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81.
We performed a series of studies to further clarify the nature of lymphocyte colony-forming cells (CFC) from normal peripheral blood. Mononuclear cells were separated into E-rosette-enriched (E+) and E- rosette-depleted (E-) populations and cultured in methylcellulose with conditioned media and irradiated mononuclear cells. Linear plating relationships were obtained with plating efficiencies of 0.26% +/- .02% (mean +/- SE) for E+ CFC and 0.18% +/- .02% for E- CFC. Cells in E+ colonies were T lymphocytes and in E- colonies were B lymphocytes as determined by cell surface marker analysis. Using the thymidine suicide technique, approximately one-half of CFC were found to be in cycle at any moment, and plating efficiencies and cell cycle status of E+ CFC were not changed by preincubation with PHA in liquid culture for 48 hr. Using antibody complement-mediated cytotoxicity, E+ CFC were found to be T101+, OKT3+, and Ia-, while E- CFC were OKT3- and Ia+. Using monocyte-depleted populations obtained by sedimentation at unit gravity, lymphocyte colony growth was absent in monocyte-depleted fractions, and optimal growth occurred with 40% monocytes in culture. In contrast to some previous studies, we find that lymphocyte CFC originate from a small, cycling population of cells bearing mature T or B lymphocyte markers. Entry into cell division, however, does not confer colony-forming capacity on lymphocytes. Monocytes are critical to growth of E+ CFC, and cultures severely depleted of monocytes would not be expected to form colonies. 相似文献
82.
Multilineage hematopoietic growth factor interleukin 3 and direct activators of protein kinase C stimulate phosphorylation of common substrates 总被引:4,自引:0,他引:4
In order to investigate early signal transduction events in myeloid cells, the phosphosubstrates of an interleukin 3 (IL 3)-dependent cell line, FDC-P1, have been analyzed. Using synthetic diacylglycerol as a direct activator of the unique calcium-phospholipid-dependent phosphotransferase protein kinase C (PK-C) and genetically engineered homogeneous IL 3, we have demonstrated a common element to signal transduction events associated with these stimulants. One novel substrate, p68 (68,000 kd), was rapidly phosphorylated in either IL 3- or diacylglycerol-stimulated cells. The phosphorylation of p68 was dose- dependent, with both the physiological ligand and diacylglycerol inducing the same maximal level of phosphorylation. Phosphorylation of p68 occurred in a time-dependent manner analogous to previously described kinetics of PK-C subcellular redistribution in the FDC-P1 cell line. The p68 substrate was also phosphorylated in a cell-free system under conditions designed to activate PK-C. Phosphoamino acid analysis demonstrated that the p68 molecule phosphorylated in intact cells as well as in a calcium-phospho-lipid-dependent cell-free system was phosphorylated on threonine residues, not tyrosine. These data support the hypothesis that the activation of PK-C that occurs after IL 3-receptor interaction which leads to the rapid phosphorylation of cellular proteins is an important element of the signal transduction mechanism in FDC-P1 cells. We propose that phosphorylation of the p68 molecule is a physiochemical marker for the activation of PK-C in myeloid cells, in response to the growth-promoting physiological ligand. 相似文献
83.
High frequency of N-ras activation in acute myelogenous leukemia 总被引:8,自引:0,他引:8
Using the NIH/3T3 cell transfection assay, activated cellular oncogenes have been detected in around 10% to 20% of human tumors. From a series of DNA preparations from tissues infiltrated with acute myelogenous leukemia (AML), 50% (3/6) caused transformation of NIH/3T3 cells. Thus AML appears to be the human tumor with the highest frequency of oncogenes detected by DNA transfection. In each case the oncogene involved was N-ras, a member of the ras gene family. Biologic and clinical parameters of AML patients with and without N-ras oncogenes in their tumors are discussed. 相似文献
84.
