Evolving technologies drive the new roles of Biomedical Engineering.

Rapidly changing technology coupled with the financial impact of organized health care, has required hospital Biomedical Engineering organizations to augment their traditional operational and business models to increase their role in developing enhanced clinical applications utilizing new and evolving technologies. The deployment of these technology based applications has required Biomedical Engineering organizations to re-organize to optimize the manner in which they provide and manage services. Memorial Sloan-Kettering Cancer Center has implemented a strategy to explore evolving technologies integrating them into enhanced clinical applications while optimally utilizing the expertise of the traditional Biomedical Engineering component (Clinical Engineering) to provide expanded support in technology / equipment management, device repair, preventive maintenance and integration with legacy clinical systems. Specifically, Biomedical Engineering is an integral component of the Medical Physics Department which provides comprehensive and integrated support to the Center in advanced physical, technical and engineering technology. This organizational structure emphasizes the integration and collaboration between a spectrum of technical expertise for clinical support and equipment management roles. The high cost of clinical equipment purchases coupled with the increasing cost of service has driven equipment management responsibilities to include significant business and financial aspects to provide a cost effective service model. This case study details the dynamics of these expanded roles, future initiatives and benefits for Biomedical Engineering and Memorial Sloan Kettering Cancer Center.

Role of Akt/protein kinase B in the activity of transcriptional coactivator p300.

Akt/protein kinase B is a downstream target of the phosphatidylinositol 3-kinase (PI3K) pathway and plays a critical role in promotion of cell survival. The function of transcriptional coactivator p300 is required by many transcription factors to either activate or repress gene expression. Here, we show that induction of PI3K enhances the metabolic stability of endogenous p300 protein. On the other hand, repression of PI3K by LY294002 induces p300 degradation through the 26S proteasome pathway and impedes the transcriptional activity of the coactivator. In addition, Akt interacts with the coactivator and the activity of Akt is required to maintain the steady-state level of p300. Our study provides a new insight into the molecular mechanisms by which the critical concentration of p300 protein is regulated and suggests a role for Akt in control of various cellular activities through the transcriptional coactivator p300.

A generalized algorithm for determining the time of release and the duration of post-release radiation precautions following radionuclide therapy.

The Nuclear Regulatory Commission has recently amended its regulation concerning patients who have received therapeutic amounts of radioactivity. The amended regulation allows patient release based on a total effective dose equivalent (TEDE) limit of 5 mSv (500 mrem) instead of the activity administered or retained [1,110 MBq (30 mCi)] or the dose rate [0.05 mSv h(-1) (5 mrem h(-1)) at 1 m]. Record-keeping and written post-release radiation safety precautions are required, however. A general algorithm, combining patient-specific kinetics and dose rate measurements, has been developed to systematically determine the actual duration of post-release radiation precautions as well as the time of release post-treatment. This algorithm is based on the maximum permissible effective dose equivalents (MPEDEs) of the respective cohorts exposed, 5 mSv (500 mrem) to non-pregnant adult family members and 1 mSv (100 mrem) to pregnant women, children, and members of the general public. Operational equations to determine the times post-radionuclide treatment of release from medical confinement, of not working, of avoiding pregnant women and children, of limiting holding of children, and of sleeping partners not sleeping together have been derived and illustrated with a hypothetical example. TEDE-based release criteria should be less restrictive than the previous activity-based or dose rate-based release criteria. However, post-release radiation precautions may be more intrusive and longer in duration than those to which most practitioners have grown accustomed. Up to now, however, the duration (typically 1-2 d) of advised post-release precautions had not been rigorously derived from MPEDEs and were generally inappropriately short. Even so, dose-based release criteria should prove more cost-effective overall than hospitalization of patients commonly imposed by activity-based and dose rate-based release criteria.

Radiation monitoring with reference to the medical environment.

This paper discusses the general principles of monitoring with some examples taken from the medical environment. The discussion is divided into two sections. The first section deals with the principles of personnel monitoring as well as the most common types of dosimeters used. Specific techniques applicable to the various areas of radiology are delineated. The second section deals with the use of portable monitors in a medical environment. The types of instruments commonly encountered and their limitations are detailed. This section also discusses the use of portable monitors as applied to the various areas of radiology. In each section some brief historical background has been added where possible.

The impact of influenza vaccination on respiratory illness at a boarding school.

