Host response to challenge with SA7-induced autochthonous tumor cells.
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Age Factors↗
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Alterations in cellular differentiation, mitogenesis, cytoskeleton and growth characteristics during Syrian hamster embryo cell multistep in vitro transformation.
In vitro Syrian hamster embryo (SHE) cell transformation is a neoplastic process that proceeds through several identifiable consecutive stages including in vitro morphological transformation (mt), acquisition of immortality (I+), acquisition of tumorigenicity (T+) and tumor-derived cells (I'TD). Eight transformed lineages consisting of cells at the mt, I+, T+ and I'TD stages were assayed for alterations in general markers of cell differentiation, mitogenic signaling pathways, cytoskeleton and cellular growth in 3D matrix. Alterations in cellular differentiation markers included a decrease in H19 gene expression and placental alkaline phosphatase enzymatic activity at the mt stage in all lineages examined with a complete absence of H19 gene expression and placental alkaline phosphatase enzymatic activity by the I'TD stage in a majority of transformed lineages. Changes in mitogenic signaling pathways included the production of autocrine growth factors and alterations in growth factor-induced immediate early gene expression by the I'TD stage of transformation in the majority of transformed lineages investigated. By the I'TD stage of transformation in most lineages, changes in both the cytoskeleton (including a decrease in tropomyosin-I gene expression) and the Matrigel growth characteristics of SHE cells were observed.
Actins↗
Physiologic and pharmacologic studies of atrial natriuretic factor: a natriuretic and vasoactive peptide.
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Atrial Natriuretic Factor↗
Variable disease severity associated with a Paget's disease predisposition gene.
We have recently identified a region on the long arm of chromosome 18 that carries a predisposition gene for Paget's disease using linkage analysis. This region was explored because of earlier studies demonstrating the presence of a gene for another bone disorder, familial expansile osteolysis (FEO) within this region. FEO has many similarities to Paget's disease including osteoclast abnormalities and viral-like nuclear inclusions. Therefore, it was proposed that FEO and Paget's disease are disorders resulting from mutations at the same locus. For our linkage study, we utilized a large kindred with a high incidence of Paget's disease. The propositus in this family had polyostotic disease symptoms beginning at age 31. During the process of characterizing this family, four other family members were diagnosed with Paget's disease. One of the proband's siblings was asymptomatic but had high normal serum alkaline phosphatase levels; Paget's disease was identified only after bone scanning (at age 50). This implies that the predisposition gene does not consistently cause severe disease and raises a question concerning the mechanism of predisposition: Does the predisposition gene affect the age of onset and/or the severity of disease? To further explore this question, two individuals from this kindred, under age 30 and carrying the affected haplotype, were evaluated for early onset Paget's disease. No evidence of disease was observed after thorough evaluation. This implies that the age of onset is highly variable for this locus, indicating variable expression of disease in individuals carrying the same mutation.
Adult↗
Hearing loss as a complication of Paget's disease of bone.
Hearing loss has long been known to be a complication of Paget's disease of bone. Older ideas about the mechanisms of hearing loss are being replaced by a new view based on experimental evidence from patients. Studies reviewed show no evidence of auditory nerve dysfunction and confirm a cochlear site of lesion. A loss of bone mineral density in the cochlear capsule is associated with both a high-tone hearing loss and a low-tone air-bone gap.
Aged↗
Cloning, expression, and functional characterization of rat MIP-2: a neutrophil chemoattractant and epithelial cell mitogen.
Macrophage inflammatory protein-2 (MIP-2) is a member of a family of cytokines that play roles in inflammatory, immune, and wound healing responses. To clone the cDNA for rat MIP-2, RNA was isolated from the lungs of Fischer 344 rats after instillation of lipopolysaccharide. Reverse transcription-polymerase chain reaction was performed by using synthetic oligonucleotide primers designed from the mouse MIP-2 cDNA sequence. A cDNA containing the coding region of rat MIP-2 was cloned and sequenced. Comparison to the mouse MIP-2 cDNA demonstrated 90.3% homology at the nucleotide level and 86% homology at the amino acid level. The rat MIP-2 cDNA was expressed in Escherichia coli and protein evaluated for bioactivity. The recombinant rat MIP-2 was chemotactic for rat neutrophils but did not stimulate migration of rat alveolar macrophages or human peripheral blood eosinophils or lymphocytes. In addition, the recombinant rat MIP-2 and the related rat chemokine, KC/CINC stimulated proliferation of rat alveolar epithelial cells but not fibroblasts in vitro.
Amino Acid Sequence↗
Evaluation of orthogonal mechanical properties and density of human trabecular bone from the major metaphyseal regions with materials testing and computed tomography.
