Pulmonary carcinogenicity of relatively low doses of beta-particle radiation from inhaled 144CeO2 in rats

This study was conducted to examine the carcinogenic effects of inhaled beta-particle-emitting radionuclides, particularly in lower dose regions in which there were substantial uncertainties associated with available information. A total of 2751 F344/N rats (1358 males and 1393 females) approximately 12 weeks of age at exposure were used. Of these, 1059 rats were exposed to aerosols of 144CeO2 to achieve mean desired initial lung burdens (ILBs) of 18 kBq (low level), 247 rats to achieve mean ILBs of 60 kBq (medium level) and 381 rats to achieve mean ILBs of 180 kBq (high level). Control rats (total of 1064) were exposed to aerosols of stable CeO2. Based on the 95% confidence intervals of the median survival times and the cumulative survival curves, there were no significant differences in the survival of groups of female and male exposed rats relative to controls. The mean lifetime beta-particle doses to the lungs of the rats in the four groups were: low level, 3.6 +/- 1.3 (+/-SD) Gy; medium level, 12 +/- 4.5 Gy; and high level, 37 +/- 5.9 Gy. The crude incidence of lung neoplasms increased linearly with increasing doses to the lungs (controls, 0.57%; low level, 2.0%; medium level, 6.1%; and high level, 19%). The estimated linear risk coefficients for lung neoplasms per unit of dose to the lung were not significantly different for the three dose levels studied. The risk coefficient at the lower level was 39 +/- 14 (+/-SE) excess lung neoplasms per 10(4) rat Gy; at the medium level the risk was 47 +/- 12; and at the higher level the risk was 50 +/- 9.0. The relationship of beta-particle dose to the lung and the crude incidence of lung neoplasms was described adequately by a linear function. We concluded that the risk of lung neoplasms in rats per unit of radiation dose did not increase with decreasing mean beta-particle dose to the lung over the range of 3.6 to 37 Gy. The weighted average of these three values was 47 +/- 6.4 (+/-SE) excess lung neoplasms per 10(4) rat Gy. To extend the risk coefficients for lung neoplasms to lower doses by experimentation will require much larger numbers of rats than used in this study.     

Rupture recurrence after surgical repair of postinfarction ventricular septal rupture. Influence of early thrombolysis

OBJECTIVES: The aim of this study was to identify factors causing rupture recurrence after surgical repair of postinfarction ventricular septal rupture and to evaluate the indication for reoperation. PATIENTS: Recurrence of rupture was analysed in 25 out of a series of 109 patients who underwent surgical repair for postinfarction ventricular septal rupture between 1980 and 1992 in our institution. RESULTS: The mean interval between initial operation and recurrence was 3.6 days with a median of 2 days. Multivariate logistic regression analysis identified early thrombolysis after infarction (P = 0.0085) as a risk factor for recurrence of the rupture. Rupture recurrence occurred more in the anterior then in the posterior infarction site, although non-significant. Reoperation was indicated in 15 patients, in 13 for postrecurrent cardiac failure. The main determinant of cardiac failure was a large postrecurrent shunt (P = 0.05). The mean interval between initial operation and reoperation was 136 days with a median of 101 days. In 6 patients a combined apical ventricular septal rupture recurrence and anterior ventricular aneurysm was found, in 9 patients the recurrent rupture was proximally located, without concomitant aneurysm formation. Of 15 patients who were reoperated, one died in hospital and three after the in-hospital period. Of 10 patients treated conservatively, one died in hospital and two after the in-hospital period. One residual ventricular septal rupture closed spontaneously. CONCLUSIONS: Rupture recurrence is mainly determined by early thrombolysis. Postrecurrent cardiac failure, as the main indication for reoperation, is dependent on postrecurrent shunt size.     

The pharmacokinetics and pharmacodynamics of the oral iron chelator deferiprone (L1) in relation to hemoglobin levels

