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Biomedical subjects

D A Calhoun

Publications and source records attributed to D A Calhoun.

At least 37 records · Page 2Linked to original sources
PubMed2000

Granulocyte colony-stimulating factor serum and urine concentrations in neutropenic neonates before and after intravenous administration of recombinant granulocyte colony-stimulating factor.

BACKGROUND: Recombinant granulocyte colony-stimulating factor (rG-CSF) has been suggested as a treatment for certain varieties of neonatal neutropenia, but little is known about the pharmacologic disposition of rG-CSF in that population. METHODS: Ten neutropenic neonates were treated with rG-CSF, 10 micrograms/kg intravenously once daily for 3 to 5 days. Serum and urine samples were obtained before rG-CSF dosing and at intervals thereafter for G-CSF quantification by enzyme-linked immunosorbent assay. RESULTS: Five of the neutropenic neonates (termed group 1) were not infected but likely had hyporegenerative neutropenia (4 were born after pregnancy-induced hypertension/intrauterine growth restriction, and 1 had Rh hemolytic disease). Five other infants (group 2) had neutropenia accompanying bacterial sepsis and shock. Before receiving the first dose of rG-CSF, endogenous G-CSF serum and urine concentrations were relatively low in group 1, averaging 130 pg/mL (range: 48-209) in serum and 53 pg/mL (range: 15-141) in urine. Serum concentrations immediately before the final dose were much higher (range: 81-24 835 pg/mL), whereas urine concentrations were unchanged (range: <7 pg/mL-126 pg/mL). In group 2 patients, before receiving the first-dose of rG-CSF, endogenous concentrations were very high, averaging 59 575 pg/mL (range: 20 028-98 280) in serum and 3189 pg/mL (range: 23-4770) in urine. Predose serum concentrations before the final dose (range: 427-14 460 pg/mL) were lower than before the first dose. The area under the concentration curve after the first dose of rG-CSF administration in group 1 was significantly lower than after the first dose in group 2, but no difference in area under the concentration curve was observed between groups 1 and 2 after the last dose of rG-CSF. SPECULATION: The principal means of clearing G-CSF from the serum is by saturable binding to specific G-CSF receptors (G-CSF-Rs). Therefore, the very high G-CSF serum and urine concentrations of group 2 patients before the first rG-CSF dose implies that their G-CSF-Rs were saturated before the dose was given. We speculate that if G-CSF-Rs are saturated with endogenous G-CSF, treatment with rG-CSF will add little or nothing to the granulocytopoietic effort. On this basis, we judge that neonates with septic shock and neutropenia are unlikely to derive benefit from rG-CSF administration.

Enzyme-Linked Immunosorbent Assay↗
PubMed2000

Neonatal alloimmune neutropenia in premature monozygous twins.

Alloimmune neonatal neutropenia (ANN) is an uncommon but potentially life-threatening disorder of the neonate and young infant. Hematologically, the mother's peripheral neutrophil count is normal. However, the passive transfer of maternal immunoglobulin G neutrophil-specific antibodies and the subsequent sensitization of fetal neutrophils can result in severe neutropenia in the neonate. Generally, ANN is a self-limiting condition, but with severe bacterial infection, mortality can be high. We present the clinical features of monozygous twins delivered at 33 weeks' postconception with this condition. This case report is unique in that it occurred in twins born prematurely and was attributable to antibodies against 2 neutrophil-specific antigens, NA1 and NB1. A brief review of the diagnosis, management, and treatment of ANN is presented.

Antibody Specificity↗
PubMed1999

Contemporary management of refractory hypertension.

Refractory or resistant hypertension is conventionally defined as systolic or diastolic blood pressure that remains uncontrolled despite sustained therapy with at least three different classes of antihypertensive agents. Refractory hypertension is estimated to affect less than 5% of the general population with hypertension; however, its prevalence increases with increasing severity of blood pressure. Patients presenting with refractory hypertension usually have progressed from mild, to moderate, to severe hypertension because of lack of or inadequate treatment. Other common contributing factors include obesity, medical nonadherence, suboptimal medical regimens, excessive dietary salt ingestion, secondary forms of hypertension, sleep apnea, and ingestion of substances that interfere with treatment. Combination therapy that includes appropriate doses of a diuretic is recommended for treatment of refractory hypertension. Use of fixed-dose combinations enhances compliance through cost savings, more convenient dosing, and reduced pill burdens.