We evaluated the orthogonal mechanical properties of human trabecular bone from the major metaphyseal regions with materials testing and quantitative computed tomography (CT). The proximal tibia, distal femur, proximal femur, distal radius, and proximal humerus from fresh cadaver specimens between the ages of 55 and 70 years were excised and prepared for experimentation. The bones were embedded and scanned at 1 or 1.5 mm intervals on a Technicare HPS 1440 and GE 9800 CT scanner. After scanning, the bones were sectioned, producing 8-mm cubes of trabecular bone which were mechanically tested in uniaxial compression at a strain rate of 1%. The testing sequence consisted of preyield tests in two of the three orthogonal directions and failure in the third. After testing, the cubes were evaluated for apparent density and ash weight. The results of the study show that the strength and stiffness of trabecular bone varies significantly within metaphyseal regions and from metaphysis to metaphysis. The power and significance of relationships between density and modulus varied as a function of metaphyseal location. Both linear and nonlinear models were significant, suggesting that trabecular deformation occurs in response to both axial and bending loads. Finally, the need for architectural measures of trabecular bone to predict mechanical properties is emphasized.
Aged↗
Femoral structure and stiffness in patients with femoral neck fracture.
Bone morphological characteristics may relate to the risk of hip fracture. We applied finite element modeling to radiologic data for two groups of women in vivo to address two questions: (a) Do individuals who have just sustained a femoral neck fracture exhibit reduced three-dimensional structural stiffness? and (b) Are victims of hip fracture disproportionately more susceptible to loads sustained in a fall than to stance-type loads? Ten white women (age: 64-76 years) who had just sustained a femoral neck fracture and 18 female volunteers (age: 65-76 years), matched as groups for race, age. and body mass index, were evaluated. From quantitative computed tomography scans, femoral morphometric and volumetric cancellous density measurements were obtained and a finite element model was constructed. Two load conditions were simulated: single-stance phase and lateral fall. Global stiffness values were determined for each model. The cancellous bone density was significantly lower at the femoral neck and the femoral neck and head diameters were significantly larger in the women in the fracture group than in those in the control group. The stiffness of the proximal femur did not differ significantly between the groups for either load condition. An apparently linear relationship was found for stiffness at stance load compared with stiffness at fall load (r = 0.84, p < 0.001). and slopes did not differ significantly between the groups. Although cancellous density was reduced at the fracture site in patients with femoral neck fractures. this did not result in a reduction in the predicted bone stiffness. Previous studies have established a very strong relationship between the stiffness and strength of bone. Since these modeling methods were thoroughly validated ex vivo, we conclude that although decreased bone density at the femoral neck may predict where fracture initiates, the risk of hip fracture per se may be more strongly dependent on issues such as the risk of falling and fall biomechanics than on the structural characteristics of bone.
Accidental Falls↗
Analgesic potencies of morphine 3- and 6-sulfates after intracerebroventricular administration in mice: relationship to structural characteristics defined by mass spectrometry and nuclear magnetic resonance.
Morphine 3-sulfate, which carries a polar, acidic group at the 3-position much like morphine, does not differ greatly in analgesic potency from morphine following intracerebroventricular administration. This differs from the non-ionizable 3-methyl and 3-ethyl ethers, which are less potent analgesics than morphine. Morphine 6-sulfate, which differs from morphine by having an ionizable group at carbon-6 at physiological pH, is a more potent analgesic than morphine following intracerebroventricular administration. Variations in analgesic potency following modifications at the hydroxyl groups appear only to reflect alterations in point charges rather than structural alterations.
Analgesics↗
Benefits of a multidisciplinary approach to breast care.
The University of Michigan Breast Care Center (BCC) was established in 1985 to provide comprehensive, multidisciplinary diagnosis and treatment of benign and malignant breast disease. This work presents an overview of our experience in the BCC and assesses the clinical, academic, financial, and educational effectiveness of the program. A database was used to generate a list of all patients seen in the BCC between February 1, 1985 and December 31, 1991. Participating departments provided information regarding outpatient, inpatient, clinical and consultative activities, and referral patterns attributable to BCC endeavors. BCC educational and academic activities were reviewed and profiled. Clinical information was culled from the BCC database, hospital records, and the hospital tumor registry. The BCC has resulted in a fivefold increase in breast care related activity at the University of Michigan Medical Center. Over half of the patients treated in the BCC with primary operable breast cancer receive breast-conserving therapy. The BCC performs a unique educational function, providing the primary breast care experience for house staff as well as one third of the third year medical school class. The BCC supports over 20 clinical research protocols, and patient enrollment in clinical trials has increased dramatically since 1985. The BCC also provides support to basic science researchers receiving over 2.5 million dollars in peer reviewed direct cost support. These data suggest that a multidisciplinary approach to patient care as embodied by the BCC can be clinically, financially, and academically superior and productive. This model warrants further investigation not only in the field of breast care, but also in other clinical situations that require multidisciplinary input and therapy.