Recently, we demonstrated that administration of the orally active iron chelating agent deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one (L1)) at 6-hour intervals results in significantly greater urinary iron excretion than that induced during administration of the drug at 12-hour intervals. That study was conducted in thalassemia patients, all of whom had received a packed red cell transfusion of 15 cc/kg. 72 hours prior to evaluation of urinary iron excretion, at a time when endogenous erythropoiesis would be expected to be at its lowest. In clinical practice however, thalassemia patients, suppression of endogenous erythropoiesis is not sustained between transfusions. We set out to determine the influence that administration of deferiprone has on urinary iron excretion at lower hemoglobin concentrations, immediately prior to transfusion. We hypothesized that hemoglobin levels will affect the ability of deferiprone to chelate iron. Ten regularly transfused patients with homozygous beta-thalassemia (HBT) aged mean +/- SD, 20.9 +/- 4.7, range 13 - 27 years, receiving long-term therapy with deferiprone, were treated with deferiprone 75 mg/kg/day, administered every 6 hours (or every 12 hours) for 72 hours immediately prior to a blood transfusion in the first month. One month later each patient received the other of the 2 dosing regimens for 72 hours immediately prior to transfusion. The deferiprone-induced 24-hour urinary iron excretion was similar during both dosing regimens; 0.56 +/- 0.45 mg/kg when L1 was given every 6 hours and 0.48 +/- 0.52 mg/kg when L1 was administered every 12 hours (p = 0.79). However, the calculated 24-hour area under the plasma concentration-time curve (AUC0-24) of deferiprone was significantly lower when deferiprone was administered at 6-hour intervals (6,762.8 +/- 1,601.6 mg*min/l), than that observed when deferiprone was administered every 12 hours (8,250.1 +/- 1,235.7 mg*min/l) (p = 0.04). The pharmacokinetics of deferiprone when administered immediately prior to transfusions are different from those following transfusions. More studies assessing total body iron excretion are needed to determine the contribution of the fecal route in iron excretion.     

Glucuronidation of N-hydroxy heterocyclic amines by human and rat liver microsomes

The food-borne carcinogenic and mutagenic heterocyclic aromatic amines undergo bioactivation to the corresponding N-hydroxy (OH)-arylamines and the subsequent N-glucuronidation of these metabolites is regarded as an important detoxification reaction. In this study, the rates of glucuronidation for the N-OH derivatives of 2-amino-3-methylimidazo[4,5-f]-quinoline (IQ), 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP), 2-amino-6-methyl-dipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) by liver microsomal glucuronosyltransferase were compared to that of the proximate human urinary bladder carcinogen, N-OH-aminobiphenyl (N-OH-ABP) and the proximate rat colon carcinogen N-OH-3,2'-dimethyl-4-amino-biphenyl (N-OH-DMABP). Human liver microsomes catalyzed the uridine 5'-diphosphoglucuronic acid (UDPGA)-dependent glucuroidation of N-OH-IQ, N-OH-PhIP, N-OH-Glu-P-1 and N-OH-MeIQx at rates of 59%, 42%, 35% and 27%, respectively, of that measured for N-OH-ABP (11.5 nmol/min/mg). Rat liver microsomes also catalyzed the UDPGA-dependent glucuronidation of N-OH-PhIP, N-OH-Glu-P-1 and N-OH-IQ at rates of 30%, 20% and 10%, respectively of that measured for N-OH-DMABP (11.2 nmol/min/mg); activity towards N-OH-MeIQx was not detected. Two glucuronide(s) of N-OH-PhIP, designated I and II, were separated by HPLC. Conjugate II was found to be chromatographically and spectrally identical with a previously reported major biliary metabolite of PhIP in the rat, while conjugate I was identical with a major urinary metabolite of PhIP in the dog. Hepatic microsomes from rat, dog and human were found to catalyze the formation of both conjugates. The rat preferentially formed conjugate II (I to II ratio of 1:15), while the dog and human formed higher relative amounts of conjugate I (I to II ratio of 2.5:1.0 and 1.3:1.0 respectively). Fast atom bombardment mass spectrometry of conjugates I and II gave the corresponding molecular ions and showed nearly identical primary spectra. However, collision-induced spectra were distinct and were consistent with the identity of conjugates I and II as structural isomers. Moreover, the UV spectrum of conjugate I exhibited a lambda max at 317 nm and was essentially identical to that of N-OH-PhIP, while conjugate II was markedly different with a lambda max of 331 nm. Both conjugates were stable in 0.1 N HCl and were resistant to hydrolysis by rat, dog and human liver microsomal beta-glucuronidases.(ABSTRACT TRUNCATED AT 400 WORDS)     

