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Relation of ventricular premature complexes during recovery from a myocardial perfusion exercise stress test to myocardial ischemia.

Ventricular premature complexes (VPCs) during exercise have long been believed to be harbingers of increased mortality. A recent study has shown that VPCs during the recovery phase of a treadmill exercise test are more predictive of mortality than VPCs that develop during exercise. However, no study to date has examined the relation of VPCs in recovery to the presence of ischemia on myocardial perfusion imaging. We examined the database of perfusion imaging at the Duke University Medical Center from September 1993 to July 2003. We examined the incidence of VPCs during exercise, during the recovery phase, and during the 2 phases. Logistic regression modeling was used to evaluate the significance of VPCs during stress and during recovery in predicting ischemia. VPCs developed during recovery in 561 of 2,828 patients (19.8%). Compared with patients without VPCs during recovery, those with VPCs during recovery were more likely to have a history of hypertension (64.0% vs 56.9%, p = 0.002) and previous coronary artery bypass grafting (25.3% vs 17.1%, p = 0.001). They were also more likely to be older, men, and Caucasian, and to have 3-vessel coronary artery disease (31.9% vs 21.0%, p = 0.001). After adjusting for differences in patient characteristics, VPCs during recovery were significantly associated with ischemia (odds ratio 1.27, 95% confidence interval 1.04 to 1.56, p = 0.017), whereas VPCs during stress were not (p = 0.128). In conclusion, VPCs during the recovery phase of an exercise study are predictive of ischemia on myocardial perfusion imaging.

Adult↗

Detection of the site and extent of the left ventricular asynergy in myocardial infarction by echocardiography and B-scan imaging.

The left ventricular wall motions in 53 patients with myocardial infarction and 14 normal subjects were studied by echocardiography and B-scan imaging (ultrosono-cardiokymography, ultrasono-cardiotomography). (1) Abnormal left ventricular wall motions corresponding to the electrocardiographic sites of infarction were seen in the echocardiograms in 80 % of total patients and 100 % of acute cases. Exaggerated wall motion in opposing noninfarcted areas was seen in 50 % of acute cases and 10 % of old cases. Quantitative analysis of asynergy could be made by comparing PWE, SE and those ratios to EDD-ESD of infarcted hearts with those of normal hearts. (2) In acute myocardial infarction, abnormal motions of left ventricular wall are marked in acute phase and diminished in extent gradually in recovery phase. But in some cases, echo-demonstrated segmental dyskinesis did not disappear in recovery phase, possibly due to the presence of irreversible myocardial damage. (3) Echographic thickness of the infarcted wall was less increased then normals or was not increased during systole and decreased when bulged out in some cases, indicating the existence of necrotized muscle. Moreover, multiple echoes sometimes seen between endocardial and epicardial echoes of infarcted myocardium were considered to display the fibrosis of the infarcted myocardium. (4) Abnormal echocardiographic motions of septum and posterior wall were observed in some cases who had no electrocardiographic abnormalities which suggest septal or posterior wall involvement. Echocardiography could detect another affected area of the left ventricle which could not be detected by electrocardiography. (5) Echocardiography in combination with B-scan imaging (UCKG, UCTG) can detect not only the location, but also the size and extent of myocardial infarction. (6) The results of this study indicate that echocardiography and B-scan imaging (UCKG, UCTG) are sensitive methods in detecting the size and location of asynergy and making a precise diagnosis of myocardial infarction. But it is necessary to distinguish abnormal septal and posterior wall motions observed in right ventricular volume overload, complete LBBB or PMD(COCM) from those of myocardial infarction.

Echocardiography↗

[Pulmonary function in infants with respiratory syncytial virus bronchiolitis].