Breast Diseases↗
Analysis of oncogenes, tumor suppressor genes, autocrine growth-factor production, and differentiation state of human osteosarcoma cell lines.
Human osteosarcoma and fibrosarcoma cell lines were investigated for alterations in oncogenes, tumor suppressor genes, and growth factors, all of which have been implicated in tumor formation. Characterization of oncogenes that are involved in osteosarcoma formation, including the c-fos and c-myc oncogenes, indicated that all six osteosarcoma cell lines examined had 5- to 20-fold amplification of the c-myc oncogene, whereas neither of two fibrosarcoma cell lines c-myc amplification. Interestingly, only three of six osteosarcoma cell lines displayed altered c-myc immediate-early gene function. c-fos was found to be normal, both at the gene and functional levels, in all six osteosarcoma and both fibrosarcoma cell lines tested. Characterization of two tumor suppressor genes, p53 and RB1, that have been implicated in osteosarcoma formation indicated that p53 was altered in five of six osteosarcoma cell lines, whereas RB1 was altered in only two or six of these cell lines. Neither RB1 nor p53 was found to be altered in the fibrosarcoma cell lines tested. An additional transformation marker, autocrine growth-factor production, was observed in all six osteosarcoma cell lines and both fibrosarcoma cell lines examined. Finally, the differentiation state of the osteosarcoma cell lines was investigated via the bone differentiation markers alkaline phosphates and osteocalcin. Alkaline phosphatase activity was observed in four of six osteosarcoma cell lines but not in the two fibrosarcoma cell lines examined. The alkaline phosphatase activity was a result of the expression of the bone/liver/kidney alkaline phosphatase isoform. High-level osteocalcin expression was observed in one of the osteosarcoma cell lines but not in the two fibrosarcoma cell lines examined, although all cell lines demonstrated low-level osteocalcin expression. Together, these data demonstrate that relatively undifferentiated osteosarcomas commonly display c-myc amplification, p53 and RB1 mutation, and autocrine growth-factor production, all of which may play a role in osteosarcomagenesis.
Base Sequence↗
Mood changes and "on-off" phenomena in Parkinson's disease.
Ten patients with idiopathic Parkinson's disease and motor fluctuations were rated for mood changes during discrete "off," "on," and "on with dyskinesia" periods. The Profile of Mood States and visual analogue scales were used. Significant changes in mood and anxiety were found to parallel changes in motor fluctuations. One patient rated his moods as consistently improving from the "off" state to the "on" state and finally to the "on with dyskinesia" state, a finding that is consistent with concomitant central dopaminergic changes. All other patients showed moods that improved significantly from the "off" state to the "on" state but then worsened significantly in the "on with dyskinesia" state, a finding that is consistent with the fact that patients feel worse when impaired by dyskinesias. It is suggested that these results argue for multiple etiologies of depression in Parkinson's disease. The literature on dopamine and depression in Parkinson's disease is briefly reviewed and the opportunity provided by "on-off" phenomena to study the effect of dopamine on mood changes is discussed.
Affect↗
Skeletal muscle hypertrophy and anti-atrophy effects of clenbuterol are mediated by the beta2-adrenergic receptor.
Analyses were performed to evaluate the roles of the beta1- and beta2-adrenergic receptors in the skeletal muscle hypertrophy and anti-atrophy response to the beta-adrenergic agonist, clenbuterol. Treatment of wild-type mice with clenbuterol resulted in statistically significant hypertrophy of the innervated tibialis anterior and medial gastrocnemius muscles and inhibition of denervation-induced atrophy of these muscles. Treatment of beta1-adrenergic receptor knockout mice with clenbuterol also resulted in statistically significant hypertrophy of the innervated tibialis anterior and medial gastrocnemius muscles and inhibition of denervation-induced atrophy of these muscles. In contrast, in beta2-adrenergic receptor knockout mice and in mice lacking both the beta1- and beta2-adrenergic receptors, clenbuterol treatment did not result in hypertrophy of the innervated tibialis anterior and medial gastrocnemius muscles, nor did it inhibit denervation-induced atrophy in these muscles. Together these data demonstrate that the beta2-adrenergic receptor is responsible for both the skeletal muscle hypertrophy and anti-atrophy effects of the beta-adrenergic agonist clenbuterol.
Adrenergic beta-Agonists↗
Purification and crystallization of insecticidal delta-endotoxin CryIIIB2 from Bacillus thuringiensis.
