Modeling and Simulation Approaches for Cardiovascular Function and Their Role in Safety Assessment.

Systems pharmacology modeling and pharmacokinetic-pharmacodynamic (PK/PD) analysis of drug-induced effects on cardiovascular (CV) function plays a crucial role in understanding the safety risk of new drugs. The aim of this review is to outline the current modeling and simulation (M&S) approaches to describe and translate drug-induced CV effects, with an emphasis on how this impacts drug safety assessment. Current limitations are highlighted and recommendations are made for future effort in this vital area of drug research.

Describing the effectiveness of immunosuppression drugs and apheresis in the treatment of transplant patients.

When any foreign object is found in the human body antibodies are generated that mark it for removal by the immune system. In most cases these are natural and healthy responses; however, when considering organ transplants the immune response to the implanted organ must be kept to a minimum to avoid host rejection. To reduce the host's immune response to the implant, clinicians are able to manipulate the antibody dynamics through drug therapy, to minimise the antibody synthesis (immunosuppression), and by the removal of antibodies directly from the patients' blood, a process known as apheresis. In this paper models are presented that describe the in vivo kinetics of three immune complexes which are routinely measured pre- and post-operatively in implant patients, namely IgA, IgG and IgM. These models are then used to analyse the effective clearance rates of different apheresis methods (plasmapheresis, plasma absorption or plasma exchange) and to quantify the impact immune-suppression drugs have on the underlying antibody synthesis. It is hoped that the simplicity of the mathematical models, and associated implementation, will allow the translation of knowledge gained of the process dynamics to positively impact future patient diagnosis and treatment.

Charge transfer and ionisation by intermediate-energy heavy ions.

The use of heavy ion beams for microbeam studies of mammalian cell response leads to a need to better understand interaction cross sections for collisions of heavy ions with tissue constituents. For ion energies of a few MeV u(-1) or less, ions capture electrons from the media in which they travel and undergo subsequent interactions as partially 'dressed' ions. For example, 16 MeV fluorine ions have an equilibrium charge of 7(+), 32 MeV sulphur ions have an equilibrium charge of approximately 11(+), and as the ion energies decrease the equilibrium charge decreases dramatically. Data for interactions of partially dressed ions are extremely rare, making it difficult to estimate microscopic patterns of energy deposition leading to damage to cellular components. Such estimates, normally obtained by Monte Carlo track structure simulations, require a comprehensive database of differential and total ionisation cross sections as well as charge transfer cross sections. To provide information for track simulation, measurement of total ionisation cross sections have been initiated at East Carolina University using the recoil ion time-of-flight method that also yields cross sections for multiple ionisation processes and charge transfer cross sections; multiple ionisation is prevalent for heavy ion interactions. In addition, measurements of differential ionisation cross sections needed for Monte Carlo simulation of detailed event-by-event particle tracks are under way. Differential, total and multiple ionisation cross sections and electron capture and loss cross sections measured for C(+) ions with energies of 100 and 200 keV u(-1) are described.

Dermal nickel exposure associated with coin handling and in various occupational settings: assessment using a newly developed finger immersion method.

BACKGROUND: The role of nickel in causing hand dermatitis in some occupations has been difficult to assess due to problems with reliable measurement of the exposure to nickel in the workplace and lack of a definitive threshold for nickel allergic contact dermatitis. It is not uncommon to find nickel allergy on patch testing but it is difficult to determine whether this is of relevance to occupational nickel exposure or simply a reflection of past exposure to nickel-plated jewellery or other nonoccupational nickel exposure. OBJECTIVES: To devise a simple and reproducible method to quantify the amount of nickel on the skin and to apply the technique to measure dermal nickel exposure in various occupational settings. METHODS: A rapid and simple sampling procedure was developed for determination of nickel on the skin of workers potentially exposed to nickel by exposing individuals to nickel-releasing coins and measuring exposure by immersing the exposed thumbs and index fingers directly into graduated sample tubes containing ultrapure water and aqueous nickel extracts. The solutions were analysed by inductively coupled plasma-optical emission spectrometry after stabilization with nitric acid. The method shows advantages over alternatives such as wipe testing and tape stripping in terms of extraction efficiency, speed and ease of operation in the field. A pilot survey of dermal nickel exposure for workers in several occupational settings was conducted. RESULTS: The study suggested that a 'normal' level of nickel on the skin is <10 ng cm(-2). Coin handling induced an appreciable increase in the amount of nickel on the skin within 2 min. Experiments indicated a linear relationship between coin handling (exposure time) and measured dermal nickel levels following standardized coin handling. A pilot survey, conducted among cashiers, shop assistants, bar staff, hairdressers and workers in the nickel industry revealed dermal nickel concentrations ranging from <0.9 to 7160 ng cm(-2). The levels of nickel on the skin of cashiers, shop assistants, bar staff and hairdressers were below the threshold level for water-soluble ionic nickel for occluded exposure at which 10% of nickel-allergic subjects react (0.01% or 100 parts per million, equivalent to 530 ng cm(-2)) and the five-times higher threshold for unoccluded exposure (500 parts per million). The levels in some nickel platers and nickel refinery workers approached or exceeded these levels. However, few cases of nickel dermatitis are observed in plating and refinery facilities, perhaps due to immune tolerance, self-selection or, for refinery workers, exposure to water-insoluble rather than water-soluble nickel compounds. The elicitation threshold for water-soluble nickel compounds cannot be compared directly with dermal exposure to water-insoluble nickel compounds as the latter release a significantly lesser amount of nickel ions. CONCLUSIONS: We describe a reproducible, simple and rapid procedure for the assessment of nickel levels in occupationally exposed individuals.

