Investigating two mobile just-in-time adaptive interventions to foster psychological resilience: research protocol of the DynaM-INT study.

BACKGROUND: Stress-related disorders such as anxiety and depression are highly prevalent and cause a tremendous burden for affected individuals and society. In order to improve prevention strategies, knowledge regarding resilience mechanisms and ways to boost them is highly needed. In the Dynamic Modelling of Resilience - interventional multicenter study (DynaM-INT), we will conduct a large-scale feasibility and preliminary efficacy test for two mobile- and wearable-based just-in-time adaptive interventions (JITAIs), designed to target putative resilience mechanisms. Deep participant phenotyping at baseline serves to identify individual predictors for intervention success in terms of target engagement and stress resilience. METHODS: DynaM-INT aims to recruit N = 250 healthy but vulnerable young adults in the transition phase between adolescence and adulthood (18-27 years) across five research sites (Berlin, Mainz, Nijmegen, Tel Aviv, and Warsaw). Participants are included if they report at least three negative burdensome past life events and show increased levels of internalizing symptoms while not being affected by any major mental disorder. Participants are characterized in a multimodal baseline phase, which includes neuropsychological tests, neuroimaging, bio-samples, sociodemographic and psychological questionnaires, a video-recorded interview, as well as ecological momentary assessments (EMA) and ecological physiological assessments (EPA). Subsequently, participants are randomly assigned to one of two ecological momentary interventions (EMIs), targeting either positive cognitive reappraisal or reward sensitivity. During the following intervention phase, participants' stress responses are tracked using EMA and EPA, and JITAIs are triggered if an individually calibrated stress threshold is crossed. In a three-month-long follow-up phase, parts of the baseline characterization phase are repeated. Throughout the entire study, stressor exposure and mental health are regularly monitored to calculate stressor reactivity as a proxy for outcome resilience. The online monitoring questionnaires and the repetition of the baseline questionnaires also serve to assess target engagement. DISCUSSION: The DynaM-INT study intends to advance the field of resilience research by feasibility-testing two new mechanistically targeted JITAIs that aim at increasing individual stress resilience and identifying predictors for successful intervention response. Determining these predictors is an important step toward future randomized controlled trials to establish the efficacy of these interventions.

Treatment of displaced intra-articular calcaneal fractures: A single-center experience study with 20 years follow-up.

INTRODUCTION: This study was conducted to identify the patient characteristics, classification, treatment, complications, and functional outcomes of operatively treated displaced intra-articular calcaneal fractures (DIACFs) in a level-I trauma center over a 20-year period. METHODS: Patients with a DIACF classified as Sanders ≥2 and operatively treated with percutaneous reduction and screw fixation (PSF) or open reduction and internal fixation (ORIF) between 1998 and 2017 were identified. Pre- and postoperative radiological assessments were performed. Functional outcomes were evaluated using the American Orthopaedic Foot & Ankle Society (AOFAS) score and the Maryland Foot Score (MFS). General health and patient satisfaction were assessed using the Short Form-36 Health Survey (SF-36) and the visual analog scale (VAS). RESULTS: In total, 120 patients with a DIACF that were operatively treated with PSF or ORIF. Of these patients, 72 with a total of 80 DIACFs completed the questionnaires (60%). The average follow-up was 130 months. Mean scores for PSF and ORIF were 74 and 75 for AOFAS, 78 and 78 for MFS, 68 and 61 for SF-36, and 7.7 and 7.5 for VAS, respectively. An infection was the most common complication associated with ORIF (31%), and hardware removal (58%) was the most common complication in patients treated with PSF. Overall, 36 patients (68%) were able to return to work after a median time 6 months (IQR, 3-7) and 6 months (IQR, 3,25-6,75) for PSF and ORIF treated, respectively CONCLUSION: This long-term follow-up study reviews ORIF using ELA and PSF in the treatment of DIACFs. This study shows that both treatments are capable of restoring the Böhler angle and yield relatively good long-term functional outcomes. Differences in complication rates were apparent, infectious problems are inherent to ORIF using ELA, and hardware removal is associated with PSF.

