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.     

THE RELATIONSHIP OF HAEMOGLOBIN TO SERUM ERYTHROPOIETIN CONCENTRATIONS IN THE ANAEMIA OF RHEUMATOID ARTHRITIS: THE EFFECT OF ORAL PREDNISOLONE

Previous studies of the erythropoietin response to anaemia inRA have yielded conflicting findings. Some have found the responseto be impaired and others have found a normal response. We havecompared erythropoietin (EPO) levels measured by radioimmunoassay,in 54 anaemic rheumatoid patients and 55 patients with irondeficiency anaemia but no inflammatory disease. The erythropoietin response in the rheumatoid patients was impairedcompared with the control group (P < 0.025) but only sevenrheumatoid patients showed a response which fell below the 95%confidence intervals predicted for the control group. Rheumatoidpatients who fell within the highest quartile for serum ferritinconcentrations (i.e. those most likely to have anaemia of chronicdisease) had significantly lower EPO levels compared with thecontrol group (P < 0.01). EPO levels in rheumatoid patientswithin the lowest quartile for ferritin (i.e. those with irondeficiency anaemia) were not significantly different from thecontrol group (P = 0.670). The difference in EPO response betweenthe RA patients in the upper and lower quartile for ferritinapproached but did not achieve significance (P = 0.056). Ina second study 15 anaemic RA patients were given a 5-day courseof oral prednisolone 1.5 mgkg^-1. Haemoglobin did not rise significantlyuntil day 4 but EPO levels fell by day 1 (P < 0.005) andremained lower than pretreatment values throughout the study.Thus, in RA patients, anaemia of chronic disease is associatedwith inappropriately low EPO concentrations but this does notappear to be the major cause of the anaemia and Hb responseto prednisolone does not depend upon an increase in EPO concentration. KEY WORDS: Rheumatoid arthritis, Anaemia of chronic disease, Erythropoietin, Prednisolone     

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.     

A communications seminar series for general practice residents

This article describes a seminar series for general practice residents dealing with communication, interpersonal relations, self-image, and patient-dentist interactions. Objectives, content, and methods of evaluation are presented.     

Signal-Averaged ECG Prior to and Serially After Thrombolytic Therapy for Acute Myocardial Infarction

Signal averaging has been performed to evaluate late potentials following infarction and the administration of thrombolytic therapy. Most studies have recorded signal-averaged electrocardiograms (SAECGs) at least 12 hours after the onset of the infarction. In this study, SAECGs were recorded before thrombolytic therapy and serially over 7–10 days following infarction in 21 patients. The high frequency QRS duration was significantly shortened at 1 and 24 hours compared to presentation (96.8 ± 11.3 ms and 93.4 ± 8.0 ms vs 103.3 ± 14.3 ms, respectively, P < 0.05) and there was an increase in the terminal voltage over time, significant at 1 hour and 3 days (57.3 ± 29.1 μV and 58.6 ± 44.7 μV vs 44.4 ± 35.5 μV, respectively, P < 0.01). Five patients met criteria for ventricular late potentials on at least one SAECG. The prevalence of late potentials was higher in patients with Q wave infarctions, or with occluded infarct related arteries. These changes in myocardial activation may be related to ischemia and reperfusion, and may not correlate with the development of a fixed substrate for reentry.     

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.     

Cardiovascular studies with impromidine (SK&F 92676), a new very potent and specific histamine H2-receptor agonist

Impromidine (SK & F 92676) has recently been identified as a potent and specific histamine H₂-receptor agonist. The present paper describes some cardiovascular studies with the drug. Impromidine lowers blood pressure in cats and rats by interaction with H₂-receptors. During continuous intravenous infusions of impromidine, the fall in blood pressure is due to a reduction in total peripheral resistance; cardiac output increases during hypotension. The responses to impromidine are similar to responses to histamine in mepyramine-treated cats. Impromidine administered intra-arterially also causes vasodilatation in the femoral and mesenteric vasculature by interaction with H₂-receptors. Impromidine stimulates all measured parameters including coronary flow in the isolated working heart of the guinea-pig. Dose-response curves to impromidine were displaced to the right in the presence of cimetidine.