Extracorporeal photochemotherapy after cardiac transplantation: a new therapeutic approach to allograft rejection

Photopheresis (ECP) is a new immunomodulatory therapy in which recipient lymphocytes are treated extracorporeally with 8-methoxypsoralen and ultraviolet light. The treatment seems to induce an inhibition of both humoral and cellular rejection after transplantation. OBJECTIVE: Since recurrent rejection (RR) continues to be a severe complication after heart transplantation (HTx) and the immunosuppressive regimes used for the treatment are often associated with increased morbidity and mortality, we investigated whether ECP could have a beneficial effect on the number and severity of rejection episodes. METHODS: Eleven HTX recipients (5 M and 6 F, mean age 48.5 yrs) with RR were enrolled in the study. ECP was performed at weekly intervals during the 1st month, at 2 week intervals during the 2nd and 3rd month, and then monthly for another 3 months. RESULTS: The fraction of biopsies (EMB) with a grade 0/1A rejection increased during ECP from 46% to 72% while the EMB showing a 3A/3B rejection decreased from 42% to 18%. It is also noteworthy that out of the 78 EMB performed during ECP only one showed a 3B rejection in comparison with 13 out of 110 EMB in the pre-ECP period. Six rejection relapses were observed in a total follow-up of 60 months, two of them occurring during the tapering of oral steroid. Four relapses were reversed by ECP, one by i.v. steroids and the last by methotrexate after the failure of both i.v. steroids and ECP. The mean doses of immunosuppressive drugs resulted lower after 6 months of ECP: steroids were reduced from 13 to 8.25 mg/day, cyclosporine from 375 to 285 mg/day, azathioprine from 55 to 35 mg/day. CONCLUSIONS: ECP is a well tolerated treatment. Its administration allows better RR control and significant reduction in immunosuppressive therapy.     

Noninvasive cardiac absolute pressure sensing: a fundamentally new approach

Noninvasive cardiac pressure sensing using an imaging modality to ascertain changes in absolute pressure would be of immense benefit as a replacement for the Swan-Ganz catheter in current use. However, very little research has been published in this area. This paper reviews the small number of relevant studies to date, points out the many gaps in the research record, and discusses possible new avenues of approach in solving the problem.     

Tracking errors in a prototype real-time tumour tracking system

In motion-compensated radiation therapy, radio-opaque markers can be implanted in or near a tumour and tracked in real-time using fluoroscopic imaging. Tracking these implanted markers gives highly accurate position information, except when tracking fails due to poor or ambiguous imaging conditions. This study investigates methods for automatic detection of tracking errors, and assesses the frequency and impact of tracking errors on treatments using the prototype real-time tumour tracking system. We investigated four indicators for automatic detection of tracking errors, and found that the distance between corresponding rays was most effective. We also found that tracking errors cause a loss of gating efficiency of between 7.6 and 10.2%. The incidence of treatment beam delivery during tracking errors was estimated at between 0.8% and 1.25%.     

Pipetting errors in viral titrations: a useful approach

A simple recursive formula, which yields an estimate for the statistical error resulting from pipetting errors accumulated throughout a dilution procedure, is described. Its influence on the variance of the end-point titre estimate is then inferred.     

Consumer-oriented groups: a new approach to interdisciplinary teaching

Difficulties in the development of primary health care teams have been demonstrated by a number of authors. The important place of interdisciplinary teaching in this development had been stressed. This paper describes an experimental series in which emphasis has been placed on the patient's view of the input of different team members. The value of this approach is discussed.     