The STRESS-NL database: A resource for human acute stress studies across the Netherlands.

Stress initiates a cascade of (neuro)biological, physiological, and behavioral changes, allowing us to respond to a challenging environment. The human response to acute stress can be studied in detail in controlled settings, usually in a laboratory environment. To this end, many studies employ acute stress paradigms to probe stress-related outcomes in healthy and patient populations. Though valuable, these studies in themselves often have relatively limited sample sizes. We established a data-sharing and collaborative interdisciplinary initiative, the STRESS-NL database, which combines (neuro)biological, physiological, and behavioral data across many acute stress studies in order to accelerate our understanding of the human acute stress response in health and disease (www.stressdatabase.eu). Researchers in the stress field from 12 Dutch research groups of 6 Dutch universities created a database to achieve an accurate inventory of (neuro)biological, physiological, and behavioral data from laboratory-based human studies that used acute stress tests. Currently, the STRESS-NL database consists of information on 5529 individual participants (2281 females and 3348 males, age range 6-99 years, mean age 27.7 ±â€¯16 years) stemming from 57 experiments described in 42 independent studies. Studies often did not use the same stress paradigm; outcomes were different and measured at different time points. All studies currently included in the database assessed cortisol levels before, during and after experimental stress, but cortisol measurement will not be a strict requirement for future study inclusion. Here, we report on the creation of the STRESS-NL database and infrastructure to illustrate the potential of accumulating and combining existing data to allow meta-analytical, proof-of-principle analyses. The STRESS-NL database creates a framework that enables human stress research to take new avenues in explorative and hypothesis-driven data analyses with high statistical power. Future steps could be to incorporate new studies beyond the borders of the Netherlands; or build similar databases for experimental stress studies in rodents. In our view, there are major scientific benefits in initiating and maintaining such international efforts.

Long-term results of displaced intra-articular calcaneal fractures treated with minimal invasive surgery using percutaneous screw fixation.

INTRODUCTION: Over the last 20 years, minimally invasive surgery using Percutaneous Screw Fixation (PSF) has been performed increasingly frequently in the treatment of Displaced Intra-Articular Calcaneal Fractures (DIACFs). The purposes of this study were to assess the long-term postoperative outcomes of mobility, foot function, stability, pain and patient satisfaction. METHODS: All patients had DIACFs and underwent PSF between 1998 and 2006 according to the method reported by Forgon and Zadravecz. Functional outcomes, range of motion and change in footwear were evaluated with the American Orthopaedic Foot & Ankle Society (AOFAS) score and the Maryland Foot Score (MFS). All patients completed a general health status form (Short Form-36 [SF-36]) and visual analogue scale (VAS) for patient satisfaction. Anatomical restoration was assessed based on the pre- and postoperative radiographic images. RESULTS: Sixty-six patients with an DIACF were observed in the period 1998-2006. Patients who had open fractures, died or were <18 years of age at trauma were excluded. A total of 46 patients were asked to complete the questionnaires, during the last quarter of 2018. Of these patients, 27 with 29 DIACFs responded (58%). Nineteen were males, and the mean age at trauma was 45 years. Seven cases were classified as Sanders type II, 14 as Sanders type III, and 8 as Sanders type IV. The mean pre- and postoperative Böhler angles were 10 ͦ and 26 ͦ, respectively. The average follow-up period was 16 years, and at the follow-up, the mean AOFAS, MFS, SF-36 and VAS scores were 76, 74, 63 and 7.7 points, respectively. In comparison to the results at 5-10 years postoperatively in a previous study, we observed a decline in the average AOFAS and MFS scores by 8 and 11 points, respectively. Patient satisfaction decreased by 0.1 points and general health by 14 points. CONCLUSION: The long-term results of this study show relatively good functional outcomes is two-thirds of the treated patients. According to the reported scores, patients described their level of function as essentially normal. PSF should therefore be considered as a good option in patients with DIAC fractures, especially in patients with Sanders II and III fractures. LEVEL OF EVIDENCE: Therapeutic Level III.

Quality of life after pelvic ring fractures: Long-term outcomes. A multicentre study.

