Reconstitution of deficient T cell receptor zeta chain restores T cell signaling and augments T cell receptor/CD3-induced interleukin-2 production in patients with systemic lupus erythematosus

OBJECTIVE: T cells from a majority of patients with systemic lupus erythematosus (SLE) display antigen receptor-mediated signaling aberrations associated with defective T cell receptor (TCR) zeta chain, a subunit of the TCR/CD3 complex. This study was undertaken to explore the possibility that forced expression of TCR zeta chain may reverse the known signaling abnormalities and defective interleukin-2 (IL-2) production in SLE T cells. METHODS: Freshly isolated SLE T cells were transfected with TCR zeta chain construct in a eukaryotic expression vector at high efficiency, by a recently developed nucleoporation technique. Restoration of TCR/CD3-mediated signaling was studied in the zeta chain-transfected cells. RESULTS: In SLE T cells transfected with TCR zeta chain, surface expression of TCR chain was increased and the TCR/CD3-induced increased free intracytoplasmic calcium concentration response was normalized, as was hyperphosphorylation of cellular substrates. Simultaneously, the previously noted increased expression of the Fc receptor gamma chain was diminished in SLE T cells transfected with the zeta chain expression vector, and the surface membrane clusters of cell signaling molecules were redistributed to a more continuous pattern. TCR zeta chain replacement also augmented the expression of diminished TCR/CD3-mediated IL-2 production in SLE T cells, associated with increased expression of the p65 subunit of nuclear factor kappaB in the nuclear fractions of these T cells. CONCLUSION: These results suggest that reconstitution of deficient TCR zeta chain can reverse the TCR/CD3-mediated signaling abnormalities as well as the defective IL-2 production in T cells of patients with SLE.     

Gastric phytobezoar associated with impaired gastric motility in a patient with spinal cord injury

Impaired gastrointestinal motility as a result of interruption of sympathetic outflow is a common occurrence in the spinal cord injury (SCI) population. In addition, frequent use of medications with anticholinergic properties in this population results in further impairment of peristalsis resulting in gastrointestinal stasis. Since SCI patients often lack sensation below the level of injury, they may present with vague symptoms, which complicates the diagnosis of intestinal obstruction. We report the first case of gastric phytobezoar in a patient with T4 ASIA A paraplegia who presented with vague upper abdominal discomfort, anorexia, weight loss, and vomiting. Because mortality rates can be as high as 30% if phytobezoars remain untreated, gastrointestinal phytobezoars should be considered in the differential diagnosis of abdominal discomfort in SCI patients. Etiologic factors for phytobezoars are discussed for the general population and in particular, for patients with SCI.     

Emergency thoracotomy in the pre-hospital setting: a procedure requiring clarification.

OBJECTIVE: The aim of this study is to investigate the influence of Emergency Thoracotomy (ET) on mortality in a group of patients suffering from severe thoracic trauma requiring Helicopter Emergency Medical Service (HEMS) transfer to hospital. This is not clearly defined especially when thoracotomy takes place in the pre-hospital setting. METHODS: A retrospective review of 670 consecutive patients with severe thoracic trauma, transferred to The Royal London Hospital by HEMS between November 1994 and December 2002. ET (on scene, in the Accident and Emergency (A&E) department or in the operating theatre) was performed in 53 patients (7.7%). Both univariate and multivariate analyses were performed to evaluate ET as an independent predictor of mortality. RESULTS: There were 510 males and 160 females with a mean Injury Severity Score (ISS) of 35.12+/-17.5. Univariate analysis identified ET to be a predictor of mortality (OR=0.15, 95% CI=0.07-0.30). However, with multivariate analysis, ET was not found to be an independent predictor of mortality (OR=1.93, 95% CI=0.61-6.1). The independent predictors of mortality identified were: age>60 years (OR 5.57, 95% CI 2.19-14.16), Glasgow Coma Score <8 at the scene (OR=7.4, 95% CI=3.15-17.46), ISS>25 (OR 5.3, 95% CI=1.64-17.11), need for intubation at the scene (OR=2.80, 95% CI=1.022-7.69), oxygen saturation in A&E (<89%) (OR=2.39, 95% CI=1.13-5.05), haemothorax (OR=3.30, 95% CI=1.53-7.13) and bilateral injury (OR=3.1, 95% CI=1.51-6.61). CONCLUSIONS: Our study has shown that when confounding variables are accounted for, ET is not a predictor of mortality following severe chest trauma. This implies that in a well-selected group of patients it may be a significant and life-saving procedure.     

