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PubMed2000

Improved orthopaedic bone cement formulations based on rubber toughening.

Poly(methylmethacrylate) (PMMA) bone cements have been used for the fixation of hip and knee implants since the early 1960s. Aseptic loosening, related to fracture of the PMMA, continues to be the primary mode of failure for these prostheses. Failed prostheses must be replaced causing additional expense and patient trauma. Furthermore, the average lifetime of the revised prosthesis is significantly lower than that of a primary prosthesis. Recent work by Moseley and co-workers led to the development of a promising new rubber toughened cement. It is comprised of a matrix of the traditional PMMA with dispersed rubber particles to modify mechanical properties and, in particular, improve fracture toughness. The fracture toughness of the experimental material was 167% greater than the toughness of a nontoughened control; however, the elastic modulus and compressive strength were reduced. The reductions in properties should not pose a clinical problem based on results of the implant model reported by Moseley. More serious concerns were mixing and delivery problems and high residual monomer concentrations. The formulation and chemical/mechanical characterization of new toughened acrylic formulations that have residual monomer levels equivalent to Simplex and better mixing properties are reported.

Bone Cements↗
PubMed2003

Unlicensed and off label drug use in acute lymphoblastic leukaemia and other malignancies in children.

BACKGROUND: The need to use unlicensed and off label drugs in children due to the lack of suitable, licensed formulations with appropriate prescribing information creates many problems on an everyday basis for healthcare professionals, carers and children. PATIENTS AND METHODS: This prospective study was designed to examine the incidence and nature of unlicensed and off label prescribing, in paediatric oncology patients with acute lymphoblastic leukaemia and other malignancies. Inpatient and outpatient prescriptions were analysed for a 4-week period. RESULTS: All patients received at least one unlicensed or off label drug. Fifty-five per cent of prescriptions were licensed, 19% were unlicensed and 26% were licensed drugs used in an off label manner. Unlicensed preparations were used in 40% of prescriptions for cytotoxic agents, due to a lack of commercially available formulations suitable for the paediatric patient. These drugs included mercaptopurine and methotrexate which have been used in the treatment of paediatric leukaemia for many years, their efficacy having been demonstrated by on-going Medical Research Council trials. CONCLUSIONS: It is disappointing that drugs, which are the mainstay of therapy for paediatric leukaemia and other malignancies, are unavailable in appropriate licensed formulations to facilitate their administration to children. This needs to be urgently addressed.

Adolescent↗
PubMed2000

A cell cycle model for somitogenesis: mathematical formulation and numerical simulation.

After many years of research, the mechanisms that generate a periodic pattern of repeated elements (somites) along the length of the embryonic body axis is still one of the major unresolved problems in developmental biology. Here we present a mathematical formulation of the cell cycle model for somitogenesis proposed in Development105 (1989), 119-130. Somite precursor cells in the node are asynchronous, and therefore, as a population, generate continuously pre-somite cells which enter the segmental plate. The model makes the hypothesis that there exists a time window within the cell cycle, making up one-seventh of the cycle, which gates the pre-somite cells so that they make somites discretely, seven per cycle. We show that the model can indeed account for the spatiotemporal patterning of somite formation during normal development as well as the periodic abnormalities produced by heat shock treatment. We also relate the model to recent molecular data on the process of somite formation.

Animals↗
PubMed2001

Chemical image fusion. The synergy of FT-NIR and Raman mapping microscopy to enable a more complete visualization of pharmaceutical formulations.

The pharmaceutical industry uses successfully both FT-NIR and Raman microscopy to produce chemical images of solid dosage forms, typically in troubleshooting roles. However, due to the chemical composition of the formulations, it is not always possible to describe the entire chemical formulation by using a single spectroscopic method. As Raman and NIR spectroscopies are complementary in nature, their combined usage offers the opportunity to describe heterogeneous mixtures in more detail. A novel sample referencing approach has been developed that allows data to be acquired from exactly the same area of the sample using both Raman and FT-NIR microscopies. The optimum images for the components are then overlaid, which gives rise to a combined chemical image that visually describes the entire formulation. We have named this approach chemical image fusion (CIF). CIF has been applied to two examples. The first shows how a simple formulation was used to validate the CIF approach. In the second, CIF allowed an entire formulation to be visualized and the cause of tabletting problems determined. CIF provides increased confidence in the results generated by each individual technique and offers a more powerful method for the evaluation of pharmaceutical formulations.

Pharmaceutical Preparations↗
PubMedDate not supplied

Prevention and health policy: a view from the social sciences.

