Increased superoxide anion production by immunologically activated and chemically elicited macrophages

We studied the capacity of cultured mouse peritoneal macrophages to generate superoxide anion (O(2-)), the initial product of conversion of oxygen to microbicidal species, during phagocytosis of opsonized zymosan or upon contact with the membrane-active agent phorbel myristate acetate (PMA). Macrophages from mice infected with Bacille Calmette-Guerin (BCG) or injected intraperitoneally with thioglycollate broth or endotoxin, released up to 12 times more O(2-) than did resident peritoneal macrophages, depending upon the cell type and whether the stimulus was zymosan or PMA. There was little if any O(2-) release from resting (unstimulated) macrophages. The density of cells on culture dishes was an important variable since crowding of the dish markedly reduced the efficiency of O(2-) production. The enhanced O(2-) release of chemically elicited and infection-activated macrophages was noted after stimulation with a wide range of concentrations of PMA and zymosan, at all time points studied (up to 120 min), and with cells maintained for 140 rain to 16 days in culture. The O(2-) response of resident cells improved twofold to zymosan and ninefold to PMA during the first 3 days in culture. The capacity to release O~ appears to be limited to actively phagocytic cell types: murine macrophage-like tumor lines and cultured human monocytes released O(2-) when stimulated by PMA or zymosan, fibroblast and endothelial lines and embryo-derived cells did not. Activity of superoxide dismutase, which removes O(2-), was not detectable in culture supernates of any cell type, and thus, differences in detectable O(2-) could not be attributed to variations in the release of this enzyme. We conclude that the phagocytosis- associated respiratory burst is significantly enhanced in mononuclear phagocytes obtained ai~r chemical inflammation or BCG infection. Increased capacity to generate O(2-) and other oxygen radicals during phagocytosis could contribute to the improved microbicidal and tumoricidal activity of activated macrophages.     

An unusual cause of hemolysis in a patient with an aortic valved conduit replacement.

Hemolytic anemia is a well-known but uncommon complication in patients with prosthetic heart valves. It is most commonly a result of prosthetic valve dysfunction, periprosthetic valvular regurgitation, or both. We report a case of a 41-year-old man who had a previous aortic valve and root replacement for acute proximal aortic dissection, now presenting with hemolytic anemia. This was a result of flow obstruction at the distal anastomosis of the aortic conduit by the presence of multiple dissection flaps resulting in severe flow turbulence. Although the pathology was at the blind spot for transesophageal echocardiography, the dissection flaps, the flow turbulence, and the degree of obstruction were well-demonstrated by this technique after careful manipulation of the probe and a high index of suspicion.     

Neutrophil heterogeneity in patients with blunt trauma

To determine whether neutrophil (PMN) dysfunction observed in patients with blunt trauma could be explained by alterations in PMN functional subpopulations and to further study the origins of PMN heterogeneity, we studied PMN subpopulations in 18 patients with severe blunt trauma by using a micropore filter chemotactic assay and a mouse monoclonal antibody (31D8 Mab). A major PMN subpopulation binds 31D8 Mab avidly (31D8 "bright") and depolarizes and responds chemotactically to formyl peptide (fMLP) and C5a; a minor PMN subpopulation binds 31D8 Mab weakly (31D8 "dull") and fails to depolarize and responds poorly to fMLP and C5a. Fourteen patients with trauma had marked alteration of PMN 31D8 expression compared with healthy controls 52% +/- 20% versus 92% +/- 4% bright PMNs, respectively (p less than 0.01). These patients also had significantly decreased PMN chemotaxis and increased band counts compared with controls 30 +/- 10 micron versus 53 +/- 19 micron (p less than 0.01) and 34% +/- 14% versus 6% +/- 1% (p less than 0.01), respectively. Four patients with less-severe injuries had unaltered 31D8 PMN expression and normal PMN chemotaxis. In patients whose band counts exceeded 20%, there was a strong correlation between the number of bands and the percentage of 31D8 dull PMNs. PMNs that weakly express the 31D8 antigen appear to be less mature than PMNs that strongly express the antigen regardless of cell morphology (i.e., bands, multilobed cells). The data suggest that the decreased PMN chemotaxis and increased infection rate in patients with blunt trauma is caused partly by an increase in the number of poorly functioning 31D8 dull PMNs.     

Using molecular diagnostic testing to personalize the treatment of patients with gastrointestinal stromal tumors

Introduction: The diagnosis and treatment of gastrointestinal stromal tumor (GIST) has emerged as a paradigm for modern cancer treatment (‘precision medicine’), as it highlights the importance of matching molecular defects with specific therapies. Over the past two decades, the molecular classification and diagnostic work up of GIST has been radically transformed, accompanied by the development of molecular therapies for specific subgroups of GIST. This review summarizes the developments in the field of molecular diagnosis of GIST, particularly as they relate to optimizing medical therapy.

