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Recent studies show that pre-stimulus band-specific power and phase in the electroencephalogram (EEG) can predict accuracy on tasks involving the detection of near-threshold stimuli. However, results in the auditory modality have been mixed, and few works have examined pre-stimulus features when more complex decisions are made (e.g. identifying supra-threshold sounds). Further, most auditory studies have used background sounds known to induce oscillatory EEG states, leaving it unclear whether phase predicts accuracy without such background sounds. To address this gap in knowledge, the present study examined pre-stimulus EEG as it relates to accuracy in a tone pattern identification task. On each trial, participants heard a triad of 40-ms sinusoidal tones (separated by 40-ms intervals), one of which was at a different frequency than the other two. Participants' task was to indicate the tone pattern (low-low-high, low-high-low, etc.). No background sounds were employed. Using a phase opposition measure based on inter-trial phase consistencies, pre-stimulus 7-10 Hz phase was found to differ between correct and incorrect trials ∼200 to 100 ms prior to tone-pattern onset. After sorting trials into bins based on phase, accuracy was found to be lowest at around π-+ relative to individuals' most accurate phase bin. No significant effects were found for pre-stimulus power. In the context of the literature, findings suggest an important relationship between the complexity of task demands and pre-stimulus activity within the auditory domain. Results also raise interesting questions about the role of induced oscillatory states or rhythmic processing modes in obtaining pre-stimulus effects of phase in auditory tasks., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Recent work studying the temporal dynamics of visual scene processing (Harel et al., 2016) has found that global scene properties (GSPs) modulate the amplitude of early Event-Related Potentials (ERPs). It is still not clear, however, to what extent the processing of these GSPs is influenced by their behavioral relevance, determined by the goals of the observer. To address this question, we investigated how behavioral relevance, operationalized by the task context impacts the electrophysiological responses to GSPs. In a set of two experiments we recorded ERPs while participants viewed images of real-world scenes, varying along two GSPs, naturalness (manmade/natural) and spatial expanse (open/closed). In Experiment 1, very little attention to scene content was required as participants viewed the scenes while performing an orthogonal fixation-cross task. In Experiment 2 participants saw the same scenes but now had to actively categorize them, based either on their naturalness or spatial expense. We found that task context had very little impact on the early ERP responses to the naturalness and spatial expanse of the scenes: P1, N1, and P2 could distinguish between open and closed scenes and between manmade and natural scenes across both experiments. Further, the specific effects of naturalness and spatial expanse on the ERP components were largely unaffected by their relevance for the task. A task effect was found at the N1 and P2 level, but this effect was manifest across all scene dimensions, indicating a general effect rather than an interaction between task context and GSPs. Together, these findings suggest that the extraction of global scene information reflected in the early ERP components is rapid and very little influenced by top-down observer-based goals., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Trisulfides and other oligosulfides are widely distributed in the biological world. In plants, for example, garlic, trisulfides are associated with potentially beneficial properties. However, an extra neutral sulfur atom covalently bound between the two sulfur atoms of a pair of cysteines is not a common post-translational modification, and the number of proteins in which a trisulfide has been unambiguously identified is small. Nevertheless, we believe that its prevalence may be underestimated, particularly with the increasing evidence for significant pools of sulfides in living tissues and their possible roles in cellular metabolism. This review focuses on examples of proteins that are known to contain a trisulfide bridge, and gives an overview of the chemistry of trisulfide formation, and the methods by which it is detected in proteins.

Protein malnutrition in utero that induces permanent changes in metabolism has been investigated intensively in various animals in recent years, but to the best of our knowledge, not yet in the mink, a strict carnivore. In the present study, minks were fed either a low-protein (LP) diet, i.e., with a protein:fat:carbohydrate ratio of 14:51:35% of metabolisable energy (ME), or an adequate-protein diet (AP), i.e. 29:56:15% of ME, from when implantation was completed until parturition (17.9 +/- 3.6 days). Respiration and balance experiments were performed during both gestation and lactation. Plasma concentrations of leptin, IGF-1, and insulin were determined by radioimmunoassay; the relative abundances of glucose-6-phosphatase (G-6-Pase), fructose-1,6-bisphosphatase (Fru-1,6-P2ase), phosphoenol-pyruvate carboxykinase (PEPCK), and pyruvate kinase (PKM2) were determined in liver, and abundances of adiponectin and leptin in adipose tissue were determined by real-time quantitative PCR (q PCR). The protein supply only affected quantitative metabolism traits during the period of differentiated feeding. The dietary composition was reflected in the nitrogen metabolism and substrate oxidation, but no effects remained during lactation. The LP dams tended to have a smaller liver mass in relation to body weight than did AP dams (2.5% vs. 2.9%; p = 0.09), significantly less leptin mRNA (p < 0.05), and 30.6% fewer kits per mated female (p = 0.03). Furthermore, F1-generation kits exposed to protein restriction during foetal life (FLP1; 10.3 g) had a lower birth weight (p = 0.004) than did F1-generation kits exposed to adequate protein (FAP1; 11.3 g). Differences remained significant until 21 days of age (120.4 g vs. 127.6 g; p = 0.005). The FLP1 foetuses displayed a lower abundance of Fru-1,6-P2ase mRNA (p = 0.007) and of PKM2 mRNA (p = 0.002) than did FAP1 foetuses. Whether these changes during foetal life cause permanent changes in the glucose homeostasis of the offspring and result in the transmission of epigenetic phenotypic changes, as seen in the rat, needs further investigation.