A theoretical framework is outlined which identifies four major problem areas which must be dealt with in the formulation, implementation, and evaluation of social policy. Certain issues relevant to policy concerning health promotion and disease prevention are discussed within this framework. The first problem area, adaptation, is concerned primarily with resources; the second area, goal attainment, deals with organizational issues; the third, integration, is concerned with motivations; the fourth, pattern maintenance, concentrates on questions of values. Policymaking is seen as an attempt by governing bodies to resolve problems in all these areas, and the success of any policy may be judged by the extent to which major issues in each area are dealt with equitably and reasonably.

Canada↗
PubMed1990

Marketing alternatives for hospitals to the nursing crisis.

The current nursing shortage problem as defined in this article, is the result of a supply and demand imbalance. The demand for nurses is growing at a faster rate than the supply. If strategies are not implemented to correct this imbalance the demand for nurses will continue to surpass the supply, negatively affecting access to and delivery of quality patient care. Factors contributing to the increased demand for nurses and the dwindling supply must be examined if solutions to the problem are to be found and implemented. Factors contributing to the growing demand for nurses include the decreasing use of ancillary personnel by hospitals in an effort to tighten their budgets; the impact of Medicare's prospective payment system on hospital lengths of stay; the increase in patient acuity with advances in medical technology; and alternative health care opportunities pulling nurses away from the hospital setting. The supply of RNs is shrinking in relation to demand because of low retention rates; declining nursing school enrollment; non-competitive wages; poor working conditions; alternative career opportunities for women; and the lack of power and support within the nursing profession. An active marketing approach that relies on this assessment of contributing factors has been formulated in an attempt to resolve the problem and meet the increasing demand. Recommendations have been made and ranked in the order of their priority and pros and cons established for each. The strategies developed have been divided into four basic marketing categories of product, price, place, and promotion. If the problem is to be resolved these strategies must be marketed to hospitals, their administrators, nurses, other allied health professionals, third party payors, educators, and the general public. The nursing profession itself must find the unity and strength within its own group of professionals to build political and economic powers to enhance their product. Nursing is at a crossroad. Much depends on how we cope with the current shortage and its related issues. Nurses have the opportunity to shape their future. Hopefully, with proactive strategies, the profession will transform from a passive role to an active, vital force of the health care environment. The authors believe that through our marketing approaches this can be accomplished.

Employee Incentive Plans↗
PubMed2005

Biodegradable microspheres for parenteral delivery.

Nowadays, emphasis is being laid to development of controlled release dosage forms. Interest in this technology has increased steadily over the past few years. Although oral administration of drugs is a widely accepted route of drug delivery, bioavailability of drug often varies as a result of gastrointestinal absorption, degradation by first-pass effect, and hostile environment of gastrointestinal tract. Transdermal administration for percutaneous absorption of drug is limited by the impermeable nature of the stratum corneum. Ocular and nasal delivery is also unfavorable because of degradation by enzymes present in eye tissues and nasal mucosa. Hence, the parenteral route is the most viable approach in such cases. Of the various ways of achieving long-term parenteral drug delivery, biodegradable microspheres are one of the better means of controlling the release of drug over a long time. Because of the lipidic nature of liposomes, problems such as limited physical stability and difficulty of freeze-drying are encountered. Similarly, for emulsions, stability on long-term basis and in suspensions, rheological changes during filling, injecting, and storage poses limitation. Also, in all these systems, the release rate cannot be tailored to the needs of the patient. Parenteral controlled-release formulations based on biodegradable microspheres can overcome these problems and can control the release of drug over a predetermined time span, usually in the order of days to weeks to months. Various FDA-approved controlled-release parenteral formulations based on these biodegradable microspheres are available on the market, including Lupron Depot Nutropin Depot and Zoladex. This review covers various molecules encapsulated in biodegradable microspheres for parenteral delivery.

Biodegradation, Environmental↗
PubMedDate not supplied

Integer programming approaches to haplotype inference by pure parsimony.

In 2003, Gusfield introduced the Haplotype Inference by Pure Parsimony (HIPP) problem and presented an integer program (IP) that quickly solved many simulated instances of the problem. Although it solved well on small instances, Gusfield's IP can be of exponential size in the worst case. Several authors have presented polynomial-sized IPs for the problem. In this paper, we further the work on IP approaches to HIPP. We extend the existing polynomial-sized IPs by introducing several classes of valid cuts for the IP. We also present a new polynomial-sized IP formulation that is a hybrid between two existing IP formulations and inherits many of the strengths of both. Many problems that are too complex for the exponential-sized formulations can still be solved in our new formulation in a reasonable amount of time. We provide a detailed empirical comparison of these IP formulations on both simulated and real genotype sequences. Our formulation can also be extended in a variety of ways to allow errors in the input or model the structure of the population under consideration.

