What 'translating science' can learn from 'translating languages'.

One of the most important steps in drug discovery is the translation of preclinical data to humans. However, the term 'translation' has numerous connotations and, often, different stakeholders literally speak different languages. Learning from many years of experience and new concepts in language translation could increase the success rate in translating biomedical research.

[Development and validation of novel clinical endpoints in intermediate age-related macular degeneration in MACUSTAR].

Background: Currently, no validated clinical endpoints for treatment studies exist for intermediate age-related macular degeneration (iAMD).

Objective: The European MACUSTAR study aims to develop and clinically validate adequate clinical endpoints for future treatment studies in iAMD and to identify early determinants of disease progression to late stage AMD.

Material And Methods: The MACUSTAR study protocol was developed by an international consortium of researchers from academia, the pharmaceutical industry and medical device companies.

The Developing Regorafenib Eye drops for neovascular Age-related Macular degeneration (DREAM) study: an open-label phase II trial.

Aims: This programme investigated topical regorafenib, a multikinase inhibitor, in patients with neovascular age-related macular degeneration (nAMD).

Methods: Topical regorafenib was investigated in an open-label, phase IIa/b study in which patients with choroidal neovascularization (CNV) secondary to nAMD received regorafenib (25 μl, 30 mg ml ) three times a day for 12 weeks. The primary endpoint of the phase II/a/b study was mean change in best-corrected visual acuity (BCVA) from baseline to weeks 4 and 12.

Topical administration of regorafenib eye drops: phase I dose-escalation study in healthy volunteers.

Aim: Regorafenib is a multikinase inhibitor under investigation for use in neovascular age-related macular degeneration. In this phase I study, regorafenib eye drops were administered to healthy volunteers to provide information on safety, tolerability and systemic exposure.

Methods: This was a single-centre, randomized, double-masked, parallel-group, dose-escalation, placebo-controlled study.

Humans, but not animals, perceive the thermal grill illusion as painful.

Simultaneous presentation of alternating innocuous warm and cold stimuli induces in most humans a painful sensation called thermal grill illusion (TGI). Here, pain is elicited although nociceptors are not activated. Upon back-translation of behavioural correlates from humans to animals, we found that neither cats nor rodents show adverse reactions when exposed to TGI stimulation.

Antigen-induced arthritis in rats is associated with increased growth-associated protein 43-positive intraepidermal nerve fibres remote from the joint.

Introduction: Pain in arthritis may be experienced in regions outside the affected joint, and hyperalgesia may even be widespread. The spread of pain is usually attributed to mechanisms in the central nervous system. We investigated whether rats with antigen-induced arthritis (AIA) exhibit peripheral changes in skin innervation remote from the inflamed joint.

Long-Lasting Activation of the Transcription Factor CREB in Sensory Neurons by Interleukin-1β During Antigen-Induced Arthritis in Rats: A Mechanism of Persistent Arthritis Pain?

Objective: In spite of successful treatment of immune-mediated arthritis, many patients still experience pain. We undertook this study to investigate whether antigen-induced arthritis (AIA) in rats triggers neuronal changes in sensory neurons that outlast the inflammatory process.

Methods: We induced unilateral AIA in the knee joint and assessed in sensory neurons the expression of CREB, a transcription factor that regulates genes involved in neuronal plasticity.

Enhanced neurogenesis in the hippocampal dentate gyrus during antigen-induced arthritis in adult rat--a crucial role of immunization.

Neurogenesis in the subgranular zone of the mammalian hippocampal dentate gyrus contributes significantly to brain neuroplasticity. There is evidence that inflammation of the central nervous system inhibits neurogenesis but peripheral inflammation such as antigen-induced arthritis may rather enhance neurogenesis. Manifest arthritis is associated with symptoms such as pain and altered locomotion indicating that peripheral inflammation is associated with changes of both the immune system and the nervous system.

Repeated autologous intraarticular blood injections as an animal model for joint pain in haemophilic arthropathy.