Municipal programs for turfgrass establishment recommend large volume-based application rates of composted municipal biosolids (CMB). This study compared runoff water quality among combinations of two common turfgrass establishment practices and two CMB sources. Bryan- or Austin-CMB were incorporated into 5 cm of soil at a rate of 12.5 or 25% by volume (v/v) on an 8.5% slope. Tifway bermudagrass [Cynodon dactylon (L.) Pers. x C. transvaalensis Burtt-Davy, var. Tifway] sprigs were planted and established; sod, produced at a separate site using either CMB amendment at the 25% v/v rate, was transplanted to the runoff plots on the same day. A mature stand of bermudagrass was used as a control. Runoff water was collected after each of eight natural rain events during the sampling period. Total runoff water loss (mm) was similar for the CMB-amended sprigged and transplanted sod stands. The concentration of total dissolved P (TDP) in runoff water was greatest from the transplanted sod in the first seven rain events (4.1 to 7.5 mg L(-1)). The concentration of TDP in runoff water was similar at both the 12.5 and 25% v/v incorporation rates. Regression analysis indicated Mehlich-3-extractable soil test P concentrations in soil amended with CMB were positively correlated to concentration and mass loss of dissolved P in runoff. At similar application rates, dissolved P loss in runoff water was reduced by incorporating CMB into the soil on site rather than transplanting sod produced with CMB.

Glucocorticoids from endogenous and exogenous sources accelerate maturation of brush-border membrane (BBM) hydrolases in omnivorous laboratory rodents and pigs. Less is known for carnivores, and whether the route of administration (oral or systemic) has an influence. The present study examined the influence of administering cortisol (hydrocortisone succinate, 5 mg/kg-day) to mink during postnatal week 4, just prior to weaning, on small intestine glucose and amino acid (aspartate, leucine, lysine, methionine, proline) absorption and on the activities of BBM disaccharidases and peptidases. Kits treated with cortisol were smaller (P<0.05), but had small intestines that were proportionally larger (P<0.05 for length and mass per kg body weight, but not for mucosal mass) than control kits with higher rates of absorption for most nutrients, except leucine, and increased activities of most BBM hydrolases, except lactase. As a consequence, cortisol increased hydrolytic and absorptive capacities of the entire small intestine, with the responses more pronounced when the cortisol was given orally. These findings indicate administration of cortisol stimulates growth of the developing mink small intestine, but does not accelerate the postnatal declines in nutrient transport, and may be a dam-to-kit signal that prepares suckling mink to digest and absorb the adult diet.

Thirty mink dams nursing litters of six kits were assigned to one of three dietary treatments [high protein (HP), medium protein (MP) and low protein (LP)], fed ad libitum for 4 week from parturition, to investigate the effects of protein supply on milk yield and milk composition in order to estimate the amino acid requirement of the lactating mink. Twelve dams were held in an intensive care unit and subjected to balance experiments and the kits were injected with deuterium oxide to determine water kinetics and milk yield. Eighteen dams were kept under normal farm conditions but with feed intake of dams and live weight gain of kits being determined and milk samples collected. The ME intake was higher (p < 0.05) in dams fed the LP and MP diets than in dams fed the HP diet, whereas the amino acid intake (g/day) was lowest (p < 0.05) in dams fed the LP diet. In the third and fourth weeks of lactation milk yield was higher (p < 0.05) in dams fed the LP and MP diets than in dams fed the HP diet. Chemical composition of milk was not affected (p > 0.05) by dietary treatment. However, protein content tended (p = 0.06) to be lower in dams fed the LP diet. Amino acid content (g/16 g N) of milk was higher (p < 0.05) in dams fed the LP and MP diets than in dams fed the HP diet. This resulted in the highest (p < 0.05) amino acid intake and highest (p < 0.001) live weights of kits nursed by dams fed the LP and MP diets, which may be explained by a combined effect of higher ME intake and reduced energetic costs for glucose production through less amino acids being used in gluconeogenesis. In conclusion, the improved performance of dams fed the LP diet suggested that their requirement of essential amino acids and non-specific N were covered, and the requirement of digestible amino acids of lactating mink (kg(0.75)) was, thereby, estimated by use of a factorial approach including the amino acid excretion in milk of LP dams.

