The effects of 5-fluorouracil and interferon-alpha on early healing of experimental intestinal anastomoses.

The continuing search for effective adjuvant therapy after resection of intestinal malignancies has prompted a growing interest in both immediate post-operative regional chemotherapy and the combination of 5-fluorouracil (5-FU) and interferon-alpha as drugs of choice. We have compared the effects of both compounds, alone and together, on early healing of intestinal anastomoses. Four groups (n = 26 each) of rats underwent resection and anastomosis of both ileum and colon: a control group and three groups receiving intraperitoneal 5-FU, interferon-alpha or both on the day of surgery and the next 2 days. Animals were killed 3 or 7 days (n = 10 each) after operation in order to measure anastomotic strength and hydroxyproline content. The remaining six animals in each group were used to study anastomotic collagen synthetic capacity at day 3. Three days after operation, ileal anastomotic bursting pressure was lowered by 37% in the 5-FU/interferon-alpha group (P = 0.0104). At day 7, anastomotic breaking strength was reduced significantly in ileum (P = 0.0221) and colon (P = 0.0054) of the 5-FU/interferon-alpha group and in colon of the interferon-alpha group (P = 0.0221). Collagen synthetic capacity was strongly suppressed by 5-FU but not by interferon-alpha. However, no differences in anastomotic hydroxyproline content were observed between groups at both days 3 and 7. Thus, post-operative use of interferon-alpha, in particular in combination with 5-FU, may be detrimental to anastomotic repair in the intestine

The influence of alcohol (0.5‰) on the control and manoeuvring level of driving behaviour, finding measures to assess driving impairment:A simulator study

Objective: The influence of psychoactive substances on driving performance and traffic safety has been extensively studied. Research on the influence of alcohol at the control level of behaviour (i.e. automated processes) has been well established and has shown that the ability to operate a vehicle decreases with rising alcohol levels. However, results one level higher at the manoeuvring level (i.e. conscious processes), are inconsistent. The current study aimed to replicate findings on the influence of alcohol on the control level of behaviour and investigate effects on the manoeuvring level in order to find suitable measures to assess driving impairment. Method: The study was double-blind, placebo-controlled with a counterbalanced treatment order and a two-way crossover design. Thirty participants performed tasks in a driving simulator under the influence of alcohol (0.5‰) and a placebo. In the driving tasks the control level of behaviour (swerving, average speed, and speed variation) was investigated, as well as the manoeuvring level of behaviour (distance to other traffic during an overtaking manoeuvre, reaction time to a traffic light turning amber, and response to a suddenly merging car). Results: As expected, alcohol affected the control level of behaviour negatively. Participants swerved more and showed more speed variation after alcohol intake. The manoeuvring level of driving behaviour was also affected by alcohol. The distance to other drivers during an overtaking manoeuvre was smaller under the influence of alcohol. Results on reaction time were however less straightforward. Reaction time increased significantly under the influence of alcohol when reacting to a traffic light but not in reaction to a car unexpectedly merging into traffic. When analysing behaviour in reaction to these different events in more detail it became clear that they were responded to in varying manners, making it difficult to find an average impairment measure. Conclusions: The deteriorating effect of alcohol at the control level of driving behaviour was replicated, confirming the suitability of the standard deviation of lateral position and the variation in speed as measures of impairment. At the manoeuvring level, the kept distance to the leading car during an overtaking manoeuvre appeared to be a suitable measure to assess impairment as well as reaction time to a traffic light. The current study also confirms the difficulties in evaluating complex driving behaviour and the need for more research on this subject

The influence of music on mood and performance while driving

Mood can influence our everyday behaviour and people often seek to reinforce, or to alter their mood, for example by turning on music. Music listening while driving is a popular activity. However, little is known about the impact of music listening while driving on physiological state and driving performance. In the present experiment, it was investigated whether individually selected music can induce mood and maintain moods during a simulated drive. In addition, effects of positive, negative, and no music on driving behaviour and physiological measures were assessed for normal and high cognitive demanding rides. Subjective mood ratings indicated that music successfully maintained mood while driving. Narrow lane width drives increased task demand as shown in effort ratings and increased swerving. Furthermore, respiration rate was lower during music listening compared to rides without music, while no effects of music were found on heart rate. Overall, the current study demonstrates that music listening in car influences the experienced mood while driving, which in turn can impact driving behaviour. Practitioners Summary: Even though it is a popular activity, little is known about the impact of music while driving on physiological state and performance. We examined whether music can induce moods during high and low simulated drives. The current study demonstrates that in car music listening influences mood which in turn can impact driving behaviour. The current study shows that listening to music can positively impact mood while driving, which can be used to affect state and safe behaviour. Additionally, driving performance in high demand situations is not negatively affected by music

Synaptic proteome changes in a DNA repair deficient Ercc1 mouse model of accelerated aging

