Effect of hirudin versus heparin on hemocompatibility of blood contacting biomaterials: an in vitro study

Hirudin serves as an alternative anticoagulant for extracorporeal blood circulation. Comparing anticoagulation with hirudin (2.5 or 5.0 microg/mL) and heparin (2.0 or 4.0 IU/mL) human blood was circulated in a modified 'Chandler System' using PVC-tubes for 2 hours at 37 degrees C. Activation of coagulation (thrombin-antithrombin III-complex, prothrombin fragment 1+2 and D-Dimer), platelet (platelet factor 4 - PF4) and complement systems was analyzed. Both heparin concentrations and 5.0 microg/dL hirudin led to as significantly less activated plasmatic coagulation as 2.5 microg/dL hirudin. Decreased levels of PF4 and anaphylatoxin C5a (p<0.05) as well as terminal complement complex demonstrated improved hemocompatibility after anticoagulation with heparin in contrast to hirudin. Because initial coagulation cascade, platelet activation and complement activation is less influenced by hirudin than by heparin, hemocompatibility is more dependent on the characteristics of the biomaterials used. This predestines hirudin as anticoagulant for in vitro studies analyzing hemocompatibility of biomaterials or surface modifications.     

Effects of Combined Vitamin K2 and Vitamin D3 Supplementation on Na[18F]F PET/MRI in Patients with Carotid Artery Disease: The INTRICATE Rationale and Trial Design

INTRICATE is a prospective double-blind placebo-controlled feasibility study, assessing the influence of combined vitamin K2 and vitamin D3 supplementation on micro-calcification in carotid artery disease as imaged by hybrid Sodium [¹⁸F]Fluoride (Na[¹⁸F]F) positron emission tomography (PET)/ magnetic resonance imaging (MRI). Arterial calcification is an actively regulated process and results from the imbalance between calcification promoting and inhibiting factors. Considering the recent advancements in medical imaging, ultrasound (US), PET/MRI, and computed tomography (CT) can be used for the selection and stratification of patients with atherosclerosis. Fifty-two subjects with asymptomatic carotid artery disease on at least one side of the neck will be included in the study. At baseline, an Na[¹⁸F]F PET/MRI and CT examination will be performed. Afterwards, subjects will be randomized (1:1) to a vitamin K (400 µg MK-7/day) and vitamin D3 (80 µg/day) or to placebo. At the 3-month follow-up, subjects will undergo a second Na[¹⁸F]F PET/MRI and CT scan. The primary endpoint is the change in Na[¹⁸F]F PET/MRI (baseline vs. after 3 months) in the treatment group as compared to the placebo arm. Secondary endpoints are changes in plaque composition and in blood-biomarkers. The INTRICATE trial bears the potential to open novel avenues for future large scale randomized controlled trials to intervene in the plaque development and micro-calcification progression.     

Evaluation of tumour hypoxia during radiotherapy using [<Superscript>18</Superscript>F]HX4 PET imaging and blood biomarkers in patients with head and neck cancer

Background and purpose

Increased tumour hypoxia is associated with a worse overall survival in patients with head and neck squamous cell carcinoma (HNSCC). The aims of this study were to evaluate treatment-associated changes in [¹⁸F]HX4-PET, hypoxia-related blood biomarkers, and their interdependence.

Material and methods

[¹⁸F]HX4-PET/CT scans of 20 patients with HNSCC were acquired at baseline and after ±20Gy of radiotherapy. Within the gross-tumour-volumes (GTV; primary and lymph nodes), mean and maximum standardized uptake values, the hypoxic fraction (HF) and volume (HV) were calculated. Also, the changes in spatial uptake pattern were evaluated using [¹⁸F]HX4-PET/CT imaging. For all patients, the plasma concentration of CAIX, osteopontin and VEGF was assessed.

Results

At baseline, tumour hypoxia was detected in 69 % (22/32) of the GTVs. During therapy, we observed a significant decrease in all image parameters. The HF decreased from 21.7?±?19.8 % (baseline) to 3.6?±?10.0 % (during treatment; P?<?0.001). Only two patients had a HV?>?1 cm³ during treatment, which was located for >98 % within the baseline HV. During treatment, no significant changes in plasma CAIX or VEGF were observed, while osteopontin was increased.

