Oral spray immunization may be an alternative to intranasal vaccine delivery to induce systemic antibodies but not nasal mucosal or cellular immunity.

Sixty-five healthy adult volunteers were immunized four times at 1-week intervals with an inactivated whole-virus influenza vaccine based on the strain A/New Caledonia/20/99 (H1N1) without adjuvant. The vaccine was administered as nasal spray with a newly developed device to secure intranasal delivery (OptiMist, OptiNose AS, Oslo, Norway), as regular nasal spray, nasal drops or as an oral spray. Significant IgA-antibody responses in nasal secretions were induced in volunteers immunized intranasally but not after oral spray immunization. In saliva, IgA antibodies were only marginally amplified even after oral spray immunizations. At least 73% of the volunteers belonging to any group of vaccine delivery reached serum haemagglutination inhibition titres of 40 or higher, considered protective against influenza, after only two vaccine doses. Those who had the vaccine delivered intranasally also showed evidence from in vitro secretion of granzyme B that cytotoxic T cells had been stimulated. Although immunization with the breath-actuated OptiMist device and nasal drops were superior with respect to both mucosal and systemic immune responses, oral spray immunization might still be considered for studies of mucosal adjuvants that are not yet acceptable for intranasal use.

Immunoglobulin-A antibodies in upper airway secretions may inhibit intranasal influenza virus replication in mice but not protect against clinical illness.

Mice immunized intranasally with a formalin-inactivated A/PR/8/34 (H1N1) influenza whole virus vaccine adjuvanted with cholera toxin, outer membrane vesicles from group B meningococci or formalin-inactivated whole cell Bordetella pertussis were protected against replication of the homologous virus in the nasal cavity. Only some mice were protected against clinical illness measured as weight loss and lowered body temperature. All mice immunized subcutaneously with one-tenth the intranasal vaccine dose without adjuvant were protected against clinical illness but not against local mucosal viral replication. Replicating virus was primarily found in animals with low concentrations of immunoglobulin (Ig)-A antibodies in saliva regardless of concentrations of IgG antibodies in serum. Clinical illness was seen only in those with low serum antibodies regardless of antibody levels in saliva. Nonreplicating nasal vaccines may not be sufficiently protective unless they also have a substantial influence on systemic immunity.

Sustained increase in arterial blood pressure and vascular resistance induced by infusion of arachidonic acid in rats.

The haemodynamic responses to arachidonic acid (AA) have been investigated in seven groups of anaesthetized rats. Sodium arachidonate was infused intravenously for 4 or 20 min, and arterial blood pressure was recorded continuously. Cardiac output and organ blood flow were measured by microspheres. Infusion of arachidonate caused first a fast drop in arterial blood pressure, thereafter it increased steadily for 5-15 min towards a pressure about 25 mmHg above control level. The high pressure was maintained for at least 1 h. Repeated infusions of arachidonate gave similar responses. Inhibition of cyclo-oxygenase by indomethacin prevented the initial pressure drop to arachidonate, but not the sustained increase in pressure. Arterial pressure, total vascular resistance and blood flow in the kidneys, adrenals and spleen were significantly reduced, whereas cardiac output was not changed 4 min after start infusion of arachidonate. However, average blood pressure was significantly increased 22 and 35 min after start infusion (from 103.9 +/- 2.9 to 128.1 +/- 6.1 and 135.8 +/- 4.6 mmHg). Mean vascular resistance increased simultaneously (from 3.5 +/- 0.2 to 4.7 +/- 0.4 and 5.2 +/- 0.4 mmHg 100 mL-1), while cardiac output, stroke volume and heart rate were maintained or slightly reduced. The renal blood flow was significantly lowered (from average 4.9 +/- 0.1 to 3.3 +/- 0.2 and 4.0 +/- 0.2 mL min-1). Indomethacin did not prevent the changes in vascular resistance or organ blood flow recorded after 20-35 min. On the other hand, inhibition of both cyclo-oxygenase, lipoxygenase and the cytochrome P450 pathways by eicosatetrayonic acid (ETYA) normalized all haemodynamic parameters. Likewise, the rise in pressure was prevented by 17-octadecynoic acid (17-ODYA), an inhibitor of the cytochrome P450 enzyme activity. Thus, arachidonate infusion caused a transient decrease, and then a sustained increase in arterial pressure and vascular resistance, and a long-lasting reduction in renal blood flow, possibly owing to release of a cytochrome P450 dependent vasoconstrictor metabolite of AA.

