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731.
Cyclosporin A (CsA) has been shown to be useful in the prophylaxis of acute graft-versus-host-disease (GVHD). However, this immunosuppressive agent produces multiple side-effects including nephrotoxicity, hypertension, hypertricosis, gum hyperplasia, infections, and neurotoxicity. We report a retrospective analysis of neurotoxicity in 625 recipients transplanted for thalassemia and given CsA as part of GVHD prophylaxis. Neurotoxicity consisted in mental status changes, tremor, headache (grade 1), visual disturbance and cortical blindness (grade 2) and seizures and coma (grade 3). The overall toxicity was 28.8% and the incidence of convulsions was 10.1%. Neurological findings were reversible after temporary reduction or discontinuation of CsA. Class 3 patients, when prepared with protocol 6 (Bu 14 + Cy 200 and CsA for GVHD) or when they developed acute GVHD, had the highest risk of convulsions. Age, sex, different conditioning regimens, different anticonvulsive prophylaxis, liver damage due to iron-overload and/or to chronic inflammation did not influence the occurrence of CsA-related CNS toxicity. The occurrence of acute GVHD with concomitant use of high-dose corticosteroids is the single significant predisposing factor in the occurrence of convulsions. Grades 1 and 2 of neurotoxicity occurred earlier and were not influenced even by acute GVHD. 相似文献
732.
SE Clarke NE Austin JC Bloomer RE Haddock FC Higham FJ Hollis M Nash PC Shardlow TC Tasker FR Woods 《Canadian Metallurgical Quarterly》1994,24(11):1119-1131
1. The disposition and metabolic fate of 14C-granisetron, a novel 5-HT3 antagonist, was studied in rat, dog, and male human volunteers after intravenous and oral administration. 2. Complete absorption occurred from the gastrointestinal tract following oral dosing, but bioavailability was reduced by first-pass metabolism in all three species. 3. There were no sex-specific differences observed in radiometabolite patterns in rat or dog and there was no appreciable change in disposition with dose between 0.25 and 5 mg/kg in rat and 0.25 and 10 mg/kg in dog. Additionally, there were no large differences in disposition associated with route of administration in rat, dog and man. 4. In rat and dog, 35-41% of the dose was excreted in urine and 52-62% in faeces, via the bile. Metabolites were largely present as glucuronide and sulphate conjugates, together with numerous minor polar metabolites. In man, about 60% of dosed radioactivity was excreted in urine and 36% in faeces after both intravenous and oral dosing. Unchanged granisetron was only excreted in urine (5-25% of dose). 5. The major metabolites were isolated and identified by MS spectroscopy and nmr. In rat, the dominant routes of biotransformation after both intravenous and oral dosing were 5-hydroxylation and N1-demethylation, followed by the formation of conjugates which were the major metabolites in urine, bile and plasma. In dog and man the major metabolite was 7-hydroxy-granisetron, with lesser quantities of the 6,7-dihydrodiol and/or their conjugates. 相似文献
733.
We report a solitary nodular form of primary cutaneous amyloidosis due to locally infiltrating plasma cells. An 81-year-old Japanese women presented with a scarlet, dome-shaped 1.5-cm nodule with an irregular surface. Histology showed thick deposits of eosinophilic, oval, and homogeneous bodies in the dermis with mild infiltrates of mononuclear cells. The homogeneous bodies stained positively with periodic acid-Schiff, Congo red, and Yanagihara's Dylon stain, and immunohistochemically with anti-human lambda light-chain antibody. Methylgreen pyronine staining revealed that approximately half of the cellular infiltrates around the vessels were plasma cells. Electron microscopy demonstrated the homogeneous bodies to be amyloid masses, a part of which were in the cytoplasm of the plasma cells. Laboratory examination showed a slight elevation of IgG but no obvious findings suspicious for systemic amyloidosis or gammopathy. 相似文献
734.
NE Riese L Buswell L Noll TF Pajak J Stetz DJ Lee CN Coleman 《Canadian Metallurgical Quarterly》1997,39(4):855-858
PURPOSE: To prospectively evaluate the pharmacokinetic monitoring and drug dose adjustment of Etanidazole (Eta) in patients treated on the RTOG randomized trial for Stage III and IV head and neck cancer. METHODS AND MATERIALS: From June, 1986 to October, 1991, 521 patients were randomized to conventional RT alone or RT plus Eta. The primary goal was to determine whether the addition of Eta to conventional radiation therapy improves local-regional control and tumor-free survival. Of the 264 patients who received Eta, 233 had their drug exposure calculated and the Eta dose and schedule adjusted accordingly to prevent the occurrence of serious peripheral neuropathy. Drug exposure was assessed using the area under the curve (AUC) for a single treatment that was calculated by the integral over time of the serum concentration of Eta. The total drug exposure (total-AUC) was estimated by multiplying the AUC by the number of drug administrations. RESULTS: Eighteen percent of patients developed Grade I and 6% developed Grade II peripheral neuropathy. There was no Grade 3 or 4 peripheral neuropathy. There is a trend for an increased risk of neuropathy by single dose AUC. The minimal difference in incidence of neuropathy by single-dose AUC was due to the use of dose and schedule modification for patients with the higher values. CONCLUSIONS: The pharmacokinetics investigated in this study confirm previous work that monitoring Eta levels, with dose adjustment, allows it to be used safely in the clinic. In a subset analysis there was a statistically significant improvement in local-regional control and survival rates for patients with N0 and N1 disease, that will require confirmation (14). However, the clinical efficacy of Eta in this trial proved to be of little overall benefit. 相似文献
735.