AIMS: This study was conducted to determine long-term (5-10 years) health-related quality of life (HRQOL) and ceiling effects in patients with a pelvic ring fracture. PATIENTS AND METHODS: We identified all patients with pelvic ring fractures after high-energy trauma admitted at two level 1 trauma centres in the Netherlands from 2006 to 2011. Patients were asked to complete the Majeed Pelvic Score (MPS), EuroQol-5D (EQ-5D) and Short Musculoskeletal Function Assessment (SMFA) questionnaires. HRQOL analysis used a multiple linear regression model. RESULTS: In total, 136 patients returned the questionnaires. The median follow-up period was 8.7 years. The mean MPS and EQ-5D-VAS scores were 85.1 and 74, respectively. The mean EQ-5D index scores were 0.87, 0.81 and 0.82 in Tile B, A and C patients, respectively. The mean SMFA index was 24. A ceiling effect was observed for 1/3 of the patients. After multiple linear regression analysis, no differences were identified among the various fracture types for each questionnaire, with the exception of 2 subscales of the MPS. CONCLUSION: Patients who suffer pelvic ring fractures generally have good HRQOL outcomes after 5-10 years. No significant differences were found among different fracture types. Long-term follow-up of patients with Tile C fractures is warranted.

Increased responses of the reward circuitry to positive task feedback following acute stress in healthy controls but not in siblings of schizophrenia patients.

Acute stress is known to affect the way we process rewards. For example, during, or directly after stress, activity within key brain areas of the reward circuitry is reduced when a reward is presented. Generally, the effects of stress on the brain are time-dependent, changing neural and cognitive processing in the aftermath of stress to aid recovery. Such a dynamic response to stress is important for resilience on the longer term. However, relatively little is known about reward processing during the recovery phase of stress and whether this is changed in individuals at increased risk for stress-related psychopathology. Healthy male individuals (N = 40) and unaffected siblings of schizophrenia patients (N = 40) were randomized to either an acute stress task (Trier Social Stress Test) or a no-stress task. Neural responses during reward anticipation and reward feedback (monetary gain or no gain) were examined 50 min later using an fMRI monetary incentive delay task. The ventral striatum and orbitofrontal cortex (OFC) were used as predefined hypothesis-driven regions of interest. Neural responses following stress differed between controls and siblings during reward feedback (group × stress interaction OFC p = 0.003, ventral striatum p = 0.031), showing increased ventral striatum and OFC responses following stress in healthy controls only. Exploratory analyses revealed that this effect was most pronounced during hit trials (compared to when a reward was omitted), and independent of monetary value. Stress did not affect subsequent reward processing in siblings of schizophrenia patients. We found no significant differences between controls and siblings in ventral striatum and OFC responses during reward anticipation following stress. This study shows that ventral striatum and OFC responses to positive task feedback are increased in the aftermath of stress in healthy male controls, regardless of monetary value. This indicates a dynamic shift from previously reported reduced responses in the striatum and OFC to reward feedback directly after stress to increased responses to both reward and non-reward feedback during the recovery phase of stress. These increased neural responses following stress were absent in siblings of schizophrenia patients. Together, these findings indicate that stress recovery is affected in this at-risk group, particularly in responses to positive feedback following stress.

Open pelvic fracture: the killing fracture?

BACKGROUND: Open pelvic fractures are rare but represent a serious clinical problem with high mortality rates. The purpose of this study was to evaluate the outcomes of open pelvic fractures in our clinic and to compare the results from our patient group with those of closed fractures and with the literature from the past decade. METHODS: Data of patients older than 16 years of age who were admitted to our hospital with a pelvic fracture between January 1, 2004, and December 31, 2014, were analyzed. The collected data were patient demographics, mechanism of injury, RTS, ISS, transfusion requirement during the first 24 h, Gustilo-Anderson and Faringer classification, number and type of interventions complications, mortality, and length of stay. RESULTS: Twenty-four of 492 patients (5% of all pelvic fracture patients) had an open fracture. Their mean age was 36 years, the mean ISS was 31, and the mean number of transfused packed red blood cells was 5.5. These numbers were all significantly higher than in the patients with a closed fracture, although they were comparable to other studies with open fractures. The mortality was 4% in the open group versus 14% in the closed group (p = 0.23). The reported mortality in the literature ranges between 4 and 45%. CONCLUSION: Open pelvic fractures are relatively rare but are a cause of significant morbidity. In this series, we treated patients with open pelvic fractures successfully, with a survival rate of 96%. There was no significant difference in survival rate between open and closed pelvic fractures. Compared with other studies, the mortality in our study was relatively low.