The efficiency of utilization of milk amino acids for body gain in suckling mink kits from small (n = 3), medium (n = 6) and large litters (n = 9) was investigated by using 36 mink dams and their litters for measurements during lactation weeks 1 through 4. Measurements on each dam and litter were performed once, hence three dams per litter size each week (n = 9). Individual milk intake of kits was determined, milk samples were collected and kits were killed for determination of amino acid composition. The most abundant amino acids in milk were glutamate, leucine and aspartate making up about 40% of total amino acids. Branched chained amino acids made up slightly more than 20% and sulphur containing amino acids less than 5% of total milk amino acids. In kit bodies the sum of glutamate, aspartate and leucine made up about 32% of amino acids, branched chain amino acids about 16% and sulphur containing amino acids about 4%. The amino acid composition of both milk and bodies changed as lactation progressed with decreasing proportions of essential amino acids. The ratio between body and milk amino acids was constantly over 1 only for lysine, suggesting that it was the most limiting amino acid in mink milk. Milk amino acids were efficiently utilized during week 1, ranging from 74.7% (lysine) to 42.1% (leucine), with an average for essential amino acids of 58.4%. Tendencies for improved utilization of lysine (74.7-78.2%), phenylalanine (61.0-70.0%), histidine (62.4-68.8%), arginine (61.3-70.4%) and all essential amino acids (58.4-60.2%) from week 1 to week 2 were recorded. During weeks 3 and 4, the efficiency declined, and for all essential amino acids the average utilization was 38.1% during week 4.

Purpose: To estimate the clinical significance of low serum concentrations of mannose-binding lectin (MBL) in patients with acute myeloid leukaemia (AML) during initial cancer chemotherapy., Patients and Methods: 80 consecutive, newly diagnosed, and unselected AML patients (age 18-77 yr) undergoing remission induction chemotherapy. The patients were examined for 28 d., Main Findings: Low levels of serum MBL (<1,000 microg/L) were found in 16/80 patients at diagnosis. This frequency is similar to what is found in the general population. In the remaining 64 patients, MBL concentrations were significantly higher than in controls and showed only a slight rise during the period of antineoplastic chemotherapy with its associated infectious complications. Low levels of MBL did not affect overall survival or morbidity in terms of incidence or duration of fever, or occurrence of septicaemia or pneumonia. Long-term survival was likewise independent of MBL concentration., Conclusion: MBL levels have no discernible influence on the occurrence or course of infections in AML patients during the initial hospitalisation. The predominant immunodeficiency during this phase is the profound granulocytopenia, which also compromises important effector functions of MBL. The finding in most AML patients of elevated MBL concentrations on admission is most likely because of the role of MBL as an acute phase reactant.

The clinical, histological, phenotypic and genotypic features of a lymphoblastoid natural killer (NK)-cell lymphoma presenting in the skin in a young caucasian woman are described. The disease behaved aggressively, but long-lasting remission was obtained by combination chemotherapy followed by autologous bone marrow transplantation. The blastoid cells were positive for terminal deoxynucleotidyl transferase, CD34, CD56 and CD4. Furthermore, the NK-cell receptor complex CD94/NKG2 was strongly expressed, as shown by examination with reverse transcription-polymerase chain reaction. The T-cell receptor (TCR)-gamma genes were in germline, and with the exception of CD4 all T-cell antigens were negative, including CD3, TCR-beta, TCR-delta, TIA-1, granzyme B and perforin. Epstein-Barr virus was negative, and no expression was seen of myeloid cell-associated markers. Molecular analysis showed no abnormalities of the CDKN2A (p16), CDKN2B (p15) or TNFRSF6 (Fas) genes. By contrast, a 34-bp deletion in exon 7 of the TP53 (p53) gene was detected. It is suggested that lymphoblastoid NK-cell lymphoma, which is a rare but distinctive disease, originates from NK cell precursors and may be associated with and possibly caused by alterations in the TP53 gene. Experience is too limited to warrant therapeutic suggestions. However, stem cell transplantation may be a useful option in younger patients.

