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Tumour-necrosis-factor antibody treatment in Crohn's disease
Moratorium
on
Kveim test
SiR-Wigley (May 15, p 1284) advocates a moratorium on the of the Kveim test because the test may transfer sarcoidosis. UK, Kveim test material is prepared from human sarcoid spleen by the Public Health Laboratory Service, under a product licence approved by the UK Medicines Commission. Before a spleen can be accepted for processing, a full clinical history of the donor is obtained with confirmation that the donor has not had an organ transplant, growth hormone treatment, or infusions of human blood or plasma. Blood from the donor is tested for HIV I and IIviruses, hepatitis viruses B and C, Coxiella burnettii, Chlamydia psittaci, Mycoplasma pneumoniae, cytomegalovirus, influenza viruses A and B, adenovirus, and respiratory syncitial virus before and not less than 90 days after splenectomy. Samples are tested for bioburden and microbial contamination in accordance with the European Pharmacopoeia, before phenolisation. Finally, the phenolised antigen is irradiated (25 kGy) and heat-sealed. Taken together, these precautions suggest that the risks of transmission of disease are negligible. Each new batch of Kveim suspension is validated alongside a reference suspension of known potency and selectivity to maintain the expected proportion of positive reactions among patients with sarcoidosis and a negligible number (1-3-3%) among others. No untoward or unexpected clinical findings have been reported after Kveim testing over 20 years, and this is in keeping with international studies in which, with the cooperation of investigators in 37 countries, 3244 individuals were given one or more Kveim tests with no adverse results.l The concept of the transfer of sarcoidosis is also refuted by studies2 in which mice, inoculated with human sarcoid tissue homogenates, developed epithelioid and giant cell granulomas but this capacity was lost when the material was autoclaved, stored at - 20°C for 1 week, or exposed to irradiation (25 kGy), which are the conditions followed in the preparation of human Kveim test material. The patients referred to our sarcoidosis clinic include many with extrathoracic lesions only, in whom biopsy confirmation is difficult if not impossible and in whom a Kveim test can provide the diagnosis. Other patients are referred for exclusion of sarcoidosis and in these a Kveim test provides important information. Because the test remains a valuable investigation, is well validated, produces few falseuse
In the
positive results, and as all known measures have been used to eliminate the risk of transferring infection, we refute the suggestion that the procedure should no longer be considered safe. R M du Bois, D M Geddes, D N Mitchell Royal Brompton National Heart and Lung Hospital,
London SW3 6NP, UK
1 Siltzbach LE. An international Kveim test study 1960-1966. In: La Sarcoidose Rapports de la IV Conference Internationale. Turief J, Chabot J, eds. Paris: Masson & Co, 1966: 200-13. 2 Mitchell DN, Rees RJW, Goswami KKA. Transmissible agents from human sarcoid and Crohn’s disease tissues. Lancet 1976; ii: 761-65.
SiR-Wigley urges caution in the use of Kveim reagent in view potential for transmitting hepatitis B, HIV, and--of interest to us-the agent of Creutzfeldt-Jakob disease (CJD). of its
As he suggests, the programme of national surveillance of CJD in the UK affords an opportunity to assess this risk. The past medical histories of all definite and probable cases of CJD in England and Wales in 1980-84, and the UK since 1985 have been ascertained. Of 346 such patients, detailed clinical information is available for 302. In none of these was a diagnosis of sarcoidosis suspected or made. In the remainder, sarcoidosis was not noted in the medical history. None of the definite or probable cases since 1990 have received Kveim
reagent. It should, however, be borne in mind that the incubation period for the development of CJD can be more than 30 years.! Wigley overestimates the theoretical risk of CJD transmission by this test. Patients with sarcoidosis who were demented before death are unlikely to be considered as potential donors of spleens or lymph nodes, and the risk of presymptomatic cases being used as donors is probably low. Although the potential infectivity of spleen and lymph nodes has been established in experimental CJD transmission,2 routine preparation of Kveim reagent by heating, phenolising, and irradiation is likely to reduce this. Even if contamination with the transmissible agent of CJD were to occur, the amount injected in a test is so small (two spleens supply between 2000 and 3000 Kveim test doses) that the infective titre in individual doses will be negligible. Although these theoretical considerations are reassuring in relation to the Kveim test, the accidental transmission of CJD by other mechanisms indicates that continued vigilance is essential
Rajith N de Silva, Robert G Will National Creutzfeldt-Jakob Disease Surveillance Unit, Western General Edinburgh EH4 2XU, UK
1
2
Hospital,
Brown P, Preece MA, Will RG. "Friendly fire" in medicine: hormones, homografts, and Creutzfeldt-Jakob disease. Lancet 1992; 340: 24-27. Tateishi J, Hikita K, Kitamoto T, Nagara H. Experimental Creutzfeldt-Jakob disease: induction of amyloid plaques in rodents. In: Prusiner SB, McKinley MP, eds. Prions: novel infectious pathogens causing scrapie and Creutzfeldt-Jakob disease. London: Academic Press, 1987: 415-26.
