Limited role of the c-Jun N-terminal kinase pathway in a neonatal rat model of cerebral hypoxia-ischemia

D-JNKI1, a cell-permeable peptide inhibitor of the c-Jun N-terminal kinase (JNK) pathway, has been shown to be a powerful neuroprotective agent after focal cerebral ischemia in adult mice and young rats. We have investigated the potential neuroprotective effect of D-JNKI1 and the involvement of the JNK pathway in a neonatal rat model of cerebral hypoxia-ischemia. Seven-day-old rats underwent a permanent ligation of the right common carotid artery followed by 2h of hypoxia (8% oxygen). Treatment with D-JNKI1 (0.3mg/kg intraperitoneally) significantly reduced early calpain activation, late caspase-3 activation and, in the thalamus, autophagosome formation, indicating an involvement of JNK in different types of cell death: necrotic, apoptotic and autophagic. However the size of the lesion was unchanged. Further analysis showed that neonatal hypoxia-ischemia induced an immediate decrease in JNK phosphorylation (reflecting mainly P-JNK1) followed by a slow progressive increase (including P-JNK3 54kDa), whereas c-jun and c-fos expression were both strongly activated immediately after hypoxia-ischemia. In conclusion, unlike in adult ischemic models, JNK is only moderately activated after severe cerebral hypoxia-ischemia in neonatal rats and the observed positive effects of D-JNKI1 are insufficient to give neuroprotection. Thus, for perinatal asphyxia, D-JNKI1 can only be considered in association with other therapies.

Predictors of favourable outcome in first-episode patients who refuse medication: results from the FEPOS study

There are suggestions that some first-episode psychosis (FEP) patients can have favourable outcome without antipsychotic medication. However, there is very limited data regarding patients' characteristics on which the decision to propose medication free treatment could be based. FEPOS is a fi le-based study of an epidemiological sample of 704 FEP patients treated at EPPIC, Melbourne, between 1998 and 2000. Among the 661 patients where data was available, 108 consistently refused medication during the entire duration of their treatment at EPPIC. In this paper we compared, within this sub-group, patients who had a favourable outcome with those who did not. Patients were aged between 15 and 29 years (M = 21.9, SD = 3.40) and the majority were male (70.4%, n = 76). Symptomatic remission data was available on 105 patients; of these patients 41.0% (n = 41) had achieved remission. Functional remission data was available on 100 patients; of these patients 33.0% (n = 33) had achieved functional remission. Combined remission was evident in 23.0% (n = 23) of patients. Three factors were associated with symptomatic remission: better premorbid functioning (based on GAF, OR = 1.07, p = 0.006), higher number of years of education (OR = 1.43, p = 0.020), and being employed or studying at service entry (OR = 2.59, p = 0.034). Three factors were associated with functional remission: shorter duration of prodrome (OR = 0.50, p = 0.043), severity of psychopathology (CGI-S, OR = 0.51, p = 0.024), and vocational status at service entry (OR = 4.29, p = 0.003). While various aspects of pre-morbid functioning seem to correlate with the possibility of a favourable outcome in FEP patients who refuse medication, various limitations need to be taken into account in this study.

Primary fluid bolus therapy for infection-associated hypotension in the emergency department.

OBJECTIVES: The physiological changes associated with fluid bolus therapy (FBT) for patients with infection-associated hypotension in the emergency department (ED) are poorly understood. We describe the physiological outcomes of FBT in the first 6 hours (primary FBT) for patients presenting to the ED with infection-associated hypotension. METHODS: We studied 101 consecutive ED patients with infection and a systolic blood pressure (SBP)<100 mmHg who underwent FBT in the first 6 hours. RESULTS: We screened 1123 patients with infection and identified 101 eligible patients. The median primary FBT volume given was 1570 mL (interquartile range, 1000- 2490 mL). The average mean arterial pressure (MAP) did not change from admission to 6 hours in the whole cohort, or in patients who were hypotensive on arrival at the ED. However, the average MAP increased from its lowest value during the first 6 hours (66 mmHg [SD, 10 mmHg]) to its value at 6 hours (73 mmHg [SD, 12 mmHg]; P<0.001). The mean heart rate, body temperature, respiratory rate and plasma creatinine level decreased (P<0.05). In patients who were severely hypotensive (SBP<90 mmHg) on arrival at the ED, the MAP increased from 54 mmHg (SD, 8 mmHg) to 70 mmHg (SD, 14 mmHg) (P<0.001). At 6 hours, however, SBP was still <100 mmHg in 44 patients and <90 mmHg in 17 patients. When noradrenaline was used, in 10 patients, hypotension was corrected in all 10 and the MAP increased from 58 mmHg (SD, 9 mmHg) to 75 mmHg (SD, 13 mmHg). CONCLUSION: Among ED patients admitted to an Australian teaching hospital with infection, hypotension was uncommon. FBT for hypotension was limited in volumes given and failed to achieve a sustained SBP of >100 mmHg in 40% of cases. In contrast, noradrenaline therapy corrected hypotension in all patients who received it.

