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PubMed2006

Plasmodium falciparum infection and exoerythrocytic development in mice with chimeric human livers.

The exoerythrocytic stage of Plasmodium falciparum has remained a difficult phase of the parasite life-cycle to study. The host and tissue specificity of the parasite requires the experimental infection of humans or non-human primates and subsequent surgical recovery of parasite-infected liver tissue to analyze this stage of the parasites development. This type of study is impossible in humans due to obvious ethical considerations and the cost and complexity in working with primate models has precluded their use for extensive studies of the exoerythrocytic stage. In this study we assessed, for the first time, the use of transgenic, chimeric mice containing functioning human hepatocytes as an alternative for modeling the in vivo interaction of P. falciparum parasites and human hepatocytes. Infection of these mice with P. falciparum sporozoites produced morphologically and antigenically mature liver stage schizonts containing merozoites capable of invading human red blood cells. Additionally, using microdissection, highly enriched P. falciparum liver stage parasites essentially free of hepatocyte contamination, were recovered for molecular studies. Our results establish a stable murine model for P. falciparum that will have a wide utility for assessing the biology of the parasite, potential anti-malarial chemotherapeutic agents and vaccine design.

Animals↗
PubMed2005

Clinical utility of the Food and Drug Administration Electrocardiogram Warehouse: a paradigm for the critical pathway initiative.

Although there are rising public expectations about the prospects for new therapies based on advances in biomedical discoveries, the rate of new product submissions to the Food and Drug Administration (FDA) has not been increasing. Alarmingly, over the past 6 years, there has been a 30% decline in submissions. The reasons for this are multifactorial and include new science not at its full potential, mergers/business arrangements have decreased candidates, chronic disease is harder to study, the failure rate has not improved, and rapidly escalating costs and complexity. Notably, societal investment in research and development to improve the drug approval process has been lacking in contrast to the large investments, both private and public, in basic research and specific product advances. The Critical Path Initiative has been developed by the FDA to combat many of these issues. This initiative is designed to be collaborative between government, academic, industry, and patient groups. The partnership is designed to expand product opportunities by sharing existing knowledge and data, allowing the development of enabling standards, to improve drug development and approval. A central tenant of Critical Path is a focus on the evaluative science of the drug approval process, including both efficacy and safety measures. The FDA Electrocardiogram Warehouse is 1 example where a government resource could be used by a confluence of groups to improve the science surrounding important components of the drug approval process such as cardiac safety evaluation.

Critical Pathways↗
PubMed2006

A general method for bead-enhanced quantitation by flow cytometry.

Flow cytometry provides accurate relative cellular quantitation (percent abundance) of cells from diverse samples, but technical limitations of most flow cytometers preclude accurate absolute quantitation. Several quantitation standards are now commercially available which, when added to samples, permit absolute quantitation of CD4+ T cells. However, these reagents are limited by their cost, technical complexity, requirement for additional software and/or limited applicability. Moreover, few studies have validated the use of such reagents in complex biological samples, especially for quantitation of non-T cells. Here we show that addition to samples of known quantities of polystyrene fluorescence standardization beads permits accurate quantitation of CD4+ T cells from complex cell samples. This procedure, here termed single bead-enhanced cytofluorimetry (SBEC), was equally capable of enumerating eosinophils as well as subcellular fragments of apoptotic cells, moieties with very different optical and fluorescent characteristics. Relative to other proprietary products, SBEC is simple, inexpensive and requires no special software, suggesting that the method is suitable for the routine quantitation of most cells and other particles by flow cytometry.

Adoptive Transfer↗
PubMed2006

The accuracy of ultrasonic indentation in detecting simulated bone displacement: a comparison of three techniques.

PURPOSE: Palpation is used most commonly to assess tissue stiffness despite its well-known deficiencies. As an improvement, a mechanical technique known as ultrasonic indentation has been proposed. The purpose of this study was to compare the accuracy of 3 ultrasonic indentation techniques in quantifying bone displacement in a specially constructed tissue simulator. METHODS: Three ultrasonic indentation techniques were tested for their accuracy: a rigid, laboratory-based method (rigid), a less rigid system actuated by hand (assisted), and a totally free-hand system (handheld). Each indentation technique was applied on a tissue simulator, which consisted of a deformable phantom overlying a displaceable piston to simulate soft tissue overlying bone. Measures of piston (ie, bone) displacement obtained by each indentation technique were compared with a gold standard of piston displacement to determine the accuracy of each technique. Statistical tests were used to determine if differences between experimental and reference measures of piston displacement were significant. RESULTS: When indented, phantom deformation preceded piston displacement because of unequal stiffness between the two. The rigid and assisted indentation techniques showed the best accuracy for measuring simulated bone displacement. Differences in accuracy between the rigid and assisted techniques were insignificant. The accuracy of the handheld technique was significantly less than the rigid and assisted techniques. CONCLUSIONS: The clinical utility of assisted ultrasonic indentation should be explored given its accuracy and the excessive size, cost, and complexity of the rigid technique. The large error magnitude of the handheld technique may exclude it from clinical use now.

