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Transplantation into sensitized recipients is contraindicated due to the potential for hyperacute rejection. In order to study the mechanism of hyperacute rejection and the role of immunosuppression in the face of presensitization, we evaluated the effect of total lymphoid irradiation, cyclosporine, and cobra venom factor, alone and in combination, on hyperacute rejection of heterotopic rat heart allografts. Lewis rats were sensitized to strongly RT-1-incompatible ACI rats by three successive skin grafts. Heart allografts were then performed, and survived for a mean period of 15.7 +/- 7.4 hours. Neither preoperative treatment of hypersensitized rats with total lymphoid irradiation alone nor with cyclosporine (5 mg/kg/day) resulted in a prolongation of survival (20.4 +/- 16.6 hours and 35.6 +/- 6.2 hours, respectively). However, complement depletion using cobra venom factor significantly prolonged mean graft survival time to 114.4 +/- 31.0 hours (p less than 0.05). Cyclosporine (10 mg/kg/day) also significantly prolonged survival to 149 +/- 29 hours (p less than 0.01), but did not lower the antibody or complement levels. The addition of total lymphoid irradiation or cyclosporine to treatment with cobra venom factor did not result in longer survival than cobra venom factor alone. In conclusion, cobra venom factor and cyclosporine delay but do not prevent hyperacute rejection, while total lymphoid irradiation has no observable effect on hyperacute rejection.

Double lumen subclavian venous hemodialysis catheters are in wide use in the United States to provide temporary vascular access. The disadvantages of these catheters include a high infection rate and short use-life (2 to 3 weeks). We evaluated a felt cuffed tunnelled jugular venous hemodialysis catheter (PermCath) to determine its ability to overcome these shortcomings and compared it with standard noncuffed double lumen dialysis catheters. Eighty PermCaths were inserted during this prospective study in patients needing temporary vascular access in excess of 1 month. Median use-life of these catheters was 8 weeks with a use range of 3 weeks to 5.4 months. Only four functioning catheters failed before elective removal. Despite the prolonged use-life there was only one episode of catheter mediated bacteremia. Seven catheters (9%) failed to function immediately after insertion. These failures were caused by catheter kinking in the region of the felt cuff. Thrombosis of the catheter lumen was the most frequent complication (137 episodes) but resolved in over 95% of the instances with urokinase instillation. Exit site infections (23 instances) were successfully treated conservatively. We conclude that the PermCath (Quinton Instrument Co, Seattle) is a safe and reliable new device with a low complication rate and a longer use-life than standard subclavian dialysis catheters. This longer use-life allows more time for maturation of primary arteriovenous (AV) fistulas and Tenckhoff peritoneal dialysis catheters, and provides time for the healing of infected vascular access grafts. Its primary disadvantage is the need for surgical insertion.

In summary, we could not document an increased incidence of HA nor a detrimental effect of CyA use in our recipients of ABO-unmatched LRD kidneys. Thus, it would appear that the incidence of HA in this situation is low enough that no special pretreatment of the kidney transplant or recipient is warranted. Since the long-term survival of ABO-unmatched LRD kidneys was equivalent to that of ABO-matched recipients there is no reason to select against them, or avoid the use of CyA. Rather a severe pretransplant anemia may predispose to a delayed recovery from anemia after transplantation.

In the course of routine pretransplant cadaveric donor kidney biopsy examination, specimens from two donors were found to exhibit intense mesangial localization of IgA by immunofluorescence, with the presence of large immune complex-type deposits in these areas confirmed ultrastructurally. Both kidneys from each donor were transplanted with the ultimate result that three of the four kidneys underwent early irreversible rejection and were removed within 3 months, while the fourth kidney has maintained normal function for a period of 8 months. Morphological and immunofluorescent evaluation of the rejected kidneys at the time of nephrectomy showed minimal residual IgA mesangial deposits, but all had changes indicative of severe acute allograft rejection. These findings suggest that glomerular lesions involving mesangial IgA deposition can resolve fairly quickly following transplantation, but that the risk of irreversible acute rejection might be greater in the recipients of such kidneys.

A necessary step in the induction of unresponsiveness to transplantation antigens is the preparation and presentation of tissue antigens in a suitable form. A method is presented for obtaining rat histocompatibility antigen in a soluble, "heptenic" form suitable for coupling to a tolerogencie carrier. Lewis and ACI spleen cell membranes are solubilized with deoxycholate and purified by Lens culinaris affinity chromatography. The ultracentrifuged, solubilized preparation of rat histocompatibility (HC) antigen is unable to initiate immunity, but is able to react specifically with the product of an already established immune response. The HC antigen preparation is neither immunogenic nor tolerogenic alone. However, an antibody response to allogeneic cells can be prevented when these rat HC preparations are chemically coupled to tolerogenic carrier as described in the accompanying paper.

