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51.
Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when a stable isotope, boron-10, is irradiated
with low energy (0.025 eV) thermal neutrons (n
th) to yield alpha (4He) particles and,7Li nuclei (10B+n
th→[11B]→4He+7Li+2.79 MeV). The success of BNCT as a tumoricidal modality is dependent on the delivery of a sufficient quantity of10B andn
th to individual cancer cells to sustain a lethal10B(n, α)7Li reaction. Boron delivery agents include a variety of compounds, such as the sulfhydryl containing polyhedral borane sodium
borocaptate (Na2B12H11SH, [BSH]), boronoporphyrins, boronophenylalanine, carboranyl uridines (CBU), and boronated monoclonal antibodies (MAb). The
present review will focus on three delivery systems that currently are under investigation in our laboratories, boronated
monoclonal antibodies, carboranyl uridines, and boronophenylalanine. Methodology has been developed to heavily boronate MAb
using a precision macromolecule, a “starburst” dendrimer, which can be linked to MAb by means of heterobifunctional reagents.
Although the resulting immunoconjugates retain their in vitro immunoreactivity, they lose their in vivo tumor localizing properties
and accumulate in the liver. In order to obviate this problem, work is now in progress to produce bispecific MAb, which can
simultaneously recognize a tumor-associated antigen and a boronated macromolecule. Boron containing, nucleosides are potential
vehicles for incorporating boron compounds into nucleic acids of neoplastic cells. For this purpose, carboranyl uridines have
been synthesized with the boron moiety on either the pyrimidine base or on the carbohydrate component. Although such structures
appear to be avidly taken up and retained by tumor cells in vitro, only the 5-carboranyl-nucleosides are converted biologically
to the nucleotide. There is no evidence, however, that the latter are incorporated into nucleic acids. Other carboranyl nucleosides
currently are being synthesized that may have better tumor localizing properties. The potential use of boronophenylalanine
as a capture agent for the treatment of melanoma metastatic to the brain also is under investigation. A nude rat model has
been developed using human melanoma cells that are stereotactically implanted into the brain. BNCT-treated animals have either
had prolonged survival times or continue to live compared to control rats that invariably died of their tumors, thereby suggesting
therapeutic efficacy. 相似文献
52.
Kobayashi T Kubota K Imamura H Hasegawa K Inoue Y Takayama T Makuuchi M 《European journal of clinical investigation》2001,31(4):356-361
BACKGROUND: The amino acid clearance test including phenylalanine is known to reflect liver functional reserve, which correlates with surgical outcome; however, the procedure is not clinically useful because of its laborious and time-consuming nature. This study evaluates whether phenylalanine oxidation capacity measured by a breath test could reflect liver functional reserve. DESIGN: We determined phenylalanine oxidation capacity in 42 subjects using the L-[1-13C]phenylalanine breath test (PBT). The 13CO2 breath enrichment was measured at 10-min intervals for 120 min after oral administration of 100 mg of L-[1-13C]phenylalanine. Subjects were divided into the following three groups according to their plasma retention rate of indocyanine green at 15 min (ICG R15): Group I (ICG R15 < 10%), Group II (ICG R15 10--20%), and Group III (ICG R15 > 20%). First, we determined the parameters of the phenylalanine oxidation capacity that differentiated these groups and then, using these parameters, we compared the PBT with the ICG clearance test, Child-Pugh classification score and standard liver blood tests. RESULTS: The %13C dose h(-1) at 30 min and cumulative excretion at 80 min were significantly different among the three groups (P < 0.05). These two parameters significantly correlated with the ICG R15, Child-Pugh classification score (P < 0.0001) and results of standard liver blood tests (P < 0.05). CONCLUSIONS: Phenylalanine oxidation capacity measured by the PBT was reduced according to the severity of liver injury assessed by the ICG clearance test, Child-Pugh classification, and standard liver blood tests. These results indicate that the PBT can be used as a noninvasive method to determine liver functional reserve. 相似文献
53.
Immunocytochemical localization of GTP cyclohydrolase I in the brain,adrenal gland,and liver of mice
I. Nagatsu H. Ichinose M. Sakai K. Titani M. Suzuki T. Nagatsu 《Journal of neural transmission (Vienna, Austria : 1996)》1995,102(3):175-188
Summary GTP cyclohydrolase I (GCH) is the first and rate-limiting enzyme for the biosynthesis of tetrahydrobiopterin (BH4), the cofactor of phenylalanine, tyrosine, and tryptophan hydroxylases, the enzymes that synthesize tyrosine, catecholamines (dopamine, noradrenaline, and adrenaline), and serotonin, respectively. We produced for the first time polyclonal antibody with highly sensitive immunoreactivity against an oligopeptide of rat enzyme, GFPERELPRPGA, by immunization of rabbits with the peptide conjugated to hemocyanin by glutaraldehyde. The specificity of the antibody was confirmed by Western blot analysis. Using this antibody specific for GCH, we observed strong GCH immunostaining in the liver cells, in the dopamine-, noradrenaline-, adrenaline-, or serotonin-containing cells of the brain, and in the adrenal gland of mice. Immunocytochemical studies revealed GCH to be localized in monoamine-containing perikarya in the periglomerular cells of the olfactory bulb, zona incerta, arcuate nucleus, ventral tegmental area, substantia nigra pars compacta, locus ceruleus, nucleus tractus solitarius, area postrema, and ventrolateral area of the medulla oblongata. GCH immunostaining was particularly strong in serotoninergic nuclei, such as dorsal and median raphe nuclei, nucleus raphe pallidus, and nucleus raphe magnus. By immunoelectron micoscopy, GCH-labeled cytoplasm and microtubules in the processes were observed ultrastructurally, but no staining was found in the mitochondria, and Golgi apparatus. Immunostaining was observed neither in the group D neurons that contain only aromatic amino acid decarboxylase without tyrosine hydroxylase, nor in glial cells and endothelial cells. These results indicate the abundant presence of GCH in catecholaminergic and serotoninergic neurons as well as in the adrenal medulla and liver, where BH4 is synthesized as the cofactor of tyrosine, tryptophan, and phenylalanine hydroxylases. 相似文献
54.