How to operate a university institute as a radiological emergency service?

The Institute of Radiation Physics (IRA) is attached to the Department of Medical Radiology at the Vaud University Hospital Center (CHUV) in Lausanne. The Institute's main tasks are strongly linked to the medical activities of the Department: radiotherapy, radiodiagnostics, interventional radiology and nuclear medicine. The Institute also works in the fields of operational radiation protection, radiation metrology and radioecology. In the case of an accident involving radioactive materials, the emergency services are able to call on the assistance of radiation protection specialists. In order to avoid having to create and maintain a specific structure, both burdensome and rarely needed, Switzerland decided to unite all existing emergency services for such events. Thus, the IRA was invited to participate in this network. The challenge is therefore to integrate a university structure, used to academic collaborations and the scientific approach, to an interventional organization accustomed to strict policies, a military-style command structure and "drilled" procedures. The IRA's solution entails mobilizing existing resources and the expertise developed through professional experience. The main asset of this solution is that it involves the participation of committed collaborators who remain in a familiar environment, and are able to use proven materials and mastered procedures, even if the atmosphere of an accident situation differs greatly from regular laboratory routines. However, this solution requires both a commitment to education and training in emergency situations, and a commitment in terms of discipline by each collaborator in order to be integrated into a response plan supervised by an operational command center.

Cultural Biases in Public Service Delivery : Evidence from a Regression Discontinuity Approach

What determines the share of public employment, at a given size of the State, in countries of similar levels of economic development? While the theoretical and empirical literature on this issue has mostly considered technical dimensions (efficiency and political considerations), this paper emphasizes the role of culture and quantifies it. We build a representative database for contracting choices of municipalities in Switzerland and exploit the discontinuity at the Swiss language border at identical actual set of policies and institutions to analyze the causal e↵ect of culture on the choice of how public services are provided. We find that French-speaking border municipalities are 50% less likely to contract with the private sector than their German-speaking adjacent municipalities. Technical dimensions are much smaller by comparison. This result points out that culture is a source of a potential bias that distorts the optimal choice for public service delivery. Systematic differences in the level of confidence in public administration and private companies potentially explain this discrepancy in private sector participation in public services provision.

In conditions of limited chromophore supply rods entrap 11-cis-retinal leading to loss of cone function and cell death.

RPE65 is a retinoid isomerase required for the production of 11-cis-retinal, the chromophore of both cone and rod visual pigments. We recently established an R91W knock-in mouse strain as homologous animal model for patients afflicted by this mutation in RPE65. These mice have impaired vision and can only synthesize minute amounts of 11-cis-retinal. Here, we investigated the consequences of this chromophore insufficiency on cone function and pathophysiology. We found that the R91W mutation caused cone opsin mislocalization and progressive geographic cone atrophy. Remnant visual function was mostly mediated by rods. Ablation of rod opsin corrected the localization of cone opsin and improved cone retinal function. Thus, our analyses indicate that under conditions of limited chromophore supply rods and cones compete for 11-cis-retinal that derives from regeneration pathway(s) which are reliant on RPE65. Due to their higher number and the instability of cone opsin, rods are privileged under this condition while cones suffer chromophore deficiency and degenerate. These findings reinforce the notion that in patients any effective gene therapy with RPE65 needs to target the cone-rich macula directly to locally restore the cones' chromophore supply outside the reach of rods.