Biomedical subjects

M S Gordon

Publications and source records attributed to M S Gordon.

At least 37 records · Page 2Linked to original sources

PubMed2000

Blunted suppression of plasma renin activity in diabetes.

We have documented, contrary to expectation, that the renin-angiotensin-aldosterone system (RAAS) is stimulated normally by restriction of sodium intake inpatients with Type 2 diabetes mellitus (DM) and hypertension. Conversely, plasma renin activity (PRA)is suppressed less than in normal subjects by a high-salt diet in these patients. Increasing plasma angiotensin II (Ang II) concentration through intravenous Ang II infusion also suppresses renin release, via the short feedback loop. In this study, we sought to ascertain whether the limited renin suppression in Type 2 diabetes mellitus via high-salt intake is a unique defect or part of a more generalised abnormality of PRA suppression. We studied 38 patients with Type 2 DM and hypertension, 158 hypertensive control patients, and 61 normotensive controls. All patients were studied while in metabolic balance on a 10 mEq sodium (Na) diet. The response to the Ang II infusion at 3 ng/kg/min for 45 minutes was measured. We found that PRA fell significantly in normal subjects, from 4.0 +/- 0.33 to 2.5 +/- 0.23 ngAngI/ml/hr (p=0.0056). In patients with essential hypertension, the Ang II infusion also led to a fall in PRA from 3.51 +/- 0.23 to 2.76 +/- 0.17 ng Angl/ml/hr(p=0.014). In patients with DM, despite a similar basal PRA (3.7 +/- 0.40 ng AngI/ml/hr), the infusion of Ang II did nor influence PRA significantly (3.43 +/- 0.42ng AngI/ml/hr; p > 0.77), though these patients had the most robust mean arterial pressure response. Our data are in complete accord with the concept of high intrarenal Ang II in DM and suggest lower systemic Ang II despite comparable PRA.

Adult↗

PubMed1999

Antibiotic susceptibility of Streptococcus pneumoniae in New Zealand.

AIMS: To determine the current antibiotic susceptibility patterns of Streptococcus pneumoniae from four centres in New Zealand. METHODS: Over a six-month period in 1997, 386 consecutive clinical isolates of S pneumoniae were collected by four laboratories (Auckland, Wellington, Hamilton and Christchurch) from general practice or inpatients. Susceptibility testing for seven antibiotics was performed by each centre using the Etest. RESULTS: Eighty-three-percent of isolates were penicillin susceptible, 12% showed intermediate resistance to penicillin and 5% were penicillin resistant. Overall, 93 and 91% of isolates were susceptible to amoxicillin/clavulanic acid and ceftriaxone, respectively. Erythromycin and tetracycline had similar rates of susceptibility (88 and 87%, respectively). Resistance to cotrimoxazole was common, with only 57% of isolates susceptible to this combination. No National Committee for Clinical Laboratory Standard (NCCLS) breakpoints were available for cefaclor to allow interpretation of the minimum inhibitory concentration data for this agent. Wellington had lower resistance rates than Auckland, Christchurch and Hamilton. Isolates from children had consistently higher resistance rates (two- to five-fold greater for beta-lactams and 1.2 to 1.3-fold for other agents) compared with isolates from adult patients. CONCLUSIONS: Resistance to multiple antibiotics among S pneumoniae is now evident in New Zealand, although rates varied between study centres. The overall rate of penicillin resistance is 5%, which is similar to that observed in many European and US cities but lower than the rates reported in badly affected areas (> 30%). These data suggest that amoxicillin (+/- clavulanic acid), erythromycin or tetracycline are appropriate agents for empirical use in less serious community acquired infections when S pneumoniae is suspected. Ceftriaxone, with or without vancomycin, should be considered in the empirical treatment of invasive, disease until sensitivities are known.

Adult↗

PubMed1999

The effect of tea consumption on oxidative stress in smokers and nonsmokers.