BENGT REDFORS GUDRUN BRAGADOTTIR JOHAN SELLGREN KRISTINA SWÄRD SVEN‐ERIK RICKSTEN 《Acta anaesthesiologica Scandinavica》2010,54(2):183-190
Background: Imbalance of the renal medullary oxygen supply/demand relationship can cause ischaemic acute renal failure (ARF). The use of dopamine for prevention/treatment of ischaemic ARF has been questioned. It has been suggested that dopamine may increase renal oxygen consumption (RVO2) due to increased solute delivery to tubular cells, which may jeopardise renal oxygenation. Information on the effects of dopamine on renal perfusion, filtration and oxygenation in man is, however, lacking. We evaluated the effects of dopamine on renal blood flow (RBF), glomerular filtration rate (GFR), RVO2 and renal O2 demand/supply relationship, i.e. renal oxygen extraction (RO2Ex). Methods: Twelve uncomplicated, mechanically ventilated and sedated post‐cardiac surgery patients with pre‐operatively normal renal function were studied. Dopamine was sequentially infused at 2 and 4 ug/kg/min. Systemic haemodynamics were evaluated by a pulmonary artery catheter. Absolute RBF was measured using two independent techniques: by the renal vein thermodilution technique and by infusion clearance of paraaminohippuric acid (PAH), with a correction for renal extraction of PAH. The filtration fraction (FF) was measured by the renal extraction of 51Cr‐EDTA. Results: Neither GFR, tubular sodium reabsorption nor RVO2 was affected by dopamine, which increased RBF (45–55%) with both methods, decreased renal vascular resistance (30–35%), FF (21–26%) and RO2Ex (28–34%). The RBF/CI ratio increased with dopamine. Dopamine decreased renal PAH extraction, suggestive of a flow distribution to the medulla. Conclusions: In post‐cardiac surgery patients, dopamine increases the renal oxygenation by a pronounced renal pre‐and post‐glomerular vasodilation with no increases in GFR, tubular sodium reabsorption or renal oxygen consumption. 相似文献
85.
Martins PS Brunialti MK Martos LS Machado FR Assunçao MS Blecher S Salomao R 《Critical care (London, England)》2008,12(1):R25
Background
Infection control depends on adequate microbe recognition and cell activation, yet inflammatory response may lead to organ dysfunction in sepsis. The aims of this study were to evaluate cell activation in the context of sepsis and its correlation with organ dysfunction. 相似文献86.
S Slater MJ Crawford MA Kabbouche SL LeCates S Cherney P Vaughan A Segers P Manning D Burdine SW Powers & AD Hershey 《Cephalalgia : an international journal of headache》2009,29(9):969-973
The aim of this study was to evaluate the impact of gender and age on headache characteristics and disability. Headache characteristics were assessed at an initial visit to a paediatric specialty care centre and five follow-up visits. A total number of 4121 patients were evaluated. Fifty-eight per cent of the sample was female. Boys were younger at their first headache and initial visit. They more frequently described headache pain as squeezing and location as top of the head. Girls reported more frequent and longer headaches. Girls more often described headache pain as sharp and location as back of the head. Age accounted for more variance than gender in headache severity, duration, frequency and disability. Gender differences exist in headache characteristics. Age is also an important factor in the variability in characteristics and disability. Longitudinal studies are needed to describe further the natural history of headaches in childhood and compare outcome between genders. 相似文献
87.
Miller R Ewy W Corrigan BW Ouellet D Hermann D Kowalski KG Lockwood P Koup JR Donevan S El-Kattan A Li CS Werth JL Feltner DE Lalonde RL 《Journal of pharmacokinetics and pharmacodynamics》2005,32(2):185-197
The idea of model-based drug development championed by Lewis Sheiner, in which pharmacostatistical models of drug efficacy
and safety are developed from preclinical and available clinical data, offers a quantitative approach to improving drug development
and development decision-making. Examples are presented that support this paradigm. The first example describes a preclinical
model of behavioral activity to predict potency and time-course of response in humans and assess the potential for differentiation
between compounds. This example illustrates how modeling procedures expounded by Lewis Sheiner provided the means to differentiate
potency and the lag time between drug exposure and response and allow for rapid decision making and dose selection. The second
example involves planning a Phase 2a dose-ranging and proof of concept trial in Alzheimer’s disease (AD). The issue was how
to proceed with the study and what criteria to use for a go/no go decision. The combined knowledge of AD disease progression,
and preclinical and clinical information about the drug were used to simulate various clinical trial scenarios to identify
an efficient and effective Phase 2 study. A design was selected and carried out resulting in a number of important learning
experiences as well as extensive financial savings. The motivation for this case in point was the “Learn-Confirm” paradigm
described by Lewis Sheiner. The final example describes the use of Pharmacokinetic and Pharmacodynamic (PK/PD) modeling and
simulation to confirm efficacy across doses. In the New Drug Application for gabapentin, data from two adequate and well-controlled
clinical trials was submitted to the Food and Drug Administration (FDA) in support of the approval of the indication for the
treatment of post-herpetic neuralgia. The clinical trial data was not replicated for each of the sought dose levels in the
drug application presenting a regulatory dilemma. Exposure response analysis submitted in the New Drug Application was applied
to confirm the evidence of efficacy across these dose levels. Modeling and simulation analyses showed that the two studies
corroborate each other with respect to the pain relief profiles. The use of PK/PD information confirmed evidence of efficacy
across the three studied doses, eliminating the need for additional clinical trials and thus supporting the approval of the
product. It can be speculated that the work by Lewis Sheiner reflected in the FDA document titled “Innovation or Stagnation:
Challenge and Opportunity on the Critical Path to New Medical Products” made this scientific approach to the drug approval
process possible. 相似文献
88.
