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BACKGROUND: Recent air travel recommendations suggest patients with precapillary pulmonary hypertension (PCPH) in New York Heart Association (NYHA) functional class 3 and 4 should have in-flight oxygen without the need for pre-flight testing. However it remains unclear as to how best to determine patients fitness to fly. METHODS: This study (i) investigates the effect of hypoxic challenge testing (HCT) on the arterial oxygen levels in a cohort of 36 patients with PCPH and (ii) compares the relative frequency with which FC and HCT predict the requirement for in-flight oxygen. RESULTS: The degree of arterial hypoxaemia induced by HCT (fall in partial pressure of oxygen in arterial blood (PaO(2)) 2.36 kPa, 95% CI 2.06-2.66 kPa) was similar to the drop observed in other published studies of chronic respiratory diseases. Following current air travel recommendations based on FC, 25 patients of the cohort would require in-flight oxygen whilst 10 subjects failed the HCT. Fourteen subjects had flown post-diagnosis. Of these, nine subjects should have had in-flight oxygen based on FC but were asymptomatic without. Also one who passed the HCT had developed symptoms during the flight whilst three who failed the HCT were asymptomatic flying without in-flight oxygen. CONCLUSIONS: Hypoxaemia induced by simulated air travel in patients with PCPH is similar to that seen in published studies of patients with other chronic respiratory diseases. HCT failed to predict correctly who had developed symptoms during an aircraft flight in a significant minority of the study subjects. Similarly guidelines based on functional class result in a major increase in the proportion of patients being advised to use oxygen, many of whom had been asymptomatic on previous flights without it. More work is required to improve prediction of need for in-flight oxygen in patients with PCPH.

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OBJECTIVE: In patients with Wegener's granulomatosis, subglottic stenosis can develop due to active disease; however, some patients develop subglottic stenosis with no clear evidence of airway inflammation. In some cases of idiopathic subglottic stenosis, an association with gastroesophageal reflux disease has been found. Our study assessed the potential role of gastroesophageal reflux as an aetiological factor in the development of subglottic stenosis in patients with Wegener's granulomatosis. DESIGN: We assessed evidence of active reflux disease, using 24-hour pH monitoring and assessment of bile salts in bronchoalveolar lavage fluid. SUBJECTS: Ten Wegener's granulomatosis patients with subglottic stenosis underwent 24-hour pH monitoring and bronchoscopy and lavage of the right middle lobe. A similar number of control patients were included. RESULTS: There was no statistically significant difference in the occurrence of bronchoalveolar bile salts in patients with subglottic stenosis (n = 2) versus control patients (zero) (p = 0.457). There was good correlation between the detection of reflux by 24-hour pH monitoring and the detection of bronchoalveolar bile salts (kappa = 0.769). CONCLUSION: In this small study of patients with Wegener's granulomatosis, there was no evidence of an association between the development of subglottic stenosis and gastroesophageal reflux.

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Severe combined immunodeficiency is one of the most common causes of primary immunodeficiencies in humans. Molecular biological techniques have allowed new, therapeutically useful treatments for these diseases to be introduced into clinical practice. This review will focus on the molecular basis and new treatments for X-linked severe combined immunodeficiency.

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Bitemporal injections of puromycin consistently induce amnesia of aversive maze learning in mice when administered within 3 days of training. These bitemporal puromycin injections lose their amnestic effectiveness if the latency between training and injection is extended beyond 6 days. Consistent with other evidence, we conclude that in our experimental paradigm, complementary memory storage sites normally develop in additional cerebral areas within 6 days following training. Previous experiments have indicated that the central adrenergic and cholinergic systems are critically involved in this process. We now present evidence that administration of the NMDA receptor antagonist, CPP, blocks the development of these complementary memory storage sites. As suggested by studies of long-term potentiation, NMDA receptor-dependent postsynaptic calcium appears to be essential for the development of these storage sites and indeed to trigger their development.

