Reduction of FK-506 requirements by combination with polyethylene glycol superoxide dismutase in orthotopic rat liver transplantation

Reperfusion after ischemia results in endothelial cell injury and Kupffer cell activation. Inflammatory cytokines thus released can induce major histocompatibility complex antigens and increase the immunogenecity of the graft. An orthotopic rat liver allotransplant model was used to test the hypothesis that prevention of reperfusion injury by infusion of polyethylene glycol superoxide dismutase (PEG-SOD) would result in long-term allograft survival in the presence of subthreshold immunosuppressive dosages. ACI rats were used as donors, and Lewis strain rats as recipients. Orthotopic liver transplantation was initially performed to identify a subthreshold dose of the immunosuppressant FK-506, which would be unable to extend survival longer than control untreated rats with this strain combination. After testing three intramuscular FK-506 doses of 0.04, 0.08, and 0.16 mg/kg, it was observed that an FK-506 dose of 0.04 mg/kg/day for 14 days was unable to extend survival longer than in untreated recipients. This dose of FK-506 was used in combination with PEG-SOD at doses of 1000, 3000, 10,000, or 30,000 units. Recipient animals were treated intravenously with PEG-SOD as a loading dose to facilitate tissue penetration on day 1, and beginning on the day of transplantation, every 2 days for the duration of the study. Results of histologic studies and mean survival time were compared in untreated recipients and in rats treated with PEG-SOD plus 0.04 mg/kg/day FK-506. Mean survival time was increased significantly in these animals (p < 0.007) to 40.6 ± 25.6 days as compared with either untreated rats (10.0 ± 2.7 days) or rats treated with 0.04 mg/kg FK-506 alone (13.7 ± 4.2 days). Histologic examination demonstrated a significant reduction in the cellular infiltrate in rats treated with PEG-SOD plus FK-506, as compared with recipients treated with either agent alone or left untreated. Our results therefore suggest a potential approach to reducing immunosuppression in transplantation. (J ALLERGY CLIN IMMUNOL 1995;95:1276-81.)     

Prophylactic intravenous use of milrinone after cardiac operation in pediatrics (PRIMACORP) study

Background Many pediatric patients undergoing cardiac surgery involving cardiopulmonary bypass have a predictable fall in the cardiac index 6 to18 hours after surgery, the so-called low cardiac output syndrome (LCOS). Because patients who have LCOS require more monitoring and support and have a prolonged stay in the intensive care unit, the syndrome is associated with a costly morbidity. Milrinone, a phosphodiesterase III inhibitor, improves cardiac muscle contractile force and vascular muscle relaxation through positive inotropic and vasodilatory effects. The purpose of the Prophylactic Intravenous Use of Milrinone After Cardiac Operation in Pediatrics (PRIMACORP) study is to evaluate the safety and efficacy of the prophylactic use of milrinone in pediatric patients at high risk for development of LCOS after undergoing cardiac surgery. Methods Patients in the multicenter, randomized, double-blind, placebo-controlled, parallel treatment study will be randomized to 1 of 3 treatment arms: (1) low-dose milrinone (25 μg/kg intravenous bolus over 60 minutes followed by a 0.25 μg/kg/min infusion for 35 hours), (2) high-dose milrinone (75 μg/kg intravenous bolus over 60 minutes followed by a 0.75 μg/kg/min infusion for 35 hours), or (3) placebo. Results The primary end point for efficacy evaluation will be based on a composite variable consisting of death or development of LCOS requiring additional mechanical or pharmacologic support, up to 36 hours after randomization. A 2-sided test with a 0.025 type I error will be used for the primary end point analysis. The PRIMACORP study will enroll a total of 240 patients. Six additional secondary end points will be analyzed. Conclusions The PRIMACORP study will address several questions regarding the safety and efficacy of prophylactic milrinone use in pediatric patients at high risk for development of LCOS after cardiac surgery. (Am Heart J 2002;143:15-21.)     

HSP 60 expression in mucocutaneous lesions of Behçet''s disease

BACKGROUND: Heat shock protein (60 kd HSP) has been implicated in the etiology of Beh?et's disease, but its expression at sites of inflammation is unknown. OBJECTIVE: Our aim was to investigate local HSP 60 expression and to quantify T-cell receptor (TCR) gamma delta-positive cells, which are known to respond to HSP peptides. METHODS: Patients with active Beh?et's disease (n = 21) and controls (n = 18) were included. Flow cytometric analysis was performed on peripheral blood to investigate TCR gamma delta-positive cell counts. Biopsies were performed on active skin lesions, and immunohistochemical analysis was performed by a streptavidin-biotin method using the monoclonal ML-30 antibody; HSP staining intensity and distribution were evaluated in a blinded fashion. Immunohistochemical studies were performed to quantify TCR gamma delta-positive cells at lesional sites. RESULTS: Mucocutaneous lesions of patients with Beh?et's disease had statistically significantly increased expression of HSP 60/65. Peripheral blood TCR gamma delta-positive cell counts were similar in both groups. However, lesional skin of patients with Beh?et's disease had significantly increased gamma delta-positive T-cell counts. CONCLUSION: Up-regulation of HSP expression was found at lesional skin sites in Beh?et's disease. The increased number of TCR gamma delta-positive cells, which are known to respond to HSP peptides, may support the function of HSPs in the etiology of Beh?et's disease. However, these findings may also be an epiphenomenon that needs to be further investigated.     