Nitrogen balance, pattern of excretion of nitrogenous end-products, endogenous urinary N excretion, postprandial plasma urea and creatinine, osmotic load, urinary electrolyte excretion and water intake/output relationships were studied in 12 adult female mink fed a high protein diet (HP; n = 6) providing about 155 g protein/kg or a low protein diet (LP; n = 6) providing about 95 g protein/kg. Two balance periods of each 3 d were used and diets were fed raw or cooked. After the last balance period followed a 48 h fasting period. Postprandial plasma urea and creatinine were studied for 48 h following a test meal given after an overnight fast. Osmotic load was determined based on collection of non-acidified urine carried out during 48 h. Level of protein supply did not affect N balance, being close to zero, whereas slightly negative balances were achieved for fasting animals. Protein supply was clearly reflected in excretion of urinary urea and allantoin but not in creatinine and uric acid. Endogenous urinary N excretion was estimated by a second order regression equation giving an intercept of 280 mg/kg0.75. Post-prandial plasma urea concentrations were strongly influenced by protein supply, HP animals having substantially higher peaks than LP animals, but values returned to fasting values within 24 h after the test meal. Plasma creatinine followed a biphasic pattern with a peak about 2 h after feeding and a nadir approximately 6 h after feeding. Physical form of diet influenced postprandial urea, animals fed raw diets having a higher peak, but not creatinine. The HP diet provided almost the double osmotic load of the LP diet and a corresponding increase in urine volume. The resulting water balances were identical irrespective of diet, showing that water intake/output relationships are very accurately regulated.

A high-affinity receptor for urokinase-type plasminogen activator (uPAR) has been identified on the plasma membrane of a number of different cell types, and has been shown to be important for plasminogen activation, cell adhesion, and possibly signal transduction. uPAR and uPA cosediment with secretory vesicles and specific granules by subcellular fractionation and translocate to the plasma membrane upon activation of neutrophils. Here the subcellular distribution of uPAR and uPA is studied by electron microscopy of neutrophils using immunogold double labeling for uPAR and uPA and a set of markers for well-defined subtypes of granules: matrix metalloproteinase type-9 (MMP-9) for gelatinase granules, lactoferrin (LF) for specific granules, and myeloperoxidase (MPO) and neutrophil elastase (NE) for primary granules. With this technique uPAR colocalizes with uPA in 71% of labeled granules. In granules containing uPAR the degree of coexpression with MMP-9, MPO and NE was 19, 66, and 74%, respectively. In granules labeled for uPA the corresponding overlap with MMP-9, MPO and NE was 24, 64, and 51%, respectively. Low levels of co-localization were found for uPAR and LF (7%) and for uPA and lactoferrin (5%). The results indicate that uPAR and uPA are present in gelatinase granules and primary granules, but rarely in specific granules. The demonstration of uPAR and uPA in primary granules is of particular interest, and may indicate that uPAR and uPA participate in the activation of latent hepatocyte growth factor of neutrophils.

Fas (APO-1/CD95) is a cell-surface receptor involved in cell death signaling. Germline mutations in the Fas gene have been associated with autoimmune lymphoproliferative syndrome, and somatic Fas mutations have been found in multiple myeloma. We have examined the entire coding region and all splice sites of the Fas gene in 150 cases of non-Hodgkin's lymphoma. Overall, mutations were identified in 16 of the tumors (11%). Missense mutations within the death domain of the receptor were associated with retention of the wild-type allele, indicating a dominant-negative mechanism, whereas missense mutations outside the death domain were associated with allelic loss. Fas mutations were identified in 3 (60%) MALT-type lymphomas, 9 (21%) diffuse large B-cell lymphomas, 2 (6%) follicle center cell lymphomas, 1 (50%) anaplastic large cell lymphoma, and 1 unusual case of B-cell chronic lymphocytic leukemia with a marked tropism for skin. Among the 16 patients with somatic Fas mutations, 15 showed extranodal disease at presentation, and 6 relapsed in extranodal areas. Ten of 13 evaluable patients showed features suggestive of autoreactive disease. Our data indicate that somatic disruption of Fas may play a role in the pathogenesis of some lymphomas, and suggest a link between Fas mutation, cancer and autoimmunity., (Copyright 1998 by The American Society of Hematology)

