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Seclusion has become a contentious practice and initiatives have commenced to reduce or eliminate its use. This paper presents the initiatives that were introduced during a seclusion reduction project that was undertaken at an Australian forensic hospital. These initiatives are based on the six core strategies that have been successfully used in North America to reduce seclusion. However, there are challenges (patient characteristics, prisoner culture and ensuring safety) and opportunities (longer admissions, higher staff-patient ratio, staff confidence, sound risk assessment and management) that can influence projects to reduce seclusion in a forensic hospital. During this project, the frequency (mainly multiple seclusions of patients) and duration of seclusion events were reduced but there was less reduction in the number of patients that were secluded. It is possible that the strategies were successfully supported by the identified opportunities to reduce the frequency and duration of seclusion but the challenges were significantly powerful in the early period of admission to prompt the need for seclusion. Reducing seclusion in a forensic hospital is a complex undertaking as nurses must provide a safe environment while dealing with volatile patients and may have little alternative at present but to use seclusion after exhausting other interventions.

Mutations of Nkx2-5 cause congenital heart disease and atrioventricular block in man. The altered expression of an electrophysiologic protein regulated by Nkx2-5 was originally presumed to cause the conduction defect, but when no such protein was found, an alternative hypothesis was considered. In pediatric patients, the association of certain cardiac malformations with congenital atrioventricular block suggests that errors in specific developmental pathways could cause both an anatomic and a physiologic defect. We therefore hypothesized that Nkx2-5 insufficiency perturbs the conduction system during development, which in turn manifests as a postnatal conduction defect. Experimental results from Nkx2-5 knockout mouse models support the developmental hypothesis. Hypoplasia of the atrioventricular node, His bundle, and Purkinje system can explain in whole or in part specific conduction and electrophysiologic defects present in Nkx2-5 haploinsufficiency.

Nkx2.5 is a conserved homeodomain (HD) containing a transcription factor essential for early cardiac development. We generated several mutations modeling some patients with congenital heart disease. Transgenic mice (tg) expressing the wildtype Nkx2.5 under beta-myosin heavy chain (MHC) promoter died during the embryonic stage. However, tg mice expressing this mutation under beta-MHC promoter (beta-MHC-TG(I183P)), the wildtype Nkx2.5 (alpha-MHC-TG(wild)), and a putative transcriptionally active mutant (carboxyl-terminus deletion, alpha-MHC-TG(DeltaC)) under alpha-MHC promoter showed postnatal lethal heart failure. Given the profound atrioventricular conduction abnormalities we recently demonstrated in beta-MHC-TG(I183P) mice, the aim of this study was to determine whether alpha-MHC-TG(wild) and alpha-MHC-TG(DeltaC) mutant mice display similar cardiac electrophysiological phenotypes. Surface ECG recordings and in vivo electrophysiology studies were performed in alpha-MHC-TG(wild) mice and controls at 6 weeks of age, and in alpha-MHC-TG(DeltaC) mice and controls at 10 weeks of age. Ambulatory ECG recordings in alpha-MHC-TG(wild) and controls were obtained using an implantable radiofrequency telemetry system. PR prolongation and atrioventricular nodal dysfunction were detected in alpha-MHC-TG(wild) and alpha-MHC-TG(DeltaC) mice. Bradycardia and prolonged PR interval were seen in ambulatory ECG of alpha-MHC-TG(wild) mice compared to controls. Several alpha-MHC-TG(wild) mice died of bradycardia. Fetal and neonatal mutant Nkx2.5 expression causes severe cardiac conduction failure. Postnatal overexpression of nonmutant (wild) Nkx2.5 also causes conduction abnormalities, although the onset is after the neonatal stage. Bradycardia and AV conduction failure may contribute to the lethal heart failure and early mortality.

Matrix metalloproteinases (MMP) types 2 and 9 (also known as gelatinase A and B) are thought to be causally involved in cancer invasion and metastasis. In normal as well as in malignant tissue, both these MMPs occur in multiple forms such as inactive precursors, active enzymes and enzyme- inhibitor complexes. Using newly developed quantitative activity assays, the levels of active MMP-2, total (active and activatable) MMP-2 and total MMP-9 were found to be significantly higher in breast carcinomas than in fibroadenomas. In addition, active MMP-2 and MMP-9 were detected more frequently in malignant than in benign breast carcinoma. These new quantitative activity assays are likely to be of use in studying the mechanism of action of both MMP-2 and -9, assessing their potential prognostic value in different cancers and in the design of MMP inhibitors for preventing cancer metastasis. (C) 2000 Wiley-Liss, Inc. Chemicals/CAS: Matrix Metalloproteinase 2, EC 3.4.24.24; Matrix Metalloproteinase 9, EC 3.4.24.35

TIMP-2 is an endogenous inhibitor of MMPs. Most data from model systems suggest that high levels of this inhibitor prevent metastasis. In human breast cancers, however, we show that high levels of TIMP-2 correlate with both shortened disease-free interval and overall survival. In primary breast cancers, TIMP-2 levels showed no significant relationship with either tumor size or axillary node status but correlated inversely with estrogen receptor levels. TIMP-2 levels also correlated significantly with those for TIMP-1. We conclude that high levels of endogenous TIMP-2, like other protease inhibitors such as PAI-1 and TIMP-1, correlate with progression of human breast cancer.

