Molecular Imaging Visualizes Recruitment of Inflammatory Monocytes and Macrophages to the Injured Heart.

RATIONALE: Paradigm shifting studies have revealed that the heart contains functionally diverse populations of macrophages derived from distinct embryonic and adult hematopoietic progenitors. Under steady-state conditions, the heart is largely populated by CCR2- (C-C chemokine receptor type 2) macrophages of embryonic descent. After tissue injury, a dramatic shift in macrophage composition occurs whereby CCR2+ monocytes are recruited to the heart and differentiate into inflammatory CCR2+ macrophages that contribute to heart failure progression. Currently, there are no techniques to noninvasively detect CCR2+ monocyte recruitment into the heart and thus identify patients who may be candidates for immunomodulatory therapy. OBJECTIVE: To develop a noninvasive molecular imaging strategy with high sensitivity and specificity to visualize inflammatory monocyte and macrophage accumulation in the heart. METHODS AND RESULTS: We synthesized and tested the performance of a positron emission tomography radiotracer (68Ga-DOTA [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-ECL1i [extracellular loop 1 inverso]) that allosterically binds to CCR2. In naive mice, the radiotracer was quickly cleared from the blood and displayed minimal retention in major organs. In contrast, biodistribution and positron emission tomography demonstrated strong myocardial tracer uptake in 2 models of cardiac injury (diphtheria toxin induced cardiomyocyte ablation and reperfused myocardial infarction). 68Ga-DOTA-ECL1i signal localized to sites of tissue injury and was independent of blood pool activity as assessed by quantitative positron emission tomography and ex vivo autoradiography. 68Ga-DOTA-ECL1i uptake was associated with CCR2+ monocyte and CCR2+ macrophage infiltration into the heart and was abrogated in CCR2-/- mice, demonstrating target specificity. Autoradiography demonstrated that 68Ga-DOTA-ECL1i specifically binds human heart failure specimens and with signal intensity associated with CCR2+ macrophage abundance. CONCLUSIONS: These findings demonstrate the sensitivity and specificity of 68Ga-DOTA-ECL1i in the mouse heart and highlight the translational potential of this agent to noninvasively visualize CCR2+ monocyte recruitment and inflammatory macrophage accumulation in patients.

Evaluation of TELEDERM for dermatological services in rural and remote areas.

OBJECTIVE: This paper describes the Web-based decision support system (TELEDERM) that provides medical services to rural and remote general practitioners (GPs), and presents qualitative results on the usefulness and usability of the system obtained from trials in the GoldFields, Western Australia. METHODS: Diagnostic methods and other functions were developed to assist medical practitioners, who may not be familiar with aspects of decision support systems, to diagnose patients with dermatological problems. GPs in rural and remote areas took part in a trial to assess the usefulness of TELEDERM in clinical situations. In evaluating and assessing a number of the system's characteristics, questionnaires, seminars and interviews were used. RESULTS AND CONCLUSIONS: Feedback concerning the usefulness of TELEDERM shows that 67% of the GPs found the system useful or very useful, and 25% found the system somewhat useful. In terms of its usability, 83% found the system easy to use. The responses concerning the user interface and interactivity of TELEDERM are encouraging as 92% of the GPs found the text easy to read, 84% were happy with the appearance of the interface, and 84% found the system easy to navigate. 89% indicated that they are likely to use the system again. An issue with such systems is the reluctance of GPs to use them, even given that the development was quite sensitive to the needs of the GPs and the consultants, e.g. by streamlining the query process and emphasising that the system is a support tool and not a replacement.

Dynamic knowledge validation and verification for CBR teledermatology system.

OBJECTIVE: Case-based reasoning has been of great importance in the development of many decision support applications. However, relatively little effort has gone into investigating how new knowledge can be validated. Knowledge validation is important in dealing with imperfect data collected over time, because inconsistencies in data do occur and adversely affect the performance of a diagnostic system. METHODS: This paper consists of two parts. First, it describes methods that enable the domain expert, who may not be familiar with machine learning, to interactively validate knowledge base of a Web-based teledermatology system. The validation techniques involve decision tree classification and formal concept analysis. Second, it describes techniques to discover unusual relationships hidden in the dataset for building and updating a comprehensive knowledge base, because the diagnostic performance of the system is highly dependent on the content thereof. Therefore, in order to classify different kinds of diseases, it is desirable to have a knowledge base that covers common as well as uncommon diagnoses. RESULTS AND CONCLUSION: Evaluation results show that the knowledge validation techniques are effective in keeping the knowledge base consistent, and that the query refinement techniques are useful in improving the comprehensiveness of the case base.

Spotlight on ixazomib: potential in the treatment of multiple myeloma.

Despite the significant therapeutic advances achieved with proteasome inhibitors (PIs) such as bortezomib and carfilzomib in prolonging the survival of patients with multiple myeloma, the development of drug resistance, peripheral neuropathy, and pharmacokinetic limitations continue to pose major challenges when using these compounds. Ixazomib is a second-generation PI with improved activity over other PIs. Unlike bortezomib and carfilzomib, which are administered by injection, ixazomib is the first oral PI approved by US Food and Drug Administration. This review discusses the biochemical properties, mechanisms of action, preclinical efficacy, and clinical trial results leading to the US Food and Drug Administration approval of ixazomib.