The anemia of chronic disorders: studies of marrow regulation and iron metabolism

Marrow regulation and iron metabolism were evaluated in 17 patients with mild or moderate anemia associated with chronic disorders. In addition, whole blood P50 and red cell 2,3-diphosphoglycerate (DPG) levels were measured. The study group consisted of seven patients with non-hematologic malignancies, nine with infection or inflammation, and one with idiopathic hypoproliferative anemia. The mean whole blood P50 and DPG levels were elevated to 28.5 +/- 1.9 mm Hg and 7.03 +/- 0.83 mumole/ml packed RBC, respectively, as compared to normal values of 26.6 +/- 0.6 mm Hg and 4.83 +/- 0.33 mumole/ml packed RBC. Erythropoietin (ESF) excretion was variable (1.1-28.7 IRP U, day), clearly elevated above normal in only three patients and, within the study group, bore no relation to hematocrit. While nine of the 17 subjects had ESF excretion rates within the 95% limits predicted by hematocrit, the remaining eight had lower than expected values. No significant differences in ferrokinetics, ESF excretion, or hematologic profile were found between patients with malignancy and those with inflammation. Marrow transit times correlated inversely with both serum and urine ESF activity (r = -0.57, p less than 0.02; and r = -0.63, p less than 0.01, respectively), indicating that the marrow reticulocyte release response to ESF stimulation was unimpaired. Erythroid iron turnovers were unrelated to serum or urinary ESF activity but were significantly correlated with serum iron levels expressed as microgram/100 ml whole blood (r = 0.56, p less than 0.02). These studies suggest that there is an intraerythrocytic response to the anemia in this group of patients, document that reduced ESF production is not a uniform finding with the anemia of chronic disorders, and provide evidence that the marrow proliferative response to anemia is limited in many patients primarily by the availability of iron.     

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.     

The changing face of gastroschisis and omphalocele in southeast Georgia

Objective: To document trends in the clinical characteristics of gastroschisis and omphalocele in southeast Georgia, USA, from 1994 to 2002.

Methods: All babies with an abdominal wall defect in a 19-county region were referred to one Perinatal Center for genetic counseling, level II ultrasound scans, pregnancy follow-up and delivery. Karyotyping was offered for omphalocele, advanced maternal age, family history predisposing to aneuploidy, and gastroschisis with an additional anomaly.

Results: There were 64 patients, 34 with gastroschisis and 30 with omphalocele. From 1994 to 2002, the birth prevalence of gastroschisis was 1:3600 and omphalocele 1:3400, but from 2000 to 2002, gastroschisis increased to 1:1667, while omphalocele increased to only 1:2709. Gender distribution was different: for gastroschisis the M:F ratio was 1:2.1; for omphalocele the ratio was 1.7:1. In the patients with omphalocele, 90% had an amniocentesis and 9/27 were aneuploid: five had trisomy 18, three had trisomy 13 and one had trisomy 21. Seventy-six per cent of the patients with omphalocele had associated anomalies, but only 17.6% of those with gastroschisis. Mothers whose babies had gastroschisis showed a trend to progressively younger age, while no such trend was observed among mothers whose babies had omphalocele.

Conclusion: The birth prevalence of abdominal wall defects in general is increasing, but more notably for gastroschisis. Maternal age continues to decrease for gastroschisis. In the study population, gender distribution showed a statistically significant variation between the defects.     

Comparison of two screen-film combinations in contact and magnification mammography: detectability of microcalcifications

A new dual-screen, dual-emulsion-film combination that allows a decrease in radiation dose of approximately 66% was compared with a widely used single-screen, single-emulsion-film system in contact and magnification mammography. Clustered microcalcifications randomly superimposed on a breast phantom were detected, and the location and number of individual calcifications were determined by four observers. The detectability of calcifications, determined with a receiver operating characteristic (ROC) analysis area, was 0.92 for magnification and 0.82 for contact mammography with the single-emulsion-film system, compared with 0.84 and 0.72, respectively, with the dual-emulsion-film system. More clusters were correctly located and more individual calcifications were counted with magnification than with contact mammography. The dual-emulsion-film system with the magnification technique performs as well as the single-emulsion-film system with the contact technique, while retaining a decrease in required dose of approximately 40%.     

Increased left ventricular torsion in hypertrophic cardiomyopathy mutation carriers with normal wall thickness

Background

Increased left ventricular (LV) torsion has been observed in patients with manifest familial hypertrophic cardiomyopathy (HCM), and is thought to be caused by subendocardial dysfunction. We hypothesize that increased LV torsion is already present in healthy mutation carriers with normal wall thickness.

