In vitro examination of the thrombolytic efficacy of tenecteplase and therapeutic ultrasound compared to rt-PA.

BACKGROUND: Optimizing thrombolytic therapy is vital for improving stroke outcomes. We aimed to develop standardized thrombolysis conditions to evaluate the efficacy of tenecteplase (TNK) compared to the current gold standard rt-PA (alteplase), with and without additional ultrasound treatment. We also wanted to introduce a new analytical approach to quantify fibrin fiber density in transmission electron microscopy (TEM). METHODS: In vitro clots that are similar to ex vivo clots concerning their histological condition and their durability were generated from whole blood. For five treatment groups we compared relative clot weight loss (each n = 60) and fibrin fiber density in TEM (each n = 5). The control group (A) was treated only with plasma. Two groups were designated for each rt-PA (B + C) and TNK (D + E). Groups C and E were additionally treated with ultrasound. Dosages were 50 µg/ml for rt-PA and 30 µg/ml for TNK. Results were evaluated by using analyses of variance (ANOVA) and post-hoc t-tests. RESULTS: Weight loss was increased significantly for all groups compared to the control group. Both TNK groups showed significantly increased weight loss compared to their counterpart rt-PA group (p ≤ 0.001). For TEM only group D showed significantly decreased fibrin fiber density (p < 0.05) compared to both rt-PA groups. Ultrasound did not significantly increase dissolution of clots with either method (best p = 0.16). CONCLUSIONS: Tenecteplase dissolved clots more effectively than rt-PA with and without ultrasound. A higher sample size could provide more convincing results for TEM.

Neural underpinnings of nocebo hyperalgesia in visceral pain: A fMRI study in healthy volunteers.

Despite the clinical relevance of nocebo effects, few studies have addressed their underlying neural mechanisms in clinically-relevant pain models. We aimed to address the contribution of nocebo effects and their underlying neural circuitry to central pain amplification in visceral pain, as it may develop over repeated painful experiences due to negative pain-related expectations. Healthy volunteers received verbal suggestions of pain sensitization (nocebo group, N=28) or neutral instructions (control group, N=16). fMRI was used to investigate changes in neural responses during cued pain anticipation and painful rectal distensions delivered in successive fMRI sessions. Pain intensity was rated trial-by-trial, and expected pain intensity, state anxiety and tension were assessed prior to each session. Behavioral analyses demonstrated significantly greater increases in both expected and perceived pain in the nocebo group. The fMRI analysis performed on nocebo-responders only (N=14) revealed that these behavioral changes were associated with increased activation within the secondary somatosensory cortex and amygdala during pain anticipation and within the thalamus, insula and amygdala during painful stimulation when compared to controls. A subsequent psycho-physiological interaction analysis of the pain phase showed increased functional connectivity between the anterior insula, which was set-up as seed region based on group results, and midcingulate cortex as a function of negative expectations. These findings support that negative pain-related expectations can play a crucial role in pain amplification of visceral pain, which is mediated, at least in part, by a neural up-regulation of pain-associated areas and their connectivity. These findings may have implications for the pathophysiology and treatment of chronic abdominal pain.