Equipment Design↗
PubMed2005

On concomitant gradients in low-field MRI.

Growing interest in magnetic resonance imaging (MRI) at ultra-low magnetic fields (ULF, approximately muT fields) has been motivated by several advantages over its counterparts at higher magnetic fields. These include narrow line widths, the possibility of novel imaging schemes, reduced imaging artifacts from susceptibility variations within a sample, and reduced system cost and complexity. In addition, ULF NMR/MRI with superconducting quantum interference devices is compatible with simultaneous measurements of biomagnetic signals, a capability conventional systems cannot offer. Acquisition of MRI at ULF must, however, account for concomitant gradients that would otherwise result in severe image distortions. In this paper, we introduce the general theoretical framework that describes concomitant gradients, explain why such gradients are more problematic at low field, and present possible approaches to correct for these unavoidable gradients in the context of a non-slice-selective MRI protocol.

Algorithms↗
PubMed2026

Proteomics in environmental pollution research: Advances, challenges, and future directions.

Environmental proteomics has emerged as a powerful approach for elucidating the molecular mechanisms underlying pollutant-induced biological effects. Although this field has developed rapidly, the systematic review of recent proteomics applications in environmental pollution research remains limited. This review explored the emerging roles of toxicoproteomics in biomarker discovery and mechanistic elucidation, as well as ecotoxicoproteomics in ecological risk assessment and bioremediation strategies. Here, we review the field, highlighting recent trends such as the integration of proteomics with genomics, transcriptomics, and metabolomics to provide a comprehensive view of biological responses to environmental stressors. We further discuss the growing application of artificial intelligence in improving proteomics data interpretation and accelerating biomarker discovery. In addition, recent technological advances in environmental proteomics are highlighted, including next-generation tissue microarray proteomics, nanoscale proteomics, single-cell proteomics, and spatial proteomics. Despite its potential, proteomics faces challenges, such as high operational costs, computational complexity in analysis, and technical limitations in low-abundance protein detection. We propose that the convergence of proteomics with artificial intelligence and multi-omics approaches offers promising solutions to these challenges, enhancing the practical application of proteomics in environmental monitoring and risk assessment.

Proteomics↗
PubMed2004

Transcervical carotid stenting with internal carotid artery flow reversal: feasibility and preliminary results.

OBJECTIVE: Transfemoral carotid artery stenting (CAS), with or without distal protection, is associated with risk for cerebral and peripheral embolism and access site complications. To establish cerebral protection before crossing the carotid lesion and to avert transfemoral access complications, the present study was undertaken to evaluate a transcervical approach for CAS with carotid flow reversal for cerebral protection. METHODS: Fifty patients underwent CAS through a transcervical approach. All patients with symptoms had greater than 60% internal carotid artery (ICA) stenosis, and all patients without symptoms had greater than 80% ICA stenosis. Twenty-one patients (42%) had symptomatic disease or ipsilateral stroke, and 8 patients (16%) had contralateral stroke. Four patients (8%) had recurrent stenosis, 7 patients (14%) had contralateral ICA occlusion, and 1 patient (2%) had undergone previous neck radiation. Twenty-seven procedures (54%) were performed with local anesthesia, and 23 (46%) with general anesthesia. Using a cervical cutdown, flow was reversed in the ICA by occluding the common carotid artery and establishing a carotid-jugular vein fistula. Pre-dilation was selective, and 8-mm to 10-mm self-expanding stents were deployed and post-dilated with 5-mm to 6-mm balloons in all cases. RESULTS: The procedure was technically successful in all patients, without significant residual stenoses. No strokes or deaths occurred. There was 1 wound complication (2%). All patients were discharged within 2 days of surgery. Mean flow reversal time was 21.4 minutes (range, 9-50 minutes). Carotid flow reversal was not tolerated in 2 patients (4%). Early in the experience, carotid flow reversal was not possible in 1 patient, and there were 1 major and 3 minor common carotid artery dissections, which resolved after stent placement. One intraoperative transient ischemic attack (2%) occurred in 1 patient in whom carotid flow was not reversed, and 1 patient with a contralateral ICA occlusion had a contralateral transient ischemic attack. At 1 to 12 months of follow-up, all patients remained asymptomatic, and all but 1 stent remained patent. CONCLUSION: Transcervical CAS with carotid flow reversal is feasible and safe. It can be done with the patient under local anesthesia, averts the complications of the transfemoral approach, and eliminates the increased complexity and cost of cerebral protection devices. Transcervical CAS is feasible when the transfemoral route is impossible or contraindicated, and may be the procedure of choice in a subset of patients in whom carotid stenting is indicated.

