Contrasting effects of recombinant human granulocyte-macrophage colony- stimulating factor (CSF) and granulocyte CSF treatment on the cycling of blood elements in childhood-onset cyclic neutropenia

Recombinant human granulocyte colony-stimulating factor (G-CSF) treatment has been shown to increase average neutrophil counts substantially in patients with childhood-onset cyclic neutropenia (or "cyclic hematopoiesis"), but not to eliminate the cyclic oscillations of neutrophil counts or those of other blood elements (monocytes, platelets, eosinophils, and reticulocytes) that are characteristic of this hematopoietic disorder. Indeed, oscillations of neutrophil counts are amplified during G-CSF treatment. We have compared the effects of recombinant granulocyte-macrophage-CSF (GM-CSF) with those of G-CSF in three patients with this disease (2 men and 1 woman, 17, 30, and 32 years of age). These patients were treated with GM-CSF (2.1 micrograms/kg/day, subcutaneously) for 6 weeks, preceded and followed by 6 to 13 weeks of detailed observation to document changes in the cyclic oscillations of blood neutrophils and other blood elements; two of the patients were subsequently treated with G-CSF (5.0 micrograms/kg/d, subcutaneously) and observed for comparable periods of time. Unlike G-CSF treatment, which increased average neutrophil counts more than 20-fold, GM-CSF increased neutrophil counts only modestly, from 1.6- to 3.9-fold, although eosinophilia of varying prominence was induced in each patient. However, at the same time, GM-CSF treatment dampened or eliminated the multilineage oscillations of circulating blood elements (neutrophils, monocytes, platelets, and/or reticulocytes) in each of the patients. In contrast, G-CSF treatment of the same patients markedly amplified the oscillations of neutrophil counts and caused the cycling of other blood elements (monocytes in particular) to become more distinct. These findings support the conclusion that the distinctive cycling of blood cell production in childhood-onset cyclic neutropenia results from abnormalities in the coordinate regulation of both GM-CSF-responsive, multipotential progenitor cells and G-CSF-responsive, lineage-restricted, neutrophil progenitors.     

Neurologic evaluation of workers previously diagnosed with solvent-induced toxic encephalopathy

We examined 52 railroad workers with long-term occupational solvent exposures (average 22 years duration) who had been previously diagnosed by others as having solvent-induced toxic encephalopathy. All described episodes of transient intoxication associated with occupational solvent exposure. Persistent symptoms developed, an average, 16 years after exposure onset and included impaired memory (38), altered mood (21), imbalance (18), and headache (17). Thirteen workers had mild mental status abnormalities, but none fulfilled conventional clinical criteria for encephalopathy or dementia. None had abnormal blink reflex (51) or abnormal electroencephalographic (39) studies. Eight of 47 magnetic resonance imaging studies showed evidence of scattered ischemic lesions among workers with known diabetes mellitus (2), elevated blood pressure (4), or peripheral vascular disease (2). One magnetic resonance imaging scan showed mild cortical atrophy. In stepwise multiple linear and logistic regression models, no statistically significant (P < 0.05) dose-response relationships were found between exposure duration and symptoms or signs that were suggestive of encephalopathy. However, the number of symptoms (P < 0.001) and the number of signs (P = 0.05) were associated with current use of central nervous system-active medications. Further, lower Mini-Mental Status Examination scores were associated with a history of alcohol abuse (P = 0.01) and lower educational level (P = 0.03). The number of chief symptoms involving memory, mood, balance, or headache differed significantly among workers in different geographic sites (F(3.48) = 2.94, P = 0.04), a finding that was not explained by job title or exposure duration. There also was a significant (P = 0.0001) inverse relationship between initial exposure year (r2 = 0.60) or total years of exposure through 1987 (r2 = 0.56) and interval to major neurologic symptom onset, suggesting that factors other than solvent exposure account in part for worker complaints. We found no objective neurologic evidence supportive of toxic encephalopathy or any other uniform syndrome among these individuals, and most complaints were explained by neuropsychological factors or conditions unrelated to occupational solvent exposure.     

Response to oral β-carotene supplementation in patients with cystic fibrosis: a 16-month follow-up study

The aim of this study was to determine the efficacy of long-term oral β -carotene supplementation for correcting impaired β -carotene status in cystic fibrosis patients. Thirty-five patients (2.3-30.5 years of age) with coefficients of fat absorption of 46-96% (median 88%) received β -carotene 0.5 mg/kg daily and were followed over a 16-month treatment period. Baseline plasma β -carotene concentrations in patients (meanSD, 0.090.06 μ mol/1) were significantly lower than those of age-matched controls (0.860.56 μ mol/1) ( p < 0.0001). Concentrations increased rapidly and reached a plateau at or before 3 weeks that was maintained throughout the study period. Values obtained at 3 weeks (0.890.64 μ mol/1) were significantly higher ( p < 0.0001) than those at baseline and did not differ from controls. Plasma retinol and α -tocopherol concentrations increased during the observation period, but remained within normal ranges. Plasma retinyl palmitate, which was below the detection limit in all but one patient at baseline, did not increase. Thus oral β -carotene supplementation is effective and normalizes β -carotene status of cystic fibrosis patients without evidence of significant side effects. β -Carotene, cystic fibrosis, LDL-cholesterol, oral supplementation, retinol, α-tocopherol     

Aspergillus endocarditis in chronic granulomatous disease

We report the first case, to our knowledge, of Aspergillus endocarditis in chronic granulomatous disease in a patient who also had an atrial septal defect. A diagnosis was made on culture of the organism from the mass despite extensive prior investigation. The presence of distinctive skin lesions as a diagnostic clue of fungaemia is highlighted. Possible advances in diagnosis by detection of fungal cell wall components and in prophylaxis by use of itraconazole are referred to. We conclude that fungal endocarditis should be considered in this condition, especially in the presence of a structural heart defect.     

