Mechanisms of immunotherapeutic intervention by anti-CD154 (CD40L) antibody in high-risk corneal transplantation.

This study aimed to determine the effects of anti-CD154 on T cell cytokine profiles and ocular chemokine gene expression after high-risk corneal transplantation and to specifically determine if CD154 blockade is associated with a switch from a Th1 to a Th2 alloimmune response. Mice were used as recipients of syngeneic or multiple minor H or MHC antigen-mismatched corneal grafts. Recipient beds were neovascularized (high-risk). Hosts were randomized to receive either anti-CD154 antibody or control immunoglobulin (Ig) perioperatively. Two weeks after corneal transplantation, allospecific delayed-type hypersensitivity (DTH) was evaluated. Frequencies of interferon-gamma (IFN-gamma)-, interleukin-2 (IL-2)-, IL-4-, and IL-5-secreting T cells in the hosts were measured by enzyme-linked immunospot (ELISPOT) assay. Ocular chemokine gene expression in anti-CD154-treated and control hamster Ig-treated groups was determined using a multiprobe ribonuclease protection assay (RPA). Leukocyte infiltration of corneal grafts was evaluated microscopically. Anti-CD154-treated mice did not exhibit allospecific DTH. The frequencies of Th1 cytokine-producing but not Th2 cytokine-producing T cells were significantly reduced in anti-CD154-treated hosts. Postoperative mRNA levels of RANTES and macrophage inflammatory protein-1beta (MIP-1beta) in anti-CD154-treated eyes were substantially suppressed compared with hamster Ig-treated controls. Leukocyte infiltration was profoundly suppressed in grafts of anti-CD154-treated hosts. These data demonstrate that blockade of the CD40-CD154 costimulatory pathway after corneal transplantation inhibits Th1-mediated responses but does not induce a switch to a Th2-specific response. In addition, anti-CD154 therapy suppresses ocular chemokine gene expression and leukocytic infiltration into allografts.     

Percutaneous transluminal coronary angioplasty in a patient with paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired chronic hemolytic anemia associated with an unusual susceptibility to hemolytic crisis, infection, and venous thrombosis which would be aggravated by a number of factors including surgery. We report a case of PNH undergoing percutaneous transluminal coronary angioplasty and discuss the corresponding perioperative management.     

Fiber Matrix Descriptors from Permeability Data Without Requiring Membrane Thickness: Theory,Results, and Optimization

Objective: Permeability of basement membrane and all other barriers contains a term for membrane thickness (Δx). This naturally leads to development of methods for measuring Δx that are imprecise, inaccurate, expensive, subject to preparation artifact, and inattentive to variability. Although height and shape of permeability (P) vs. probe radius (α) curves are sensitive to Δx, ln(P) or ln(P/free diffusivity or D_o) curves have shapes independent of Δx. It should, thus, be possible using such characteristics to determine fiber radius (r_f) and void volume ratio (ε) without Δx. We developed such a method to derive membrane structure by the standard model of Ogston and present its experimental evaluation. Methods: Basement membranes were self-assembled using 1: 1 Matrigel: 0.01 M Tris/150 mM NaCl/1.0 mM CaCl₂ buffer on 0.4-μ polycarbonate supports with transport measured in diffusion chambers using FITC-labeled hydroxyethyl starch probes from 25 to 102 Å in radius. Sampling was at 0.5 hr and then for each hour up to 5. Other membranes were measured 7 days after formation. Results: The best fit of the new technique occurred at 3 hr with R² = 0.949 ± 0.003 SEM, r_f = 36.8 ± 2.4 Å, and ε = 0.87 ± 0.02. Membranes studied for 7 days showed more variability but essentially the same characteristics. Conclusions: Membrane thickness is not necessary to reduce permeability of basement membrane to structure, and optimum sampling time is 3 hr.     

The importance of calcium ions forin vitro malignant hyperthermia testing

Intracellular Ca++ levels in skeletal muscle are elevated during the in vitro contracture response of muscle from subjects with malignant hyperthermia. The role of Ca++ in the bathing medium and the consequences of substitution of Sr++ for Ca++ in the response to agents associated with malignant hyperthermia were examined. When Ca++ was omitted from the bathing medium the contractures induced in human vastus lateralis by halothane (three per cent) or succinylcholine (50 mM) were reduced by 80 and 100 per cent, respectively, while contractures induced by caffeine (8 mM) were only reduced by 50 per cent. Substitution of Ca++ by another divalent cation, Sr++, completely restored contractures induced by caffeine, but only partially restored contractures induced by halothane or succinylcholine (to 50 and 30 per cent of Ca(++)-containing medium, respectively). Mepacrine (10 microM) was effective in antagonizing contractures by caffeine, whereas verapamil and nifedipine (10 microM) were not. These results support an essential role for extracellular Ca++ not fulfilled by Sr++ in contracture induction by halothane and succinylcholine, but not by caffeine.     

Lack of correlation after reperfusion between ventricular function and infarct size estimated by thallium single-photon emission computed tomography

In 32 patients with acute myocardial infarction, who had undergone successful intracoronary thrombolysis, the results of regional wall motion measured from contrast cineangiograms 10 to 21 days after thrombolysis were related to the results of thallium single-photon emission computed tomography (SPECT) after intravenous dipyridamole. Wall motion was measured by means of the centerline method, and thallium defect size was estimated by comparing the patient's circumferential profile with that of 20 normals. No correlation was found between ejection fraction or regional wall motion and thallium defect size. The time from symptom onset to thrombolysis was inversely correlated with the degree of hypokinesis (r=–0.51) but not with thallium defect size. In patients treated within 3 hours, hypokinesis was significantly less than in patients treated later (–1.1±0.6 SD vs –2.2±0.8 SD, p<0.01) whereas thallium defect size was not significantly different in both groups. It is concluded that, in patients after thrombolysis, thallium defect size determined by SPECT does not reflect the degree of left ventricular dysfunction.     