While the anticarcinogenic effects of tea in animal models have been reported by several groups, human epidemiological studies examining tea consumption and cancer prevention have produced equivocal results. The beneficial properties of tea to human health may be related to the antioxidant properties of tea components. However, little evidence has been provided that tea consumption can either increase the antioxidant capacity or decrease oxidative stress in humans. In the present study, the effects of tea treatment (green tea) on biomarkers of oxidative stress were investigated in smokers and nonsmokers in two volunteer study groups (one in China and the other in United States). Green tea consumption in both study groups decreased oxidative DNA damage (8-OHdG in white blood cells and urine), lipid peroxidation (MDA in urine), and free radical generation (2, 3-DHBA in urine) in smokers. Nonsmokers (US study group) also exhibited a decrease in overall oxidative stress.

3,4-Methylenedioxyamphetamine↗

PubMed1999

Advances in supportive care of myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) are a heterogenous family of hematologic disorders characterized by ineffective hematopoiesis. Because of the variability between patients regarding prognosis and morbidity related to the disease, consensus regarding the management of these patients has been difficult. Over the past several years, new prognostic scoring systems such as the International Prognostic Scoring System (IPSS) have attempted to provide a projection for long-term stability of the percentage of patients who have "low-grade" or indolent MDS. Unfortunately, its lack of prospective use in clinical trials and other settings has thus far failed to validate it as a functional decision-making tool. Thus, investigators have hypothesized that separating patients based on more simplistic treatment-oriented guidelines may be more efficient. For the majority of patients with MDS, no curative option exists. Patients who are young enough and have an available matched sibling or matched unrelated donor may undergo an allogeneic bone marrow transplant (BMT) with a potential cure rate of 30% to 50%. The major issue regarding this approach is the relatively high morbidity and the risk that the patient's lives may be shortened, that their quality of life will be worsened, or that no overall benefit will occur (relapse). Compounding the issue of selection and timing for BMT is the fact that the best results in terms of relapse-free survival appear to be in the subset of patients with early or low-grade MDS, characterized by refractory anemia with or without ringed sideroblasts. For these patients, lacking a donor for BMT, the major issue has become the consideration of induction chemotherapy. While dose-intensive chemotherapy may improve outcome in a small percentage of patients, the majority of elderly patients with MDS are not optimal candidates for such an approach. As a result, supportive care has a major role for patients with MDS and depending on the French-American-British (FAB) presentation and comorbid illnesses may be the preferred approach. Erythropoietin, a growth factor, is perhaps the most commonly used supportive care after transfusion. The use of colony-stimulating growth factors to support leukopenia is currently under investigation. The use of thrombopoietic agents has lagged behind in the management of MDS patients. Investigation of interleukin-6 (IL-6), a thrombopoietic cytokine, showed some ability to increase platelets through significant toxicity. Investigation of IL-11, an approved thrombopoietic growth factor, is preparing to start and should aid in determining its role in this setting.

Cytokines↗

PubMed1999

Immunological effects of interleukin 12 administered by bolus intravenous injection to patients with cancer.

The immunological effects of recombinant human interleukin 12 (rhIL-12) administration were examined during the conduct of a Phase I clinical trial. Forty patients with advanced cancer received bolus i.v. injections of rhIL-12 in doses ranging between 3 and 1000 ng/kg. Dose-dependent increases in serum IFN-gamma levels were seen during rhIL-12 therapy. Significant lymphopenia was observed 24 h after single i.v. injections of rhIL-12 at each dose level. The degree of lymphopenia was dose dependent, and a plateau effect was seen with rhIL-12 doses of 100 ng/kg and higher. Lymphocyte counts reached nadir levels at approximately 10 h after rhIL-12 injection and returned to baseline within 14 days postinjection. Rebound lymphocytosis, as seen after interleukin 2 therapy, was not observed after recovery from rhIL-12-induced lymphopenia. rhIL-12-induced lymphopenia involved all major lymphocyte subsets, although natural killer (NK) cell numbers were the most profoundly affected, and CD4 T-cell numbers were the least affected. CD2, LFA-1, and CD56 were transiently up-regulated on the surface of NK cells exposed to rhIL-12 in vivo. Peripheral blood mononuclear cells obtained from cancer patients before rhIL-12 therapy exhibited defective NK cell cytotoxicity and T-cell-proliferative responses. Peripheral blood mononuclear cells obtained after lymphocyte recovery following the administration of a single 500 ng/kg dose of rhIL-12 displayed augmented NK cell cytolytic activity in four of four patients tested and enhanced T-cell proliferation in three of four patients tested. These studies confirm that doses of rhIL-12 resulting in significant immunological activity can be administered with acceptable toxicity to cancer patients. Furthermore, rhIL-12 therapy can reverse defects in NK cell and T-cell function that are associated with advanced cancer in humans.