Immunosuppression generated by total lymphoid irradiation (TLI) may be of use in solid organ transplantation. We have investigated the use of TLI in the rat cardiac allograft model. Lewis rats received TLI from a cobalt-60 machine. The daily dose was 1.25 Gy and treatments were administered 4 days per week. We performed experiments to assess the effect of dose rate upon graft survival. The dose rate was varied by changing the source to animal distance and by using a lead attenuator. Cardiac allografts from each ACI donor rat were transplanted to the recipient Lewis rat's abdomen utilizing microvascular surgical technique. Heart graft survival times (GST) were monitored by direct palpation of the cardiac impulse. Immune function was measured by an activity index of the mixed lymphocyte reaction. In the absence of any immunosuppression there was a mean GST of 6.9 +/- 0.3 days. When a graft was placed the day following completion of TLI, there was an increase in GST as the total TLI dose was increased. Mean GST (+/- S.E.) following 5, 10, and 15 Gy were 12.3 +/- 1.3, 14.5 +/- 1.3, and 25.5 +/- 1.1 days, respectively. Following 20 Gy, GST decreased because of irradiation induced pulmonary toxicity and host death. When 3.5 weeks were allowed to elapse between the completion of TLI and transplantation, GST were less than those seen with equivalent doses of TLI and early transplantation. Mean GST following 5, 10, and 15 Gy and a delayed transplant were 7.2 +/- 0.1, 10.7 +/- 1.2, and 19.0 +/- 3.5 days, respectively. We tested the effect of dose rate upon GST.(ABSTRACT TRUNCATED AT 250 WORDS)

Although the use of antithymocyte globulin/antilymphocyte serum (ATG/ALS) has been shown to be beneficial in treating renal allograft rejection, the incidence and nature of serum sickness reactions following such treatment have received limited attention. In the setting of rejection or infection, the diagnosis of serum sickness is often difficult on clinical grounds, and biopsy may be an undesirable means of obtaining documentation. A sensitive enzyme-linked immunosorbent assay (ELISA) was developed to detect antibodies against ATGAM (Upjohn) and was utilized in 35 patients treated for rejection with ATGAM following clinical unresponsiveness to bolus methylprednisolone therapy. Serum sickness was diagnosed clinically in 7 of these patients (20%) during or immediately following ATGAM therapy. Significant titers of anti-ATGAM antibody were found in these 7 cases, as well as 5 additional cases (14%). Upon retrospective review, the diagnosis of serum sickness was also made in each of these 5 additional cases based upon the immunopathologic detection of horse immunoglobulin deposits in vessels of tissue (lung or kidney) examined. In 2 other cases where serologic testing was negative, there was some clinical suggestion of serum sickness that could not be documented pathologically. ELISA for anti-ATGAM antibodies was negative in testing 46 control patients and pooled normal sera. In one case, retrospective testing of pre-ATGAM therapy serum samples showed significant antihorse antibodies. Despite a negative skin test prior to administration, this patient developed symptoms of serum sickness 15 days after the onset of ATGAM therapy. Extremely high titers of antibody were detected 5 days earlier (10 days posttherapy), and the presence of horse immunoglobulin immune complexes in the kidney was documented following graft loss that occurred within 4 weeks. These findings indicate (1) serologic testing for anti-ATGAM antibodies using a sensitive ELISA method provides a quick, inexpensive, noninvasive means for the presumptive diagnosis of serum sickness in complicated clinical situations, and (2) screening of patient sera prior to administration of ATGAM may be useful in avoiding potential serum sickness reactions.

In an attempt to study the role of class I major histocompatibility complex antigens in inducing immunological unresponsiveness, the survival rates of hepatic allografts were compared in rats pretreated with blood taken from various rat strains. A single intravenous injection of 1 ml fresh heparinized whole blood seven days before transplantation significantly prolonged the survival of subsequent donor-specific hepatic allografts in the fully allogeneic ACI(RT1a)-to-LEW(RT1l) rat combination. However, pretreatment with blood taken from the third-party strain BN(RT1n) did not produce suppression of rejection, attesting to the specificity of the pretransplant transfusion effect. Interestingly, pretransplant transfusion of PVG.r1 blood, sharing only the RT1.A MHC region with ACI, significantly prolonged the survival of ACI-to-LEW hepatic allografts. In addition, no lymphocytotoxic antibodies could be detected at 30 or 100 days after transplantation in animals with long-surviving hepatic allografts pretreated with either PVG.r1 or ACI whole blood. On the other hand, pretreatment with PVG(RT1c) blood increased the survival of ACI-to-LEW hepatic allografts only moderately compared with controls. This finding may be consistent with a partial effect of some third-party blood transfusion. The experimental data suggest that the class I MHC antigens can be immunosuppressive in rat hepatic allografts. Adoptive transfer of 5 x 10(7) splenocytes taken from long-term-surviving hepatic allografts pretreated with donor ACI whole blood or PVG.r1 blood into irradiated (750 rads) LEW rats prolonged the survival of donor-type skin grafts, whereas third-party strain (BN) grafts were rejected. This finding suggests the presence of donor-specific suppressor cells.