CryIIIB2, an insecticidal protein from Bacillus thuringiensis has been crystallized from 0.6 M NaBr and HEPES buffer at pH 7.0 and X-ray diffraction data collected on a native crystal to 2.4 A. The insecticidal protein was obtained from a Bacillus thuringiensis (Bt) strain EG7231. Crystals of the endotoxin are orthorhombic, space group C2221, with unit cell dimensions of a = 122.44, b = 131.81, and c = 105.37 A. A unit cell contains one molecule of the 67,000 Da endotoxin per asymmetric unit.
Bacillus thuringiensis↗
Substitution of glutamic acids for the conserved lysines in the alpha domain affects metal binding in both the alpha and beta domains of mammalian metallothionein.
Lysine residues are highly conserved in mammalian metallothioneins (MTs). Recombinant mutant Chinese hamster MT2 in which all of the lysines (K) in the alpha-domain were substituted by glutamic acids (E) was assayed with, expressed in and purified from a cadmium sensitive strain of yeast Saccharomyces cerevisiae. Circular dichroism analyses of the mutated protein, mutein K43,51,56E, revealed that the overall structure remained unchanged. However, a 1-D 113Cd NMR study detected significant differences in the chemical shifts of the corresponding resonances between wild type protein and the recombinant mutein. Reduction of integrated intensity in the NMR spectra was also observed for resonances from the four-metal cluster (I and V-VII) in the alpha-domain of the mutein. At various temperatures, facile intermolecular exchange of metals in the beta-domain of the mutein was also observed, which was unexpected and was different from wild type. Our results thus demonstrate that replacing all three lysines by glutamic acids in the alpha-domain changed metal-thiolate interactions in both domains of the recombinant mutein. This may explain the reduced ability of the mutein to convey cadmium resistance. We propose that while the lysine residues in the alpha-domain of wild type MT are not critical for maintaining protein structure, they play a role in regulating the microenvironment and stability of both metal-binding clusters, a feature critical to metal detoxification.
Amino Acid Sequence↗
Replacement of all alpha-domain lysines with glutamates reduces metallothionein detoxification function.
Mammalian metallothioneins (MTs) possess eight highly conserved lysine residues, including three in each of two metal binding domains. We used site-directed mutagenesis to replace these intradomain lysines in Chinese hamster ovary MT2 with glutamic acid and/or glutamine. These mutant MTs were expressed in a metal sensitive yeast host. One mutant which had all three lysines in the alpha-domain replaced by glutamates (K43,51,56E) exhibited a reduced ability, relative to native MT, to protect yeast transformants against otherwise toxic levels of cadmium. This triply substituted mutant also exhibited anomalous migration on a non-denaturing gel relative to wild type MT and other MT lysine mutants, suggesting that the intradomain lysines are important in maintaining the conformational integrity of MT.
Binding Sites↗
Pharmacological differences between rat and human endothelin B receptors.
Cloned rat and human endothelin-B receptors (ETBR) were utilized to determine if there are significant pharmacological differences between highly homologous ETBR from different species. Recombinant rat and human ETBR were expressed in CHO-K1 cells, and radioligand binding studies were carried out with [125I]-ET-3 to determine the affinities of various ET receptor agonists and antagonists for rat and human ETBR. These receptors had similar affinities for a number of ETBR agonists (ET-1, ET-3, S6C, BQ 3020) and antagonists (Ro 47-0203, PD 142893). However, several peptide (PD 147452, PD 151583, BQ 788) and non-peptide (PD 156707, SB 209670) antagonists had different affinities for rat and human ETBR, with differences in Ki values between species ranging from 4.1- to 53.4-fold. The ETBR-selective agonist IRL 1620 also had a 5.7-fold higher affinity for rat ETBR than human ETBR. Thus despite their high degree of homology, rat and human ETBR show significant pharmacological differences with respect to both antagonist and agonist binding.
Amino Acid Sequence↗
Effect of Navy chaff release on aluminum levels in an area of the Chesapeake Bay.
The U.S. Navy uses aluminized glass chaff as a passive countermeasure for radar-guided threats to aircraft and surface ships. Over the last 25 years, several hundred thousand pounds of aluminized chaff have been released during flight operations over a training area on the Chesapeake Bay. There is concern that these releases have resulted in the accumulation of significant amounts of aluminum in the soil and sediment of this training area. This study compares the exchangeable and monomeric aluminum content of sediment within the affected area with that of samples taken from outside the training area. We found a less than twofold increase in the content of organic monomeric aluminum in samples taken from the affected area versus background samples, whereas inorganic monomeric aluminum concentrations within the affected area were significantly lower than background. These results suggest that chaff releases have not resulted in a significant accumulation of aluminum in this training area.
Aircraft↗