The purpose of this study was to evaluate the early infectious complications following autologous transplantation in haematological patients. Sixty-one patients who underwent either autologous bone marrow (BM; 28 patients) or peripheral blood stem cell (PBSC; 33 patients) transplantation for haematological malignancies were reviewed retrospectively. Engraftment happened significantly faster and the length of hospital stay was shorter in the PBSC group compared with the BM group. All patients in the study developed fever and all but two experienced temperatures > or = 38.5 degrees C. Overall, 57 patients had signs of oral mucositis, 23 with ulceration. Twenty patients had bacteraemia, 12 developed pneumonia, 6 systemic fungal infection. No major differences were found between the two groups in distribution or incidence of infections. This study indicates that the use of peripheral blood stem cells results in faster engraftment and shorter hospital stay, whereas the effect on the incidence of early infections seems to be unaffected.

In a multicentre study of 635 consecutive newly diagnosed patients with B-CLL, the histological bone marrow (BM) specimens were reviewed independently by each of 3 pathologists and found evaluable for BM infiltration pattern in 575 patients, 404 of whom had a CD5+, mainly FMC7-, faint surface-membrane immunoglobulin (SIg) fluorescence-intensity ppenotype. In these 404 patients the following BM infiltration patterns were found: mixed nodular-interstitial (30%), moderate interstitial (44%), heavy interstitial (20%) and diffuse packed (6%). In univariate survival analysis, significant differences were found according to BM pattern (p < 0.05), the presence of nodules being a favorable prognostic sign. In multivariate survival analysis in a model including age, clinical stage, BM pattern, BM lymphocytosis, WBC and sex, only age and stage but not BM pattern or BM lymphocytosis had independent prognostic significance. In stage A, progression-free survival was significantly longer in patients with nodular than in patients with non-nodular bone-marrow pattern. The overall survival of these patients, however, did not differ, possibly owing to the prompt and prolonged treatment given to most patients at the time of progression to stage B or C. We conclude that in CD5+, SIg(faint), mainly FMC7-B-CLL, bone-marrow histology may predict unstable disease in early clinical stage but is not important for treatment decisions, when these are based on clinical stage.

Migration of neutrophils in patients with paroxysmal nocturnal haemoglobinuria (PNH) was studied using two different complement-free in vitro model systems, subagarose and transendothelial migration. In the subagarose migration assay the mean migration distance of PNH neutrophils was slightly, but significantly, reduced to 1236 microns (range 753-1586, n = 6) compared to a normal mean of 1476 microns (range 1076-1768, n = 6, P = 0.016). By immunocytochemical staining for the urokinase type plasminogen activator receptor (uPAR) which is a glycosyl-phosphatidyl-inositol (GPI) anchored protein expressed by normal, but not by PNH-affected, neutrophils, it was shown that the uPAR-positive subpopulation of normal neutrophils predominated among the faster migrating cells (60-80% normal cells at the front of migration) while uPAR-negative (i.e. PNH-affected neutrophils) were more numerous close to the application well (5-30% normal cells). When migration of neutrophils was tested across a monolayer of human umbilical vein endothelial cells (HUVEC) cultured on polycarbonate filters, there was a 3-4-fold impairment of the migration of the PNH-affected neutrophils both in the absence of stimulation and after stimulation with fMLP (P < 0.001 in both cases). After IL-1 stimulation of the endothelium the impairment was even more pronounced (8-fold difference, P < 0.001). When the endothelial cells were grown on collagen-coated filters the impairment of the migration of PNH neutrophils was less pronounced, but still significant after stimulation with fMLP and IL-1 (2-fold, P < 0.05 in both cases). These results demonstrate that there is a complement-independent impairment of migration of neutrophils from patients with PNH which may be related to their failure to express GPI-linked proteins involved in cell migration and/or adhesion such as the uPA receptor and the CD66b antigen.

