Blood usage in lung transplantation

BACKGROUND: Few published data are available regarding perioperative blood usage in lung transplantation. STUDY DESIGN AND METHODS: The medical records of all patients undergoing lung transplantation at a university medical center in 1994 and 1995 were reviewed. RESULTS: Ninety patients underwent lung transplantation during this period. Six patients were excluded: two received a living related-donor lung, three underwent retransplantation and one underwent concomitant repair of a tetralogy of Fallot. Of the 84 evaluable patients, 59 underwent single lung transplantation and 25 double lung transplantation. Double-lung recipients used more red cells (6.4 vs. 1.7 units, p = 0.0002) and were more likely to receive red cells, platelets, plasma, or any component (92 vs. 32%, p< or =0.0001) than were single-lung recipients. Double- lung recipients were more likely to require cardiopulmonary bypass (40 vs. 12%, p = 0.003), and cardiopulmonary bypass was associated with greater transfusion requirements (p< or =0.0001). However, among patients requiring cardiopulmonary bypass, blood use did not differ between those undergoing double lung transplantation and those undergoing single lung transplantation. In the subset of patients not requiring cardiopulmonary bypass, double-lung recipients received more red cells (4.5 vs. 0.7 units, p< or =0.0001) and more plasma (2.0 vs. 0.2 units, p = 0.006). CONCLUSION: Double-lung recipients require more perioperative transfusions than single-lung recipients. The greater transfusion requirement is due to the more frequent need for cardiopulmonary bypass as well as the greater complexity of the procedure. These data are useful for developing surgical blood ordering guidelines for lung transplantation.     

PJ34, a poly-ADP-ribose polymerase inhibitor, modulates visceral mitochondrial activity and CD14 expression following thoracic aortic ischemia-reperfusion

Background

Visceral ischemia-reperfusion injury (VI) contributes to adverse outcomes following the repair of thoracoabdominal aneurysms. Experiments were designed to determine whether a poly-adenosine diphosphate-ribose polymerase (PARP) inhibitor modulates indexes of metabolic function (mitochondrial activity), inflammatory cell activation, and tissue inflammation (lipopolysaccharide receptor CD14 messenger ribonucleic acid) following VI.

Methods

129S1/SvImj mice were subjected to thoracic aortic occlusion followed by 48 hours of reperfusion. Normal saline was administered to 25 untreated control mice and PJ34 to 21 mice before and immediately after thoracic aortic ischemia-reperfusion. Sham mice (n = 13) underwent median sternotomy alone. At 48 hours, all animals were euthanized and tissues harvested for quantitative analysis.

Results

PJ34 improved intestinal (P < .05) but not hepatic mitochondrial activity following reperfusion. CD14 messenger ribonucleic acid levels in liver (P < .004), kidney (P < .003), and spinal cord (P < .03) tissue were less in PJ34-treated mice.

Conclusions

PJ34 preserved the metabolic function of intestinal but not hepatic tissue during reperfusion. PJ34 uniformly decreased the expression of an important marker of inflammatory cell activation and tissue inflammation in visceral tissue following VI. PARP inhibitors may serve as a therapeutic modality to abrogate the stress response to VI.     

Mechanistic basis for the chemopreventive effects of black raspberries at a late stage of rat esophageal carcinogenesis

The present study used a postinitiation protocol to investigate molecular mechanisms by which black raspberries (BRBs) influence the late stages of N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in rats. F344 rats were injected with NMBA and then fed either control diet or a diet containing 5% BRB powder. Control rats were injected with DMSO/water (20:80), the vehicle for NMBA. Esophagi from control, NMBA- and NMBA?+?BRB-treated rats were collected at 35 wk for histopathological, molecular, and immunohistochemical analyses. Treatment with 5% BRBs reduced the number of dysplastic lesions and the number and size of esophageal papillomas in NMBA-treated rats. When compared to esophagi from control rats, NMBA treatment led to the differential expression of 4807 genes in preneoplastic esophagus (PE) and 17?846 genes in esophageal papillomas. Dietary BRBs modulated 626 of the 4807 differentially expressed genes in PE and 625 of the 17?846 differentially expressed genes in esophageal papillomas towards normal levels of expression. In both PE and in papillomas, BRBs modulated the mRNA expression of genes associated with carbohydrate and lipid metabolism, cell proliferation and death, and inflammation. In these same tissues, BRBs modulated the expression of proteins associated with proliferation, apoptosis, inflammation, angiogenesis, and both cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism. Interestingly, matrix metalloproteinases involved in tissue invasion and metastasis, and proteins associated with cell-cell adhesion, were also modulated by BRBs. This is the first report of the effects of berries on the expression of genes associated with the late stages of rat esophageal carcinogenesis.     

Flavocoxid,a dual inhibitor of cyclooxygenase and 5-lipoxygenase,blunts pro-inflammatory phenotype activation in endotoxin-stimulated macrophages

Background and purpose:

The flavonoids, baicalin and catechin, from Scutellaria baicalensis and Acacia catechu, respectively, have been used for various clinical applications. Flavocoxid is a mixed extract containing baicalin and catechin, and acts as a dual inhibitor of cyclooxygenase (COX) and 5-lipoxygenase (LOX) enzymes. The anti-inflammatory activity, measured by protein and gene expression of inflammatory markers, of flavocoxid in rat peritoneal macrophages stimulated with Salmonella enteritidis lipopolysaccharide (LPS) was investigated.

