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Selective integration of multiple biological data for supervised network inference.

MOTIVATION: Inferring networks of proteins from biological data is a central issue of computational biology. Most network inference methods, including Bayesian networks, take unsupervised approaches in which the network is totally unknown in the beginning, and all the edges have to be predicted. A more realistic supervised framework, proposed recently, assumes that a substantial part of the network is known. We propose a new kernel-based method for supervised graph inference based on multiple types of biological datasets such as gene expression, phylogenetic profiles and amino acid sequences. Notably, our method assigns a weight to each type of dataset and thereby selects informative ones. Data selection is useful for reducing data collection costs. For example, when a similar network inference problem must be solved for other organisms, the dataset excluded by our algorithm need not be collected. RESULTS: First, we formulate supervised network inference as a kernel matrix completion problem, where the inference of edges boils down to estimation of missing entries of a kernel matrix. Then, an expectation-maximization algorithm is proposed to simultaneously infer the missing entries of the kernel matrix and the weights of multiple datasets. By introducing the weights, we can integrate multiple datasets selectively and thereby exclude irrelevant and noisy datasets. Our approach is favorably tested in two biological networks: a metabolic network and a protein interaction network. AVAILABILITY: Software is available on request.

Algorithms↗

Cyclosporin: an updated review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation (neoral)1 in organ transplantation.

UNLABELLED: Cyclosporin is a lipophilic cyclic polypeptide immunosuppressant that interferes with the activity of T cells chiefly via calcineurin inhibition. The original oil-based oral formulation of this drug (Sandimmun)l was characterised by high intra- and interpatient pharmacokinetic variability, with poor bioavailability in many patients; a novel microemulsion formulation (Neoral)1 was therefore developed to circumvent these problems. Studies show increases, attributable chiefly to improved absorption in patients who absorb the drug only poorly from the original formulation, in mean systemic exposure to cyclosporin with the microemulsion, with no clinically significant differences in tolerability or drug interaction profiles. Cyclosporin microemulsion is at least as effective as the oil-based formulation in renal, liver and heart transplant recipients, with trends towards decreased incidence of acute rejection with the microemulsion formulation in some (statistically significant in a few) trials. Cyclosporin microemulsion and tacrolimus appear to have similar efficacy in preventing acute rejection episodes in most renal, pancreas-kidney, liver and heart transplant recipients. However, there are indications of superior efficacy for tacrolimus in some trials, particularly in the prevention of severe acute rejection and in Black transplant recipients. Current 12-month data also indicate equivalent efficacy of sirolimus in renal transplantation. Conversion from the oil-based to microemulsion formulation in stable renal, liver and heart transplant recipients is achievable with no change in acute rejection rates. The addition of an anti-interleukin-2 receptor monoclonal antibody and/or mycophenolate mofetil to cyclosporin microemulsion plus corticosteroids decreases rates of acute rejection; corticosteroid withdrawal without increased acute rejection rates was also achieved on the addition of these agents in some trials. Pharmacoeconomic analyses have shown savings in direct healthcare costs in kidney or liver transplantation when cyclosporin microemulsion is used in preference to the oil-based formulation, although studies incorporating indirect costs or expressing costs in terms of therapeutic outcomes are currently unavailable. CONCLUSIONS: The introduction of cyclosporin microemulsion has consolidated the place of the drug as a mainstay of therapy in all types of solid organ transplantation; research into optimisation of outcomes through more effective therapeutic monitoring in patients receiving this formulation is ongoing. Several novel immunosuppressants have been introduced in recent years: further clinical and pharmacoeconomic research will be needed to clarify the relative positioning of these agents, particularly with respect to specific patient groups. Other new drugs (basiliximab/daclizumab and mycophenolate mofetil) offer particular advantages when used in combination with cyclosporin.

Cyclosporine↗

Arrangement of anatomic-type artificial teeth into balanced occlusion.

The mechanical factors which are involved in the arrangement of anatomic type artificial teeth into balanced occlusion have been described. Many of the mechanical problems encountered during artificial tooth arrangement have been listed, together with suggestions for their solution. Hanau's Laws of Articulation have been utilized in a practical manner in formulating some of the solutions to tooth arrangement problems when establishing balanced occlusion. Trial dentures which present ideal occlusions in the articulator may not always do so when examined in the patient's mouth. Possible reasons for these differences are listed, and methods for making the necessary corrections are described.

Dental Articulators↗

Issues in the development of statistical and epidemiological data for mental health services research.