Methods

Seventeen carriers with an LV wall thickness <10 mm, and seventeen age and gender matched controls had cardiovascular magnetic resonance (CMR) cine imaging and tissue tagging. LV volumes and mass were calculated from the cine images. LV torsion, torsion rate, endocardial circumferential strain and torsion-to-endocardial-circumferential-shortening (TECS) ratio, which reflects the transmural distribution in contractile function, were determined using tissue tagging.

Results

LV volumes, mass and circumferential strain were comparable between groups, whereas LV ejection fraction, torsion and TECS-ratio were increased in carriers compared to controls (63 ± 3% vs. 60 ± 3%, p = 0.04, 10.1 ± 2.5° vs. 7.7 ± 1.2°, p = 0.001, and 0.52 ± 0.14°/% vs. 0.42 ± 0.10°/%, p = 0.02, respectively).

Conclusions

Carriers with normal wall thickness display increased LV torsion and TECS-ratio with respect to controls, which might be due to subendocardial myocardial dysfunction. As similar abnormalities are observed in patients with manifest HCM, the changes in healthy carriers may be target for clinical intervention to delay or prevent the onset of hypertrophy.     

Effects of 7,8-dihydro-8-oxo-deoxyguanosine on antigen challenge in ovalbumin-sensitized mice may be mediated by suppression of Rac

Background and purpose:

Earlier we reported that 7,8-dihydro-8-oxo-deoxyguanosine (8-oxo-dG), an oxidatively modified guanine nucleoside, exerted anti-inflammatory activity through inactivation of the GTP binding protein, Rac. In the present study, the effects of 8-oxo-dG were investigated on responses to antigen challenge in sensitized mice, as Rac is also involved at several steps of the immune process including antigen-induced release of mediators from mast cells.

Experimental approach:

Mice were sensitized and challenged with ovalbumin without or with oral administration of 8-oxo-dG during the challenge. Effects of 8-oxo-dG were assessed by measuring lung function, cells and cytokines in broncho-alveolar lavage fluid (BALF) and serum levels of antigen-specific IgE. Rac activity in BALF cells was also measured.

Key results:

8-oxo-dG inhibited the increased airway resistance and decreased lung compliance of sensitized and challenged mice to the levels of non-sensitized control mice and lowered the increased leukocytes particularly, eosinophils, in BALF. Furthermore, 8-oxo-dG suppressed allergy-associated immune responses, such as raised anti- ovalbumin IgE antibody in serum, increased expression of CD40 and CD40 ligand in lung, increased interleukin-4, -5, -13, interferon-γ and tumour necrosis factor-α in BALF and mRNA levels of these cytokines in BALF cells, dose-dependently. The corresponding purine, 8-oxo-guanine, showed no effects in the same experiments. Finally, 8-oxo-dG, but not 8-oxo-guanine, inhibited the increased Rac activity in sensitized and challenged mice.

Conclusion and implications:

8-Oxo-dG had anti-allergic actions that might be mediated by Rac inactivation. This compound merits further evaluation of its therapeutic potential in allergic asthma.     

The influence of chronic diseases and poor working conditions in working life expectancy across educational levels among older employees in The Netherlands

ObjectivesThis study aims to estimate the influence of chronic diseases and poor working conditions – across educational levels – on working life expectancy (WLE) and working years lost (WYL) in the Dutch workforce after age 50.MethodsInformation on demographics, chronic diseases, and working conditions from 11 800 Dutch workers aged 50–66 years participating in the Study on Transitions in Employment, Ability and Motivation (STREAM) from 2010/2015 was enriched with monthly information on employment status from Statistics Netherlands up to 2018. In a multistate model, transitions were calculated between paid employment and involuntary exit (disability benefits, unemployment) and voluntary exit (economic inactivity, early retirement) to estimate the impact of education, chronic diseases, and working conditions on WLE and WYL between age 50 and 66.ResultsWorkers with a chronic disease (up to 1.01 years) or unfavorable working conditions (up to 0.63 years) had more WYL due to involuntary pathways than workers with no chronic disease or favorable working conditions. The differences in WYL between workers with and without a chronic disease were slightly higher among workers with a lower education level (male: 0.85, female: 1.01 years) compared to workers with a high educational level (male: 0.72, female: 0.82 years). Given the higher prevalence of chronic diseases and unfavorable working conditions, WYL among lower educated workers were higher than among higher educated workers.ConclusionsThe presence of a chronic disease or unfavorable working conditions, more prevalent among lower educated workers, contribute substantially to WYL among older workers. This will increase educational inequalities in working careers.