Antineoplastic Agents↗

PubMed1998

Myeloid progenitor cell proliferation and mobilization effects of BB10010, a genetically engineered variant of human macrophage inflammatory protein-1alpha, in a phase I clinical trial in patients with relapsed/refractory breast cancer.

Macrophage Inflammatory Protein (MIP)-1alpha is myelosuppressive in vitro and in vivo for hematopoietic stem and immature subsets of myeloid progenitor cells, demonstrates some myeloprotective effects in mice treated with Ara-C and hydroxyurea, and has stem/progenitor cell mobilizing activity in mice. Based on these observations, BB10010, a genetic variant of MIP-1alpha, was assessed for effects on marrow and blood myeloid progenitor cells in patients with relapsed/refractory breast cancer. MIP-1alpha readily polymerizes, whereas BB10010 has a reduced tendency to form large polymers at physiological pH and ionic strength and retains biological activity. Patients were injected with 5, 10, 30 or 100 microg/kg BB10010 s.c. daily for 3 days. BB10010 significantly reduced the cycling status of marrow myeloid progenitors from pretreatment levels of 39-58% to 0 - 11% one day after the third and last injection of BB10010. This was associated with significant decreases in frequency of marrow progenitors (number of colonies formed per number of cells plated) and percent biopsied marrow CD34+ cells. The suppressive effects were reversible in patients and the rapidity of this reversal demonstrated in mouse studies. BB10010 had no effect on nucleated cellularity or on the proliferation of nucleated cells as assessed in marrow biopsies from the patients. These latter effects may in part reflect the noted decreased apoptosis of nucleated cells by BB10010. BB10010 also demonstrated significant but modest myeloid progenitor cell mobilizing capacity. Blood progenitors were in a slow or non-cycling state prior to treatment and this did not change after administration of BB10010. The above effects of BB10010 were similar at the four different dosage levels assessed. These results demonstrate in humans the suppressive and mobilizing effects of MIP-1alpha and BB10010 previously noted in vivo in mice.

Adult↗

PubMed1998

MacMolPlt: a graphical user interface for GAMESS.

A description of MacMolPlt, a graphical user interface for the General Atomic and Molecular Electronic Structure System, GAMESS, is presented. Major features include an input builder for GAMESS; and display and animation of molecular structure, normal modes of vibration, reaction paths, orbitals, total electron densities, molecular electrostatic potentials, and density differences. The strategy for direct computation of orbital, total electron density, and molecular electrostatic potential surfaces is discussed.

Chemical Phenomena↗

PubMed1998

The construction and interpretation of MCSCF wavefunctions.

The multiconfiguration self-consistent field (MCSCF) method offers the most general approach to the computation of chemical reactions and multiple electronic states. This review discusses the design of MCSCF wavefunctions for treating these problems and the interpretation of the resulting orbitals and configurations. In particular, localized orbitals are convenient both for selection of the appropriate active space and for understanding the computed results. The computational procedures for optimizing these wavefunctions and the techniques for recovery of dynamical correlation energy are reviewed.

Journal Article↗

PubMed1997

Recombinant methionyl human stem cell factor and filgrastim for peripheral blood progenitor cell mobilization and transplantation in non-Hodgkin's lymphoma patients--results of a phase I/II trial.