Antihypertensive Agents↗
PubMed1999

Thrombopoietin (Tpo) in the fetus and neonate: Tpo concentrations in preterm and term neonates, and organ distribution of Tpo and its receptor (c-mpl) during human fetal development.

Little is known about thrombopoietin (Tpo) production in human fetuses and neonates. As a step toward determining whether Tpo is relevant to platelet production in the fetus and neonate, we hypothesized that: (1) like other cytokines, Tpo is present in the cord blood in higher concentrations than in adult plasma; (2) Tpo and its receptor (c-mpl) are expressed in fetuses at, and following, 5-6 weeks post-conception (when platelet production begins); and (3) the sites of Tpo and c-mpl production in the fetus are similar to those of adults. We quantified Tpo, by ELISA, in the plasma of 50 adults, as well as in the umbilical cord plasma of 50 preterm and term infants. We also characterized, by RT-PCR, the organ distribution of Tpo and c-mpl during fetal development (at 8 and 16 weeks). Tpo concentrations were measurable (> or =41 pg/ml) in only two of the 50 adult samples (44 and 46 pg/ml), but in 24 of the 50 cord plasma samples (of the 24 samples, the median was 62 pg/ml; mean+/-SD, 80+/-39 pg/ml). Tpo levels did not correlate with either gestational age or platelet count at birth. Similarly to adults, in the fetal tissues, Tpo transcripts were found in all organs tested, but the most dense bands were from liver. C-mpl transcripts were also predominantly from liver. We conclude that: (1) Tpo is present in higher concentrations in cord plasma than in venous plasma of adults; (2) Tpo and c-mpl transcripts are detected in human fetuses as early as the onset of platelet appearance; and(3) Tpo and c-mpl have a similar organ distribution in fetuses and adults.

Adult↗
PubMed1999

Plasma thrombopoietin concentrations in thrombocytopenic and non-thrombocytopenic patients in a neonatal intensive care unit.

Thrombocytopenia is a frequent occurrence in the neonatal intensive care unit (NICU), but the role of thrombopoietin (Tpo) in the pathophysiology is unknown. We obtained serial plasma Tpo concentrations in 20 thrombocytopenic neonates in our NICU, and performed bone marrow studies in 15. The initial Tpo levels ranged from undetectable (<41 pg/ml) to 1112 pg/ml and did not correlate with gestational age or platelet count. Neonates with decreased marrow megakaryocytes did not have plasma Tpo levels as high as those reported in adults, particularly in small for gestational age infants (Tpo < 300 pg/ml). In 14/15 neonates followed until resolution, the Tpo concentration decreased as the platelet count increased.

Biopsy↗
PubMed1999

Pretreatment with enalaprilat blunts nicardipine-induced sympathetic activation in spontaneously hypertensive and Wistar-Kyoto rats.

OBJECTIVE: We measured changes in heart rate and lumbar sympathetic nerve activity in conscious, spontaneously hypertensive and Wistar-Kyoto rats during acute blood pressure lowering with nicardipine, enalaprilat and concomitant nicardipine/enalaprilat administration. In a second experiment, we determined the effect of these drugs on arterial baroreflex control of lumbar sympathetic nerve activity. METHODS: Male spontaneously hypertensive and Wistar-Kyoto rats were instrumented for continuous heart rate, blood pressure and lumbar sympathetic nerve activity recordings. Twenty-four hours later in conscious rats, nicardipine, enalaprilat and enalaprilat/nicardipine were infused at sufficient doses to reduce mean arterial pressure by 20 mmHg over 30 min. In a second experiment with the same drugs, baroreflex curves relating lumbar sympathetic nerve activity to mean arterial pressure were analyzed using a logistic curve-fitting program. RESULTS: Blood pressure reductions induced by the three infusion protocols were similar in magnitude and profile. In both spontaneously hypertensive and Wistar-Kyoto rats, nicardipine induced greater reflexive increases in lumbar sympathetic nerve activity than enalaprilat Pretreatment with a reduced dose of enalaprilat blunted subsequent nicardipine-induced sympathetic activation. Nicardipine tended to induce greater increases in the heart rate than enalaprilat, but overall, the difference was not significant Baroreflex sensitivity was similar regardless of drug class. Nicardipine significantly increased minimum nerve activity compared with enalaprilat in spontaneously hypertensive rats (similar trends were observed in Wistar-Kyoto rats). This increase in minimum nerve activity was blunted by enalaprilat CONCLUSIONS: These results indicate that pretreatment with an angiotensin converting enzyme inhibitor minimizes dihydropyridine-induced increases in sympathetic activity. This beneficial effect is attributable to suppression of minimum sympathetic activity. These data suggest that co-administration of an angiotensin converting enzyme inhibitor may improve the long-term cardiovascular benefit of dihydropyridine calcium channel blockers.