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Bitemporal injections of puromycin consistently induce amnesia of aversive maze learning in mice when given within 3 days after training. These injections consistently fail to induce amnesia when given 6 or more days after training. Consistent with the evidence from other laboratories, we interpret these results to indicate that the initial, temporal memory storage sites are supplemented 6 days after training by the development of complementary storage sites in other cerebral areas. Previous experiments have shown that this process is suppressed for 30-60 days by a single SC injection of scopolamine, a muscarinic antagonist. We now find that this suppressive action of scopolamine can be completely nullified by haloperidol, a dopaminergic antagonist. This finding supports the view that there may be a therapeutic role for dopamine antagonists in the treatment of cognitive dysfunction associated with cholinergic loss.

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Bitemporal injections of puromycin consistently induce amnesia of aversive maze-learning in mice when administered within 3 days of training. These bitemporal puromycin injections lose their amnestic effectiveness, if the latency between training and injection is extended beyond 6 days. Consistent with other evidence, we conclude that in our experimental paradigm, complementary memory storage sites normally develop in additional cerebral areas during the 6 days following training. Previous experiments have indicated that the central adrenergic system is critically involved in this process. We now present evidence that the central cholinergic system is also critically involved. This conclusion is based upon our results with the muscarinic receptor antagonists, scopolamine and methyl scopolamine.

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Bitemporal injections of puromycin consistently induce amnesia of aversive maze-learning in mice when administered within 3 days of training. These bitemporal puromycin injections lose their amnestic effectiveness if the latency between training and injection is extended beyond 6 days. Consistent with other evidence, we believe that memory (in our task) "spreads" during the 6 days following training. Since previous experiments have indicated that the central noradrenergic system is involved in this process of "memory spread," we have examined the effect of stimulation or blockade of the alpha 2-receptor. To this end, we administered a single dose of the alpha 2-adrenoceptor antagonist, idazoxan, or the alpha 2-agonist, clonidine. Idazoxan (1 mg/kg, SC) had no effect on engram spread. Clonidine (25 micrograms-125 ng/kg, SC), by contrast, suppressed engram spread for at least 30 days after treatment. When mice were tested at 60 and 90 days after treatment, spontaneous recovery (i.e., engram spread) was evident in only about 50% of the clonidine treated mice. Coadministration of idazoxan with clonidine blocked the effects of clonidine on "memory spread."

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Bitemporal injections of puromycin that primarily affect the hippocampal-entorhinal area induce amnesia of aversive maze-learning in mice for 3 days after training but are ineffective 6 or more days after training. At these later times, additional puromycin sites covering widespread forebrain areas are necessary to induce amnesia, a result that we attribute to the cerebral spread of the engram during the 6-day period. We have reported that blockade of about 60% of cerebral beta-adrenergic receptors by a single, subcutaneous injection of (-)-propranolol, a nonselective beta-receptor antagonist, inhibited engram spread for 60-90 days, at which time engram spread spontaneously occurred. In the present experiments using single doses of antagonists that appeared to block 60% of beta 2- or beta 1-adrenergic receptors, it was found that the selective beta 2 antagonist ICI 118,551 was without effect on engram spread, whereas the selective beta 1 antagonist betaxolol inhibited the spread for at least 3 months. Propranolol's effect consequently appears to be accounted for by its blockade of beta 1 receptors.

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Using bitemporal injections of puromycin, we have reported observations interpreted to indicate that a systemic injection of (-)-propranolol (50 micrograms/kg) drastically suppressed the spread of an engram in mice from the hippocampalentorhinal area to widespread cerebral areas. The present experiments were made with a non-selective, irreversible beta-adrenergic receptor antagonist that fails to cross the blood-brain barrier in order to test the possibility that the propranolol-induced blockade of peripheral beta-receptors might contribute to its effect on engram spread. Prolonged blockade of peripheral receptors by the irreversible antagonist had no effect on engram spread, suggesting that propranolol's effect was centrally mediated.

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This study was conducted to show that local autoimmune reactions could be observed in rat sciatic nerve after a single injury. Furthermore, we attempted to correlate the intensity of the immunological reaction with the severity of nerve damage, with the type of surgical treatment and with the degree of functional recovery. Through the use of direct immunofluorescence techniques, we found that the severity of the initial damage was associated with the intensity of the local immunological response assessed 2.5 months after surgery. There was an association between type of surgical treatment and intensity of the autoimmune reaction. A correlation between autoimmune reaction and degree of long-term functional impairment was not immediately clear. The probable factors that underlie these results are discussed.

