Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes

Vascular endothelial growth factor (VEGF) inhibits differentiation and maturation of dendritic cells (DC), suggesting a potential immunosuppressive role for this proangiogenic factor. Bevacizumab, sorafenib and sunitinib target VEGF-mediated angiogenesis and are active against several types of cancer, but their effects on the immune system are poorly understood. In this study, VEGF and supernatants of renal carcinoma cell lines cultured under hypoxia were found to alter the differentiation of human monocytes to DC. Resulting DC showed impaired activity, as assessed by the alloreactive mixed T-lymphocyte reaction. Bevacizumab and sorafenib, but not sunitinib, reversed the inhibitory effects of VEGF, but not of those mediated by tumour supernatants. Dendritic cells matured under the influence of VEGF expressed less human leukocyte antigen-DR (HLA-DR) and CD86, and this effect was restored by bevacizumab and sorafenib. Finally, tumour-cell supernatants decreased interleukin-12 (IL-12) production by mature DC, and such inhibition was not restored by any of the tested drugs, delivered either as single agents or in combination. The deleterious effects of tumour-cell supernatants were mainly mediated by thermostable molecules distinct from VEGF. These results indicate that inhibition of the differentiation of monocytes to DC is a multifactorial effect, and that they support the development of combinations of angiogenesis inhibitors with immunological modulators.     

Changes in Morphology of the Paced QRS Complex Related to Pacemaker Output

The influence of pacemaker output on the morphology of the paced QRS complex was studied from standard lead electrocardiograms in 69 patients with bipolar pacemakers. In 40 of the 69 patients (58%), there was a significant (P less than 0.001) change in electrical axis, from -75 degrees at the low output setting (2.7 V, 0.15 msec) to -67 degrees at the high output setting (8.1 V, 2.29 msec). In 30 patients, these changes were also associated with changes in the QRS morphology and in the T-wave. This phenomenon may be explained by additional stimulation from the proximal electrode at high output, thus altering the pattern of depolarization.     

Upper Rate Pacing After Radiofrequency Catheter Ablation in a Minute Ventilation Rate Adaptive DDD Pacemaker

A 58-year-old man with an implanted minute ventilation rate adaptive DDD pacemaker underwent RF ablation of the AV junction because of symptomatic supraventricular tachyarrhythmias. Immediately after ablation, while the pacemaker was programmed in the DDDR mode, AV sequential pacing at upper rate was observed. After programming the pacing system to the DDD mode and repeated ablation, no abnormalities were observed. It was concluded that AV sequential upper rate pacing was caused by false interpretation of the RF current by the sensor measuring transthoracic impedance as an indicator for minute ventilation.     

Myopotential Interference Inducing Pacemaker Tachycardia in a DVI Programmed Pacemaker

A 67-year-old male, suffering from ventricular tachycardia unresponsive to drug therapy, received a universal AV sequential pacemaker (DDD,M). Tim pacemaker was programmed in the DVI mode, pacing role 100 bpm, AV interval 250 ms. After implantation, the patient experiences two episodes of tachycardia that proved to be pacemaker tachycardia with a rate of 150 bpm. The first period was self-terminating, and the second had to be stopped by reprogramming the pulse generator. Pacemaker tachycardia could easily be provoked by instructing the patient to contract the pectoral muscle adjacent to the pulse generator. To our knowledge, this is the first report to pacemaker tachycardia provoked by myopotentials in a pulse generator programmed in the DVI mode.     

Enhancement of t lymphocyte functions by Fc fragments of immunoglobulins. I. Augmentation of allogeneic mixed lymphocyte culture reactions requires I-A- or I-B-subregion differences between effector and stimulator cell populations

Fc fragments derived from human Ig were found to be capable of enhancing T cell-mediated, antigen-induced proliferative and mixed lymphocyte culture responses. Maximum enhancement occurred when suboptimal amounts of antigen or suboptimal numbers of stimulator cells were employed. Augmentation of the allogeneic mixed lymphocyte culture reaction requires an I-A and/or I-B subregion difference between effector and stimulator cell populations. Although a significant proliferative response was observed with K- or D- region differences, Fc fragments were unable to enhance the response. The T cell population acted upon by Fc fragments in the potentiation of these responses bears the Lyt-1(+)23(-) phenotype.     

