Total and active thymoglobulin levels: effects of dose and sensitization on serum concentrations.

A group of 79 renal transplant patients undergoing acute rejection episodes were treated with Thymoglobulin (rabbit anti-thymocyte globulin), 1.5 mg/kg/day for 6-14 days as part of a double-blinded trial comparing the efficacy of Thymoglobulin and Atgam (horse anti-thymocyte globulin). Serial serum samples from the patients were tested to determine the level of Thymoglobulin (i.e. rabbit IgG levels = total Thymoglobulin) and anti-Thymoglobulin using ELISAs. Antibodies binding to human lymphocytes (active Thymoglobulin), were determined by flow cytometry; no correlation was seen between treatment efficacy and either active or total Thymoglobulin concentrations; the overall treatment success rate was 86%. Pharmacokinetics of total and active Thymoglobulin were distinctly different; active Thymoglobulin disappeared much more rapidly: only 12% of patients had detectable active Thymoglobulin by day 90 compared to 81% of patients with detectable total Thymoglobulin; percent active Thymoglobulin decreased from a peak of 0.56-0.7% during treatment, to 0.07-0.35% by day 21, and less than 0.14% by day 30. Thymoglobulin and active Thymoglobulin concentrations were modeled by multiple regression. Using dose number and sensitization as independent variables, 47-76% of the variability seen in interpatient Thymoglobulin levels could be explained, while for active Thymoglobulin levels, the measured variables accounted for 13-48% of the observed interpatient variation. We conclude that: (1) for a group of patients receiving primary Thymoglobulin treatment (averaging nine full and one partial dose per patient), neither Thymoglobulin nor active Thymoglobulin levels are predictive of treatment outcome; (2) active Thymoglobulin disappears more rapidly from the circulation than total Thymoglobulin; and (3) patients that develop anti-rabbit IgG antibodies clear Thymoglobulin and active Thymoglobulin more rapidly than unsensitized patients.

Safety and efficacy of a steerable temperature monitoring microwave catheter system for ventricular myocardial ablation.

INTRODUCTION: Radiofrequency current delivered during cardiac ablation is limited by a rise in impedance secondary to coagulum formation on the ablation electrode. Microwave antennas continue to deliver energy despite the presence of coagulum; thus, temperature control of the ablation electrode may be even more important for microwave than for radiofrequency ablations to avoid thromboembolic risks. The purpose of this study was to test the safety and efficacy of an ablation system utilizing a feedback control system to maintain a fixed target temperature for creating lesions with multiple applications of microwave energy. METHODS AND RESULTS: Microwave ablation was assessed using an 8.5-French catheter at 2 to 4 sites in 11 dogs. Microwave energy delivery was performed for 60 seconds three times at the same site. Power was regulated using a feedback control mechanism to maintain a target temperature of 75 degrees C. Ambulatory ECG monitoring was performed before and after ablation to assess arrhythmia occurrence. After follow-up, the dogs were euthanized, and lesion dimensions measured after fixation. The mean power applied to achieve the target temperature of 75 degrees C was 9.3+/-44 W. The mean depth of the lesions was 8.8+/-4.2 mm. The mean volume of the lesions was 304+/-240 mm3. Forty-four percent of the lesions were transmural. No endocardial thrombus was found. Ventricular tachycardia was observed acutely but resolved after 1 week. CONCLUSION: Temperature feedback control systems for microwave ablation using a temperature-controlled system is feasible for myocardial ablation and creates uniform and large lesions; however, such large lesions can be acutely proarrhythmic.

Sensitization following Thymoglobulin and Atgam rejection therapy as determined with a rapid enzyme-linked immunosorbent assay. US Thymoglobulin Multi-Center Study Group.

Monoclonal and polyclonal anti-thymocyte preparations play an important role in solid organ transplant immunosuppression. While it is generally accepted that blocking anti-idiotypic antibodies can decrease the efficacy of retreatment with mouse monoclonal antibody preparations, sensitization levels and subsequent effects on treatment efficacy are less clear for polyclonal preparations. Serum samples were obtained from 148 patients participating in a multicentre, double-blind randomized phase III trial comparing Atgam (Pharmacia Upjohn, horse anti-thymocyte globulin) with Thymoglobulin (SangStat Medical Corporation, rabbit anti-thymocyte globulin). Recipients of a first or second renal allograft undergoing biopsy proven acute rejection were randomized to treatment with Atgam or Thymoglobulin. Serum samples were analysed for presence of anti-thymoglobulin and anti-Atgam antibodies. Sensitization levels to rabbit IgG in Thymoglobulin-treated patients (68%, n = 54) was similar to sensitization to horse IgG in Atgam-treated patients (78%, n = 54) (two-sided p value = 0.4, Fisher's exact test), although Atgam-treated patients remained sensitized longer (at day 90, 67% anti-horse IgG positive in Atgam treated vs 24% anti-rabbit IgG in Thymoglobulin positive, p = 0.001). No difference was seen in the production of a crossreactive response. Similarly, sensitization had no significant effect on treatment success or failure. For Thymoglobulin-treated patients, the sensitization rate in successfully treated patients was 68%, while inpatients with treatment failures it was 71% (p = not significant, ns). In Atgam-treated patients, the sensitization rate in successfully treated patients was 82%, while in patients with treatment failures it was 67% (p = ns). In conclusion, patients treated with Thymoglobulin and patients treated with Atgam exhibited similar levels of sensitization, presensitization and crossreactive sensitization, although the anti-horse response was longer lasting; neither presensitization nor treatment-induced sensitization appeared to effect treatment efficacy.

Vascularized collagen-glycosaminoglycan matrix provides a dermal substrate and improves take of cultured epithelial autografts.