Carcinogenic polycyclic aromatic hydrocarbons increase intracellular Ca2+ and cell proliferation in primary human mammary epithelial cells 总被引:1,自引:1,他引:1
Previous studies have shown that polycyclic aromatic hydrocarbons (PAHs)
mobilize intracellular Ca2+ in human T cells by inositol
trisphosphate-dependent mechanisms resulting from activation of
phospholipase C-gamma by SRC-related protein tyrosine kinases, thereby
mimicking antigen-receptor activation. Ca2+ appears to play an important
second messenger role in growth factor control of cell proliferation in
human mammary epithelial cells (HMEC), such as the epidermal growth factor
receptor pathway. The purpose of the present studies was to determine if
PAHs are able to increase intracellular Ca2+ in primary cultures of HMEC
and increase cell proliferation. Two carcinogenic and two non-carcinogenic
PAHs were tested for their ability to increase intracellular Ca2+ in HMEC.
The carcinogenic PAHs dimethylbenz[a]anthracene (DMBA) and benzo[a] pyrene
(BaP) were able to cause Ca2+ elevation in HMEC at early time points (2 h)
and caused sustained alterations in Ca2+ homeostasis (18 h). DMBA showed
maximal effects at early time points (2 h), while BaP showed maximal
effects on sustained Ca2+ (18 h). 2,3,7,8-Tetrachlorodibenzo-p-dioxin
(TCDD), a potent dioxin and tumor promoter, produced maximal Ca2+ elevation
at 2 h, with a return to near baseline levels by 6 h. The non-carcinogenic
PAHs benzo[e]pyrene and anthracene did not significantly alter
intracellular Ca2+ at any time point. alpha-Naphthoflavone significantly
reduced the Ca2+ response induced by BaP treatment, but not by DMBA or
TCDD, suggesting that P450 1A or 1B metabolism of BaP may be important in
the sustained Ca2+ elevating response. In evaluating the effects of BaP on
HMEC proliferation, BaP was found to increase the number of cells recovered
after 4 days in culture in the absence or presence of various
concentrations of epidermal growth factor. These studies provide initial
evidence that Ca2+ signaling may be associated with mitogenesis in HMEC,
which may play a role in tumor promotion and progression produced by PAHs.
相似文献
89.
Three cases of asymptomatic intussusception in adults are reported, discovered incidentally during a CT scan of the abdomen. It is being increasingly observed in adults, possibly aided by the reformatting capabilities of the new multislice CT scanners. It has been documented in children where it is considered to be transient and of no clinical significance. 相似文献
90.
Roessler E; Belloni E; Gaudenz K; Vargas F; Scherer SW; Tsui LC; Muenke M 《Human molecular genetics》1997,6(11):1847-1853
Holoprosencephaly (HPE) is the most common brain anomaly in humans,
involving abnormal formation and septation of the developing central
nervous system. Among the heterogeneous causes of HPE, mutations in the
Sonic Hedgehog (SHH) gene have been shown to result in an autosomal
dominant form of the disorder. Here we describe a total of five different
mutations in the processing domain encoded by exon 3 of SHH in familial and
sporadic HPE. This is the first instance in humans where SHH mutations in
the domain responsible for autocatalytic cleavage and cholesterol
modification of the N-terminal signaling domain of the protein have been
observed.
相似文献