Introduction: Haemophilic arthropathy following recurrent joint bleedings is one of the major disease-related complications in people with haemophilia (PWH), leading to mostly chronic joint pain. Since many antinociceptive principles interfere with the clotting system, PWH are restricted in treatment options, thereby defining a medical need for novel therapeutic principles. However, we lack the availability of an animal model for joint pain in haemophilic arthropathy for testing these.

Neuronal prostaglandin E2 receptor subtype EP3 mediates antinociception during inflammation.

The pain mediator prostaglandin E2 (PGE2) sensitizes nociceptive pathways through EP2 and EP4 receptors, which are coupled to Gs proteins and increase cAMP. However, PGE2 also activates EP3 receptors, and the major signaling pathway of the EP3 receptor splice variants uses inhibition of cAMP synthesis via Gi proteins. This opposite effect raises the intriguing question of whether the Gi-protein-coupled EP3 receptor may counteract the EP2 and EP4 receptor-mediated pronociceptive effects of PGE2.

Assessment of rat antigen-induced arthritis and its suppression during glucocorticoid therapy by use of hemicyanine dye probes with different molecular weight in near-infrared fluorescence optical imaging.

Purpose: Arthritic joints are ideal disease entities to be assessed via optical imaging. Here, we investigated the selective accumulation behavior of two differently sized hemicyanine optical probes in arthritic joints and its modification during glucocorticoid therapy in the course of inflammation.

Materials And Methods: The well-standardized preclinical antigen-induced arthritis (AIA) model in rats was used.

Thresholds and perception of cold pain, heat pain, and the thermal grill illusion in patients with major depressive disorder.

Objective: The thermal grill illusion (TGI) in which interlacing cold and warm bars create the illusion of a painful sensation has been suggested as an experimental model for central pain states and pain processing. The aim of this study was to use this technique to gain further insights into the altered pain perception in major depressive disorder (MDD).

Methods: In 18 unmedicated patients with MDD, cold and heat pain thresholds (CPT/HPT) as well as the perception of the TGI were examined and compared with 18 matched controls.

Neuronal IL-17 receptor upregulates TRPV4 but not TRPV1 receptors in DRG neurons and mediates mechanical but not thermal hyperalgesia.

In addition to the proinflammatory cytokines tumor necrosis factor-α, interleukin-6 and interleukin-1ß, the cytokine interleukin-17 (IL-17) is considered an important mediator of autoimmune diseases such as rheumatoid arthritis. Because tumor necrosis factor-α and interleukin-1ß have the potential to influence the expression of transduction molecules such as transient receptor potential vanilloid 1 (TRPV1) in dorsal root ganglion (DRG) neurons and thus to contribute to pain we explored in the present study whether IL-17A activates DRG neurons and influences the expression of TRPV1. The IL-17A receptor was visualized in most neurons in dorsal root ganglion (DRG) sections as well as in cultured DRG neurons.

Vagus nerve stimulation ameliorated deficits in one-way active avoidance learning and stimulated hippocampal neurogenesis in bulbectomized rats.

Background: Vagus nerve stimulation (VNS) has been introduced as a therapeutic option for treatment-resistant depression. The neural and chemical mechanisms responsible for the effects of VNS are largely unclear.

Methods: Bilateral removal of the olfactory bulbs (OBX) is a validated animal model in depression research.

The anti-inflammatory effects of sympathectomy in murine antigen-induced arthritis are associated with a reduction of Th1 and Th17 responses.

Background: Both facilitatory and inhibitory effects of the sympathetic nervous system (SNS) on experimental arthritis have been reported. It is unknown whether such bidirectional effects are inherent to all experimental arthritis models and/or whether critical time windows exist for influences of the SNS on inflammation.

Objectives: To assess the effect of sympathectomy at different time points on the course and severity of murine antigen-induced arthritis (AIA).

Evaluation of long-term antinociceptive properties of stabilized hyaluronic acid preparation (NASHA) in an animal model of repetitive joint pain.

Introduction: Clinical trials provided controversial results on whether the injection of hyaluronan preparations into osteoarthritic joints reduces pain. Problems of clinical studies may be the substantial placebo effects of intra-articular injections, different severity and rate of progression of the disease and others. We hypothesize that the use of preclinical pain models may help to clarify whether a certain hyaluronan exerts antinociceptive effects upon intra-articular injection.