Urokinase plasminogen activator (uPA) is a serine protease causally involved in cancer invasion and metastasis. Consistent with its role in cancer spread, uPA has been shown to be a prognostic marker in a variety of malignancies, especially breast cancer. Approximately 20 different groups have shown that high levels of uPA in breast tumor tissue predict poor outcome. As a prognostic marker in breast cancer, uPA provides information that is independent of traditionally used factors such as tumor size, tumor grade, axillary node status and estrogen receptor status. Furthermore, uPA is prognostic in node-negative patients, and a clinical trial is currently under way to assess whether uPA and its inhibitor, plasminogen activator inhibitor-1, can differentiate between the majority of node-negative breast cancer patients who are cured by surgery from the minority who might benefit from adjuvant therapy. uPA is also prognostic in other malignancies, such as gastric, colorectal, esophageal, renal, endometrial, and ovarian cancers. uPA may thus be a prognostic indicator for multiple types of adenocarcinoma.

BACKGROUND The pretherapy prediction of occult lymph node involvement and the avoidance of otherwise futile and potentially morbid definitive local therapy is paramount in men with newly diagnosed prostate carcinoma. To identify patients with prostate carcinoma who likely have lymph node involvement and would benefit from staging lymphadenectomy prior to definitive local therapy, the authors compared the ability of several predictive staging algorithms and a radiolabeled monoclonal antibody scan to predict lymphatic metastases prior to treatment. METHODS Between August 1991 and June 1994, 198 men with clinical T2 or T3 classified (TNM) prostate carcinoma (bone scan negative) who were at high risk of lymph node involvement underwent a 111In-capromab pendetide scan prior to staging lymphadenectomy. Several predictive models based on preoperative prostate specific antigen level, biopsy Gleason score, and clinical stage were selected to predict those men having a ≥20% probability of lymph node involvement. The ability to predict pathologic stage using several clinical algorithms and the monoclonal antibody scan was compared with pathologic examination of the lymph nodes. RESULTS Overall, 39% of the pelvic lymph node specimens were positive for metastatic disease by pathologic analysis. Published algorithms predicting lymph node metastases had a positive predictive value (PPV) ranging from 40.5% to 46.6% and an area under the receiver operating characteristic curve (AUC) ranging from 0.52 to 0.61. The monoclonal antibody scan had a PPV of 66.7% and an AUC of 0.71. The differences between the PPV and the AUC for the individual clinical algorithms when compared with immunoscintigraphy were statistically significant. Combining the radiolabeled monoclonal antibody scan with clinical predictive models, a PPV of up to 72.1% could be obtained. CONCLUSIONS These data suggest that the PPVs for the clinical predictive algorithms are similar and that the PPV of the radiolabeled monoclonal antibody scan alone or in combination with the algorithms has additional value in predicting lymph node involvement in prostate carcinoma patients at high risk of regional disease spread. These algorithms and the 111In-capromab pendetide scan may be used for the appropriate selection of candidates for definitive local therapy in men with clinically localized prostate carcinoma and significant risk of lymph node involvement. Cancer 1999;85:1586–92. © 1999 American Cancer Society.

Studies from model systems suggest that matrix metalloproteinases (MMPs) are causally involved in tumor progression while tissue inhibitors of MMPs (TIMPs) prevent this progression. Here, we show that concentrations of TIMP-1 are significantly higher in breast carcinomas than in fibroadenomas. In primary breast cancers, TIMP-1 concentrations increased with increasing tumor size but showed an inverse relationship with estrogen receptor concentrations. In primary breast cancers also, TIMP-1 levels were weakly but significantly correlated with those for MMP-1, proMMP-2, active MMP-2, MMP-3 and proMMP-9. Contrary to what might be expected from published data on model systems, high concentrations of TIMP-1 predicted a poor outcome in patients with breast cancer. We conclude that in human breast cancer, endogenous TIMP-1 does not inhibit tumor progression but may enhance the process. Int. J. Cancer (Pred. Oncol.) 84:44–48, 1999. © 1999 Wiley-Liss, Inc.

