1,25-dihydroxycholecalciferol in renal osteodystrophy. Epiphysiolysis--anticonvulsant therapy

Three children with azotaemic renal osteodystrophy were treated with 1,25-dihydroxycholecalciferol (1,25(OH)2D3). All showed clinical, biochemical, and radiological improvement within 6 months of starting treatment. There were no complications. The dose of 1,25(OH)2D3 required was 0-5 microgram per day for 2 children aged 22 and 30 months, and 2 microgram per day for a 15-year-old boy. 2 of the patients were receiving phenobarbitone and phenytoin and in one of them prior treatment with dihydrotachysterol 0-5 mg daily and 6 microgram 1alpha-hydroxycholecalciferol (1alphaOHD3) daily had failed to induce improvement. In one patient, in whom serial iliac bone samples were available, 2 microgram 1,25(OH)2D3 resulted in histological improvement in previously severe osteomalacia. 1,25(OH)2D3 appears to be an effective and safe drug in the treatment of uraemic osteodystrophy.     

Override of the radiation-induced mitotic block in human tumour cells by methylxanthines and its relationship to the potentiation of cytotoxicity

The four methylated xanthine derivatives, caffeine, theophylline, theobromine and paraxanthine, were tested for their ability to override the mitotic block induced by ionizing radiation in the human bladder carcinoma cell line RT112. All four agents were found to partially override the block, ranking in terms of potency at a concentration of 1 mM in the order caffeine greater than theophylline greater than theobromine = paraxanthine. However, the effects of the four agents on the clonal survival of irradiated cells failed to correlate with the extent of override, both in terms of the relative effects of the four agents and the dose-response relationships; at a concentration of 1 mM only caffeine was found to potentiate cell killing as well as causing block override, whilst at higher concentrations all the agents had a significant effect on survival but little or no further influence on the degree of block override. It is therefore concluded that override of a mitotic block is not in itself sufficient to cause the increased killing seen when irradiated cells are incubated in the presence of caffeine, and that caffeine exerts its potentiating effect either by directly inhibiting repair of damage in DNA or by causing override of the radiation-induced inhibition of DNA synthesis.     

Silica,compensated silicosis,and lung cancer in Western Australian goldminers

OBJECTIVES: Silica has recently been reclassified as carcinogenic to humans based largely on the observed increase in rates of lung cancer in subjects with silicosis. Other recent reviews have arrived at different conclusions as to whether silicosis or silica itself is carcinogenic. This study aims to examine exposure-response relations between exposure to silica and subsequent silicosis and lung cancer in a cohort of goldminers. METHODS: 2,297 goldminers from Kalgoorlie in Western Australia were examined in 1961, 1974, and 1975. Data were collected on respiratory symptoms, smoking habits, and employment history. Subjects were followed up to the end of 1993. Survival analyses for lung cancer mortality and incidence of compensated silicosis were performed with age and year matched conditional logistic regression analyses. RESULTS: 89% of the cohort were traced to the end of 1993. 84% of the men had smoked at some time and 66% were current smokers. 1386 deaths occurred during the follow up period, 138 from lung cancer, and 631 subjects were compensated for silicosis. A strong effect of smoking on mortality from lung cancer, and a smaller effect on the incidence of compensated silicosis was found. There was a strong effect of duration and intensity of exposure on the incidence of silicosis. The risk of mortality from lung cancer increased after compensation for silicosis. Of all direct measures of exposure to silica, only log cumulative exposure was significantly related to incidence of lung cancer, but this effect disappeared once the onset of silicosis was taken into account. CONCLUSIONS: The incidence of silicosis was clearly related to exposure to silica and the onset of silicosis conferred a significant increase in risk for subsequent lung cancer, but there was no evidence that exposure to silica caused lung cancer in the absence of silicosis.       

Molecular cloning of a mammalian gene involved in the fixation of UV-induced mutations

A mammalian DNA damage tolerance gene has been isolated by DNA transfection and cosmid rescue. Following cotransfection of mouse genomic DNA and pSV2neo into SVM, the UV hypersensitive mutant Indian muntjac cell line, clones with a 1.7 to 2.0-fold greater D₃₇ value for UV killing were isolated. This trait was carried through three rounds of transfection. A neo gene and flanking sequences from a tertiary transfectant were cloned by cosmid rescue. The cosmid clone confers UV resistance to SVM and improves the ability of the cell to replicate UV damaged DNA. This replication appears to be error-prone; UV-induced 6-thioguanine-resistant mutants occur four to fivefold more frequently than in SVM or a wild-type Indian muntjac line. Thus, the gene isolated is not homologous to that defective in SVM. We believe that this is the first mammalian gene to be isolated that is directly involved in mutation fixation.     

Digital imaging of the chest

During the past several years, image acquisition in nuclear medicine, computed tomography, ultrasonography, subtraction angiography, and magnetic resonance has been by digitization. Despite these advances, research in the development of digital imaging in conventional radiography has lagged behind. Although studies with a variety of digital techniques have been carried out on several fronts, we still do not possess a method that has captured the imagination of the majority of radiologists and other physicians to a point where it could replace conventional screen-film imaging. This article reviews the current status and general principles of the technology, focusing on the four digital radiographic techniques that have shown the greatest promise - film digitization, an image intensifier - based system, photostimulable phosphor plates, and a scanned projection system. The physical aspects of each of the four systems and the clinical results that have been reported to date, as well as the advantages and disadvantages of each system, are presented.     

