A ventral striatal prediction error signal in human fear extinction learning.

Animal studies have shown that the prediction error (PE) signal that drives fear extinction learning is encoded by phasic activity of midbrain dopamine (DA) neurons. Thus, the extinction PE resembles the appetitive PE that drives reward learning. In humans, fear extinction learning is less well understood. Using computational neuroimaging, a previous study from our group reported hemodynamic activity in the left ventral putamen, a subregion of the ventral striatum (VS), to correlate with a PE function derived from a formal associative learning model. The activity was modulated by genetic variation in a DA-related gene. To conceptually replicate and extend this finding, we here asked whether an extinction PE (EPE) signal in the left ventral putamen can also be observed when genotype information is not taken into account. Using an optimized experimental design for model estimation, we again observed EPE-related activity in the same striatal region, indicating that activation of this region is a feature of human extinction learning. We further observed significant EPE signals across wider parts of the VS as well as in frontal cortical areas. These results may suggest that the prediction errors during extinction learning are available to larger parts of the brain, as has also been observed in human neuroimaging studies of reward PE signaling. Conclusive evidence that the human EPE signal is of DAergic nature is still outstanding.

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.

Prospective, randomized, controlled trial comparing lightweight versus heavyweight mesh in chronic pain incidence after TEP repair of bilateral inguinal hernia.

BACKGROUND: This prospective, clinical, randomized, controlled study was performed to define the incidence of chronic pain after total extraperitoneal (TEP) repair with a light-weighted mesh compared with heavyweight mesh in patients with bilateral inguinal hernias. METHODS: Consecutive patients with bilateral inguinal hernias were recruited for TEP inguinal hernia repair under general anesthesia. Heavyweight mesh was randomly assigned to one side of the groin and lightweight mesh to the other. Patients were followed up regularly for up to 1 year by an independent surgeon who was unaware of the mesh assignment. The postoperative pain score by means of a visual analogue scale (VAS) and other data were recorded. RESULTS: Fifty bilateral TEP hernia repairs were performed between September 2007 and February 2009. Six patients (12%) complained of chronic pain 3 months after the operation. A higher average pain score was observed for the side of hernia repaired by heavyweight mesh compared with lightweight mesh, but the difference was not statistically significant. More patients complained about foreign body sensation on the side repaired with heavyweight mesh (24%) compared with the side with lightweight mesh (8%; P < 0.05). There was no recurrence or need for reintervention for either type of mesh. CONCLUSIONS: Lightweight polypropylene mesh may be preferable to heavyweight mesh for TEP inguinal hernia repair because it provides less postoperative foreign body sensation; however, there was no significant difference in the incidence of chronic pain.

alpha-Tocopherol, an inhibitor of epidermal lipid peroxidation, prevents ultraviolet radiation from suppressing the skin immune system.

We investigated the involvement of epidermal lipid peroxidation in the induction of ultraviolet radiation (UVR)-induced suppression of the skin immune system. The shaved dorsal skin of C3H/HeJ mice was irradiated with one of two subinflammatory solar-simulated UVR protocols 3 days per week for 4 weeks. Then half of 1 mg, 1, 2.5 or 5 mg alpha-tocopherol in a vehicle of acetone was topically applied to the shaved dorsal skin before UVR, A 5 mg dose of vitamin E gave complete protection against a UVR protocol that induced a 55% reduction in the contact hypersensitivity response to 2,4,6-trinitrochlorobenzene and a 23% reduction in epidermal Langerhans cell density. Lower doses were ineffective. alpha-Tocopherol was unable to protect against a higher UVR protocol. As 5 mg alpha-tocopherol did not prevent postirradiation inflammatory edema it is unlikely that the antioxidant acted as a sunscreen. However, 5 mg alpha-tocopherol inhibited UVR-induced epidermal lipid peroxidation, suggesting that this may be one mechanism by which alpha-tocopherol prevented UVR-induced local immunosuppression. Scavenging of UVR-generated lipid peroxides and reactive oxygen may have inhibited loss of cell membrane integrity preventing depletion of LC numbers, thus protecting from local immunosuppression.

Effect of inhibitors of oxygen radical and nitric oxide formation on UV radiation-induced erythema, immunosuppression and carcinogenesis.

