Ischemia-modified albumin increases after skeletal muscle ischemia during arthroscopic knee surgery

BACKGROUND: Ischemia can alter the ability of albumin to bind free metal atoms. Based on these biochemical changes, methods to quantify ischemia modified albumin (IMA) were developed to assist in the evaluation of patients with symptoms of cardiac ischemia. Since ischemia can occur in any vascular bed, the specificity of IMA for cardiac muscle ischemia is unclear and requires further investigation. METHODS: We evaluated the specificity of an IMA test in patients with skeletal muscle ischemia during arthroscopic knee surgery. A pressurized thigh cuff was continuously inflated to 300 mm Hg on the operative leg, in order to arrest blood flow during the procedure. Samples were collected before surgery, 15 min after surgery, and prior to discharge. RESULTS: Twenty-three patients were enrolled in the study. Median tourniquet time was 29 min (range 19-108). Median pre-operative IMA was 90.2 KU/l (range 77-101.6). Statistically significant (p<0.05) increases in IMA and myoglobin concentrations, and decreases in albumin concentrations were observed following tourniquet release and before discharge. CONCLUSIONS: Post-operative myoglobin elevations indicated that skeletal muscle ischemia was sufficient to produce detectable myocyte necrosis. Post-operative IMA increases are consistent with ischemic modification of albumin during exposure to ischemic conditions in skeletal muscle during and /or immediately after tourniquet application. However, the negative correlations between IMA and albumin results suggest that increases in IMA were in part due to lower post-operative albumin concentrations resulting in decreased cobalt binding.     

Platelet and plasma levels of glutamate and glutamine in migraine with and without aura

We evaluated plasma and platelet glutamate and glutamine levels in migraine with and without aura during headache-free periods and compared the results with those of normal controls. The plasma and platelet levels of glutamine in migraine with and without aura were normal. Migraine without aura patients had higher glutamate levels in plasma, and normal platelet levels. In migraine with aura patients, glutamate levels were high in platelets, but not in plasma. This suggests different profiles of excitatory amino acid metabolism in migraine with and without aura.     

Role of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in the development of an acute neutrophil inflammatory response in mice

The intraperitoneal injection into mice of casein preparations containing bacteria induced a rapid accumulation of neutrophils within 3 hours due to selective release of mature cells from the bone marrow. Significant increases in the concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) occurred in the peritoneal cavity during the process, but the intraperitoneal injection of neither CSF induced a significant accumulation of neutrophils and the coinjection of G-CSF and casein failed to enhance the neutrophil response. The lack of involvement of either CSF in the neutrophil migration was confirmed by the development of typical neutrophil exudates when casein was injected into mice with inactivation of the genes encoding GM-CSF, G-CSF, or the beta-common chain of the GM-CSF receptor. However, preinjection of G-CSF increased the number of marrow neutrophils available for migration and did result in increased numbers of neutrophils in the peritoneal cavity after casein injection. Typical eosinophil inflammatory responses to the injection of casein or thioglycollate occurred in GM-CSF -/ -mice but not in beta c -/- mice, suggesting that interleukin-5 was necessary for this response.     

Predictors of early morbidity after major lung resection in patients with and without airflow limitation

BACKGROUND: The aim of the present study was to identify predictors of morbidity after major lung resection for non-small cell lung carcinoma in patients with forced expiratory volume in 1 second (FEV1) greater than or equal to 70% of predicted and in those with FEV1 less than 70% of predicted. METHODS: Five hundred forty-four patients who underwent lobectomy or pneumonectomy from 1993 through 2000 were retrospectively analyzed. The patients were divided into two groups: group A (450 cases), with FEV1 greater than or equal to 70%, and group B (94 cases), with FEV1 less than 70%. Differences between complicated and uncomplicated patients were tested within each group. RESULTS: Morbidity rate was not significantly different between group A and group B (20.4% and 24.5%, respectively; p = 0.4). In group A, multivariate analysis showed that predicted postoperative FEV1 was the only significant independent predictor of complications. In group B, no significant predictor was identified. CONCLUSIONS: In patients with preoperative FEV1 less than 70% of predicted, predicted postoperative FEV1 was not predictive of postoperative morbidity. Thus, predicted postoperative FEV1 should not be used alone as a selection criteria for operation in these high-risk patients.     