The planning of health services consists of a process that generally involves the following steps: (a) situational analysis, or the description, definition and statement of the problem, its characteristics and dimensions in relation to population and time; (b) the formulation of alternative tactical approaches to the handling and solution of the problem; (c) decision analysis or the selection of a plan; (d) discussion and implementation of the plan selected; (e) evaluation of the results achieved in relation to the problem, situations or populations concerned. This paper discusses the content of a programme of mental health services research for collecting and analysing the information needed to apply these processes to the planning of mental health services, monitoring the manner in which the plan is being implemented, and assessing its effectiveness in achieving short-term and intermediate objectives and long-term goals. Statistical and epidemiological information play an important role in these processes, particularly in the situational analysis and the evaluation processes. Illustrations have been provided of types of data that are produced in the national mental health statistics programme in the United States. Difficulties in using such data to answer questions concerning the needs for mental health services, and manpower requirements for delivering services to meet these needs are discussed. In many instances, currently available data are quite inadequate for answering key issues such as these, plus others related to living arrangements of the population, the effect of services on the persons who receive them, their families and the communities in which they live. Thus, much still remains to be done to develop systematic, comparative morbidity statistics on the incidence, duration and prevalence of mental disorders in the general population, on the needs for mental health services, and on the effectiveness of our efforts to prevent disorders that can be prevented, and to reduce the amount of disability and distress caused by those that cannot be prevented or terminated. A series of problems have been identified, the solutions to which would assist materially in providing data that would narrow gaps between available knowledge and that which is needed. The importance of establishing well-staffed research units at the catchment area level with stable funding to accomplish this is underscored. It is a matter of the greatest urgency that adequate resources--financial, manpower, scientific and administrative--be made available to solve these problems. If this is not done, then effordts to document quantitatively the effectiveness of programmes to prevent and control mental disorders will continue to suffer from many of the same shortcomings that have impeded our past and continue to impede current efforts to accomplish this.

Adolescent↗

Effects of radiolysis on yttrium-90-labeled Lym-1 antibody preparations.

UNLABELLED: The physical half-life of 2.6 days and 2.2 MeV beta emissions of 90Y provide excellent properties for radioimmunotherapy applications. However, the clinically useful beta particles may be a source of radiation-induced damage of 90Y-labeled immunoconjugate radiopharmaceuticals during preparation or short-term storage. The stability of 90Y-labeled Lym-1 antibody was studied in standard radiopharmacy conditions to establish a formulation at which radiolysis is not a problem. METHODS: Lym-1-21T-BAD immunoconjugate intermediate was prepared according to our standard procedure, then labeled with 90Y at 1, 2, 4 and 9.4 mCi/mg Lym-1 using 0.5 M tetramethylammonium acetate, pH 7, labeling buffer. Each mixture was challenged in diethylenetriaminepentaacetic acid to remove nonspecifically bound 90Y. The 90Y-21T-BAD-Lym-1 products were purified by centrifuged molecular sieving column chromatography. The radiochemical purity and immunoreactivity of each preparation was monitored daily by high-performance liquid chromatography (HPLC) and solid-phase radioimmunoassay, respectively, for 3 days. The preparation at 2 mCi/mg was also formulated in 4% (wt/vol) human serum albumin (HSA) overall and at 9.4 mCi/mg in five-fold water, 4 and 10% (wt/vol) HSA overall; all were monitored as above. RESULTS: The monomeric quality and purity profile of products at 1 and 2 mCi/mg were retained (> or = 80%) as was their immunoreactivity (> or = 75%) over 3 days. The radiochemical purity and immunoreactivity of the product at 4 mCi/mg declined to 65% and 28%, respectively, by 3 days after preparation and in just 48 hr, the product at 9.4 mCi/mg had degraded to 21% in radiochemical purity with only 3% immunoreactivity. The current HPLC data and earlier published chromatographic evidence did not support a compromised radiochemical integrity of 90Y-DOTA complexes by loss of 90Y from the DOTA chelate. CONCLUSION: Radiolysis of 90Y-labeled antibody preparations did not appear to be a problem at 90Y-21T-BAD-Lym-1 products < or = 2 mCi/mg. Human serum albumin proved to be an effective radioprotectant as the initial 100% immunoreactivity of the product at 2 mCi/mg was retained for 72 hr. The results underscore the need for appropriate formulations and dilutions of clinical doses of 90Y immunopharmaceuticals immediately after manufacture.

Antibodies, Monoclonal↗

Topographic profiling and refractive-index analysis by use of differential interference contrast with bright-field intensity and atomic force imaging.