Tumour-necrosis-factor antibody treatment in Crohn’s disease SiR-We report a girl with Crohn’s disease who was not responsive to medical therapy but in whom complete but temporary remission could be achieved by treatment with tumour necrosis factor (TNF) monoclonal antibodies. At age 12 years the patient was examined because of diarrhoea of 4 months’ duration, rectal blood loss, abdominal pain, fever, and loss of 4-5 kg. Colonoscopy showed multiple aphthoid lesions, skip lesions, erythema, friability, and granularity in the distal 70 cm of the colon extending into the anus. Biopsy specimens revealed severe inflammation, crypt abscesses, and granulomas. A small bowel follow-through was normal. Prednisone 30 mg per day, mesalazine 250 mg three times a day, and enemas containing 2 g aspirin and 40 mg prednisone were started. Her complaints initially abated but the disease soon relapsed despite continued anti-inflammatory treatment. Because of severe side-effects the prednisone dose had to be reduced. Colonoscopy 3 months after diagnosis showed no improvement. The treatment was intensified by raising the dose of mesalazine and adding azathioprine. Some clinical improvement was noted but her growth stunted, and it was not possible to withdraw any medication. A semielemental diet for 2 months and the addition of metronidazole had no effect. A year after diagnosis, she had increasing anorexia, abdominal pain, and frequent bloody diarrhoea. Colonoscopy again showed extensive colitis and perianal lesions. Over the next 14 months the patient was treated with prednisone (daily alternating up to 40 mg a day), azathioprine 75 mg a day, mesalazine 500 mg three times a day, and enemas containing beclomethasone and aspirin. Because of unresponsive disabling disease, the possibility of anti-TNF treatment was discussed with the patient and her parents. Written consent was obtained. She was infused twice over a fortnight with anti-TNFa (chimeric monoclonal cA2, 173
Transfer of insulin-dependent diabetes between HLA-identical siblings by bone marrow
Figure: Response to anti-TNF (arrows) In Crohn’s disease PCDAI = paediatric Crohn’s disease activity index; CDAI = Crohn’s disease activity index.
kindly supplied by Centocor, Malvern, USA) 10 mg/kg intravenously over 2 h. The other therapy was unchanged from 2 months before until 3 months after anti-TNF treatment. Immediately after the first dose of anti-TNF, the clinical symptoms improved, body temperature became normal, and the girl started to gain weight (3-2 kg in 10 weeks). Crohn’s disease activity index fell from 311 to 85 (paediatric Crohn’s disease activity index: 77-5 to 10) (figure). Complete endoscopic remission was observed, which lasted for 3 months, after which symptoms recurred. No side-effects were seen. The inflammatory reaction in Crohn’s disease is presumably initiated and propagated by local release of cytokines. During exacerbation of inflammatory bowel disease production of interleukins and TNFcx is increased. 1,2 TNFoc is a potent
SIR—We would support and broaden Lampeter and colleagues’ recommendation (May 15, p 1243) about the risk of adoptive transfer of type 1 diabetes after bone marrow transplantation (BMT) when the HLA identical donor is diabetic. We have reported a similar case1 in which both autoimmune hypothyroidism and type 1 diabetes were transferred into the bone marrow recipient from her HLA-identical sister. The donor was neither diabetic nor hypothyroid at the time of the donation. She later developed hypothyroidism and usual signs of preclinical type 1 diabetes2-ie, high titre islet cell antibody (ICA), anti-GAD antibody, and low acute insulin response to glucose. However, her HLA DR-DQ identical brother has type 1 diabetes and her mother Graves’ disease. Thus, the risk of transfer of diabetes after BMT also exists when both donor and recipient have a genetic background predisposing to the disease. This immunogenetic receptivity is probably a prerequisite since ICA and thyroid antibody positivity seem to be rare after BMT.3 In addition, Lampeter, referring to Sutherland et awl4 concludes that the course of diabetes is longer if diabetogenic lymphoid cells are transferred to an HLA-identical pancreas, as is seen with the transfer of HLA-identical pancreas into a subject with diabetogenic lymphoid cells. In our patient, the time lag between BMT and onset of diabetes was 3 years, which is very close to the 4 years reported by Lampeter. To document the natural history of autoimmune processes, we have followed the time course of anti-organ humoral reactivity and noted that ICA appeared 15 months and thyroid antibodies 7 months after transplantation. This late complication of BMT can be predicted in the recipient by the monitoring of ICA and other antibodies related to diabetes. B
Bert Derkx, Jan Taminiau, Sandra Radema, Arnold Stronkhorst, Cees Wortel, Guido Tytgat, Sander van Deventer Departments of Paediatric Gastroenterology, Nutrition, and Gastroenterology, Academic Medical Centre, 1105 AZ Amsterdam, Netherlands
1
2
3
4
Pullman WE, Elsbury S, Kobayashi M, Hapel AJ, Doe WF. Enhanced mucosal cytokine production in inflammatory bowel disease.
Gastroenterology 1992; 102: 529-37. Brynskov J, Tvede N, Andersen CB, Vilien M. Increased production of interleukin-1&agr;, interleukin-2 and soluble interleukin-2 receptor in endoscopic mucosal biopsy specimens with active inflammatory bowel disease. Gut 1992; 33: 55-58. Murch SH, Lamkin VA, Savage MO, Walker Smith JA, MacDonald TT. Serum concentrations of tumour necrosis factor-&agr; in childhood chronic inflammatory bowel disease. Gut 1991; 32: 913-17. Braegger CP, Nicholls S, Murch SH, Stephens S, MacDonald TT. Tumour necrosis factor alpha in stool as a marker of intestinal inflammation. Lancet 1992; 339: 89-91.
174
Vialettes, D Maraninchi
Department of Diabetology and Paoli Calmettes Institute, University of Marseille, 13385 Marseille, France
1
Vialettes B, Maraninchi D, San Marco MP,
2
polyendocrine failure-type 1 (insulin-dependent) diabetes mellitus and hypothyroidism after allogeneic bone marrow transplantation. Diabetologia 1993; 36: 541-46. San Marco M, Vialettes B, Maraninchi D, Bernard D. Auto antibody formation after bone marrow transplantation: a comparison between autologous and allogeneic grafts. Autoimmunity 1991; 11: 7-12. MacLaren NK. How, when and why to predict IDDM. Diabetes 1988;
pro-inflammatory protein, produced by monocytes and activated T cells, which are abundant inflammatory lesions in Crohn’s disease. Serum TNFoc was increased in children with relapse of ulcerative colitis and colonic Crohn’s disease.3 Stool samples show increased TNFcx concentrations that vary with severity of disease.’ TNFcx also activates leucocytes and endothelial cells to express molecules involved in neutrophil adhesion (including 02-integrins and selectins). Because cellular adhesion to vascular epithelium is required for leucocyte diapedesis and entry into the parenchyma, TNFa may have a key role in leucocyte recruitment into the bowel mucosa.
transplantation
3 4
et
al. Autoimmune
37: 1591-94. Sutherland DE, Goetz FC, Sibley RK. Recurrence of disease in pancreas transplantation. Diabetes 1989; 38 (suppl 1): 85-87.