Analysis of 2778 primary and 606 regrafted cadaveric donor renal allograft recipients transplanted between June 1977 and July 1982 as part of the South-Eastern Organ Procurement Foundation (SEOPF) Prospective Study was performed to determine the influence of changes in presensitization on graft and patient outcome. Four mutually exclusive groups of patients were identified based on the relative difference in the percentage of panel-reactive antibody (PRA) from highest ever (peak) to most recent (current) pretransplant levels as follows: group 1 (unsensitized): peak = current PRA = 0; group 2 (rising or stable PRA): (peak = current PRA) greater than 0; group 3 (small decrease): (peak - current PRA) = 1-40%;) and group 4 (large decrease): (peak - current PRA) greater than 40%. First-transplant recipients in group 4 had significantly higher mortality when compared with groups 1-3 (P less than 0.002). This decrease in patient survival was evident at 6 months (81% +/- 4 vs 91% +/- 1) and persisted to three years (68% +/- 8 vs 78% +/- 2), and it was associated with a significant (P less than 0.037) increase in death from infectious causes. This finding was even more striking when only transfused recipients were considered: at three years the difference in patient survival was 63% +/- 11 vs. 77% +/- 2. In addition, transfused patients with a decrease in pretransplant PRA of greater than 40% had significantly lower overall graft survival (P less than 0.02) and a higher incidence of irreversible graft rejection (50% +/- 8 vs 33% +/- 1 at two years). For regrafted recipients, there were no differences in patient survival among groups, but those in group 4 had significantly lower graft survival (P less than 0.0033) than groups 1-3. These findings suggest that a substantial decrease in PRA prior to transplant does not necessarily indicate a decrease in potential donor alloreactivity, and in first-graft recipients it may reflect an increased susceptibility to life-threatening infections following transplantation.

In a patient with acute cholecystitis whose body habitus precluded cholecystectomy, we used percutaneous transhepatic ultrasonic cholelithotripsy. We compare it with other modalities applicable in such cases. Although not commonly used, these alternatives may be the most appropriate therapy in certain unusual circumstances.

A technique is described to remove the entire liver in a single stage with preservation of intestinal absorptive function. An inverted V-shape polyethylene cannula, either heparin bonded or silicon coated, was inserted into the portal vein and inferior vena cava to maintain venous return from the splanchnic and lower caval regions of the anhepatic rat. Blood glucose fell at a rate of 7 to 11 mg per hr per total plasma volume (4% body weight), usually resulting in hypoglycemia within the initial 2 hr. Euglycemia could be maintained in the first 3 hr after hepatectomy with hourly intravenous infusions of 2.5 to 5 mg per 100 gm body weight of glucose. Larger infusions of glucose (10 to 12.5 mg per hr per 100 gm body weight) were necessary for normal levels at later times. A 0.5 gm per 100 gm rat weight intestinal glucose bolus restored euglycemia for at least a 2-hr interval. Intestinal absorption of cholesterol and oleic acid was demonstrated in the anhepatic rat, although the latter was not so efficiently absorbed as in the control. The plasma cholesterol decreased with time in the anhepatic rat. Prompt increases were observed in plasma free fatty acid and glycerol concentrations after hepatectomy. Progressive increases in both direct and indirect plasma bilirubin levels were noted after hepatectomy. With appropriate maintenance of blood sugar, survival of 36 hr was observed. This procedure for single stage total hepatectomy in the rat can be performed in less than 30 min. The model is particularly useful for studies of the influence of the liver on postabsorptive metabolism.

From 1966 through 1985, a total of 640 patients received 739 renal transplants at a single center transplantation program. Of 245 total deaths, a slide and chart review of all 116 autopsied cases (47%) identified the major causes of death as pneumonia (n = 43), sepsis (n = 32), hemorrhage (n = 15), peritonitis (n = 11), meningitis (n = 7), and pulmonary embolism (n = 5). Eighty-five (73.3%) of these patients died of complications directly associated with immunosuppression, almost all (n = 82) as a result of infection. Organisms most frequently identified at death were gram-negative bacilli (n = 72), Candida species (n = 23), cytomegalovirus (n = 17), enterococcus (n = 14), Staphylococcus aureus (n = 11), Aspergillus species (n = 10), Pneumocystis carinii (n = 5), and mycobacteria (n = 5). Significant associations were found between bolus steroid antirejection therapy and infection with Aspergillus cytomegalovirus. Diabetics had a higher incidence of fungal infections and bowel perforation than nondiabetics. During this 20-year period, overall one-year actual patient survival rates for the four respective five-year intervals increased dramatically (69.9%, 68.2%, 83.3%, and 91.8%), but the normalized death rate showed a smaller decrease for infectious vs noninfectious causes.