At-risk individuals display altered brain activity following stress.

Stress is a major risk factor for almost all psychiatric disorders, however, the underlying neurobiological mechanisms remain largely elusive. In healthy individuals, a successful stress response involves an adequate neuronal adaptation to a changing environment. This adaptive response may be dysfunctional in vulnerable individuals, potentially contributing to the development of psychopathology. In the current study, we investigated brain responses to emotional stimuli following stress in healthy controls and at-risk individuals. An fMRI study was conducted in healthy male controls (N = 39) and unaffected healthy male siblings of schizophrenia patients (N = 39) who are at increased risk for the development of a broad range of psychiatric disorders. Brain responses to pictures from the International Affective Picture System (IAPS) were measured 33 min after exposure to stress induced by the validated trier social stress test (TSST) or a control condition. Stress-induced levels of cortisol, alpha-amylase, and subjective stress were comparable in both groups. Yet, stress differentially affected brain responses of schizophrenia siblings versus controls. Specifically, control subjects, but not schizophrenia siblings, showed reduced brain activity in key nodes of the default mode network (PCC/precuneus and mPFC) and salience network (anterior insula) as well as the STG, MTG, MCC, vlPFC, precentral gyrus, and cerebellar vermis in response to all pictures following stress. These results indicate that even in the absence of a psychiatric disorder, at-risk individuals display abnormal functional activation following stress, which in turn may increase their vulnerability and risk for adverse outcomes.

How the brain connects in response to acute stress: A review at the human brain systems level.

The brain's response to stress is a matter of extensive neurocognitive research in an attempt to unravel the mechanistic underpinnings of neural adaptation. In line with the broadly defined concept of acute stress, a wide variety of induction procedures are used to mimic stress experimentally. We set out to review commonalities and diversities of the stress-related functional activity and connectivity changes of functional brain networks in healthy adults across procedures. The acute stress response is consistently associated with both increased activity and connectivity in the salience network (SN) and surprisingly also with increased activity in the default mode network (DMN), while most studies show no changes in the central executive network. These results confirm earlier findings of an essential, coordinating role of the SN in the acute stress response and indicate a dynamic role of the DMN whose function is less clear. Moreover, paradigm specific brain responses have to be taken into account when investigating the role and the within and between network connectivity of these three networks.

Paediatric pelvic fractures: how do they differ from adults?

BACKGROUND: The aim of this article was to review the incidence, presentation, treatment and complications of paediatric pelvic fractures of children who were admitted to our level 1 trauma centre and to compare them with our data from adult pelvic fracture patients. METHODS: We conducted a retrospective chart review of all children with pelvic fractures who were managed at our institution between January 1993 and December 2013 and compared the data with our database on pelvic fractures in adults during the period 2007 to 2012. RESULTS: We identified 51 children and 268 adults with pelvic fractures. The median age of the paediatric patients was 11 years. Children were significantly more involved in traffic accidents than adults (p < 0.001). Adults had a significantly higher Injury Severity Score (ISS) (31 vs 24.5; p < 0.03) and were significantly more often haemodynamically unstable (p < 0.01). Adults had a type C fracture more often, while children had a type B fracture (p < 0.001). Associated injuries were seen in both groups; however, thoracic injuries were significantly higher in adults (p < 0.01) and injuries to the extremities were higher in children (p < 0.01). Adults were significantly more often treated with open reduction and internal fixation (p < 0.001). Mortality in both groups, however, did not differ (6% vs 8%). CONCLUSION: Paediatric pelvic fractures are rare. They differ from adult pelvic fractures in presentation, associated injuries and management. Mortality, however, is substantial and does not differ from the adult population. Mortality is often due to concomitant injuries and not to exsanguination from the pelvic fracture.