Bathing donor-livers in University of Wisconsin solution SiR-Human donor livers are flushed in-situ with cold University of Wisconson organ preservative (UW). Then, after donor hepatectomy, these livers are usually bathed in UW in plastic bags stored on melting ice. A retrospective analysis of the magnetic relaxation times of 50 isolated human donor livers obtained from various hospitals showed that the relaxation times of the livers were all in the same range. A similar (narrow) range was found for the relaxation times of the bathing fluid. However, one exception was noted in which the bathing fluid had exceptionally long T1 (data not shown) and T2 (figure) relaxation times, closely resembling the relaxation times of saline. Liver parenchyma itself had relaxation times similar to livers that were known to be adequately perfused with UW. The preservation records
on
Kveim test
SiR-Wigley (May 15, p 1284) advocates a moratorium on the of the Kveim test because the test may transfer sarcoidosis. UK, Kveim test material is prepared from human sarcoid spleen by the Public Health Laboratory Service, under a product licence approved by the UK Medicines Commission. Before a spleen can be accepted for processing, a full clinical history of the donor is obtained with confirmation that the donor has not had an organ transplant, growth hormone treatment, or infusions of human blood or plasma. Blood from the donor is tested for HIV I and IIviruses, hepatitis viruses B and C, Coxiella burnettii, Chlamydia psittaci, Mycoplasma pneumoniae, cytomegalovirus, influenza viruses A and B, adenovirus, and respiratory syncitial virus before and not less than 90 days after splenectomy. Samples are tested for bioburden and microbial contamination in accordance with the European Pharmacopoeia, before phenolisation. Finally, the phenolised antigen is irradiated (25 kGy) and heat-sealed. Taken together, these precautions suggest that the risks of transmission of disease are negligible. Each new batch of Kveim suspension is validated alongside a reference suspension of known potency and selectivity to maintain the expected proportion of positive reactions among patients with sarcoidosis and a negligible number (1-3-3%) among others. No untoward or unexpected clinical findings have been reported after Kveim testing over 20 years, and this is in keeping with international studies in which, with the cooperation of investigators in 37 countries, 3244 individuals were given one or more Kveim tests with no adverse results.l The concept of the transfer of sarcoidosis is also refuted by studies2 in which mice, inoculated with human sarcoid tissue homogenates, developed epithelioid and giant cell granulomas but this capacity was lost when the material was autoclaved, stored at - 20°C for 1 week, or exposed to irradiation (25 kGy), which are the conditions followed in the preparation of human Kveim test material. The patients referred to our sarcoidosis clinic include many with extrathoracic lesions only, in whom biopsy confirmation is difficult if not impossible and in whom a Kveim test can provide the diagnosis. Other patients are referred for exclusion of sarcoidosis and in these a Kveim test provides important information. Because the test remains a valuable investigation, is well validated, produces few falseuse
In the
positive results, and as all known measures have been used to eliminate the risk of transferring infection, we refute the suggestion that the procedure should no longer be considered safe. R M du Bois, D M Geddes, D N Mitchell Royal Brompton National Heart and Lung Hospital,
London SW3 6NP, UK
1 Siltzbach LE. An international Kveim test study 1960-1966. In: La Sarcoidose Rapports de la IV Conference Internationale. Turief J, Chabot J, eds. Paris: Masson & Co, 1966: 200-13. 2 Mitchell DN, Rees RJW, Goswami KKA. Transmissible agents from human sarcoid and Crohn’s disease tissues. Lancet 1976; ii: 761-65.
SiR-Wigley urges caution in the use of Kveim reagent in view potential for transmitting hepatitis B, HIV, and--of interest to us-the agent of Creutzfeldt-Jakob disease (CJD). of its
As he suggests, the programme of national surveillance of CJD in the UK affords an opportunity to assess this risk. The past medical histories of all definite and probable cases of CJD in England and Wales in 1980-84, and the UK since 1985 have been ascertained. Of 346 such patients, detailed clinical information is available for 302. In none of these was a diagnosis of sarcoidosis suspected or made. In the remainder, sarcoidosis was not noted in the medical history. None of the definite or probable cases since 1990 have received Kveim
reagent. It should, however, be borne in mind that the incubation period for the development of CJD can be more than 30 years.! Wigley overestimates the theoretical risk of CJD transmission by this test. Patients with sarcoidosis who were demented before death are unlikely to be considered as potential donors of spleens or lymph nodes, and the risk of presymptomatic cases being used as donors is probably low. Although the potential infectivity of spleen and lymph nodes has been established in experimental CJD transmission,2 routine preparation of Kveim reagent by heating, phenolising, and irradiation is likely to reduce this. Even if contamination with the transmissible agent of CJD were to occur, the amount injected in a test is so small (two spleens supply between 2000 and 3000 Kveim test doses) that the infective titre in individual doses will be negligible. Although these theoretical considerations are reassuring in relation to the Kveim test, the accidental transmission of CJD by other mechanisms indicates that continued vigilance is essential
Rajith N de Silva, Robert G Will National Creutzfeldt-Jakob Disease Surveillance Unit, Western General Edinburgh EH4 2XU, UK
1
2
Hospital,
Brown P, Preece MA, Will RG. "Friendly fire" in medicine: hormones, homografts, and Creutzfeldt-Jakob disease. Lancet 1992; 340: 24-27. Tateishi J, Hikita K, Kitamoto T, Nagara H. Experimental Creutzfeldt-Jakob disease: induction of amyloid plaques in rodents. In: Prusiner SB, McKinley MP, eds. Prions: novel infectious pathogens causing scrapie and Creutzfeldt-Jakob disease. London: Academic Press, 1987: 415-26.