The sunken nuclear submarine Komsomolets and its effects on the environment.

This paper discusses the possible release mechanisms for radionuclides on board the sunken nuclear submarine Komsomolets. With an aim to determine whether or not the sunken submarine presents any significant hazards to man, a worst-case approach is taken in estimating the environmental effects of the released radionuclides. It is found that neither the submarine hull nor the reactor vessel will be destroyed by corrosion for at least 1000 years. While the total radionuclide inventory presently is estimated to be approx. 8 PBq, only approx. 1 TBq is released annually into the surrounding environment. The distribution of the released radionuclides in the ocean has been modeled, and it was found that not even in the most heavily affected waters will the present contamination levels change significantly due to the Komsomolets. In short, this study, which does not pretend to completely answer all environmental questions related to the sunken submarine, clearly indicates that the Komsomolets represents no significant hazard to man, today or in the future.

Effects of calcitonin gene-related peptide (CGRP) on regional haemodynamics and on selected hepato-splanchnic arteries from the rat: a comparison with VIP and atriopeptin II.

The neuropeptides calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) were compared with atriopeptin II (AP II) for vasodilatory responses in the rat. The haemodynamic changes following intravenous infusion of non-hypotensive doses were measured by the microsphere technique. Isolated segments of arteries from the hepato-splanchnic region were assayed for tension responses. CGRP (2.9 pmol kg-1 min-1) caused significant reductions in vascular resistances in the spleen, the stomach and the myocardium. VIP was without detectable effects at a similar dose. At a 10-times higher dose, AP II was still without hypotensive effect and vascular resistance was reduced only in the submaxillary gland. CGRP, VIP and AP II produced endothelium-independent relaxations of isolated segments of the left gastric artery, the splenic artery and the hepatic artery. In the superior mesenteric artery (SMA) the response to CGRP was reduced by 90% after the endothelium was disrupted. When a functional endothelium was present, the potencies for CGRP were higher in the gastric artery, the splenic artery and the SMA than in the hepatic artery. The orders of potencies for the peptides were, for the gastric artery and the SMA CGRP greater than AP II greater than VIP, and for the splenic artery and the hepatic artery CGRP = AP II greater than VIP. In conclusion, vasodilations in the spleen and the stomach occurred only in response to infusion of CGRP. Consistently, significantly higher potency values were found for CGRP than for VIP in isolated arteries from these organs. However, there were examples of discrepancies between the in vitro and the in vivo responses to CGRP and AP II.

Renal vasoconstriction induced by arachidonic acid during burn shock in rats.

Metabolites of arachidonic acid are possible mediators of local renal vasoconstriction in burn shock. The prostanoid precursor arachidonic acid (AA) therefore was infused in the control period and at 1 and 2 h after scalding in anaesthetized rats. To avoid systemic effects. AA was infused at low doses directly into the renal artery through a thin cannula introduced through the aortic wall. After control observations 40% of the body surface was scalded in 80 degrees C water. Renal arterial blood flow (RBF), measured by an electromagnetic probe, fell to 70% and 58% of the control level at 1 h and 2 h after scalding respectively. Arterial blood pressure was almost maintained. Infusion of AA (5, 15 and 25 nmol) in the renal artery over 15 s caused no effects in the control period, whereas a dose-dependent decrease in RBF was observed after scalding, and was most pronounced 2 h post-burn. The highest dose of AA reduced RBF by 37% at 1 h and by 80% of preinfusion flow at 2 h after scalding. The AA-induced decrease in RBF was abolished by blocking the thromboxane A2 receptors with AH23848. In contrast, inhibition of prostacyclin synthesis or blocking of serotonin S2 receptors did not significantly influence the response to AA during shock. Thus, infusion of AA into the renal artery caused a marked reduction of RBF after scalding, at doses that did not induce a change during the control period. The augmented effect of AA infusion may be due to an increased capacity for synthesis of thromboxane A2 (TxA2), and possibly PGH2 and PGF2 alpha, after scalding.