We studied the impact of influenza vaccine during an outbreak of influenza at a 989-student boarding school in January to March, 1989. By February 6, 120 (17%) of 690 students completing survey questionnaires had been ill with fever and respiratory symptoms. Eighty-seven students had received influenza vaccine in the previous 18 months; these students had an attack rate half that of the unvaccinated students (9% v 19%; vaccine efficacy = 50%, confidence interval = 0%-70%). We estimate that, if the entire student body had been vaccinated, influenza-like illness could have been prevented in 162 students (16% of the school), and that preventing this illness could have avoided at least 482 student-days of missed classes, or approximately one student-day for each 1.8 additional doses of vaccine given. This study suggests that, when feasible, a broad influenza immunization policy for healthy students at residential schools should substantially decrease the disruption of school activities caused by influenza.

Technical challenges associated with the radiolabeling of monoclonal antibodies utilizing short-lived, positron emitting radionuclides.

Many factors, both physical and chemical, affect the radiolabeling of a chemical compound. These factors add a new dimension of complexity when the labeling of monoclonal antibodies is attempted with short-lived, positron emitting radionuclides. A lack of appreciation for the unique chemical separations associated with the radionuclide incorporated into the synthetic precursor can often lead to unexpected or non-reproducible results.

The radioactive patient.

Patients containing diagnostic or therapeutic amounts of radionuclides present exposure problems for medical and technical personnel. It is essential that personnel be aware of the magnitude of exposure expected and the methods available for its reduction. The design of a nuclear medicine facility should consider patients as sources of exposure. The size of imaging areas may be increased to reduce exposure to attending personnel. Patients containing radioactivity should be segregated from other patients and their families. Hospitalized patients given therapeutic amounts of radionuclides represent sources of exposure and contamination to personnel providing care. The use of disposable materials and the monitoring of these materials for contamination will reduce contamination of the hospital environment. Adequate instruction of personnel is essential to programs using therapeutic amounts of radionuclides so that patients are not made to feel isolated because of the form of treatment they are receiving.

Institutional storage and disposal of radioactive materials.

Storage and disposal of radioactive materials from nuclear medicine operations must be considered in the overall program design. The storage of materials from daily operation, materials in transit, and long-term storage represent sources of exposure. The design of storage facilities must include consideration of available space, choice of material, occupancy of surrounding areas, and amount of radioactivity anticipated. Neglect of any of these factors will lead to exposure problems. The ultimate product of any manipulation of radioactive material will be some form of radioactive waste. This waste may be discharged into the environment or placed within a storage area for packaging and transfer to a broker for ultimate disposal. Personnel must be keenly aware of packaging regulations of the burial site as well as applicable federal and local codes. Fire codes should be reviewed if there is to be storage of flammable materials in any area. Radiation protection personnel should be aware of community attitudes when considering the design of the waste program.

Radiation protection programs in nuclear medicine.

The development of radiation protection programs in nuclear medicine has been stimulated by the greater degree of regulation that exists in this form of medical imaging. A program within an institution will depend on the amount and type of work to be undertaken, the resources available, and the commitment of the individuals involved. These factors may be part of a licensing program or exist within a broader framework. General policy may be set forth in a manual or guidelines distributed to all employees. The continuing review and development of policy is the function of the institutional committee on radiation. This review must consider patients and workers with the objective of reducing overall dose while obtaining the maximum amount of clinical information. The responsibility for radiation protection is shared by the institution, the licensee, and the individual employee.

The in vitro production of anti-DNA antibody by cultured peripheral blood or tonsillar lymphoid cells from normal donors and SLE patients.

Anti-DNA antibody responses by cultured circulating lymphocytes from SLE patients and by the tonsillar lymphoid cells of normal donors were detected and enumerated by a sensitive specific ELISA of culture supernatants, or by a hemolytic anti-DNA PFC assay. Although spontaneous IgM and IgG anti-DNA and anti-ssDNA responses were characteristic of SLE lymphocytes and spontaneous IgM anti-ssDNA responses were characteristic of tonsillar lymphocytes, the circulating lymphocytes of normal controls never produced anti-DNA antibodies spontaneously, and rarely after PWM stimulation. The anti-DNA antibody PFC response of tonsil lymphocytes correlated directly with the total number of immunoglobulin-producing cells measured by a reverse hemolytic PFC assay. Mixing experiments in which we employed cultures of comparable numbers of separately enriched autologous circulating and tonsillar B and T cells revealed that tonsillar tissue contained an enriched population of anti-DNA antibody precursor B cells and/or helper T cells.

