Diagnosis and treatment of cervical spine clinical instability.
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Adult↗
Biomedical subjects
K A Olson
Publications and source records attributed to K A Olson.
Prevention of human prostate tumor metastasis in athymic mice by antisense targeting of human angiogenin.
PURPOSE: Angiogenin is a potent positive mediator of neovascularization, a process required for both primary tumor growth and metastasis. In the present study, the effect of a fully phosphorothioated antisense oligodeoxynucleotide, designated JF2S, targeting the AUG translation initiation codon region of human angiogenin, on human prostate tumor development and metastasis in athymic mice was examined. EXPERIMENTAL DESIGN: JF2S was evaluated for its capacity to affect in vitro synthesis of angiogenin and subsequent tumorigenicity of transiently transfected prostate tumor cells in mice. In vivo treatment experiments were then conducted in which JF2S was used to prevent formation of tumors in an ectopic model and metastasis in an orthotopic model. RESULTS: Transient transfection of tumor cells with JF2S inhibited both angiogenin gene expression in vitro and tumorigenicity of these transfected cells in athymic mice. In therapy experiments, local treatment with JF2S completely protected mice from developing prostate tumors after s.c. injection of PC-3 human prostate tumor cells (P < 0.0001, survivor analysis). Most importantly, systemic prophylactic administration of JF2S prevented, in 47% of mice, formation of regional iliac lymph node micrometastases arising from primary tumors growing in the more natural orthotopic prostate setting (P = 0.0003, Fisher's exact test). Furthermore, total protection from regional metastasis occurred in those mice in which JF2S treatment successfully diminished human angiogenin expression in vivo. Tumor-associated angiogenesis was also impaired by JF2S treatment. When therapy was delayed until all of the mice harbored primary tumors in the prostate, the incidence of regional metastasis was still significantly decreased (P < 0.005, survivor analysis). CONCLUSIONS: These findings demonstrate that human prostate cancer establishment and spread in athymic mice is extremely susceptible to targeted disruption of tumor-derived human angiogenin gene expression. Therefore, angiogenin is a valid target against which to devise preventative strategies for prostate cancer metastasis.
Animals↗
Two regulators of Ste12p inhibit pheromone-responsive transcription by separate mechanisms.
The yeast Saccharomyces cerevisiae transcription factor Ste12p is responsible for activating genes in response to MAP kinase cascades controlling mating and filamentous growth. Ste12p is negatively regulated by two inhibitor proteins, Dig1p (also called Rst1p) and Dig2p (also called Rst2p). The expression of a C-terminal Ste12p fragment (residues 216 to 688) [Ste12p(216-688)] from a GAL promoter causes FUS1 induction in a strain expressing wild-type STE12, suggesting that this region can cause the activation of endogenous Ste12p. Residues 262 to 594 are sufficient to cause STE12-dependent FUS1 induction when overexpressed, and this region of Ste12p was found to bind Dig1p but not Dig2p in yeast extracts. In contrast, recombinant glutathione S-transferase-Dig2p binds to the Ste12p DNA-binding domain (DBD). Expression of DIG2, but not DIG1, from a GAL promoter inhibits transcriptional activation by an Ste12p DBD-VP16 fusion. Furthermore, disruption of dig1, but not dig2, causes elevated transcriptional activation by a LexA-Ste12p(216-688) fusion. Ste12p has multiple regions within the C terminus (flanking residue 474) that can promote multimerization in vitro, and we demonstrate that these interactions can contribute to the activation of endogenous Ste12p by overproduced C-terminal fragments. These results demonstrate that Dig1p and Dig2p do not function by redundant mechanisms but rather inhibit pheromone-responsive transcription through interactions with separate regions of Ste12p.
Fungal Proteins↗
Regulation of angiogenin expression in human HepG2 hepatoma cells by mediators of the acute-phase response.