Tumour-necrosis-factor antibody treatment in Crohn’s disease SiR-We report a girl with Crohn’s disease who was not responsive to medical therapy but in whom complete but temporary remission could be achieved by treatment with tumour necrosis factor (TNF) monoclonal antibodies. At age 12 years the patient was examined because of diarrhoea of 4 months’ duration, rectal blood loss, abdominal pain, fever, and loss of 4-5 kg. Colonoscopy showed multiple aphthoid lesions, skip lesions, erythema, friability, and granularity in the distal 70 cm of the colon extending into the anus. Biopsy specimens revealed severe inflammation, crypt abscesses, and granulomas. A small bowel follow-through was normal. Prednisone 30 mg per day, mesalazine 250 mg three times a day, and enemas containing 2 g aspirin and 40 mg prednisone were started. Her complaints initially abated but the disease soon relapsed despite continued anti-inflammatory treatment. Because of severe side-effects the prednisone dose had to be reduced. Colonoscopy 3 months after diagnosis showed no improvement. The treatment was intensified by raising the dose of mesalazine and adding azathioprine. Some clinical improvement was noted but her growth stunted, and it was not possible to withdraw any medication. A semielemental diet for 2 months and the addition of metronidazole had no effect. A year after diagnosis, she had increasing anorexia, abdominal pain, and frequent bloody diarrhoea. Colonoscopy again showed extensive colitis and perianal lesions. Over the next 14 months the patient was treated with prednisone (daily alternating up to 40 mg a day), azathioprine 75 mg a day, mesalazine 500 mg three times a day, and enemas containing beclomethasone and aspirin. Because of unresponsive disabling disease, the possibility of anti-TNF treatment was discussed with the patient and her parents. Written consent was obtained. She was infused twice over a fortnight with anti-TNFa (chimeric monoclonal cA2, 173
Transfer of insulin-dependent diabetes between HLA-identical siblings by bone marrow
Figure: Response to anti-TNF (arrows) In Crohn’s disease PCDAI = paediatric Crohn’s disease activity index; CDAI = Crohn’s disease activity index.
kindly supplied by Centocor, Malvern, USA) 10 mg/kg intravenously over 2 h. The other therapy was unchanged from 2 months before until 3 months after anti-TNF treatment. Immediately after the first dose of anti-TNF, the clinical symptoms improved, body temperature became normal, and the girl started to gain weight (3-2 kg in 10 weeks). Crohn’s disease activity index fell from 311 to 85 (paediatric Crohn’s disease activity index: 77-5 to 10) (figure). Complete endoscopic remission was observed, which lasted for 3 months, after which symptoms recurred. No side-effects were seen. The inflammatory reaction in Crohn’s disease is presumably initiated and propagated by local release of cytokines. During exacerbation of inflammatory bowel disease production of interleukins and TNFcx is increased. 1,2 TNFoc is a potent
SIR—We would support and broaden Lampeter and colleagues’ recommendation (May 15, p 1243) about the risk of adoptive transfer of type 1 diabetes after bone marrow transplantation (BMT) when the HLA identical donor is diabetic. We have reported a similar case1 in which both autoimmune hypothyroidism and type 1 diabetes were transferred into the bone marrow recipient from her HLA-identical sister. The donor was neither diabetic nor hypothyroid at the time of the donation. She later developed hypothyroidism and usual signs of preclinical type 1 diabetes2-ie, high titre islet cell antibody (ICA), anti-GAD antibody, and low acute insulin response to glucose. However, her HLA DR-DQ identical brother has type 1 diabetes and her mother Graves’ disease. Thus, the risk of transfer of diabetes after BMT also exists when both donor and recipient have a genetic background predisposing to the disease. This immunogenetic receptivity is probably a prerequisite since ICA and thyroid antibody positivity seem to be rare after BMT.3 