Managing the cost of cardiovascular prevention in primary care.

Prescribing costs for the prevention of cardiovascular disease are rising nationally, particularly in relation to implementation of the National Service Framework for coronary heart disease. Prescribing effective treatment that is going to benefit the patient's overall management--evidence based medicine--is the key to funding drugs for cardiovascular prevention. It is clear that there is a lot of waste within the system. If the current waste in prescribing can be reduced, it should be possible to fund new developments, not only in cardiovascular disease but also in other therapeutic areas.

MR imaging in the assessment of residual tumour following inadequate primary excision of soft tissue sarcomas.

The purpose of this retrospective study was twofold: firstly, to assess the ability of MR imaging in confirming/excluding the presence of residual tumour following inadequate primary excision of soft tissue sarcomas; and secondly, to assess the accuracy of the original radiologists report as compared with a retrospective review of the scan hard copy in confirming/excluding. A total of 111 cases were identified that fulfilled the inclusion criteria of inadequate primary surgery followed by a MR scan and subsequent wide re-excision of the surgical field. The gold standard for the assessment of the MR imaging studies was histological examination of the re-excision specimens. Histological examination revealed residual tumour in 63 (56.7%) cases. In 48 cases the residual tumour was classified macroscopic (maximum diameter >10 mm) and 15 cases microscopic (maximum diameter

Should preterm infants born after 29 weeks' gestation be screened for intraventricular haemorrhage?

OBJECTIVES: To determine whether the current incidence of intraventricular haemorrhage (IVH) of grade 2 or more is high enough in preterm infants born after 29 weeks gestation to justify the cost of screening with ultrasound and to explore clinical indicators for risk of IVH in the more mature preterm infant. METHODS: This cohort study examined the incidence and severity of IVH in 800 preterm infants born between January 1992 and August 1996, of whom 436 were born after 29 weeks. Demographic and clinical details were collected from a prospectively maintained database. The Medicare schedule charge rate for cerebral ultrasound was used to calculate costs. RESULTS: 1.1% of preterm babies born after 29 weeks gestation who had routine ultrasound scans had an IVH of grade 2 or 3, no infant had a grade 4 IVH. Two infants had a grade 3 IVH, both of which were symptomatic. IVH was poorly predicted by other clinical criteria. Using the Medicare schedule to estimate costs, detecting the five grade 2 or 3 IVH cost A$42,000. CONCLUSIONS: The incidence of grade 2-4 IVH is low in infants born after 29 weeks gestation. Screening of this population is expensive and probably not justified. It may be most appropriate to scan these infants only if their condition raises concern.

On the design and assessment of a 2.45 GHz radio telecommand system for remote patient monitoring.

This paper discusses the design and operational assessment of a minimum-power, 2.45 GHz portable pulse receiver and associated base transmitter comprising the interrogation link in a duplex, cross-band RF transponder designed for short-range, remote patient monitoring. A tangential receiver sensitivity of - 53 dBm was achieved using a 50 ohms microstrip stub-matched zero-bias diode detector and a CMOS baseband amplifier consuming 20 microA from + 3 V. The base transmitter generated an on-off keyed peak output of 0.5 W into 50 ohms. Both linear and right-hand circularly-polarised antennas were employed in system evaluations carried out within an operational Coronary Care Unit ward. For transmitting antenna heights of between 0.3 and 2.2 m above floor level. transponder interrogations were 95% reliable within the 82 m2 area of the ward, falling to an average of 46% in the surrounding rooms and corridors. Separating the polarisation modes, using the circular antenna set gave the higher overall reliability.