Animals↗
PubMed1999

Interaction between lifetime captopril treatment and NaCI-sensitive hypertension in spontaneously hypertensive rats and Wistar-Kyoto rats.

DESIGN: Previous studies that were based on daytime arterial pressure recordings indicate that lifetime treatment with captopril exacerbates the hypertensive response to a high NaCl diet in spontaneously hypertensive rats (SHR) but has no such effect in normotensive Wistar-Kyoto (WKY) rats. The present study used 24-h recording methods to examine the hypothesis that during the normal waking hours of rats (night-time) the hypertensive response to a high NaCl diet is exacerbated in SHR and induced in WKY rats treated with lifetime captopril. METHODS: SHR and WKY rats were (1) untreated, (2), lifetime captopril treated or (3) lifetime captopril treated but removed from the treatment 2 weeks prior to exposure to a high (8%) NaCl diet RESULTS: Compared to untreated SHR, in SHR that were continuously treated with captopril, the high NaCl diet caused a more rapid and greater rise in arterial pressure. Discontinuation of the captopril treatment did not significantly diminish this NaCl-sensitivity. In untreated WKY rats, the high NaCl diet did not alter mean arterial pressure, but in the lifetime captopril-treated WKY rats the high NaCl diet induced a rapid rise in arterial pressure. In WKY rats, discontinuation of the lifetime captopril treatment did not diminish this NaCl-induced rise in arterial pressure, even though baseline mean arterial pressure in this group is similar to that in untreated WKY rats. CONCLUSIONS: Lifetime captopril treatment accelerates the hypertensive response to a high NaCl diet in SHR, and it induces a similar response in WKY rats. In both strains, the lifetime captopril treatment causes a change in the response that is not dependent on concurrent administration of the drug. This finding further suggests that lifetime captopril treatment causes a long-term resetting of cardiovascular response mechanisms.

Animals↗
PubMed1999

Distribution of granulocyte colony-stimulating factor (G-CSF) and G-CSF-receptor mRNA and protein in the human fetus.

Granulocyte colony-stimulating factor (G-CSF) promotes neutrophil proliferation, differentiation, and survival. It acts by binding to specific cell-surface receptors (G-CSF-R), which are expressed on cells of granulocytic lineage, human endothelial cells, and placenta. It has been postulated that the administration of recombinant G-CSF (rG-CSF) to preterm neonates might be useful in treating infections or in reducing nosocomial infections. Whereas it is known that G-CSF and G-CSF-R are present in the developing fetal bone marrow and liver, no information is available as to the existence or distribution of nonhematopoietic G-CSF-R in other tissues of the developing human fetus. We hypothesized that G-CSF and its receptor might be expressed in various fetal tissues, as has been shown for other growth factors such as erythropoietin and fibroblast growth factor. Therefore, we studied the anatomical distribution of mRNA-encoding G-CSF and G-CSF-R, using RT-PCR and in situ RT-PCR in a variety of human fetal tissues ranging from 8 to 24 weeks postconception. The cellular distributions of the corresponding proteins were determined by immunohistochemistry. Both G-CSF and G-CSF-R were present in nearly every organ and tissue examined, but in discrete cellular localizations. G-CSF-R in kidney and intestine underwent changes in anatomical distribution with fetal development. These results indicate that G-CSF and G-CSF-R have wide anatomical expression in the developing human fetus.