Algorithms↗
PubMedDate not supplied

Calculation of the radiological depth.

The concept of the radiological depth is central to all algorithms which calculate radiation dose in a heterogeneous medium. For a discrete heterogeneous medium, consisting of regions of inhomogeneity, the radiological depth is usually presented as the sum over segments of the product of the segment length and the inhomogeneity density of the region corresponding to the segment. This paper illustrates that the usual formulation is inefficient because it requires the solution of the topological problem of which region corresponds to each segment. For simple heterogeneity problems involving just three regions of inhomogeneity, it is found that the topological problem constitutes at least 85% of the time required to calculate the radiological depth. It is shown in this paper that formulating the radiological depth as a sum over regions rather than as a sum over segments allows one to avoid this topological problem entirely.

Humans↗
PubMed1999

The formulation and stability of erythromycin-benzoyl peroxide in a topical gel.

The combination of benzoyl peroxide and erythromycin is used for the local treatment of acne and available as a commercial preparation. Because of the stability problems of erythromycin an extempore preparation is required. The influence of storage temperature and non active ingredients on the stability of benzoyl peroxide and erythromycin in topical gel preparations for extempore compounding is described. A microbiological and an HPLC method were used to determine the erythromycin and the benzoyl peroxide concentrations, respectively. For a formulation compounded with hydroxyethylcellulose no stability problems were observed. For the formulation containing Carbopol 940, the levels of erythromycin varied over a wide range due to precipitation and aggregation of the drug during compounding.

Acrylic Resins↗
PubMed1986

A new visible light-cured resin system applied to removable prosthodontics.

Preliminary studies of VLC resins have produced promising results; however, additional research is necessary to completely define qualities of this material. Biologic testing of VLC (Triad) resins indicated that they are nontoxic and biocompatible. They have a wide range of uses in all subdisciplines of prosthodontics. Advantages such as accuracy of fit, superior strength, complete polymerization without residual compounds, ease of fabrication and manipulation, patient acceptance, ability to bond with other denture base resins, and low bacterial adherence make this material an important addition to the choices available to dentists. As with many new materials, there are initial problems or hurdles that must be overcome before there is widespread use. Initial formulations of material had insufficient flexural strength and tended to fracture when flexed over uncut sites on a stone cast. This problem has been reduced by Dentsply International, Inc. with the introduction of the new improved formulation. The original VLC bonding agent did not provide sufficient bond strength with acrylic resin denture base materials, but this also has been improved with development of a new VLC bonding agent. The problem of microporosity and small voids produced when adapting VLC resin sheets against a stone cast may be overcome with pressure or vacuum adaptation techniques. A promising application of VLC resin material is in direct intraoral procedures such as relining of dentures. Physical and chemical properties are superior to autopolymerizing methacrylates. Preliminary studies have shown successful patient acceptance to this clinical procedure. It is of particular advantage to the patient not to be without dentures for the period of at least 1 day necessary for a laboratory-processed relining. Immediate light-curing is time-saving and convenient compared to indirect (heat-cured) relining. Until recently, most direct intraoral applications of autopolymerizing acrylic resin reliner material were considered temporary or expedient to a permanent procedure. The patient and dentist may now have another treatment choice. The release of residual methyl methacrylate, among other shortcomings of AP materials, is not a concern when using the VLC reliner material. Some patients may notice a nonobjectionable taste to the uncured material; however, they can be reassured that the taste will be only temporary until the material is completely polymerized in the curing unit. The flow of the material can be regulated by selection of appropriate viscosity, warming and cooling measures, and partial intraoral polymerization with hand-held curing lights.(ABSTRACT TRUNCATED AT 400 WORDS)

Acrylic Resins↗
PubMed1998

Development of metoprolol tartrate extended-release matrix tablet formulations for regulatory policy consideration.