Angiogenin is a potent inducer of neovascularization in vivo. However, like other angiogenic molecules, its specific physiologic roles and mechanisms regulating its expression remain to be elucidated. Angiogenin is a liver-derived component of normal serum whose concentration can increase in various disease states. This suggests that it might participate in the acute-phase response. In an initial study we showed that angiogenin protein and mRNA levels transiently increased in mice following an acute inflammatory stimulus. We now report that IL-6, a major inducer of acute-phase proteins, stimulates the synthesis and secretion of angiogenin protein in human HepG2 cells within 24 hr following treatment, an effect enhanced by dexamethasone. IL-6 also increases the amount of angiogenin mRNA without altering its half-life. This increase, suppressible by cycloheximide, peaks at 12 hr following stimulation and returns to basal levels by 48 hr. IL-1 alone slightly decreases the basal production of angiogenin protein and mRNA, but essentially abolishes the response to IL-6 in the absence or presence of dexamethasone. This antagonistic effect by IL-1 on IL-6 activity is not a result of changes in mRNA stability nor is it dependent on new protein synthesis. Thus, the combined effects of IL-6, IL-1, glucocorticoids, and perhaps other related factors may specifically control angiogenin expression. Since angiogenin is regulated in a manner similar to that of acute phase proteins both in vitro and in vivo, it may play a role in the host response to injury.
Acute-Phase Proteins↗
Representations of knowledge about dominoes in demented and normal elderly players.
1. Dementia patients who retain musical and game-playing skills exhibit impaired performance on explicit memory tests of knowledge about their retained skill. 2. Dementia patients who retain skill at playing dominoes can answer complex questions about the play of the game almost as well as normal elderly domino players when the questions are presented with real dominoes. 3. The aim of this study was to determine if skilled dementia patients could answer questions about domino play when the stimuli were two-dimensional drawings of dominoes. 4. Seventeen dementia patients and eight normal elderly domino players were tested on two forms of the Domino Quiz: first with real dominoes, then with two-dimensional drawings; other neuropsychological tests were given at the same time. 5. Fourteen of the 17 patients and all of the controls showed no decline in answering questions about domino play when two-dimensional drawings were used. These patients showed retained symbolic processing of information about dominoes despite declines in overall mental status, generation of words from specific semantic categories, and recognition memory for domino terminology. 6. Because the 14 patients with retained domino skill performed as accurately as controls on both administrations of a letter cancellation task, the ability to process familiar symbols may be important to their game-playing skill.
Aged↗
Chimeric anti-angiogenin antibody cAb 26-2F inhibits the formation of human breast cancer xenografts in athymic mice.
Angiogenin (Ang), an inducer of neovascularization, is secreted by several types of human tumor cells and appears critical for their growth. The murine anti-Ang monoclonal antibody (mAb) 26-2F neutralizes the activities of Ang and dramatically prevents the establishment and metastatic dissemination of human tumor cell xenografts in athymic mice. However, for use clinically, the well-documented problem of the human anti-globulin antibody response known to occur with murine antibodies requires resolution. As a result, chimeric as well as totally humanized antibodies are currently being evaluated as therapeutic agents for the treatment of several pathological conditions, including malignancy. Therefore, we have constructed a chimeric mouse/human antibody based on the structure of mAb 26-2F. Complementary DNAs from the light and heavy chain variable regions of mAb 26-2F were cloned, sequenced, and genetically engineered by PCR for subcloning into expression vectors that contain human constant region sequences. Transfection of these vectors into nonproducing mouse myeloma cells resulted in the secretion of fully assembled tetrameric molecules. The chimeric antibody (cAb 26-2F) binds to Ang and inhibits its ribonucleolytic and angiogenic activities as potently as mAb 26-2F. Furthermore, the capacities of cAb 26-2F and its murine counterpart to suppress the formation of human breast cancer tumors in athymic mice are indistinguishable. Thus cAb 26-2F, with its retained neutralization capability and likely decreased immunogenicity, may be of use clinically for the treatment of human cancer and related disorders where pathological angiogenesis is a component.
Amino Acid Sequence↗
Angiogenin is regulated in vivo as an acute phase protein.
Angiogenin (Ang), a potent mediator of neovascularization, is secreted by and is critical for the growth of human tumor cells in experimental animals. However, control mechanisms that regulate its expression under normal physiological conditions have not been described. We have determined previously that Ang is present in normal human serum and that its concentration, normally falling within a narrow range, can vary widely in hospitalized patients. This observation, plus a report that Ang is synthesized in the adult liver, led us to investigate whether it can be regulated as an acute phase protein (APP). Ang concentration in the serum of mice placed into the acute phase by injection with 3% thioglycollate do indeed increase transiently as is typical for APPs. Moreover, a liver-specific rise and subsequent fall in Ang mRNA transcripts also follows entrance into acute inflammation. We conclude that Ang can be regulated in vivo in a manner that is characteristic of an APP and, therefore, may contribute to the angiogenic component of tissue repair that accompanies host response to inflammation and trauma. To our knowledge, this is the first demonstration that a well-characterized angiogenic mediator can be regulated as an APP.
