Conventional allografting produces considerable regimen-related toxicities that generally limit this treatment to patients younger than 55 years and in otherwise good medical condition. T cell-mediated graft-versus-tumor (GVT) effects are known to play an important role in the elimination of malignant disease after allotransplants. A minimally myelosuppressive regimen that relies on immunosuppression for allogeneic engraftment was developed to reduce toxicities while optimizing GVT effects. Pre-transplant total-body irradiation (200 cGy) followed by post-transplant immunosuppression with cyclosporine (CSP) and mycophenolate mofetil (MMF) permitted human leukocyte antigen (HLA)-matched sibling donor hematopoietic cell engraftment in 82% of patients (n = 55) without prior high-dose therapy. The addition of fludarabine (90 mg/m(2)) facilitated engraftment in all 28 subsequent patients. Overall, fatal progression of underlying disease occurred in 20% of patients after transplant. Non-relapse mortality occurred in 11% of patients. Toxicities were low. Grade 2-4 acute graft-versus-host disease (GVHD) associated with primary engraftment developed in 47% of patients, and was readily controlled in all but two patients. Donor lymphocyte infusions (DLI) were not very effective at converting a low degree of mixed donor/host chimerism to full donor chimerism; however, the addition of fludarabine reduced the need for DLI. With a median follow-up of 244 days, 68% of patients were alive, with 42% of patients in complete remission, including molecular remissions. Remissions occurred gradually over periods of weeks to a year. If long-term efficacy is demonstrated, such a strategy would expand treatment options for patients who would otherwise be excluded from conventional allografting.

The development of nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) from the preclinical studies to the clinic has permitted the treatment of a larger number of patients who previously had not been candidates for the standard approach with myeloablation. This includes older patients and those patients who had contraindications to intensive cytotoxic regimens. Regimen-related toxicities (RRT) after myeloablation result in prolonged periods of hospitalization and the development of significant morbidity and potential mortality including veno-occlusive disease and idiopathic interstitial pneumonitis. Severe RRT can generally be avoided after nonmyeloablative conditioning. A graft-versus-leukemia reaction is critical to the eradication of many hematological malignancies after transplantation and has been shown to be effective in those patients who have been infused with lymphocytes from the donor (DLI) after relapse.