OBJECTIVE: To observe the dynamics of pulmonary function in infants with respiratory syncytial virus (RSV) bronchiolitis. METHODS: The to test the pulmonary function of 31 infants with RSV bronchiolitis during acute phase at admission was tested. Pulmonary fuction test was performed for the second time among 17 out of the 31 infants during the clinical recovery phase, and performed for the third time among 10 out of the 17 infants one week after discharge. In the meantime pulmonary function test was performed in 74 healthy infants as controls. RESULTS: During the acute phase of RSV bronchiolitis, the respiratory rate (RR), peak tidal expiratory flow (PTEF), peak tidal flow/tidal volume (PF/Ve), respiratory system resistance (Rrs), and functional residual capacity per kilogram (FRC/kg) were significantly increased, while the inspiratory tidal volume (Vi), inspiratory volume per kilogram (Vi/kg), expiratory tidal volume (Ve), percent of tidal volume to peak tidal expiratory flow (%V-PF), terminal flows/peak expiratory flow (25/PF), respiratory system compliance (Crs), and respiratory system compliance per kilogram (Crs/kg) were significantly decreased as compared with those in healthy infants. Ratio of mid-expiratory to mid-inspiratory flow (ME/MI) and respiratory system time constant (Trs) showed no statistically significant differences. The tidal breathing flow-volume (TBFV) loop displayed a concave expiratory curve. During the clinical recovery phase, the above abnormal indexes showed significant improvement, except for the %V-PF, 25/PF and Crs/kg which were still lower as compared with those in healthy infants, most indexes had returned to normal. The TBFV loop showed mild decelerating expiratory limb. One week after discharge all of the indexes returned to normal. CONCLUSION: In the acute phase of RSV bronchiolitis higher resistance in small airway and obstructive ventilatory disturbance can be seen. Some of the indexes remain abnormal during the clinical recovery phase. However, the abnormalities disappear in a short time. Pulmonary function test is a valuable way for surveillance of the course and prognosis of RSV bronchiolitis. %V-PF, 25/PF, and FRC/kg are sensitive indexes.

Bronchiolitis, Viral↗

[Six-month chronic toxicity study of miporamicin in rats].

A six-month oral toxicity test of the new macrolide antibiotic miporamicin (MPM) was carried out in male and female rats receiving the compound in feed at concentrations of 1,280, 3,200, 8,000, or 20,000 ppm. The animals were further observed for recovery for 2 months after the completion of the treatment period. 1. No death occurred at any dosage levels throughout the study period. The only notable signs observed were marginal blepharitis and aging-associated changes that were seen occasionally among the treated and control rats. There were no symptomatic changes of particular note. 2. Body weight, feed intake and water consumption data did not reveal any noticeable change. 3. The achieved test compound intake was 69 mg/kg/day for males and 82 mg/kg/day for females in the MPM-1,280 group, 176 mg/kg/day for males and 207 mg/kg/day for females in the MPM-3,200 group, 436 mg/kg/day for males and 519 mg/kg/day for females in the MPM-8,000 group, and 1,080 mg/kg/day for males and 1,280 mg/kg/day for females in the MPM-20,000 group. 4. No changes attributable to these treatments were noted in the hematological examination or serum biochemical tests. 5. Urinalysis disclosed mild changes with respect to urine volume, urinary electrolyte concentration and osmolarity. Animals recovered from all these changes during the recovery phase observation. 6. At gross pathologic examination a dose-related enlargement of the caecum was observed. The change disappeared or diminished following the 2-month recovery phase observation. 7. Organ weight analysis showed a dose-related increase of weight of the caecum. Animals recovered or abated in this respect during the 2-month recovery phase observation. 8. Histopathologic examination revealed no adverse toxicologic changes other than spontaneous or aging-associated ones. 9. No abnormalities were noted in the liver or in the kidneys as examined by electron microscopy. 10. The maximum non-effective level of MPM thus was estimated to be 20,000 ppm at which no organic damage occurred.

Administration, Oral↗

Karyometry of liver biopsies in virus hepatitis.

