Preventing vaccinia virus class-I epitopes presentation by HSV-ICP47 enhances the immunogenicity of a TAP-independent cancer vaccine epitope.

Herpes simplex virus protein ICP47, encoded by US12 gene, strongly downregulates major histocompatibility complex (MHC) class-I antigen restricted presentation by blocking transporter associated with antigen processing (TAP) protein. To decrease viral vector antigenic immunodominance and MHC class-I driven clearance, we engineered recombinant vaccinia viruses (rVV) expressing ICP47 alone (rVV-US12) or together with endoplasmic reticulum (ER)-targeted Melan-A/MART-1(27-35) model tumor epitope (rVV-MUS12). In this study, we show that antigen presenting cells (APC), infected with rVV-US12, display a decreased ability to present TAP dependent MHC class-I restricted viral antigens to CD8+ T-cells. While HLA class-I cell surface expression is strongly downregulated, other important immune related molecules such as CD80, CD44 and, most importantly, MHC class-II are unaffected. Characterization of rVV-MUS12 infected cells demonstrates that over-expression of a TAP-independent peptide, partially compensates for ICP47 induced surface MHC class-I downregulation (30% vs. 70% respectively). Most importantly, in conditions where clearance of infected APC by virus-specific CTL represents a limiting factor, a significant enhancement of CTL responses to the tumor epitope can be detected in cultures stimulated with rVV-MUS12, as compared to those stimulated by rVV-MART alone. Such reagents could become of high relevance in multiple boost protocols required for cancer immunotherapy, to limit vector-specific responsiveness.

Long-term outcome in patients with mild traumatic brain injury: a prospective observational study.

BACKGROUND: Mild traumatic brain injury (MTBI) is common; up to 37% of adult men have a history of MTBI. Complaints after MTBI are persistent headaches, memory impairment, depressive mood disorders, and disability. The reported short- and long-term outcomes of patients with MTBI have been inconsistent. We have now investigated long-term clinical and neurocognitive outcomes in patients with MTBI (at admission, and after 1 and 10 years). METHODS: Patients of a previous study investigating MTBI short-term outcome were prospectively reassessed after ±10 year using the same standardized data entry form and validated questionnaire (Beltztest with Beltz Score [BeSc]) for evaluation of Quality of life (QoL) and neurocognitive outcome (higher scores indicate lower QoL). RESULTS: Eighty-six of 176 patients (49%) could be reassessed (n = 75 lost to follow-up; n = 8 second brain trauma; n = 7 death), 10.4 ± 2 years after initial evaluation. Over time, overall BeSc was significantly increased (5.92 ± 10.3 [admission] vs. 10.7 ± 12.8 [1 year] vs. 20.86 ± 17.1 [10 year]; p < 0.0001); only 54 of 86 patients (62.8%) presented with a normal BeSc. Long-term complaints were fatigue, insomnia, and exhaustion. Ten of eighty-six patients (11.6%) had intracranial injury (ICI) and initial BeSc was almost twofold higher in patients with ICI than in patients without ICI (10.0 ± 8.4 vs. 5.3 ± 9.6; p = 0.007). This difference was not seen after 1 year or after 10 years (10.3 ± 11.6 vs. 10.3 ± 10.1 and 21.4 ± 17.3 vs. 16.1 ± 16.4, respectively). Eight of eighty-six patients (9.3%) lost their jobs because of persistent complaints after MTBI. CONCLUSION: BeSc deteriorates over time; our data suggest a decline in general health and QoL in a substantial proportion of patients (37.2%) 10 years after MTBI. Patients without ICI appear to have a better long-term outcome with regard to subjective complaints and QoL.

Decision making in patients with acute abdominal pain at a university and at a rural hospital: does the value of abdominal sonography differ?

INTRODUCTION AND OBJECTIVES: Abdominal sonography is regarded as a quick and effective diagnostic tool for acute abdominal pain in emergency medicine. However, final diagnosis is usually based on a combination of various clinical examinations and radiography. The role of sonography in the decision making process at a hospital with advanced imaging capabilities versus a hospital with limited imaging capabilities but more experienced clinicians is unclear.The aim of this pilot study was to assess the relative importance of sonography and its influence on the clinical management of acute abdominal pain, at two Swiss hospitals, a university hospital (UH) and a rural hospital (RH). METHODS: 161 patients were prospectively examined clinically. Blood tests and sonography were performed in all patients. Patients younger than 18 years and patients with trauma were excluded. In both hospitals, the diagnosis before and after ultrasonography was registered in a protocol. Certainty of the diagnosis was expressed on a scale from 0% to 100%.The decision processes used to manage patients before and after they underwent sonography were compared. The diagnosis at discharge was compared to the diagnosis 2 - 6 weeks thereafter. RESULTS: Sensitivity, specificity and accuracy of sonography were high: 94%, 88% and 91%, respectively.At the UH, management after sonography changed in only 14% of cases, compared to 27% at the RH. Additional tests were more frequently added at the UH (30%) than at the RH (18%), but had no influence on the decision making process-whether to operate or not. At the UH, the diagnosis was missed in one (1%) patient, but in three (5%) patients at the RH. No significant difference was found between the two hospitals in frequency of management changes due to sonography or in the correctness of the diagnosis. CONCLUSION: Knowing that sonography has high sensitivity, specificity and accuracy in the diagnosis of acute abdominal pain, one would assume it would be an important diagnostic tool, particularly at the RH, where tests/imaging studies are rare.However, our pilot study indicates that sonography provides important diagnostic information in only a minority of patients with acute abdominal pain.Sonography was more important at the rural hospital than at the university hospital. Further costly examinations are generally ordered for verification, but these additional tests change the final treatment plan in very few patients.

Patients with mild traumatic brain injury: immediate and long-term outcome compared to intra-cranial injuries on CT scan.

BACKGROUND: Mild traumatic brain injury (MTBI) defined as Glasgow Coma Scale (GCS) 14 or 15 has shown contradictory short- and long-term outcomes. The objective of this study was to correlate intra-cranial injuries (ICI) on CT scan to neurocognitive tests at admission and to complaints after 1 year. METHODS: Two hundred and five patients with MTBI underwent a CT scan and were examined with neurocognitive tests. After 1 year complaints were assessed by phone interviews. RESULTS: The neurocognitive tests in 51% of the patients showed significant deficits; there was no difference for patients with GCS 14-15, nor was there a difference between patients with ICI to patients without. After 1 year patients with ICI had significantly more complaints than patients without ICI, the most frequent complaint was headache and memory deficits. CONCLUSIONS: No correlation was found between GCS or ICI and the neurocognitive tests upon admission. After 1 year, patients with ICI have significantly more complaints than patients without ICI. No cost savings resulted by doing immediate CT scan on all.