To examine the safety and efficacy of recombinant-methionyl human stem cell factor (r-metHuSCF), 38 patients with intermediate-grade or immunoblastic high-grade non-Hodgkin's lymphoma who were eligible for autologous transplantation were randomized to receive r-metHuSCF (5, 10, 15, or 20 microg/kg/d) plus Filgrastim (10 microg/kg/d) or Filgrastim (10 microg/kg/d) alone to mobilize peripheral blood progenitor cells. Subcutaneous administration of r-metHuSCF was well tolerated in conjunction with a multi-agent pre-medication regimen; local injection site reactions were the most commonly seen adverse event. The total mononuclear cell count, CD34+ cell content, granulocyte-macrophage colony-forming cells (GM-CFC), and burst-forming units-erythroid (BFU-E) per kilogram in the apheresis product was similar when all patients were analyzed by treatment cohort and mobilization regimen (Filgrastim or r-metHuSCF in combination with Filgrastim); however, when prior chemotherapy was taken into account in a supplementary analysis, clinically important differences were observed. Extensive prior therapy was defined as the amount of exposure to specific stem cell toxic chemotherapeutic agents that patients received. These agents include procarbazine, nitrogen mustard, melphalan, nitrosoureas (> or = 2 cycles of any of these drugs) or greater than 7.5 g of cytosine arabinoside. In these patients, there was an increased number of CD34+ cells (1.76 v 0.28 x 10(6)/kg), GM-CFC (20.5 v 5.0 x 10(4)/kg), and BFU-E (36.9 v 8.9 x 10(4)/kg) in patients receiving r-metHuSCF and Filgrastim (N = 18) compared with Filgrastim alone (N = 5). These patients also had a decreased time to an untransfused platelet count of 20 x 10(9)/L that was 10.5 days shorter in the patients who received r-metHuSCF and Filgrastim (12.5 v 23 days). These differences were not found to be statistically significant, possibly because of small size, but are clinically important.

Adult↗

PubMed1997

Sodium balance modulates thirst in normal man.

Several lines of evidence suggest that angiotensin II (AII) plays an important physiologic role in the control of thirst in laboratory animals but a conflicting one in humans. Sodium (Na+) balance plays a key role in the control of the renin-angiotensin system, but studies assessing the effect of sodium balance on thirst perception in humans are limited at best. To address this question, we studied the relationship between thirst perception and plasma osmolality during 5% saline infusion (.08 ml/kg/min x 120 min) in 5 healthy volunteers while in metabolic balance on both a 10 mEq. sodium (LS) and 200 mEq. sodium (HS) diet with and without infusion of AII (5 ng/kg/min). Thirst perception was quantified using a linear visual analogue scale. The relationship between serum Na+ (a measure of osmolality) and thirst perception was analyzed using linear regression. The mean x-intercept ([Na+] mEq/l) which represents the osmotic threshold to thirst was 138.2 +/- 0.5 in LS vs 140.7 +/- 0.8 in HS, p < 0.05. We conclude that the osmotic threshold for thirst is lower in LS (high endogenous AII) vs HS (low endogenous AII). There was no evidence for substantial extracellular volume change in HS vs LS with no significant differences in weight, hematocrit or total serum protein. Acute AII infusion did not result in changes in slope or x-intercept, but the pressor response to exogenous AII may have inhibited its dipsogenic effect (as has been shown in animal studies). These data suggest a physiologic role of sodium balance (possibly mediated via endogenous AII) in the control of thirst in normal humans.

Aldosterone↗

PubMed1996

A randomized placebo-controlled trial of recombinant human interleukin-11 in cancer patients with severe thrombocytopenia due to chemotherapy.

Thrombocytopenia is a complication of cancer treatment that can limit dose intensity. Interleukin-11 (IL-11) is a growth factor that increases platelet production. We conducted a multicenter, randomized, placebo-controlled trial of recombinant human IL-11 (rhIL-11) in 93 patients with cancer who had already been transfused platelets for severe thrombocytopenia resulting from chemotherapy. The patients had received platelet transfusions for nadir platelet counts of < or = 20,000/microL during the chemotherapy cycle immediately preceding study entry. Chemotherapy was continued during the study without dose reduction. Patients were randomized to receive placebo or rhIL-11 at 50 or 25 micrograms/kg subcutaneously once daily for 14 to 21 days beginning 1 day after chemotherapy. Eight of 27 (30%) evaluable patients treated with rhIL-11 at a dose of 50 micrograms/kg did not require platelet transfusions versus 1 of 27 (4%) patients who received placebo (P < .05). Five of 23 (18%) patients treated with rhIL-11 at 25 micrograms/kg avoided platelet transfusions (P = .23). Side effects were fatigue and cardiovascular symptoms, including a low incidence of atrial arrhythmias and syncope. There were no differences among treatment groups in the incidence of neutropenic fever, days of hospitalization, or number of red blood cell transfusions. This study shows that rhIL-11 treatment of a dose of 50 micrograms/kg significantly increases the likelihood that patients who have already been transfused platelets for severe chemotherapy-induced thrombocytopenia will not require platelet transfusions during a subsequent chemotherapy cycle.