Endothelial dysfunction during acute alcohol withdrawal syndrome.

Background: Endothelial dysfunction (EF) is a central phenomenon in a variety of conditions associated with increased cardiovascular morbidity. Here, we investigated EF during acute alcohol withdrawal syndrome before and 24h after medication. We aimed to analyze microcirculation, applying the post-occlusive reactive hyperemia (PORH) test and spectral analysis of skin vasomotion as markers of EF.

Videoradiographic analysis of the range of motion in unilateral experimental knee joint arthritis in rats.

Introduction: The translational and predictive value of animal models highly depends on the validity of respective readout parameters. In arthritis research, there has been a shift from sole threshold testing for pain-related behavior, as well as from swelling and histology assessment for inflammation, toward an analysis of joint function as indicated, for instance, by an increasing number of studies on gait abnormalities. Clinically, the range of motion (ROM) of the affected joint plays a major role in diagnosis and the assessment of treatment benefits.

Joint pain in people with hemophilia depends on joint status.

Recurrent joint bleedings in people with hemophilia (PWH) often progress into the full clinical picture of hemophilic arthropathy, accompanied by chronic pain. Although chronic pain is commonly present in PWH, investigations assessing pain thresholds have not been performed yet. Thus, the aim of this study was to obtain objective and subjective measures of joint pain in PWH and to relate these to the severity of joint pathology.

Nonlinear relationship between electrodermal activity and heart rate variability in patients with acute schizophrenia.

We investigated to what degree tonic skin conductance levels (SCL) and cardiac autonomic dysfunction are interrelated in schizophrenia. Heart rate variability (HRV) and SCL were simultaneously assessed in 18 unmedicated patients and 18 controls matched for age, sex, weight, and smoking habits. For comparison to prior studies, phasic sympathetic skin responses (SPR) were also recorded.

Gender-dependent impact of major depression on autonomic cardiovascular modulation.

Depression has been shown to increase the risk for cardiovascular disease (CVD) more strongly in women than in men. Although the underlying mechanisms are unknown, a putative role of increased sympathetic modulation has been suggested for the association of CVD and depression. The aim of this study was to investigate possible gender-associated differences of autonomic function in healthy volunteers and patients suffering from major depressive disorder (MDD).

Peripheral endothelial dysfunction in patients suffering from acute schizophrenia: a potential marker for cardiovascular morbidity?

Patients suffering from schizophrenia have an increased standardized ratio for cardiovascular mortality compared to the general population. Endothelial function was identified as a prominent parameter for cardiac risk stratification in patients with heart disease. Here, we aimed to analyze the reactivity of the microcirculation applying the post-occlusive reactive hyperemia (PORH) test and spectral analysis of skin vasomotion as markers of endothelial function.

Pseudohypoalgesia on the skin: a novel view on the paradox of pain perception in depression.

Previous studies reported increased heat pain thresholds and decreased ischemic pain thresholds in patients experiencing depression. The increased sensitivity to ischemic muscle pain was assumed to represent a model for the investigation of physical symptoms in the disease. Here, we explored how the serotonin and noradrenaline reuptake inhibitor duloxetine influences experimental pain thresholds and tolerances in depressed patients during treatment.

Sad mood increases pain sensitivity upon thermal grill illusion stimulation: implications for central pain processing.

In different fields of neuroscience research, illusions have successfully been used to unravel underlying mechanisms of stimulus processing. One such illusion existing for the field of pain research is the so-called thermal grill illusion. Here, painful sensations are elicited by interlacing warm and cold bars, with stimulus intensities (temperatures) of these bars being below the respective heat pain or cold pain thresholds.

Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition.

Synaptic inhibition is a central factor in the fine tuning of neuronal activity in the central nervous system. Symptoms consistent with reduced inhibition such as stiffness, spasms and anxiety occur in paraneoplastic stiff person syndrome with autoantibodies against the intracellular synaptic protein amphiphysin. Here we show that intrathecal application of purified anti-amphiphysin immunoglobulin G antibodies induces stiff person syndrome-like symptoms in rats, including stiffness and muscle spasms.