Aged↗
PubMed2006

Assessment and management of chronic pressure ulcers in the elderly.

Pressure ulcers remain a complex and costly problem to the health care system. As the population ages, a greater number of individuals will be at high risk for developing pressure ulcers. An understanding of the physiologic changes that occur with aging skin is important in preventing and treating chronic wounds. Risk factor assessment and modification, when possible, can help to reduce the development of pressure ulcerations. Although the goal continues to be prevention, once a pressure ulcer does occur, a systematic and comprehensive approach to assessment and treatment is necessary to reduce healing times.

Aged↗
PubMed2003

Why is big Pharma getting out of antibacterial drug discovery?

Since the advent of the antibiotic era in the late 1940s drug discovery and development has evolved into an expensive, time consuming, cumbersome and bureaucratic process involving multiple interest groups such as pharmaceutical manufacturers, governmental regulatory authorities, patent officers, academic and clinical researchers and trial lawyers. It would seem that the least involved among the interest groups are the consumers of health care themselves. Politicians and the public alike complain loudly about drug prices although fewer and fewer new therapies are being developed. The cost and complexities of drug discovery and development have shifted the investment equation away from the development of drugs targeting short course therapies for acute diseases and towards long-term treatment of chronic conditions. Coupled with the failure of large investments into target-based approaches to produce novel antibacterial agents, companies large and small have exited from this field despite a growing clinical need.

Anti-Bacterial Agents↗
PubMed2007

Clinical development of antiepileptic drugs in adults.

Over the last two decades, ten so-called newer antiepileptic drugs (AEDs) have been approved around the world, the majority of which have found and maintained a place in the seizure-fighting armamentarium for the whole spectrum of epilepsies and epileptic syndromes; some of these drugs have features that are improved compared with the older drugs. Within that same time period, the process of clinical development of AEDs has also undergone changes and has become much more complex and costly. Efforts are underway to shift decision-making about the clinical viability of AED candidates to earlier development stages, using the concept of translational medicine. However, thus far all of the newer AEDs have undergone a standard development as an adjunct in the control of adult partial seizures; in some cases, development has been expanded to other seizure types and pediatric syndromes. Currently, the path to global approval for use in monotherapy is under review and is often debated with regulatory authorities. Clinical treatment guidelines consider randomized, blinded, well controlled studies as the premier level of evidence-based medicine; these studies originate mostly in confirmatory phases of the development program. However, with the rigid designs and criteria in regulatory driven trials, effectiveness in the clinical practice setting may not be sufficiently predicted by these studies, leading to frustrations from individual practitioners. Finally, additional safety issues regularly occur only after the postlaunch exposure to a broader population making necessary a continuing, and thorough, pharmacovigilance after the AED has come to market.

Adult↗
PubMed2007

The fatty acid profiles in a drop of blood from a fingertip correlate with physiological, dietary and lifestyle parameters in volunteers.

Limited data are available on the fatty acid (FA) composition of circulating lipids and the associations with diet, physiological and pathological conditions, due to the complexity and costs of the analytical process. The aim of our study was to evaluate the FA composition in 108 healthy subjects and to correlate the data with gender, pregnancy, dietary habits, lifestyle, and short-term controlled intake of n-3 FA, using an innovative analytical approach for the collection and processing of blood samples. Ten subjects were also supplemented with n-3 polyunsaturated FA as smoked salmon or capsules for 3 weeks. The resulting blood FA composition was affected by gender, pregnancy, diet and smoking. The data indicate that this new analytical methodology is suitable for assessing associations between circulating FA and various parameters in large population groups, and is applicable to epidemiological studies and in the assessment of the effects of controlled FA supplementation in clinical studies.