Local renal ischemia during burn shock in rat effected by thromboxane A2 and serotonin.

Intermittent patchy ischemia in the renal cortex during traumatic shock has previously been observed in dogs and rats. In recent experiments on rats a high rate of abrupt changes in local blood flow was observed after scalding. To try to reveal endogenous factors causing such ischemic episodes, we scalded six series of anesthetized rats (50% of body surface for 30 s in 80 degrees C water) and measured arterial pressure (AP), hematocrit (Hct), and local renal cortical blood flow (RCF). RCF was recorded by the local H2 washout technique. After scalding, RCF decreased markedly in all series whereas AP was relatively well preserved. In accordance with previous experiments, 11% of the washout curves recorded 0-75 min after scalding showed abrupt changes in local blood flow, rising to 27% during the next 60 min in drug-untreated rats. In contrast, blocking of serotonin S2 receptors with Ketanserin abolished the phenomenon. However, in rats treated with the prostaglandin synthesis blockers, indomethacin (general) or 3-ethyl pyridin (thromboxane A2 blocker), the phenomenon was observed in only 2-3% of the washout curves. Furthermore, after blocking the AngII receptors by saralasin or alpha receptors by phentolamine in separate series, the frequency of abrupt flow shifts was reduced in comparison to the frequency in untreated rats. The results indicate that intermittent, patchy vasoconstriction is mediated by serotonin and thromboxane A2 (TxA2), probably released from platelets. The occurrence of ischemic episodes also depends on the local AngII and alpha-adrenergic tonus present after scalding.

Blood flow heterogeneity in the renal cortex during burn shock in dogs.

Blood flow distribution and occurrence of intermittent, patchy ischaemia in the renal cortex were investigated in anaesthetized dogs before and during burn shock. Severe or moderate thermal injury was induced by scalding 30% of body surface by 90 degrees C or 70 degrees C hot water. Local blood flow in outer and inner cortex was measured by microspheres and by electrodes recording hydrogen gas washout rates. The haematocrit rose much more in the moderately than in the severely scalded dogs, due to marked haemolysis in the latter group. Cortical blood flow was reduced more after severe than after moderate thermal injury. A significant redistribution of blood flow from outer to inner cortex was not demonstrated. Abrupt shifts in local washout rates were observed in most dogs during shock, but was consistently more frequent in the moderately scalded dogs. Such episodes of patchy intermittent ischaemia were not seen after inhibition of prostaglandin synthesis by indomethacin. Thus, prostaglandins may mediate focal vasoconstriction in the renal cortex during burn shock in dogs.

Local blood flow changes in the renal cortex during tourniquet and burn shock in rats.

Intermittent patchy ischemia in the renal cortex has been observed in dogs during traumatic shock. In search of a model for further studies of this phenomenon in anesthetized rats, we induced tourniquet shock by bilateral hindlimb occlusion for 3 1/2 h, and burn shock by scalding the hind 50% of body surface for 30 sec in 90 degrees C water. Local cortical blood flow (RCF) was repeatedly measured by the H2-washout technique. After releasing the tourniquets, mean arterial pressure (AP) and RCF decreased by 44 and 68% whereas hematocrit (Hct) rose to 66 vol%. Only two episodes of local ischemia were observed. After scalding, Hct first fell to 49 vol%, probably due to hemolysis, but rose toward 54 vol% in the next 2 h. Following an initial drop to 99 mmHg, AP was relatively well maintained throughout the experiment. The RCF fell to 53% of control within 15 min with a further decrease to 40% during the next 2 h. The cortical vascular resistance was increased by 89%. Increased local flow heterogeneity and episodes of patchy intermittent ischemia were observed in six out of eight rats. During the second hour postburn, 21% of the washout curves showed abrupt shifts of washout rates, indicating local cortical ischemia. The burn shock model seems well suited for studies of the mechanisms causing intermittent local ischemia.