Liver biopsies from ten patients with clinically mild or moderate acute virus hepatitis, taken in the acute phase of the disease and in the recovery phase or later, were assessed for the size of liver cell nuclei and the number of binuclear nuclei. A parametric model of the distributions of the nuclear radii was used to estimate the mean nuclear radius of diploid nuclei and the frequencies of di-, tetra- and octaploid nuclei. During the acute phase of virus hepatitis the liver cell nuclei were often larger, with greater variation in size, than in the recovery phase. This pleomorphism was not only due to pyknotic and necrotic nuclei as these were not measured. It is assumed that the enlargment of the nuclei was due to increased metabolic activity of the nuclei. The frequencies of polyploid nuclei and binuclear liver cells were higher in the first biopsies, probably reflecting regenerative activity. No correlation was found between the severity of the disease as judged by liver histology or routine liver tests and the degree of nuclear changes with respect to size and frequency of polyploid or binuclear liver cells.

Acute Disease↗

[Dynamic 31phosphorus magnetic resonance spectroscopy of the quadriceps muscle: metabolic changes under 2 different forms of loading].

PURPOSE: The aim of the present investigation was to examine the metabolism of the quadriceps muscles of normal young individuals using dynamic 31phosphorus magnetic resonance spectroscopy. METHODS: 22 normal individuals were examined in a 1.5T-MRT using a 6 cm surface coil. The metabolic changes in the quadriceps muscle as shown by the phosphorus spectrum were evaluated during rest, exercise (isometric and isotonic exercise) and during a 36-second period of recovery. RESULTS: The Pi/PCr quotient rose from its resting value of 0.11 +/- 0.02 following exercise to a maximum of 0.83 +/- 0.47 (isometric) or 1.40 +/- 0.59 (isotonic) (difference p = 0.0001). Half-time recovery of Pi/PCr was 35 +/- 11 s or 31 +/- 10 s, respectively (p = 0.13). During the recovery phase Pi/PCr fell briefly but significantly below its rest value. Following an initial rise in pH, there was a continual fall. Minimum pH (6.68 +/- 0.21 and 6.53 +/- 0.27 respectively; p = 0.01) occurred in the early recovery phase. The recovery process of pH values lasted longer following isotonic than after isometric exercise (half-value recovery time 229 +/- 72 s and 146 +/- 55 s, respectively; p = 0.001). CONCLUSION: Compared with isometric exercise, isotonic stress is more expensive in terms of metabolism. Dynamic 31phosphorus MRT spectroscopy can differentiate changes in muscle metabolism during different forms of exercise.

Adult↗

Tension transients during steady lengthening of tetanized muscle fibres of the frog.

1. Steady lengthenings at different velocities (0.02-1.6 microns/s per half-sarcomere, temperature 2.5-5.5 degrees C) were imposed on isolated frog muscle fibres at the plateau of the isometric tetanus (tension T0). When tension during lengthening had attained a steady value (Ti), which varied from about 1.5 to about 2 times T0 depending on lengthening velocity, tension transients were elicited by applying step length changes of different amplitudes. The change in length of a selected segment, close to the end of the fibre connected to the force transducer, was controlled by means of a striation follower. 2. The instantaneous plots of tension versus the length change during the step itself showed that at the high forces developed during steady lengthening, as at the plateau of isometric tetanus, the elasticity of the fibre was almost undamped in the whole range of lengthening velocities used. 3. The tension transient elicited by step length changes imposed in isometric conditions exhibited the characteristic four phases described previously: following the tension change simultaneous with the step (phase 1), there was a quick partial recovery (phase 2, the speed of which increased going from the largest step stretch to the largest step release), a subsequent pause or inversion in recovery (phase 3) and finally a slower approach to the tension before the step (phase 4). 4. In the region of small steps the plot of the extreme tension attained during the step (T1) versus step amplitude appeared more linear during steady lengthening than in isometric conditions and deviated progressively from linearity with increase in the size of step releases. The amount of instantaneous shortening necessary to drop tension to zero (Y0), measured by the abscissa intercept of the straight line drawn through T1 points for small steps, was about 4.1 nm per half-sarcomere in isometric conditions and 5.4 nm per half-sarcomere during lengthening at low speed (0.09 microns/s per half-sarcomere, Ti about 1.6 T0). Taken altogether this indicates, in agreement with previous work, that force enhancement during steady lengthening is due to increase in both number and extension of attached cross-bridges. During lengthening at high speed (0.8 microns/s per half-sarcomere), further enhancement in steady force (Ti about 1.9 T0) was accompanied by increase of Y0 to 6.3 nm per half-sarcomere, indicating that increase in lengthening velocity exclusively produces increase in cross-bridge extension.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Branched-chain amino acid supplementation during bed rest: effect on recovery.

