Drug-induced haemolysis in glucose-6-phosphate dehydrogenase deficiency

People with the variants of glucose-6-phosphate dehydrogenase (GPD) deficiency common in the southern Chinese (Canton, B(-)Chinese, and Hong Kong-Pokfulam) have a moderate shortening of red-cell survival but no anaemia when they are in the steady state. With a cross-transfusion technique, primaquine, nitrofurantoin, and large doses of aspirin were found to aggravate the haemolysis while sulphamethoxazole did so only in some people. Individual differences in drug metabolism may be the reason for this. Many commonly used drugs reported to accentuate haemolysis in GPD deficiency did not shorten red-cell survival.     

HLA antigens and erythrocyte glucose-6-phosphate dehydrogenase (G-6-PD) deficiency in Sardinia

Wind enhances the carcinogenic effect of chronic Iltraviolet radiation (UVL). This was demonstrated in hairless mice that were irradiated for 42 weeks with mercury are lamps. One group of animals was exposed to continuous wind flow of 2.7 m/s except for the daily I-2 min time interval when they were removed from the wind tunnel and irradiated. Another group of animals received identical irradiation but were protected from wind. The first tumour appeared in the UVL and wind group after 105 days of irradiation, and at 164 days of irradiation all surviving mice in the group had developed tumours. The group of mice receiving identical irradiation but protected from wind had their first tumour appear at 154 days of irradiation, and by 164 days of irradiation only 40% of the mice had developed tumours.     

Molecular genetics of glucose-6-phosphate dehydrogenase deficiency in Mexico

PURPOSE: To report the results of a prospective study of the incidence of peripheral visual field loss after macular hole surgery. METHODS: Prospectively, 30 eyes of 30 consecutive patients with full-thickness macular holes operated on between December 1995 and April 1996 had preoperative and postoperative Goldmann visual field tests. The surgical procedure consisted of three-port pars plana vitrectomy, posterior hyaloid removal, nonexpansile fluid-hexafluoroethane (C2F6) exchange, and, in 19 of 30 patients, autologous platelet injection, followed by face-down positioning. RESULTS: Twenty-nine of these 30 cases were considered to be anatomic successes. Comparison of preoperative and postoperative visual fields disclosed that four patients (13%) had a peripheral scotoma, including one patient with stage 4 macular hole. Three other patients (10%) had a postoperative relative arcuate defect. Mean postoperative intraocular pressure was higher in the latter group. None of the patients complained of peripheral scotoma. CONCLUSIONS: Overall, seven of 30 patients (23%) had a postoperative visual field defect. Two categories of scotomas were observed: peripheral and relative arcuate. The cause of peripheral visual field loss is unclear. Increased intraocular pressure may be the cause of relative arcuate scotomas.     

Molecular characterization of erythrocyte glucose-6-phosphate dehydrogenase deficiency in Al-Ain District, United Arab Emirates

Operational skills involved in controlling a motor vehicle were measured in two groups of very healthy elderly drivers and a young control group to test the hypothesis that there are age-related declines in operational performance that may influence driver safety. An actual behind-the-wheel, standardized road test was employed using a motor vehicle equipped with sensors to record speed, braking activity, and lane position, as well as direction and magnitude of front-wheel and eye-movement excursions. The data from these sensors were used as dependent measures of operational performance. Older drivers made fewer steering and eye-movement excursions and drifted across the center line more frequently than the young control group. Younger drivers drove significantly faster and executed more braking applications than did their older counterparts. The motor-vehicle operational performance of older healthy drivers was related to visual-spatial attentional declines and the useful field of vision associated with the normal aging process.     