Preliminary experience with inhaled milrinone in cardiac surgery

Background: Inhaled administration of milrinone reduces pulmonary artery pressure. Pulmonary hypertension (PH) and right heart failure are associated with difficult separation from cardiopulmonary bypass (CPB). Therefore, inhaled milrinone could facilitate separation from CPB. Objective: To determine the impact and timing of administration of inhaled milrinone. Methods: A retrospective analysis of our experience on high-risk patients receiving inhaled milrinone was conducted to evaluate the postoperative course after administration of the drug. Results: Seventy-three patients received inhaled milrinone from June 2002 to February 2005. Mean age was 64 ± 13 years, with a mean preoperative Parsonnet score of 27 ± 14. Inhaled milrinone (5 mg) was administered before (n = 30) or after (n = 40) CPB, three patients had off-pump procedures and were excluded. CPB time was 145 ± 78 min with cross-clamping times of 91 ± 56 min without any significant difference between groups. Fifty-four patients (74%) had difficult separation from CPB, 14 patients (19%) required an intra-aortic balloon pump and 10 patients (14%) needed emergency reinitiation of CPB for hemodynamic instability. Ten patients died in the perioperative period (13.7%). Patients receiving inhaled milrinone prior to CPB initiation had a lowering pulmonary artery pressure after CPB (p < .01) and had less emergency reinitiation of CPB after weaning (3% vs 23%, p = .02) as compared to those with administration after CPB. No detectable side effects were directly linked to the administration of the drug. Conclusion: In this high-risk cohort, use of inhaled milrinone was well tolerated. Administration before initiation of CPB could help weaning from CPB.     

Endovascular management of pseudo-aneurysms after previous surgical repair of congenital aortic coarctation

Objective: Whatever the surgical technique used, false aneurysm formation is one of the long-term complications of repair of aortic coarctation. Conservative management is associated with a 100% rate of rupture. The conventional surgical approach is complex and associated with high morbidity and mortality rates. We report our experience of endovascular management of pseudo-aneurysms after previous surgical repair of congenital aortic coarctation. Methods: Between October 2005 and 2006, stent-grafting of pseudo-aneurysms after previous surgical repair of congenital aortic coarctation was performed in four patients. Median age was 31.5 years (range: 24–38). Two patients had undergone two previous interventions. The last previous surgery consisted of graft interposition (N = 2), subclavian flap aortoplasty (N = 1) and aorto-aortic bypass (N = 1). Median size of the pseudo-aneurysm was 31.5 mm (range: 20–58). Mean time between the last surgery and endovascular treatment was 24 years (range: 3–32). One patient was treated emergently because of hemoptysis in relation with an aorto-bronchial fistula, the three other patients were treated electively. A transfemoral approach was used in all patients. The Zenith TX2^® (Cook) thoracic stent-graft was used in all the patients, one patient underwent previous dilatation at the coarctation level. When present, the ostium of the left subclavian artery was always covered (N = 3). Results: No major complication occurred during the procedure and no patient died during the follow-up. One patient presented a type II endoleak which spontaneously healed during the first month. Another patient with his left subclavian artery covered presented claudication of the left arm requiring a carotid-subclavian bypass. After a median follow-up of 7.5 months (range: 1–12.9), the patients were asymptomatic and CT scans demonstrated complete exclusion of all treated postcoarctation aneurysms without recoarctation and without any stent-graft-related complication. Conclusions: The endovascular management of pseudo-aneurysms after previous surgical repair of congenital aortic coarctation is feasible. This approach was safe and effective. Long-term clinic and imaging follow-up is mandatory.     

Improvement in quality of life after initiation of lamotrigine therapy in patients with epilepsy in a naturalistic treatment setting.

Quality of life is impaired in patients with epilepsy and can be improved by effective therapy. Randomised clinical trials have shown that lamotrigine treatment is associated with improved quality of life. However, little information is available on quality of life or treatment effects in patients with epilepsy in the general population. The objective of this study was to estimate the impact of lamotrigine on quality of life in a naturalistic treatment setting. The study included adult patients with epilepsy in whom lamotrigine therapy was initiated. Each subject completed the Quality of Life in Epilepsy Inventory (QOLIE)-31 quality of life questionnaire at inclusion and at a follow-up visit in the next 4 months. Demographic information and medical history were provided by the investigator. These were evaluated as potential determinants of change in quality of life using logistic regression. Three hundred and forty-one patients were evaluated, 192 starting lamotrigine in combination with another drug, 90 as a first-line monotherapy, 45 as a switch from another drug and 14 as a reduction to monotherapy from a previous combination. Baseline scores on the QOLIE-31 ranged from 53.8 in the combination group to 69.5 in the first-line group. 34.6% of patients were considered to be responders, with no significant differences between treatment regimen. Most improvement was seen for the energy-fatigue and medication effects subscales and, for the first-line group, seizure worry. Seizure type was the only determinant of improvement of quality of life identified. In conclusion, lamotrigine treatment is associated with improved quality of life, regardless of treatment regimen.