This research study was designed to develop model extended-release (ER) matrix tablet formulations for metoprolol tartrate (100 mg) sufficiently sensitive to manufacturing variable and to serve as the scientific basis for regulatory policy development on scale-up and post approval changes for modified-release dosage forms (SUPAC-MR). Several grades and levels of hydroxypropyl methylcellulose (Methocel K4M, K15M, K100M and K100LV), fillers and binders and studied. Three granulation processes were evaluated; direct compression, fluid-bed or high-shear granulation. Lubrication was performed in a V-blender and tablets were compressed on an instrumented rotary tablet press. Direct compression formulations exhibited poor flow, picking and sticking problems during tableting. High-shear granulation resulted in the formation of hard granules that were difficult to mill but yielded good tablets. Fluid-bed granulations were made using various binders and appeared to be satisfactory in terms of flow and tableting performance. In vitro drug release testing was performed in pH 6.8 phosphate buffer using USP apparatus 2 (paddle) at 50 rpm. At a fixed polymer level, drug release from the higher viscosity grades (K100M) was slower as compared to the lower viscosity grades (K100LV). In addition, release from K100LV was found to be more sensitive to polymer level changes. Increased in polymer level from 10 to 40% and/or filler change from lactose to dicalcium phosphate resulted in about 25-30% decrease in the amount of metoprolol release after 12 h. The results of this study led to the choice of Methocel K100LV as the hydrophilic matrix polymer and fluid-bed granulation as the process of choice for further evaluation of critical and non-critical formulation and processing variables.

Adrenergic beta-Antagonists↗
PubMed1999

Conditions for equivalency of countercurrent vessel heat transfer formulations.

Previous models of countercurrent blood vessel heat transfer have used one of two, different, equally valid but previously unreconciled formulations, based either on: (1) the difference between the arterial and venous vessels' average wall temperatures, or (2) the difference between those vessels' blood bulk fluid temperatures. This paper shows that these two formulations are only equivalent when the four, previously undefined, "convective heat transfer coefficients" that are used in the bulk temperature difference formulation (two coefficients each for the artery and vein) have very specific, problem-dependent relationships to the standard convective heat transfer coefficients. (The average wall temperature formulation uses those standard coefficients correctly.) The correct values of these bulk temperature difference formulation "convective heat transfer coefficients" are shown to be either: (1) specific functions of (a) the tissue conduction resistances, (b) the standard convective heat transfer coefficients, and (c) the independently specified bulk arterial, bulk venous and tissue temperatures, or (2) arbitrary, user defined values. Thus, they are generally not equivalent to the standard convective heat transfer coefficients that are regularly used, and must change values depending on the blood and tissue temperatures. This dependence can significantly limit the convenience and usefulness of the bulk temperature difference formulations.

Arteries↗
PubMed2005

A voting-based computational framework for visual motion analysis and interpretation.

Most approaches for motion analysis and interpretation rely on restrictive parametric models and involve iterative methods which depend heavily on initial conditions and are subject to instability. Further difficulties are encountered in image regions where motion is not smooth-typically around motion boundaries. This work addresses the problem of visual motion analysis and interpretation by formulating it as an inference of motion layers from a noisy and possibly sparse point set in a 4D space. The core of the method is based on a layered 4D representation of data and a voting scheme for affinity propagation. The inherent problem caused by the ambiguity of 2D to 3D interpretation is usually handled by adding additional constraints, such as rigidity. However, enforcing such a global constraint has been problematic in the combined presence of noise and multiple independent motions. By decoupling the processes of matching, outlier rejection, segmentation, and interpretation, we extract accurate motion layers based on the smoothness of image motion, then locally enforce rigidity for each layer in order to infer its 3D structure and motion. The proposed framework is noniterative and consistently handles both smooth moving regions and motion discontinuities without using any prior knowledge of the motion model.

Algorithms↗
PubMed2006

Pairwise alignment of protein interaction networks.

With an ever-increasing amount of available data on protein-protein interaction (PPI) networks and research revealing that these networks evolve at a modular level, discovery of conserved patterns in these networks becomes an important problem. Although available data on protein-protein interactions is currently limited, recently developed algorithms have been shown to convey novel biological insights through employment of elegant mathematical models. The main challenge in aligning PPI networks is to define a graph theoretical measure of similarity between graph structures that captures underlying biological phenomena accurately. In this respect, modeling of conservation and divergence of interactions, as well as the interpretation of resulting alignments, are important design parameters. In this paper, we develop a framework for comprehensive alignment of PPI networks, which is inspired by duplication/divergence models that focus on understanding the evolution of protein interactions. We propose a mathematical model that extends the concepts of match, mismatch, and gap in sequence alignment to that of match, mismatch, and duplication in network alignment and evaluates similarity between graph structures through a scoring function that accounts for evolutionary events. By relying on evolutionary models, the proposed framework facilitates interpretation of resulting alignments in terms of not only conservation but also divergence of modularity in PPI networks. Furthermore, as in the case of sequence alignment, our model allows flexibility in adjusting parameters to quantify underlying evolutionary relationships. Based on the proposed model, we formulate PPI network alignment as an optimization problem and present fast algorithms to solve this problem. Detailed experimental results from an implementation of the proposed framework show that our algorithm is able to discover conserved interaction patterns very effectively, in terms of both accuracies and computational cost.