55.
The concentration of 13 neutral and acidic plasma amino acids was measured before, during and after either 40 min of control relaxation or 40 min of the process known as transcendental meditation (TM). An electro-oculogram, electroencephalogram, and electromyogram were simultaneously monitored in these subjects. Increased phenylalanine concentration was noted during TM practice with no change during control relaxation; no difference between the groups of total time slept or sleep stage percent was observed. The stability of phenylalanine concentration in controls and lack of correlation of increased phenylalanine with sleep in the long-term practitioners seem to suggest a relationship of the phenylalanine increase to TM practice. 相似文献
56.
S.P. Bagchi 《Neuropharmacology》1981,20(9):845-851
In the present study some effects of phencyclidine on synaptosomal (P2) synthesis and release of labelled dopamine, continuously appearing from [14C]phenylalanine, were investigated in vitro. Also examined was the sensitivity of such effects of phencyclidine to reserpine, acting either in vitro or in vivo. Synaptosomal (P2) preparations from rat caudate nuclei were incubated with the drugs added at various concentrations in the presence of [14C]phenylalanine substrate. The particulates were quickly separated from the medium after incubation and the separated fractions were analyzed for labelled dopamine and the synaptosomal uptake of [14C]phenylalanine. Of the total labelled dopamine formed, the fraction that was present in the medium was determined and taken as a measure of the spontaneous or basal release and its enhancement by any drug addition. Phencyclidine (3.1–36.4 μM) stimulated both the total (medium plus particulates) formation and the synaptosomal release of labelled dopamine, while reserpine (0.09–1.80 μM) inhibited the formation and enhanced the release. A coaddition of reserpine (0.09–1.80 μM) and phencyclidine to the incubation medium blocked the stimulating effect of the latter drug on the labelled dopamine synthesis; the same experiments revealed furthermore, an inhibitory effect of phencyclidine (0.91–36.4 μM) on the synthesis, an effect that was additive to the inhibition due to reserpine alone. The enhancing effect of phencyclidine on labelled dopamine release was however maintained in the presence of reserpine. Phencyclidine (0.22–36.4 μM) also inhibited the formation of labelled dopamine and enhanced its release when the P2 fraction was prepared from reserpine-pretreated rats (5.0 and 2.5 mg/kg, i.p., at 24 and 2 hr before the experiment). Reserpine (1.80 μM) itself, added in vitro to the same P2 preparation, was without any significant effect. The phencyclidine congener Ketamine, with or without reserpine, had little effect either on the synthesis or the release. In none of the incubations did the addition of drugs affect the synaptosomal uptake of labelled phenylalanine. 相似文献
57.
J. D. Fernstrom 《Journal of neural transmission (Vienna, Austria : 1996)》1989,75(2):159-164
Summary The ingestion of aspartame, a phenylalanine-containing dipeptide, raises plasma phenylalanine levels. These increments are much greater in humans than rats, because the rat hydroxylates phenylalanine five times faster than man. Accordingly, dose comparisons of aspartame (or phenylalanine) between humans and rats have usually been corrected by a factor of five. Recently, a correction factor of sixty has been proposed (Wurtman and Maher, 1987); the rationale is based on a novel calculation of competitive phenylalanine transport into brain. An analysis of the logic behind this postulation reveals there to beno basis for accepting the higher dose conversion of 60 between rat and man. 相似文献
58.
L-deprenyl plus l-phenylalanine in the treatment of depression 总被引:2,自引:0,他引:2
W. Birkmayer P. Riederer W. Linauer J. Knoll 《Journal of neural transmission (Vienna, Austria : 1996)》1984,59(1):81-87
Summary The antidepressive efficacy of l-deprenyl (5–10 mg daily) plus l-phenylalanine (250 mg/day) has been evaluated in 155 unipolar depressed patients. Both oral and intravenous administration showed beneficial effects in 90% of outpatients and 80.5% of inpatients. It is concluded that this combined treatment has a potent antidepressive action based on the accumulation of l-phenylethylamine in the brain. 相似文献
59.
A simplified PKU gene carrier detection test using fasting blood 总被引:1,自引:0,他引:1
By fluorometric analysis of fasting phenylalanine and tyrosine plasma levels, we could discriminate classic gene PKU carriers from non-carriers with 99% confidence in 67 of 74 adults. Results on the remaining seven subjects were non-discriminating. However, we could not determine their carrier status by other accepted testing parameters either (such as phenylalanine dosing). In contrast to the latter, our method: (1) allows for 90% of the population a relatively accurate but more benign test for carriers of the classical PKU gene (requiring only fluorometry on a single fasting blood specimen); (2) identifies the remaining 10% of the population who require the more cumbersome-noxious testing by phenylalanine dosing. 相似文献
60.