Adolescent↗

PubMed1996

A phase I trial of recombinant human interleukin-11 (neumega rhIL-11 growth factor) in women with breast cancer receiving chemotherapy.

We performed a phase I trial of recombinant human interleukin-11 (rhIL-11) in women with breast cancer. Cohorts of three to five women were accrued to five dosage levels of rhIL-11 (10, 25, 50, 75, and 100 micrograms/kg/d). rhIL-11 alone was administered by a daily subcutaneous injection for 14 days during a 28-day prechemotherapy "cycle 0." Patients (pts) subsequently received up to four 28-day cycles of cyclophosphamide (1,500 mg/m2) and doxorubicin (60 mg/m2) chemotherapy followed by rhIL-11 at their assigned dose (days 3 through 14). Sixteen pts (13 stage IV, 3 stage IIIB) were accrued to this study. Median age was 53 years and median Eastern Cooperative Oncology Group Performance Status was 0. A grade 3 neurologic event was seen in 1 pt at 100 micrograms/kg. Because of the degree of grade 2 constitutional symptoms (myalgias/arthralgias and fatigue) at 75 micrograms/kg, dose escalation was stopped and 75 micrograms/kg was the maximally tolerated dose. No other grade 3 or 4 adverse events related to rhIL-11 were seen. The administration of rhIL-11 was not associated with fever. Reversible grade 2 fatigue and myalgias/arthralgias were seen in all pts at 75 micrograms/kg. Weight gain of 3% to 5% associated with edema was seen at doses > 10 micrograms/kg but a capillary leak syndrome was not seen. rhIL-11 alone was associated with a mean 76%, 93%, 108%, and 185% increase in platelet counts at doses of 10, 25, 50, and 75 micrograms/kg, respectively. No significant changes in leukocytes were seen. A mean 19% decrease in hematocrit was observed. Acute-phase proteins increased with treatment at all doses. Compared with patients at the 10 micrograms/kg dose, patients receiving doses > or = 25 micrograms/kg experienced less thrombocytopenia in the first two cycles of chemotherapy. We conclude that rhIL-11 has thrombopoietic activity at all doses studied, is well tolerated at doses of 10, 25, and 50 micrograms/kg, and at doses > or = 25 micrograms/kg has the potential to reduce chemotherapy-induced thrombocytopenia in this model.

Adult↗

PubMed1996

Alternatively spliced exons encode the tissue-specific 5' termini of leukocyte pp52 and stromal cell S37 mRNA isoforms.

The pp52 gene encodes an intracellular, F-actin-binding phosphoprotein (also designated LSP1 and WP34) postulated to function in cytoskeleton dynamics and cell motility. We previously reported that different mRNA isoforms are expressed from this gene in cells of the leukocyte lineage versus mesodermally derived cells. These tissue-specific mRNA isoforms are identical except for 5'-untranslated regions and sequences coding for unique N-termini of 23 and 21 amino acids, respectively. As this is a single-copy gene, we predicted that these tissue-specific mRNA isoforms would be generated by alternative RNA splicing. We report that the unique 5' sequences in these mRNA isoforms are encoded in two separate exons containing ATG initiation codons. These features confirm that the pp52 and S37 mRNA isoforms are generated by alternative RNA splicing and establish that they are independently translated. Other results presented here indicate that the differential expression of these exons in leukocytes versus mesodermally derived cells is regulated at the level of transcription by tissue-specific promoters.

Alternative Splicing↗

PubMed1996

In vivo/in vitro correlations for four differently dissolving ketorolac tablets.

