A novel GalR2-specific peptide agonist

The galanin peptide family and its three receptors have with compelling evidence been implicated in several high-order physiological disorders. The co-localization with other neuromodulators and the distinct up-regulation during and after pathological disturbances has drawn attention to this neuropeptide family. In the current study we present data on receptor binding and functional response for a novel galanin receptor type 2 (GalR2) selective chimeric peptide, M1145 [(RG)₂-N-galanin(2-13)-VL-(P)₃-(AL)₂-A-amide]. The M1145 peptide shows more than 90-fold higher affinity for GalR2 over GalR1 and a 76-fold higher affinity over GalR3. Furthermore, the peptide yields an agonistic effect in vitro, seen as an increase in inositol phosphate (IP) accumulation, both in the absence or the presence of galanin. The peptide design with a N-terminal extension of galanin(2-13), prevails new insights in the assembly of novel subtype specific ligands for the galanin receptor family and opens new possibilities to apply the galanin system as a putative drug target.     

Spinal Cord Stimulation in a Mouse Chronic Neuropathic Pain Model

Objective. Development of a spinal cord stimulation (SCS) system in a mouse model of chronic neuropathic pain. Materials and Methods. Male C57BL/6 mice (N = 6) underwent a partial ligation of the sciatic nerve. Development of mechanical hyperalgesia was tested using the withdrawal response to tactile stimuli with the von Frey test. An SCS system was implanted on day 14. On day 16, the mice were stimulated for 30 min (f = 50 Hz; pulse width 0.2 msec and stimulation at 2/3 of motor threshold). Repeated measure analysis of variance (anova ) and paired Student's t‐test with Bonferroni correction were used to evaluate the development of mechanical hyperalgesia and the therapeutic effect of SCS. Results. Five out of six mice developed marked mechanical hyperalgesia in the nerve‐lesioned paw that persisted for the duration of the study (16 days). No changes contralateral to the injury were observed. In four out of five mice, a successful implantation of the electrodes followed by stimulation was achieved. Then, SCS resulted in a fast and robust increase of withdrawal threshold back to pre‐injury levels. After termination of the SCS, the withdrawal threshold of the ipsilateral paw slowly decreased. No effect of SCS on the contralateral paw was noted. Conclusion. The development of a mouse SCS system is described that is practical in use, is reproducible, and shows a comparative therapeutic effect in treatment of chronic neuropathic pain as reported in rat.     

The breakdown of Fitts' law in rapid,reciprocal aiming movements

According to Fitts' law, there is speed-accuracy trade-off in a wide variety of discrete aiming movements. However, it is unknown whether the same law applies to cyclic aiming movements. In the present study, a comparison is made between discrete versus cyclic aiming movements. A group of 24 healthy participants made graphical pen movements in 12 different aiming tasks in which successive finger and wrist movements were emphasized, consecutively executed as discrete and cyclic movements and varying in three target widths. In the cyclic condition, aiming movements consisted of back-and-forth movements that were performed in immediate succession for 20 s. In the discrete condition, back-and-forth aiming movements were drawn as 20 single strokes, starting after a go signal and stopping after reaching the target area. The targets had various levels of spatial accuracy and the movements had different directions (from lower left to upper right; from lower right to upper left) elicit either predominantly wrist or finger movements. The amount of information processed per unit of time (bits per second; index of performance, IP), tangential velocity, the pen pressure, and the ratio of peak-over-mean velocity were studied to gain understanding about the differences in control between discrete and cyclic movements. It was found that the IP and movement velocity were almost twice as large in cyclic versus discrete movements. In contrast, the axial pen pressure and the ratios of peak-over-mean velocity were much lower in cyclic movements (1.24 N versus 0.94 N; 2.26 N versus 1.81 N). The results of our study indicate that the predicted constant IP does not hold for rapid cyclic aiming movements and that speed-accuracy trade-off is different. It is concluded that cyclic movements exploit the energetic and physiological properties of the neuromotor system. Expected differences in brain activity related to discrete and cyclic aiming movements are discussed as well as several neurophysiological mechanisms, which predict more economic force recruitment and information processing in cyclic than in discrete movements.     