Acute-Phase Proteins↗
Correlates of coping style in patients with multiple sclerosis.
To examine certain correlates of patterns of coping with stress, 43 patients with multiple sclerosis (MS) read a vignette describing a stressful social situation and completed the Ways of Coping Checklist, describing how they would cope with the stressful situation. Performance on a test of solving problems in everyday living was positively correlated with the total number of coping responses and with the number of problem-focused strategies, but neither vocabulary nor verbal abstract reasoning were related to coping patterns. In agreement with earlier work, increases in psychological distress were positively correlated with endorsement of emotion-focused coping strategies but unrelated to the use of other coping responses.
Activities of Daily Living↗
Characterization of the basal and pheromone-stimulated phosphorylation states of Ste12p.
The Saccharomyces cerevisiae transcription factor Ste12p is required for basal and activated expression of pheromone-responsive genes, and for invasive growth in haploid cells. In diploid yeast, Ste12p is implicated in pseudohyphal development. The ability of Ste12p to effect these various responses in three different cell types must require stringent regulation of its transcriptional activation function and interaction with additional transcription factors. We have examined the phosphorylation state of Ste12p in untreated and pheromone-treated haploid cells, and found eight constitutively phosphorylated peptides. Phosphorylation at the constitutive sites does not require the protein kinases of the pheromone-response pathway. Treatment of haploid yeast with mating pheromone causes the appearance of novel relatively minor phosphorylations on Ste12p. Brief [35S]methionine labeling reveals novel pheromone-dependent, electrophoretically slower migrating Ste12p species. Similarly, the sole difference we observe in tryptic phosphopeptides generated from Ste12p from pheromone-treated and untreated cells is the transient appearance of two novel minor hydrophobic phosphopeptides. The pheromone-dependent phosphorylation of Ste12p requires an intact pheromone-response pathway and localization of Ste12p to the nucleus, but does not require the Ste12p DNA-binding domain. We conclude from these experiments that the pheromone-response pathway induces the formation of specific hyperphosphorylation on Ste12p, which can only be detected as apparently minor modifications in vivo. We argue that, if Ste12p is regulated by direct pheromone-responsive phosphorylation, then that phosphorylation must be represented by the two novel phosphopeptides. However, we cannot exclude the possibility that pheromone-responsive transcription is controlled by direct phosphorylation of a target other than Ste12p.
Calcium-Calmodulin-Dependent Protein Kinases↗
Expression of game-related and generic knowledge by dementia patients who retain skill at playing dominoes.
Patients with dementia who remain skilled at musical performance or playing bridge fail explicit memory tests for information related to their skills, suggesting that implicit memory mediates their preserved skills. To reexamine this issue, 23 dementia patients and 15 elderly controls of comparable domino-playing skill were compared on tests of naming, verbal fluency, and domino knowledge. On an explicit test of domino knowledge, the patients scored well below the elderly controls, performing no better than students who were unfamiliar with the game. But when game-like situations were created with real dominoes, both the skilled controls and the patients with dementia chose optimal moves and verbally explained their choices equally well. On naming and fluency tests, the skilled patients showed no advantage over patients of comparable dementia severity who had no retained skill. In dementia, some complex knowledge seems intact but is accessible only in particular contexts.
Aged↗
Angiogenin single-chain immunofusions: influence of peptide linkers and spacers between fusion protein domains.