Experimental approach:

LPS-stimulated (1 µg·mL⁻¹) peritoneal rat macrophages were co-incubated with different concentrations of flavocoxid (32–128 µg·mL⁻¹) or RPMI medium for different incubation times. Inducible COX-2, 5-LOX, inducible nitric oxide synthase (iNOS) and inhibitory protein κB-α (IκB-α) levels were evaluated by Western blot analysis. Nuclear factor κB (NF-κB) binding activity was investigated by electrophoretic mobility shift assay. Tumour necrosis factor-α (TNF-α) gene and protein expression were measured by real-time polymerase chain reaction and enzyme-linked immunosorbent assay respectively. Finally, malondialdehyde (MDA) and nitrite levels in macrophage supernatants were evaluated.

Key results:

LPS stimulation induced a pro-inflammatory phenotype in rat peritoneal macrophages. Flavocoxid (128 µg·mL⁻¹) significantly inhibited COX-2 (LPS = 18 ± 2.1; flavocoxid = 3.8 ± 0.9 integrated intensity), 5-LOX (LPS = 20 ± 3.8; flavocoxid = 3.1 ± 0.8 integrated intensity) and iNOS expression (LPS = 15 ± 1.1; flavocoxid = 4.1 ± 0.4 integrated intensity), but did not modify COX-1 expression. PGE₂ and LTB₄ levels in culture supernatants were consequently decreased. Flavocoxid also prevented the loss of IκB-α protein (LPS = 1.9 ± 0.2; flavocoxid = 7.2 ± 1.6 integrated intensity), blunted increased NF-κB binding activity (LPS = 9.2 ± 2; flavocoxid = 2.4 ± 0.7 integrated intensity) and the enhanced TNF-α mRNA levels (LPS = 8 ± 0.9; flavocoxid = 1.9 ± 0.8 n-fold/β-actin) induced by LPS. Finally, flavocoxid decreased MDA, TNF and nitrite levels from LPS-stimulated macrophages.

Conclusion and implications:

Flavocoxid might be useful as a potential anti-inflammatory agent, acting at the level of gene and protein expression.     

Augmentation of aripiprazole with low-dose clozapine

An issue under much clinical debate is whether treatment with two antipsychotic agents simultaneously is advantageous for optimizing response in patients whose previous monotherapy with antipsychotic agents has failed. Minimal evidence supports treatment with multiple antipsychotics, even when the agents have different mechanisms of action. The standard of care for treating schizophrenia is to first use monotherapy of adequate dosage and duration, including a trial of clozapine before adding a second agent. We report the case of a 32-year-old man whose monotherapy with various antipsychotic agents failed. During attempted conversion from aripiprazole to clozapine, the patient experienced a significant reduction in psychiatric features. Despite this improvement, the patient became resistant to the clozapine titration schedule due to complaints of sedation. Aripiprazole combined with low-dose clozapine as maintenance therapy resulted in a positive clinical outcome despite a clozapine serum level that is generally considered subtherapeutic. This case emphasizes the importance of making interventions based on individual patient response.     

The impact of surgical excision in chest wall rhabdomyosarcoma: a report from the Children's Oncology Group

Aims

Rhabdomyosarcoma (RMS) is the most common soft tissue tumor of childhood. Patient age, size, histologic finding, and site of the tumor are primary determinants of prognosis in RMS. Chest wall RMS is a site in which the limitations of surgical excision are realized. We aim to determine the impact of surgical excision in chest wall RMS.

Methods

A retrospective chart review was conducted of all 130 pediatric patients enrolled in the Intergroup Rhabdomyosarcoma Study (IRS) with chest wall rhabdomyosarcoma from the first (I) through fourth (IV) IRS with follow-up to June 2005. Median follow-up was 12.1 years (4.6-27.2 years).

Results

There was a significant improvement in failure-free survival (FFS) and overall survival (OS) between the first IRS study, I, and IRS-IV. The estimated FFS and OS at 5 years in IRS I was 30% and 40%, respectively, compared to 68% and 78%, respectively, in IRS-IV (P = .03 and P = .05, respectively). There was no association between histologic finding or size and FFS or OS. However, all patients who presented without metastasis had an FFS and OS of 49% and 61%, respectively, compared with metastatic patients, 7% and 7%, respectively (P < .001). Five-year FFS of group I, II, and III patients was 52%, 52%, and 45%, respectively, and OS was 65%, 60%, and 59%, respectively. There was no significant difference in 5-year FFS or OS in patients who had a complete resection (group I), complete resection with positive microscopic margins (group II), or biopsy or partial resection only (group III). In groups I to III patients, the local and regional failure rate at 5 years is 25% and 6%, respectively.

Conclusions

The most significant impact on outcome in chest wall RMS patients is metastatic disease at diagnosis. The locoregional failure rate is high but does not appear to impact survival. Alternative treatment strategies are needed for chest wall RMS, but aggressive surgical excision may not be necessary.