Conclusions

[¹⁸F]HX4-PET/CT imaging allows monitoring changes in hypoxia during (chemo)radiotherapy whereas the blood biomarkers were not able to detect a treatment-associated decrease in hypoxia.

     

Striatal dopamine release and impaired reinforcement learning in adults with 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11DS) is a genetic disorder caused by a microdeletion on chromosome 22q11.2 and associated with an increased risk for developing psychosis. The catechol-O-methyltransferase (COMT) gene is located in the deleted region and involved in dopamine (DA) breakdown. Impaired reinforcement learning (RL) is a recurrent feature in psychosis and thought to be related to abnormal striatal DA function. This study aims to examine RL and the potential association with striatal DA-ergic neuromodulation in 22q11DS. Twelve non-psychotic adults with 22q11DS and 16 healthy controls (HC) were included. A dopamine D_2/3 receptor [¹⁸F]fallypride positron emission tomography (PET) scan was acquired while participants performed a modified version of the probabilistic stimulus selection task. RL-task performance was significantly worse in 22q11DS compared to HC. There were no group difference in striatal nondisplaceable binding potential (BP_ND) and task-induced DA release. In HC, striatal task-induced DA release was positively associated with task performance, but no such relation was found in 22q11DS subjects. Moreover, higher caudate nucleus task-induced DA release was found in COMT Met hemizygotes relative to Val hemizygotes. This study is the first to show impairments in RL in 22q11DS. It suggests that potentially motivational impairments are not only present in psychosis, but also in this genetic high risk group. These deficits may be underlain by abnormal striatal task-induced DA release, perhaps as a consequence of COMT haplo-insufficiency.     

Significance of PET for ENT-tumors

Significance for ENT-tumors. Molecular imaging with PET is based on the use of specific radioactive molecules as source of image contrast. In ENT-tumors mostly glucose and occasionally amino acid/protein metabolism were assessed with PET for tumor diagnosis. Thymidine salvage pathway and proliferation as well as tissue hypoxia are tested already in clinical studies and bear considerable potential for modulation of radiation ports and therapeutic response of cytoreductive regimens. This short review summarises actual clinical indications and potential of PET in ENT-tumors. For both nodal staging as well as detection of recurrent disease, sensitivity and specifity of FDG-PET were 80 - 100 %. FDG-PET proved to be superior to conventional imaging in most published studies. In CUP-syndrome the primary could be detected in 25 - 50 % of patients. Acquisition of PET and CT images in a combined scanner allow versatile PET based metabolic imaging in combination with high resolution and anatomical precise CT-based morphological imaging and thus combines advantages of both imaging modalities. Clinical as well as scientific potential of this functional metabolic and high resolution morphological imaging approach is high.     

Modulation of premotor mirror neuron activity during observation of unpredictable grasping movements

Using transcranial magnetic stimulation, we explored the properties of premotor mirror neurons during the passive observation of a reaching-grasping movement in human subjects. Two different experiments were run using video-clips as visual stimuli. Video-clips showed a normally performed (control stimulus) or an anomalous reaching-grasping movement executed by delaying the time of the appearance of the maximal finger aperture (experiment 1), or substituting it with an unpredictable closure (experiment 2). Motor evoked potentials were recorded at different time-points during the observation of the video-clips. Profiles of cortical excitability were drawn and compared with the kinematic profiles of the corresponding movement. Passive observation of the natural movement evoked a profile of cortical excitability that is in concordance with the timing of the kinematic profile of the shown finger movements. Observation of the uncommon movements did not exert any modulation (experiment 1) or evoked an activity that matched, at the beginning, the modulation obtained with observation of the natural movement (experiment 2). Results show that the resonant motor plan is loaded as whole at the beginning of observation and once started tends to proceed to its completion regardless of changes to the visual cues. The results exclude the possibility of a temporal fragmentation of the resonant plan, because activation of different populations of mirror neurons for each phase of the ongoing action. They further support the notion of the role of the mirror system as neural substrate for the observing-execution matching system and extend the current knowledge regarding mechanisms that trigger the internal representation of an action.