Fetus↗
PubMed1999

Concentrations of granulocyte colony-stimulating factor in human milk after in vitro simulations of digestion.

Human milk contains proteins that survive digestion in the neonatal gastrointestinal tract. Our group and others have reported that granulocyte colony-stimulating factor (G-CSF), a hematopoietic cytokine that influences neutrophil proliferation and differentiation, is present in human milk. We also reported that specific receptors for G-CSF are expressed on the villous enterocytes of neonates. However, the physiologic role of milk-borne G-CSF is not known. Thus, we sought to evaluate the capacity of human milk to protect G-CSF against proteolytic degradation after exposure to gastric secretions obtained from preterm (PT) and term (T) neonates at pH concentrations of 3.2, 5.8, and 7.4. Specifically, we examined degradation of 1) endogenous G-CSF in PT (n = 15) and T (n = 15) human milk; 2) recombinant human G-CSF (rhG-CSF) added to a protein-free buffer (n = 10, 5 PT and 5 T); and 3) rhG-CSF added to human milk (n = 12, 6 PT and 6 T), various commercially prepared infant formulas (n = 15), and cow's milk (n = 5). Endogenous G-CSF and rhG-CSF added to human milk resisted degradation at 1 and 2 h. However, when rhG-CSF was added to commercial formulas, >95% was degraded at 1 and 2 h at each pH level. Similarly, approximately 60% of rhG-CSF added to cow's milk was degraded at I and 2 h. We conclude that 1) endogenous G-CSF and rhG-CSF added to human milk are protected from degradation after exposure to gastric secretions at physiologic pH levels, 2) rhG-CSF added to infant formulas is not protected from degradation, and 3) it is likely that the G-CSF present in human milk is biologically available to the neonate.

Digestion↗
PubMed1998

Managing the patient with hard-to-control hypertension.

Less than 25 percent of patients with hypertension in the United States have their blood pressure under control, mainly because of inadequate or inappropriate therapy and noncompliance. Approximately one half of these treatment failures are related to factors such as cost and adverse effects of medication, complex drug regimens, failure of clinicians to fully realize the benefits of antihypertensive therapy and lack of patient education. Other major causes of unresponsiveness to antihypertensive therapy include "white coat" hypertension, pseudohypertension, obesity, volume overload, excess alcohol intake and sleep apnea, as well as inappropriate antihypertensive drugs and drug combinations, and unfavorable interactions with prescription and other drugs. In many patients, these factors must be dealt with before blood pressure can be controlled.

Antihypertensive Agents↗
PubMed1998

A randomized pilot trial of administration of granulocyte colony-stimulating factor to women before preterm delivery.

OBJECTIVE: The object was to determine whether administering recombinant human granulocyte colony-stimulating factor to women before a preterm delivery (< or = 30 weeks' gestation) would improve fetal neutrophil production and neonatal outcome without adverse maternal effects. STUDY DESIGN: A single dose (25 microg/kg) of recombinant human granulocyte colony-stimulating factor or placebo was given to 26 women in preterm labor in a randomized, double-blind study. Neutrophil production was assessed by marrow aspirations of neonates 24 hours after delivery, blood neutrophil counts were measured in neonates for 1 week, and Scores for Neonatal Acute Physiologic State were calculated on days 1 and 7 of life. RESULTS: Of the 26 women enrolled, 16 were delivered of 20 infants within 3 weeks of receiving recombinant human granulocyte colony-stimulating factor. We found no apparent adverse effect on pregnancy duration or maternal comfort. The neonates born to mothers treated with recombinant human granulocyte colony-stimulating factor had a significantly greater marrow proliferative pool (P < .05 vs placebo) and a significant improvement in Scores for Neonatal Acute Physiologic State between days 1 and 7 (P < .02). CONCLUSIONS: Recombinant human granulocyte colony-stimulating factor administration to women before preterm delivery appears to have no significant immediate adverse effects on either the mother or the infant, and it could increase fetal neutrophil production and improve neonatal outcome.

Adult↗
PubMed1998

The first-appearance of neutrophils in the human fetal bone marrow cavity.