CardioClasp: a new passive device to reshape cardiac enlargement

In dilated heart failure, geometric distortions place an extra load on the myocardial cells. If this extra burden can be eliminated, the myocardial wall stress would decrease leading to improved systolic ventricular performance. In a dilated heart failure model, we wanted to see whether the CardioClasp (which uses two indenting bars to reshape the left ventricle [LV] as two widely communicating "lobes" of reduced radius) could improve systolic performance by passively reshaping the LV and reducing the wall stress. In mongrel dogs (n = 7; 25-27 kg), rapid ventricular pacing (210 ppm 1st week to 240 ppm 4th week) induced dilated heart failure. After 4 weeks, LV performance was evaluated at baseline and with the CardioClasp by measuring LV end-diastolic and peak LV systolic pressure, LV +dP/dt, LV -dP/ dt, and cardiac output. With the Clasp on, LV wall stress was reduced to 58.6+/-3.5 from 108.3+/-8.2 g/cm2. The fractional area of contraction (FAC) with the Clasp on (28.4+/-4.4) was significantly increased (p < 0.05) from baseline (20.8+/-4.6) and consistent with improved systolic performance. Cardiac output, LV peak systolic and end-diastolic pressures, and regional myocardial blood flow were unaltered. The Clasp was able to acutely reshape the left ventricle, while preserving the contractile mass, and reduced the tension on the myocardial cells and increased the fractional area of contraction without decreasing the systolic blood pressure.     

Quantitative architectural analysis: a new approach to cortical mapping

Recent progress in anatomical and functional MRI has revived the demand for a reliable, topographic map of the human cerebral cortex. Till date, interpretations of specific activations found in functional imaging studies and their topographical analysis in a spatial reference system are, often, still based on classical architectonic maps. The most commonly used reference atlas is that of Brodmann and his successors, despite its severe inherent drawbacks. One obvious weakness in traditional, architectural mapping is the subjective nature of localising borders between cortical areas, by means of a purely visual, microscopical examination of histological specimens. To overcome this limitation, more objective, quantitative mapping procedures have been established in the past years. The quantification of the neocortical, laminar pattern by defining intensity line profiles across the cortical layers, has a long tradition. During the last years, this method has been extended to enable a reliable, reproducible mapping of the cortex based on image analysis and multivariate statistics. Methodological approaches to such algorithm-based, cortical mapping were published for various architectural modalities. In our contribution, principles of algorithm-based mapping are described for cyto- and receptorarchitecture. In a cytoarchitectural parcellation of the human auditory cortex, using a sliding window procedure, the classical areal pattern of the human superior temporal gyrus was modified by a replacing of Brodmann’s areas 41, 42, 22 and parts of area 21, with a novel, more detailed map. An extension and optimisation of the sliding window procedure to the specific requirements of receptorarchitectonic mapping, is also described using the macaque central sulcus and adjacent superior parietal lobule as a second, biologically independent example. Algorithm-based mapping procedures, however, are not limited to these two architectural modalities, but can be applied to all images in which a laminar cortical pattern can be detected and quantified, e.g. myeloarchitectonic and in vivo high resolution MR imaging. Defining cortical borders, based on changes in cortical lamination in high resolution, in vivo structural MR images will result in a rapid increase of our knowledge on the structural parcellation of the human cerebral cortex.     

Proteomics: a new approach to the study of disease

The global analysis of cellular proteins has recently been termed proteomics and is a key area of research that is developing in the post-genome era. Proteomics uses a combination of sophisticated techniques including two-dimensional (2D) gel electrophoresis, image analysis, mass spectrometry, amino acid sequencing, and bio-informatics to resolve comprehensively, to quantify, and to characterize proteins. The application of proteomics provides major opportunities to elucidate disease mechanisms and to identify new diagnostic markers and therapeutic targets. This review aims to explain briefly the background to proteomics and then to outline proteomic techniques. Applications to the study of human disease conditions ranging from cancer to infectious diseases are reviewed. Finally, possible future advances are briefly considered, especially those which may lead to faster sample throughput and increased sensitivity for the detection of individual proteins.     

An approach to avoiding errors in cytotoxic testing

It is shown that time and temperature influence the results of cytotoxic assays considerably. In order to avoid errors depending upon these factors a simple modification in counting the cells is recommended.     