A methodology is described for phase restoration of an object function from differential interference contrast (DIC) images. The methodology involves collecting a set of DIC images in the same plane with different bias retardation between the two illuminating light components produced by a Wollaston prism. These images, together with one conventional bright-field image, allows for reduction of the phase deconvolution restoration problem from a highly complex nonlinear mathematical formulation to a set of linear equations that can be applied to resolve the phase for images with a relatively large number of pixels. Additionally, under certain conditions, an on-line atomic force imaging system that does not interfere with the standard DIC illumination modes resolves uncertainties in large topographical variations that generally lead to a basic problem in DIC imaging, i.e., phase unwrapping. Furthermore, the availability of confocal detection allows for a three-dimensional reconstruction with high accuracy of the refractive-index measurement of the object that is to be imaged. This has been applied to reconstruction of the refractive index of an arrayed waveguide in a region in which a defect in the sample is present. The results of this paper highlight the synergism of far-field microscopies integrated with scanned probe microscopies and restoration algorithms for phase reconstruction.

Journal Article↗

Models and theories of brain function in cognition within a framework of behavioral cognitive psychology.

The present article presents a nonexhaustive collection of contemporary models and theories on brain function and discusses these models and theories within a framework of explanatory formulations in behavioral cognitive psychology. Such a mission was accomplished by evaluating the cognitive implications in the explanatory formulations with respect to established laws/principles and models/theories of behavioral cognitive psychology. The article also points to problem areas of behavioral cognitive psychology for which the explanatory formulations have solutions to offer. The article shows that the cinematographic hypothesis, the new visual model, the synergetic model, and the theory of whole-brain-work emphasize various aspects of perception. The formulations on P300 theory emphasize attention and also working memory. The theory on cognits is a comprehensive account of memory. Characteristic to all of these explanatory formulations and also to that on the complexity and its evolution and that on neurocognitive networks is the emphasis on selective distribution, integration to the point of supersynergy, and dynamicity. Such a viewpoint was not only applied to the operations of the brain but also of cognition. With such a conceptualization, the explanatory formulations could account for cognitive processes other than the ones emphasized. A common aspect in a majority of the formulations is the utilization of the oscillatory activity as the valid activity of the brain. The article points out that a frontier in cognitive psychophysiology would be the study of the genetics of brain oscillations.

Brain↗

Bioequivalence trials of rifampicin containing formulations: extrinsic and intrinsic factors in the absorption of rifampicin.

Rifampicin shows variable bioavailability from solid oral dosage forms and the reasons for this variable absorption reported in literature varies from extrinsic formulations factors to intrinsic variability in rifampicin absorption. Hence, we have undertaken a systematic and comprehensive evaluation of all the factors to study contribution of all the factors on rifampicin absorption. As a first step, data from eight bioequivalence studies conducted at National Institute of Pharmaceutical Education and Research (NIPER) bioavailability center was compared across the trials to understand the effect of extrinsic/intrinsic factors on the bioavailability of rifampicin, isoniazid and pyrazinamide. Out of eight fixed dose combination (FDC) formulations, six formulations were bioequivalent for rifampicin to separate formulations whereas one formulation was below and one was above the limits of bioequivalence. It was observed that more variability in rifampicin blood levels is associated with FDC formulations when compared to rifampicin-only formulations and was attributed to complexity involved in the manufacturing of FDCs. Further, one of the rifampicin-only capsule showed unexpectedly lower plasma levels indicating role of physical characteristics of rifampicin bulk material. It was also seen that rifampicin shows dose-dependent pharmacokinetics even at the modest increase in dose due to saturation of efflux system at absorption site and metabolizing enzymes for elimination. Other components of FDC formulations such as isoniazid and pyrazinamide due to high solubility and permeability have shown very less variability and were bioequivalent to separate formulations even from formulations those were failed for rifampicin. The comparison of data across the trials suggested that rifampicin bioavailability problem is more attributable to the extrinsic factors such as formulation or rifampicin bulk material rather than intrinsic variability of rifampicin absorption.

Adolescent↗

The couple assessment summary: a bridge from assessment to treatment.

Treatment of couples presenting for therapy typically necessitates a process of riding out the storm of contention, entering the contextual framework in which the couple is relating and developing an understanding of the couple's interactive as well as intrapsychic world. The therapist's emerging conceptualization of the relational problems addressed in the assessment process provides an important foundation for the treatment process to follow. This formulation is recorded in the "Couple Assessment Summary" (CAS), which is developed in the diagnostic stage of the treatment process. A clearly conceptualized and structured document, the CAS is the suggested vehicle for engaging the couple in the treatment process to follow. The CAS serves as a logical extension of the Couple Assessment Outline, which is a therapist's tool for engaging the partners in the process of self-assessment and formulation. The CAS offers the therapist's perspective on the problems presented to the couple for review. This paper will demonstrate the utilization of the CAS with couples in distress and will illustrate its use with a couple engaged in the assessment process. The CAS is seen as a useful method for developing a shared understanding of the problems presented as the assessment process is often fraught with tension, anger, and chaotic interaction.