Bolus dispersal through the lungs in surfactant replacement therapy

A model is presented of surfactant replacement therapy. An instilled bolus is pushed into the lungs on the first inspiration, coating the airways with a layer of surfactant and depositing some in the alveoli. Layer thickness depends on the capillary number (muU/gamma, where mu, U, and gamma are bolus viscosity, advancing meniscus velocity, and surface tension, respectively). Larger capillary number leads to thicker layers, reducing alveolar delivery. Subsequently, surface tension gradients sweep surfactant into alveoli not receiving surfactant during the first inspiration. The effects on spreading of sorption kinetics, bolus viscosity, initial layer thickness, initial penetration of surfactant, gravity, and shear stress are examined. Sorption nearly eliminates surface tension gradients in central airways but produces a sharp transition at the leading edge of the exogenous layer. Local thinning of the liquid layer results, trapping 95% of the surfactant in the airways. Gravity and ventilation augment transport somewhat. Transport to the periphery takes 4-170 s for the leading edge but considerably longer for the bulk of the surfactant. The model demonstrates how the various physical parameters governing surfactant distribution might alter the response to surfactant replacement therapy.     

Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein

A line of mice deficient in vitamin D binding protein (DBP) was generated by targeted mutagenesis to establish a model for analysis of DBP's biological functions in vitamin D metabolism and action. On vitamin D-replete diets, DBP-/- mice had low levels of total serum vitamin D metabolites but were otherwise normal. When maintained on vitamin D-deficient diets for a brief period, the DBP-/-, but not DBP+/+, mice developed secondary hyperparathyroidism and the accompanying bone changes associated with vitamin D deficiency. DBP markedly prolonged the serum half-life of 25(OH)D and less dramatically prolonged the half-life of vitamin D by slowing its hepatic uptake and increasing the efficiency of its conversion to 25(OH)D in the liver. After an overload of vitamin D, DBP-/- mice were unexpectedly less susceptible to hypercalcemia and its toxic effects. Peak steady-state mRNA levels of the vitamin D-dependent calbindin-D9K gene were induced by 1,25(OH)2D more rapidly in the DBP-/- mice. Thus, the role of DBP is to maintain stable serum stores of vitamin D metabolites and modulate the rates of its bioavailability, activation, and end-organ responsiveness. These properties may have evolved to stabilize and maintain serum levels of vitamin D in environments with variable vitamin D availability.     

Critical appraisal by reading for medical students--a case study from Pakistan

Doctors read literature to keep abreast of medical advances. A recommendation from the 1993 World Summit for Medical Education is that medical schools should teach medical students to critically appraise scientific reports. The Department of Community Health Sciences of Aga Khan University Medical College teaches basic research methods to medical students. This is now supplemented with "Critical Reading". Critical reading was first taught to 67 third year students between October, 1993 and May, 1994. A "validity check-list for critical readers" was introduced in a two week orientation consisting of three one-hour classroom sessions and four one-hour small group sessions. Thereafter, small groups met monthly to critique clinical epidemiological reports relevant to current organ system teaching. The students reading attitudes and critical appraisal skills were assessed through continuous assessment and a written final examination with questionnaire. All but three students passed the final examination (mean score (74%, standard deviation 12%). Sixty-four of 67 (96%) completed questionnaires. All (73% strongly) agreed that critical reading skills were essential, but only 30% strongly agreed that they had, indeed, mastered the skills. Ninety-seven percent (56% strongly) disagreed that year three was too early to start critical reading. Clinical teaching staff expressed interest in learning these skills. Students benefited from and enjoyed this first critical reading course. It strengthened ties between clinical and community health sciences teaching staff. The critical reading skills of the clinical teaching staff is being addressed in seminars to strengthen institutional research capacity.     

Phosphorous and proton spectroscopy in relation to near incarceration and incarceration of the human brain

The yeast gene, YTA10, encodes a member of a novel family of putative ATPases. Yta10p, as deduced from the nucleotide sequence, is 761 amino acids in length (predicted molecular mass 84.5 kDa). The amino acid sequence of Yta10p exhibits high similarity to two other yeast proteins, Yta11 and Yta12, and to E. coli FtsH. Several features of Yta10p are compatible with its localization in mitochondria. We report here that Yta10p is a yeast mitochondrial protein and that import is dependent on a membrane potential and accompanied by processing to a protein of approximately 73 kDa. Disruption of YTA10 leads to a nuclear petite phenotype and to a loss of respiratory competence, as shown by spectrophotometric measurement of the activities of respiratory complexes I-III and IV, respectively. These findings together with the high similarity of Yta10p to several ATP-dependent proteases suggest that Yta10p is a mitochondrial component involved, directly or indirectly, in the correct assembly and/or maintenance of active respiratory complexes.     

