Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses

The tyrosine kinase inhibitors sorafenib and sunitinib are approved for the treatment of patients with malignant diseases. To analyze the possible use of these compounds in combination with immunotherapeutic approaches, we analyzed the effects of both inhibitors on the immunostimulatory capacity of human dendritic cells (DCs) and the induction of primary immune responses in vivo. Sorafenib, but not sunitinib, inhibits function of DCs, characterized by reduced secretion of cytokines and expression of CD1a, major histocompatibility complex, and costimulatory molecules in response to TLR ligands as well as by their impaired ability to migrate and stimulate T-cell responses. These inhibitory effects are mediated by inhibition of PI3 and MAP kinases and NFB signaling. In contrast, sorafenib had no influence on the phenotype and proliferation of T cells. To analyze the effects of both TKIs on cytotoxic T-cell induction in vivo, C57BL/6 mice were pretreated with sorafenib or sunitinib and immunized with OVA_257-264 peptide. Sorafenib, but not sunitinib, application significantly reduced the induction of antigen-specific T cells. Numbers of regulatory T cells were reduced in peripheral blood mononuclear cells from mice treated with sunitinib. These results indicate that sunitinib, but not sorafenib, is suitable for combination with immunotherapeutic approaches for treatment of cancer patients.     

Too little aspirin for secondary prevention after acute myocardial infarction in patients at high risk for cardiovascular events: Results from the MITRA study

Background

A meta-analysis of randomized trials has shown a significant reduction of mortality rate in patients receiving aspirin for secondary prevention after acute myocardial infarction (AMI). However, a significant number of patients do not receive aspirin after AMI. Little is known about why aspirin is withheld or the long-term outcome of these patients today.

Methods

The Maximal Individual Therapy in Acute Myocardial Infarction (MITRA) registry is a multicenter registry of patients with AMI in Germany.

Results

Of 4902 patients, 509 (10%) did not receive aspirin at the time of discharge from the hospital. The mean follow-up period for these patients was 17 months. Relative contraindications to aspirin were significantly associated with the withholding of aspirin (in-hospital bleeding: odds ratio [OR], 3.56; 95% CI, 1.86-6.80; history of peptic ulcer: OR, 2.49; 95% CI, 1.62-3.83). Absolute contraindications to aspirin were rare (2.2%). Other medications of proven benefit were also given less often in these patients (β-blockers: 49.0% vs 61.9%, P <.001; angiotensin-converting enzyme inhibitors: 65.6% vs 70.2%, P = .06; statins: 12.2% vs 15.1%, P = .10). Patients who were not given aspirin were at high risk for vascular events. They were more likely to have a history of prior AMI (OR, 1.34; 95% CI, 1.02-1.79), were in critical clinical condition at admission more often (cardiogenic shock: OR, 1.98; 95% CI, 1.09-3.56; overt heart failure: OR, 1.6; 95% CI, 1.05-2.3), and received acute revascularization less often (OR, 1.32; 95% CI, 1.05-1.67). The 1-year mortality was 2-times higher in patients who did not receive aspirin than in patients who did receive aspirin (16.5% vs 8.3%, P <.001). A significant association of withheld aspirin at discharge with a higher long-term mortality rate was confirmed with multivariate analysis (OR, 1.62; 95% CI, 1.15-2.29).

Conclusions

Ten percent of patients who sustained an AMI did not receive aspirin at the time of hospital discharge. Most of these patients were at high risk for cardiovascular events. Withheld aspirin was significantly associated with higher mortality rate during follow up.     

Muscle-Activation Onset Times With Shoes and Foot Orthoses in Participants With Chronic Ankle Instability

Context

Participants with chronic ankle instability (CAI) use an altered neuromuscular strategy to shift weight from double-legged to single-legged stance. Shoes and foot orthoses may influence these muscle-activation patterns.

Objective

To evaluate the influence of shoes and foot orthoses on onset times of lower extremity muscle activity in participants with CAI during the transition from double-legged to single-legged stance.

Design

Cross-sectional study.

Setting

Musculoskeletal laboratory.

Patients or Other Participants

A total of 15 people (9 men, 6 women; age = 21.8 ± 3.0 years, height = 177.7 ± 9.6 cm, mass = 72.0 ± 14.6 kg) who had CAI and wore foot orthoses were recruited.

