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G M Brittenham

Publications and source records attributed to G M Brittenham.

At least 73 records · Page 4Linked to original sources
PubMed1991

Detection of two-component mixtures of lognormal distributions in grouped, doubly truncated data: analysis of red blood cell volume distributions.

We have examined the statistical requirements for the detection of mixtures of two lognormal distributions in doubly truncated data when the sample size is large. The expectation-maximization algorithm was used for parameter estimation. A bootstrap approach was used to test for a mixture of distributions using the likelihood ratio statistic. Analysis of computer simulated mixtures showed that as the ratio of the difference between the means to the minimum standard deviation increases, the power for detection also increases and the accuracy of parameter estimates improves. These procedures were used to examine the distribution of red blood cell volume in blood samples. Each distribution was doubly truncated to eliminate artifactual frequency counts and tested for best fit to a single lognormal distribution or a mixture of two lognormal distributions. A single population was found in samples obtained from 60 healthy individuals. Two subpopulations of cells were detected in 25 of 27 mixtures of blood prepared in vitro. Analyses of mixtures of blood from 40 patients treated for iron-deficiency anemia showed that subpopulations could be detected in all by 6 weeks after onset of treatment. To determine if two-component mixtures could be detected, distributions were examined from untransfused patients with refractory anemia. In two patients with inherited sideroblastic anemia a mixture of microcytic and normocytic cells was found, while in the third patient a single population of microcytic cells was identified. In two family members previously identified as carriers of inherited sideroblastic anemia, mixtures of microcytic and normocytic subpopulations were found. Twenty-five patients with acquired myelodysplastic anemia were examined. A good fit to a mixture of subpopulations containing abnormal microcytic or macrocytic cells was found in two. We have demonstrated that with large sample sizes, mixtures of distributions can be detected even when distributions appear to be unimodal. These statistical techniques provide a means to characterize and quantify alterations in erythrocyte subpopulations in anemia but could also be applied to any set of grouped, doubly truncated data to test for the presence of a mixture of two lognormal distributions.

Adolescent↗
PubMed1990

Limitations of the erythropoietic response to serial phlebotomy: implications for autologous blood donor programs.

Autologous blood (AB) deposit before elective surgery is a widely endorsed and rapidly expanding transfusion practice that reduces homologous blood (HB) needs but does not minimize HB transfusion in donors who are unsuccessful in predonating the amount of AB requested by their surgeon. To study limitations of the erythropoietic response in AB donors we have conducted a prospective analysis of 72 consecutive adult AB donors scheduled for orthopedic surgery. The data in this report indicate that endogenous erythropoietin response is inadequate in at least 58% of AB donors who are successful in predonating the requested amount of AB and that AB donors with lower initial body iron reserves relative to the amount of blood requested have a greater risk of deferral; 15 of 45 female patients (33%) were unable to predonate the requested amount of AB. Lower circulating red cell volumes (reflecting anemia at first blood donation, smaller body size, or both) and/or lower storage iron pools are contributing factors in this population. This report also indicates that a significant number of AB units have red cell volumes below minimum standards for blood donation, which has important implications in a risk/benefit analysis of whether nontransfused AB units should be "crossed-over" for HB transfusion, and that future studies designed to maximize AB procurement should include an evaluation of recombinant erythropoietin therapy in AB programs and therapeutic alternatives to ferrous sulfate as iron supplementation in AB donors.

Blood Donors↗
PubMed1988

Interleukin 1 administration in mice produces hypoferremia despite neutropenia.

To determine whether the hypoferremic response to inflammation requires neutrophils, we administered human recombinant IL-1 to mice made neutropenic with cyclophosphamide. With single intraperitoneal injections of IL-1 the plasma iron concentrations decreased significantly in mice with either normal neutrophil counts or neutropenia. After single injections transferrin concentrations were not significantly changed, but the decrease in serum iron lowered mean transferrin saturations from a baseline of 45 to 24-30% in nonneutropenic mice, and from 99 to 70-77% in neutropenic mice. Similar changes were observed after intraperitoneal injections of Escherichia coli. 4-d continuous infusions of IL-1 also led to reductions in serum iron concentrations, but transferrin concentrations doubled. The combination of a decrease in serum iron and an increase in transferrin concentration after chronic infusion in neutropenic mice led to a greater decline in mean transferrin saturations, from a baseline of 110 to 25%. In mice not given cyclophosphamide, chronic IL-1 infusion was associated with a reduction in mean hemoglobin concentrations from 14.7 to 13.5 g/dl, consistent with restricted availability of iron for erythropoiesis associated with low saturation of transferrin. We conclude that IL-1 can decrease the serum iron despite profound peripheral neutropenia and that transferrin in a positive acute phase reactant in the mouse.