This study assesses whether in vitro immediate release ketorolac tablet dissolution profiles (utilizing the recently proposed USP dissolution test for ketorolac tablets) can be correlated with in vivo plasma pharmacokinetic parameters. Four batches of ketorolac tablets were utilized: a ketorolac tablet batch that demonstrated a rapid dissolution rate during USP in vitro dissolution testing, two tablet batches that were manufactured such that they dissolved at moderate rates, and a tablet batch that was manufactured such that it dissolved at a distinctly slow rate. The single-dose mean pharmacokinetic characteristics and relative bioavailability of the four different 10 mg ketorolac tromethamine tablets were evaluated in 12 healthy volunteers in a randomized study of Latin square design. The amount dissolved of the various tablets at 10, 20, and 30 min was in the order of fast-dissolving tablets > medium-1-dissolving tablets = medium-2-dissolving tablets > slow-dissolving tablets. In general, the profiles of the average plasma concentrations for ketorolac were similar for the fast- and the two medium-dissolving tablet batches (even though a statistically significant difference was found between the tmax of the fast-dissolving tablet and one of the medium-dissolving tablet batches). The mean plasma concentrations for the slow-dissolving tablet, however, reached peak levels much later, with the peak also being significantly smaller. There were no statistically significant differences in the total AUC or in the mean plasma half-lives among the four formulations. Good correlations were obtained for mean tmax versus the percentage dissolved at 20, 30, and 45 min. Correlations were generally weaker for percentage dissolved versus Cmax or percentage bioavailability. This indicates that in vitro dissolution testing for immediate release ketorolac tablets can be a useful indicator of in vivo time to maximum plasma concentration when comparing similarly formulated tablets. Further, the proposed USP dissolution test and specification would have appropriately failed the slow-dissolving tablet batch, which demonstrated a significantly slower rate of absorption as per tmax and Cmax.

Adult↗

PubMed1996

Thrombopoietic activity of recombinant human interleukin 11 in cancer patients receiving chemotherapy.

Interleukin 11 (IL-11) is a newly identified hematopoietic growth factor that exerts its primary effect on megakaryocyte maturation and platelet production. It has a unique receptor, signaling by which is mediated by the glycoprotein (GP) 130 pathway. IL-11 is synergistic with stem-cell factor (c-kit ligand) in vitro, enhancing proliferation of primitive hematopoietic stem cells, and has been shown to be critical to the process of polyploidization and maturation. In preclinical models, IL-11 was shown to enhance platelet recovery following intensive chemotherapy, and in murine bone-marrow transplant models it accelerates the recovery of all hematopoietic lineages. Nonhuman primate studies have demonstrated a dose-related thrombopoietic effect; however, no myeloid effect has been observed. In clinical phase I trials, subcutaneous IL-11 was well tolerated and induced a dose-related thrombopoietic effect in women with breast cancer. IL-11 at doses of > 25 micrograms/kg per day appeared to reduce the severity of chemotherapy-induced thrombocytopenia. In a randomized phase II trial, IL-11 at 50 micrograms/kg reduced the requirement for platelet transfusions as compared with that in placebotreated controls. IL-11 is an interesting factor; however, further studies are needed to confirm its activity and are in progress.

Antineoplastic Agents↗

PubMed1996

Effects of recombinant human interleukin-11 (Neumega rhIL-11 growth factor) on megakaryocytopoiesis in human bone marrow.

