Variations in the T-cell repertoire against HLA antigens in humans.

Allospecific anti-HLA class I antigen cytotoxic T-lymphocyte precursor frequencies (CTLpf) have been estimated in peripheral blood of healthy blood donors with responder stimulator combinations mismatched for one HLA-A,B antigen. The CTLpf ranged from 1 in 400 to 1 in 10,000, with most frequent values of 1 in 600 to 4000. The following observations were made: (1) CTLpf against the same HLA antigen vary among different responders; (2) CTLpf of one responder against various HLA antigens may be different; (3) "narrow" responders produce cytotoxic T lymphocytes that recognize only the private (stimulator) alloantigen, while "broad" responders produce mainly broadly cross-reactive cytotoxic T lymphocytes with public specificity. Split-well analysis shows that very few cytotoxic T lymphocytes of "broad" responders recognize the private alloantigen only. These individual variations are not dependent on the HLA phenotype, because they also occurred in unrelated HLA-identical responders stimulated against the same mismatched stimulator cells.     

Survival after transfusion in the Netherlands

Background Cost‐effectiveness analyses of blood safety interventions require estimates of the life expectancy after blood product transfusion. These are best derived from survival after blood transfusion, per age group and blood component type. Study design and methods In the PROTON (PROfiles of TransfusiON recipients) study transfusion recipient data was collected from a hospital sample covering 28% of the total blood use between 1996 and 2006 in the Netherlands. The dataset includes date of transfusion, blood component type transfused and recipient identification details. PROTON data were individually matched to mortality data of the Netherlands. Survival after first transfusion and after any transfusion was calculated, per blood component type and age group. PROTON mortality rates were compared to mortality rates in the general population. The results were used to estimate survival beyond the study period and to estimate life expectancy after transfusion. Results Of all 2 405 012 blood product transfusions in the PROTON dataset, 92% was matched to the national Dutch Municipal Population Register, which registers all deaths. After 1 year, survival after any transfusion was 65·4%, 70·4% and 53·9% for RBC, FFP and PLT respectively. After 5 years, this was 46·6%, 58·8% and 39·3% for RBC, FFP and PLT, respectively. Ten years after transfusion, mortality rates of recipients are still elevated in comparison with the general population. Conclusion Mortality rates of transfusion recipients are higher than those of the general population, but the increase diminishes over time. The mortality rates found for the Netherlands are lower than those found in comparable studies for other countries.     

Paying for blood donations: still a risk?

It is presently disputed whether studies indicating a higher risk of infectious diseases among paid blood donors are lessons of the past, or still hold relevance. Comparative studies published between 1968 and 2001 were assessed for a possible trend of change in the relative risk for infectious disease markers between paid and unpaid blood or plasma donors. Studies reporting that paid donors had lower risk were found, but most studies, including recent ones, continued to report that paid donors have higher rates of infectious disease markers than unpaid donors. By log-linear regression analysis of the relative risk estimates for infectious disease markers among paid and unpaid donors from 28 published data sets, evidence was not found to indicate that the difference in risk for infectious disease markers between paid donors and unpaid donors had diminished over time (P = 0.128, not significant). Paid donors are still more likely than unpaid donors to donate blood in the period during which infectious donations escape detection by blood-screening tests (the "window-period"). Therefore, paid donations have a higher risk that labile blood components (such as red blood cells and platelets) are infected. Additional safety measures for handling plasma donations, and the preparation, purification and viral-inactivation steps employed for the production of plasma derivatives, may render the difference in infectious disease marker rates in donors irrelevant for plasma products. However, not all viruses are inactivated and paid donors were repeatedly found to have higher frequencies of markers for emerging agents. In a quality system, critical steps of the process should be addressed, and selection of the donor population is one of the first steps in this process. It is advised that blood establishments present yearly reports (with complete and raw data) to authorities on the incidence and prevalence of infectious disease markers among their donors as an ongoing surveillance on the "quality" of their donor populations. Paid blood or plasma donors still have higher rates for infectious disease markers than unpaid donors.     