Bed rest is associated with a loss of protein from the weight-bearing muscle. The objectives of this study are to determine whether increasing dietary branched-chain amino acids (BCAAs) during bed rest improves the anabolic response after bed rest. The study consisted of a 1-day ambulatory period, 14 days of bed rest, and a 4-day recovery period. During bed rest, dietary intake was supplemented with either 30 mmol/day each of glycine, serine, and alanine (group 1) or with 30 mmol/day each of the three BCAAs (group 2). Whole body protein synthesis was determined with U-(15)N-labeled amino acids, muscle, and selected plasma protein synthesis with l-[(2)H(5)]phenylalanine. Total glucose production and gluconeogenesis from alanine were determined with l-[U-(13)C(3)]alanine and [6,6-(2)H(2)]glucose. During bed rest, nitrogen (N) retention was greater with BCAA feeding (56 +/- 6 vs. 26 +/- 12 mg N. kg(-1). day(-1), P < 0.05). There was no effect of BCAA supplementation on either whole body, muscle, or plasma protein synthesis or the rate of 3-MeH excretion. Muscle tissue free amino acid concentrations were increased during bed rest with BCAA (0.214 +/- 0.066 vs. 0.088 +/- 0.12 nmol/mg protein, P < 0.05). Total glucose production and gluconeogenesis from alanine were unchanged with bed rest but were significantly reduced (P < 0.05) with the BCAA group in the recovery phase. In conclusion, the improved N retention during bed rest is due, at least in part, to accretion of amino acids in the tissue free amino acid pools. The amount accreted is not enough to impact protein kinetics in the recovery phase but does improve N retention by providing additional essential amino acids in the early recovery phase.

Adult↗

Characterization of cytokine and iNOS mRNA expression in situ during the course of experimental autoimmune myocarditis in rats.

Ribonuclease protection assay was used to demonstrate mRNA expression of several cytokines as well as inducible NO synthase (iNOS), constitutive endothelial NO synthase (cNOS) and perforin in the myocardium during the course of experimental autoimmune myocarditis (EAM) in rats. Interleukin 2 (IL-2) appeared in the initial inflammatory phase (day 14), subsided in the maximum inflammatory phase (day 19) and disappeared by the recovery phase (day 25). mRNA of IL-3 beta, interferon gamma INF-gamma and tumor necrosis factor alpha (TNF-alpha) were detected only in the maximum inflammatory phase and iNOS also appeared for several days at this time. In contrast. IL-10 mRNA was detected after the maximum inflammatory stage and persisted into the recovery phase (days 25-36). Although transforming growth factor beta 1 (TGF-beta 1) could be detected in all phases, the expression was markedly enhanced in the maximum inflammatory phase and gradually diminished (around day 36) to basal levels. Perforin mRNA was not detected at any point in the disease. Besides macrophages and CD4 T cells, a number of neutrophils were found in the myocardium especially at peak inflammatory stage. We suggest that antigen (Ag) primed Ag presenting cells or macrophages interact with T cells (Th1) to produce IL-2 and subsequent IFN-gamma, which further activates macrophages in the myocardium. Consequently, TNF-alpha and iNOS may inflict tissue damage to myocardium. It is also suggested that TGF-beta) and one representative Th2 cytokine, IL-10, help inhibit inflammation. These findings suggest that Th1 and Th2 cytokines are produced at different stages of EAM and modulate the inflammation and the course of EAM.