A multicenter dose-escalation trial with denileukin diftitox (ONTAK, DAB389IL-2) in patients with severe psoriasis

Background: Denileukin diftitox, a fusion protein targeting both malignant and normal activated lymphocytes, has been shown previously to have antipsoriatic activity. However, the ideal dosing regimen for treating psoriasis was not established. Objective: We examined the safety and efficacy of denileukin diftitox in patients with severe plaque-type psoriasis. Methods: This was a cohort dose-escalation trial. Patients were administered denileukin diftitox on 3 consecutive days every other week. Patients were evaluated for toxicity, improvement in psoriasis, immunogenicity, and serum levels. Results: Thirty-five patients were treated at 3 dose levels. Eight patients had a 50% decrease or more in Psoriasis Area and Severity Index score from baseline (0/10 at 0.5 μg/kg per day, 1/10 at 1.5 μg/kg per day, and 7/15 at 5 μg/kg per day). Adverse events primarily consisted of constitutional events and skin reactions. Conclusions: The potential antipsoriatic activity of denileukin diftitox demonstrated in this study was comparable to that observed in other psoriasis studies with this agent. However, this dosing regimen was better tolerated than the dosing regimen used in the last study with denileukin diftitox in psoriasis patients. (J Am Acad Dermatol 2001;45:871-81.)     

Quantitative IgE antibody assays in allergic diseases

During the past several years, immunoassays for specific IgE antibodies have been refined to permit reporting results in mass units. Thus quantitative immunoassays for IgE antibodies may be an adjunct to skin tests. In cases of food allergy among children with atopic dermatitis, cutoff values for IgE antibody concentrations to egg, milk, peanut, and fish have been derived to provide 95% positive and 90% negative predictive values. Food-specific IgE antibody determinations can also be used to predict which food allergies are resolving spontaneously. Elevated egg-specific IgE antibody levels in infancy are associated with significantly increased risk for development of inhalant allergies later in childhood. In cases of inhalant allergy, specific IgE antibody levels correlate closely with results of inhalation challenge studies in cat-sensitive persons. Also, mite-specific IgE antibody levels correlate significantly with the mite allergen contents of reservoir dust in the homes of mite-sensitive persons. Immunoassays for quantitation of specific IgE antibodies may be used to document allergen sensitization over time and to evaluate the risk of reaction on allergen exposure. However, immunoassays and skin tests are not entirely interchangeable, and neither will replace the other in appropriate circumstances. (J Allergy Clin Immunol 2000;105:1077-84.)     

Finasteride in the treatment of men with frontal male pattern hair loss

Background: Finasteride, a specific inhibitor of type II 5α-reductase, decreases serum and scalp dihydrotestosterone and has been shown to be effective in men with vertex male pattern hair loss. Objective: This study evaluated the efficacy of finasteride 1 mg/day in men with frontal (anterior/mid) scalp hair thinning. Methods: This was a 1-year, double-blind, placebo-controlled study followed by a 1-year open extension. Efficacy was assessed by hair counts (1 cm² circular area), patient and investigator assessments, and global photographic review. Results: There was a significant increase in hair count in the frontal scalp of finasteride-treated patients (P < .001), as well as significant improvements in patient, investigator, and global photographic assessments. Efficacy was maintained or improved throughout the second year of the study. Finasteride was generally well tolerated. Conclusion: In men with hair loss in the anterior/mid area of the scalp, finasteride 1 mg/day slowed hair loss and increased hair growth. (J Am Acad Dermatol 1999;40:930-7.)     

Unique inflammatory features noted in intraorally transferred skin flapsCorrelation with Candida albicans infection