Intervention(s)

A transition task from double-legged to single-legged stance was performed with eyes open and with eyes closed. Both limbs were tested in 4 experimental conditions: (1) barefoot (BF), (2) shoes only, (3) shoes with standard foot orthoses, and (4) shoes with custom foot orthoses (SCFO).

Main Outcome Measure(s)

The onset of activity of 9 lower extremity muscles was recorded using surface electromyography and a single force plate.

Results

Based on a full-factorial (condition, region, limb, vision) linear model for repeated measures, we found a condition effect (F_3,91.8 = 9.39, P < .001). Differences among experimental conditions did not depend on limb or vision condition. Based on a 2-way (condition, muscle) linear model within each region (ankle, knee, hip), earlier muscle-activation onset times were observed in the SCFO than in the BF condition for the peroneus longus (P < .001), tibialis anterior (P = .003), vastus medialis obliquus (P = .04), and vastus lateralis (P = .005). Furthermore, the peroneus longus was activated earlier in the shoes-only (P = .02) and shoes-with-standard-foot-orthoses (P = .03) conditions than in the BF condition. No differences were observed for the hip muscles.

Conclusions

Earlier onset of muscle activity was most apparent in the SCFO condition for ankle and knee muscles but not for hip muscles during the transition from double-legged to single-legged stance. These findings might help clinicians understand how shoes and foot orthoses can influence neuromuscular control in participants with CAI.Key Words: footwear, insoles, ankle sprains, neuromuscular system, electromyography

Key Points

• Shoes and foot orthoses accelerated muscle-activation onset times of the ankle and knee but not the hip in participants with chronic ankle instability.
• Earlier muscle-activation onset times were most prominent in the shoes-with-custom-foot-orthoses condition.
• At the ankle, the muscle-activation onset time of the peroneus longus was earlier in the shoes-only, shoes-with-standard-foot-orthoses, and shoes-with-custom-foot-orthoses conditions than in the barefoot condition, and the muscle-activation onset time of the tibialis anterior was earlier in the shoes-with-custom-foot-orthoses condition than in the barefoot condition.
• At the knee, the muscle-activation onset times of the vastus medialis obliquus and vastus lateralis were earlier in the shoes-with-custom-foot-orthoses condition than in the barefoot condition.
• The results may help clinicians understand how shoes and foot orthoses can influence neuromuscular control of the lower extremity in participants with chronic ankle instability.

Lateral ankle sprains are estimated to account for approximately 15% of all sport injuries.¹ Even more concerning than the initial ankle sprain is the large proportion of patients with residual symptoms and recurrent ankle sprains for months to years after the initial injury.² The occurrence of repetitive ankle sprains and the feeling of the ankle “giving way” with slight or no perturbation has been defined as chronic ankle instability (CAI).³The transition task from double-legged to single-legged stance during barefoot (BF) conditions has been shown to discriminate between uninjured participants and participants with CAI. Researchers have reported that muscle-activation onset times typically were delayed^4,5 and postural stability was impaired⁶ in participants with CAI, indicating the use of another strategy to shift weight from double-legged to single-legged stance. However, it is unclear whether findings from BF tests represent typical daily situations when shoes, and for some persons foot orthoses, are often worn.The human foot is the first point of contact between the body and a supporting surface. The cutaneous mechanoreceptors on the planar surface of the foot are an important source of sensory information,⁷ which is considered essential for achieving and maintaining functional joint stability.⁸ Shoes and foot orthoses act as an interface between the body and a supporting surface and can influence the sensory feedback from these mechanoreceptors by increasing the contact area between the foot and the supporting surface.^7,9 Furthermore, the small kinematic alterations of the rear foot and tibia that have been described with the use of shoes and foot orthoses¹⁰ may put the ankle joint in a more neutral position, thereby improving the capacity of the ankle mechanoreceptors to provide more accurate proprioceptive input toward the central nervous system.¹¹ Changing the sensory input to these mechanisms consequently would change the motor output.⁷Evidence is increasing that shoes and foot orthoses can influence lower extremity muscle activation.^10,12–14 Dingenen et al¹⁴ were the first investigators to measure the influence of shoes and foot orthoses on muscle-activation onset times of the entire lower extremity in uninjured participants during the transition from double-legged to single-legged stance. Their results showed that shoes and foot orthoses can accelerate muscle-activation onset times of the peroneus longus. No differences were reported in more proximal muscles. Recently, researchers have suggested that future investigators should be focused on the influence of shoes and foot orthoses on neuromuscular control, especially in participants with injuries, such as CAI,^10,13,14 to increase our understanding of how positive clinical outcomes from the use of shoes and foot orthoses can be achieved.¹¹ Altering or improving proprioceptive information and muscle-activation patterns in participants with CAI would be clinically beneficial, given that their proprioceptive and neuromuscular deficits have been described.¹⁵To our knowledge, no investigators have focused on the influence of shoes and foot orthoses on muscle-activation onset times of the entire lower extremity in participants with CAI during the transition from double-legged to single-legged stance. Therefore, the purpose of our study was to evaluate the influence of shoes and foot orthoses on muscle-activation onset times during the transition from double-legged to single-legged stance in participants with CAI. Based on the proposed effects of shoes and foot orthoses on lower extremity neuromuscular control, we hypothesized that shoes and foot orthoses would accelerate muscle-activation onset times compared with a BF condition.     

