The acceleration of cosmic-ray protons in the supernova remnant RX J1713.7-3946.

Protons with energies up to approximately 10(15) eV are the main component of cosmic rays, but evidence for the specific locations where they could have been accelerated to these energies has been lacking. Electrons are known to be accelerated to cosmic-ray energies in supernova remnants, and the shock waves associated with such remnants, when they hit the surrounding interstellar medium, could also provide the energy to accelerate protons. The signature of such a process would be the decay of pions (pi(0)), which are generated when the protons collide with atoms and molecules in an interstellar cloud: pion decay results in gamma-rays with a particular spectral-energy distribution. Here we report the observation of cascade showers of optical photons resulting from gamma-rays at energies of approximately 10(12) eV hitting Earth's upper atmosphere, in the direction of the supernova remnant RX J1713.7-3946. The spectrum is a good match to that predicted by pion decay, and cannot be explained by other mechanisms.

Effects of ascorbic acid on interactions between ciprofloxacin and ferrous sulphate, sodium ferrous citrate or ferric pyrophosphate, in mice.

The absorption of ciprofloxacin has been reported to be impaired by concomitant administration of ferrous sulphate. The effects of sodium ferrous citrate and ferric pyrophosphate, which have been used as extensively as ferrous sulphate, on the absorption of ciprofloxacin were compared with that of ferrous sulphate. The effects of ascorbic acid on the interactions between ciprofloxacin and each iron compound were studied in mice. Mice were treated orally with ciprofloxacin (50 mg kg(-1)) alone, the iron compound (ferrous sulphate, sodium ferrous citrate or ferric pyrophosphate; 50 mg elemental iron kg(-1)) alone, ciprofloxacin with each iron compound or ciprofloxacin in combination with each iron compound and ascorbic acid (250 mg kg(-1)). The maximum serum concentration of ciprofloxacin was significantly (P < 0.01) reduced from 1.15+/-0.11 microg mL(-1) (ciprofloxacin alone) to 0.17+/-0.01, 0.27+/-0.01 or 0.28+/-0.02 microg mL(-1), respectively, when ferrous sulphate, sodium ferrous citrate or ferric pyrophosphate was administered along with ciprofloxacin. The addition of ascorbic acid did not affect the inhibitory effects of each iron compound on the absorption of ciprofloxacin. Ciprofloxacin did not affect the variation of serum iron levels after administration of each iron compound. The addition of ascorbic acid significantly (P < 0.01) enhanced the increase in serum iron concentration after administration of sodium ferrous citrate, showing an increase from 270+/-6 microg dL(-1) to 463+/-11 microg dL(-1) compared with an increase from 248+/-8 microg dL(-1) to 394+/-18 microg dL(-1) after administration of sodium ferrous citrate alone. Ascorbic acid also caused a significant (P < 0.01) increase in serum iron concentration from 261+/-16 microg dL(-1) to 360+/-12 microg dL(-1) after administration of ferric pyrophosphate, although it did not affect the levels after ferrous sulphate administration. The results suggest that sodium ferrous citrate and ferric pyrophosphate should not be administered with ciprofloxacin (as for ferrous sulphate) and that sodium ferrous citrate is converted to the ferric form more easily than ferrous sulphate. This difference in convertibility might contribute to a clinical difference between sodium ferrous citrate and ferrous sulphate.

[Relationship between hippocampal arachidonic acid content and induction of LTP in aged rats].

There are several lines of evidence indicating that membrane AA correlates with the ability of aged rats to sustain LTP. The age-related decrease in membrane AA seems to be triggered by increased lipid peroxidation, which is involved with the decline of LTP. The chronic treatment of DHA could decrease membrane AA without an increase in lipid peroxidation. We have thus investigated the effect of chronic treatment of DHA on hippocampal LTP to assess whether the decrease in membrane AA could directly affect the induction of LTP. The effects of daily supplementation of DHA for 3 months on membrane AA, LTP, and Ca2+ response were evaluated using hippocampal slices from 26-month-old Wistar rats. Chronic treatment of DHA reduced the hippocampal AA significantly, but did not change the amplitude of LTP. Neither 30 mM K+ nor 500 microM NMDA-induced Ca2+ response was affected by chronic treatment of DHA, while the 500 microM carbachol-induced Ca2+ response was reduced. From these results, the reduction of membrane AA might suppress the carbachol-induced Ca2+ response by inhibiting the muscarinic receptor function, IP3 formation and/or Ca2+ release from Ca2+ stores by IP3. However, the reduction of membrane AA is not likely to be a main causal factor of the decline of LTP.

The angiotensin AT1 receptor antagonist, losartan, induces barrel rotation in the rat.