Schwann cell migration and neurite outgrowth are influenced by media conditioned by epineurial fibroblasts.

The regenerative capacity of the peripheral nervous system is largely related to Schwann cells undergoing proliferation and migration after injury and forming growth-supporting substrates for severed axons. Novel data show that fibroblasts to a certain extent regulate the pro-regenerative behavior of Schwann cells. In the setting of peripheral nerve injury, the fibroblasts that form the epineurium come into close contact with both Schwann cells and peripheral axons, but the potential influence on these latter two cell types has not been studied yet. In the present study we explored whether culture media, conditioned by epineurial fibroblasts can influence Schwann cells and/or neurite outgrowth from dorsal root ganglia neurons in vitro. Our data indicate that epineurial fibroblast-conditioned culture media substantially increase Schwann cell migration and the outgrowth of neurites. Schwann cell proliferation remained largely unaffected. These same read-out parameters were assayed in a condition where epineurial fibroblasts were subjected to stretch-cell-stress, a mechanical stressor that plays an important role in traumatic peripheral nerve injuries. Stretch-cell-stress of epineurial fibroblasts did not further change the positive effects of conditioned media on Schwann cell migration and neurite outgrowth. From these data we conclude that an as yet unknown pro-regenerative role can be attributed to epineurial fibroblasts, implying that such cells may affect the outcome of severe peripheral nerve injury.

PICK1 expression in reactive astrocytes within the spinal cord of amyotrophic lateral sclerosis (ALS) rats.

AIMS: The protein interacting with C kinase 1 (PICK1), a PDZ domain-containing protein mainly expressed in the central nervous system, interacts with the glutamate receptor subunit GluR2, with the glutamate transporter GLT-1b and with the enzyme serine racemase. These three proteins appear as key actors in the glutamate-mediated excitotoxicity associated with amyotrophic lateral sclerosis (ALS), in both patients and animal models of the disease. In this study, we examined the expression of PICK1 in the spinal cord of transgenic rats expressing a mutated form of the human superoxide dismutase 1 (hSOD1(G93A) ) during the progression of the disease. METHODS: Expression of PICK1 was examined by real-time qPCR at presymptomatic and symptomatic stages as well as at end-stage. The expression of PICK1 in the different cell types of the spinal cord was examined by immunohistochemistry. RESULTS: The overall expression of PICK1 is not modified in cervical and lumbar spinal cord of transgenic (hSOD1(G93A) ) rats during the progression of the disease. Nonetheless, immunohistochemical studies of lumbar ventral horns revealed a shift of PICK1 expression from motor neurones in healthy rats to activated astrocytes in end-stage hSOD1(G93A) animals. CONCLUSIONS: Considering the documented influence of PICK1 expression on d-serine release and glutamate transport in astrocytes, these findings point to a potential implication of PICK1 in the progression of ALS.

Opposite regulation of metabotropic glutamate receptor 3 and metabotropic glutamate receptor 5 by inflammatory stimuli in cultured microglia and astrocytes.

Metabotropic glutamate receptors (mGluRs) were previously shown to modulate several essential functions in glial cells, including cell proliferation, glutamate uptake, neurotrophic support, and inflammatory responses. As these receptors are regularly proposed as promising targets for the treatment of a wide range of neurological disorders, we herein examined the reciprocal modulation of glial mGluRs by inflammation. Such regulation of mGluRs was also studied in cultures from an experimental model of amyotrophic lateral sclerosis (ALS). Indeed, ALS is characterized by increased neuroinflammation, and glial cell cultures derived from the animal model (rat expressing hSOD1(G93A)) show enhanced glial reactivity. Within 72 h, the pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 1ß (IL-1ß) induced an increase in mGluR3 and a decrease in mGluR5 gene expression. A similar regulation of these receptors was observed in microglia 48 h after an initial 4-h exposure to lipopolysaccharide. In hSOD1(G93A)-derived glial cultures, the gene up-regulation of mGluR3 (but not the gene down-regulation of mGluR5) was found to be enhanced in both astrocytes and microglia. Together, these results indicate that an inflammatory environment triggers an opposite regulation in the gene expression of the two predominant mGluR subtypes found in glial cells, and that these regulations were particularly robust in hSOD1(G93A) glial cultures. As neuroinflammation commonly occurs in several nervous diseases, its influence on mGluR expression should be taken into account when considering these receptors as future drug targets.