Agranulocytosis↗
PubMed1987

High-dose carbonyl iron for iron deficiency anemia: a randomized double-blind trial.

To determine if high doses of oral iron could shorten the duration of therapy necessary to treat Fe deficiency anemia, high-dose Fe 600 mg three times per day (given as nontoxic carbonyl Fe) was compared with standard ferrous sulfate 60 mg Fe++ three times per day in a randomized, double-blind, 3-wk trial involving 36 female blood donors with mild Fe deficiency anemia. In animal studies, both forms of Fe have similar bioavailability when administered in equal amounts. High-dose carbonyl Fe was well tolerated with gastrointestinal side effects similar those observed with standard FeSO4 therapy. The 10-fold larger amount of Fe resulted in a mean 1.5-fold increase in estimated Fe absorption. Both regimens corrected anemia but neither replenished storage Fe. These results suggest that the principal advantage to the use of carbonyl Fe would derive from its safety rather than from the large doses that can be given.

Adolescent↗
PubMed1987

Statistical and graphical evaluation of erythrocyte volume distributions.

A protocol for the statistical and graphical evaluation of erythrocyte volume distributions has been developed using expectation-maximization methods for distribution parameter estimation. In a reference sample group of 50 healthy individuals, none of the red cell volume distributions determined by an aperture impedance method differed significantly from a log normal model. Measurements in 211 patients with anemia provided evidence that similar statistical methods could be used for the characterization of abnormal red cell volume distributions. Graphical displays accurately summarize the quantitative information derived from the analysis of volume distributions and show a reference distribution fitted to the observed distribution against the range of distributions found in healthy individuals. This protocol provides a specific, statistically valid implementation of the general principles for the analysis of cell volume distributions proposed by the International Committee for Standardization in Hematology.

Anemia↗
PubMed1987

Iron deficiency anemia and iron therapy effects on infant developmental test performance.

The behavioral effects of iron deficiency and its treatment were evaluated in a double-blind randomized controlled community-based study of 191 Costa Rican infants, 12 to 23 months of age, with various degrees of iron deficiency. The Bayley Scales of Infant Development were administered before and both 1 week and 3 months after IM or oral administration of iron. Appropriate placebo-treated control infants were also tested. Infants with iron deficiency anemia showed significantly lower mental and motor test scores, even after considering factors relating to birth, nutrition, family background, parental IQ, and the home environment. After 1 week, neither IM nor oral iron treatments differed from placebo treatment in effects on scores. After 3 months, lower mental and motor test scores were no longer observed among iron-deficient anemic infants whose anemia and iron deficiency were both corrected (36%). However, significantly lower mental and motor test scores persisted among the majority of initially anemic infants (64%) who had more severe or chronic iron deficiency. Although no longer anemic, they still showed biochemical evidence of iron deficiency after 3 months of treatment. These persistent lower scores suggest either that iron therapy adequate for correcting anemia is insufficient to reverse behavioral and developmental disturbances in many infants or that certain ill effects are long-lasting, depending on the timing, severity, or chronicity of iron deficiency anemia in infancy.

Anemia, Hypochromic↗
PubMed1987

Behavioral alterations in iron deficiency.