Cognitive decline is one of the earliest hallmarks of both normal and pathological brain aging. Here we used Ercc1 mutant mice, which are impaired in multiple DNA repair systems and consequently show accelerated aging and progressive memory deficits, to identify changes in the levels of hippocampal synaptic proteins that potentially underlie these age-dependent deficits. Aged Ercc1 mutant mice show normal gross hippocampal dendritic morphology and synapse numbers, and Ercc1 mutant hippocampal neurons displayed normal outgrowth and synapse formation in vitro. However, using isobaric tag for relative and absolute quantification (iTRAQ) of hippocampal synaptic proteins at two different ages, postnatal days 28 and 112, we observed a progressive decrease in synaptic ionotropic glutamate receptor levels and increased levels of G-proteins and of cell adhesion proteins. These together may cause long-term changes in synapse function. In addition, we observed a downregulation of mitochondrial proteins and concomitant upregulation of Na,K-ATPase subunits, which might compensate for reduced mitochondrial activity. Thus, our findings show that under conditions of apparent intact neuronal connectivity, levels of specific synaptic proteins are already affected during the early stages of DNA damage-induced aging, which might contribute to age-dependent cognitive decline

Driving performance and neurocognitive skills of long-term users of sedating antidepressants

Objective: To assess driving performance and neurocognitive skills of long‐term users of sedating antidepressants, in comparison to healthy controls. Methods: Thirty‐eight long‐term (>6 months) users of amitriptyline (n = 13) and mirtazapine (n = 25) were compared to 65 healthy controls. Driving performance was assessed using a 1‐h standardised highway driving test in actual traffic, with road‐tracking error (standard deviation of lateral position [SDLP]) being the primary measure. Secondary measures included neurocognitive tasks related to driving. Performance differences between groups were compared to those of blood alcohol concentrations of 0.5 mg/ml to determine clinical relevance. Results: Compared to controls, mean increase in SDLP of all antidepressant users was not significant, nor clinically relevant (+0.75 cm, 95% CI: - 0.83 cm; +2.33 cm). However, users treated less than 3 years (n = 20) did show a significant and clinically relevant increase in SDLP (+2.05 cm). No significant effects were observed on neurocognitive tasks for any user group, although large individual differences were present. Most results from neurocognitive tests were inconclusive, while a few parameters confirmed non‐inferiority for users treated longer than 3 years. Conclusion: The impairing effects of antidepressant treatment on driving performance and neurocognition mitigate over time following long‐term use of 3 years

Reducing Microvascular Dysfunction in Revascularized Patients with ST-Elevation Myocardial Infarction by Off-Target Properties of Ticagrelor versus Prasugrel. Rationale and Design of the REDUCE-MVI Study

Microvascular injury is present in a large proportion of patients with ST-elevation myocardial infarction (STEMI) despite successful revascularization. Ticagrelor potentially mitigates this process by exerting additional adenosine-mediated effects. This study aims to determine whether ticagrelor is associated with a better microvascular function compared to prasugrel as maintenance therapy after STEMI. A total of 110 patients presenting with STEMI and additional intermediate stenosis in another coronary artery will be studied after successful percutaneous coronary intervention (PCI) of the infarct-related artery. Patients will be randomized to treatment with ticagrelor or prasugrel for 1 year. FFR-guided PCI of the non-infarct-related artery will be performed at 1 month. Microvascular function will be assessed by measurement of the index of microcirculatory resistance (IMR) in the infarct-related artery and non-infarct-related artery, immediately after primary PCI and after 1 month. The REDUCE-MVI study will establish whether ticagrelor as a maintenance therapy may improve microvascular function in patients after revascularized STEMI

An explorative approach to understanding individual differences in driving performance and neurocognition in long-term benzodiazepine users

Objective: Previous research reported cognitive and psychomotor impairments in long‐term users of benzodiazepine receptor agonists (BZRAs). This article explores the role of acute intoxication and clinical complaints. Methods: Neurocognitive and on‐road driving performance of 19 long‐term (≥6 months) regular (≥twice weekly) BZRA users with estimated plasma concentrations, based on self‐reported use, exceeding the therapeutic threshold (CBZRA+), and 31 long‐term regular BZRA users below (CBZRA−), was compared to that of 76 controls. Results: BZRA users performed worse on tasks of response speed, processing speed, and sustained attention. Age, but not CBZRA or self‐reported clinical complaints, was a significant covariate. Road‐tracking performance was explained by CBZRA only. The CBZRA + group exhibited increased mean standard deviation of lateral position comparable to that at blood‐alcohol concentrations of 0.5 g/L. Conclusions: Functional impairments in long‐term BZRA users are not attributable to self‐reported clinical complaints or estimated BZRA concentrations, except for road‐tracking, which was impaired in CBZRA + users. Limitations to address are the lack of assessment of objective clinical complaints, acute task related stress, and actual BZRA plasma concentrations. In conclusion, the results confirm previous findings that demonstrate inferior performance across several psychomotor and neurocognitive domains in long‐term BZRA users