Enhanced expressions of glucose-6-phosphate dehydrogenase and cytosolic aldehyde dehydrogenase and elevation of reduced glutathione level in cyclophosphamide-resistant human leukemia cells

PURPOSE: To determine the involvement of p53 in ionizing radiation-induced excision and recombination repair. MATERIALS AND METHODS: Shuttle vector pZ189 containing radiation-induced single strand breaks plus base damage (ocDNA), ultraviolet-radiation damage (uvDNA), or a restriction enzyme-produced double strand break (linDNA) were processed in unirradiated or irradiated p53wt and p53mut lymphoblasts. Mutation frequencies in the supF-tRNA target gene and survival of plasmids processed in p53wt and p53mut hosts were compared. RESULTS: Mutation frequencies of oc-, uv- or linDNA were similar after processing in unirradiated p53wt and p53mut hosts. However, the mutation frequency of ocDNA and uvDNA decreased 50% when processed in irradiated p53wt hosts but was unaltered in irradiated p53mut hosts. In contrast, linDNA mutation frequencies varied similarly whether processed in irradiated p53wt or p53mut hosts: mutation frequency decreased twofold when linDNA was transfected immediately after host irradiation but increased twofold when transfection was delayed by 2h. Double strand break rejoining capacity, determined by the ratio of the number of progenies from linDNA to that from undamaged pZ189, differed both qualitatively and quantitatively in irradiated p53wt and p53mut hosts. CONCLUSIONS: These studies show induction of DNA repair in mammalian cells by ionizing radiation and indicate the involvement of p53 in the modulation of excision repair fidelity and double strand break rejoining capacity.     

Mortality in a cohort of men expressing the glucose-6-phosphate dehydrogenase deficiency

The objective of this study was to test the hypothesis of a lower mortality from cancer and cardiovascular diseases among men expressing glucose-6-phosphate dehydrogenase (G6PD) deficiency. We designed a mortality study based on death certificates from January 1, 1982 through December 31, 1992 in a cohort of G6PD-deficient men. Cohort members were 1,756 men, identified as expressing the G6PD-deficient phenotype during a 1981 population screening of the G6PD polymorphism. The setting was the island of Sardinia, Italy. Outcome measures were cause-specific standardized mortality ratios (SMRs), which were computed as 100 times the observed/expected ratio, with the general Sardinian male population as the reference. Deaths from all causes were significantly less than expected due to decreased SMRs for ischemic heart disease (SMR, 28; 95% confidence interval [CI], 10 to 62), cerebrovascular disease (SMR, 22; 95% CI, 6 to 55), and liver cirrhosis (SMR, 12; 95% CI, 0 to 66), which explained 95.6% of the deficit in total mortality. All cancer mortality was close to the expectation, with a significant increase in the SMR for non-Hodgkin's lymphoma (SMR, 545; 95% CI, 147 to 1,395). A decrease in mortality from cardiovascular diseases was one of the study hypotheses, based on an earlier human report and experimental evidence. However, selection bias is also a likely explanation. Further analytic studies are warranted to confirm whether subjects expressing the G6PD-deficient phenotype are protected against ischemic heart disease and cerebrovascular disease. This cohort study is consistent with more recent case-control studies in rejecting the hypothesis of a decreased cancer risk among G6PD-deficient subjects. The observed increase in mortality from non-Hodgkin's lymphoma and decrease in mortality from liver cirrhosis were not previously reported.     

Genetic analysis of the glucose-6-phosphate dehydrogenase deficiency in a southern Croatia