We investigated whether supplementation of a sunscreen containing the UVB absorber 2-ethyl-hexyl-methoxycinnamate (cinnamate) with oxygen radical inhibitors (ORI) would improve protection from sunburn, immunosuppression and carcinogenesis. Mice were exposed to solar-simulated UV radiation (ssUV) containing a mixture of UVB and UVA. In initial studies, the ORI 2,2'-dipyridyl and N(G)-monomethyl-L-arginine acetate (L-NMMA) were shown to prevent UVA-induced suppression of contact sensitivity (CS) in mice. Addition of these inhibitors to the sunscreen did not affect the sun protection factor (SPF), but lowered the level of edema when mice were exposed to ssUV. Combination of both inhibitors with the sunscreen, however, increased the SPF from 5 to 5.5. The immune protection factor (IPF) of the sunscreen was only 1.18, but addition of neither dipyridyl nor L-NMMA singly or in combination measurably improved immune protection. However, the ORI improved the ability of the sunscreen to prevent carcinogenesis. The results indicate that reactive oxygen or nitrogen species produced in response to UV radiation are important for erythema, immunosuppression and carcinogenesis, and addition of inhibitors improves the protective capacity of sunscreens.

UVA-induced immunosuppression.

It has previously been demonstrated that chronic low-dose solar-simulated ultraviolet (UV) radiation can induce both local and systemic immunosuppression as well as tolerance to a topically applied hapten. Epidermal cells from UV-irradiated mice inhibit spontaneous regression of tumours indicating that UV-induced immunosuppression is likely to permit the outgrowth of developing UV-induced skin tumours. We have used a chronic low-dose UV-irradiation protocol to investigate the effects of UVA on the skin immune system of C3H/HeJ mice. Irradiation with UVA + B significantly suppressed the local and systemic primary contact sensitivity (CS) response to the hapten TNCB. Furthermore UVA + B reduced Langerhans cell (LC) and dendritic epidermal T cell (DETC) numbers in chronically UV-irradiated mice. UVA-irradiation induced local, but not systemic, immunosuppression and reduced LC (32%) but not DETC from the epidermis compared to the shaved control animals. Treatment of mice with UVA + B or UVA radiation also induced an impaired secondary CS response, and this tolerance was transferable with spleen cells. Therefore exposure of C3H/HeJ mice 5 days per week for 4 weeks with UVA can induce local immunosuppression and tolerance. One of the mechanisms by which UVA affects biological systems is production of reactive oxygen species. We have also shown that Vitamin E, an inhibitor of lipid peroxidation, prevents UV-induced immunosuppression and loss of LC. It is possible that the UVA in UV radiation induces epidermal lipid peroxidation which stimulates LC migration from the epidermis, thus contributing to UV-induced immunosuppression. Hence, inhibition of epidermal lipid peroxidation by Vitamin E may provide some protection to the skin immune system from these effects of UV.

Treatment of childhood phimosis with a moderately potent topical steroid.

BACKGROUND: Recently, topical steroid application has been shown by a small number of studies to be an effective alternative to circumcision for the treatment of phimosis. However, only potent or very potent corticosteroids have been more thoroughly studied in this treatment option. A prospective study was conducted to determine whether comparable results could be achieved using a weaker steroid cream. METHODS: Boys, 3-13 years of age, with non-retractable foreskin due to a tight ring at the tip were offered the regimen of twice-daily preputial retraction and topical application of 0.02% triamcinolone acetonide cream. The degree of preputial retractability was assessed at presentation and at 4 and 6 weeks of treatment. Success was defined as full retraction or free retraction up to agglutination of the foreskin to the glans. RESULTS: Eighty-three boys completed the treatment. Successful retraction was achieved in 48/83 (58%) patients after 4 weeks and 70/83 (84%) patients after 6 weeks of application. The overall response rate aggregated from six published series using 0.05% betamethasone was 87% at 4 weeks and 90% on completion of treatment. Thus, the results appear inferior when analysed at 4 weeks but compare favourably with those reported for a more potent steroid on completion of the full course of treatment. CONCLUSIONS: Even though the triamcinolone cream used in the present study is less potent than the more commonly used 0.05% betamethasone valerate cream, it could effect comparable improvements in foreskin retractability after 6 weeks of treatment.

Modified endoscopic dacryocystorhinostomy with posterior lacrimal sac flap for nasolacrimal duct obstruction.