Cultured epithelial autografts are an important adjunct in treating severely burned patients, greatly expanding the epidermis using a small donor site. Problems with cultured epithelial autografts include the time delay to culture cells to confluence and variable take on full-thickness wounds. Dermal allografts have been used as a substrate to improve the take of cultured epithelial autografts. This study examined the effect of a vascularized collagen-glycosaminoglycan matrix as a substrate for cultured epithelial autografts. The matrix was grafted onto 12 full-thickness wounds in Yorkshire pigs and allowed to vascularize for 10 days. The cultured epithelial autografts were applied over the vascularized collagen-glycosaminoglycan matrix (n = 12) or onto freshly excised full-thickness wounds (n = 10). Gross and histologic observations were made over a 3-week period. Gross observations at 7 days indicated cultured epithelial autografts to have nearly complete confluence when applied to wounds treated by collagen-glycosaminoglycan, whereas cultured epithelial autografts applied to freshly excised wounds did not take. Gross determination of epithelial confluence was verified by histologic analysis of randomly selected wounds. Histologic epithelial confluence of cultured epithelial autografts on collagen-glycosaminoglycan (98 +/- 4 percent) was significantly greater than that on full-thickness wounds (4 +/- 10 percent). Electron microscopy of the cultured epithelial autografts/collagen-glycosaminoglycan construct demonstrated anchoring fibrils at the dermal-epidermal junction at day 7. The neoepidermis of wounds treated by cultured epithelial autografts/collagen-glycosaminoglycan was hyperplastic at day 7 but developed a normal maturation sequence by 21 days. Results from this study suggest that vascularized collagen-glycosaminoglycan matrices produce a favorable substrate for cultured epithelial autografts and may improve cultured epithelial autografts take in burn patients.

Polyethylene glycol/microfibrillar collagen composite as a new resorbable hemostatic bone wax.

Although bone wax is effective at achieving hemostasis, it is nonresorbable, causes a foreign body reaction, and inhibits osteogenesis. We report development of a polyethylene glycol/microfibrillar collagen composite (PEG/MFC) that has inherent hemostatic qualities, is biodegradable, and is compatible with bone repair. PEG/MFC composite (n = 42) was placed in 5 mm cranial defects in New Zealand white rabbits. Hemostasis and healing were compared to unfilled defects (n = 32) and defects filled with standard bone wax (n = 10). Both PEG/MFC and bone wax handled well and stopped bleeding. The polyethylene glycol component was resorbed by 8 h, and the microfibrillar collagen was resorbed over 2 months, eliciting only a minor inflammatory response during the first month. Defects filled with the PEG/MFC composite showed similar amounts of bony regeneration as did unfilled control defects. At 4 weeks, healing bone accounted for 43 +/- 13% in those treated with PEG/MFC and 47 +/- 19% defect area in untreated holes. In contrast, less than 1% of the area was bone in defects filled with bone wax (p < 0.05). PEG/MFC composite provided excellent bony hemostasis and did not inhibit bone growth.

Triaxial force transducer for investigating stresses at the stump/socket interface.

Although normal pressures at the stump socket interface of the lower-limb amputee have been investigated, little is known about the shear stresses that also occur. Studies suggest that the combination of both shear and normal stresses significantly exacerbates discomfort and vascular and tissue damage. A means of simultaneously measuring normal and shear stresses will aid in the investigation and improvement of prosthetic fit. A miniature triaxial force transducer (4.9 x 16 mm diameter) has been developed which can be recessed into the socket wall. The principle of operation, construction, performance and limitations of the device are described. Preliminary measurements of the interface stress variations over the gait cycle in a supra-condylar PTB socket are presented. These show clear differences in the stress patterns present when two different prosthetic feet are used.

Stimulation and inhibition of myoblast differentiation by hormones.

The growth and differentiation of L6 myoblasts are subject to control by two proteins secreted by cells of the Buffalo rat liver line. The first of these, rat insulinlike growth factor-II (formerly designated multiplication stimulating activity) is a potent stimulator of myoblast proliferation and differentiation, as well as associated processes such as amino acid uptake and incorporation into protein, RNA synthesis, and thymidine incorporation into DNA. In addition, this hormone causes a significant decrease in the rate of protein degradation. All of these actions seem to be attributable to a single molecular species, although their time courses and sensitivity to the hormone differ substantially. The second protein, the differentiation inhibitor (DI), is a nonmitogenic inhibitor of all tested aspects of myoblast differentiation, including fusion and the elevation of creatine kinase. Indirect immunofluorescence experiments demonstrated that DI also blocks accumulation of myosin heavy chain and myomesin. Upon removal of DI after 72 h incubation, all of these effects were reversed and normal myotubes containing the usual complement of muscle-specific proteins were formed. Thus, this system makes it possible to achieve specific stimulation or inhibition of muscle cell differentiation by addition of purified proteins to cloned cells in serum-free medium.

Tumors of the appendix.

An analysis of 101 tumors of the appendix is presented. During the period under study (from 1949 to 1972), 8,699 appendectomies had been performed. Only 17 of the 101 tumors were malignant. In this group, there were two primary carcinomas, 12 metastatic carcinomas, and three lymphomas. Most of the tumors (84) were benign, including 43 carcinoids, 32 mucoceles, five neuromas, two leiomyomas, and two villous adenomas, Some of the clinical and pathologic features of carcinoids, adenocarcinoma, and mucoceles are discussed. The most significant observation in this study is the statistically significant evidence that, even without associated acute appendicitis, mucoceles 2 cm or more in diameter probably do cause clinical symptoms, which may be alleivated by appendectomy.