Changes in the Occurrence,Severity, and Distress of Symptoms in Patients With Gastrointestinal Cancers Receiving Chemotherapy

Context

Studies on multiple dimensions of the symptom experience of patients with gastrointestinal cancers are extremely limited.

Contextual Information Drives the Reconsolidation-Dependent Updating of Retrieved Fear Memories

Stored memories enter a temporary state of vulnerability following retrieval known as ‘reconsolidation'', a process that can allow memories to be modified to incorporate new information. Although reconsolidation has become an attractive target for treatment of memories related to traumatic past experiences, we still do not know what new information triggers the updating of retrieved memories. Here, we used biochemical markers of synaptic plasticity in combination with a novel behavioral procedure to determine what was learned during memory reconsolidation under normal retrieval conditions. We eliminated new information during retrieval by manipulating animals'' training experience and measured changes in proteasome activity and GluR2 expression in the amygdala, two established markers of fear memory lability and reconsolidation. We found that eliminating new contextual information during the retrieval of memories for predictable and unpredictable fear associations prevented changes in proteasome activity and glutamate receptor expression in the amygdala, indicating that this new information drives the reconsolidation of both predictable and unpredictable fear associations on retrieval. Consistent with this, eliminating new contextual information prior to retrieval prevented the memory-impairing effects of protein synthesis inhibitors following retrieval. These results indicate that under normal conditions, reconsolidation updates memories by incorporating new contextual information into the memory trace. Collectively, these results suggest that controlling contextual information present during retrieval may be a useful strategy for improving reconsolidation-based treatments of traumatic memories associated with anxiety disorders such as post-traumatic stress disorder.     

A randomized,placebo‐controlled,double‐masked clinical trial of etanercept for the treatment of uveitis associated with juvenile idiopathic arthritis

Objective

To investigate the safety and efficacy of etanercept in the treatment of uveitis associated with juvenile idiopathic arthritis (JIA).

Methods

Children who met the American College of Rheumatology diagnostic criteria for JIA with active uveitis, who had anterior chamber cells of ≥1+ or requiring topical corticosteroid ≥3 times daily, and who were on a stable regimen for arthritis treatment were eligible. Study participants received etanercept (0.4 mg/kg) or placebo administered subcutaneously twice weekly for 6 months. All participants received open‐label etanercept for an additional 6 months.

Results

Five patients received placebo and 7 received etanercept. Three of the 7 patients treated with etanercept and 2 of the 5 placebo‐treated patients were considered ophthalmic successes (P = 1.0). One patient in each treatment group was considered a treatment failure. Three of the 7 etanercept‐treated and 2 of the 5 placebo‐treated patients were neither successes nor failures by our definition. There were no serious adverse events for any patient during the entire study period. Reports of minor infections were comparable in each treatment group, 71% for etanercept and 60% for placebo (P = 0.58).

Conclusion

In this small pilot study there was no apparent difference in the anterior segment inflammation between patients treated with etanercept and placebo. The stringent criteria used to measure ophthalmic success of treatment and the small patient population limit the implications of our findings.

     

Budget impact analysis on the introduction of a guideline based hepatitis B and C screening into a routine check-up in the German primary care setting

Objectives: Systematic screening for chronic hepatitis B and C does not yet exist in Germany. Therefore, the implementation of a screening approach within a preventive medical examination performed by primary care physicians (‘Check-Up 35+’) was evaluated in a recent prospective multicenter study. The present analysis estimates the financial consequences for the statutory health insurance by budget impact analysis.

Materials and methods: A Markov cohort model was developed consisting of 21 health states. Four different screening scenarios derived from the previous multicenter study were compared to usual care, a strategy without screening for hepatitis. Actual cost data for Germany were calculated and systematic literature searches for all input parameters were performed.

Results: The base case results in incremental costs for the screening strategies compared to no hepatitis screening of 165–227 € per patient in a 20-year horizon. Two main parameters influence the financial consequences: (A) detection and treatment increase the costs in the beginning. (B) Screening avoids hepatitis induced end-stage liver disease. The initial higher costs exceed the later savings. Sensitivity analyses demonstrate a strong impact of medication costs for the treatment of additionally detected hepatitis infections on the outcome. This finding is robust to sensitivity analysis.

Conclusions: The screening strategy proposed here implies additional costs for the statutory health insurance, however, a decision regarding its usefulness must consider criteria other than cost. For example, the high burden of disease due to liver cirrhosis and liver carcinoma should be considered. Therefore, an additional cost-effectiveness-analysis should be conducted.     