The aim of this study was to evaluate the efficacy, safety and toxicity of short-term priming with recombinant human granulocyte colony-stimulating factor (rhG-CSF) immediately after diagnosis but before combination chemotherapy (CHOP) for non-Hodgkin's lymphomas. Of fourteen patients entering the study, seven received five days subcutaneous injection of rhG-CSF (5 micrograms/kg/day) before CHOP (CSF-group), and seven were treated with CHOP alone (control group). Blood samples were studied before and on days 1-5 during rhG-CSF priming as well as twice weekly after treatment. The number of blood and bone marrow progenitors was identified by clonogenic growth day 7, 14 and 21 of GM-CFU in semisolid medium. Blood absolute neutrophil counts increased in all rhG-CSF primed patients. The expansion of marrow myelopoiesis resulted in increased myeloid:erythroid ratios, increased bone marrow cellularity and increased numbers of myeloid progenitors both in the blood as well as the marrow. Chemotherapy induced neutropenia developed on day 9-12 in all patients independent of myeloid growth factor priming. However, neutropenia appeared earlier in the cytokine primed group (P = .0038). Five patients in the CSF-group and three patients in the control group were hospitalized with neutropenic fever, and septicemia was documented in three patients in the CSF-group. RhG-CSF induced expansion of myelopoiesis immediately before combination chemotherapy mobilized sufficient number of blood progenitors for apheresis but did not result in reduction of duration and degree of neutropenia in patients with newly diagnosed non-Hodgkin's lymphoma. Although the small number of patients prevents drawing definite conclusions, this time schedule for priming should be used with caution in the future due to an increased risk of hematologic toxicity.

The urokinase plasminogen activator (uPA) is a proteolytic enzyme which converts the proenzyme plasminogen to the active serine protease plasmin. A cell surface receptor for uPA (uPAR) is attached to the cell membrane by a glycosyl-phosphatidylinositol anchor. Binding of uPA to uPAR leads to an enhanced plasmin formation and thereby an amplification of pericellular proteolysis. We have shown previously that uPAR is expressed on normal blood monocytes and granulocytes, but is deficient on affected blood monocytes and granulocytes in patients with paroxysmal nocturnal haemoglobinuria (PNH), and that uPAR is present in plasma from these patients. In this study a newly established sensitive enzyme-linked immunosorbent assay (ELISA) has been applied for quantitation of uPAR in plasma. Unexpectedly, we found that uPAR is not only present in PNH plasma but also in plasma from healthy individuals. In 39 healthy individuals the mean plasma-uPAR value +/- SD was 31 +/- 15 pM, median 28 (range 11-108), and the corresponding value for six PNH patients was 116 +/- 67 pM, median 90 (range 61-228). The elevated uPAR-level in PNH patients was highly significant (Mann-Whitney test; P < 0.0001), and may possibly contribute to the propensity for thrombosis in PNH by inhibition of the fibrinolytic system. Binding of pro-uPA by uPAR in plasma may interfere with the appropriate binding of pro-uPA to cell-bound uPAR and therefore inhibit cell-associated plasmin generation and fibrinolysis. It is likely that the uPAR in normal plasma reflects the overall level of activity of the uPAR-mediated cell surface proteolysis. The present ELISA may be used for studies of uPAR levels in plasma from patients with conditions in which this activity might be increased, such as cancer and inflammatory disorders. Future studies will determine if uPAR in plasma is a parameter of clinical importance in these diseases.

It has been known for decades that blood neutrophilia occurs after the administration of etiocholanolone, adrenocortical steroids, and endotoxins. Neutrophil leukocytosis in general may be due to several mechanisms such as increased stimulation of the myelopoiesis, increased release from the marrow, a shift from the marginated to the circulating pool (demargination), prolongation in the peripheral half-life, and decreased migration of neutrophils from the blood to the tissue. However, the principal cause of the neutrocytosis for each of the above mentioned agents is increased release of neutrophils from the bone marrow reserves. Since a sufficient reserve capacity is a prerequisite for optimal defenses against infections, the marrow response has been used to estimate the dose of chemotherapy expected to be tolerated without life-threatening neutropenia. However, none of the above "test substances" have gained widespread use due to adverse reactions or undesirable effects on neutrophil function. Recent progress in biotechnology has developed recombinant human (rh) hematopoietic growth factors ready for clinical use. Marrow myelopoiesis is stimulated by granulocyte colony-stimulating factor (rhG-CSF) and granulocyte-macrophage CSF (rhGM-CSF). The immediate effect, however, is mobilization of mature neutrophil granulocytes to the blood. Bone marrow cellularity seems to influence the neutrophil number mobilized during 24 hours by one subcutaneous injection of either rhG-CSF or rhGM-CSF. A recent pilot study has suggested such a "24 hour stimulation test" to predict severe neutropenia following cyclic chemotherapy. This concept is illustrated by two case reports. The "stimulation test" suggests that we may devise strategies to define patient subsets which may benefit from prophylactic growth factor administration during cyclic chemotherapy.