ES Roberts NE Hopkins M Foroozesh WL Alworth JR Halpert PF Hollenberg 《Canadian Metallurgical Quarterly》1997,25(11):1242-1248
The time-dependent loss of the 7-ethoxy-4-trifluoromethylcoumarin (EFC) O-deethylase activity of rat P450 2B1, rabbit P450 2B4, or dog P450 2B11 by 1-ethynylnaphthalene (1EN), 2-ethynylnaphthalene (2EN), 2-(1-propynyl)naphthalene (2PN), 1-ethynylanthracene (1EA), 2-ethynylanthracene, 2-ethynylphenanthrene, 3-ethynylphenanthrene, 9-ethynylphenanthrene (9EPh), 9-(1-propynyl)phenanthrene (9PPh), 4-ethynylpyrene (4EP), and 4-(1-propynyl)biphenyl (4PbP) was investigated. The rate constants for inactivation by the arylalkynes in descending order of effectiveness for the top five compounds were 9EPh>9PPh>1EN, 2EN, 2PN for 2B1, 9EPh>2EN>4EP>1EN, 1EA for 2B4, and 9EPh>1EA>4EP, 9PPh>2EN for 2B11. The size and the shape of the aromatic ring system and the placement of the alkyne functional group were important for inactivation. The most effective inactivator with all the isozymes was 9EPh. This compound also inactivated the EFC activity in microsomes from human lymphoblastoid cells expressing human P450 2B6. The specificity of 9EPh for the inhibition or inactivation of different P450 activities in microsomes from rats treated with various inducing agents was determined by measuring lidocaine, testosterone, p-nitrophenol, or erythromycin metabolism. The greatest effect was observed with the 2B-specific products from lidocaine and testosterone, whereas no effect was seen with p-nitrophenol or erythromycin. When the covalent binding of [3H]2EN to microsomal protein was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography, a radiolabeled protein band that corresponds to 2B1 was observed in the lanes containing microsomes from rats treated with phenobarbital and, to a lesser extent, pyridine and isosafrole after incubation with NADPH. When these microsomes were incubated with [3H]9EPh or [3H]1EP, two NADPH-dependent bands were radiolabeled. One corresponded to 2B1/2 and the other to a protein of approximately 59 kDa, which was observed in the lanes from phenobarbital-treated male and female rats and pyridine-treated male rats. No radiolabeled bands were observed with [3H,14C]4PbP with any of the microsomes. 相似文献
736.
Tolerance and sensitization to the behavioral effects of cocaine were investigated in rats responding under a fixed-consecutive-number eight schedule of food reinforcement. The development of tolerance or sensitization was induced by delivering the drug either immediately before or after each behavioral session during chronic administration. Chronic cocaine administered before each session resulted in tolerance, as indicated by the shift to the right in the cocaine dose response curve. This tolerance was more likely to develop in the presence of an external discriminative stimulus. On the other hand, when cocaine was delivered after each session, the injections did not disrupt responding and sensitization or increased sensitivity rather than tolerance developed. This sensitization was more likely to occur when the external discriminative stimulus was not present. These data suggest that either tolerance or sensitization to the behavioral effects of cocaine can occur following the same number of chronic injections, with the effect dependent on the context under which the drug is delivered. Significant differences in benzodiazepine receptor binding measured autoradiographically using [3H]flumazenil were observed between rats that received cocaine before or after each session, suggesting that the development of tolerance and sensitization may be mediated through changes in benzodiazepine receptors in discrete brain regions. 相似文献
737.
OBJECTIVE: To determine the effect of bilateral hypoglossal and and glossopharyngeal nerve block on epiglottic and soft palate position and tracheal and pharyngeal pressures in exercising horses. ANIMALS: 5 Standardbreds. PROCEDURE: Tracheal and pharyngeal pressures were measured in 5 Standardbreds exercising at the speed at which the horses achieved 50, 75, and 100% of maximal heart rate after bilateral hypoglossal and glossopharyngeal nerve block and without nerve block. Nerve block was achieved by injection of 1 to 2 ml of 2% mepivicaine hydrochloride between the glossopharyngeal and hypoglossal nerves, as they coursed through the medial compartment of the diverticulum of the auditory tube (guttural pouch), using videoendoscopic guidance and an injection apparatus. RESULTS: Compared with control values, peak inspiratory tracheal pressure was significantly (P = 0.02) more negative, and peak pharyngeal inspiratory pressure was less negative (P = 0.004) after bilateral hypoglossal and glossopharyngeal nerve block. Respiratory frequency was significantly (P = 0.024) lower after nerve block, compared with control values. The epiglottis was unstable and retroflexed through the rima glottis during inspiration after bilateral hypoglossal and glossopharyngeal nerve block. Despite loss of contact between the epiglottis and the caudal free margin of the soft palate, dorsal displacement of the soft palate did not occur. CONCLUSIONS AND CLINICAL RELEVANCE: Loss of contact of the epiglottis with the soft palate did not affect soft palate position, suggesting that when the soft palate is normal, the epiglottis does not function as a support, holding the soft palate in a ventral position. Therefore, epiglottic dysfunction is not solely responsible for intermittent dorsal displacement of the soft palate in horses, and neuromuscular dysfunction involving the hyoepiglotticus muscle, geniohyoideus muscle, or the hypoglossal nerve may cause epiglottic retroflexion in horses. 相似文献
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