BACKGROUND Stored serum from clinical trial cases undergoing ProstaScint® (CYT-356) scanning were available for Prostate Specific Membrane Antigen (PSMA) assay. Prostate Specific Antigen (PSA) levels had already been determined. This provided an opportunity to see what correlations existed between the serum markers and the ProstaScint® scan. A group of patients had the studies preprostatectomy, whereas another group had the studies postprostatectomy. METHODS The scan results, serum PSA, serum PSMA, and clinical data were separately analyzed. PSMA serum levels were determined by Western blot. RESULTS Preoperatively, radical prostatectomy patients showed a correlation between serum PSA or PSMA levels and the ProstaScint® scan in the total group (n = 86), or in an untreated group (n = 38). Preoperatively, PSMA correlated with the pathological stage, whereas PSA correlated with the scan. Postoperatively, only PSMA serum levels correlated with the scan in an untreated group (n = 40). CONCLUSIONS Preoperatively or postoperatively, Western blot PSMA serum levels predict the stage of disease or local, regional, or distant metastases, as shown by ProstaScint® scan. Both the scan and the serum tests provide prognostic information and evaluate the extent of disease to a more significant degree than previously possible. Prostate 33:281–285, 1997. © 1997 Wiley-Liss, Inc.

Application of monoclonal antibody (MoAb) technology to cancer management is discussed by reviewing the development and clinical evaluation of two MoAb-based immunoscintigraphic agents (111In-satumomab pendetide [OncoScint CR/OV-In] and 111In-CYT-356; Cytogen Corporation, Princeton, NJ). Both agents were prepared using a site-specific MoAb modification method that preserves the immunoreactivity of the radiolabeled immunoconjugate. 111In-satumomab pendetide is an 111In-labeled conjugate of the murine MoAb B72.3, which is directed to TAG-72, an antigen expressed by the majority of adenocarcinomas. By providing information that complements the results of standard radiographic diagnostic modalities, this imaging agent can aid in the treatment of patients with colorectal or ovarian cancer. Immunoscintigraphy with 111In-satumomab pendetide has been shown to assist in medical-surgical management by detecting occult extrahepatic lesions, clarifying equivocal results of other diagnostic imaging tests, and evaluating the extent and resectability of known tumor lesions. 111In-CYT-356 is an 111In-labeled conjugate of the murine MoAb 7E11-C5.3, which is reactive with prostatic carcinoma, benign prostatic hypertrophy, and, to a lesser extent, normal prostatic tissue. Results of preliminary clinical investigations suggest that 111In-CYT-356 immunoscintigraphy can be useful for the presurgical staging of prostatic carcinoma and for the detection of occult distant disease in patients with negative or equivocal results on standard imaging tests. Results with these site-specifically radiolabeled immunconjugates demonstrate the clinical utility of MoAb-based imaging agents in the treatment of patients with solid tumors.

Basal cell carcinoma of the skin (BCC) is the most common cancer worldwide. Unlike most other human malignancies, BCCs rarely metastasise. In this investigation, we show that the serine protease urokinase plasminogen activator (u-PA), which is causally involved in metastasis, is expressed at lower levels in BCCs compared to other skin cancers, such as squamous-cell carcinomas (SCCs) or malignant melanomas. Similarly, the u-PA receptor as well as the inhibitor PAI-1 were present at lower levels in BCCs relative to both SCCs and melanomas. In contrast to u-PA, tissue-plasminogen activator, which is not thought to be involved in metastasis, was present at similar levels in the different types of skin lesion investigated. We conclude that the failure of BCCs to metastasise may at least be partially related to low expression of components of the u-PA system. Int. J. Cancer 85:457–459, 2000. © 2000 Wiley-Liss, Inc.

Because many dentists were trained before HIV disease was recognized and its implications for dentistry understood, there is a need for effective continuing education programs about the disease for health professionals. Unfortunately, much of the continuing professional education about AIDS in the last few years has been poorly evaluated and the value of continuing education itself has increasingly been called into question. In order to clarify how continuing educational efforts can be designed and evaluated, we report on our continuing educational projects and research which culminated in research on a nationwide educational intervention about AIDS for dentists. We outline and evaluate the steps taken in designing both the intervention and the research. The strengths and weaknesses of the design are discussed and suggestions made about how the design could be improved.

To assess recent dental graduates' perceptions about the adequacy of their education, a random sample of individuals who graduated between 1980 and 1982 was surveyed. The 362 respondents (56 percent response rate) indicated their perceived level of preparedness and the importance to practice of 75 topics in the dental school curriculum. The means for level of preparedness and importance to practice were plotted for each of the 75 topics. Those topics that new dentists believed to be underemphasized or overemphasized in the curriculum were identified. These findings have implications for planning curricular changes for dental education.