The Biomedical Mutual Organization: a new approach to developing new medical treatments

Self-experimentation is an efficient, productive and proven way to generate new treatments for mild and serious disease. But it is limited by materials available to the individual and the amount of testing one person can do. I advocate the formation of Biomedical Mutual Organizations, self-funded groups of individuals that provide mutual support for exploring new ideas in medical treatment. Such groups could achieve three things. Firstly, they could pool analytical services to validate the quality of materials and analytical services used in self-testing and self-medication, including verification of the identity and purity of medicine ingredients sourced from non-traditional sources. Secondly, they could pool resources to conduct group experiments in new treatments, interpret the results, and generate new hypotheses which could in turn be tested. Thirdly they could conduct more formal clinical trials on the group as a whole of new, indeed radical, therapies, in effect becoming a self-funded biotechnology company. While many practical objections remain to all of these, especially the last, and the last option may actually be illegal in some countries, some of the ethical objections that prevent such arrangements outside the context of a Mutual Organizations are overcome by the alignment of interests of those involved.     

Macroprolactin detection: a new approach

Macroprolactin is a complex of prolactin with immunoglobulins (IgG) that has limited or no biological activity in vivo. Immunoassays for prolactin have variable reactivity with macroprolactin. Therefore the presence of macroprolactin should be considered in the differential diagnosis of hyperprolactinemia. We compared a valid screening test for macroprolactin, polyethyleneglycol (PEG) precipitation, with the determination of the ratio of the results of two prolactin assays: Elecsys with high cross-reactivity with macroprolactin and Centaur with low cross-reactivity. In 59 negative samples subjected to the PEG test (precipitation < 50%), the Elecsys/Centaur ratio ranged between 1.11 and 1.45. Among 35 positive samples (precipitation > 60%), 33 had, as expected, an increased ratio (over 1.45), 1 a normal ratio and 1 a decreased ratio (1.07). This decreased ratio could be due to a particular form of macroprolactin poorly recognised by the Elecsys assay. Among 5 samples in the grey zone (precipitation between 50 and 60%), the ratio was increased in 2, normal in 1 and decreased in 2. Apart from one false negative case (normal ratio with positive PEG test), the results of the Elecsys/Centaur ratio method were in good agreement with those of the PEG test. The ratio method could be helpful for samples with PEG test results in the grey zone, before undertaking a complete analysis of circulating molecular forms by gel filtration chromatography. Out of the 5 five samples in the grey zone, the ratio was 4 times out of the reference range: 2 increased, 2 decreased. Our results also underline the necessity of reevaluating the Centaur prolactin reference range from samples without macroprolactin.     

Neural response to action and reward prediction errors: Comparing the error‐related negativity to behavioral errors and the feedback‐related negativity to reward prediction violations

The error‐related negativity (ERN) is thought to index an anterior cingulate (ACC) behavioral monitoring system. The feedback ERN (FRN) is elicited to error feedback when the correct response is not known, but also when a choice outcome is suboptimal and to passive reward prediction violation, suggesting that the monitoring system may not be restricted to actions. This study used principal components analysis to show that the ERN consists of a single central component whereas the reward prediction violation FRN is comprised of central and prefrontal components. A prefrontal component is also present in action monitoring but occurs later, at the error positivity latency. This suggests that ACC monitors both actions and events for reward prediction error. Prefrontal cortex may update reward expectation based on the prediction violation with the latency difference due to differential processing time for motor and perceptual information.     

PREPS and L-particles: a new approach to virus-like particle vaccines

Conventional virus-like particles are usually composed of a single structural protein which spontaneously assembles into particles. L-particles, a little-known type of virus-like particle, are produced as part of the natural infectious process of many, if not all, alpha-herpesviruses. L-particles lack the nucleocapsid present in the infectious virion but contain all of the virus envelope and tegument proteins. L-particles contain no virus DNA and are noninfectious, though they are biologically competent, since they are capable of delivering viral envelope and tegument proteins to cells. When cells are infected with herpes simplex virus Type 1 under conditions where viral DNA synthesis is blocked, previral DNA replication enveloped particles are produced. These are similar to L-particles, but differ slightly in protein composition. This article reviews the available data regarding these vaccine candidates and explores the wide-ranging potential applications, including vaccine candidates against infectious diseases and cancer, as well as a protein delivery vector.     