Predictors of Ventricular Tachvcardia Inducibility in Programmed Electrical Stimulation and the Effectiveness of Serial Drug Testing: Polish Multicenter Study

WNUK-WOJNAR, A.M., ET AL.: Predictors of Ventricular Tachycardia Inducibility in Programmed Electrical Stimulation and Effectiveness of Serial Drug Testing: Polish Multicenter Study. In 100 patients with IHD and complex ventricular arrhythmias, programmed electrical stimulation was performed using up to three extrastimuli at sinus rhythm, and paced 100, 120, and 140 beats/min delivered from the RV apex, outflow tract or the LV with ventricular mapping to evaluate late potentials (LP) in 41 patients. Sustained monomorphic VT (SMVT) was provoked in 91% of 42 patients with a history of VT/VF, p < 0.001, all five patients had SMVT in 24-hour ECG, p < 0.005, and 91% of 21 patients with LV dyskinesis, p < 0.01. After depolarizations were found in 62% of 21 patients with a history of VT, in 58% of 31 patients with inducible VT, p < 0.01 and in five of six patients with LV dyskinesis. In patients with inducible VT, LP had a higher amplitude (105 ± 35 vs 60 ± 47 µV) and were more delayed (202 ± 96 vs 133 ± 75 msec) than in noninducible patients. In 17 patients, serial drug testing was performed after oral administration using mexilitene, disopyramide, chinidine, propafenone, sotalol, and amiodarone. If one drug was tested, the therapy efficacy was 25% if two drugs-60%, and if three drugs-75%. In eight patients, VT was inducible in all tests, but in only one of these patients chronic antiarrhythmic therapy was not effective. We conclude that the most important predictors of VT inducibility are a history of VT or 24-hour ECG, and LV dyskinesis. Serial drug testing is efficient only when many drugs are tested, but even if VT is inducible, it does not exclude the possibility of a good clinical outcome in chronic therapy.     

Naratriptan: biological profile in animal models relevant to migraine

The biological profile of naratriptan (N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethane-sulphona-mide), a novel 5HT_1B/1D receptor agonist, was investigated in a variety of experimental models of relevance to migraine. Naratriptan has high affinity for human recombinant 5HT_1B and 5HT_1D receptors (pKi = 8.70.03 and 8.30.1, respectively) and causes contractions of dog isolated basilar and middle cerebral artery (EC₅₀ values of 0.11 and 0.07 M, respectively). Naratriptan causes small contractions of human isolated coronary arteries (EC₅₀ value of 0.17 M; maximum contraction equivalent to 33% of 5HT maximum). In anaesthetized dogs, naratriptan causes selective vasoconstriction of the carotid arterial bed (CD₅₀ dose = 193 g kg⁻¹) and, in anaesthetized rats, naratriptan selectively inhibits neurogenic plasma protein extravasation in the dura (ID₅₀ = 4.1 g kg⁻¹). In a variety of antinociceptive tests, naratriptan has no effect even at high doses. In conscious rats and dogs, naratriptan has high oral bioavailability (71% and 95%, respectively). The data show that naratriptan is a selective agonist at 5HT_1B/1D receptors, with a pharmacological profile very similar to that of sumatriptan, albeit 2-3 fold more potent. These observations, coupled with high oral bioavailability in animals, suggest that naratriptan has the profile of an orally effective anti-migraine drug.     

Combined CA125 and mesothelin levels for the diagnosis of malignant mesothelioma

BACKGROUND: Malignant mesothelioma is an aggressive, uniformly fatal tumor. Serum markers would be useful for the diagnosis of this disease. One potential marker is mesothelin. The purpose of this study was to study the mesothelin biomarker in a large patient cohort and to determine if another biomarker, CA125, improves on the sensitivity of mesothelin in the diagnosis of mesothelioma. METHODS: Serum levels of mesothelin and CA125 were determined by commercially available assays in 117 samples obtained at diagnosis from patients with pleural malignant mesothelioma, 33 healthy, asbestos-exposed individuals, 53 patients with asbestos-related lung or pleural disease, and 30 patients presenting with benign pleural effusions. Cross-validated sensitivities were determined, and receiver operator characteristic curves were generated to compare the diagnostic accuracy of the biomarkers. RESULTS: CA125 had a cross-validated sensitivity of 27% for mesothelioma patients at a specificity of 95% relative to asbestos-exposed individuals, or 50% relative to individuals with benign pleural effusions. Mesothelin had a cross-validated sensitivity of 52% for mesothelioma patients, at a sensitivity of 95% relative to individuals with benign lung or pleural disease. CA125 and mesothelin levels were discordant in > 50% of mesothelioma patients. Combining the data from the two biomarkers using a logistic regression model did not improve sensitivity for detecting mesothelioma above that of the mesothelin marker alone. CONCLUSION: Combining mesothelin and CA125 data does not improve the sensitivity of mesothelioma diagnosis over mesothelin alone. The use of both markers potentially increases the number of patients who can be monitored.     

Y染色体或将在进化中消失

美国宾夕法尼亚州立大学的2位科学家在性染色体进化变异机制的研究上取得进展。研究发现,Y染色体比X染色体的演化速率快得多,这将导致Y染色体上的基因急剧丢失,如此,Y染色体将会完全消失,人类的传宗接代将受威胁。     

Early recognition of heart failure in patients with diabetes type 2 in primary care. A prospective diagnostic efficiency study. (UHFO-DM2)

Background  

We hypothesize that the prevalence of unknown heart failure in diabetic patients aged 60 years and over is relatively high (15% or more) and that a cost-effective strategy can be developed to detect heart failure in these patients. The strategy is expected to include some signs and symptoms (such as dyspnoea, orthopnoea, pulmonary crepitations and laterally displaced apical beat), natriuretic peptide measurements (Amino-terminal B-type natriuretic peptide) and possibly electrocardiography. In a subset of patients straightforward echocardiography may show to be cost-effective. With information from our study the detection of previously unknown heart failure in diabetic patients could be improved and enable the physician to initiate beneficial morbidity and mortality reducing heart failure treatment more timely.