Cyclosporine A alleviates severe anaemia associated with refractory large granular lymphocytic leukaemia and chronic natural killer cell lymphocytosis

Large granular lymphocytic (LGL) leukaemia and chronic natural killer cell lymphocytosis (CNKL) are chronic indolent disorders often associated with neutropenia and constitutional symptoms. Severe anaemia occurs in about 20% of patients and is currently treated with corticosteroids followed by oral cyclophosphamide in non-responders. 30% of patients fail initial measures, and salvage therapy is inadequate. We describe three transfusion-dependent patients (two with T-LGL leukaemia, one with CNKL) refractory to corticosteroids, cyclophosphamide, and in one case fludarabine. Cyclosporine A (CSA) initiation resulted in prompt transfusion-independence and was well tolerated in all patients, making it an attractive alternative therapy for this disorder.     

Heterotopic heart transplantation: a radiographic review

Heterotopic heart transplantation can be performed in the presence of high pulmonary vascular resistance. The authors call attention to a rare, but potentially life-saving procedure.     

The effects of low-energy 60-Hz environmental electromagnetic fields upon the growth-related enzyme ornithine decarboxylase

People living in the industrial society of today are unavoidablyexposed to low-energy electromagnetic (EM) radiation. The potentialrisk to human health of such exposure has received much study.In this regard, numerous epidemiological studies have linkedexposure to low-energy EM fields to increased cancer risk. Weinvestigated the ability of low-energy 60-Hz EM fields to alterthe activity of ornithine decarboxylase (ODC) in a number ofestablished cell lines. The activity of ODC, the controllingenzyme in polyamine biosynthesis, has been shown to be elevatedin growing cells or tissues and during the process of tumorpromotion. A 1-h exposure to a 60-Hz EM field of an intensityof 10 mV/cm produced a 5-fold increase in ODC activity in humanlymphoma CEM cells and a 2- to 3-fold increase in mouse myelomacells (P3) relative to the unexposed cultures. Depending uponthe cell type, ODC activity increased during the 1-h exposureperiod and remain ed elevated for several hours after the fieldexposure ended. In another series of experiments, fields ofan intensity as low as 0.1 mV/cm for a 1-h period produced a30% increase in the activity of ODC in Reuber H35 hepatoma cellsgrown in monolayer culture. In the H35 cells, continuous exposureto the 60-Hz EM field (10 mV/cm) for periods of 2 and 3 h resultedin either no increase in ODC activity (2 h) or a decrease inenzyme activity (3 h) compared to the unexposed control cultures.The data is discussed in relation to possible molecular mechanismsof field-cell interaction, the importance of the exposure intervalsaltering cellular ODC activity and the potential ability of60-Hz EM fields to serve as a tumor promoting stimulus.     

Increased ornithine decarboxylase activity in cultured cells exposed to low energy modulated microwave fields and phorbol ester tumor promoters

Ornithine decarboxylase (ODC) is present in all nucleated cells and is the rate-limiting enzyme for synthesis of polyamines. In turn, the polyamines are required for DNA synthesis and cell growth. In Reuber H35 hepatoma cells, we show that ODC activity is increased by about 50% during exposure to a 1-h "athermal" (less than 0.1 degree C temperature rise) (450 MHz, 1.0 mW/cm2 peak-envelope-power) microwave field sinusoidally amplitude-modulated at 16 Hz. The increased activity of ODC persisted for several hours following the 1-h exposure to the field. A similar field amplitude-modulated at 60 and 100 Hz did not alter the hepatoma cell ODC activity. The stimulated ODC activity in the cultured cells that followed treatment with a phorbol ester tumor promoter (12-O-tetradecanoylphorbol-13-acetate) was further potentiated by prior exposure to the same low energy electromagnetic field. This field did not alter either basal or 12-O-tetradecanoylphorbol-13-acetate-stimulated DNA synthesis. We observed a similar increase in the basal ODC activity of cultures of two additional cell lines (Chinese hamster ovary; and 294T melanoma) exposed for 1 h to the amplitude-modulated field. Chinese hamster ovary cells exposed to the radio frequency field for 1 h also responded to subsequent treatment with 12-O-tetradecanoylphorbol-13-acetate by exhibiting a further increase in ODC activity. We have observed previously that the activity of this enzyme is increased in cultured cells following a transient exposure to a 60-Hz electric field. Altered ODC activity may serve as a sensitive and specific molecular marker of the transductive coupling of weak pericellular electromagnetic fields to biological systems.     