Collaborative online learning: a new approach to distance CME.

OBJECTIVE: Continuing medical education (CME) has not taken advantage of the ability to communicate and collaborate online. Collaborative learning is an important learning principle, yet online CME programs are generally completed in a one-on-one relationship between the computer and the learner. This limits opportunities for reflective learning, and does not access the rich learning available from interacting with peers. We believe online CME will benefit from interaction between learners and from opportunities for reflection. DESCRIPTION: We implemented a prototype online course designed to improve the skills of general practitioners (GPs) in the care of patients with type 2 diabetes. The course design reflects adult learning principles but, uniquely, applies them to online learning. Currently, 20 GPs from England are enrolled, including one based in Bosnia, and one GP from New Zealand. The course uses BlackBoard(TM) software. Participants log in twice weekly for seven weeks to study one of seven interactive modules on diabetes from evidence-based sources. Modules provide for branched learning via links to additional resources. Subsequently, GPs engage in two online discussions, which are at the learner's convenience rather than requiring adherence to a set schedule. One discussion group is for reflection on the modules, with an assignment to discuss how the material is being applied clinically. Participants also respond to colleagues' postings each week. In a second discussion group, learners apply concepts from the modules to the collaborative management of a problem-based case of a patient with newly diagnosed diabetes. The patient is presented via an online medical chart and streaming videos. She returns each week of the course to mimic 18 months of care. Faculty facilitate the discussion groups and provide feedback. DISCUSSION: We are in the last week of the class and the participant feedback has been overwhelmingly positive. Many note how well the course design and timing match their learning styles and schedule constraints. A powerful feature has been our ability to identify additional educational needs, and quickly add corresponding content online. So far, participants have provided 340 postings, which include evidence of course effectiveness and documentation of application of course objectives and disease management strategies to change actual practice patterns. GPs report changing: screening practices for diabetic renal disease; prescribing of diabetic medications; screening protocols for diabetes; and organizing practice management systems to better track diabetic care. After diagnosing and managing a new diabetic patient during the course, one participant wrote: "It was fantastic to feel that I am offering an up-to-date evidence-based approach in something that I am deskilled in." This course is unique in online CME. It is international in scope, collaborative, asynchronous in delivery, flexible, responsive to learner needs in real time, and has yielded evidence of its effectiveness in changing the actual clinical practices of participants. It will next enroll GPs in Singapore and additional UK-based GPs. Additional CME courses will be developed using this method.     

Columbia respiratory-chamber indirect calorimeter: a new approach to air-flow modelling

A new air-flow modelling approach for respiratory-chamber indirect calorimetry is introduced. Based on thermodynamic theory, differential equations describing the dynamics of the calorimeter are derived. These equations are then developed into a linear state space model that can be conceptualized as a modern control system. Furthermore, both the system/output noises and input/output delays are considered in the model in the context of real applications. Finally, system accuracy is analysed so that the parameters in the calorimeter can be selected to minimise the error in estimating energy expenditure in humans.     

Ebselen: a new approach to the inhibition of peroxide-dependent inflammation

Ebselen is a novel organo-selenium compound which catalytically inactivates peroxides in vitro in a manner similar to that of glutathione peroxidase (GSH-Px). In addition, ebselen also inactivates leukotriene B4 (LTB4) generated by pig leukocytes in vitro by isomerizing this eicosanoid to its biologically inactive 6-trans isomer. In vivo, ebselen is a weak oral inhibitor of carrageenan paw oedema and adjuvant arthritis in the rat, differentiating it from classical NSAIDs such as indomethacin and diclofenac. In contrast, oral ebselen, like (intra-articular) catalase, is an effective inhibitor of monoarthritis induced in mice with amidated glucose oxidase (aGO) and dose-dependently inhibits cobra-venom-factor-induced paw oedema in rats. Indomethacin and piroxicam are weakly active or ineffective in these models. The data indicate that ebselen is likely to be useful in the therapy of inflammatory conditions in which reactive oxygen species, such as peroxides, play an aetiological role.