Animals↗

Different recovery process of ST depression on postexercise electrocardiograms in women in standing and supine positions.

False-positive exercise test responses are frequently observed in women. To differentiate a false-positive from a true-positive test response, the effect of postures for recording a postexercise electrocardiogram to the recovery process of ST depression was investigated in 26 women with nonischemic ST depression and in 14 patients with typical angina pectoris. Exercise tests were performed twice, and the postexercise electrocardiogram was recorded while standing during the first test and in the supine position during the second test. In the false-positive test, maximal ST depression occurred immediately after exercise and showed a rapid recovery process in the early recovery phase. However, ST depression persisted without complete recovery, or increased in the late recovery phase as long as subjects were kept standing. In contrast, ST depression returned to the control level when subjects changed to the supine position after exercising. This discrepant pattern in the recovery process of ST depression by changing postures was not observed in the true-positive test results. Changing postures for recording postexercise electrocardiograms could be helpful in differentiating a false-positive response from a true ischemic response.

Adult↗

Propionate-initiated changes in intracellular pH in rabbit colonocytes.

BACKGROUND/AIMS: Because regulation of intracellular pH (pHi) is critical to basic cell functions, most cells have evolved mechanisms to closely regulate intracellular acid-base balance. Short-chain fatty acids (SCFAs), the predominant luminal anion in the colon, acidify the cell interior in several cell systems, but their effect on their "natural target," the colonocytes, has not been examined thoroughly. METHODS: We monitored the pHi response to a model SCFA, propionate, in isolated cells and epithelial sheets from rabbit proximal colon loaded with the pH-sensitive dye 2',7'-bis-(2-carboxyethyl)-5-(and -6)carboxyfluorescein. RESULTS: SCFAs induced a characteristic pHi response curve in colonocytes: an immediate acidification and a recovery phase returning to baseline in 100-200 seconds. Acidification was altered by increasing concentrations of SCFAs, by increasing SCFA chain length, extracellular osmolarity, and intracellular pH, and finally, Na+ removal. The recovery phase was slowed by amiloride and 4-alpha-OH cinnamate, an inhibitor of proton-monocarboxylate cotransport. CONCLUSIONS: Physiological concentrations of SCFAs have profound effects on intracellular pH. Simple diffusion of the SCFA may not explain the complexities of propionate-induced protonated acidification; the pH recovery phase may involve multiple processes including Na(+)-H+ exchange and H(+)-SCFA cotransport. Luminal constituents such as SCFAs may have significant effects on the intracellular pH and function of colonocytes.

Acid-Base Equilibrium↗

Theophylline metabolism after cardiac surgery.

The effect and metabolism of theophylline administration after cardiac surgery has never been reported. Two series of 2-hour intravenous aminophylline administrations (3 mg/kg/h) were conducted in 10 adult patients on the operative day (acute phase) and on the 4th or 5th postoperative day (recovery phase). Both blood and urine samples were collected for 24 hours after dosing. Heart rate increased in both phases, but the cardiac index increased with the decrease of diastolic blood pressure only in the acute phase (p < 0.05). Plasma concentration levels of theophylline tended to be slightly higher in the acute phase, and renal clearance increased in the recovery phase (p < 0.05). The urinary ratio of 3-methylxanthine to theophylline was significantly higher in the acute phase (p < 0.05). This suggests that cytochrome P4501A2 is partially activated rather than depressed and that N-demethylation is promoted more than hydroxylation immediately after surgery.

Adult↗

Effects of fibrin sealant-containing antibiotics in a rabbit model of chronic sinusitis.