Adult↗
PubMed2004

Comparative evaluation of coagulase-negative staphylococci (CoNS) adherence to acrylic by a static method and a parallel-plate flow dynamic method.

The main goal of this work was to evaluate the adhesion to acrylic of several clinical strains of Staphylococcus epidermidis and Staphylococcus haemolyticus using both static and dynamic adhesion methods, and to compare the results obtained with these two methods. Adhesion was evaluated using the static slide method with different washing procedures, and the parallel plate flow chamber method. The extent of S. epidermidis adhesion, assessed by both methods, was greater than that of S. haemolyticus. The number of bacteria which adhered using the static method was lower than that using the dynamic method. It was found that the simple static method, when performed with an accurate washing procedure, can be as effective as the dynamic flow method for assessing differences in the adherence capacity of strains. Although the dynamic flow method yielded more overall information, its greater complexity and cost may not always justify its use for certain experimental comparisons. This investigation has shown that simple static adhesion methods, when performed accurately, can be used to evaluate differences in adhesion capacity.

Acrylates↗
PubMed2006

Alternative methods for intensity-modulated radiation therapy inverse planning and dose delivery.

A large number of IMRT systems are currently being marketed. Many of these systems appear to be unique, and manufacturers often emphasize design differences as they argue the merits of their particular approach. This paper focuses on highlighting the underlying feature that is intrinsically part of all IMRT systems. On the other hand, major differences often appear at the implementation stage for dose delivery. Such variations are evident because each manufacturer has a unique approach to balancing the issues of treatment time, leakage radiation reaching the patient's total body, aperture approximation of the ideal intensity maps, increasing the angles of approach for the treatment fields, integration of on-line imaging, selection of treatment distance, availability of different photon energies, and overall system complexity (i.e., cost). How these different issues are handled in the process of system design affects the relative advantages and disadvantages that appear in the final product. This paper takes the approach of dividing the various IMRT methods into categories that are divided roughly along the lines of the technique used during dose delivery to approximate the intensity patterns. Other features of each system are included under these sub-sections.

Humans↗
PubMed2005

Managing uncertainty around HIV/AIDS in an urban setting: private medical providers and their patients in Pune, India.

Changing epidemiological patterns and the advent of new rapid diagnostic technologies and therapies have created considerable uncertainty for providers working in HIV. In India, the demand for HIV care is increasingly being met by private practitioners (PPs), yet little is known about how they deal with the challenges of managing HIV patients. To explore HIV management practices in the private medical sector, a survey was conducted with 215PPs in Pune, India, followed by in-depth interviews focusing on the social context of practice among a sub-set of 27PPs. Drawing primarily on interview data, this paper illustrates a number of uncertainties that underlie the reported actions of providers in a competitive medical market. PPs perceive HIV as a 'new' and challenging disease for which they lack adequate knowledge and skills. Combined with the perceived high cost and complexity of antiretroviral treatment, preconceptions about HIV patients' social, financial and mental capacity lead to highly individualistic management practices. While these fall short of clinical 'best practice' guidelines, they reflect adaptive responses to the wider uncertainties surrounding HIV care in urban India. By highlighting contextual issues in PPs' management of HIV patients, the paper suggests the need to explicitly acknowledge the social, moral and economic bases of uncertainty beyond the clinical setting.

Antiretroviral Therapy, Highly Active↗
PubMed2004

2D arrays device for calcaneus bone transmission: an alternative technological solution using crossed beam forming.