The physiologic and performance effects of low-level reconnaissance flying in hot environments were documented and quantitated. RF-4C pilots and weapons system operators were studied in hot and cool seasons during both high and low missions to distinguish environmental temperature from flight level effects. ECG, sternal and thigh skin temperatures, and cockpit temperature at helmet level were monitored continuously. Body weights, oral temperatures, sweat Na/K ratios, and urine electrolytes, steroids, and catecholamines, as well as sleep and fatigue scores, were measured. Mission performance was assessed using photo target acquisition scores. RF-4C aircrews are exposed to moderate heat stress and acute dehydration (1.2% over 90 min) during low-level summer flights were cockpit temperature occasionally exceeded 50 degrees C. Photo target scores indicated that the potential for crew error was increased, and that the margin of safety was accordingly decreased, during such hot missions. The RF-4C cockpit air conditioning system proved inadequate.

Fracture stabilization is often desirable prior to vascular repair in the management of major extremity injuries. This principle is particularly important when long vein grafts are required to minimize the risk of anastomotic disruption during the orthopedic portion of the procedure. However, in situations associated with prolonged periods of preoperative ischemia, early reperfusion of the injured extremity would be optimal. This report illustrates two cases of brachial artery injury in which heparin-bonded shunts were used to establish blood flow to the distal extremity before fracture fixation. The shunts were interposed between disrupted arterial segments and reestablished distal perfusion while associated fractures were internally stabilized. Thus, early revascularization allowed the orthopedic repair to proceed in an unhurried fashion. After adequate stabilization of the fracture, arterial reconstruction was completed using saphenous vein interposition grafts. This technique potentially could improve extremity salvage rates and facilitate the repair of arterial injuries associated with unstable long bone fractures.

The effects of several treatments involving alpha-adrenergic mechanisms upon the early stages of rat liver regeneration were examined. Catecholamine concentrations in rat plasma were measured at various times after hepatectomy and were found to be elevated relative to those in plasma from sham-operated rats. Surgical hepatic denervation or injection of an alpha 1-adrenergic receptor antagonist (prazosin) reduced incorporation of [3H]thymidine into liver DNA during the first 24 hr after partial hepatectomy. Chronic guanethidine injections (3 to 6 weeks) reduced liver catecholamine levels, but did not affect its ability to regenerate. The inhibition of regenerative DNA synthesis by prazosin was preceded by an alteration in the binding of epidermal growth factor to regenerating liver, which was apparently the result of an increased number of epidermal growth factor receptors. Thus, alpha 1-adrenergic blockade, which affects both epidermal growth factor receptor binding and subsequent DNA synthesis in hepatocyte primary cultures, can also modulate these processes during liver regeneration in vivo.

The urinary excretion of free amino acids was measured in 15 men who participated in a continuous airborne alert for an extended period of time. These men made up one of three teams which took turns so as to assure that at least one team remained airborne in an EC-135J aircraft at all times during the 96-h alert. The team making up the test group herein reported was airborne for 8.5 h on each of four successive days; flights were flown during the daytime. The data strongly suggest that the participants experienced anticipatory stress during the early part of the first two flight days of the alert, after which the excretion of amino acids was virtually unaltered. Additionally, amino acid excretion during the 24-h period following the alert was essentially in accord with baseline values established for another groups of subjects.

This study has shown that repetitive exchanges between the American Apollo space vehicle atmosphere of 100% oxygen at 5 psia (258 torr) and the Russian Soyuz spacecraft atmosphere of 30% oxygen-70% nitrogen at 10 psia (523 torr), as simulated in altitude chambers, will not likely result in any form of decompression sickness. This conclusion is based upon the absence of any form of bends in seven crewmen who participated in 11 tests distributed over three 24-h periods. During each period, three transfers from the 5 to the 10 psia environments were performed by simulating passage through a docking module which served as an airlock where astronauts and cosmonauts first adapted to each other's cabin gases and pressures before transfer. Biochemical tests, subjective fatigue scores, and the complete absence of any form of pain were also indicative that decompression sickness should not be expected if this spacecraft transfer schedule is followed.