We read with interest the recent report by Bolan et al (2001) which summarized the experience at the National Institutes of Health with regard to haemolytic complications from minor ABO incompatibility after human leucocyte antigen (HLA)-matched sibling, non-myeloablative peripheral blood stem cell (PBSC) transplantation. The authors reported two severe cases of delayed immune haemolysis owing to a 'passenger lymphocyte syndrome' in nine consecutive patients given non-myeloablative transplants. One of the patients died on post-transplant d 16 owing to multiorgan failure resulting from severe haemolysis; the other required multiple red blood cell transfusions but eventually recovered with complete resolution of haemolysis. Haemolysis developed on post-transplant d 7 and 10 respectively. Both patients received cyclophosphamide and fludarabine as their preparative non-myeloablative regimen, and cyclosporine (CSA) alone was given for post-grafting immunosuppression. This relatively high incidence of a passenger leucocyte syndrome with associated fatal haemolysis is concerning. Minor ABO mismatches constitute approximately 30% of all conventional haematopoietic stem cell transplants, and clinically detectable haemolysis has been reported in 10–30% of patients (Gajewski et al, 1992). Two types of haemolysis owing to minor ABO incompatibility can be distinguished. 'Early' haemolysis is caused by haemagglutinins (HA) present in the plasma of marrow or PBSC products. In contrast, 'delayed' haemolysis is owing to active antibody production by transplanted donor lymphocytes. Although delayed haemolysis is usually mild and self-limited, it has been associated with severe haemolytic episodes (Sniecinski & O'Donnell, 1999). Non-myeloablative haematopoietic cell transplantation is a relatively novel treatment approach (McSweeney & Storb, 1999; Carella et al, 2000). It entails preparative regimens and post-grafting immunosuppression aimed at preventing graft rejection and clinically intolerable graft-versus-host disease while relying on graft-versus-tumour effects for disease eradication. At our institution, the non-myeloablative preparative regimen consists of fludarabine, 30 mg/m2, given on d −4, −3 and −2, and total body irradiation (200 cGy) administered on d 0, which is followed by infusion of unmodified PBSC. CSA (6·25 mg/kg p.o. b.i.d.) and mycophenolate mofetil (MMF) (15 mg/kg p.o. b.i.d.) given for post-grafting immunosuppression are started on d −3 and d +1 respectively. The advantage of this approach is a considerable reduction in early regimen-related toxicities compared with myeloablative transplantation. Whether non-myeloablative regimens confer a greater risk for developing delayed haemolytic complications is currently unknown. Based on our institutional experience, this complication has only been seen in 2 out of 40 (5%) HLA-matched non-myeloablative PBSC transplants (23 with related donors; 17 with unrelated donors) in which minor ABO incompatibility was present. Our first patient who developed this complication was a 52-year-old woman with chronic myelogenous leukaemia who showed severe haemolysis 10 d after transplant from a major and minor ABO-mismatched, HLA-matched unrelated female donor (unpublished observations). She fully recovered from this complication and is alive and well more than 5 months later. The second patient, a 38-year-old male with chronic myelogenous leukaemia, developed hyperacute graft-versus-host disease of the skin and haemolysis on d 7 following a transplant from a minor ABO-mismatched, HLA-matched unrelated male donor. He experienced an initial 10% decline in his haematocrit over a 24-h period and has ongoing mild haemolysis owing to destruction of host red blood cells (RBCs) by donor HAs. He is currently 3 weeks post transplant and otherwise doing well. Graft-versus-host disease is under control after initiation of methylprednisolone therapy on post-transplant d 12. The higher incidence of a passenger leucocyte syndrome reported by Bolan et al (2001) than in our series (22% versus 5%) may be owing to differences in the kind of post-grafting immunosuppression used. Under steady-state conditions, B cells producing naturally occurring HAs are under T-cell control. However, after transplantation of PBSC into ABO-mismatched hosts, HA-producing B cells might escape T-cell control when T-cell activation is blocked by CSA given for post-grafting immunosuppression. Accordingly, one report described that the use of CSA alone was associated with a relatively high incidence of severe delayed haemolysis in myeloablative haematopoietic cell transplantation (Gajewski et al, 1992). Bolan et al (2001) used CSA only whereas in our series CSA was given in combination with the antimetabolite MMF (Niederwieser et al, 2000). In vitro and in vivo data suggest that MMF is a potent suppressor of both T- and B-cell activity (Allison & Eugui, 1996). Delayed haemolysis has rarely been described in patients given the antimetabolite methotrexate (MTX) either alone or in combination with T-cell activation blockers CSA or FK 506. Presumably, MTX not only inhibited proliferation of T cells but also of HA-producing B cells. There are two principal differences between MTX and MMF which may explain why delayed haemolysis was seen in a minority of MMF/CSA-treated non-myeloablative recipients. First, MTX has a long circulating half-life of 7·2 h compared with only 3·6 h for MMF (John Slattery, personal communication). Second, MTX binds firmly to dihydrofolate reductase with a 300-fold higher affinity than folic acid, while the bond of MMF to inosine monophosphate dehydrogenase is rapidly reversible. Thus, the currently used twice-a-day dosing of MMF may provide only suboptimal immunosuppression, thereby permitting antigen-primed B cells to 'escape'. Whether the low-intensity pretransplant conditioning used for non-myeloablative haematopoietic blood cell transplantation, which may leave the host's antigen-presenting machinery relatively intact, results in more potent stimulation of donor memory B cells with pronounced recall antibody production and, thereby, an overall greater risk of a passenger leucocyte syndrome is unclear. Nevertheless, based on Bolan et al (2001), the use of CSA alone compared with CSA plus MMF for post-grafting immunosuppression appears to be associated with an increased risk of severe delayed haemolysis in minor ABO-mismatched non-myeloablative transplant recipients. Until more experience has been gained with non-myeloablative transplants, these patients deserve close attention regarding signs and symptoms of this potentially life-threatening haemolytic complication during the early post-transplant period.

The myeloablative doses of chemotherapy and radiation used with conventional allogeneic hematopoietic cell transplantation produce considerable morbidity and mortality that generally limit this treatment to patients younger than 55 years of age and in good general medical condition. It has become clear that T-cell-mediated graft-versus-tumor effects play an important role in the elimination of malignant disease after allotransplants. Several investigators have sought to reduce regimen-related toxicities while optimizing graft-versus-tumor effects. Strategies can be broadly categorized as reduced-intensity regimens that retain some toxicities and require hospitalization, and minimally myelosuppressive regimens that rely on immunosuppression for allogeneic engraftment and resultant graft-versus-tumor effects. The latter approach can be performed in the ambulatory care setting. Preliminary results are encouraging. If long-term efficacy is demonstrated, such strategies would expand treatment options for patients who would otherwise be excluded from receiving conventional allografts.

