T cell subsets mediating rejection of established fetal pancreas grafts and failure to observe graft adaptation

The present study has attempted to elucidate the cellular mechanisms by which long-term established fetal pancreas allografts are rejected. We used an experimental model in which H-2b nude mice were made hyperglycemic by streptozotocin treatment and then engrafted with allogeneic fetal pancreas grafts. These grafts were functional in that engrafted animals returned to near normoglycemia while all animals left unengrafted subsequently died. The fetal pancreas grafts were allowed to reside in the immunoincompetent nude host for 6-9 months prior to T cell reconstitution, at which time animals were reconstituted with either negatively selected CD4+ or CD8+ H-2b T cell subpopulations. We found that a 6-9 month residence in an immunoincompetent host did not lead to a change in the immunogenicity of fetal pancreatic grafts in that both CD4+ and CD8+ T cell subsets were capable of rejecting these long-term established fetal pancreas grafts. The finding that isolated CD8+ spleen T cell subpopulations, which are only activated by antigen-presenting cells of donor origin bearing MHC class I alloantigen, were capable of effecting graft rejection suggested that APC of donor origin persisted in these long-term fetal pancreas allografts.     

Screening for alcoholism

Alcoholism is one of the largest public health problems of the nation and is a significant cofactor in such ubiquitous diseases as hypertension, developmental abnormalities, heart failure, liver failure, and many other conditions. The cost to the nation's health is immense. One strategy for reducing morbidity and cost has been to establish methods for screening in order to increase recognition rates leading to increased rates of therapeutic intervention. In this article, the rationale for two methods of alcohol screening, brief interviews and biological markers of excessive drinking, the relevant statistical issues bearing on this problem, and the current research on screening exams are reviewed and summarized. Finally, some of the newer approaches toward alcoholism screening as well as the consequences to the medical care system should alcohol screening eventuate on a large scale are briefly described.     

INAUGURAL ARTICLE by a Recently Elected Academy Member:From oligonucleotide shapes to genomic SELEX: Novel biological regulatory loops

The SELEX method and oligonucleotide combinatorial chemistry discovery process yields high-affinity/high-specificity ligands for virtually any molecular target. Typically, the enormous starting libraries used in the SELEX process contain 10¹⁴–10¹⁵ sequences. We now ask if the smaller sequences, complexity of extant organisms, and evolutionary history provide useful interactions between oligonucleotides and at least some unexpected targets. That is, do organisms contain a robust “linkage map” between their oligonucleotides and proteins and/or small molecules that enriches life?     

Ventilatory effects of dexmedetomidine, atipamezole, and isoflurane in dogs.

Dexmedetomidine (DMED) is a novel alpha 2 adrenergic agonist that has been shown to have potent analgesic and anesthetic sparing effects. This study was designed to investigate the effects of DMED, both alone and combined with isoflurane, on resting ventilation, the hypercapnic response, and the hypoxic response in dogs. When given alone, 1 microgram/kg decreased resting ventilation by 22% but at larger doses (10, 20, and 100 micrograms/kg) resting ventilation increased, doubling at 100 micrograms/kg. Doses of 10 micrograms/kg and greater caused a maximum depression of 60% in the slope of the hypercapnic response, but no dose had a significant effect on the hypoxic ventilatory response. A dose of 3 micrograms/kg of DMED reduced isoflurane MAC from 1.3% to 0.37%, and the ventilatory effects of this 1 MAC combination were intermediate between the awake values and those of isoflurane-anesthetized (1.3%) dogs. Atipamezole is a specific centrally acting alpha 2 receptor antagonist and when given with DMED in isoflurane-anesthetized dogs prevented the ventilatory depression. However, atipamezole alone also ventilatory stimulating effects, which may indicate tonic alpha 2 adrenergic activity. The ventilatory depression caused by DMED, either alone or combined with isoflurane, at doses that significantly reduce anesthetic requirements are relatively mild.     