Couples Therapy↗

Potential of microparticles for diagnostic tracer imaging.

The development of tracer imaging agents with sufficiently high label activity can lead to problems of poor aqueous solubility of the labeled tracer, causing formulation difficulty, inadvertent accumulation by phagocytic cells, or inadequate signal to noise. Our approach to solving these problems is to administer the tracer in the form of monodispersed nanoparticles which can safely be administered intravenously. Since the phagocytosis of these particles can be controlled or avoided in a predictable manner by altering particle size and surface characteristics, imaging tracers can be designed for a variety of intended applications. This paper summarizes the results and ideas for several applications involving computed tomography, ultrasound, magnetic resonance imaging, and radioisotope imaging modalities.

Animals↗

Generic propoxyphene: need for clinical bioavailability evaluation.

Plasma level data on two investigational capsule formulations of propoxyphene with similar physicochemical parameters demonstrate that the formulations have different in vivo bioavailabilities. The potential bioavailability problems with water-soluble drugs and the lack of correlation of in vitro and in vivo parameters for equivalent drug formulations are discussed.

Adult↗

Accuracy of newly formulated fast-setting elastomeric impression materials.

STATEMENT OF PROBLEM: Elastomeric impression materials have been reformulated to achieve a faster set. The accuracy of fast-setting elastomeric impression materials should be confirmed, particularly with respect to disinfection. PURPOSE: The purpose of this study was to assess the accuracy of 2 types of fast-setting impression materials when disinfected with acid glutaraldehyde. MATERIAL AND METHODS: Impressions of the mandibular arch of a modified dentoform master model were made, from which gypsum working casts and dies were formed. Measurements of the master model and working casts included anteroposterior (AP) and cross-arch (CA) dimensions. A stainless steel circular crown preparation incorporated within the master model was measured in buccolingual (BL), mesiodistal (MD), and occlusogingival (OG) dimensions and compared to measurements from recovered gypsum dies. The impression materials examined were a fast-set vinyl polysiloxane (VPS-FS, Aquasil Ultra Fast Set), a fast-set polyether (PE-FS, Impregum Penta Soft Quick Step), and a regular-setting polyether as a control (PE, Impregum Penta). Disinfection involved immersion in 3.5% acid glutaraldehyde (Banicide Advanced) for 20 minutes, and nondisinfected impressions served as a control. Linear measurements were made with a measuring microscope. Statistical analysis utilized a 2-way and single-factor analysis of variance with pair-wise comparison of mean values when appropriate. Hypothesis testing was conducted at alpha = .05 RESULTS: No differences were shown between the disinfected and nondisinfected conditions for all locations. However, there were statistical differences among the 3 materials for AP, CA, MD, and OG dimensions. AP and CA dimensions of all working casts were larger than the master model. Impressions produced oval-shaped working dies for all impression materials. PE and PE-FS working dies were larger in all dimensions compared to the stainless steel preparation, whereas VPS-FS-generated working dies were reduced in OG and MD dimensions. Differences detected were small and may not be of clinical significance. CONCLUSIONS: Impression material accuracy was unaffected by immersion disinfection. The working casts and dies were similar for PE and PE-FS. VPS-FS generated gypsum dies that were smaller in 2 of the 3 dimensions measured and may require additional die relief. Overall accuracy was acceptable for all 3 impression materials.

Analysis of Variance↗

An advanced boundary element method (BEM) implementation for the forward problem of electromagnetic source imaging.

The forward problem of electromagnetic source imaging has two components: a numerical model to solve the related integral equations and a model of the head geometry. This study is on the boundary element method (BEM) implementation for numerical solutions and realistic head modelling. The use of second-order (quadratic) isoparametric elements and the recursive integration technique increase the accuracy in the solutions. Two new formulations are developed for the calculation of the transfer matrices to obtain the potential and magnetic field patterns using realistic head models. The formulations incorporate the use of the isolated problem approach for increased accuracy in solutions. If a personal computer is used for computations, each transfer matrix is calculated in 2.2 h. After this pre-computation period, solutions for arbitrary source configurations can be obtained in milliseconds for a realistic head model. A hybrid algorithm that uses snakes, morphological operations, region growing and thresholding is used for segmentation. The scalp, skull, grey matter, white matter and eyes are segmented from the multimodal magnetic resonance images and meshes for the corresponding surfaces are created. A mesh generation algorithm is developed for modelling the intersecting tissue compartments, such as eyes. To obtain more accurate results quadratic elements are used in the realistic meshes. The resultant BEM implementation provides more accurate forward problem solutions and more efficient calculations. Thus it can be the firm basis of the future inverse problem solutions.