PURPOSE: To evaluate objectively the effects of a microbubble contrast agent on the color Doppler ultrasound (US) examination of breast lesions. MATERIALS AND METHODS: Forty-seven patients aged 23-71 years underwent color Doppler US before and after intravenous injection of a microbubble contrast agent. A 3-minute computer-assisted assessment of the color pixel density (CPD) was used to evaluate objectively the increase in the number of color Doppler US signals, the transit time of the microbubble bolus, and the potential additional differential diagnostic information. RESULTS: Peak CPD at contrast agent-enhanced color Doppler US was 14.3% +/- 8.1 (mean +/- 1 standard deviation) for carcinomas and 9.3% +/- 4.9 for benign lesions (P = .04). The time to peak enhancement was shorter in carcinomas (38 seconds +/- 20) than in benign tumors (71 seconds +/- 48, P = .02). Final CPD was close or equal to baseline values. With the median of 13% for peak CPD as a threshold, the sensitivity for this parameter was 55%, the specificity was 79%, and the accuracy was 62% (P = .04). For a median time to peak of 50 seconds, the sensitivity was 84%, the specificity was 57%, and the accuracy was 76%. CONCLUSION: After microbubble contrast agent injection, carcinomas and benign lesions behave differently in degree, onset, and duration of Doppler US enhancement. High interindividual variability and temporal variations in the Doppler US signal still limit the value of these criteria for prospective diagnosis.     

Analysis of common mutations and associated haplotypes in Chinese patients with glucose-6-phosphate dehydrogenase deficiency

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a rare disease in North China. In the present investigation, DNA samples from 17 patients with G6PD deficiency from Tianjin area in North China were studied for the two G6PD common mutations (R459L and R463H) and two single nucleotide polymorphisms (1311C/T and 1365-13T/C) using a dideoxy fingerprinting method. Five patients were positive for mutation R459L, and six patients were positive for mutation R463H. Further haplotype analyses using three flanking dinucleotide repeat polymorphism loci, DXS1123, DXS1113, and F8C(IVS13), were performed on 14 patient families and 16 control Chinese females. The results indicated that the two common mutations were from different haplotypes. Also, the data suggested a possible allelic association between the two G6PD common mutations and the F8C(IVS13) locus and a different allelic distribution for loci DXS1113 and F8C(IVS13) between Chinese and Caucasian populations.     

Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia

Severe jaundice leading to kernicterus or death in the newborn is the most devastating consequence of glucose-6-phosphate dehydrogenase (EC 1.1.1.49; G-6-PD) deficiency. We asked whether the TA repeat promoter polymorphism in the gene for uridinediphosphoglucuronate glucuronosyltransferase 1 (EC 2.4.1.17; UDPGT1), associated with benign jaundice in adults (Gilbert syndrome), increases the incidence of neonatal hyperbilirubinemia in G-6-PD deficiency. DNA from term neonates was analyzed for UDPGT1 polymorphism (normal homozygotes, heterozygotes, variant homozygotes), and for G-6-PD Mediterranean deficiency. The variant UDPGT1 promoter allele frequency was similar in G-6-PD-deficient and normal neonates. Thirty (22.9%) G-6-PD deficient neonates developed serum total bilirubin >/= 257 micromol/liter, vs. 22 (9.2%) normals (P = 0.0005). Of those with the normal homozygous UDPGT1 genotype, the incidence of hyperbilirubinemia was similar in G-6-PD-deficients and controls (9.7% and 9.9%). In contrast, in the G-6-PD-deficient neonates, those with the heterozygous or homozygous variant UDPGT1 genotype had a higher incidence of hyperbilirubinemia than corresponding controls (heterozygotes: 31.6% vs. 6.7%, P < 0.0001; variant homozygotes: 50% vs. 14.7%, P = 0.02). Among G-6-PD-deficient infants the incidence of hyperbilirubinemia was greater in those with the heterozygous (31.6%, P = 0.006) or variant homozygous (50%, P = 0.003) UDPGT1 genotype than in normal homozygotes. In contrast, among those normal for G-6-PD, the UDPGT1 polymorphism had no significant effect (heterozygotes: 6.7%; variant homozygotes: 14.7%). Thus, neither G-6-PD deficiency nor the variant UDPGT1 promoter, alone, increased the incidence of hyperbilirubinemia, but both in combination did. This gene interaction may serve as a paradigm of the interaction of benign genetic polymorphisms in the causation of disease.     

