CTLA-4-Mediated inhibition of early events of T cell proliferation.

CTLA-4 engagement by mAbs inhibits, while CD28 enhances, IL-2 production and proliferation upon T cell activation. Here, we have analyzed the mechanisms involved in CTLA-4-mediated inhibition of T cell activation of naive CD4+ T cells using Ab cross-linking. CTLA-4 ligation inhibited CD3/CD28-induced IL-2 mRNA accumulation by inhibiting IL-2 transcription, which appears to be mediated in part through decreasing NF-AT accumulation in the nuclei. However, CTLA-4 ligation did not appear to affect the CD28-mediated stabilization of IL-2 mRNA. Further, CTLA-4 engagement inhibited progression through the cell cycle by inhibiting the production of cyclin D3, cyclin-dependent kinase (cdk)4, and cdk6 when the T cells were stimulated with anti-CD3/CD28 and with anti-CD3 alone. These results indicate that CTLA-4 signaling inhibits events early in T cell activation both at IL-2 transcription and at the level of IL-2-independent events of the cell cycle, and does not simply oppose CD28-mediated costimulation.

Regulation by non-major histocompatibility complex genes of the allo-4-hydroxy-phenylpyruvate dioxygenase (F liver protein) response.

Although rapid progress is being made in the quantitative genetics of multifactorial disease, no response to a simple antigen has yet been subjected to full genomic analysis. The well-characterized antigen allo-HPPD (4-hydroxy-phenylpyruvate dioxygenase, previously known as F liver antigen) is a good candidate for such treatment. Old and new data bearing on this possibility are here assembled. In respect of antibody production and an early burst of interleukin-4 (IL-4) transcription, introduction of the non-major histocompatibility complex (MHC) background from A/J strain mice into F1 hybrids with C57BL10 strains up-regulates the response. These findings can be aligned with previous quantitative genetics carried out on airway hyper-responsiveness in related strains, and to a lesser extent with the genetics of autoimmune diabetes in the mouse. Taken together, the findings suggest that regulation of the pro-inflammatory cytokines are largely responsible for the variation. Additional data indicate that these non-MHC genes are are to a variable extent (depending on the response parameter) epistatic to the down-regulatory MHC allele H-2Ab.

Percutaneous interventions in adults receiving pediatric "en bloc" double renal grafts.

PURPOSE: To present technical adaptations of percutaneous interventional techniques required for the small size vessels and ureters of "en bloc" transplanted pediatric kidneys. METHODS: Over a 4-year period, 12 adult patients received en bloc pediatric double renal transplants. Small system percutaneous interventional techniques were used in seven patients to approach the infantile renal arteries and urinary collecting systems for 11 percutaneous transluminal renal angioplasties, 4 antegrade pyelograms, and 3 nephrostomies. RESULTS: Prior to intervention, these patients averaged a creatinine of 2.5 mg%, which decreased to 1.4 mg% at 46 months (range, 22-68) following the first intervention. With a mean follow-up of 42 months (range, 5-47), 9 of 12 (75%) transplants are functioning with an average serum creatinine of 1.3 mg%. CONCLUSION: With the assistance of percutaneous management of postoperative arterial and ureteral lesions, the prognosis of en bloc renal grafts can approach that of the standard adult renal allograft.

Transjugular intrahepatic portosystemic shunt in nonliver transplant candidates: is it indicated?

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) is an effective treatment of severe portal hypertension complications. Liver transplantation (LT) candidacy has not been a prerequisite to TIPS placement in some medical centers. OBJECTIVES: To investigate the outcome and survival of non-LT candidates after TIPS. METHODS: From November 1991 to February 1994, all patients referred for TIPS placement were evaluated for LT candidacy. Exclusions for LT included: age (> 70 yr), other significant medical conditions, or noncompliance. Indications for TIPS included refractory variceal bleeding during an acute bleed, recurrent bleeding after more than or equal to four sessions of sclerotherapy, or refractory ascites. RESULTS: Sixty patients received TIPS. Nineteen were considered non-LT candidates. Over a 2-yr follow-up, 14 of these non-LT candidates did not survive. Their median age was 63.5 compared with 56.5 yr for LT candidate nonsurvivors (p < 0.05). Among the 14 non-LT candidate nonsurvivors, 10 were Childs C class, and eight had emergent TIPS placement. The 2-year mortality rate was 84% for non-LT candidates versus 24% for LT candidates. Median survival time for non-LT candidates was 2.6 months compared with 20 months in the LT candidates (p < 0.001). Only one death was due to a TIPS-related complication. CONCLUSIONS: TIPS is unquestionably an advancement in the management of patients with portal hypertension complications. Non-LT candidates, compared with LT candidates, tended to be older and of a Child-Pugh C class, and they had survival rates often less than 90 days post-TIPS. Given these high mortality rates, we need to address whether TIPS is indicated in these non-LT candidates.

Association of H2Ab with resistance to collagen-induced arthritis in H2-recombinant mouse strains: an allele associated with reduction of several apparently unrelated responses.