Algorithms↗

Associations between phenomenal and objective aspects of concentration problems in depressed patients.

The paper explores a distinction between different kinds of lapse of concentration in depressed patients. The strategy is to begin with the phenomenological distinction between the mind (a) 'wandering' on to something else or (b) going 'blank'. Blanking, but not mind-wandering, is associated with longer planning times on the 'Tower of London' task. In contrast, mind-wandering but not blanking, is associated with poor memory for prose, at least under ordinary processing conditions. Different phenomenal forms of concentration problem thus have different task performance correlates. A tentative formulation is offered in terms of Shallice's model of the regulation of attention. Mind-wandering is seen as a problem of 'contention scheduling', and blanking as the result of generalized inhibition by the Supervisory Attentional System. It is evident that not all performance deficits in depression can be attributed to the cognitive capacity taken up by competing thoughts.

Adult↗

The problem-oriented medical record: modification and simplification for rehabilitation medicine.

A modified POMR has been formulated for use in rehabilitation medicine. It incorporates the concept of the Weed system, modifies rehabilitation problems into seven functional categories, and modifies the problem-oriented progress note. It uses a problem-oriented team conference and a functional status form. These modifications, I believe, improve patient care, medical education, and facilitate the medical audit.

Aged↗

Inverse planning for x-ray rotation therapy: a general solution of the inverse problem.

Rotation therapy with photons is currently under investigation for the delivery of intensity modulated radiotherapy (IMRT). An analytical approach for inverse treatment planning of this radiotherapy technique is described. The inverse problem for the delivery of arbitrary 2D dose profiles is first formulated and then solved analytically. In contrast to previously applied strategies for solving the inverse problem, it is shown that the most general solution for the fluence profiles consists of two independent solutions of different parity. A first analytical expression for both fluence profiles is derived. The mathematical derivation includes two different strategies, an elementary expansion of fluence and dose into polynomials and a more practical approach in terms of Fourier transforms. The obtained results are discussed in the context of previous work on this problem.

Mathematics↗

The chronic kidney disease initiative.

The Chronic Kidney Disease Initiative was implemented at the request of the Council of American Kidney Societies to formulate a plan of action to solve many of the perceived problems associated with identifying, caring for, and attaining the best outcomes for patients with chronic kidney disease. With the assistance of a community of stakeholders and a formalized workshop and process, the Chronic Kidney Disease Initiative identified the barriers to solving this complicated problem. Barriers were given hierarchical significance, and solutions and action plans to the barriers were formulated. This article describes the process, the barriers encountered, and the solutions required to fully identify and manage this large and complicated population of patients.

Humans↗

Development of a parenteral formulation of trimelamol, a synthetic S-triazine carbinolamine-containing cytotoxic agent.

Trimelamol is a synthetic s-triazine carbinolamine-containing agent exhibiting poor aqueous solubility and stability characteristics. The present studies were conducted to provide a stable parenteral dosage form of trimelamol, which could be used for clinical evaluation of the drug and also be manufactured on a commercial scale without undue drug decomposition occurring. Solubility and stability of trimelamol were found to increase in the presence of aqueous-polyethylene glycol (PEG) solutions of increasing average PEG molecular weight (up to mol wt = 1000); PEG 1000 (75%) in water provided the optimum formulation vehicle. In contrast to the optimum liquid formulation of the drug (detailed above) it was necessary to make various compromises to the formulation in terms of drug solubility and stability, because of the problems encountered in processing (e.g., sterile filtration, lyophilization, and reconstitution). Freeze-drying of the formulation extended the product shelf-life relative to the liquid formulation. Differential Scanning Colorimetry (DSC) studies, to determine the freeze-drying cycle parameters, showed that the freezing and melting characteristics of the trimelamol-PEG formulations were dependent upon the rate of cooling, as well as the concentration and average molecular weight of PEG used. The prototype containing 30 mg/mL trimelamol in a 50% PEG 3400-aqueous vehicle was found to be the optimal formulation for sterile filtration, lyophilization, and subsequent reconstitution. Through the use of in vitro techniques, the possibility of hemolysis occurring upon injection resulting from the inclusion of high molecular weight PEGs in the vehicle, was shown to be unlikely.

Animals↗