OBJECTIVES: To evaluate a new technique of modified endoscopic dacryocystorhinostomy involving the creation of a large posterior flap at the lacrimal sac and to compare its success rate with that of the conventional endoscopic method of excising the entire medial lacrimal sac wall as a surgical treatment for epiphora caused by nasolacrimal duct obstruction. DESIGN: Retrospective, interventional, and comparative case series. SETTING: University teaching hospital, Hong Kong. PATIENTS AND METHODS: Only adults with primary nasolacrimal duct obstruction were included. Consecutive endoscopic dacryocystorhinostomy was performed using two different techniques from July 1999 to June 2001. The new technique involved the creation of a large posterior flap at the medial lacrimal sac wall, reflecting it posteriorly, followed by removal of the remaining small anterior flap (the LSF group). Other patients had the entire medial lacrimal sac wall excised (the ELS group). MAIN OUTCOME MEASURES: Surgical success was defined by free fluorescein drainage from the conjunctival sac into the rhinostomy site at least 3 months after silicone stent removal. RESULTS: Ninety-nine procedures were performed in 99 patients. The success rate was 89.1% (41/46) in the LSF group and 71.7% (38/53) in the ELS group. The difference between the two groups was statistically significant (Chi squared test, P=0.031). CONCLUSIONS: Our new and modified technique of endonasal dacryocystorhinostomy has a greater success rate than conventional endonasal dacryocystorhinostomy. A large-scale prospective randomised controlled trial to further evaluate the efficacy and safety of this surgical technique is under way.

Pattern classification of valence in depression.

Neuroimaging biomarkers of depression have potential to aid diagnosis, identify individuals at risk and predict treatment response or course of illness. Nevertheless none have been identified so far, potentially because no single brain parameter captures the complexity of the pathophysiology of depression. Multi-voxel pattern analysis (MVPA) may overcome this issue as it can identify patterns of voxels that are spatially distributed across the brain. Here we present the results of an MVPA to investigate the neuronal patterns underlying passive viewing of positive, negative and neutral pictures in depressed patients. A linear support vector machine (SVM) was trained to discriminate different valence conditions based on the functional magnetic resonance imaging (fMRI) data of nine unipolar depressed patients. A similar dataset obtained in nine healthy individuals was included to conduct a group classification analysis via linear discriminant analysis (LDA). Accuracy scores of 86% or higher were obtained for each valence contrast via patterns that included limbic areas such as the amygdala and frontal areas such as the ventrolateral prefrontal cortex. The LDA identified two areas (the dorsomedial prefrontal cortex and caudate nucleus) that allowed group classification with 72.2% accuracy. Our preliminary findings suggest that MVPA can identify stable valence patterns, with more sensitivity than univariate analysis, in depressed participants and that it may be possible to discriminate between healthy and depressed individuals based on differences in the brain's response to emotional cues.

Precautions in ophthalmic practice in a hospital with a major acute SARS outbreak: an experience from Hong Kong.

Many new infectious diseases in humans have been derived from animal sources in the past 20 years. Some are highly contagious and fatal. Vaccination may not be available and antiviral drugs are not effective enough. Infectious control is important in clinical medicine and in Ophthalmology. Severe acute respiratory syndrome (SARS), as an example, is a highly contagious respiratory disease that has recently been reported in Asia, North America, and Europe. Within a matter of weeks, the outbreak has evolved to become a global health threat and more than 30 countries have been afflicted with a novel Coronavirus strain (SARS-CoV) that is the aetiologic agent of SARS. The primary route of transmission of SARS appears involving close person-to-person contact through droplets. Ophthalmologists may be particularly susceptible to the infection as routine ophthalmic examinations like direct ophthalmoscopy and slit-lamp examination are usually performed in a setting that has close doctor-patient contact. Being the Ophthalmology Department of the only hospital in the world that has just gone through the largest outbreak of SARS, we would like to share our strategy, measures, and experiences of preventing contracting or spreading of SARS infection as an infection control model. SARS is one of the many viruses against which personnel will need protecting in an ophthalmic setting. The experiences attained and the measures established might also apply to other infectious conditions spreading by droplets such as the avian influenza with H5N1.

Immediate pars plana vitrectomy for dislocated intravitreal lens fragments during cataract surgery.