Increased erythrocyte deformability in fetal erythropoiesis and in erythrocytes deficient in glucose-6-phosphate dehydrogenase and other glycolytic enzymes

We evaluated the results of an excision of the radial head in 25 patients (27 operated-on elbows) younger than 18 years with stiff painful radiocapitellar joints. The mean age was 14.2 years (range, 4.6-17.8 years) with average follow-up of 7.8 years. Analysis of the results with a postoperative elbow score revealed excellent or good results in 19 of the 27 elbows of patients. Skeletal maturity of the patient did not alter the results based on the rating scale. Revision surgery to remove appositional bone growth was needed in six of the 12 posttraumatic cases and one of 15 developmental elbows. Cubitus valgus, wrist pain, and ulnar neuropathy were not clinical problems at follow-up examination. Excision of the radial head was beneficial for 70% of patients younger than 18 years with stiff, painful radiocapitellar joints. Results were not improved in patients who had reached skeletal maturity.     

The correlation of membranous glycoprotein-gp-170, cytoplasmic glutathione and glucose-6-phosphate dehydrogenase levels with multidrug resistance in transitional cell carcinoma cell lines of the urinary tract

The expression of membranous glycoprotein gp-170, cytoplasmic glutathione (GSH) and energy-related glucose-6-phosphate dehydrogenase (G-6-PD) in cultured normal urothelial cells and transitional cell carcinoma (TCC) cell lines was analyzed by flow cytometric and enzymatic methods. The chemosensitivity of these tumor cells to four major types of anticancer drugs, including cisplatin, thiotepa, methotrexate, 5-fluorouracil, adriamycin and vinblastine, was correlated with biological activities in TCC cell lines. The TCC cell lines displayed a general sensitivity to anticancer drugs with a low incidence of highly resistant cell lines (23%). The expression of multidrug resistance was not related to cellular differentiation or invasiveness of cancer cells. Only 24% of TCC cell lines had an elevated expression of gp-170, but their expression was not related to drug resistance. Increased cytoplasmic GSH and G-6-PD was observed in over 90 per cent of TCC cell lines, but no correlation with drug resistance and cellular differentiation was observed. The biological activities of GSH and G-6-PD were not related to the drug resistance of TCC. The low expression rate of gp-170 in TCC cells indicates that other mechanisms should be involved in the development of MDR in TCC cells.     

Sickle cell haemoglobin and glucose-6-phosphate dehydrogenase deficiency among Rellis of Visakhapatnam, Andhra Pradesh, South India

Sickle cell haemoglobin and glucose-6-phosphate dehydrogenase deficiency have been investigated in two endogamous subgroups of the Rellis, a scheduled caste population of Visakhapatnam of Andhra Pradesh (South India). The frequency for the sickle cell gene is higher among Relli-I (0.1216) than in Relli-II (0.0454). The incidence of G-6-PD deficiency is higher among Relli-II (0.0454) than in Relli-I (0.0328). The results were also compared with those available from other Andhra Pradesh populations.     

Synthesis and loss of activity of glucose-6-phosphate dehydrogenase in dividing plant cells

1. Using the technique of density-labelling with deuterium oxide, evidence has been obtained for the de novo synthesis of glucose-6-phosphate dehydrogenase (D-glucose-6-phosphate:NADPH+ 1-oxidoreductase, EC 1.1.1.49), during the culture of synchronously growing plant cells. 2. The entire increase in enzyme activity during the early cell cycles in this material can be accounted for by the appearance of an enzyme species with increased buoyand density. 3. A method is described for resolving overlapping distribution profiles after density centrifugation, which allows estimation of the amount of each species present at different times, and calculation of the loss of activity of the light species present from the start of culture. 4. Loss of activity of glucose-6-phosphate dehydrogenase in normal growing conditions in the presence of 2,4-dichlorophenoxyacetic acid is very much faster than in conditions which do not lead to cell division: in the absence of 2,4-dichlorophenoxyacetic acid, or in the presence of the inhibitor of RNA synthesis, 6-methylpurine.