Leendert C. Paul

Restless sleep, illness intrusiveness, and depressive symptoms in three chronic illness conditions: Rheumatoid arthritis, end-stage renal disease, and multiple sclerosis

Restless sleep was compared across 110 out-patients with rheumatoid arthritis (RA), 101 with end-stage renal disease (ESRD), 94 with multiple sclerosis (MS), and an unselected control group of 176 individuals attending their family practitioners (FP). It was also investigated in the three chronic illness groups as a contributor to illness intrusiveness--the extent to which ones illness and/or its treatment interfere with continued involvements in valued activities and interests--a determinant of depression and emotional distress in chronic conditions. Reported frequencies of restless sleep were highest in RA, lower in ESRD, and lowest in MS; FP patients reported frequencies that were similar, overall, to those observed in MS. These differences were evident among nondepressed, (chi 2 9, N = 309, p < 0.0001), but not depressed, individuals. The occurrence of restless sleep correlated significantly with increased illness intrusiveness, r (279) = 0.31, p < 0.001, in RA, ESRD, and MS. Results supported the hypothesis that the relation between restless sleep and emotional distress is mediated by illness intrusiveness. Treatment of restless sleep may offer the added benefit of diminishing illness intrusiveness and may, thereby, enhance quality of life in chronic physical illness.

Anti-integrin (LFA-1, VLA-4, and Mac-1) antibody treatment and acute cardiac graft rejection in the rat.

Cell adhesion molecules mediate interactions with other cells and extracellular matrix, control cell infiltration in sites of inflammation, and regulate cell activation. Previous studies have shown that treatment of rat cardiac transplant recipients with a combination of antibodies against the T-cell integrins LFA-1 and VLA-4 gave a modest prolongation of graft survival. Current experiments were designed to examine the effect of blocking Mac-1, an important monocyte adhesion receptor and mediator of monocyte migration, together with anti-LFA-1 and anti-VLA-4 antibodies on cardiac graft survival and on the graft rejection pattern. The anti-Mac-1, CD11b-specific antibody OX-42 did not affect graft survival time although it did decrease the graft infiltration by rounded, ED-2-positive macrophages.

Human papillomavirus type 16 associated with oral squamous carcinoma in a cardiac transplant recipient

Human papillomavirus type 16 (HPV 16) has been associated with a variety of squamous carcinomas, particularly those involving the anogenital tract. The authors report the development of an oropharyngeal carcinoma in a 43‐year‐old man approximately 20 months after cardiac transplantation while he was on a maintenance regimen of cyclosporine A and prednisone. The carcinoma was resistant to treatment, and he died of complications related to metastatic disease 3 years posttransplantation. Molecular biologic studies using nonisotopic‐labeled viral DNA probes were done. In situ hybridization demonstrated the presence of HPV 16 DNA in the tumor cells. DNA dot blot analysis confirmed the presence of multiple copies of HPV 16 DNA within the tumor cells and their absence from adjacent normal‐appearing tissue. Southern blot analysis suggested that the HPV 16 DNA was integrated into the tumor cell genome. With increasing recognition of the carcinogenicity of HPV type 16 infection, a role for this virus in the development of squamous cell malignancies in immunosuppressed organ transplant recipients is likely to be noted with increasing frequency.

Cyclosporine-associated reduction in systolic myocardial function in the rat

The cardiotoxic effect of cyclosporine in the inbred rat was investigated in the isolated perfused heart model. Diastolic and systolic function was studied in 5 groups of (Lewis x Brown Norway) F1 rats treated with different doses of cyclosporine for different time intervals and in a group which received the vehiculum cremophor. Of the cyclosporine-treated rats, one group was studied four weeks after drug discontinuation to assess reversibility of the effect. To control for the nephrotoxic side effects of cyclosporine, a group of animals that had undergone 1.5-1.75 renal ablation was included. Left ventricular pressures were measured with a balloon catheter; stepwise increases in preload were obtained by small increments in the balloon volume. Over the range of left ventricular volumes studied, no differences were found in diastolic pressure between the groups. Peak systolic pressures were significantly lower in hearts obtained from cyclosporine treated rats which had received 15 or 7.5 mg/kg/24 h subcutaneously for three weeks (P less than 0.05). Our results indicate that cyclosporine treatment resulted in a reversible decrease in myocardial contractile force apparently unrelated to decreases in renal function or to changes in mean arterial pressure.

Xenoantibodies in the rat against guinea pig tissues

Abstract. The role of naturally occurring antibodies in discordant xenograft rejection is poorly defined. This is partly attributable to a lack of information regarding their tissue specificity and titers. Sera from different rat strains were studied for naturally occurring antibodies against guinea pig tissues using immunofluorescence and immunoperoxydase staining techniques. All sera contained IgG and IgM antibodies in low titers against erythrocytes. lymphoid cells, and a variety of tissue structures. Intentional immunizations of adult rats with guinea pig cells resulted in the production of xenoantibody specificities that were not detectable in nonimmunized animals. Immunizations of Munich‐Wistar rats with guinea pig skin grafts occasionally resulted in the formation of antibodies that reacted with allogeneic and syngeneic cells of the liver, lung, and lymphoid organs. We conclude that rats have low titers of naturally occurring xenoantibodies against various tissue structures of the guinea pig, but their importance in xenograft rejection remains to be established.