Comparison of stent versus balloon angioplasty for pulmonary vein stenosis complicating pulmonary vein isolation

Introduction: Pulmonary vein stenosis (PVS) is a rare but significant complication of pulmonary vein isolation (PVI). Dilation and stent angioplasty have been described but not compared.
Methods and Results: All percutaneous interventions for PVS complicating PVI between December 2000 and March 2007 were reviewed. Acute success, defined as post-intervention stenosis ≤30%, and long-term outcome of dilation versus stent angioplasty were compared. Freedom from restenosis was defined as freedom from repeat intervention. Overall outcome for all interventions was examined. We studied 34 patients with 55 stenotic veins followed for a mean of 25 months. Dilation was performed in 39 veins and stenting in 40 veins (16 primarily, 24 after dilation restenosis). Acute success and restenosis rates were 42% and 72% for dilation versus 95% (P < 0.001) and 33% for stenting. Time to restenosis was greater for stent angioplasty (P = 0.003). Stents ≥10 mm in diameter had lower restenosis than smaller stents. Risk factors for restenosis included small reference vessel diameter and longer time from PVI to intervention for PVS. All but two patients experienced improvement (n = 10) or resolution of symptoms (n = 22). The mean percent stenosis decreased from 82% to 21% for the entire cohort and mean flow to the lung quadrant increased from 10% to 17%.
Conclusion: Stent angioplasty results in less restenosis than dilation, particularly for stents ≥10 mm. Early referral may improve long-term patency by minimizing reference vessel atrophy. Most patients with PVS post-PVI can be improved symptomatically with catheter intervention.     

Bcl-2 protein expression is the strongest independent prognostic factor of survival in primary cutaneous large B-cell lymphomas

Bcl-2 protein expression has been associated with poor prognosis in patients with noncutaneous diffuse large B-cell lymphomas. In primary cutaneous large B-cell lymphomas, the location on the leg, the round-cell morphology defined as the predominance of centroblasts and immunoblasts over large centrocytes, and multiple skin lesions were identified as adverse prognostic factors. The prognostic value of bcl-2 protein expression has not been studied in large series of patients. We evaluated 80 primary cutaneous large B-cell lymphomas collected by the French Study Group on Cutaneous Lymphomas. The prognostic value of age, sex, number of lesions, cutaneous extent, location, serum lactate dehydrogenase (LDH) level, B symptoms, morphology, and bcl-2 protein expression was studied. The overall 5-year specific survival rate was 65%. In univariate analysis, advanced age, multiple skin lesions (n = 48), location on the leg (n = 25), round-cell morphology (n = 32), and bcl-2 expression (n = 39) were significantly related to death from lymphoma. In multivariate analysis, bcl-2 expression (P =.0003), multiple skin lesions (P =.004), and age remained independent prognostic factors. The 5-year specific survival rates in bcl-2-positive and bcl-2-negative patients were 41% and 89%, respectively (P <.0001). A new prognostic classification of primary cutaneous B-cell lymphoma should be based primarily on bcl-2 protein expression rather than the location of skin lesions.     

Outcomes for children with acute myocarditis

The optimum treatment for myocarditis in children is unknown. We present outcomes for this disease as seen in a large series of children. Thus, we identified all children seen with myocarditis at Children's Hospital of Pittsburgh since 1985, including only those with biopsy-proven myocarditis, or cardiac dysfunction and proof of concomitant cardiotropic viral infection. Outcomes were defined as complete recovery, incomplete recovery, and death or transplantation. We identified 41 patients, 37 proven by histology, and 4 patients who were too unstable for biopsy but had proof of viral infection. Of the group, 27 (66%) made a complete recovery, 4 (10%) had incomplete recovery, and 10 (24%) either died (5) or underwent transplantation (5). The median time to death or transplantation was 8.4 months, with a range from 1 day to 49 months. Steroids had been administered to 16 patients, of whom 10 made a complete recovery, 2 an incomplete recovery, 2 died, and 2 were transplanted. Intravenous immune globulin was given in isolation to one patient, who made a complete recovery, and to 18 in combination with steroids, of whom 12 made a complete recovery, 2 an incomplete recovery, 2 died, and 2 were transplanted. The remaining 6 patients received neither steroids nor intravenous immune globulin, and of these, 4 made a complete recovery, 1 was transplanted, and 1 died. Freedom from death or transplantation was 81% at 1 year, and 74% at 5 years, with no difference between the modes of treatments. The median time to recovery of function was also comparable between the groups. Thus, in our patients, treatment with intravenous immune globulin appeared to confer no advantage to steroid therapy alone. These data emphasise the need for randomised trials to assess the efficacy of current treatments, as well as that of new therapies.     

Fc-Fc interactions of human IgG4 require dissociation of heavy chains and are formed predominantly by the intra-chain hinge isomer

Human IgG4 antibodies are remarkable not only because they can dynamically exchange half-molecules (Fab-arm exchange) but also for their ability to interact with the Fc part of IgG4 and other IgG subclasses. This rheumatoid factor-like binding of IgG4 does not appear to take place spontaneously, because it is only observed to solid-phase or antigen-bound IgG. We hypothesized that Fc-Fc interactions might involve (partial) dissociation of heavy chains. We investigated the molecular basis of these Fc-Fc interactions, and found that the structural features important for the exchange reaction also control the Fc binding activity. In particular, if arginine-409 in the CH(3)-CH(3) interface in IgG4 is mutated to lysine (the equivalent in IgG1), Fc-Fc interactions are formed 3 orders of magnitude less efficiently compared to the wild-type. This mutation was previously found to increase the CH(3)-CH(3) interaction strength in IgG4. Furthermore, of the two hinge isomers of IgG4, the intra-chain (non-covalently linked) form was found to form Fc-Fc interactions, but not the inter-chain form. Together, these results demonstrate that Fc-Fc interactions of IgG4 involve (partial or complete) dissociation of heavy chains. The promiscuity to other IgG subclasses suggests that IgG4 might act as scavenger to IgG molecules with impaired structural integrity.