Antibody-Recruitment as a Therapeutic Strategy: A Brief History and Recent Advances.

Antibodies are a significant and growing sector within the global pharmaceutical industry. The popularity of antibodies as therapeutics derives from - at least in part - evolvable affinity for virtually any disease-relevant cell surface receptor, as well as unique immunotherapeutic mechanisms of action, including neutralization, antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular cytotoxicity (ADCC). While advances in the large-scale expression and purification of therapeutic antibodies have been made, these remain costly and laborious tasks. Agents that redirect endogenous antibodies to target a pathogen or malignant cell obviate the need for new antibody discovery and production. Chimeric antibody-recruiting technologies consist of a target cell surface receptor binding domain, and an endogenous antibody-binding domain. By design, these agents bring endogenous antibodies to the surface of a target pathogen or diseased cell, which can result in targeted cytotoxicity by antibody-dependent mechanisms. This review highlights seminal contributions and recent advances in this growing and important therapeutic field.

Fluorescent Labeling and 2-Photon Imaging of Mouse Tooth Pulp Nociceptors.

Retrograde fluorescent labeling of dental primary afferent neurons (DPANs) has been described in rats through crystalline fluorescent DiI, while in the mouse, this technique was achieved with only Fluoro-Gold, a neurotoxic fluorescent dye with membrane penetration characteristics superior to the carbocyanine dyes. We reevaluated this technique in the rat with the aim to transfer it to the mouse because comprehensive physiologic studies require access to the mouse as a model organism. Using conventional immunohistochemistry, we assessed in rats and mice the speed of axonal dye transport from the application site to the trigeminal ganglion, the numbers of stained DPANs, and the fluorescence intensity via 1) conventional crystalline DiI and 2) a novel DiI formulation with improved penetration properties and staining efficiency. A 3-dimensional reconstruction of an entire trigeminal ganglion with 2-photon laser scanning fluorescence microscopy permitted visualization of DPANs in all 3 divisions of the trigeminal nerve. We quantified DPANs in mice expressing the farnesylated enhanced green fluorescent protein (EGFPf) from the transient receptor potential cation channel subfamily M member 8 (TRPM8EGFPf/+) locus in the 3 branches. We also evaluated the viability of the labeled DPANs in dissociated trigeminal ganglion cultures using calcium microfluorometry, and we assessed the sensitivity to capsaicin, an agonist of the TRPV1 receptor. Reproducible DiI labeling of DPANs in the mouse is an important tool 1) to investigate the molecular and functional specialization of DPANs within the trigeminal nociceptive system and 2) to recognize exclusive molecular characteristics that differentiate nociception in the trigeminal system from that in the somatic system. A versatile tool to enhance our understanding of the molecular composition and characteristics of DPANs will be essential for the development of mechanism-based therapeutic approaches for dentine hypersensitivity and inflammatory tooth pain.

Inter-institutional variation of systolic time intervals in normal subjects.

The study was designed to evaluate inter-institutional variability in systolic time interval (STI) measurement. STI records were obtained from 8 institutions in Czechoslovakia. Altogether 262 normal subjects of both sexes were evaluated. The conclusions of three independent investigators were compared for inter-observer variability assessment. No significant differences were found among the participating centres for electromechanical systole, left ventricular ejection time and pre-ejection time dependence on heart rate and for ratio preejection time-left ventricular ejection time. The regression equations obtained for these indicators were suggested as a national standard for normal subjects.

Automatized determination of left ventricular systolic intervals and assessment of their significance in the epidemiology of ischaemic heart disease.

Knowledge of the functional state of the myocardium in patients with coronary heart disease is of essential importance for the prognosis and therapy of the disease. The PEP/LVET index is closely correlated with the ejection fraction and is a reliable criterion for separating patients with normal and disturbed function of the left ventricle, but it does not suffice for uncovering an initial haemodynamic alteration either at rest or during isometric exercise test. The good reproducibility of systolic intervals makes possible a long-term follow-up of patients, especially in cases in which direct examination methods have limited applicability. Computer processing of polygraph tracings makes possible to analyse data of large groups of patients. The accuracy of systolic intervals determination matches that of the classical reading by two independent observes. The use of computing techniques in the analysis of curves and in their statistical evaluation contributes to the standardization of the whole measuring procedure and makes possible a wide clinical use of non-invasive polygraphic methods.

Measurement of systolic time intervals through non-invasive polygraphic techniques in healthy subjects and in patients with ischaemic heart disease. Comparison of results obtained by conventional and computer assisted means.

Computer processing of carotidograms is an incontestable methodical asset. Electronic detection of systolic time intervals excludes human errors, makes possible evaluation of a greater number of systoles, and reduces the effect of nonlinearities of recording. The proposed computerized system saves tedious manual calculations and can yield results with mutual correlations within a short period of time.