This review has examined recent evidence from human studies that iron deficiency adversely affects behavior by impairing cognitive function, producing noncognitive disturbances, and limiting activity and work capacity. The body of research taken as a whole provides increasingly persuasive arguments for intensifying efforts to prevent and treat iron deficiency anemia. Cognitive Function. There is reasonably good evidence that mental and motor developmental test scores are lowered among infants with iron deficiency anemia. Although the research on cognitive function in iron-deficient older children and adults is sparse and diverse, it suggests that there may be alterations in attentional processes associated with iron deficiency. Iron therapy has not yet been shown effective in completely correcting the observed disturbances. Although some aspects of cognitive function seem to change with iron therapy, lower developmental, IQ, and achievement test scores have still been noted after treatment. Noncognitive Disturbances. A variety of noncognitive alterations during infant developmental testing has also been observed, including failure to respond to test stimuli, short attention span, unhappiness, increased fearfulness, withdrawal from the examiner, and increased body tension. Exploratory analyses suggest that such behavioral abnormalities may account for poor developmental test performance in infants with iron deficiency anemia. These studies indicate the fruitfulness of examining noncognitive aspects of behavior, such as affect and activity, in addition to specific cognitive processes. Activity and Work Capacity. There has been a steady accumulation of evidence that iron deficiency anemia limits maximal physical performance, submaximal endurance, and spontaneous activity in the adult, resulting in diminished work productivity with attendant economic losses. The mechanisms underlying these effects, the extent to which anemia or iron deficiency separate from anemia is responsible, and the counterpart in infants and children remain to be established.

Adolescent↗
PubMed1987

Uniformity of liver density and nonheme (storage) iron distribution.

The extent of variation in tissue density and hepatic nonheme iron concentration has been examined at autopsy in 21 adult livers. Samples were taken from each liver at inferior and superior sites in the midaxillary, anterior axillary, and midclavicular lines. Histologic examination showed diffuse metastatic carcinoma, cirrhosis, fibrosis, necrosis, steatosis, or congestion in 19 livers; two livers were normal. Density was determined by saline displacement of 0.5- to 1.0-g specimens. Nonheme iron concentration was measured at each site in samples of the size obtained by wedge (0.5 to 1.0 g) and percutaneous needle (0.005 to 0.010 g) biopsy using specially developed chemical assays. Density was uniform within each liver. Despite the inclusion of diseased tissues, the variation in density among the 21 livers was small (coefficient of variation, 1.25%). The mean (+/- 1 SD) hepatic density was 1.051 +/- 0.013 g/mL (range, 1.017 to 1.077 g/mL). Within each liver, the nonheme iron also was uniformly distributed among the six sites. Chemical measurements of nonheme iron concentration were not significantly different in samples of the size obtained by wedge or percutaneous liver biopsy. All the hepatic nonheme iron determinations were below the upper 95% confidence limit of concentrations in adult males (480 micrograms/g). In the absence of focal lesions, the uniformity in hepatic density and nonheme iron distribution supports the assumption of several clinical methods for measuring liver storage iron (wedge and needle biopsy, determination of hepatic magnetic susceptibility, computed tomography, and magnetic resonance imaging) that one sample of liver tissue is representative of the whole organ.

Adult↗
PubMed1987

Pathology of dietary carbonyl iron overload in rats.

Serial light microscopic and ultrastructural studies were performed in rats with experimental iron overload produced by dietary supplementation with carbonyl (elemental) iron over a 12-month period. Hepatic iron increased rapidly to concentrations approximately 40 to 90 times those of control rats by 3 months. Within the liver, iron deposition was initially confined to periportal (zone 1) hepatocytes but subsequently extended to midzonal (zone 2) and centrilobular (zone 3) hepatocytes. Reticuloendothelial cell deposits of iron increased gradually and became prominent after 3 months. At this time, morphologic evidence of hepatocellular injury was mild and subtle with occasional foci of spotty necrosis and ultrastructural subcellular organelle damage. By 8 months, iron deposition was massive. Portal areas were enlarged with collections of iron-loaded macrophages and increased collagenous tissue. This portal fibrous tissue extended between periportal (zone 1) hepatocytes at sites of maximal iron deposition and around iron-loaded Kupffer cells and macrophages. At 12 months, the periportal (zone 1) fibrosis was more pronounced. These serial morphologic studies are the first to demonstrate the production of hepatic fibrosis by chronic dietary iron overload. This experimental model may reproduce important components of the pathophysiologic sequence of chronic liver damage seen in iron overload states in humans.

Animals↗
PubMed1986

Dietary iron overload persists in rural sub-Saharan Africa.

In a survey of 505 rural Zimbabweans, iron overload was found almost exclusively among men who consumed traditional beer brewed in steel drums. Among drinkers aged over 45 years, 23 of 111 men (21%) had high serum ferritin and a transferrin saturation of over 70%, a combination that indicates a risk of liver disease and other pathological effects from excess body iron. Iron overload, which is reported to be decreasing among urban Africans, may remain a public health issue in rural areas where more than 80% of the people of sub-Saharan Africa live.

Adult↗