OBJECTIVE: The purpose of this study was to evaluate how well intraorally transferred skin flaps endure their new surroundings. STUDY DESIGN: Biopsy specimens were taken from 20 patients who had undergone microsurgical reconstruction and as pretransferred skin from 5 of these patients at the time of surgery. The study used immunohistochemistry for immunocompetent cells, differentiation markers for the epidermis and desmosomal proteins, and immunoelectron microscopy for desmosomal protein, in addition to routine histologic examination, including Sudan IV, periodic acid Schiff, and Grocott stains. We also measured the thickness of the epidermis and stratum corneum. Oral swabs from the skin flaps were examined for the presence of yeasts, particularly Candida albicans, by means of a culture method. RESULTS: According to the results of periodic acid-Schiff and Grocott staining, 20 cases were divided into 2 groups: fungal element-positive cases (n = 15) and fungal element-negative cases (n = 5). All swabs from the former were positive for Candida albicans. In these fungus-positive cases, histopathologic evaluation revealed marked diminution of stratum corneum and pronounced epidermal hyperplasia. Immunohistochemistry demonstrated the dermal infiltration of numerous immunocompetent cells-CD4+, CD8+, CD20+, CD68+, neutrophil elastase+, and HLA-DR+ cells-and the scarce infiltration of IgA+ and IgG+ cells. There were scattered CD1a+, CD4+, CD8+, and HLA-DR+ cells and elastase+ neutrophils in the epidermis. Expression of cytokeratin subtypes (10, 14, 16, and 19), involucrin, and tenascin showed the characteristic features of epidermal proliferation. Enumeration of Ki-67+ keratinocytes showed an increase, indicating epidermal proliferation. Expression of desmoglein 1 and desmocollin 1 in the epidermal keratinocytes was decreased in comparison with that in the pretransferred skin. Immunoelectron microscopy for desmoglein 1 confirmed the reduced immunoreactive deposits along the desmosomal plaques. In the fungus-negative cases, all such changes were a great deal milder. CONCLUSIONS: Taken together, our results demonstrate that most intraorally transferred flaps are affected by an inflammatory process that is induced by the influence of the wet oral environment. They present psoriasiform tissue reactions characterized by epidermal hyperproliferation that are mostly due to Candida albicans infection.     

A nonfatal case and 2 fatal cases of paraneoplastic pemphigus: Can a complement indirect immunofluorescent test help to identify fatal “group A” paraneoplastic pemphigus cases?

We studied 3 recent cases of paraneoplastic pemphigus (PNP) in detail. Two patients died despite concerted management efforts. One patient received no treatment after the appearance of PNP and recovered completely from both PNP and lymphoma. Multiple serum studies of these 3 patients plus 9 other proven PNP cases revealed that 8 of 9 fatal PNP cases (referred to here as “group A”) had distinctive cell surface antibodies detected by complement indirect immunofluorescent (CIIF) tests on monkey esophagus sections. By contrast, none of the sera from 3 patients with PNP who experienced long-term survival (referred to here as “group B”) and none of 20 pemphigus vulgaris or 10 pemphigus foliaceus control sera revealed similar beaded cell surface CIIF reaction patterns, a difference that is statistically significant (P < .0001). Cell surface CIIF reaction patterns of group A PNP antibodies resemble the pattern of pemphigus antibody reactions in indirect immunofluorescent tests on the same substrate; however, the latter tend to be thinner and more linear, whereas the cell surface CIIF pattern tends to be more beaded, suggesting possible desmosomal reactions. We believe this test is useful in identifying an aggressive group A form of PNP. (J Am Acad Dermatol 2002;47:841-51.)     

Preterm delivery in women with pregestational diabetes mellitus or chronic hypertension relative to women with uncomplicated pregnancies

Objective: The purpose of this study was to compare the rates of indicated and spontaneous preterm delivery among women with chronic hypertension or pregestational diabetes mellitus with the rates among healthy women. Study Design: This was a secondary analysis of data from healthy women with singleton gestations enrolled in a prospective observational study for prediction of preterm delivery (control group, N = 2738), women with pregestational diabetes mellitus requiring insulin therapy (n = 461), and women with chronic hypertension (n = 761). The two latter groups were enrolled in a randomized multicenter trial for prevention of preeclampsia. The main outcome measures were rates of preterm delivery, either spontaneous (preterm labor or rupture of membranes) or indicated (for maternal or fetal reasons), and neonatal outcomes. Results: The overall rates of preterm delivery were significantly higher among women with diabetes mellitus (38%) and hypertension (33.1%) than among control women (13.9%). Rates were also significantly higher for delivery at <35 weeks’ gestation. Women with diabetes mellitus had significantly higher rates of both indicated preterm delivery (21.9% vs 3.4%; odds ratio, 8.1; 95% confidence interval, 6.0-10.9) and spontaneous preterm delivery (16.1% vs 10.5%; odds ratio, 1.6; 95% confidence interval, 1.2-2.2) than did women in the control group. In addition, they had significantly higher rates of both indicated preterm delivery (odds ratio, 4.8; 95% confidence interval, 3.0-7.5) and spontaneous preterm delivery (odds ratio, 2.1; 95% confidence interval, 1.4-3.0) at <35 weeks’ gestation than did control women. Compared with control women those with chronic hypertension had higher rates of indicated preterm delivery at both <37 weeks’ gestation (21.9% vs 3.4%; odds ratio, 8.1; 95% confidence interval, 6.2-10.6) and at <35 weeks’ gestation (12.1% vs 1.6%; odds ratio, 8.2; 95% confidence interval, 5.7-11.9), but there were no differences in rates of spontaneous preterm delivery. Conclusion: The increased rate of preterm delivery among women with chronic hypertension relative to control women was primarily an increase in indicated preterm delivery, whereas the rates of both spontaneous and indicated preterm delivery were increased among women with pregestational diabetes mellitus. (Am J Obstet Gynecol 2000;183:1520-4.)