Contracting through district health authorities.

Contracts are the glue of the new NHS, the vital tool linking the two main structures: health-care commissioning and health-care provision, carried out by GP fund holders and district health authorities (the purchasers) and the NHS trusts and others (the providers) respectively. Like all adhesives, contracts are of great benefit if used carefully, but if applied inappropriately or with an overly heavy hand they have the potential to become an obstructive mess.

Assessment of ductus arteriosus shunt in preterm infants supported by mechanical ventilation: effect of interatrial shunting.

We studied 51 preterm infants (< 1500 gm) with serial color Doppler echocardiography to determine the impact of incompetence of the foramen ovale on the hemodynamic implications of shunting through a patent ductus arteriosus. Doppler and two-dimensional echocardiographic measures included left atrial/aortic root ratio, right (RVSV) and left ventricular stroke volumes (LVSV), and outputs to determine relative ventricular outputs (RVSV/LVSV) and to calculate the pulmonary/systemic flow ratio (Qp/Qs), the diameter of the color flow Doppler mapping of interatrial and ductal shunts, pulsed Doppler pattern, and velocity of those shunts. The dominant direction of shunting at the ductal and atrial levels was left to right. In studies with minimal atrial shunting, there was a weak but significant correlation between RVSV/LVSV (1/(Qp/Qs)) and the left atrial/aortic root ratio, LVSV, and output index, but there was a close correlation with the diameter of the color flow Doppler of the shunt within the ductus (r = -0.8). With this diameter used as a constant, increasing color flow Doppler diameter of atrial shunt significantly reduced LVSV and increased RVSV/LVSV (1/(Qp/QS)). In infants with large ductal and atrial shunts, right ventricular output was often greater than left ventricular output. We conclude that atrial shunting has a significant impact on the hemodynamic implications of ductal shunting in many very preterm infants. This renders use of the relative ventricular outputs to calculate Qp/Qs inaccurate as a single measure of shunt size in patent ductus arteriosus. If the shunt is predominantly left to right, the most accurate assessment is provided by color flow ductal shunt diameter.

Assessment of left ventricular regional wall motion with blood pool tomography: comparison of 11CO PET with 99Tcm SPECT.

Left ventricular contraction is routinely assessed by radionuclide ventriculography. Although a planar image is conventionally used, tomography has been to improve the detection of wall motion abnormalities. A blood pool image is often used in positron emission tomography on which to superimpose metabolic tracers. Can this image also be used to assess left ventricular contraction? Nine healthy controls, mean (S.D.) age 55 (5) years, and 12 patients, mean (S.D.) age 61 (8) years, with normal, proven or suspected left ventricular damage underwent blood pool tomography with 11CO positron emission tomography (PET) and 99Tcm single photon emission computed tomography (SPECT). A normal value of ejection fraction and range of phase were defined. The normal left ventricular ejection fraction was > or = 37% for PET and > or = 40% for SPECT. The ejection fractions obtained by the two methods in the patient group were positively correlated (r = 0.89, P < 0.001). Abnormalities of left ventricular contraction were detected in nine patients by PET and 10 patients by SPECT imaging. The discrepancy was in a patient with a previous inferior myocardial infarction. Blood pool imaging with 11CO PET can be used to assess left ventricular ejection fraction and regional wall motion.

Doppler assessment of pulmonary artery pressure during recovery from hyaline membrane disease.

The changes in pulmonary artery pressure during recovery from hyaline membrane disease were studied by serial Doppler echocardiography on 37 preterm infants. Pulmonary artery pressure was assessed noninvasively by its inverse relationship with the ratio of pulmonary artery Doppler time to peak velocity and right ventricular ejection time. The pattern of rise in ratio after the acute phase of hyaline membrane disease divided into three types. In 25 infants the ratio returned to the normal range: in 12 (group 1) at the same time as the fractional inspired oxygen fell below 0.5 and in 13 (group 2) after a delay of at least 24 hours. In 12 infants (group 3) the ratio remained below the normal range during their hospital stay, suggesting pulmonary artery pressure remained high. Infants in group 3 were of significantly lower gestation and required oxygen treatment for significantly longer than infants in groups 1 and 2. Persistently raised pulmonary pressures in group 3 may reflect lung damage either directly affecting pulmonary vasculature or exerting a secondary effect on pulmonary vascular resistance through hypoxaemia.