The effect of supplementing induction chemotherapy with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was studied in a randomized trial of 18 patients with acute myeloid leukemia (AML). Ten patients received rhGM-CSF, starting on day one to three before chemotherapy and continued for a maximum of 21 days after the start of induction treatment. Unexpected adverse effects of rhGM-CSF and chemotherapy combination included a transient decline in plasma coagulation factors II, VII, and X (5 of 5 patients) and an increased transcapillary escape rate of albumin (in 3 of 3 patients tested). The decline in coagulation factors was prevented in subsequent patients by prophylactic treatment with vitamin K. Although the small number of patients studied may not allow a definite conclusion, caution with regard to liver function should be shown in combining rhGM-CSF with intensive chemotherapy.

The mink is a strict carnivore and a seasonal breeder, which may be used as an experimental model for other carnivores. The present investigation comprised a total of 44 balance experiments, each including a 24-h measurement of heat production by indirect calorimetry, carried out from mating until close to parturition. For observations with a nonprotein respiratory quotient between 0.7 and 1.0 (n = 42), quantitative oxidation of nutrients was calculated. The weight gain of the uterus during pregnancy was studied in 41 females killed either before mating, before implantation, after implantation or in mid or late true gestation, and energy retention was calculated. Heat production did not increase with advancing stage of gestation. Mean energy retention was low and in some individuals with repeated measurements even negative, indicating that part of the energy requirement for pregnancy may be supplied by mobilization of body reserves. This was reflected by a high level (42%) of fat oxidation in relation to total heat production. Protein oxidation accounted for 38% of heat production. The weight gain of the uterus during pregnancy could be described by logarithmic functions. Energy deposition in fetal tissue was low and only averaged approximately 350 kJ 47 d after mating.

Expression of the receptor for the urokinase type plasminogen activator (uPAR) has been studied by flow cytometry and immunohistology in normal blood and bone marrow cells, in vitro activated lymphoid cells, and tissue samples from reactive lymph nodes (n = 6), thymus (n = 2) and malignant lymphomas (n = 82), or leukemias (n = 32). HL-60 myeloid precursor cells and CD34-positive normal stem cells also were analyzed. In the normal cells, staining was confined to monocytes, macrophages, neutrophils, and myeloid precursors. No labelling was seen of normal or activated lymphoid cells. Purified CD34-positive hematopoietic progenitors were uPAR negative, but expressed uPAR during differentiation in short-term liquid culture stimulated in vitro by recombinant interleukin (IL)-1, IL-3, IL-6, granulocyte-macrophage colony stimulating factor (CSF), granulocyte-CSF, and stem cell factor. Enhanced uPAR expression was also seen in HL-60 cells after induction of differentiation with dimethyl sulfoxide or 1 alpha,25-dihydroxyvitamin D3. In lymphomas and leukemias, the staining pattern was similar to that seen in the normal cells with labelling of monocytic and myeloid that seen in the normal cells with labelling of monocytic and myeloid malignancies, but not of the neoplastic cells in B-cell or T-cell lymphomas or Hodgkin's disease. In conclusion, uPAR is a differentiation marker for myeloid and monocytic cells, and may act to facilitate migration of these cells in normal and pathologic conditions by cell-associated plasminogen activation. Whether expression of uPAR in myeloid and monocytic malignancies relates to their growth and behavior will be an important topic for investigations in the future.

Eight histiocytic sarcomas, identified by examination of more than 2000 malignant lymphomas, are described. For comparison, tumor infiltrates from five monoblastic leukemias were also analyzed. The histiocytic sarcomas were all high-grade malignancies consisting of markedly pleomorphic large cells with many mitotic figures. At presentation, six of the patients had systemic symptoms (fever, fatigue, loss of weight), skin infiltrates, and lymphadenopathy. Despite aggressive chemotherapy, clinical remissions were short, and six patients died of disease .5-48 months (mean, 6.5 months) after diagnosis. The remaining two patients are alive and in partial or complete remission 7 and 12 months after diagnosis. Immunotypic examination showed that all the histiocytic sarcomas were positive for macrophage-related antigens and negative for antigens on B cells, T cells, myeloid cells, epithelial cells, and melanocytes. T-cell receptor and immunoglobulin genes were studied in three cases and were present in a germline configuration. One of the histiocytic sarcomas resembled Langerhans' cells in phenotype and morphology; it was classified as a Langerhans' cell sarcoma. The remaining histiocytic sarcomas did not express accessory cell-associated antigens, but more closely resembled "ordinary" tissue macrophages; they were positive for lysozyme and/or CD68, followed in frequency by CD11c, CD4, CD11b, CDw32, peanut agglutinin receptor, and CD13. Similar features were seen in the monoblastic leukemias. These conditions could only be distinguished from histiocytic sarcoma by clinical and morphologic, rather than immunophenotypic, criteria. Expression of oncoprotein p53 was studied in nine cases and was positive in six of six histiocytic sarcomas and one of three monoblastic leukemias. Rare malignancies show features consistent with the derivation from macrophages. Two entities may be distinguished: those that resemble antigen-presenting accessory cells and those that more closely resemble ordinary tissue macrophages. Recognition of these tumors is important clinically and requires assessment of clinical, morphologic, and immunophenotypic features, supplemented by analysis of T-cell receptor and immunoglobulin genes. Whether (or how) p53 gene mutations are implicated in their pathogenesis will be an important topic for future investigation.