Action of beer and its ingredients on gastric acid secretion and release of gastrin in humans

The intragastric action of beer and its known ingredients before and after fermentation on gastric acid secretion and release of gastrin was studied in healthy humans. None of 11 tested ingredients of fermented beer (2 x 500 mL, pH 5.5, given either alone or in combination) or hop extract had any significant effect. Finished beer (6 weeks old) and new beer were potent stimuli of acid output, causing 93% and 76% of the incremental maximal acid output in response to pentagastrin (6 micrograms/kg SC), respectively. Before the addition of yeast, preproducts of beer were considerably less potent. Thus, first and finished wort caused only a minor acid response which was 48% and 46% of maximal acid output. Foreign fermentation in first and finished wort is presumably the reason for the stimulatory action because glucose solutions in concentrations (11.5% wt/vol) seen in wort did not stimulate acid secretion. However, glucose solutions to which yeast was added, resulting in fermentation, were as potent stimuli of acid secretion as beer. Lyophilization of beer at pH 11.0 and dialysis (cutoff mol wt, 1000) removed the stimulatory substances. The plasma gastrin responses paralleled the gastric acid response to the different stimulants. It was concluded that (a) the addition of yeast to finished wort and the following alcoholic fermentation are the essential steps for the stimulatory action of beer on gastric acid secretion and release of gastrin; (b) carbohydrate metabolites with a molecular weight of less than 1000 are the acid-stimulatory agents in fermented beer; and (c) gastrin is the mediator of the stimulation of acid secretion because all substances that had a potent acid-stimulatory action also were potent stimuli of gastrin release.     

Developmental changes in the susceptibility to long-term potentiation of neurones in rat visual cortex slices.

We investigated with intracellular recordings from rat visual cortex slices whether the susceptibility to undergo long-term potentiation (LTP) is age-dependent and whether it is correlated with the expression of synaptic responses mediated by N-methyl-D-aspartate (NMDA) receptors. Test and tetanic stimuli were applied to the white matter and post-tetanic modifications of the amplitude of postsynaptic potentials (PSPs) were assessed in regular spiking cells of supragranular layers. At 2 weeks of age, the amplitudes of early (8-10 ms post-stimulus) and late (20 ms post-stimulus) PSP-components increased after tetanic stimulation to 137.1 +/- 13.4% and 141.3 +/- 12.1% of the pretetanic controls, respectively. At 3 weeks, potentiation of both PSP-components was less pronounced but still significant, the late component being on average more potentiated than the early one. At 4 weeks, PSPs were no longer potentiated. Bath application of 25 microM DL-2-amino-5-phosphonovalerate (APV), an NMDA receptor antagonist, blocked LTP induction both at 2 and at 3 weeks. We also studied developmental changes of two synaptic responses known to influence the susceptibility of cortical neurones to LTP, the NMDA receptor-mediated excitatory PSP (EPSP) and the initial inhibitory PSP (iIPSP). The amplitude of the APV-sensitive EPSP decreased with age and reached adult values in 4-week-old animals. The iIPSPs were pronounced already at 2 weeks and showed no marked change during further development. The results suggest a close correlation between the susceptibility to undergo LTP and the extent to which NMDA receptor-gated conductances contribute to the synaptic response.(ABSTRACT TRUNCATED AT 250 WORDS)     

高效液相色谱法测定右旋儿茶素血浆浓度及药代动力学参数

本文建立了体液中右旋儿茶素的RP-HPLC测定方法。采用C_(18)键合相硅胶为填料的固相提取柱进行样品预处理,右旋儿茶素的提取回收率为79.8%.应用二极管阵列检测器对色谱峰纯度进行鉴定。该法精密度好,方法回收率近100%,日内、日间的变异系数为2.4～5.6%,血浓69.6～1160 ng/ml范围内呈线性关系,r=0.9993。家兔静注右旋儿茶素18mg/kg,其药代动力学过程符合二室模型,分布相半衰期为0.129 h,消除相半衰期为1.19h。