Gonadal hormone regulation of the emotion circuitry in humans.

Gonadal hormones are known to influence the regulation of emotional responses and affective states. Whereas fluctuations in progesterone and estradiol are associated with increased vulnerability for mood disorders, testosterone is mainly associated with social dominance, aggressive, and antisocial behavior. Here, we review recent functional neuroimaging studies that have started to elucidate how these hormones modulate the neural circuitry that is important for emotion regulation, which includes the amygdala and the medial prefrontal (mPFC) and orbitofrontal cortex (OFC). The amygdala is thought to generate emotional responses, and the prefrontal brain regions to regulate those responses. Overall, studies that have investigated women during different phases of the menstrual cycle suggest that progesterone and estradiol may have opposing actions on the amygdala and prefrontal cortex. In addition, the influence of exogenous progesterone appears to be dose-dependent. Endogenous testosterone concentrations are generally positively correlated to amygdala and OFC responses, and exogenous testosterone increases amygdala reactivity. Whereas the administration of progesterone increases amygdala reactivity and its connectivity with the mPFC, testosterone administration increases amygdala reactivity but decreases its connectivity with the OFC. We propose that this opposing influence on amygdala-prefrontal coupling may contribute to the divergent effects of progesterone and testosterone on emotion regulation and behavioral inhibition, respectively, which may promote the differential vulnerability to various psychiatric disorders between women and men. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.

Outcome of colonic surgery in elderly patients with colon cancer.

Introduction. Colonic cancer is one of the most commonly diagnosed malignancies and most often occurs in patients aged 65 years or older. Aim. To evaluate the outcome of colonic surgery in the elderly in our hospital and to compare five-year survival rates between the younger and elderly patients. Methods. 207 consecutive patients underwent surgery for colon cancer. Patients were separated in patients younger than 75 and older than 75 years. Results. Elderly patients presented significantly more (P < .05) as a surgical emergency, had a longer duration of admission and were more often admitted to the ICU (P < .01). Also, elderly patients had significant more co-morbidities, especially cardiovascular pathology (P < .01). Post-operative complications were seen more often in the elderly, although no significant difference was seen in anastomotic leakage. The five-year survival rate in the younger group was 62% compared with 36% in the elderly (P < .05). DFS was 61% in the younger patients compared with 32% in the elderly (P < .05). Conclusion. Curative resection of colonic carcinoma in the elderly is well tolerated and age alone should not be an indication for less aggressive therapy. However, the type and number of co-morbidities influence post-operative mortality and morbidity.

Micro-metastases in stages I and II colon cancer are a predictor of the development of distant metastases and worse disease-free survival.

Approximately 30% of the patients with Dukes A/B colon carcinoma will develop loco-regional recurrence or distant metastases. The aim of this study was to evaluate if patients with micro-metastases are at higher risk for developing distant metastases and therefore a worse disease-free survival and overall survival. In the period January 2000-January 2002, 137 patients underwent curative surgery for colon cancer. When patients had a Dukes A/B colon carcinoma, additional staining and sectioning on the harvested lymph nodes were performed retrospectively. Lymph nodes were examined using 4 multilevel sections at 250-microm intervals and stained with Pan-Cytokeratin. There were 11 patients with a Dukes A and 61 patients with a Dukes B colon carcinoma. Twenty-two patients developed metastases in time (group I) whereas 50 patients did not (group II). After additional staining and sectioning 41% of the patients of group I and 16% of the patients of group II showed micro-metastases (p<0.05). The 5-year overall survival rate in the group with micro-metastases was 62% against 79% in the group without micro-metastases. The disease-free survival (DFS) was 51% and 72% (p<0.05), respectively. Patients with micro-metastases develop significant more distant metastases in time and have a significant worse DFS.