We sought to define the time of first-appearance of neutrophils within the developing human bone marrow cavity, and to compare this with the time of appearance of G-CSF and its receptor (G-CSF-R) at that site. We hypothesized that the onset of G-CSF production is an initiation signal for neutrophil production within the marrow cavity, and that therefore G-CSF mRNA and G-CSF protein in the marrow cavity would immediately precede the first-appearance of neutrophils. To test this, we determined the time of first-appearance of neutrophils in the clavicular marrow space using a monoclonal antibody against myeloperoxidase (MPOAb), and then validated these findings by flow cytometric analyses, for neutrophil cell-surface markers, of cells flushed from the marrow cavity. After thus defining the time of first-appearance of neutrophils, specific mRNA transcripts for G-CSF and G-CSF-R were sought from clavicles of varying gestational ages, using RT-PCR, and the presence of these proteins in the clavicles were sought using immunohistochemistry. We observed that; (1) MPO+ cells first appeared in the clavicular marrow cavity between the 10 to 11th weeks post-conception, (2) Flow cytometric analyses confirmed that these MPO+ marrow cells included CD11b+, CD15+ neutrophils, (3) Transcripts for G-CSF and G-CSF-R, and the specific G-CSF and G-CSF-R proteins, were present in the clavicles by 6 weeks post-conception, 4 to 5 weeks before the first-appearance of neutrophils. Thus, neutrophils first appear in the human clavicular marrow at 10-11 weeks post-conception, and G-CSF and G-CSF-R are present in the developing bone rudiment preceding the appearance of neutrophils. It is unclear whether neutrophils arise in the marrow cavity in response to the onset of production of G-CSF or to other initiation signals.

Bone Marrow↗
PubMed1998

"Idiopathic neutropenia" in very low birthweight infants.

We employed a standardized investigative approach to evaluate four cases of "idiopathic neutropenia" in very low birthweight infants. The evaluation included maternal anti-neutrophil antibodies, a marrow aspiration, and a three-day trial of recombinant granulocyte colony-stimulating factor (rG-CSF). All patients had neutropenia at or shortly following delivery, and remained neutropenic (generally <500/microl) for 1-9 weeks until rG-CSF was administered. Blood and bone marrow studies in all 4 indicated that the neutropenia was: (i) the kinetic result of diminished neutrophil production; (ii) not alloimmune; (iii) not cyclic; and (iv) not associated with recognized inborn errors, bacterial or viral infections, or medications. All responded to rG-CSF by transiently increasing their blood neutrophils to normal, and the neutropenia resolved in all cases with time. It is likely that "idiopathic neutropenia" in this population represents a common phenotype of several different causes, rather than a single entity. Some cases, perhaps the majority, will respond to a short course of rG-CSF administration.

Diseases in Twins↗
PubMed1998

Recent advances in the pathogenesis and treatment of nonimmune neutropenias in the neonate.

Neutropenia in the neonate is defined as a significantly lower than normal concentration of neutrophils in the peripheral blood and can be broadly classified as immune or nonimmune. Nonimmune neutropenias are those that are not the direct or indirect result of antibodies directed against neutrophils. Recent advances have been made in the pathogenesis and treatment of several types of neonatal neutropenia, including reticular dysgenesis, Schwachman-Diamond syndrome, Kostmann syndrome, neutropenia in infants of hypertensive women, and "idiopathic neutropenia." This review of nonimmune neutropenias highlights these developments.

Female↗
PubMed1998

Hematopoiesis in the liver and marrow of human fetuses at 5 to 16 weeks postconception: quantitative assessment of macrophage and neutrophil populations.