Oral Prolonged‐Release Oxycodone/Naloxone for Managing Pain and Opioid‐Induced Constipation: A Review of the Evidence

Background

Opioids provide effective relief from moderate‐to‐severe pain and should be prescribed as part of a multifaceted approach to pain management when other treatments have failed. Fixed‐dose oxycodone/naloxone prolonged‐release tablets (OXN PR) were designed to address the opioid class effect of opioid‐induced constipation (OIC) by combining the analgesic efficacy of oxycodone with the opioid receptor antagonist, naloxone, which has negligible systemic availability when administered orally. This formulation has abuse‐deterrent properties, since systemic exposure to naloxone by parenteral administration would antagonize the euphoric effects of oxycodone.

Methods

A literature search was conducted to assess the evidence base for OXN PR to treat moderate‐to‐severe pain and its impact on bowel function, based on published clinical trials and observational studies.

Results

Extensive data demonstrate that OXN PR provides effective analgesia and clinically relevant improvements in bowel function in patients with OIC and moderate‐to‐severe cancer‐related pain and noncancer pain types such as low back pain, neuropathic pain, and musculoskeletal pain. OXN PR has also been found to improve bowel function in patients with OIC refractory to multiple types of laxatives, and improve Parkinson's disease–related pain. No unanticipated safety concerns have been reported in elderly patients.

Conclusions

Evidence from clinical trials and observational studies confirms that for selected patients OXN PR significantly improves moderate‐to‐severe chronic pain and provides relief from OIC. Treatment should be tailored to individual patients to establish the lowest effective dose. An absence of analgesic ceiling effect was seen across the clinically relevant dose range investigated (≤ 160/80 mg/day).     

Fully-automated left ventricular mass and volume MRI analysis in the UK Biobank population cohort: evaluation of initial results

UK Biobank, a large cohort study, plans to acquire 100,000 cardiac MRI studies by 2020. Although fully-automated left ventricular (LV) analysis was performed in the original acquisition, this was not designed for unsupervised incorporation into epidemiological studies. We sought to evaluate automated LV mass and volume (Siemens syngo InlineVF versions D13A and E11C), against manual analysis in a substantial sub-cohort of UK Biobank participants. Eight readers from two centers, trained to give consistent results, manually analyzed 4874 UK Biobank cases for LV end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF) and LV mass (LVM). Agreement between manual and InlineVF automated analyses were evaluated using Bland–Altman analysis and the intra-class correlation coefficient (ICC). Tenfold cross-validation was used to establish a linear regression calibration between manual and InlineVF results. InlineVF D13A returned results in 4423 cases, whereas InlineVF E11C returned results in 4775 cases and also reported LVM. Rapid visual assessment of the E11C results found 178 cases (3.7%) with grossly misplaced contours or landmarks. In the remaining 4597 cases, LV function showed good agreement: ESV ?6.4?±?9.0 ml, 0.853 (mean?±?SD of the differences, ICC) EDV ?3.0?±?11.6 ml, 0.937; SV 3.4?±?9.8 ml, 0.855; and EF 3.5?±?5.1%, 0.586. Although LV mass was consistently overestimated (29.9?±?17.0 g, 0.534) due to larger epicardial contours on all slices, linear regression could be used to correct the bias and improve accuracy. Automated InlineVF results can be used for case-control studies in UK Biobank, provided visual quality control and linear bias correction are performed. Improvements between InlineVF D13A and InlineVF E11C show the field is rapidly advancing, with further improvements expected in the near future.     