Intracerebroventricular injections of [Arg8]vasopressin (500 ng/rat) or endothelin-1 (70 ng/rat) into the right lateral ventricle induced rotation along the long axis of the body (barrel rotation) in rats. Losartan (10-200 microg/rat), an angiotensin AT1 receptor antagonist, also evoked barrel rotation, which was not inhibited by vasopressin and endothelin receptor antagonists. However, barrel rotation was not observed after injections of high doses of another angiotensin II receptor antagonist, [Sar1,Ile8]angiotensin II (100 microg/rat), or after angiotensin II (10 microg/rat). The results indicate that losartan does evoke barrel rotation which may be not mediated via vasopressin and endothelin receptors.

Protective effect of MK-801 on the anoxia-aglycemia induced damage in the fluorocitrate-treated hippocampal slice of the rat.

We investigated electrophysiological responses induced by ischemia-like insult (anoxia and aglycemia, AA) in the rat hippocampal CA1 pyramidal cells in an in vitro slice preparation devoid of glial metabolism. In the slice treated with fluorocitrate (100 microM), a glia-specific metabolic inhibitor, 10 min AA induced hyperexcitation as evidenced by an appearance of multiple population spikes evoked by stimulation of the Schaffer collateral/commissural pathway in the CA1 region prior to elimination of the response. Readministration of oxygen and glucose failed to restore the population spike amplitude. Intracellular recordings revealed that 10 min AA induced slow EPSPs with relative long duration. The induction of the slow EPSPs was followed by a rapid membrane depolarization with a large amplitude. When the fluorocitrate-treated slice was exposed to MK-801 (10 microM), a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, 10 min AA failed to induce either the hyperexcitation of synaptic responses or the rapid depolarization. Furthermore, synaptic responses were fully restored after readministration of oxygen and glucose. In contrast, neither the synaptic hyperexcitation nor the rapid depolarization was observed during 10 min AA in the hippocampal CA1 pyramidal cells of the control slice. In addition, an irreversible synaptic failure associated with AA was not induced in the control slice. These results strongly suggest that fluorocitrate increases NMDA receptor-dependent AA-induced damage in the hippocampal slice by interfering glial spatial buffering of K+.

The chronic administration of docosahexaenoic acid reduces the spatial cognitive deficit following transient forebrain ischemia in rats.

The purpose of this study was to investigate whether chronic administration of docosahexaenoic acid is able to reduce spatial cognitive deficit following transient ischemia in rats. In addition, we investigated whether the chronic treatment of docosahexaenoic acid is able to protect the hippocampal neuronal damage induced by either hypoxia in vitro or cerebral ischemia in vivo. A chronic administration of 200 mg/kg/day docosahexaenoic acid over 21 days did not affect the content of docosahexaenoic acid in the hippocampus, but did tend to increase it in the frontal cortex. On the other hand, this chronic administration decreased the content of arachidonic acid significantly both in the hippocampus and the frontal cortex. Under hypoxic conditions, the onset of the increase in the NADH fluorescence in the hippocampal slice was made significantly slower relative to the control by the chronic administration of docosahexaenoic acid. Rats were subjected to 10 min of transient forebrain ischemia by the method of four-vessel occlusion and were tested in a radial eight-arm maze task after cerebral reperfusion. Docosahexaenoic acid was administered either once 1 h before occlusion or daily for 21 days before occlusion. The single treatment of docosahexaenoic acid (1, 10, 100 or 200 mg/kg) did not significantly affect any aspect of the spatial learning deficit following occlusion. On the other hand, chronic treatment with docosahexaenoic acid (10, 100 or 200 mg/kg/day) significantly improved the spatial learning deficit following occlusion. A comparison of the neuronal densities in the hippocampal CA1 region of the chronically docosahexaenoic acid-treated (200 mg/kg/day) rats with those of the ischemic control revealed a significant neuronal preservation. From these results, it appears that chronic administration of docosahexaenoic acid may be valuable in ameliorating the spatial cognitive deficit induced by transient forebrain ischemia. In addition, docosahexaenoic acid might contribute to the protection of hippocampal neuronal damage caused by either hypoxia or ischemia.

Activation of murine T cells by staphylococcal enterotoxin E: requirement of MHC class II molecules expressed on accessory cells and identification of V beta sequence of T cell receptors in T cells reactive to the toxin.

We investigated a mechanism leading to activation of murine T cells by staphylococcal enterotoxin E (SEE). L cells transfected with I-Ab genes but not control L cells supported IL-2 production by SEE-induced C57BL/6 T lymphoblasts upon restimulation with SEE. mAb to I-Ab markedly inhibited the above response. Flow cytometric analyses showed that SEE-induced C57BL/6 T lymphoblasts are composed of both CD4+ T cells and CD8+ T cells, and that larger parts of them bore V beta 11 (40-75%). mAb to V beta 11 markedly inhibited the SEE-induced proliferative response and IL-2 production by T cells. Analysis of SEE-induced IL-2 production in spleen cells from various mouse strains showed that C57BL/6 and B10.A(4R) mice (I-E, not expressed; V beta 11+ T cells, normally generated) are highly responsive to SEE. In contrast, BALB/c, C3H/HeN, (C57BL/6 x BALB/c or C3H/HeN) F1 mice (I-E, normally expressed and V beta 11+ T cells, deleted), and SJL and C57L mice (V beta 11 genes, deleted) are weakly responsive to SEE. The results indicate that SEE activates mainly T cells bearing V beta 11 in physical association with MHC class II molecules expressed on AC. In addition, the results indicate that SEE activates both CD4+ T cells and CD8+ T cells.

