Adenosine A(1) receptors in the central nervous system: their functions in health and disease, and possible elucidation by PET imaging

Adenosine is a neuromodulator with several functions in the central nervous system (CNS), such as inhibition of neuronal activity in many signaling pathways. Most of the sedating, anxiolytic, seizure-inhibiting and protective actions of adenosine are mediated by adenosine A(1) receptors (A(1)R) on the surface of neurons and glia. Positron Emission Tomography (PET) is a powerful in vivo imaging tool which can be applied to investigate the physiologic and pathologic roles of A(1)R in the human brain, and to elucidate the mechanism of action of therapeutic drugs targeting adenosine receptors, nucleoside transporters and adenosine-degrading enzymes. In this review article, we discuss (i) functions of adenosine and its receptors in cerebral metabolism; (ii) radioligands for A(1)R imaging: xanthine antagonists, non-xanthine antagonists, and agonists; (iii) roles of A(1)R in health and disease, viz. sleep-wake regulation, modulation of memory retention and retrieval, mediating the effects of alcohol consumption, protecting neurons during ischemia and reperfusion, suppression of seizures, modulating neuroinflammation and limiting brain damage in neurodegenerative disorders. The application of PET imaging could lead to novel insights in these areas. Finally (iv), we discuss the application of PET in pharmacodynamic studies and we examine therapeutic applications of adenosine kinase inhibitors, e.g. in the treatment of pain, inflammation, and epilepsy.     

The relationship between baseline health and longitudinal costs of hospital use

In this paper, we investigate the relationship between baseline health and costs of hospital use over a period of eight years. We combine cross-sectional survey data with information from the Dutch national hospital register. Four different indicators of health (self-perceived health, long-term impairments, ADL limitations and comorbidity) are considered. We find that for ages 50 to 70, differences in hospital costs between good health and bad health are substantial and persist during the whole time period. However, for higher ages expected hospital costs for individuals in bad health decline rapidly and become lower than those for people in good health after about six to seven years. The higher mortality rate among people in bad health is the primary cause here. Our results are confirmed for all four health indicators. We conclude that relying on better health to contain healthcare expenditures is too optimistic, and the interaction between health and mortality should be taken into account when projecting healthcare costs. Healthy ageing is important, but more for health gains than for cost savings.     

The impact of late treatment-toxicity on generic health-related quality of life in head and neck cancer patients after radiotherapy

To examine the impact of late treatment-related xerostomia and dysphagia on health-related quality of life (HRQOL) in head and neck cancer (HNC) patients after radiotherapy. A multi-center cross-sectional survey was performed. Patients with a follow-up of at least 6months after curative radiotherapy, without evidence of recurrent disease were eligible for inclusion. The Euroqol-5D questionnaire (EQ-5D) was filled out and toxicity was scored and converted to the RTOG scale. The EQ-5D measures generic HRQOL in terms of utility and visual analogue scale (VAS) scores. Missing data on the EQ-5D were imputed using multiple imputation. HRQOL was compared between subgroups of patients with and without toxicity. Subsequently, the impact of xerostomia and dysphagia on HRQOL was analyzed using multivariate regression analyses. Both analyses were performed separately for utility scores and VAS scores. The study population was composed of 396 HNC patients. The average utility and VAS scores were 0.85 (scale 0-1) and 75 (scale 0-100). Subgroups of patients with xerostomia and/or dysphagia showed statistically significantly lower utility and VAS scores (P=0.000-0.022). The multivariate regression model showed that xerostomia and dysphagia were negative predictors of both utility and VAS scores. Other factors which influenced HRQOL in at least one of the two regression models were: sex, tumor location and the addition of surgery to radiotherapy. Xerostomia and dysphagia diminish generic HRQOL. Moreover dysphagia affects patients' HRQOL stronger than xerostomia.     

Contrast-enhanced MRI of murine myocardial infarction - part II

Mouse models are increasingly used to study the pathophysiology of myocardial infarction in vivo. In this area, MRI has become the gold standard imaging modality, because it combines high spatial and temporal resolution functional imaging with a large variety of methods to generate soft tissue contrast. In addition, (target-specific) MRI contrast agents can be employed to visualize different processes in the cascade of events following myocardial infarction. Here, the MRI sequence has a decisive role in the detection sensitivity of a contrast agent. However, a straightforward translation of clinically available protocols for human cardiac imaging to mice is not feasible, because of the small size of the mouse heart and its extremely high heart rate. This has stimulated intense research in the development of cardiac MRI protocols specifically tuned to the mouse with regard to timing parameters, acquisition strategies, and ECG- and respiratory-triggering methods to find an optimal trade-off between sensitivity, scan time, and image quality. In this review, a detailed analysis is given of the pros and cons of different mouse cardiac MR imaging methodologies and their application in contrast-enhanced MRI of myocardial infarction.     

COSARA: Integrated Service Platform for Infection Surveillance and Antibiotic Management in the ICU

The Intensive Care Unit is a data intensive environment where large volumes of patient monitoring and observational data are daily generated. Today, there is a lack of an integrated clinical platform for automated decision support and analysis. Despite the potential of electronic records for infection surveillance and antibiotic management, different parts of the clinical data are stored across databases in their own formats with specific parameters, making access to all data a complex and time-consuming challenge. Moreover, the motivation behind physicians' therapy decisions is currently not captured in existing information systems. The COSARA research project offers automated data integration and services for infection control and antibiotic management for Ghent University Hospital. The platform not only gathers and integrates all relevant data, it also presents the information visually at the point of care. In this paper, we describe the design and value of COSARA for clinical treatment and infectious diseases monitoring. On the one hand, this platform can facilitate daily bedside follow-up of infections, antibiotic therapies and clinical decisions for the individual patient, while on the other hand, the platform serves as management view for infection surveillance and care quality improvement within the complete ICU ward. It is shown that COSARA is valuable for registration, real-time presentation and management of infection-related and antibiotics data.     