In addition, Lampeter, referring to Sutherland et awl4 concludes that the course of diabetes is longer if diabetogenic lymphoid cells are transferred to an HLA-identical pancreas, as is seen with the transfer of HLA-identical pancreas into a subject with diabetogenic lymphoid cells. In our patient, the time lag between BMT and onset of diabetes was 3 years, which is very close to the 4 years reported by Lampeter. To document the natural history of autoimmune processes, we have followed the time course of anti-organ humoral reactivity and noted that ICA appeared 15 months and thyroid antibodies 7 months after transplantation. This late complication of BMT can be predicted in the recipient by the monitoring of ICA and other antibodies related to diabetes. B
Bert Derkx, Jan Taminiau, Sandra Radema, Arnold Stronkhorst, Cees Wortel, Guido Tytgat, Sander van Deventer Departments of Paediatric Gastroenterology, Nutrition, and Gastroenterology, Academic Medical Centre, 1105 AZ Amsterdam, Netherlands
1
2
3
4
Pullman WE, Elsbury S, Kobayashi M, Hapel AJ, Doe WF. Enhanced mucosal cytokine production in inflammatory bowel disease.
Gastroenterology 1992; 102: 529-37. Brynskov J, Tvede N, Andersen CB, Vilien M. Increased production of interleukin-1&agr;, interleukin-2 and soluble interleukin-2 receptor in endoscopic mucosal biopsy specimens with active inflammatory bowel disease. Gut 1992; 33: 55-58. Murch SH, Lamkin VA, Savage MO, Walker Smith JA, MacDonald TT. Serum concentrations of tumour necrosis factor-&agr; in childhood chronic inflammatory bowel disease. Gut 1991; 32: 913-17. Braegger CP, Nicholls S, Murch SH, Stephens S, MacDonald TT. Tumour necrosis factor alpha in stool as a marker of intestinal inflammation. Lancet 1992; 339: 89-91.
174
Vialettes, D Maraninchi
Department of Diabetology and Paoli Calmettes Institute, University of Marseille, 13385 Marseille, France
1
Vialettes B, Maraninchi D, San Marco MP,
2
polyendocrine failure-type 1 (insulin-dependent) diabetes mellitus and hypothyroidism after allogeneic bone marrow transplantation. Diabetologia 1993; 36: 541-46. San Marco M, Vialettes B, Maraninchi D, Bernard D. Auto antibody formation after bone marrow transplantation: a comparison between autologous and allogeneic grafts. Autoimmunity 1991; 11: 7-12. MacLaren NK. How, when and why to predict IDDM. Diabetes 1988;
pro-inflammatory protein, produced by monocytes and activated T cells, which are abundant inflammatory lesions in Crohn’s disease. Serum TNFoc was increased in children with relapse of ulcerative colitis and colonic Crohn’s disease.3 Stool samples show increased TNFcx concentrations that vary with severity of disease.’ TNFcx also activates leucocytes and endothelial cells to express molecules involved in neutrophil adhesion (including 02-integrins and selectins). Because cellular adhesion to vascular epithelium is required for leucocyte diapedesis and entry into the parenchyma, TNFa may have a key role in leucocyte recruitment into the bowel mucosa.
transplantation
3 4
et
al. Autoimmune
37: 1591-94. Sutherland DE, Goetz FC, Sibley RK. Recurrence of disease in pancreas transplantation. Diabetes 1989; 38 (suppl 1): 85-87.
Bathing donor-livers in University of Wisconsin solution SiR-Human donor livers are flushed in-situ with cold University of Wisconson organ preservative (UW). Then, after donor hepatectomy, these livers are usually bathed in UW in plastic bags stored on melting ice. A retrospective analysis of the magnetic relaxation times of 50 isolated human donor livers obtained from various hospitals showed that the relaxation times of the livers were all in the same range. A similar (narrow) range was found for the relaxation times of the bathing fluid. However, one exception was noted in which the bathing fluid had exceptionally long T1 (data not shown) and T2 (figure) relaxation times, closely resembling the relaxation times of saline. Liver parenchyma itself had relaxation times similar to livers that were known to be adequately perfused with UW. The preservation records