During human development, the liver and marrow both function as hematopoietic organs, but little is known about differences in the production of macrophages and neutrophils by these two organs. We used immunohistochemical stains to quantify the ratio of neutrophils to macrophages within the liver and the marrow of 16 fetuses from 5 to 16 wk postconception. At 5 wk the liver had a ratio of one granulocyte [myeloperoxidase (MPO)-positive cell] to every 9 +/- 5 (X +/- SD) macrophages (KP-1-positive cells). Between 5 and 16 wk, the granulocyte to macrophage ratio in the liver was constant, whereas it changed markedly in the marrow. Before 8 wk no MPO-positive or KP-1-positive cells were observed in bones. At 10 wk, bones still had no MPO-positive cells, but KP-1-positive cells were abundant. At 11-12 wk the granulocyte to macrophage ratio was 1 to 1 +/- 1, but by 13-16 wk it had increased to 8 +/- 3 MPO-positive cells to one KP-1-positive cell. We hypothesized that at 13-16 wk the abundance of MPO-positive cells in the marrow and their scarcity in the liver was the result of production of granulocyte colony-stimulating factor (G-CSF) and its receptor (G-CSF-R) in the marrow and their absence in the liver. However, by reverse transcriptase-PCR mRNAs for G-CSF and G-CSF-R were positive in both organs at all gestations, and G-CSF and G-CSF-R proteins (by immunohistochemistry) were also abundant in all liver and marrow specimens. We then hypothesized that progenitors in the fetal liver were intrinsically different from those in the marrow, and were unable to generate clones of neutrophils. However, progenitors from the liver produced neutrophils abundantly in culture. Thus, the explanation is likely related to as yet undescribed environmental differences between the fetal liver and marrow.

Bone Marrow↗
PubMed1997

Race, family history of hypertension, and sympathetic response to cold pressor testing.

This laboratory recently reported that the blood pressure and muscle sympathetic nerve activity (MSNA) responses to cold pressor testing are greater in normotensive blacks than in age- and weight-matched normotensive whites. The present study was designed to determine the relationship between race, family history of hypertension, and sympathetic response to cold pressor testing. The study used microneurography to measure MSNA responses to cold pressor testing in normotensive blacks with (n = 8) and without (n = 8) and normotensive white subjects with (n = 8) and without (n = 10) a positive family history of hypertension. Resting blood pressure was lower in black subjects without a positive family history of hypertension but otherwise resting blood pressure, heart rate, and MSNA were similar in the four groups. Black subjects with a family history of hypertension manifested a greater increase in blood pressure and MSNA than both white groups. Blood pressure and sympathetic responses of black subjects with a negative family history of hypertension tended to be intermediate and were not statistically different from the other three groups. These results indicate that the greater sympathetic response to cold stress observed in normotensive African-Americans is true only of black subjects with a positive family history of hypertension.

Adult↗
PubMed1996

Assessment of the contribution of the spleen to granulocytopoiesis and erythropoiesis of the mid-gestation human fetus.

Several current textbooks of hematology describe the spleen of the mid-gestation human fetus as a granulocytopoietic and an erythropoietic organ. Although studies in fetal rodents support this view, a convincing demonstration of such in normal human fetuses is lacking. We tested the hypothesis that the human mid-gestation fetal spleen is normally (1) a site of active granulocytopoiesis and erythropoiesis, or (2) a site of production of specific granulocytopoietic or erythropoietic growth factors. This was accomplished using the spleens, livers, and long-bones of 18 human fetuses, 13-22 weeks gestation, immediately following elective, induced, pregnancy terminations. Organs of some of the abortuses were placed directly into formalin for histologic evaluation. Organs from others were subjected to RNA extraction for subsequent probing for specific hematopoietic growth factor mRNA. Cell suspensions were created from the organs of other abortuses for quantification of the absolute number of neutrophils and erythrocytes and their precursors and progenitors. Evidence of active hematopoiesis was present in marrow and liver but not spleen. Transcripts for granulocyte colony-stimulating factor (G-CSF) were detected in the marrow but not the spleen or liver, and transcripts for erythropoietin (Epo) were detected in the liver but not the spleen or marrow. The populations of hematopoietic progenitor cells and normoblasts in the fetal spleen cell were similar to those in fetal blood. Thus, it is likely that the hematopoietic progenitors recovered from fetal spleen cell suspensions are the result of blood within the spleen, rather than from hematopoiesis within the organ. The spleen of mid-gestation human fetuses, unlike the spleen of fetal rats, does not normally function as an active site of granulocytopoiesis or erythropoiesis, nor is it an active site for production of G-CSF or Epo.

Abortion, Induced↗