The gene for human angiogenin (Ang), a member of the ribonuclease superfamily, was fused to a gene encoding a single-chain antibody (sFv) against the human transferrin receptor. Three Ang single-chain immunofusion proteins (AngsFvs) were constructed with variations in the type of linker connecting the VL and VH chain [EGKSSGSGSESKEF, L1 or (GGGGS)3, L2] as well as with or without a spacer (FB) connecting the Ang and sFv (AngFBsFvL1 or L2; AngsFv(L2)]. Although the nature of the linker did not affect the enzymatic activity of the FB-containing fusion proteins, the fusion protein containing the L2 linker was 2.3-fold more effective than the L1 linker in competing with the labeled monoclonal IgG1 antibody for binding to the transferrin receptor. The fusion protein containing the L2 linker without the FB spacer exhibited a 13-fold decrease in binding to the transferrin receptor as well as a decrease in its capacity to degrade tRNA and to inhibit translation in the rabbit reticulocyte lysate compared to its counterpart containing the FB spacer. Binding of placental ribonuclease inhibitor (PRI) to Ang also was affected by the nature of the linker and by the presence or absence of a spacer. PRI bound to Ang and AngFBsFv(L2) and inhibited their ribonuclease activity. A 3-fold greater concentration of PRI, however, did not affect the activity of AngFBsFv(L1) or AngsFv(L2), suggesting that the conformation of these fusion proteins was altered. Binding of monoclonal and polyclonal anti-Ang antibodies to AngsFvs was also used to investigate conformational alterations of the fusion proteins. AngFBsFv(L2) was the least altered while AngFBsFv(L1) exhibited the greatest change in structure. Yet maximal concentrations of all AngsFvs elicited angiogenesis in the chick chorioallantoic membrane assay, demonstrating that Ang in all three fusion proteins remained functionally active. Consistent with all the activities, the fusion protein containing the FB spacer and L2 linker was the most cytotoxic to three different human tumor cell lines. The fusion protein lacking the FB spacer exhibited the least cytotoxicity. These data demonstrate that the linker connecting the VH-VL chains can affect the binding and cellular cytotoxicity of Ang immunofusions and that placement of a spacer between the antibody binding domains and Ang is necessary for optimal activity. Thus, a new class of targeted therapeutic agents containing Ang as the toxic moiety can be designed that potentially will be less immunogenic and less toxic than immunotoxins available currently.
Amino Acid Sequence↗
Fall-related occupational injuries on farms.
We assessed risk factors for fall-related farm injuries in a population-based, case-control study. Cases had to reside in a defined geographic region served by a single medical center. Multiple sources reported cases, and a special farm census enabled random selection of controls, The annual risk of farm fall injury was 7.5 (95% CI: 5.7, 10.0) per 1,000 person-years. The crude incidence rate was higher in men, while the rate based on hours of farmwork was higher in women. In a multivariate analysis of risk factors, three factors were significantly associated with the risk. The risk of fall injury increased 2% (95% CI: 1%, 4%) per hour worked. Residents of farms with some farm workers not living on the farm had a fall injury rate 2.5 (95% CI: 1.0, 6.2) times greater than residents of other farms. Residents of farms with registered cows had one-third (95% CI: 0.14, 0.93) the risk of residents of other farms. To identify environmental hazards for fall injuries, researchers from several disciplines may need to collaborate in the design and conduct of studies that include injury site investigations.
Accidental Falls↗
Case control study of agricultural injuries to older farmers in central Wisconsin.
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Accidents, Occupational↗
Angiogenin antagonists prevent tumor growth in vivo.
A noncytotoxic neutralizing monoclonal antibody (mAb), 26-2F, to human angiogenin (Ang), a potent inducer of neovascularization, has been reported to prevent or delay the establishment of HT-29 human tumor xenografts in athymic mice. In the present study the tumor model was modified to increase sensitivity to Ang antagonists to facilitate further investigations and comparisons of their capacity to inhibit tumor growth. An increase in the percentage of tumor-free mice from 10-25% to 65% is observed in this modified model after treatment with mAb 26-2F. An additional neutralizing mAb, 36u, that interacts with a different epitope on Ang similarly prevents the appearance of tumors, both alone and in combination with mAb 26-2F. In those tumors that develop in mice treated with these agents, the number of vascular elements is reduced. Actin, an Ang antagonist that unlike the mAbs binds both human and mouse Ang, also prevents the establishment of tumors while exhibiting no toxic effects at daily doses > 50 times the molar amount of circulating mouse Ang. Ang antagonists also inhibit the appearance of tumors derived from two other Ang-secreting human tumor cell lines--i.e., A549 lung adenocarcinoma and HT-1080 fibrosarcoma. These results demonstrate that inhibition of the action of Ang is an effective therapeutic approach for the treatment of malignant disease.
Actins↗
Incidence of farm-work-related acute injury in a defined population.
To determine occurrence and sources of farm-work-related injury, we conducted a population-based, prospective study in a large clinic and hospital serving a defined rural area. The population at risk was identified through a unique demographic and medical records linkage system and a special agricultural census. Cases were 510 individuals who sought inpatient or outpatient care from May 1990 through April 1992 from a physician or chiropractor for harm resulting from acute exposure to energy. One per 31 farm residents was treated annually for a farm-work-related injury. Eight percent of these cases were hospitalized. Animals were the most frequent source of injury. Severity did not differ between cases associated with animals, machinery, falls, or chemicals. Thirty-eight percent of farm-work-related injury cases occurred in nonfarm residents. Injury risk was 2.5 times greater among dairy farm residents than among nondairy farm residents, 352.0 vs. 141.0 cases per 10,000 person-years, respectively. Adult male farm residents had 556.9 injuries per 10,000 person-years and 21.3 injuries per million hours of farm work.