HLA class II alleles can protect against immunological diseases. Seeking an animal model for a naturally occurring protective allele, we screened a panel of H2-congenic and recombinant mouse strains for ability to protect against collagen-induced arthritis. The strains were crossed with the susceptible strain DBA/1, and the F1 hybrids immunized with cattle and chicken type II collagen. Hybrids having the H2Ab allele displayed a reduced incidence and duration of the disease. They also had a reduced level of pre-disease inflammation, but not of anti-collagen antibodies. The allele is already known to be associated with reduction of other apparently unrelated immune responses, suggesting that some form of functional differentiation may operate that is not exclusively related to epitope-binding. It is suggested that this may reflect allelic variation in the class II major histocompatibility complex promoter region.

Percutaneous transluminal angioplasty for transplant renal artery stenosis.

A recent report has challenged the efficacy and safety of percutaneous transluminal angioplasty (PTA) for the treatment of transplant renal artery stenosis (TRAS). From January 1983 to December 1990, 24 PTA procedures were performed for TRAS in 18 patients. The stenoses were anastomotic in two cases, in the main renal artery in 14, and segmental in eight. After PTA, the residual stenosis was less than 20% in 14 (58%), 20%-50% in four (17%), and greater than 50% in six (25%). The mean diastolic blood pressure decreased from 106 mm Hg 1 day prior to PTA to 82 mm Hg 1 day after PTA. Long-term follow-up mean diastolic blood pressure (at 2-32 months) was 93 mm Hg (P less than .01). Eleven of the 18 patients (63%) had a 10% or greater reduction in diastolic blood pressure on long-term follow-up. Major complications occurred in two patients; one groin hematoma required surgical evacuation, and one polar infarct led to hypertension that was difficult to control. No surgical revisions of the transplant renal artery were necessary. The authors' data indicate that PTA should remain the treatment of choice for nonanastomotic TRAS.

Ultrarapid urokinase in hemodialysis access occlusion.

Over a 3-month period, 14 consecutive hemodialysis access occlusions were treated with 1-1.25 million IU of urokinase (UK) delivered at a rate of 20,000 IU/min. After systemic heparin administration, lytic infusion via the crossed-catheter technique was performed with use of pediatric microdrip pumps, with determination of success within 1 hour. Patency was established radiographically in 11 of 14 occlusions, for a 79% immediate success rate. At 285-day mean follow-up, 9% (one of 11) remained patent without further radiologic or surgical intervention; graft survival was 64% (seven of 11). No significant complications occurred with use of ultrarapid UK. The 1-hour outpatient procedure safely allowed for rapid triage between surgical and radiologic intervention, minimal catheter manipulation or physician dependency, shorter duration compression of any bleeding venipuncture sites during UK administration, and greater patient comfort because of shortened procedure times.

Biliary strictures in hepatic transplantation.

Between August 1985 and December 1990, 198 liver transplantations were performed. Among 18 patients, 20 biliary strictures were identified, which were categorized as anastomotic (n = 6), nonanastomotic central hilar (n = 8), and nonanastomotic peripheral (n = 6). Pretransplant disease, hepatic artery patency, presence of acute or chronic rejection, and donor cold ischemia times were tabulated for each case. Among the six patients with peripheral strictures, three had sclerosing cholangitis prior to transplantation. Three patients with nonanastomotic strictures experienced chronic rejection. The mean cold ischemia time for patients with nonanastomotic strictures was 9.75 hours versus 8.1 hours for nonstrictured transplants (P = .025). Balloon dilation was performed in 13 patients; follow-up longer than 6 months was available for nine patients. Dilation was successful in four cases. Among the five failures, only one patient has needed surgery. An association was noted between nonanastomotic biliary strictures and prolonged donor cold ischemia time, between peripheral nonanastomotic strictures and pretransplant sclerosing cholangitis, and between nonanastomotic strictures and chronic rejection. Percutaneous balloon dilation was found useful in the treatment of the strictured transplant.

Magnetic resonance imaging of knee menisci. Comparison of spin echo pulse sequences.

Magnetic resonance imaging (MRI) is accurate in evaluating meniscal tears using spin echo pulse sequences. The purpose of this study was to systematically compare T1-weighted pulse sequences to two echo proton density/T2 (2eT2)-weighted sequences. Menisci were separated into four grades based on signal characteristics. In addition, all menisci were graded as positive or negative for tear. Twenty-three patients (46 menisci) were studied with both pulse sequences and the results were compared with arthroscopic findings. Using T1 sequences, 14 of 18 torn menisci and 26 of 28 untorn menisci were identified. Using 2eT2 sequences, 13 of 18 torn menisci and 26 of 28 untorn menisci were correctly identified. There was high correlation between T1 and 2eT2 sequences for torn versus untorn menisci and for grade of injury (P = .99). There is very little difference between T1- and 2eT2-weighted pulse sequences in evaluation of meniscal tears.

A directed approach to MRI of the athletic knee.