The value of s-Transferrin Receptor (s-TfR) measurements in recognizing simultaneous iron deficiency in anaemia of chronic disease was examined in 35 anaemic patients with active rheumatoid arthritis. Based on a quantification of stainable bone marrow (marrow iron grade 0-4) and serum ferritin concentrations (levels < 60 micrograms l-1) compatible with iron deficiency) the anaemia was found to be aggravated by iron deficiency in 19/35 or 54% of the patients. There was no significant difference between the mean s-TfR concentrations in patients with adequate iron in comparison to patients with iron depletion [2.9 (1.6) mg l-1 v. 2.7 (1.4) mg l-1; t = 0.273; p = 0.786; Student's t-test]. Mean s-TfR levels in both patients with adequate iron and depleted iron stores were within the normal range, but tended to be higher than in normal individuals [mean (SD): 1.54 (0.43) mg l-1]. In patients with no stainable marrow iron (MIG 0; N = 15) a significant inverse correlation was found between s-TfR concentrations and s-ferritin levels (r = 0.57; p < 0.05). 5/15 patients with MIG = 0 exhibited significantly raised concentrations of s-TfR values > 3.05 mg l-1 (the highest normal value of the normal range). Increases of s-TfR levels were consistently moderate, and never exceeded a level of 7 mg l-1, which is markedly lower than concentrations measured in patients with iron deficiency anaemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Background and Aim: Short-term liquid marrow cultures (STLMC) are a potential source for autografting. We have previously shown that the quality of such grafts from transplantation candidates may be improved by hematopoietic cytokine support, especially if purified CD34-positive progenitors are cultured. The aim of this preclinical work was to quantitate ex vivo recovery of myeloid progenitors (colony-forming units-granulocyte/macrophage [CFU-GM]) in STLMC before and after short-term, in vivo treatment with recombinant human granulocyte colony-stimulating factor (rhG-CSF), granulocyte-macrophage colony-stimulating factor (rhGM-CSF), or interleukin-3 (rhIL-3)., Experimental Setup: Twenty-two sequential patients in marrow remission for hematological malignancies and eligible for autologous marrow transplantation received rhG-CSF or rhGM-CSF for 5 days or rhIL-3 for 10 days before marrow harvest. Marrow samples before and after in vivo priming were studied for CFU-GM in pre- and post-STLMC., Results: After priming with rhG-CSF, rhGM-CSF, or rhIL-3, the number of isolated light-density cells increased nine-, six-, and two-fold, respectively. The total number of sampled (18 mL marrow) myeloid progenitors preculture (day 7/14 CFU-GM x 10(4) increased significantly from median 0.7/1.1 before to 37.3/26.7 after priming with rhG-CSF (n = 8) and from 5.6/3.4 before to 46.6/44.9 after priming with rhGM-CSF (n = 8) but remained unchanged (3.7/1.5 to 3.6/5.7) after priming with rhIL-3 (n = 6). The number of myeloid progenitors postculture (day 7/14 CFU-GM x 10(4) per 18 mL marrow) in cytokine-supported STLMC significantly increased from median 0.3/0.6 before to 7.0/5.3 after priming with rhG-CSF and from 1.9/1.6 before to 24.4/14.4 after priming with rhGM-CSF but remained unchanged (0.4/0.6 to 0.4/0.2) after priming with rhIL-3. Cytokine-primed and purified CD34+ marrow cells may be expanded in STLMC by a cytokine-driven differentiation into late myeloid progenitors and endstage cells., Conclusion: In vivo priming of bone marrow cells by hematopoietic cytokines significantly increases the recovery of harvested pre- and postculture myeloid progenitors. During cytokine-supported STLMC, early myeloid progenitors may differentiate into a "very late" progenitor pool with a potential for fast marrow regeneration. The number of such progenitors in cytokine-supported short-term liquid cultures may be sufficient for fast myeloid engraftment and complete peripheral blood or marrow stem-cell support after high-dose chemotherapy.