Accidents, Occupational↗
Machine-related occupational injuries in farm residents.
Farm machinery is an important contributor to the high rates of occupational injury in agriculture. As part of a population-based case-control study, we studied risk factors for machine-related farm injuries. Case patients were farm residents residing in a geographically defined area of central Wisconsin who experienced a farm injury associated with a tractor, farm implement, or other machine which required medical or chiropractic care from May 1990 through April 1992. Controls were selected from an ad hoc census of farm residents in the same area. Telephone interviews regarding demographic characteristics, safety behaviors, and farming practices were completed for 97.8% of 90 case patients and for 82.8% of 221 control subjects. Personal characteristics significantly associated with an increased risk of machine-related injury included the number of hours worked per week and working primarily as a farmer. Dairy farms, farms with nonresident workers, and large farms were associated with an increased risk of injury while farms with registered cows and farms where cows were fed in the barn even in summer experienced fewer injuries. Based on a logistic regression model, the independent risk factors for machine-related farm injury included hours worked per week (2% increased risk/nonresident workers on farm (odds ratio) (OR) = 2.32; 95% confidence interval (CI): 1.07 to 5.06), cows fed in barn in summer (OR = 0.28; 95% CI: 0.12 to 0.64), and registered cows on farm (OR = 0.36; 95% CI: 0.17 to 0.79). Farm safety practices did not appreciably influence the risk of machine-related farm injury.
Accidents, Occupational↗
Prognostic factors of spinal cord stimulation for chronic back and leg pain.
Spinal cord stimulation (SCS) has been used for more than 20 years in the treatment of diverse pain conditions. Although recent studies have identified more clearly those conditions for which SCSoffers a favorable prognosis, the identification of a patient population in whom reasonably long-term success can be expected has been difficult. In an effort to improve patient selection and increase the overall success rate of treatment, we have examined various physical, demographic, and psychosocial variables as predictors of SCS outcome. The study population consisted of 40 patients with chronic low back and/or leg pain, 85% of whom were diagnosed with failed back surgery syndrome. Medical history and demographic data were collected as part of an initial assessment along with patient responses to the Minnesota Multiphasic Personality Inventory, the visual analogue pain rating scale (VAS), the McGill Pain Questionnaire, the Oswestry Disability Questionnaire, the Beck Depression Inventory, and the Sickness Impact Profile. Treatment outcomes were examined and found to improve significantly after 3 months of stimulation. Subsequent regression analysis revealed that patient age, the Minnesota Multiphasic Personality Inventory depression subscale D, and the evaluative subscale of the McGill Pain Questionnaire (MPQe) were important predictors of posttreatment pain status. Increased patient age and D subscale scores correlated negatively with pain status, as measured by the percentage of changes in pretreatment and posttreatment VAS scores, % delta VAS. In contrast, higher MPQe correlated with improved pain status. By the use of the following equation and the definition commonly associated with SCS success (at least 50% decrease in the VAS pain level), the success or failure of 3 months of SCS was correctly predicted in 88% of the study population. Our results suggest that patient age, Minnesota Multiphasic Personality Inventory depression, and MPQe may be clinically useful in the prediction of pain status after 3 months of SCS in patients with chronic low back and/or leg pain. % delta VAS = 112.57 - 1.98 (D)-1.68 (Age) + 35.54 (MPQe).
Adult↗
A monoclonal antibody to human angiogenin suppresses tumor growth in athymic mice.
Human angiogenin, a potent inducer of neovascularization, is secreted by HT-29 colon adenocarcinoma cells. microgram doses of a monoclonal antibody that neutralizes the in vitro and in vivo activities of angiogenin prevent or delay the appearance of s.c. HT-29 tumors in athymic mice in a statistically significant, dose-dependent manner. The antibody is not cytotoxic to tumor cells in vitro, which indicates that inhibition of tumor growth most likely occurs by neutralization of the activity of angiogenin in vivo and further implies a critical role for angiogenin in the early development of HT-29 tumors. The results suggest a therapeutically useful approach to the treatment of angiogenin-dependent malignancy.
Adenocarcinoma↗