Conventional myeloablative allogeneic hematopoietic cell transplantation produces considerable morbidity and mortality. These generally limit this treatment to patients in good medical condition who are younger than 55 years of age. T-cell-mediated graft-versus-tumor effects play a key role in the elimination of malignancy after allografting. Several investigators have sought to reduce regimen-related toxicities while optimizing graft-versus-tumor effects. Strategies can be broadly classified as (1) reduced-intensity regimens that retain some toxicity, and (2) minimally myelosuppressive regimens that rely on immunosuppression for allogeneic engraftment and resultant graft-versus-tumor effects. Although follow-up has been short, preliminary results are encouraging. Current challenges include defining a regimen that will facilitate full donor engraftment while minimizing toxicities and graft-versus-host disease. If long-term efficacy is demonstrated, such strategies will expand the options for patients who would not qualify for conventional allogeneic transplants.

When an insulator, sandwiched between metals of dissimilar work functions, is irradiated with x-radiation, a voltage related to the contact potential difference of the metals is observed. This phenomenon, known as the bulk photovoltaic effect, has been demonstrated in a variety of metal-insulator-metal combinations. Evidence that the voltage is not generated by junctions, barrier layers, or similar other phenomena is presented.

Annals of the New York Academy of SciencesVolume 110, Issue 1 p. 343-348 ANESTHESIA AND ITS RELATIONSHIP TO BODY COMPOSITION Louis Feinstein, Louis Feinstein United States Department of Agriculture Beltsville, Md.Search for more papers by this authorRichard L. Hiner, Richard L. Hiner United States Department of Agriculture Beltsville, Md.Search for more papers by this author Louis Feinstein, Louis Feinstein United States Department of Agriculture Beltsville, Md.Search for more papers by this authorRichard L. Hiner, Richard L. Hiner United States Department of Agriculture Beltsville, Md.Search for more papers by this author First published: September 1963 https://doi.org/10.1111/j.1749-6632.1963.tb17099.xCitations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume110, Issue1Body Composition Part ISeptember 1963Pages 343-348 RelatedInformation

Measurements were made of the gammaray emission of single hams from 34 hogs, using a sensitive low level gamma-ray detector. The hams were then separated by physical dissection into separable lean, separable fat, bone, and skin so that the gammaray measurements could be evaluated as to their usefulness for predicting ham composition. The separable lean content of the hams ranged from 6.5 to 11.7 lb., averaging 9.27 lb. Net counts per minute from potassium-40 were highly related (r=0.96) to pounds of separable lean. The sample standard deviation from regression was 0.38 lb. of separable lean. There was a much lower degree of correlation (r=0.47) between net counts per minute from the fission product cesium-137 and pounds of separable lean. The average ratio of cesium-137/potassium-40 gamma ray emission was the same for the rations fed (0.25) as for the intact hams.

WITH the development of highly sensitive γ-ray detectors, it has become possible to carry out nondestructive measurements of the low levels of γ-ray activity emitted by various biological materials. Since γ-ray measurements may be made rapidly without any special preparation or modification of the material measured, the application of this technique to agricultural research problems has much to recommend it. The advantages of the nondestructive γ-ray measurement technique appear to justify exploratory research to determine if such measurements may be used to estimate other factors to which they may be related1.

The results of a study in which measurements were made of the beta radioactivity emitted by the ash of ham fat trimmings samples and samples with variable proportions of ham lean and fat trimmings from 34 hogs are presented. There is evidence of a relationship between the amount of beta radioactivity emitted, expressed on a fresh weight basis, and the percent of fat-free lean (fresh basis). Data pertaining to the correlation of beta radioactivity and the content of ether extract, protein and moisture in these samples are presented.

A mechanical method of determining dispersibility of nonfat dry milk using a Hobart Model 3C Kitchen Aid Mixer is described. A 5-sec. stirring time is used which gives better differentiation of grades than can be obtained by previously described procedures using longer stirring times. The mixture is screened and the amount of solids dispersed is determined by a hydrometric procedure developed for this purpose. The hydrometric procedure used was demonstrated to be as accurate as gravimetric determination of solids by oven drying. The approximate percentages of various types of nonfat dry milks dispersed using this procedure are: instant, 80%; ordinary spray-dried, 37%; and roller-dried, 0%. The differences in dispersibility observed between various brands of instant milks are large enough to be significant for grading purposes. The procedure, besides readily separating nonfat dry milk into dispersibility classes, has the feature of being very fast, the whole procedure requiring only 10min.

A simple spot-color test is described for use with nonfat dry milk, to estimate the amount of undenatured protein present and the baking quality. This method consists of precipitating casein and denatured whey proteins with 0.5% acetic acid and spotting the supernatant on filter paper. The paper is dried, stained with 0.1% bromphenol blue in ethanol saturated with mercuric chloride, washed with water, and dried. The intensity of the blue stain is used to estimate undenatured whey protein. The undenatured whey protein content of 17 samples was estimated by this technique. Samples of good baking quality and low undenatured whey-protein contents give pale spots, with characteristic diffuse edges. Results from 20 samples of nonfat dry milk show that this method is also satisfactory for estimating baking quality.