Portrayal of organ donation and transplantation on American primetime television

Recently, both living and deceased organ donation rates have hit a plateau, despite increases in need for viable organs. One approach to improve donation rate is public education and policy; thus, it is necessary to understand the information the public is receiving regarding organ donation. We hypothesized that primetime medical dramas portray organ donation and transplantation in a negative manner. We compiled data on all primetime medical drama episodes with transplant themes from November 2008 through June 2010 and assessed depictions of organ donors and transplant candidates. Positive and negative thematic elements surrounding the process and individuals involved were also identified. One hundred and fifty-five million and 145 million households watched episodes containing any negative message and any positive message, respectively. Episodes containing only negative messages had over twice the household viewership per episode compared to episodes containing only positive messages (8.4 million vs. 4.1 million, p = 0.01). Widespread exposure to these representations may reinforce public misconceptions of transplantation. The transplant community should consider the popularity of medical dramas as an opportunity to impact the perception of organ donation and transplantation for millions of Americans.     

Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization

Mice lacking granulocyte colony-stimulating factor (G-CSF) were generated by targeted disruption of the G-CSF gene in embryonal stem cells. G-CSF-deficient mice (genotype G-CSF-/-) are viable, fertile, and superficially healthy, but have a chronic neutropenia. Peripheral blood neutrophil levels were 20% to 30% of wild-type mice (genotype G- CSF+/+) and mice heterozygous for the null mutation had intermediate neutrophil levels, suggesting a gene-dosage effect. In the marrow of G- CSF-/- mice, granulopoietic precursor cells were reduced by 50% and there were reduced levels of granulocyte, macrophage, and blast progenitor cells. Despite G-CSF deficiency, mature neutrophils were still present in the blood and marrow, indicating that other factors can support neutrophil production in vivo. G-CSF-/- mice had reduced numbers of neutrophils available for rapid mobilization into the circulation by a single dose of G-CSF. G-CSF administration reversed the granulopoietic defect of G-CSF-/- mice. One day of G-CSF administration to G-CSF-/- mice elevated circulating neutrophil levels to normal, and after 4 days of G-CSF administration, G-CSF+/+ and G-CSF- /- marrows were morphologically indistinguishable. G-CSF-/- mice had a markedly impaired ability to control infection with Listeria monocytogenes, with diminished neutrophil and delayed monocyte increases in the blood and reduced infection-driven granulopoiesis. Collectively, these observations indicate that G-CSF is indispensible for maintaining the normal quantitative balance of neutrophil production during "steady-state" granulopoiesis in vivo and also implicate G-CSF in "emergency" granulopoiesis during infections.     

Circulating monoclonal B cells expressing P glycoprotein may be a reservoir of multidrug-resistant disease in multiple myeloma

Multiple myeloma is basically an incurable cancer. Most patients respond initially to chemotherapy with reduction in bone marrow (BM) plasma cells and monoclonal Ig levels, but the disease nearly always recurs and becomes refractory to therapy. The objective of this study was to characterize the expression of the multidrug transport pump, P- glycoprotein 170 (P-gp), in myeloma. The great majority of B cells from peripheral blood mononuclear cells (PBMCs) in myeloma express P-gp, detected by the monoclonal antibody MRK-16. P-gp+ blood B cells exhibit extensive DNA hyperdiploidy, suggesting replicative abnormality characteristic of malignant growth. We speculate these represent a stem cell population in myeloma. The proportion of B cells expressing P-gp was comparable among untreated myeloma patients and those treated with chemotherapy, biologic response modifiers, or off treatment. Among BM cells, P-gp was absent or low in untreated myeloma patients but was expressed at high levels on BM cells from patients previously treated with chemotherapy. For untreated patients the majority of B/plasma cells expressing P-gp are located in PBMCs, not the BM cells. Flow cytometric analysis of rhodamine 123 dye efflux indicated a functional P-gp that was efficiently blocked by verapamil or cyclosporin A (CsA). Both the CD11bhi CD19+ B cells and the T cells in myeloma PBMCs had active CsA-inhibited dye efflux, but monocytes lacked the ability to efflux dye. Nearly all CD38hi plasma cells from myeloma BM cells retained dye, indicating their lack of a functional transport pump. Thus, PBMC B cells may be the predominant set of drug-resistant tumor cells. Myeloma PBMC B cells were cultured with Adriamycin with or without CsA and drug toxicity evaluated by the induction of apoptosis, using flow cytometry to quantitate DNA disruption. No apoptosis was detectable at 0.01 microgram/mL adriamycin, the in vivo steady-state level, with or without CsA. With 0.1 microgram adriamycin, no apoptosis was detectable in the absence of CsA, but with CsA, 66% of B cells initiated DNA disruption, whereas most T cells were spared. This work suggests that currently used drug dosages are too low to effect P-gp+ B- cell death, even in the presence of CsA. We suggest that blood B cells comprise a highly drug-resistant subset of the myeloma B lineage that escapes conventional chemotherapy and may underlie the almost uniform fatal relapse in myeloma patients.