Multiplicity and regulation of G-protein couplings.

During the last twenty years, molecular and biochemical data concerning G-protein coupled receptors have accumulated, providing a detailed characterisation of the structure and functions of this large family of receptors. Initially viewed as simple transducing proteins interacting with intracellular adapters which confer signalling specificity and amplification, the last decade has revealed the extreme complexity and flexibility offered by these membrane receptors. Indeed, there is accumulating evidence that these receptors can interact with several unrelated G-proteins and that some ligands can specifically orientate the functional response. This article summarizes my contributions to the study of the multiplicity and regulation of cell signallings associated with three unrelated systems: the neurotensin receptor, the type 1 metabotropic glutamate receptor and the type 1 cannabinoid receptor. Along with other studies, these experimental data emphasise on the importance of the emerging concept of functional selectivity which should lead to the development of drugs showing enhanced clinical efficacy with lower unwanted side effects.

Differential modulation of AP-1- and CRE-driven transcription by cannabinoid agonists emphasizes functional selectivity at the CB1 receptor.

BACKGROUND AND PURPOSE: Long-term adaptations to pharmacological stimuli frequently originate from modulation of complex intracellular signalling pathways. We previously reported that HU210 and CP55940, two CB1 cannabinoid receptor agonists, induced opposite effects on TH expression. Herein, we characterized their influence on cAMP response element (CRE) and activator protein 1 (AP-1)-mediated regulation of gene transcription. EXPERIMENTAL APPROACH: The activity of the agonists was examined on transfected N1E-115 cells in which expression of the luciferase reporter gene was controlled by transcription promoters consisting of repeats of either CRE or AP-1 elements. In addition, the implication of classical signalling pathways was investigated using a variety of kinase inhibitors. KEY RESULTS: Consistent with the CB1-mediated reduction of cAMP accumulation, both ligands decreased CRE-driven luciferase expression with similar potencies. HU210 also exhibited a concentration-dependent reduction of luciferase activity in cells engineered to examine AP-1-controlled transcription, whereas such response was not obtained with CP55940. Responses were all inhibited by SR141716A and were modified in Pertussis toxin-treated cells, suggesting agonist-selective regulations of distinct Gi/o-dependent mechanisms through CB1 receptor activation. Finally, PKC inhibitors efficiently inhibited the paradoxical effect of HU210 on AP-1-mediated transcription, indicating selective regulation of PKC-dependent responses. CONCLUSIONS AND IMPLICATIONS: Together, our results demonstrate that two cannabinoid ligands, commonly used as reference agonists acting on the same receptor with similar affinities, differentially modulate gene transcription through distinct controls of AP-1. This could reflect activation of distinct subsets of Gi/o-proteins, supporting the concept of functional selectivity at CB1 receptors.

Change in the accommodative force on the lens of the human eye with age.

The aim of the study was to determine the age-dependence of the accommodative force on the lens in order to make it clear whether the causes of presbyopia are due to lenticular or extralenticular changes. A finite element model of the lens of an 11-, 29- and 45-year-old human eye was constructed to represent the fully accommodated state. Subsequently, the force that was needed to mould the lens into its unaccommodated state was calculated. The force on the lens appeared to be preserved with age, with only a slight increase to a value of approximately 0.06N. In conclusion, the preservation of the net force delivered by the extralenticular ciliary body indicates that the causes of presbyopia must be ascribed to lenticular changes.

Estimating the external force acting on the human eye lens during accommodation by finite element modelling.

Using new geometric information on the shape of the lens that has recently become available, a finite element model has been developed in order to estimate the forces that act on the lens during accommodation for a typical 29-year-old human eye. To investigate the influence of the anterior, posterior and central zonular fibres insertion regions, three models with different configurations were built. All three configurations appeared to be capable of inducing the required accommodative changes in the lens. Based on material properties from the literature, the estimated summed net force for each of the three models was approximately 0.08 N.