Retinal slip during active head motion and stimulus motion

Gaze control in various conditions is important, since retinal slip deteriorates the perception of 3-D shape of visual stimuli. Several studies have shown that visual perception of 3-D shape is better for actively moving observers than for passive observers watching a moving object. However, it is not clear to what extent the improved percept of 3-D shape for active observers has to be attributed to corollary discharges to higher visual centers or whether the improved percept might be due to improved gaze stabilization during active head movements. The aim of this study was to measure binocular eye movements and to make a quantitative comparison of retinal slip for subjects instructed to fixate a visual stimulus in an active condition (subject makes an active head movement, object is stationary) and in a passive condition (the stimulus moves, the subject is stationary) for various movement frequencies, viewing distances, and stimulus diameters. Retinal slip remains below the acuity threshold of about 4 deg/s in active conditions, except for the highest frequency tested in this study (1.5 Hz) for nearby targets (0.25 cm). Retinal slip exceeds this threshold for most passive conditions. These results suggest that the enhanced performance in the visual perception of 3-D shape during active head movements can, at least partly, be explained by better fixation by actively moving observers.     

Clericuzio type poikiloderma with neutropenia is distinct from Rothmund-Thomson syndrome

Two siblings from a consanguineous family presented with a poikiloderma of limbs and face, plantar keratoderma, and toenail pachyonychia. Neutropenia and neutrophil dysfunction with impairment of the respiratory burst and bacterial killing resulted in frequent respiratory tract infections. A bronchocentric granulomatous pneumonia was a fatal complication. The clinical presentation is consistent with Clericuzio type poikiloderma with neutropenia. Literature review identified several additional probable patients. Genetic linkage analysis excluded the locus of the RECQL4 gene, mutations in which have been described in some patients with the Rothmund-Thomson poikiloderma syndrome. This report confirms the clinical and genetic identity of the Clericuzio type of poikiloderma with neutropenia syndrome.     

Breeding for 50-kHz Positive Affective Vocalization in Rats

Adolescent and adult rats exhibit at least two distinct ultrasonic vocalizations that reflect distinct emotional states. Rats exhibit 22-kHz calls during social defeat, drug withdrawal, as well as in anticipation of aversive events. In contrast, 50-kHz calls are exhibited in high rates during play behavior, mating, as well as in anticipation of rewarding events. The neurochemistry of 22-kHz and 50-kHz calls closely matches that of negative and positive emotional systems in humans, respectively. The aim of this study was to replicate and further evaluate selective breeding for 50-kHz vocalization, in preparation for the analysis of the genetic underpinnings of the 50-kHz ultrasonic vocalization (USV). Isolate housed adolescent rats (23–26 days old) received experimenter administered tactile stimulation (dubbed tickling), which mimicked the rat rough-and-tumble play behavior. This stimulation has previously been shown to elicit high levels of 50-kHz USVs and to be highly rewarding in isolate-housed animals. Each tickling session consisted of 4 cycles of 15 seconds stimulation followed by 15 seconds no stimulation for a total of 2 min, and was repeated once per day across 4 successive days. Rats were then selected for either High or Low levels of sonographically verified 50-kHz USVs in response to the stimulation, and a randomly selected line served as a control (Random group). Animals emitted both 22-kHz and 50-kHz types of calls. After 5 generations, animals in the High Line exhibited significantly more 50-kHz and fewer 22-kHz USVs than animals in the Low Line. Animals selected for low levels of 50-kHz calls showed marginally more 22-kHz USVs then randomly selected animals but did not differ in the rate of 50-kHz calls. These results extend our previous findings that laboratory rats could be bred for differential rates of sonographically verified 50-kHz USVs.     

Resting-State Functional Connectivity of Antero-Medial Prefrontal Cortex Sub-Regions in Major Depression and Relationship to Emotional Intelligence

Background:

Major depressive disorder has been associated with abnormal resting-state functional connectivity (FC), especially in cognitive processing and emotional regulation networks. Although studies have found abnormal FC in regions of the default mode network (DMN), no study has investigated the FC of specific regions within the anterior DMN based on cytoarchitectonic subdivisions of the antero-medial pre-frontal cortex (PFC). Studies from different areas in the field have shown regions within the anterior DMN to be involved in emotional intelligence. Although abnormalities in this region have been observed in depression, the relationship between the ventromedial PFC (vmPFC) function and emotional intelligence has yet to be investigated in depressed individuals.

Methods:

Twenty-one medication-free, non–treatment resistant, depressed patients and 21 healthy controls underwent a resting state functional magnetic resonance imaging session. The participants also completed an ability-based measure of emotional intelligence: the Mayer-Salovey-Caruso Emotional Intelligence Test. FC maps of Brodmann areas (BA) 25, 10m, 10r, and 10p were created and compared between the two groups.