Areas covered: Based on an extensive literature search of the molecular and clinical aspects of GIST, the authors review the most important developments in this field with an emphasis on the differential diagnosis of GIST including mutation testing, therapeutic implications of each molecular subtype, and emerging technologies relevant to the field.

Expert commentary: The use of molecular diagnostics to classify GIST has been shown to be successful in optimizing patient treatment, but these methods remain under-utilized. In order to facilitate efficient and comprehensive molecular testing, the authors have developed a decision tree to aid clinicians.     

Circadian elevation of IL-6 levels in Muckle-Wells syndrome: a disorder of the neuro-immune axis?

Muckle-Wells syndrome (MWS) is a rare autosomal dominant hereditary disorder characterized by chronic recurrent urticaria, arthralgia, sensorineural deafness, and in some cases nephropathy due to amyloidosis (AA type). We report a 21-year-old woman and her father, both suffering from this syndrome, in whom elevated serum levels of IL- 6 could be documented during the flares of urticaria, and discuss the relevance of this finding for MWS.      

Incubation of platelet concentrates before transfusion does not improve posttransfusion recovery

Incubation of stored platelet concentrates (PCs) at 37 degrees C for 1 hour has been reported to result in a better morphology score and improved platelet recovery. A study was conducted in adult patients with leukemia to determine whether incubation of stored PCs results in an improved platelet recovery as measured by 10-minute posttransfusion corrected count increments (CCI). Eligible patients had platelet counts of less than 30,000 per microL and were clinically stable. Patients were transfused with 6 to 10 units of PC stored for 3 days (15 studies) or 4 days (5 studies). Platelets were pooled and then split in two equal volumes so that each patient received two sequential half-transfusions, one incubated at 37 degrees C for 1 hour and the other kept at 22 degrees C for 1 hour. Patients were randomized as to which half-transfusion was received first. The mean CCI of the incubated half-transfusions was 13.6 x 10(3) when they were given first and 14.5 x 10(3) when given second; this was not significantly different from the mean CCI of the nonincubated half-transfusions: 13.8 x 10(3) when they were given first and 13.8 x 10(3) when given second. In contrast to earlier reports, it can be concluded that incubation of pooled PCs does not improve platelet recovery.     

Platelet transfusions administered to patients with splenomegaly

It is generally felt that increments in platelet counts following platelet transfusions to patients with splenomegaly are severely reduced as a result of splenic sequestration. The results of 631 random-donor platelet transfusions administered to 66 thrombocytopenic patients with palpable splenomegaly were analyzed. Increasing splenomegaly had a significant effect on corrected count increments (CCIs), with the greatest deterioration occurring in patients whose spleens were palpable greater than 2.0 cm below the left costal margin. A similar trend was noted when the percentage of transfusions with satisfactory CCIs was compared, although it should be noted that 42 percent of the transfusions produced CCIs greater than 7500, and a large proportion produced clinically helpful absolute increments. Splenomegaly also had an effect on platelet survival: in patients with CCIs greater than 7500, the mean ratio of 24-hour CCIs to 1-hour CCIs was 0.29 to 0.47 in patients with various degrees of splenomegaly, as compared to an expected value of 0.6 to 0.7. Sixteen patients, most with spleens palpable less than 5.0 cm below the left costal margin, consistently had CCIs greater than 7500. A significant fraction of patients with splenomegaly can benefit from platelet transfusion, and thus splenomegaly should not preclude intensive therapeutic approaches.     

Impact of serious mental illness on surgical patient outcomes

Background

People with comorbid mental illness have poorer health status and disparate access to healthcare. Several studies internationally have reported mixed findings regarding the association between mental illness and surgical patient outcomes. This study examines the surgical outcomes in people with decompensated serious mental illness (SMI) within the setting of the Australian universal healthcare system.

Methods

Retrospective cohort study involving elective overnight surgical patients aged 18 years and above who attended a large public tertiary referral hospital in Sydney, Australia, between 2010 and 2014. Patients were identified using ICD‐10‐AM diagnosis codes. Outcomes measure including in‐hospital mortality, post‐operative complications, morbidity, admission and time in intensive care, length and cost of hospitalization, discharge destination and 28‐day re‐admission rates were examined.

Results

Of 23 343 surgical patient admissions, 451 (2%) patients had decompensated comorbid SMI with a subset of 47 (0.2%) having a specific psychotic illness. Patients with SMI comorbidity had significantly higher in‐hospital mortality (2% versus 0%), post‐operative complications (22% versus 8%), total comorbidity (7.6 versus 3.4 secondary codes), admissions (29% versus 9%) and time in intensive care (34.6 h versus 5.0 h), stay in hospital (12.2 days versus 4.6 days), admission costs ($24 162 versus $12 336), re‐admission within 28 days (14% versus 10%) and discharges to another facility (11% versus 3%).

Conclusion

Patients with comorbid SMI had significantly worse surgical outcomes and incur much higher costs compared with the general surgical population. These results strongly highlight that specific perioperative interventions are needed to proactively improve the identification, management and outcomes for these disadvantaged patients.