Human myeloid alpha 3-fucosyltransferase is involved in the expression of the sialyl-Lewis(x) determinant, a ligand for E- and P-selectin

The sialyl-Lex determinant (NeuAc alpha 2-->3Gal beta 1-->4[Fuc alpha- 1-->3]GlcNAc) has been identified as a major ligand in the selectin- mediated adhesion of neutrophils and monocytes to activated endothelium or platelets. This carbohydrate epitope is formed by the sequential action of alpha 3-sialyltransferase and alpha 3-fucosyltransferase on N- acetyllactosamine (Gal beta 1-->4GlcNAc) disaccharide termini of glycoconjugates. We have addressed the role of the human myeloid alpha 3-fucosyltransferase in the expression of this epitope at the leucocyte surface by determining its activity in human-mouse leukemic cell hybrids (WEGLI), normal human granulocytes and chronic myeloid leukemia (CML) cells using sialylated and desialylated glycoproteins and oligosaccharides as acceptor substrates. In contrast to what has been reported for the myeloid-type enzyme, we found that the alpha 3- fucosyltransferase of the cells studied can use sialylated acceptors be it that the activity is several times lower than with asialo- substrates. Characterization of the product obtained with a sialylated oligosaccharide indicated that the enzyme can catalyze the formation of the sialyl-Le(x) structure. Flow cytometry of the WEGLI cells using a sialyl-Le(x)-specific monoclonal antibody (MoAb) showed that these cells indeed express sialyl-Lex at their surface, provided that they contain human chromosome 11. Earlier the presence of this chromosome had been correlated with the expression of alpha 3-fucosyltransferase activity. In addition to sialyl-Le(x), WEGLI cells containing chromosome 11 showed high-expression levels of related structures recognized by antibodies VIM-2 and VIM-8, suggesting that fucose addition can occur at both distal and proximal GlcNAc residues in poly- N-acetyl-lactosaminoglycan sequences. Based on the human chromosome contents it could be ruled out that the alpha 3-fucosyltransferase of WEGLI cells is a Lewis-type alpha 3/4- or plasma-type alpha 3- fucosyltransferase, the genes of which have been mapped to chromosome 19. It is concluded that the enzyme studied is of the myeloid-type and indeed is involved in the synthesis of sialyl-Le(x) (and also VIM-2 and VIM-8 structures) in leukocytes provided that its expression is at a sufficiently high level.     

The effects of occupational exposure to chlorpyrifos on the neurologic examination of central nervous system function: a prospective cohort study

Questions persist about adverse effects such as impaired cognition and attention, incoordination, spasticity, or parkinsonism from chronic, low-level exposures to organophosphate (OP) compounds. In a prospective cohort study, we evaluated chlorpyrifos-manufacturing workers and a referent group on 2 occasions, 1 year apart, to determine whether occupational exposure to chlorpyrifos produced clinically evident central nervous system (CNS) dysfunction. Chlorpyrifos subjects had significantly higher TCP excretion and lower average BuChE activity than referents in a range in which physiological effects on B-esterases exist. Few subjects had neurologic symptoms or signs, and there were no significant group differences in terms of signs at baseline or second examinations. Chronic chlorpyrifos exposure produced no clinical evidence of cortical, pyramidal tract, extrapyramidal, or other CNS dysfunction among chlorpyrifos subjects compared with referents, either at baseline or after 1 year of additional chlorpyrifos exposure.     

The effects of occupational exposure to chlorpyrifos on the peripheral nervous system: a prospective cohort study

Aims: To determine whether chronic occupational exposure to chlorpyrifos at levels associated with various aspects of manufacturing produced a clinically evident or subclinical peripheral neuropathy.

Methods: Clinical and quantitative nerve conduction study (NCS) examinations were performed on two occasions on chlorpyrifos manufacturing workers who had measurable chlorpyrifos exposure and a referent group. Baseline evaluations were performed on 53 of 66 eligible chlorpyrifos subjects and on 60 of 74 eligible referent subjects; one-year evaluations were completed on 111 of the 113 subjects evaluated at baseline.

Results: Chlorpyrifos and referent groups differed significantly in measures of 3,5,6 trichloro-2-pyridinol excretion and plasma butyrylcholinesterase (BuChE) activity, indicating substantially higher exposures among chlorpyrifos subjects. Few subjects had clinically important neurological symptoms or signs. NCS results were comparable to control values, and there were no significant group differences in NCS results at baseline, one year, or change over one year. No chlorpyrifos subject fulfilled conventional criteria for confirmed peripheral neuropathy at baseline or one-year examinations. The odds ratios for developing any diagnosable level of peripheral neuropathy among the chlorpyrifos subjects was not increased at baseline or at one year compared to referents at baseline. Mixed regression models used to evaluate subclinical group-by-time interactions showed numerous significant NCS differences attributable to near-nerve temperature differences among all subjects between the baseline and one-year examinations, but only a few disparate effects related to group.

Conclusions: Chronic chlorpyrifos exposure during the manufacturing process sufficient to produce biological effects on BuChE activity was not associated with clinically evident or subclinical peripheral neuropathy at baseline or with measurable deterioration among chlorpyrifos subjects compared to referents after one year of additional exposure.