Effects of amino acids on the transport and cytotoxicity of melphalan by human bone marrow cells and human tumor cells.

In human tumor cells freshly obtained from patients with breast cancer, ovarian cancer, or adenocarcinoma of unknown etiology and in normal human bone marrow cells, the cell-to-medium ratio (intracellular/extracellular concentration) in vitro of 5.42 microM melphalan rose rapidly to levels of 6-17 after 35 min at 37 degrees C in Dulbecco's phosphate-buffered saline containing bovine serum albumin and glucose. Only patient C (breast cancer) had received chemotherapy. In all cells studied, L amino acids (1 mM) such as leucine, glutamine, tyrosine, and methionine reduced the cell-to-medium ratio of melphalan at 3 and 35 min. There was a good correlation between the reduction of melphalan transport at 35 min in the heterogeneous nucleated bone marrow cell population by amino acids and their effect on melphalan cytotoxicity in the CFU-C system. Aminoisobutyric acid (A1B), a specific substrate of the A system of amino acid transport, at a concentration between 1 and 50 mM had no significant effect on melphalan uptake at 3 min in any of the human cells studied except those of patient C. At 35 min A1B (10 or 50 mM) significantly reduced the intracellular melphalan concentration in normal bone marrow cells and tumor cells from patients B and C. At 2 mM, 2-aminobicyclo-(2, 2,1)-heptane-2-carboxylic acid (BCH), a specific substrate of the L system of amino acid transport, reduced the cell-to-medium ratio to 70% of control at 3 and 35 min in human bone marrow cells. In tumor cells from patients A, B, D, and F, 2 mM BCH had no significant effect on melphalan uptake at 3 min; it slightly decreased uptake in tumor cells from patient C. At 35 min, 2 mM BCH significantly reduced melphalan transport in tumor cells from patients C and F only. The lack of a BCH-suppressible component to melphalan uptake into human tumor cells freshly obtained from previously untreated patients contrasts with the presence of this component in murine L1210 leukemia cells, murine P388 leukemia cells, and human tumor cell lines. This suggests that minor differences in melphalan transport may exist amongst species and also between human tumor cells which are freshly obtained and cell lines maintained in culture.

Effect of administration of sodium cyanate and melphalan on the lifespan of P388 tumor-bearing CD2F1 mice.

Sodium cyanate (NaOCN) at a dose of 250 mg/kg was shown to decrease protein synthesis in P388 leukemia tumor cells to approximately 52% of control values at 2 h and 32% at 5 h after NaOCN administration, without a corresponding decrease in various normal tissues of the tumor-bearing CD2Fl mice. CD2Fl mice that had received P388 tumor cells IP 1 day prior to drug administration underwent various schedules of treatment with NaOCN and melphalan (MLN). NaOCN (200 mg/kg or 250 mg/kg) administered IP has no significant antitumor activity (increased mean lifespan [ILS] less than 20%). The simultaneous IP administration of NaOCN (250 mg/kg) plus MLN (15 mg/kg) resulted in a significantly greater antitumor activity (approximately 265% of control, with 21 of 30 animals being long-term survivors) than MLN (15 mg/kg) alone (approximately 156% of control, with 11 of 30 animals being long-term survivors). This synergism was not observed when MLN was administered 4 h after NaOCN administration. The synergistic activity of MLN with NaOCN does not appear to be secondary to alterations in the absorption from the peritoneal cavity into the systemic circulation as determined by 3H2O. NaOCN does not increase the intracellular concentration of [chloroethyl-14C]MLN into P388 cells. The mechanism of the synergistic antitumor activity of simultaneous IP administration of NaOCN and MLN is unknown.

Evaluation of the response to xenon-133 radiations by thermoluminescent dosimeters used during the accident at Three Mile Island.

An evaluation is presented of the accuracy and sensitivity of three types of TLD's used during the accident at the Three Mile Island Nuclear Station. This evaluation indicated that, due to the method of calibration, all the dosimeters over-responded to 133Xe radiations. The response ranged from slightly above unity to almost two. Exposures of the TLD's were of two types, namely, the characteristic X-rays either were or were not filtered from the beam. The angular sensitivity of the dosimeters is also reported.