In the context of manned space flight with the European Space Agency, a quantitative ultrasound device for transmission imaging through the calcaneus bone has been developed. It includes two matrix transducers of 576 elements each in order to electronically perform the scanning and the focusing of the 500 kHz ultrasonic beam. This device called the BEAM scanner, provides two parametric images of attenuation (BUA, broadband ultrasonic attenuation) and velocity (SOS, speed of sound) of the investigated skeletal site. The cost and complexity of such a device has motivated the study of an alternative solution, less demanding in terms of technology, based on a crossed beam former [H. Ermert et al., A new concept for a real-time ultrasound transmission camera, in: IEEE Ultrasonics Symposium Proceedings, 2000, pp. 1611-1614]. It consists in forming two perpendicular cylindrically focused planes, one in emission, one in reception, instead of two spherically focused apertures. The crossing line of the two planes replaces the focused beam. The 2D beam forming technological challenge is moved to a 1D simpler and cheaper architecture. In this work the two solutions have been compared for in vivo measurements. Data sets have been acquired using all spatial combinations of emission and reception single elements of the matrix. Then signals have been processed using either the cylindrical or the spherical focussing mode. For cylindrical focussing, the increased level of the side lobes caused severe artefacts. Several apodization techniques have been implemented to reduce these artefacts, resulting in encouraging results. After a brief description of this new ultrasonic method for bone quantitative assessment, several reconstructed images using both processing schemes are presented. Corresponding statistical results obtained in 29 subjects are also provided.

Algorithms↗
PubMed2006

Enhanced hydrolysis of carbohydrates in primary sludge under biosulfidogenic conditions.

The potential for using readily available and cost-effective complex carbon sources, such as primary sludge (PS), for the bioremediation of sulfate-rich effluent streams, including acid mine drainage, has been constrained by the slow rate of solubilization and low yield of soluble products. Disposal of PS also remains a global problem. Recent studies of a patented recycling sludge bed reactor have shown that the solubilization of PS is enhanced under biosulfidogenic conditions. The current study investigated the enhanced solubilization of the carbohydrate fraction of PS under these conditions, using selective metabolic inhibitors. The mean maximum rate of reducing sugar production was significantly higher under sulfidogenic (167 mg L(-1)h(-1)) than methanogenic (51 mg L(-1)h(-1)) conditions and the utilization of volatile fatty acids under sulfidogenic conditions was rapid. Analysis of VFA profiles indicated preferential utilization of longer chain acids under sulfidogenic conditions and of acetate in the methanogenic systems and that the acetogenic step was unlikely to be rate-limiting in the solubilization of complex carbon.

Carbohydrates↗
PubMed1986

Positron emission tomography imaging--technical considerations.

Positron imaging instrumentation has improved rapidly in the last few years. Scanners currently under development are beginning to approach fundamental limits set by positron range and noncolinearity effects. This report reviews the latest developments in positron emission tomography (PET) instrumentation, emphasizing the development of coding schemes that reduce the complexity and cost of high-resolution scanners. The relative benefits of using time-of-flight (TOF) information is discussed as well.

Biophysical Phenomena↗
PubMed1987

SPECT instrumentation: performance, lesion detection, and recent innovations.

The use of a gamma camera for single photon emission computed tomography (SPECT) imaging places greater demand on camera performance than does planar imaging, since camera specifications that are adequate for planar imaging may produce serious image artifacts in SPECT. Manufacturers have responded to the challenge with improvements in both hardware and software, but the user must pay careful attention to quality control procedures. Field nonuniformity is caused mainly by spatial distortion, which may vary during rotation; some cameras incorporate a means of automatically correcting for angular changes. The purpose of performing SPECT is to improve lesion detection, ie, to improve contrast, which is influenced by many factors. Attenuation corrections may be applied either before or after reconstruction. For Tc-99m an attenuation coefficient less than that for water, ie, either 0.11 or 0.12, would appear to give better results; the visual appearance is improved but the effect on contrast is minimal. Scattered photons are the major cause of loss of contrast in SPECT images. Recent developments in on-line energy corrections allow the use of narrower photopeak windows as well as asymmetric energy windows. Offpeak energy windows have demonstrated significant improvements in contrast; however, the increase in nonuniformity can cause artifacts which may limit their use. Simultaneous collection of separate images, one in the photopeak region and the other in the scatter region (92 to 125 keV) may enable a transaxial scatter image to be subtracted from the transaxial photopeak image. This may permit quantification of the true radioactivity distribution. New collimator designs introduced to improve SPECT resolution include cast collimators which can be made with more uniform hole construction than the lead-foil type; for brain imaging, long bore parallel hole and converging fan beam collimators as well as astigmatic collimators which converge in both planes with different lines of focus. Some of these improve both sensitivity and resolution compared to parallel hole collimators. Noncircular orbits have also been introduced in order to improve resolution, but their use presents many problems which require careful monitoring. Transaxial multicrystal systems have been developed over many years, but have not been widely used, primarily because of their inherent complexity, high costs, and limited applicability. Some of these drawbacks may be overcome by a new type of SPECT camera currently under development by several different groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Humans↗