Prematurity Reduces Functional Adaptation to Intestinal Resection in Piglets

Background: Necrotizing enterocolitis and congenital gastrointestinal malformations in infants often require intestinal resection, with a subsequent risk of short bowel syndrome (SBS). We hypothesized that immediate intestinal adaptation following resection of the distal intestine with placement of a jejunostomy differs between preterm and term neonates. Methods: Preterm or term piglets were born by cesarean section and fed enterally for 2 days. On day 2, piglets were subjected to 50% distal intestinal resection with placement of a jejunostomy. On the following 4–5 days, piglets received parenteral nutrition with gradually increasing doses of enteral nutrition (bovine colostrum). Intestinal tissue samples were collected at delivery and 2 and 6–7 days after birth for histological examination and assessment of digestive enzyme activities. Results: Preterm and term piglets showed similar increases in intestinal weight and digestive enzyme activities from birth to 2 days. On days 6–7 after birth, the remnant intestine showed a similar density (g/cm) and mucosal mass in term and preterm piglets, but villus height, crypt depth, enzyme activities (sucrase, maltase, dipeptidyl peptidase IV [DPPIV]), and hexose uptake capacity were significantly higher in term piglets (P < .05). Preterm piglets were more prone to develop hypoglycemia, respiratory distress syndrome, dehydration, and circulatory instability after surgery compared with term piglets. Conclusion: Studies on intestinal adaptation after resection are feasible in both preterm and term piglets, but intensive clinical support is required when rearing preterm piglets with SBS. Physiological instability and immaturity of the intestine may explain the fact that immediate adaptation after resection is reduced in preterm vs term neonates.     

Attentional Bias in Children with Social Anxiety Disorder

Previous research stated a robust attentional bias to threat in adult anxiety. However, the number of studies analyzing attentional biases in clinically anxious children is limited and results are inconsistent. The present study aims to assess attentional biases in children with social anxiety disorder (n?=?37) and healthy control children (n?=?42) using a free-viewing eye-tracking paradigm. Children viewed different picture pairs consisting of social and non-social stimuli under two conditions (with/without a stressor to activate social threat perception). We found the direction of gaze regarding threatening stimuli to be context-dependent. Both groups showed a hypervigilance-avoidance pattern to angry faces when they were paired with houses. In face–face trials, angry faces were less often initially fixated than neutral or happy faces in both groups. However, schema activation differentially affected initial fixations in angry-neutral face pairs across groups. Children with social anxiety disorder more often initially directed their gaze to angry faces than did healthy control children, indicating a lack of inhibiting threat representations rather than a hypervigilance to threat.     

Obsessive–Compulsive Disorder is Characterized by a Lack of Adaptive Coping Rather than an Excess of Maladaptive Coping

The present study aimed to elucidate the profile of coping in patients with obsessive–compulsive disorder (OCD) in order to discern whether the disorder is characterized by an excess of maladaptive coping skills and/or a lack of adaptive coping skills. Sixty individuals with OCD were compared with 110 individuals with depression and 1050 nonclinical controls on the Maladaptive and Adaptive Coping Styles Questionnaire (MAX). Psychopathology was assessed with the Obsessive–Compulsive Inventory-Revised (OCI-R), the Yale-Brown Obsessive–Compulsive Scale (Y-BOCS), and the Patient Health Questionnaire-9 for depression (PHQ-9). Individuals with OCD and depression displayed more maladaptive coping and avoidance as well as less adaptive coping than nonclinical controls. Importantly, adaptive coping was significantly lower in individuals with OCD than in those with depression at a medium effect size, whereas the clinical groups were indistinguishable on maladaptive coping and avoidance. Lack of adaptive coping was strongly correlated with resistance to symptoms and poor insight in OCD (Y-BOCS), even after controlling for depression. Lack of adaptive coping skills may represent a specific pathogenetic factor in OCD. Longitudinal studies need to clarify whether strengthening adaptive skills during childhood and adolescence may help to prevent the progression from subclinical to manifest OCD.