Systemic hematologic effects of PEG-rHuMGDF-induced megakaryocyte hyperplasia in mice

PEG-rHuMGDF injected daily in normal mice causes a rapid dose-dependent increase in megakaryocytes and platelets. At the same time that platelet numbers are increased, the mean platelet volume (MPV) and platelet distribution width (PDW) can be either decreased, normal, or increased depending on the dose and time after administration. Thus, PEG-rHuMGDF at a low dose causes decreases in MPV and PDW, MGDF at an intermediate dose causes an initial increase followed by a decrease in MPV and PDW, and PEG-rHuMGDF at higher doses causes an increase in MPV and PDW followed by a gradual normalization of these platelet indices. In addition to the expected thrombocytosis after 7 to 10 days of daily injection of high doses of PEG-rHuMGDF, a transient decrease in peripheral red blood cell numbers and hemoglobin is noted accompanied in the bone marrow by megakaryocytic hyperplasia, myeloid hyperplasia, erythroid and lymphoid hypoplasia, and deposition of a fine network of reticulin fibers. Splenomegaly, an increase in splenic megakaryocytes, and extramedullary hematopoiesis accompany the hematologic changes in the peripheral blood and marrow to complete a spectrum of pathologic features similar to those reported in patients with myelofibrosis and megakaryocyte hyperplasia. However, all the PEG-rHuMGDF-initiated hematopathology including the increase in marrow reticulin is completely and rapidly reversible upon the cessation of administration of PEG-rHuMGDF. Thus, transient hyperplastic proliferation of megakaryocytes does not cause irreversible tissue injury. Furthermore, PEG-rHuMGDF completely ameliorates carboplatin-induced thrombocytopenia at a low-dose that does not cause the hematopathology associated with myelofibrosis.     

Colorectal cancer extracellular acidosis decreases immune cell killing and is partially ameliorated by pH-modulating agents that modify tumor cell cytokine profiles

Tumor cells upregulate myriad proteins that are important for pH regulation, resulting in the acidification of the extracellular tumor microenvironment (TME). Abnormal pH is known to dampen immune function, resulting in a worsened anti-tumor immune response. Understanding how extrinsic alterations in pH modulate the interactions between immune cells and tumors cells will help elucidate opportunities for new therapeutic approaches. We observed that pH impacts the function of immune cells, both natural killer (NK) and T cells, which is relevant in the context of a highly acidic TME. Decreased NK and T cell activity was correlated with decreasing pH in a co-culture immune cell-mediated tumor cell-killing assay. The addition of pH-modulating drugs cariporide, lansoprazole, and acetazolamide to the co-culture assay was able to partially mitigate this dampened immune cell function. Treatment of colorectal cancer (CRC) cells with NHE1 inhibitor cariporide increased CRC cell-secreted cytokines involved in immune cell recruitment and activation and decreased cytokines involved in epithelial-mesenchymal transition (EMT). Cariporide treatment also decreased CRC cell shed TRAIL-R2, TRAIL-R3, and PD-L1 which is relevant in the context of immunotherapy. These experiments can help inform future investigations into how the pH of the tumor microenvironment may be extrinsically modulated to improve anti-tumor immune response in solid tumors such as colorectal cancer.     

Simultaneous measurement of gallbladder emptying with cholescintigraphy and US during infusion of physiologic doses of cholecystokinin: a comparison

Both ultrasonography (US) and cholescintigraphy are used to study gallbladder dynamics. The present study was undertaken to determine whether the two methods provide the same or different information relating to gallbladder emptying. Emptying was simultaneously studied with both methods during infusion of graded physiologic doses of cholecystokinin (CCK) in six healthy subjects. Infusion of stepwise increasing doses of CCK, ranging from 0.03 to 0.5 Ivy dog units per kilogram of body weight per hour (IDU/kg.h), induced significant dose-related increases in plasma CCK, decreases in gallbladder volume assessed with US, and gallbladder emptying assessed with cholescintigraphy. The threshold dose for inducing significant gallbladder emptying was 0.13 IDU/kg.h, as determined with both techniques, indicating similar detection limits. There was a highly significant correlation between decreases in gallbladder volume and decreases in radioactive counts over the gallbladder region, with a tendency toward greater gallbladder responses at sonography during the early phase of gallbladder contraction and toward greater responses at cholescintigraphy during the later phase of gallbladder contraction. It is concluded that these methods can be used interchangeably for the quantitation of gallbladder emptying.     

Major motor atrophic patterns in the face and neck: CT evaluation

Cranial nerve deficits from various pathologic processes of the head and neck may result in characteristic patterns of denervation muscular atrophy. Such atrophic patterns may be clues to the location and extent of the lesion, particularly when cranial nerves are involved early in the course of the disease process. Thirty-six patients with computed tomographic (CT) evidence of muscular atrophy secondary to pathologic conditions involving the motor division of cranial nerves were examined. Five characteristic denervation muscular atrophy patterns seen on CT scans were identified. In several patients, identification of the muscular atrophy pattern was the only clue to the presence of a pathologic condition. Recognition of these atrophic patterns can prevent misinterpretation of their CT appearance and direct the CT examination to the course of the compromised cranial nerve from the brainstem to its peripheral innervation.