Algorithms↗
PubMed2005

Statistical methods for the analysis of two-arm non-inferiority trials with binary outcomes.

The aim of this contribution is to give an overview of approaches to testing for non-inferiority of one out of two binomial distributions as compared to the other in settings involving independent samples (the paired samples case is not considered here but the major conclusions and recommendations can be shown to hold for both sampling schemes). In principle, there is an infinite number of different ways of defining (one-sided) equivalence in any multiparameter setting. In the binomial two-sample problem, the following three choices of a measure of dissimilarity between the underlying distributions are of major importance for real applications: the odds ratio (OR), the relative risk (RR), and the difference (DEL) of both binomial parameters. It is shown that for all three possibilities of formulating the hypotheses of a non-inferiority problem concerning two binomial proportions, reasonable testing procedures providing exact control over the type-I error risk are available. As a particularly useful and versatile way of handling mathematically nonnatural parametrizations like RR and DELTA, the approach through Bayesian posterior probabilities of hypotheses with respect to some non-informative reference prior has much to recommend it. In order to ensure that the corresponding testing procedure be valid in the classical, i.e. frequentist sense, it suffices to use straightforward computational techniques yielding suitably corrected nominal significance levels. In view of the availability of testing procedures with satisfactory properties for all parametrizations of main practical interest, the discussion of the pros and cons of these methods has to focus on the question of which of the underlying measures of dissimilarity should be preferred on grounds of logic and intuition. It is argued that the OR clearly merits to be given preference also with regard to this latter kind of criteria since the non-inferiority hypotheses defined in terms of the other parametric functions are bounded by lines which cross the boundaries of the parameter space. From this fact, we conclude that the exact Fisher type test for one-sided equivalence provides the most reasonable approach to the confirmatory analysis of non-inferiority trials involving two independent samples of binary data. The marked conservatism of the nonrandomized version of this test can largely be removed by using a suitably increased nominal significance level (depending, in addition to the target level, on the sample sizes and the equivalence margin), or by replacing it with a Bayesian test for non-inferiority with respect to the odds ratio.

Biopharmaceutics↗
PubMed2000

Continuous topical administration of a petrolatum formulation by a novel disposable diaper. 1. Effect on skin surface microtopography.

BACKGROUND: Cutaneous problems are commonly associated with the use of diapers. Aiming to help reduce them, we have explored the use of the inner layer of diapers as a means to deliver to the skin dermatological formulations intended to help protect it from overhydration and irritation. OBJECTIVE: To determine the feasibility of using the inner layer of the diaper as a vehicle for topical delivery of a petrolatum-based formulation and to determine its impact on skin surface microtopography. METHODS: Two independent, blinded, randomized clinical trials were conducted, on children 16-24 months of age. All comparisons were done versus a control diaper, identical to the test product except for the absence of the petrolatum formulation. The studies determined the effects of the novel diaper on transfer of formulation to the skin and skin surface microtopography. RESULTS: During normal diaper use, formulation transfer from the diaper to the skin occurred in a cumulative, time-dependent manner and use of the formulation-treated diaper was associated with significant reductions in skin surface roughness compared to the control diaper. CONCLUSIONS: The results demonstrated the feasibility and skin surface benefits associated with continuous topical administration of a petrolatum-based formulation by this novel diaper. This unprecedented dosimetric approach offers new avenues to reduce further the dermatological problems commonly associated with diaper use.

Administration, Topical↗
PubMed1987

Existence and uniqueness of solutions to the multispecies virtual population analysis equations.

This paper deals with the question of existence and uniqueness of solutions to multispecies virtual population analysis equations for predator-prey systems. By formulating the question as a fixed-point problem for a certain function F, it is shown that at least one solution always exists. By using Brouwer degree, sufficient conditions for uniqueness are derived which are more likely to be satisfied than those based on the requirement that F be a contraction. Some of these are formulated as inequalities which could be verified in the course of solving the equations numerically.

Animals↗