Results:

Mixed-effects analyses showed that the more anterior seeds encompassed larger areas of the DMN. Compared to healthy controls, depressed patients had significantly lower connectivity between BA10p and the right insula and between BA25 and the perigenual anterior cingulate cortex. Exploratory analyses showed an association between vmPFC connectivity and emotional intelligence.

Conclusions:

These results suggest that individuals with depression have reduced FC between antero-medial PFC regions and regions involved in emotional regulation compared to control subjects. Moreover, vmPFC functional connectivity appears linked to emotional intelligence.     

Low dialysate potassium and central arterial pressure waveform

Background

Cardiovascular mortality is high in hemodialysis (HD) patients. Early arterial pressure wave reflections predict mortality in HD patients, and HD acutely improves the central pressure waveform. Potassium (K) plays a crucial role in cardiac electrophysiology, and patients with end-stage kidney disease depend on HD for neutral K balance. We aimed to study the impact of dialysate K concentrations on central arterial pressure waveform.

Methods

Thirty-three chronic HD patients were studied before and after a HD session, and the prescribed dialysate K concentration was recorded. In a subset of 23 patients without arrhythmias, pulse wave analysis was performed on radial arteries. Nine patients had dialysate K set to 1 mmol/L (group 1), and 14 patients had K set to 2 or 3 mmol/L (group 2). Augmentation index (AIx), defined as difference between the second and first systolic peak divided by central pulse pressure, was used as a measure of arterial stiffness.

Results

HD reduced the AIx in group 1 only (p = 0.0005). Likewise, central systolic pressure was reduced in group 1 only (p = 0.006). The relative reduction of AIx post-HD was significantly higher in group 1 compared with group 2 (p < 0.0001). The association between low dialysate K and AIx reduction remained statistically significant after adjustment for variables including the change in central and peripheral systolic pressure and mean arterial pressure.

Conclusion

Low dialysate K is strongly and independently associated with the acute improvement of AIx.     

On the monitoring of dabigatran treatment in “real life” patients with atrial fibrillation

Introduction

The oral direct thrombin inhibitor dabigatran is increasingly used to prevent thromboembolic stroke in patients with atrial fibrillation (AF). Routine laboratory monitoring is currently not recommended, but measurements of dabigatran and/or its effect are desirable in certain situations. We studied dabigatran exposure and compared different tests for monitoring of dabigatran in a real-life cohort of AF patients.

Material and methods

Ninety AF patients (68 ± 9 years, 67% men, mean CHADS₂ score 1.5) were treated with dabigatran 150 (n = 73) or 110 mg BID (n = 17). Trough plasma concentrations of total and free dabigatran by liquid chromatography-tandem mass-spectrometry (LC-MS/MS) were compared to indirect measurements by Hemoclot thrombin inhibitors (HTI) and Ecarin clotting assay (ECA), as well as PT-INR and aPTT.

Results

Total plasma dabigatran varied 20-fold (12–237 ng/mL with 150 mg BID) and correlated well with free dabigatran (r² = 0.93). There were strong correlations between LC-MS/MS and HTI or ECA (p < 0.001) but these assays were less accurate with dabigatran below 50 ng/mL. The aPTT assay was not dependable and PT-INR not useful at all. There were weak correlations between creatinine clearance (Cockcroft-Gault) and LC-MS/MS, HTI and ECA (p < 0.001 for all). A high body weight with normal kidney function was associated with low dabigatran levels.

Conclusions

HTI and ECA reflect the intensity of dabigatran anticoagulation, but LC-MS/MS is required to quantify low levels or infer absence of dabigatran. Most real life patients with a normal creatinine clearance had low dabigatran levels suggesting a low risk of bleeding but possibly limited protection against stroke.     

Age-related differences in attentional cost associated with postural dual tasks: Increased recruitment of generic cognitive resources in older adults

Dual-task designs have been used widely to study the degree of automatic and controlled processing involved in postural stability of young and older adults. However, several unexplained discrepancies in the results weaken this literature. To resolve this problem, a careful selection of dual-task studies that met certain methodological criteria are considered with respect to reported interactions of age (young vs. older adults) × task (single vs. dual task) in stable and unstable postural conditions. Our review shows that older adults are able to perform a postural dual task as well as younger adults in stable conditions. However, when the complexity of the postural task is increased by dynamic conditions (surface and surround), performance in postural, concurrent, or both tasks is more affected in older relative to young adults. In light of neuroimaging studies and new conceptual frameworks, these results demonstrate an age-related increase of controlled processing of standing associated with greater intermittent adjustments.