OKT3-induced sterile peritonitis : report of a case

L.C. Paul, Division of Nephrology, Foothills Hospital, 1403-29th Street N.W. Calgary, Alberta T2N 2T9 (Canada) Dear Sir, The use of OKT3 monoclonal antibodies to treat acute renal transplant rejection is frequently accompanied by a constellation of side effects [1,2]. About 5080% of patients experience some combination of fever, chills, dyspnea, wheezing, tachycardia, hypotension, nausea and vomiting within hours following the 1 st or 2nd dose [2]. Two to five days after initiation of therapy, symptoms of gastrointestinal and nervous system irritability may predominate fl] with frank aseptic meningitis between 3 and 14% of cases [2-4]. We observed a case of sterile peritonitis in association with OKT3 therapy and postulated a causal relationship. A 58-year-old male with end-stage renal disease of unknown etiology received a cadaveric renal transplant in 1989. He had been on chronic ambulatory peritoneal dialysis (CAPD) since 1987 and had experienced two episodes of bacterial peritonitis. A specimen of CAPD fluid taken immediately before transplantation contained no polymorphonu-clear granulocytes or microorganisms. Post-transplant immunosuppression consisted of prednisone and ciclosporin and the transplant functioned immediately. On the 10th post-transplant day, serum creatinine started to rise and antirejection treatment with Solu-Medrol was instituted. A Finney ureter catheter was removed on day 12 and a 4-day course of Norfloxacin was started prophylac-tically. Because of a further rise in serum creatinine, OKT3 therapy in a dose of 5 mg/ day was started on day 17. No immediate reaction to the treatment was noted but the next morning the patient complained of generalized weakness. Because of declining graft function, CAPD was reinstituted and it was noted that the effluent was cloudy. The next day, the CAPD effluent continued to be cloudy and repeated gram stainings of the dialysate revealed numerous polymorphonu-clear granulocytes, but no microorganisms while repeated cultures remained sterile. Antibiotic therapy with vancomycin and to-bramycin was nevertheless instituted per CAPD catheter and the effluent became clear within 12 h; daily OKT3 therapy was continued for 10 days. Plasma creatinine, which had risen to 861 μmol/l on the 2nd day of OKT 3 administration, declined to 225 μmol/ 1 at discharge. Based on the temporal relationship between the administration of OKT3 and the diagnosis of sterile peritonitis, we postulated a causal relationship. It is, however, difficult to exclude that the patient had developed asymptomatic bacterial peritonitis in the early post-transplant days which had been treated with the Norflaxacin that was prescribed for other reasons. Furthermore, up to one third of cases of peritonitis are culture negative [5]. The post-transplant episode of increased leukocyte counts in the peritoneal fluid was, however, clinically extremely mild and coincided with an increase in the peripheral white blood cell count. We hypothesize that the cytokine and inflammatory mediators released following OKT3 therapy [6] that cause leukocyte accumulation in the cerebrospinal fluid may also produce influx of leukocytes into other compartments such as the peritoneal cavity. Such increases in the intraperito-neal leukocyte count are very likely clinically asymptomatic and only detected when CAPD exchanges are instituted. References Todd PA, Brogden RN: Muromonab CD3: A review of its pharmacology and therapeutic potential. Drugs 1989;37:871-899. Thistlethwaite Jr JR, Stuart JK, Mayes JT, Gaber AO, Woodle S, Buckingham MR, Stuart FP: Monitoring and complications of monoclonal therapy: Complications and monitoring of OKT3 therapy. Am J Kidney Dis 1988; 11:112-119. Martin MA Massanari RM, Nghiem DD, Smith JL, Corry RJ: Nosocomial aseptic meningitis associated with administration of OKT3. JAMA 1988;259:20022005. Rizzo JD, Rowe S A: Meningism in a ten-month-old infant during OKT3 therapy. J Heart Transplant 1990;9:727-728. Males BM, Walshe JJ, Amsterdam D: Laboratory indices of clinical peritonitis: Total leukocyte count, microscopy and microbiologic culture of peritoneal dialysis effluent. J Clin Micro-biol 1987;25:2367-2371. Gaston RS, Deierhoi MH, Patterson T, Prast-hofer E, Julian BA, Barber H, Laskow DA, Diethelm AG, Curtis JJ: OKT3 first-dose reaction: Association with T cell subsets and cytokine release. Kidney Int 1991 ;39:141-148.