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We studied the influence of previous nerve damage on the evolution of recovery that follows a second nerve injury. Recovery from nerve injury was assessed by analyzing rats' foot prints during a 74-day period. In addition, at the end of this period, the surgically treated sciatic nerves were immunohistochemically stained for the presence of immunoglobulins, an indicator of an autoimmune reaction. We found there was a moderately adverse effect of previous nerve damage on the sciatic functional recovery, a fact that suggests some systemic response to the distantly placed initial damage. Immunohistochemical staining showed various degrees of immunoglobulin deposition depending on the type of the two injuries. An interpretation of our results is proposed.

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We studied local autoimmune reactions in rat sciatic nerve after two successive injuries at the same site. The behavioral consequences of these injuries were also examined. We found that repetitive injuries had a moderately adverse effect on function and were accompanied by local autoimmune reactions. A causal relation between the two phenomena was possible but not clearly established.

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Learning and interhemispheric transfer of visual flux, pattern and form discriminations were studied in the cat after selected exposure of one suprasylvian cortex to 6-hydroxydopamine (6-OHDA). Biochemical assay using High Performance Liquid Chromatography (HPLC) two weeks after 6-OHDA revealed no discernible norepinephrine or dopamine in the treated cortex, but elevated concentrations of these transmitters in the cortex of the opposite hemisphere. Visual discriminations learned before treatment with 6-OHDA were retained at a high level using either the eye on the side of chemical lesion or the eye on the untreated side. An asymmetric deficit in learning new form discriminations was present, however, when the eye on the untreated side was used, in contrast to normal learning using the eye on the side of the hemisphere with depleted adrenergic nerve supply. Once learning was achieved using the lesioned hemisphere transfer of the engram was found to the untreated hemisphere. Thus, the unlesioned hemisphere was unable to learn normally using direct retinal input from the ipsilateral eye, but showed good capacity for learning using indirect visual input from the contralateral eye. This suggests a powerful influence of the callosum on the learning abilities of the two hemispheres, an influence proved by sectioning the callosum. Callosotomy resulted in a reversal of the discriminative capacities seen after 6-OHDA, i.e. the lesioned hemisphere was defective relative to the unlesioned hemisphere.

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The distribution of Met5-enkephalin-Arg6-Phe7 (Met-Enk-Arg-Phe)-like immunoreactivity in the rat gastrointestinal tract was studied by immunohistochemical techniques. Antiserum against a Met-Enk-Arg-Phe-thyroglobulin conjugate was raised in rabbits and was found to be specific for synthetic Met-Enk-Arg-Phe. Met-Enk-Arg-Phe-like immunoreactivity was found in neuronal structures in all parts of the rat gastrointestinal tract. Immunostained somata were primarily located in myenteric plexus; immunostained processes were mostly present in myenteric plexus and circular muscle layer. This distribution pattern is similar to that of the three other opioid polypeptides, Met5-enkephalin, Leu5-enkephalin and Met5-enkephalin-Arg6-Gly7-Leu8.

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Bi-temporal injections of puromycin that primarily affect the hippocampal-entorhinal areas consistently induce amnesia of aversive maze-learning in mice for 3 days after training but are consistently ineffective if given 6 or more days after training. At these later times, additional puromycin sites covering widespread areas of the forebrain are necessary to induce amnesia. Consistent with other evidence, these observations are interpreted to indicate that the locus of the memory trace becomes more widespread during the 6-day period. A single subcutaneous injection of (-)-propranolol (50 micrograms/kg) given either before or 2 days after training suppressed engram spread for 60-90 days, at which time engram spread spontaneously occurred. This effect of propranolol was stereospecific. Suppression of engram spread persisted for a prolonged period in spite of the rapid recovery (about 4 hr), following treatment, of the normal level of specific binding of 3H-dihydroalprenolol in membrane preparations of the cerebral hemispheres and of 125I-pindolol in selected areas of the forebrain, diencephalon and brainstem.

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