Treatment of severe Raynaud's phenomenon with bosentan in a patient with systemic sclerosis.
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Adult↗
Biomedical subjects
B Ng
Publications and source records attributed to B Ng.
Poliovirus 3C protease-mediated degradation of transcriptional activator p53 requires a cellular activity.
Infection of HeLa cells with poliovirus leads to rapid shut-off of host cell transcription by RNA polymerase II. Previous results have suggested that both the basal transcription factor TBP (TATA-binding protein) and transcription activator proteins such as CREB (cyclic AMP-responsive element-binding protein) and Oct-1 (the octamer-binding factor) are cleaved by the viral-encoded protease, 3C(Pro). Here we demonstrate that the transcriptional activator (and tumor suppressor) p53 is degraded by the viral protease 3C both in vivo and in vitro. Unlike other transcription factors that are directly cleaved by 3C(pro), degradation of p53 requires a HeLa cell activity in addition to 3C(Pro). The degradation of p53 by 3C(Pro) does not appear to involve the ubiquitin pathway of protein degradation. Vaccinia virus infection of HeLa cells leads to inactivation of the cellular activity required for 3C(Pro)-mediated degradation of p53. The vaccinia-encoded protein (CrmA) is known to inhibit caspase I (ICE protease) that converts inactive IL-1beta to an active secreted form. Incubation of HeLa cells with caspase I inhibitor Z-VAD-fmk does not interfere with 3C(Pro)-mediated degradation of p53. The cellular activity present in extracts of HeLa cells can be fractionated through phosphocellulose. A partially purified fraction that elutes at 0.6 M KCl from phosphocellulose contains the activity that degrades p53 in a 3C(Pro)-dependent manner. These results suggest that both poliovirus-encoded protease 3C(Pro) and a cellular activity are required for the degradation of p53 observed in cells infected with poliovirus.
3C Viral Proteases↗
A proapoptotic peptide for the treatment of solid tumors.
We have designed a novel peptide, DP1, which is able to mediate significant induction of apoptosis in solid tumors by local injection. This peptide, comprised of a protein transduction domain (PTD), PTD-5, fused to an antimicrobial peptide, (KLAKLAK)2, was able to trigger rapid apoptosis in a variety of cell lines in vitro, including MCA205 murine fibrosarcomas and human head and neck tumors. Furthermore, direct injection of DP1 into day 7 established MCA205 tumors in C57BL/6 mice resulted in the induction of tumor apoptosis and subsequent reduction in tumor volume. These results suggest that DP1 may be used clinically to treat accessible solid tumors or as an adjuvant therapy in conjunction with radiotherapy, standard chemotherapy, immunotherapy, or surgical debulking.
Amino Acid Sequence↗
Selective neurodegeneration, without neurofibrillary tangles, in a mouse model of Niemann-Pick C disease.
The BALB/c mouse model of Niemann-Pick type C (NPC) disease exhibits neuropathological similarities to the human condition. There is an age-related cerebral atrophy, demyelination of the corpus callosum, and degeneration of cerebellar Purkinje cells in the NPC mouse. In human NPC, many cortical and subcortical neurons contain neurofibrillary tangles, which are thought by some investigators to play an important role in the neurodegenerative process. The purpose of the present study was to determine whether neurodegeneration occurs in the NPC mouse, in brain regions other than the cerebellum and whether the degeneration is related to the presence of neurofibrillary tangles. Using light microscopic methods with immunohistochemistry, electron microscopy, and cell counting methods, 11-week-old NPC(+/+) and NPC(-/-) animals were examined. In the NPC(-/-) mice, there were 96% fewer Purkinje cells, 28% fewer neurons in the prefrontal cortex, 20% fewer neurons in the thalamus, and 63% fewer glial cells in the corpus callosum. On the other hand, previous studies indicate normal numbers of neurons and glial cells in these same neuroanatomical regions in young NPC(-/-) mice. There were normal numbers of cholinergic neurons in sections assessed in the striatum and basal forebrain in the 11-week-old animals and no evidence of neurofibrillary tangles within cells. The present data indicate that both neurons and glial cells die in the NPC mouse but that all cells are not equally vulnerable. There was no evidence for neurofibrillary tangles in the NPC mouse, and therefore the degenerative process in the mouse is unrelated to the neurofibrillary tangle.
