrast enhanced images, was performed in all cases. All patients showed brain involvement: four patients showed lesions mainly less than 3 mm in diameter, better seen on contrast-enhanced images. These patients showed oedema around the lesions after 2 months of treatment, with subsequent regression on follow-up. The remaining three patients had multiple lesions, 3 mm or more in diameter, which showed a gradual decrease on follow-up. We conclude that the brain may commonly be involved in miliary pulmonary tuberculosis. The response to treatment depends on the stage of the granuloma and shows a definite pattern of healing on follow-up.