PURPOSE: To assess the outcome of patients who underwent instantaneous pars plana vitrectomy for dislocated lens fragments during cataract surgery. METHODS: The medical records of 29 patients who underwent immediate pars plana vitrectomy for dislocated lens fragments at the same sitting of phacoemulsification surgery were reviewed. Data including patients' demographics, preoperative and postoperative vision, risk factors for lens fragment dislocation, and intraoperative and postoperative complications were recorded. RESULTS: The mean follow-up period of the patients was 12.3 months (range, 3-47 months). The median preoperative visual acuity was 6/90 (range, LP to 6/15). The median final postoperative visual acuity was 6/18 (range, NLP to 6/9) and the mean improvement in vision after the operation was 4.5 lines. The commonest risk factors for dislocation of lens fragment were late detection of posterior capsule tear, splitting of anterior capsulorrhexis, and hard nucleus. After excluding nine eyes with other pre-existing ocular comorbidities, 10 (50%) eyes had a final visual acuity of 6/12 or better. Complications after surgery included three (10%) cases of retinal detachment and one (3%) patient developed epiretinal membrane. None of the patients in the study developed secondary glaucoma or cystoid macular oedema following surgery. CONCLUSION: Immediate vitrectomy in the same sitting of the cataract surgery is a surgical option in the management of dislocated intravitreal lens fragments when vitreoretinal support is available. Most patients achieve a good visual outcome with reduced risk of secondary glaucoma and cystoid macular oedema after surgery.

Protective immunity to UV radiation-induced skin tumours induced by skin grafts and epidermal cells.

There is little evidence that cutaneous dendritic cells (DC), including epidermal Langerhans cells (LC), can induce immunity to UV radiation (UVR)-induced skin tumours. Here, it is shown that cells within skin can induce protective antitumour immunity against a UVR-induced fibrosarcoma. Transplantation of the skin overlying subcutaneous tumours onto naïve recipients could induce protective antitumour immunity, probably because the grafting stimulated the tumour Ag-loaded DC to migrate to local lymph nodes. This suggests that cutaneous APC can present tumour Ag to induce protective antitumour immunity. Previously, it has been shown that immunization of mice with MHC class II+ epidermal cells (EC) pulsed with tumour extracts could induce delayed-type hypersensitivity against tumour cells. Here, this same immunization protocol could induce protective immunity against a minimum tumorigenic dose of UVR-induced fibrosarcoma cells, but not higher doses. Epidermal cells obtained from semiallogeneic donors and pulsed with tumour extract could also induce protective immunity. However, presentation of BSA Ag from the culture medium was found to contribute to this result using semiallogeneic EC. The results suggest that LC overlying skin tumours may be able to induce protective immunity to UVR-induced tumours if stimulated to migrate from the skin.

Differential age-related change of prose memory in older Hong Kong Chinese of higher and lower education.

BACKGROUND: Memory difficulty is one of the most common complaints of older people, with or without psychiatric conditions. It is therefore of utmost important to understand how normal ageing process impacts upon prose memory so as to gain insight into ways to differentiate pathological vs normal age-related changes of the recall of prose observed among older people. OBJECTIVES: To understand the differential age-related change of prose memory in older Hong Kong Chinese of higher and lower education. METHOD: Forty-eight normal, healthy Cantonese-speaking Chinese were recruited. Seventeen of them were younger, highly educated participants. Among the 31 older people recruited, 19 of them received education comparable with the younger participants and 12 were older people of low education. A prose passage was constructed to measure the different processes of prose memory, including learning efficiency, rate of forgetting, recall accuracy, accuracy of temporal sequence of information recalled, distortions, and recognition memory. RESULTS: As expected, ageing affected all the processes of prose memory measured, except the rate of forgetting. Apart from learning efficiency and rate of forgetting, education was observed to modify the effect of ageing on all the processes studied. CONCLUSIONS: Changes of prose memory associated with ageing and the differential effect of education on prose recall among older people were discussed. The findings seem to suggest that prose memory is a multifaceted construct.

Sunscreens and vitamin E provide some protection to the skin immune system from solar-simulated UV radiation.

Previous studies have indicated that sunscreens designed to protect from erythema do not adequately prevent immunosuppression. Mice were irradiated with suberythemal doses of solar-simulated ultraviolet radiation (ssUVR) to assess the immunoprotective ability of sunscreens. Whereas C3H/HeJ and BALB/c mice had similar sensitivities to ssUVR-induced inflammation, C3H/HeJ mice were more sensitive to ssUVR-induced immunosuppression. Octyl dimethyl-p-aminobenzoic acid did not protect from immunosuppression and, thus, had an immune protection factor (IPF) of 1. 2-Ethylhexyl-p-methoxycinnamate and microfine titanium dioxide provided limited protection, both having IPF values of 1.127. Immune protection by the sunscreens appeared to be dependent upon absorption of UVA as well as UVB, and was much less than predicted from the sun protection factor. Vitamin E, an inhibitor of lipid peroxidation, also protected the immune system, with an IPF of 1.2, indicating that oxidation of lipids is involved in UVR-induced immunosuppression, and that it should be possible to develop sunscreens which protect the immune system.