Studies on the enhanced effect of acupuncture analgesia and acupuncture anesthesia by D-phenylalanine (2nd report)--schedule of administration and clinical effects in low back pain and tooth extraction.

D-phenylalanine (DPA) is known to block the activity of carboxypeptidase, an enzyme which degrades enkephalins, endogenous morphine-like substances. Therefore, it is considered that DPA administered as an inhibiting drug of this degrading enzyme might prolong analgesia induced by acupuncture. 1) Thirty patients suffering from chronic low back pain were treated with acupuncture 30 minutes after the oral administration of 4.0 grams of DPA. The results were: excellent in 7 cases, good in 11, fair in 6 and poor in 6. Cases graded excellent and good were then compared with a placebo group. The effect was increased 26% in the DPA-acupuncture group, which shows no statistically significant difference (P less than 0.1). 2) In 56 patients, tooth extraction was performed under acupuncture anesthesia: 18 had received 4.0 gram of DPA (P.O.) 30 minutes earlier. The results were excellent in 8, good in 6, fair in 3, and poor in 1. The excellent and good cases were compared with 38 placebo group cases. The effect in the DPA-acupuncture anesthesia group was significantly increased by 35% (P less than 0.01). 3) In order to determine the optimum time for the administration of DPA, two schedules of administration were compared. [1] DPA was given on the previous day in three 0.5 gram doses (26 cases). [2] A single 4 gram dose was administered 30 minutes before treatment (30 cases). The results from the "excellent", "good" and "fair" cases showed a 16% increase in effectiveness when DPA was administered the day before, not a statistically significant difference (P less than 0.1), but a clear tendency to increase was observed. The above findings show that DPA has an enhancing effect on acupuncture analgesia and anesthesia in clinical practice.

Relative strength of the mitogenic and interleukin-2-production-inducing activities of staphylococcal exotoxins presumed to be causative exotoxins of toxic shock syndrome: toxic shock syndrome toxin-1 and enterotoxins A, B and C to murine and human T cells.

Several observations suggest that staphylococcal enterotoxins A, B and C (SEA, SEB and SEC, respectively), in addition to toxic shock syndrome toxin-1 (TSST-1), are causative exotoxins of toxic shock syndrome (TSS). Based on the view that polyclonal T cell activation with the causative exotoxins, resulting in over-production of lymphokines, is involved in the development of the pathological changes observed in TSS, we investigated the activities of these four exotoxins to induce proliferation and interleukin 2 production in murine and human lymphocytes by using in vitro culture systems. The results showed that all these exotoxins are strong polyclonal inducers of proliferation and interleukin 2 production in human T cells, whereas TSST-1 and SEA are strong and SEB and SEC are weak polyclonal inducers in murine T cells. These results suggest that SEA, SEB and SEC, in addition to TSST-1, are possibly involved as causative exotoxins in the development of the pathological changes observed in TSS.

Studies on the enhanced effect of acupuncture analgesia and acupuncture anesthesia by D-phenylalanine (first report)--effect on pain threshold and inhibition by naloxone.

It has been claimed that the mechanism of acupuncture analgesia can be explained in part by endogenous opioids. If so, it might be possible to enhance the analgesic effect of acupuncture by the administration of endorphins. If D-phenylalanine (DPA), an inhibitor of the endorphin degrading enzyme, is administered, the analgesic effect of acupuncture should be prolonged due to the increased level of endorphins. From the changes of the pain threshold (PT), we investigated whether or not the pre-administration of DPA can enhance the analgesic effect of acupuncture in humans. In addition, we examined the inhibitory effect of naloxone. 1) In all five subjects whose PT was raised after acupuncture anesthesia (respondents), the rise in PT was significantly prolonged by DPA. 2) Out of 10 subjects whose PT remained almost unchanged after acupuncture anesthesia (non-respondents), the PT was increased by DPA in 5 cases. 3) The rise in PT was most prominent when DPA was administered 30 minutes before the start of acupuncture anesthesia. 4) In all 4 respondents in whom the rise in PT persisted after DPA and acupuncture anesthesia, their raised PT dropped after the intravenous injection of naloxone (10 mg). 5) These findings show that DPA enhances the analgesic effect of acupuncture by the "endorphin mechanism."