TACI deficiency impairs sustained Blimp-1 expression in B cells decreasing long-lived plasma cells in the bone marrow

Deficiencies in transmembrane activator and CAML interactor (TACI) result in common variable immune deficiency, a syndrome marked by recurrent infections with encapsulated microorganisms, impaired production of antibodies, and lymphoproliferation. How TACI promotes antibody production and inhibits lymphoproliferation is not understood. To answer this question, we studied the generation of immunity to protein antigens in both TACI-deficient and TACI-proficient mice. We show that TACI promotes sustained Blimp-1 expression by B cells responding to antigen, which in turn limits B-cell clonal expansion and facilitates differentiation of long-lived antibody-secreting cells. Short-term IgG secretion occurs independently of TACI as DNA double-strand breaks associated with isotype class switching induce Blimp-1 transiently, independently of TACI. Our results showing that TACI induces and maintains Blimp-1 provide, for the first time, a unified molecular and cellular mechanism explaining the primary features of common variable immune deficiency, exquisite vulnerability to infection with encapsulated organisms, lymphoproliferation, and hypogammaglobulinemia.     

Diffusion-weighted imaging for non-invasive and quantitative monitoring of bone marrow infiltration in patients with monoclonal plasma cell disease: a comparative study with histology

Bone marrow plasma cell infiltration is a crucial parameter of disease activity in monoclonal plasma cell disorders. Until now, the only way to quantify such infiltration was bone marrow biopsy or aspiration. Diffusion-weighted imaging (DWI) is a magnetic resonance imaging-technique that may mirror tissue cellularity by measuring random movements of water molecules. To investigate if DWI is capable of assessing bone marrow cellularity in monoclonal plasma cell disease, we investigated 56 patients with multiple myeloma or monoclonal gammopathy of undetermined significance, and 30 healthy controls using DWI of the pelvis and/or the lumbar spine. In 25 of 30 patients who underwent biopsy, bone marrow trephine and DWI could be compared. Of the patients with symptomatic disease 15 could be evaluated after systemic treatment. There was a positive correlation between the DWI-parameter apparent diffusion coefficient (ADC) and bone marrow cellularity as well as micro-vessel density (P<0·001 respectively). ADC was significantly different between patients and controls (P<0·01) and before and after systemic therapy (P<0·001). In conclusion, DWI enabled bone marrow infiltration to be monitored in a non-invasive, quantitative way, suggesting that after further investigations on larger patient groups this might become an useful tool in the clinical work-up to assess tumour burden.     

Regional contrast agent quantification in a mouse model of myocardial infarction using 3D cardiac T1 mapping

Background

Quantitative relaxation time measurements by cardiovascular magnetic resonance (CMR) are of paramount importance in contrast-enhanced studies of experimental myocardial infarction. First, compared to qualitative measurements based on signal intensity changes, they are less sensitive to specific parameter choices, thereby allowing for better comparison between different studies or during longitudinal studies. Secondly, T₁ measurements may allow for quantification of local contrast agent concentrations. In this study, a recently developed 3D T₁ mapping technique was applied in a mouse model of myocardial infarction to measure differences in myocardial T₁ before and after injection of a liposomal contrast agent. This was then used to assess the concentration of accumulated contrast agent.

Materials and methods

Myocardial ischemia/reperfusion injury was induced in 8 mice by transient ligation of the LAD coronary artery. Baseline quantitative T₁ maps were made at day 1 after surgery, followed by injection of a Gd-based liposomal contrast agent. Five mice served as control group, which followed the same protocol without initial surgery. Twenty-four hours post-injection, a second T₁ measurement was performed. Local ΔR₁ values were compared with regional wall thickening determined by functional cine CMR and correlated to ex vivo Gd concentrations determined by ICP-MS.

Results

Compared to control values, pre-contrast T₁ of infarcted myocardium was slightly elevated, whereas T₁ of remote myocardium did not significantly differ. Twenty-four hours post-contrast injection, high ΔR₁ values were found in regions with low wall thickening values. However, compared to remote tissue (wall thickening > 45%), ΔR₁ was only significantly higher in severe infarcted tissue (wall thickening < 15%). A substantial correlation (r = 0.81) was found between CMR-based ΔR₁ values and Gd concentrations from ex vivo ICP-MS measurements. Furthermore, regression analysis revealed that the effective relaxivity of the liposomal contrast agent was only about half the value determined in vitro.

Conclusions

3D cardiac T₁ mapping by CMR can be used to monitor the accumulation of contrast agents in contrast-enhanced studies of murine myocardial infarction. The contrast agent relaxivity was decreased under in vivo conditions compared to in vitro measurements, which needs consideration when quantifying local contrast agent concentrations.     

Computer-aided diagnosis: how to move from the laboratory to the clinic

Computer-aided diagnosis (CAD), encompassing computer-aided detection and quantification, is an established and rapidly growing field of research. In daily practice, however, most radiologists do not yet use CAD routinely. This article discusses how to move CAD from the laboratory to the clinic. The authors review the principles of CAD for lesion detection and for quantification and illustrate the state-of-the-art with various examples. The requirements that radiologists have for CAD are discussed: sufficient performance, no increase in reading time, seamless workflow integration, regulatory approval, and cost efficiency. Performance is still the major bottleneck for many CAD systems. Novel ways of using CAD, extending the traditional paradigm of displaying markers for a second look, may be the key to using the technology effectively. The most promising strategy to improve CAD is the creation of publicly available databases for training and validation. This can identify the most fruitful new research directions, and provide a platform to combine multiple approaches for a single task to create superior algorithms.