Prenatal diagnosis of partial monosomy 13q associated with occipital encephalocoele in a fetus

The pre- and postnatal findings of a fetus with a de novo del(13)(pter-->q21:) and an occipital encephalocoele are described. Maternal serum alpha-fetoprotein (AFP) screening at 19 weeks' gestation demonstrated a high level of 2.5 multiples of the median (MOM) and ultrasonography at 27 weeks' gestation showed severe intrauterine growth retardation, cardiomegaly, an occipital encephalocoele, and a calvarial defect. Genetic amniocentesis revealed a karyotype of 46,XX,del(13)(pter-->q21:). The proband postnatally displayed additional abnormalities such as microphthalmia, hypertelorism, large low-set ears, and micrognathia. We discuss the association of central nervous system (CNS) malformations with 13q deletions and emphasize that pregnancies with neural tube defects warrant cytogenetic analysis, especially when additional fetal abnormalities and neonatal dysmorphism are observed.     

Particle clearance and histopathology in lungs of F344/N rats and B6C3F1 mice inhaling nickel oxide or nickel sulfate

The goals of this study were to (1) determine the effects of repeated inhalation of relatively insoluble nickel oxide (NiO) and highly soluble nickel sulfate hexahydrate (NiSO4.6H2O) on lung particle clearance, (2) investigate the effects of repeated inhalation of NiO or NiSO4 on the pulmonary clearance of subsequently inhaled 85Sr-labeled microspheres, (3) correlate the observed effects on clearance with accumulated Ni lung burden and associated pathological changes in the lung, and (4) compare responses in F344 rats and B6C3F1 mice. Male F344/N rats and B6C3F1 mice were exposed whole-body to either NiO or NiSO4.6H2O 6 hr/day, 5 days/week for up to 6 months. NiO exposure concentrations were 0, 0.62, and 2.5 mg NiO/m3 for rats and 0, 1.25, and 5.0 mg NiO/m3 for mice. NiSO4.6H2O exposure concentrations were 0, 0.12, and 0.5 mg NiSO4.6H2O/m3 for rats and 0, 0.25, and 1.0 mg NiSO4.6H2O/m3 for mice. After 2 and 6 months of whole-body exposure, groups of rats and mice were acutely exposed nose-only to 63NiO (NiO-exposed animals only), 63NiSO4.6H2O (NiSO4.6H2O-exposed animals only), or to 85Sr-labeled polystyrene latex (PSL) microspheres (both NiO- and NiSO4.6H2O-exposed animals) to evaluate lung clearance. In addition, groups of rats and mice were euthanized after 2 and 6 months of exposure and at 2 and 4 months after the whole-body exposures were completed to evaluate histopathological changes in the left lung and to quantitate Ni in the right lung. Repeated inhalation of NiO results in accumulation of Ni in lungs of both rats and mice, but to a greater extent in lungs of rats. During the 4 months after the end of the whole-body exposures, some clearance of the accumulated Ni burden occurred from the lungs of rats and mice exposed to the lower, but not the higher NiO exposure concentrations. Clearance of acutely inhaled 63NiO was also impaired in both rats and mice, with the extent of impairment related to both exposure concentration and duration. However, the clearance of acutely inhaled 85Sr PSL microspheres was not impaired. The repeated inhalation of NiO resulted in alveolar macrophage (AM) hyperplasia with accumulation of NiO particles in both rats and mice, chronic alveolitis in rats, and interstitial pneumonia in mice. These lesions persisted throughout the 4-month recovery period after the NiO whole-body exposures were terminated. In contrast, repeated inhalation of NiSO4.6H2O did not result in accumulation of Ni in lungs of either rats or mice and did not affect the clearance of 63NiSO4.6H2O inhaled after either 2 or 6 months of NiSO4.6H2O exposure. Clearance of the 85Sr-labeled microspheres was significantly impaired only in rats exposed to the microspheres after 2 months of exposure to NiSO4.6H2O. Histopathological changes in rats were qualitatively similar to those seen in NiO-exposed rats. Only minimal histopathological changes were observed in NiSO4.6H2O-exposed mice. These results suggest that repeated inhalation of NiO at levels resulting in AM hyperplasia and alveolitis may impair clearance of subsequently inhaled NiO. The potential effects of repeated inhalation of soluble NiSO4.6H2O on the clearance of subsequently inhaled poorly soluble particles are less clear.