Animals↗
Radiosensitization of tumor-targeted radioimmunotherapy with prolonged topotecan infusion in human breast cancer xenografts.
Clinical radioimmunotherapy (RIT) of solid tumors holds great promise, but as yet has been unable to deliver tumoricidal radiation doses without unacceptable toxicity. Our experimental approach aims to potentiate the therapeutic action of radioimmunoconjugates at the tumor site and thus improve the efficacy of RIT by combination with other treatment modalities. The topoisomerase I inhibitors are a unique class of chemotherapeutic agents that interfere with DNA breakage-reunion by inhibiting the action of topoisomerase I. Preclinical studies suggest that prolonged infusion of topoisomerase I inhibitors enhances cell toxicity due to ionizing radiation. We evaluated the efficacy of combined treatment with continuous administration of topotecan and 90Y-MX-DPTA BrE3 monoclonal antibody (which recognizes an epitope of breast epithelial mucin expressed in most breast cancers) on human mammary carcinoma xenografts in nude mice. Topotecan or 90Y-BrE3 treatment alone delayed overall tumor growth rate transiently but did not affect survival. The combination of RIT with topotecan substantially reduced growth of relatively large established tumors and caused complete tumor regressions and prolonged tumor-free survival in a substantial proportion of treated animals. In vitro studies demonstrated an increase in apoptotic rate and a decrease in cell proliferation of tumor cell lines treated with this combination. We combined the radiosensitization property of topotecan and the specificity of systemic RIT to establish a novel therapy for solid tumors in an experimental tumor xenograft model.
Animals↗
Specific organ gene transfer in vivo by regional organ perfusion with herpes viral amplicon vectors: implications for local gene therapy.
BACKGROUND: Many gene therapy strategies would benefit from efficient, regional organ delivery of therapeutic genes. METHODS: Regional perfusions of lung, liver, or bladder were performed to determine if rapid and efficient gene transfer can be accomplished in vivo, and to determine if in vivo gene transfer can be limited to the organ of interest. In addition, herpes simplex virus tumor necrosis factor (HSVtnf), carrying the human tumor necrosis factoralpha gene was used as a treatment for methylcholanthrene sarcoma in a syngeneic lung metastases model in Fisher rats. RESULTS: A 20-minute perfusion using HSV carrying beta-galactosidase (HSVlac) produced significant expression of this marker gene isolated to the target organs, without organ-specific tissue injury or inflammation. Regional perfusion of organs with HSV carrying the cytokine gene tumor necrosis factor alpha also resulted in high-level local organ production of this cytokine (2851 +/- 53 pg/g tissue in perfused lung versus 0 for the contralateral lung). For the current vector construct, expression of the gene of interest peaked between 2 and 4 days and was undetectable by 2 weeks after perfusion. In animals undergoing perfusion as treatment for pulmonary sarcoma, there was no difference between tumor counts in lungs perfused with HSVlac (17 +/- 6) or HSVtnf (22 +/- 8), but either treatment resulted in lower tumor counts than controls (111 +/- 24 nodules per lung, P <.02). CONCLUSIONS: Regional organ perfusion using herpes viral vectors is an effective and well-tolerated in vivo method of transiently delivering potentially toxic gene products to target organs in directing gene therapy. Regional lung perfusion with HSV amplicons reduces tumor burden in a rat model of pulmonary metastases, though HSVtnf cannot be demonstrated to augment the cytopathic effect of the HSV amplicon alone in the current model.
Animals↗
Ward crowding and incidents of violence on an acute psychiatric inpatient unit.
OBJECTIVE: Violence in psychiatric wards is common, and it is on the rise. This study examined the relationship between ward occupancy level and staff-to-patient ratio and incidents of aggressive behavior, both physical and verbal, on an acute inpatient unit in rural New Zealand. METHODS: Logistic regression was used to analyze data collected from the ward's log of adverse incidents and the ward census over a 12-month period. A physical incident was defined as an unwelcome physical contact or willful damage to property. Incidents of self-harm were excluded. Verbal aggression was any threat of physical or sexual harm. RESULTS: Among 381 admissions during the study period, 58 incidents were recorded--25 incidents of verbal aggression and 33 incidents of physical violence. Logistic regression demonstrated that the occupancy level was positively associated with the occurrence of any type of violent incident. The average occupancy level when an incident occurred was 77 percent, compared with 69 percent when no incidents occurred. The average occupancy level was significantly higher when verbal incidents occurred (80 percent) than when physical incidents occurred (70 percent). No association was found between violence and staff-to-patient ratio. Incidents were significantly more likely to occur during the afternoon shifts (3 p.m. to 11 p.m.). CONCLUSIONS: Crowding was found to be significantly associated with aggressive incidents, and in particular with verbal aggression.