Seroprevalence of human T-lymphotropic virus, hepatitis C virus, and human immunodeficiency virus in Asian American potential bone marrow donors

BACKGROUND: Asian Americans are generally underrepresented both as volunteer blood and bone marrow donors. STUDY DESIGN AND METHODS: To investigate the risk of transfusion transmission of viruses that is associated with increasing participation by Asian American donors, antibodies to human T-lymphotropic virus (HTLV), hepatitis C, and human immunodeficiency virus in Asian American volunteers recruited as potential bone marrow donors were measured. A total of 1354 Asian Americans were enrolled in the study, of whom 54 percent were Chinese, 26 percent Japanese, 9 percent Filipino, 4 percent Korean, 3 percent Indian, and 5 percent of other Asian or mixed Asian and other ethnicity. The majority of the study population was aged 20 through 49 and of high socioeconomic status, as indicated by education and income. Viral antibodies were measured with both screening enzyme-linked immunosorbent assays and supplemental testing, and polymerase chain reaction was used to resolve discrepant HTLV results. RESULTS: Confirmed seroprevalence rates for HTLV were 0.15 percent with one manufacturer's Western blot and 0.3 percent with the other; however, no sample was positive for HTLV types I or II in polymerase chain reaction. Confirmed seroprevalence to hepatitis C virus was 0.5 percent. No subject was seropositive for human immunodeficiency virus. CONCLUSION: On the basis of the moderate size and high education level of this study population, it is concluded that Asian American volunteer bone marrow donors do not pose a greater risk for transmission of HTLV type I or II, human immunodeficiency virus, or hepatitis C virus than does the average American blood donor.     

Fusion or Confusion on Holter Recording

Holter recording of a patient with an implanted dual chamber rate responsive pacemaker revealed an electrocardiogram, where ventricular depolarization seemed to be initiated by the atrial stimulus. In a second patient with a VVI pacemaker, Holter recording showed delay of the pacemaker impulse that was registered after the onset of ventricular depolarization. Misalignment in one of the recorder heads of the display system was responsible for this phenomenon, which in case of dual chamber pacing could have been easily misinterpreted as pacemaker malfunction.     

Cytokine generation in stored platelet concentrates

BACKGROUND: Cytokines, because of the nature of their immunoinflammatory actions, are potential mediators of the symptom complex of nonhemolytic transfusion reactions. One possible source of cytokines in the transfusion setting is the stored blood component itself. STUDY DESIGN AND METHODS: To test this possibility, the plasma portion of stored platelet concentrates (PCs) was assayed for the presence of interleukins 1 beta (IL-1 beta), 6 (IL-6), and 8 (IL-8) and tumor necrosis factor alpha (TNF-alpha). Samples were taken from PCs obtained from the inventory of a regional blood center (n = 120; 30 each of 2-, 3-, 4-, and 5-day-old units). RESULTS: Detectable levels of IL-8 were measured in 59 percent of the PCs sampled, ranging from 30 percent of the 2-day-old units to 83 percent of the 5-day-old units. The median IL-8 concentration ranged from undetectable levels in 2-day- old units up to 1100 pg per mL in 5-day-old units. The mean IL-8 concentration in 5-day-old units, 11,600 pg per mL, was 100 times the mean for 2-day-old units, which was 116 pg per mL (p < 0.0001). The highest levels of IL-8, 50,000 to 200,000 pg per mL, in general were found in units with the longest storage times and highest white cell counts. Sequential sampling of 17 individual PCs over 7 days of storage confirmed that IL-8 increases progressively with increasing storage time. Parallel, but smaller, increases in IL-1 beta were observed in those units with high IL-8 concentrations. TNF-alpha was detected in 3 (10%) of 30 five-day-old PCs, but never exceeded 55 pg per mL in any unit tested. IL-6 at levels of 740 and 508 pg per mL was detected in two 5-day-old units with high white cell counts of 9500 and 14,800 per microL, respectively, but not in 21 additional units tested with white cells < or = 9200 per microL or storage time of < or = 2 days. White cell reduction by third-generation filters on Day 1 of platelet storage prevented the generation of IL-8 and IL-1 beta to Day 5 of storage. CONCLUSION: Although IL-8 achieved levels in some units of PCs that appear capable of causing physiologic changes, the potential adverse effect on transfusion recipients of the infusion of cytokines in PCs remains to be investigated.