Postoperative complications of sinus surgery include bleeding, infection, and synechiae. Improved subjective outcomes in humans treated with fibrin sealant (FS) after endoscopic sinus surgery (ESS) have been reported. Streptococcus pneumoniae was used to initiate chronic sinusitis in occluded rabbit sinuses in order to evaluate the role of FS in mucosal healing. Six weeks later, all animals had maxillary antrostomies. Homologous FS-containing ciprofloxicin (100 mg/mL) and clindamycin (15 mg/mL) was applied topically to treatment rabbits (n = 9). Control rabbits (n = 10) received no antibiotics. Two weeks into the recovery phase after antrostomies, all animals were re-examined. Mucociliary transport velocity (mean +/- standard deviation in mm/minute) was measured in all sinuses (n = 38) during healthy (100% measurable, 13.82 +/- 4.16), infected (18% measurable, 4.74 +/- 0.42), and recovery phases (5% measurable, 6.30 +/- 4.67). In both groups, mucopurulent discharge was present in the majority of sinuses (control group 18/20, FS group 16/18). In addition, there was no significant difference in the recovery phase between the two groups when comparing changes in the size of antrostomies, light microscopy, or culture clearance. Scanning electron microscopy did suggest a possible improvement in ciliary regeneration in the FS group. Application of FS-containing antibiotics did not appear to improve healing after ESS in our rabbit model of chronic sinusitis.

Animals↗

T lymphocyte subsets, suppressor and contrasuppressor cell functions, and production of interleukin-2 in the peripheral blood of rheumatic fever patients and their apparently healthy siblings.

We studied CD4 and CD8 T cell subsets, suppressor cell function, production of IL-2, and immune contrasuppressor cell activity in 21 patients with rheumatic fever (RF), both at the time of their first acute episode and 3 months later (recovery phase). As controls we studied their healthy sibling nearest in age, as well as age- and sex-matched unrelated normal subjects. In the acute phase we found CD4+ T cells to be high, concanavalin A-induced suppression to be low, and production of IL-2 to be significantly decreased, as compared to the normal unrelated controls. The addition of contrasuppressor cells (VV+) to cell cocultures resulted in an increase in proliferation by mononuclear cells (MNC) in response to streptococcal M antigen but not to C carbohydrate antigen. In the recovery phase, CD4+ T cells became normal, CD8+ T cells rose above normal, and the suppressor cell functions (concanavalin-A-induced and spontaneously expanded), as well as the production of IL-2, fell further. Siblings were found to have increased CD8+ T cells and decreased production of IL-2, as compared to the unrelated controls. These findings indicate that important immunoregulatory disturbances occur during the acute phase of rheumatic fever, some of which persist, accentuate, or change during the recovery phase. The findings in siblings could be related either to streptococcal infection or to a familial immunoregulatory aberration.

Adolescent↗

The elevated markers of hypercoagulability in children with Henoch-Schönlein purpura.

Twenty-eight children with HSP and 79 healthy children were entered into study. Activities of protein C, free-protein S and antithrombin, activated protein C resistance, levels of fibrinogen. D-dimer, thrombin-antithrombin complex (TAT), prothrombin fragments 1 + 2 (PF(1+2)), and von Willebrand factor antigen (vWAg) and its activity (RiCof) were investigated in acute and recovery phases of HSP and controls. Fibrinogen, D-dimer, TAT, PF(1+2), vWAg, and RiCof levels in patients with HSP during the acute phase were significantly higher than those of recovery phase and of the controls. A significant correlation was detected between severity of disease and TAT, PF(1+2), vWAg, and D-dimer levels.

Adolescent↗

A simple technique to determine thrombopoiesis level using immature platelet fraction (IPF).