Surface coil MRI is now frequently utilized to assess acutely injured knees. In dedicated athletes, unique considerations exist which modify standard diagnosis and therapy. Concrete clinical findings must justify the potential loss of livelihood from even a "negative" arthroscopy. Seventeen injured athletes were evaluated by an orthopedic surgeon experienced in sports injuries and a preliminary localizing diagnosis was rendered, followed by knee MRI. Of 17 patients with significant injuries, MRI agreed with operative findings or clinical follow-up in 15 cases. Knee MRI prompted early intervention in those patients with conflicting subjective and/or objective findings. Furthermore, it helped direct the arthroscopist's surgical approach and encouraged close examination of areas less optimally visualized arthroscopically. MR and arthroscopy were complementary modalities in diagnosing certain ligamentous and cartilaginous lesions. MR effectively evaluated the cruciate ligaments often difficult to visualize by arthroscopy; arthroscopy better assessed articular surfaces. A cooperative effort existed between orthopedic surgeon and radiologist in directing both the MR study and arthroscopy. This was of particular benefit in maximizing scan efficiency in these large individuals who often filled the gantry. The team directed approach between orthopedic surgeon and radiologist affords deliberate and efficient diagnosis and therapy in this select population.

MRI of the athletic knee. Findings in asymptomatic professional basketball and collegiate football players.

For the dedicated athlete in whom minor injuries are frequent and major injuries relatively common, a noninvasive knee assessment could either obviate the need for arthroscopy or focus its direction. The opportunity to study asymptomatic athletes was not feasible before the advent of magnetic resonance imaging (MRI). In this preliminary work, we examined 40 knees in 20 asymptomatic volunteer athletes, including five professional basketball players and 15 collegiate football players. Images were obtained at 0.5 T or 1.5 T. Spin echo sequences were used to obtain 5.0 mm thick coronal and sagittal sections. Fifty percent of asymptomatic athletes (10/20) had significant baseline MRI abnormalities that could have adversely affected scan interpretation in the context of an acute injury. Half of these athletes with MRI abnormalities, or 25% of the total (5/20), had no previous surgery and were unaware of significant injury.

MR imaging diagnosis of rotator cuff tears.

Thirty-one symptomatic patients were studied with MR imaging to evaluate the sensitivity and specificity of shoulder MR in the diagnosis of rotator cuff tears. Correlative studies included arthroscopy in 19 patients and arthrography in 12 patients. Images were obtained on either a 0.5- or 1.5-T Philips superconducting magnet using spin-echo pulse sequences (650-850/30 [TR, TE], 2000/30, 100) with 5-mm slices oriented in an oblique coronal plane perpendicular to the glenohumeral joint. The MR studies were initially interpreted without knowledge of the results of other diagnostic procedures. The MR diagnosis of cuff tear was made when irregularity, discontinuity, and increased signal were identified in the rotator cuff. MR images showed tears in 10 patients (32%) and were negative for tear in 21 patients (68%). MR correlated with arthroscopy and arthrography in 17 of 18 normal patients, in eight of 10 patients with complete tears, and in one of three patients with partial tears. For complete rotator cuff tears, the sensitivity, specificity, and accuracy were 80%, 94%, and 89%, respectively. For all tears (partial and complete), the sensitivity, specificity, and accuracy were 69%, 94%, and 84%, respectively. These data suggest that MR imaging is an accurate procedure for the diagnosis of complete rotator cuff tears. The number of partial tears (three) in this series is too small to evaluate the value of MR imaging in the diagnosis of partial tears.

Prosthetic graft infection: limitations of indium white blood cell scanning.

The lack of a rapid, noninvasive, and accurate method to confirm or rule out prosthetic graft infection continues to constitute a compelling and vexing clinical problem. A host of adjunctive diagnostic techniques has been used in the past, but early promising results subsequently have usually not yielded acceptable sensitivity (reflecting false negatives) and specificity (reflecting false positive) data. White blood cell (WBC) indium 111 scanning has recently been added to this list. The utility and accuracy of 111In WBC scans were assessed by retrospective review of WBC scan results in 70 patients undergoing evaluation for possible prosthetic graft infection over a 7-year period. Operative and autopsy data (mean follow-up, 18 months for survivors with negative scans) were used to confirm the 22 positive, 45 negative, and three equivocal WBC scans. The false positive rate (+/- 70% confidence limits) was 36% +/- 6% (n = 8) among the 22 patients with positive scans (44% +/- 6% [11 of 25] if the three equivocal scans are included as false positive), yielding a specificity of 85% +/- 5% and an overall accuracy rate of 88% +/- 4% (80% +/- 5% and 84% +/- 5%, respectively, if the three equivocal cases are considered as false positive). All three patients with equivocal scans ultimately were judged not to have prosthetic graft infection. As implied by the high accuracy rate, the sensitivity of the test was absolute (100% [14 of 14]); there were no false negative results. (ABSTRACT TRUNCATED AT 250 WORDS)