Acute Disease↗
Crowding and violence on psychiatric wards: explanatory models.
OBJECTIVE: Violence is widely prevalent on acute-care psychiatric wards, and crowding has been identified as a major risk factor. This paper explores why patients may respond to crowding with violence. METHOD: We carried out a literature review on Medline, using the key words "violence" and "crowding." We conducted an additional hand search of the references collected from the reviewed papers. RESULTS: Factors specific to the relation between crowding on acute-care inpatient psychiatric wards and violence can be divided under the following headings: 1) patient density, privacy, and control; 2) ward architecture; 3) the social organization of psychiatric wards; 4) interpersonal space; 5) phylogenic theories; and 6) anthropological theories of human behaviour. CONCLUSIONS: We offer explanatory models for this relation and suggest strategies to counter the effects of crowding. Recommendations are made for future studies.
Crowding↗
49-year-old woman with acute abdominal pain and nausea.
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Abdominal Pain↗
Regulation of DNA-dependent protein kinase activity by ionizing radiation-activated abl kinase is an ATM-dependent process.
Ionizing radiation (IR) treatment results in activation of the nonreceptor tyrosine kinase c-Abl because of phosphorylation by ATM. In vitro evidence indicates that DNA-dependent protein kinase (DNA-PK) can also phosphorylate and thus potentially activate Abl kinase activity in response to IR exposure. To unravel the role of ATM and DNA-PK in the activation of Abl, we assayed Abl, ATM, and DNA-PK activity in ATM- and DNA-PKcs-deficient cells after irradiation. Our results show that despite the presence of higher than normal levels of DNA-PK kinase activity, c-Abl fails to become activated after IR exposure in ATM-deficient cells. Conversely, normal activation of both ATM and c-Abl occurs in DNA-PKcs-deficient cells, indicating that ATM but not DNA-PK is required for activation of Abl in response to IR treatment. Moreover, activation of Abl kinase activity by IR correlates well with activation of ATM activity in all phases of the cell cycle. These results indicate that ATM is primarily responsible for activation of Abl in response to IR exposure in a cell cycle-independent fashion. Examination of DNA-PK activity in response to IR treatment in Abl-deficient cells expressing mutant forms of Abl or in normal cells exposed to an inhibitor of Abl suggests an in vivo role for Abl in the down-regulation of DNA-PK activity. Collectively, these results suggest a convergence of the ATM and DNA-PK pathways in the cellular response to IR through c-Abl kinase.
Animals↗
Variation of psychiatric emergencies across seasons in San Diego county.
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Acute Disease↗
Acoustic rhinometry and computed tomography scans for the diagnosis of nasal septal deviation, with clinical correlation.
OBJECTIVE: The aim in this study was to analyze the efficiency and reliability of acoustic rhinometry (AR) readings in recognition of nasal septal deviation. METHOD: We compared 24 patients' AR readings with their sinus CT scans. The patient data were analyzed by comparison with normative data, area, and percentage differences between the two sides. Additionally, the data further analyzed by receiver operating characteristic curve and Spearman correlation of CT and AR in determining nasal septal deviation. RESULTS: The sensitivity of AR in detecting anterior septal deviations was found to be 54%, with a specificity of 70%. A very highly significant correlation (P < or = 0.001) was found between minimal cross-sectional area (CSA) 1 values and CT results. DISCUSSION: In the interpretation of AR readings, comparison of each CSA value should be included, in addition to use of the total absolute CSA values. CONCLUSION: According to our findings the diagnosis of nasal septal deviation can be supported by AR readings.
Acoustics↗
Predictors of post-hospital employment status for psychiatric patients in Hong Kong: from perceptions of rehabilitation professionals to empirical evidence.