Immature platelet fraction (IPF) has been measured by fully automated analyzer (XE-2100) as reticulated platelet (RP) which is reflected with thrombopoiesis in bone marrow. IPF value in the healthy volunteers was 3.3% (1.0-10.3) and upper 95% confidential interval (95% CI) of IPF was determined as 7.7%. IPF was significantly high in the patients with idiopathic thrombocytopenic purpura (ITP; 17.4%, 1.2-53.2%) and recovery phase of post-chemotherapy, and significantly low in nadir phase of post-chemotherapy, and within normal range in the patients with ITP in complete remission (CR) and with aplastic anemia (AA). Total count of IPF was significantly low in patients with ITP, AA or post-chemotherapy. Mean platelet volume (MPV) was significantly high in only patients with ITP. IPF 7.7% is best point for highest sensitivity (86.8%) and specificity (92.6%) in diagnosis of ITP and recovery phase of post-chemotherapy. In receiver operating characteristic curve for diagnosis of ITP and recovery phase of post-chemotherapy, IPF was significantly more useful than MPV. These results show that IPF reflects the pathology of thrombocytopenic disorders, and that measurement of IPF is useful for the differential diagnosis and analysis of platelet kinetics.

Adult↗

Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome.

Patients with the chronic fatigue syndrome (CFS) complain consistently of delay in recovery of peripheral muscle function after exercise. The purpose of this study was to try to confirm this observation. A fatiguing exercise test was carried out on the quadriceps muscle group of ten patients and ten control subjects. The test consisted of 18 maximum voluntary contractions (MVCs) with a 50% duty cycle (10 s contraction, 10 s rest), and the force generated by each contraction was recorded using a KinCom dynamometer. This was followed by a recovery phase lasting 200 min in which quadriceps strength was evaluated at increasing intervals, and a follow-up session at 24 h post-exercise involving three 10 s MVCs. Throughout the exercise period, the MVCs obtained from the control group were significantly higher than those of the patient group (P = 0.006), but both groups showed a parallel decline in force over the 18 contractions, in keeping with a similar endurance capacity. Recovery was prolonged in the patient group, however, with a significant difference compared to initial MVCs being evident during the recovery phase after exercise (P = 0.001) and also at 24 h (P < 0.001). In contrast, the control group achieved MVCs which were not significantly different from initial values during the recovery phase, and maintained these at 24 h. These findings support the clinical complaint of delayed recovery after exercise in patients with CFS.

Adult↗

Increase in peripheral blood megakaryocyte progenitors following cancer therapy with high-dose cyclophosphamide and hematopoietic growth factors.

Seven patients received cancer chemotherapy with high-dose cyclophosphamide (HD-CTX) associated with either recombinant human granulocyte colony-stimulating factor (rhG-CSF), rh interleukin-3 (rhIL-3), rh granulocyte-macrophage CSF (rhGM-CSF) plus rh erythropoietin (rhEpo), rhIL-3 plus rhGM-CSF, or rhIL-3 plus rhG-CSF. In the steady-state blood samples (before HD-CTX), megakaryocyte burst-forming units (BFU-Meg) and megakaryocyte colony-forming units (CFU-Meg) were virtually undetectable (< or = 1/mL BFU-Meg and CFU-Meg, range 0 to 1) by assaying unfractionated leukocytes. In contrast, in the recovery-phase blood samples (after HD-CTX), BFU-Meg and CFU-Meg increased several hundred-fold over steady-state values. This occurred regardless of the in vivo growth factors used and in parallel with increases in mixed, erythroid, and myeloid progenitors. In vitro, recovery-phase BFU-Meg and CFU-Meg responded to the novel GM-CSF/IL-3 fusion protein PIXY321 similarly as to optimal concentrations of rhIL-3 and rhGM-CSF. However, these progenitors differed from those in the steady state because BFU-Meg had faster duplication time and CFU-Meg prevailed numerically (CFU-Meg to BFU-Meg ratio 3.4 [recovery] vs. 0.52 [steady state]). Furthermore, soluble c-kit ligand/rh stem cell factor (rhSCF), in vitro in combination with rhIL-3 and rhGM-CSF or PIXY321, increased the size but not the number of colonies derived from recovery-phase BFU-Meg and CFU-Meg. These quantitative and qualitative changes occurring in circulating megakaryocyte progenitors contribute to the understanding of the rapid platelet recovery that occurs when peripheral blood hematopoietic progenitors elicited by HD-CTX and growth factor(s) are transplanted into patients treated with myeloablative chemoradiotherapy.

Adult↗