Transduction of umbilical cord blood CD34+ NOD/SCID-repopulating cells by simian foamy virus type 1 (SFV-1) vector

Foamy viruses are nonpathogenic retroviruses that offer unique opportunities for gene transfer into various cell types including hematopoietic stem cells. We used a simian foamy virus type 1 vector (SFV-1) containing a LacZ reporter gene with a titer of 1-5 x 10(6) viral particles/ml that was free of replication-competent retrovirus to transduce human umbilical cord blood CD34+ cells. Transduced CD34+ cord blood cells were transplanted into NOD/SCID mice and plated in serum-free methylcellulose culture to determine the transduction efficiency of human hematopoietic progenitor cells. A transduction efficiency of about 20% was obtained. At 6-10 weeks posttransplantation, human hematopoietic cell engraftment and marking were determined. Marrow from transplanted mice demonstrated human cell engraftment by the presence of human (CD45+) cells containing both CD19+ lymphoid and CD33+ myeloid cells. Serial sampling of NOD/SCID bone marrow revealed the presence of 6.7-14.0% CD45+ cells at 6 weeks posttransplant as compared to 3.6-27.2% CD45+ cells at 9-10 weeks posttransplant. Human progenitors examined from NOD/SCID bone marrow cells 9 weeks posttransplant revealed from 7.4 to 25.9% of the colonies exhibiting X-gal staining. Our study demonstrates the ability of a simian foamy virus vector to transduce the SCID-repopulating cell and offers a promising new gene delivery system for use in hematopoietic stem cell gene therapy.     

Polymorphonuclear leukocytes from patients with severe sepsis have lost the ability to degrade fibrin via u-PA

Fibrin persistence in the vasculature is an important complication of sepsis that can often lead to mortality. We have previously established that polymorphonuclear leukocytes (PMN) from healthy individuals have the capacity to degrade fibrin via urokinase-type plasminogen activator (u-PA). We have also demonstrated an increase in u-PA antigen in the plasma of patients suffering from septic shock. In this study, we investigate the hypothesis that PMN from patients with sepsis have lost their fibrinolytic ability and that this might contribute to the persistence of fibrin deposits. We show here that PMN from these patients do not express any u-PA activity, despite retaining some u-PA antigen. Additionally, thrombi prepared from the whole blood of the patients exhibit reduced endogenous lysis compared with those from healthy individuals. These data indicate that loss of fibrinolytic activity from PMN may be a contributing factor in fibrin persistence in the microvasculature in sepsis.     

Racial Disparities in Eligibility for Preemptive Waitlisting for Kidney Transplantation and Modification of eGFR Thresholds to Equalize Waitlist Time

BackgroundPatients may accrue wait time for kidney transplantation when their eGFR is ≤20 ml/min. However, Black patients have faster progression of their kidney disease compared with White patients, which may lead to disparities in accruable time on the kidney transplant waitlist before dialysis initiation.MethodsWe compared differences in accruable wait time and transplant preparation by CKD-EPI estimating equations in Chronic Renal Insufficiency Cohort participants, on the basis of estimates of kidney function by creatinine (eGFR_cr), cystatin C (eGFR_cys), or both (eGFR_cr-cys). We used Weibull accelerated failure time models to determine the association between race (non-Hispanic Black or non-Hispanic White) and time to ESKD from an eGFR of ≤20 ml/min per 1.73 m². We then estimated how much higher the eGFR threshold for waitlisting would be required to achieve equity in accruable preemptive wait time for the two groups.ResultsBy eGFR_cr, 444 CRIC participants were eligible for waitlist registration, but the potential time between eGFR ≤20 ml/min per 1.73 m² and ESKD was 32% shorter for Blacks versus Whites. By eGFR_cys, 435 participants were eligible, and Blacks had 35% shorter potential wait time compared with Whites. By the eGFR_cr-cys equation, 461 participants were eligible, and Blacks had a 31% shorter potential wait time than Whites. We estimated that registering Blacks on the waitlist as early as an eGFR of 24–25 ml/min per 1.73 m² might improve racial equity in accruable wait time before ESKD onset.ConclusionsPolicies allowing for waitlist registration at higher GFR levels for Black patients compared with White patients could theoretically attenuate disparities in accruable wait time and improve racial equity in transplant access.