Fifty participants with mental illness and a concrete discharge plan were selected from two mental hospitals in Hong Kong and assessed on their Psychosocial support by the Chinese Version of the Significant Others Scale, social vocational competence using the Workshop Behavior Checklist and the Vocational Social Skills Scale, medical history, work history, and demographic variables. At three months after discharge, the employed participants (n = 12) were shown to have better psychosocial support and social vocational competence than the unemployed participants (n = 24) by univariate comparison. The employed and unemployed participants did not differ in their medical and work history, and demographic variables. Implications of the results for rehabilitation programming are discussed.
Adolescent↗
Loratadine/pseudoephedrine for nasal symptoms in seasonal allergic rhinitis: a double-blind, placebo-controlled study.
In this double-blind, placebo-controlled, crossover, parallel study, we treated 20 adults who had seasonal allergic rhinitis with once-daily fixed-combination loratadine/pseudoephedrine sulfate to observe its effect on relieving symptoms, primarily nasal congestion. Acoustic rhinometry detected a trend toward improvement in nasal patency, although the difference between pre- and post-treatment measures was not statistically significant. Endoscopic inferior turbinate photography documented that treatment led to statistically significant reductions in the amount of nasal edema and nasal secretions. The results of a quality-of-life questionnaire suggested that treatment alleviated nasal and ocular symptoms of rhinoconjunctivitis. An analysis of subjective visual analog scale scores showed a trend toward improvement in most but not all nasal symptoms. We conclude that once-a-day fixed-combination loratadine/pseudoephedrine is effective in relieving nasal congestion in patients with seasonal allergic rhinitis.
Adult↗
Cardiac operations in patients with low-grade small lymphocytic malignancies.
BACKGROUND: Low-grade small lymphocytic (B cell) malignancies (encompassing chronic lymphocytic leukemia and some types of non-Hodgkin lymphoma) are diseases of the elderly. Open cardiac procedures are known to have increased risk of postoperative infection and other morbidities in these immunodeficient patients. Outcome of open cardiac procedures in these patients was reviewed retrospectively. PATIENTS: Thirteen patients (aged 58-82 years, 11 men, 2 women) with these lymphocytopathologic diseases (8 with chronic lymphocytic leukemia and 5 with non-Hodgkin lymphoma) underwent cardiac operations between January 1977 and June 1998. Mean age was 72 +/- 2.1 years. Isolated coronary artery bypass grafting was performed in 11 and combined procedures and double valve replacement were performed in 1 each. Preoperatively, 9 patients were in a low-risk clinical stage. Mean preoperative duration of lymphocytopathologic disease was 6.1 +/- 1.6 years. Mean preoperative New York Heart Association functional class was 2.8. RESULTS: There was no operative death. Average stay in the intensive care unit was 41.4 +/- 8.6 hours. Postoperative leg and superficial sternal wound infections were encountered in 3 patients. Average postoperative hospital stay was 10.0 +/- 1.7 days. During the follow-up up to 72 months, 1 patient underwent a second cardiac operation. There was 1 late death 4 years later. Coronary stenting was done in 1 patient and a cardioverter-defibrillator was implanted in another patient for recurrent angina. Three patients underwent chemotherapy. Cardiac and lymphocytopathologic status remained stable in others. CONCLUSIONS: Acceptable outcome may be anticipated after cardiac operations in patients with low-grade chronic lymphocytic leukemia and non-Hodgkin lymphoma in early stages. However, the possibility of infection and progression of cardiac and lymphocytopathologic status in these patients should call for caution.
Age Factors↗
Scanning laser Doppler is a useful technique to assess foot cutaneous perfusion during femoral artery cannulation.
BACKGROUND: Measurement of cardiac output and extravascular lung water in critically ill patients using femoral artery double-indicator dilution involves femoral artery catheterization. The potential risk of vascular compromise to the limb may be exacerbated in patients receiving vasopressors. The utility of scanning laser Doppler flowmetry to measure changes in pedal perfusion following catheterization was assessed. RESULTS: There were no significant changes in mean occlusion pressures or in cutaneous perfusion between either leg or between measurement time points, immediately after or 24 h following insertion of the catheters. CONCLUSIONS: Scanning laser Doppler flowmetry is easily used to assess changes in foot perfusion and the effect of interventions that may reduce blood flow to the skin of the foot. Femoral artery catheterization for double-indicator dilution measurements does not reduce calf occlusion pressures or foot skin perfusion in patients receiving vasopressor drugs.
Journal Article↗