We examined the effects of recombinant human interleukin 11 (rhIL-11) on in vivo human hematopoiesis. Twelve women with advanced breast cancer and no evidence of bone marrow (BM) involvement were treated with 10, 25, 50, or 75 micrograms/kg/day of rhIL-11 administered subcutaneously for 14 consecutive days. Examination of bone marrow trephine biopsies obtained before and after rhIL-11 treatment revealed unchanged BM cellularity at all doses, and a statistically significant increase in megakaryocyte (MK) frequencies (from 0.5 +/- 0.1% to 1.0 +/- 0.3%) following administration of the two highest doses (p < 0.001). The BM biopsies also showed an increased proportion of immature myeloid and erythroid precursors following 14 days of treatment in all cases. The mean proportion of marrow cells stained with PC10, a monoclonal antibody (mAb) that recognizes the proliferating cell nuclear antigen (PCNA), increased from 16.3 +/- 5.7% to 45.8 +/- 17.1% (p < 0.001) following the two highest treatment doses. Most of the PC10+ cells were promyelocytes and proerythroblasts. In this same group, the proportion of PC10+ MKs increased from 28.3 +/- 11.5% to 56.8 +/- 24.3% (p < 0.01) after treatment, while megakaryocyte ploidy analysis revealed a greater number of higher ploidy (64N) megakaryocytes following rhIL-11 treatment (p < 0.012). Numbers of BM and peripheral blood (PB) CD34+, CD34+DR+, and CD34+DR- cells did not change following rhIL-11 treatment. Following rhIL-11 therapy at the highest dose studied, a 3- and 10-fold increase in the number of committed BM MK progenitor cells (CFU-MK) was observed in two of three patients, while no change was seen in the number of the other BM or PB progenitor cells examined. rhIL-11 administration was also associated with an increase in BM reticulin content (fibrosis grade 1-2) in 7 patients. These results indicate that the administration of rhIL-11 to patients with normal hematopoiesis stimulates MK endoreduplication, PCNA expression, and, at high doses, increases MK and CFU-MK progenitor cell numbers. In addition, rhIL-11 was able to stimulate precursor cells of different marrow lineages without affecting the number of assayable progenitor cells.

Administration, Cutaneous↗

PubMed1995

Genetic heterogeneity in isogenic homozygous clonal zebrafish.

The C32 isogenic homozygous diploid (IHD) strain of the zebrafish (Danio rerio) was found to be polyallelic at a malate dehydrogenase locus (sMdh-A). A variant allele is thought to have arisen via mutation within the past 10 bisexual generations that have maintained the strain since its last gynogenetic cloning event; this unique allele now predominates at the sMdh-A locus. The estimated mutation rate in this species is sufficiently high that long-term genetic homogeneity of its IHD clones cannot be assumed. Researchers using such bisexually maintained clones should be aware that they are not necessarily using genetically uniform subjects. Genetic uniformity of cloned IHD zebrafish will be maximized if experimental subjects are obtained soon after a cloning event.

Alleles↗

PubMed1995

A phase I trial of recombinant human interleukin-6 in patients with myelodysplastic syndromes and thrombocytopenia.

To evaluate the hematologic effects of recombinant human interleukin-6 (rhIL-6, Escherichia coli, SDZ ILS 969, IL-6), and determine its toxicity profile, we performed a phase I trial of IL-6 in 22 patients with various myelodysplastic syndromes (MDS), platelet counts < 100,000/microL, and < 5% bone marrow (BM) blasts. Patients received one of four doses of IL-6 (1.0, 2.5, 3.75, and 5.0 micrograms/kg/d) as a subcutaneous injection on day 1, followed by a 7-day wash-out period, and then 28 days of IL-6 therapy. Dose-limiting toxicities of fatigue, fever, and elevated alkaline phosphatase were seen at 5.0 micrograms/kg/d; the maximum tolerated dose was 3.75 micrograms/kg/d. All patients experienced at least grade II fever and all had an increase in acute phase proteins. Eight patients (36%) experienced at least a transient improvement in platelet counts; three fulfilled the criteria for response, whereas five others had clinically significant increases that failed to meet response criteria. Various IL-6-related toxicities prevented more than three patients from receiving maintenance therapy. Two of the three patients who received maintenance IL-6 therapy had a persistent increase in platelet counts, during 3 and 12 months of IL-6 therapy, respectively. Laboratory studies indicated that IL-6 increased the frequency of higher ploidy megakaryocytes but did not significantly increase the number of assayable megakaryocytic progenitor cells, suggesting that IL-6 acts as a maturational agent rather than a megakaryocyte colony-stimulating factor. Although IL-6 therapy can promote thrombopoiesis in some MDS patients, its limited activity and significant therapy-related toxicity preclude its use as a single agent in this patient population. Further studies, combining low doses of IL-6 with other hematopoietic growth factors, are underway.

Acute-Phase Proteins↗