Vascular Access in Hemodialysis Patients with Central Venous Obstruction or Stenosis: One Center’s Experience

The purpose of this study was to evaluate the value of complex hemodialysis access procedures among patients with central venous obstruction who were running out of access sites. Between September 2002 and December 2003 we performed a total of 640 new hemodialysis access procedures in 3 renal units. Ten of these patients presented central vein stenosis or obstruction and were not suitable for peritoneal dialysis. Each of the 10 patients had 3 or 4 previous failed access procedures and numerous infected central lines and their dialysis catheters were not functioning adequately. Nine patients presented with a severely stenosed or occluded superior vena cava and 1 had both subclavian veins occluded. Three patients were diabetics, 2 were obese and 6 had hypertension. We performed 12 procedures on these 10 patients. Saphenous veins were used 6 times, twice as a loop to the femoral artery and 4 times as a transposition to the popliteal artery above the knee. Femoral vein transposition to the popliteal artery was carried out in 2 cases. We performed 3 axillary artery to popliteal vein polytetrafluoroethylene (PTFE) bypasses, 1 on an obese woman who had no saphenous vein and was not suitable for a femoral vein transposition, 1 on a diabetic woman whose saphenous vein loop clotted after 5 months and 1 on a female patient with severe peripheral vascular disease. The patient with bilateral subclavian vein occlusion had a brachial artery to internal jugular vein PTFE graft. The PTFE graft to the jugular vein has been patent and regularly needled with a follow-up of 4 months. Four saphenous vein fistulae were regularly used for dialysis; 2 were never used. Five saphenous fistulae clotted after an average life span of 4 months (range 3 weeks-9 months) and 1 is still patent and in use (5 months). Both femoral vein transpositions have been patent and have been needled 3 times a week with a follow-up of 10 and 4 months; one had to be revised surgically after 9 months. Of the 3 axillary artery to popliteal vein grafts, 1 had to be tied off after a week because of severe steal syndrome and 2 have been patent (20 months follow-up) and have been needled regularly ever since. Seventy percent of these patients have been dialyzed line-free through their fistula despite severe central vein stenosis or obstruction for periods of 9-18 months when this review was undertaken. Although the follow-up needs to be longer, we discuss the surgical, radiologic, and dialysis features of these patients and propose a management pathway for central vein stenosis or occlusion.     

Rescue in situ thrombolysis for acute coronary thromboembolism in an angiographically normal coronary artery

Coronary thromboembolism in an angiographically normal coronary artery is extremely uncommon. There are few instances where normal coronary arteries have been documented just prior to an episode of acute thromboembolic insult. We now report such a case of acute coronary thromboembolism in a patient with widely patent coronary vessels documented just prior to the event during preoperative screening angiogram with successful in situ revascularization.     

Genetic signatures of high- and low-risk aberrant crypt foci in a mouse model of sporadic colon cancer

To determine whether cancer risk is related to histopathological features of preneoplastic aberrant crypt foci (ACF), gene expression analysis was performed on ACF from two mouse strains with differing tumor sensitivity to the colonotropic carcinogen, azoxymethane. ACF from sensitive A/J mice were considered at high risk, whereas ACF from resistant AKR/J mice were considered at low risk for tumorigenesis. A/J and AKR/J mice received weekly injections of azoxymethane (10 mg/kg body weight), and frozen colon sections were prepared 6 weeks later. Immunohistochemistry was performed using biomarkers associated with colon cancer, including adenomatous polyposis coli, beta-catenin, p53, c-myc, cyclin D1, and proliferating cell nuclear antigen. Hyperplastic ACF, dysplastic ACF, microadenomas, adjacent normal-appearing epithelium, and vehicle-treated colons were laser captured, and RNA was linearly amplified (LCM-LA) and subjected to cDNA microarray-based expression analysis. Patterns of gene expression were identified using adaptive centroid algorithm. ACF from low- and high-risk colons were not discriminated by immunohistochemistry, with the exception of membrane staining of beta-catenin. To develop genetic signatures that predict cancer risk, LCM-LA RNA from ACF was hybridized to cDNA arrays. Of 4896 interrogated genes, 220 clustered into six broad clusters. A total of 226 and 202 genes was consistently altered in lesions from A/J and AKR/J mice, respectively. Although many alterations were common to both strains, expression profiles stratified high- and low- risk lesions. These data demonstrate that ACF with distinct tumorigenic potential have distinguishing molecular features. In addition to providing insight into colon cancer promotion, our data identify potential biomarkers for determining colon cancer risk in humans.