Surviving the siege. My experience at Omaha Beach from D-Day to D+3.
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Europe↗
Biomedical subjects
J Hughes
Publications and source records attributed to J Hughes.
Development of recombinant Salmonellae expressing hybrid hepatitis B virus core particles as candidate oral vaccines.
This paper provides a review on the development of hepatitis core antigen as a vaccine carrier moiety and the use of recombinant Salmonella vaccine strains expressing hybrid HBcAg particles as live oral vaccines. Salmonella spp. can be attenuated by defined genetic means so that they become avirulent, yet preserve invasiveness after oral uptake. Oral immunization of mice with such avirulent candidate Salmonella typhimurium vaccine strains elicited serum antibody responses against a limited number of bacterial antigens. A highly immunogenic viral nucleocapsid antigen, hepatitis B virus core antigen (HBcAg) that can be expressed in prokaryotes was used as a carrier moiety for B-cell epitopes. Insertion sites with an enhanced immunogenicity for the carried epitopes were defined using HBV envelope protein virus neutralizing epitopes. An internal insertion site in HBcAg was found that drastically enhanced the immunogenicity of the foreign (pre-S1) epitope while reducing the immunogenicity of the carrier protein. Internally fused HBc/pre-S hybrid particles were expressed in Salmonella typhimurium and S. typhi vaccine strains. A single oral immunization of mice with such live recombinant S. typhimurium strains elicited a high titred serum anti-pre-S1 IgG response. Similarly, circumsporozoite repeat epitopes of three different malaria parasites were expressed as HBcAg/CS hybrids in recombinant S. spp. and were found to be highly immunogenic.
Administration, Oral↗
Molecular medicine: oligonucleotides.
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Biotechnology↗
Primary lymphoma of the cauda equina: myelographic, CT myelographic, and MR appearance.
This case demonstrates the myelographic, CT myelographic, and MR appearance of primary lymphoma of the cauda equina. It also illustrates the utility of high-resolution CT myelography in certain lesions of the cauda equina. The authors feel that CT myelography, with its inherent ability to depict individual nerve roots and therefore any pathologic involvement as well, should be considered an adjunct to MR in imaging the cauda equina.
Aged↗
PD 135158, a CCKB/gastrin receptor antagonist, stimulates rat pancreatic enzyme secretion as a CCKA receptor agonist.
The CCKB/gastrin receptor antagonist, PD 135158 (CAM 1028), surprisingly stimulates lipase release from isolated rat pancreatic acini dose dependently in a biphasic manner, with identical efficacy but lower potency compared to cholecystokinin octapeptide (CCK-8). Half-maximal stimulation occurred at 0.6 microM and maximal secretion was induced at 50 microM. Supramaximal concentrations decreased lipase release. Acinar lipase secretion in response to 25 pM CCK-8 or 1 microM CAM-1028 was abolished by 5 microM of the specific CCKA receptor antagonist loxiglumide (CR 1505), half-maximal inhibition was observed at 0.6 microM for CCK-8 and 0.4 microM for PD 135158. These data demonstrate that the CCKB/gastrin receptor antagonist, PD 135158, acts as a full agonist at the rat pancreatic CCKA receptor.
Animals↗
Up-regulation of cholecystokinin in primary sensory neurons is associated with morphine insensitivity in experimental neuropathic pain in the rat.
We examined the distribution of mRNA for the peptide cholecystokinin (CCK) with in situ hybridization in adult rat lumbar dorsal root ganglia following unilateral section of the sciatic nerve, as well as the effect of systemic CI 988, a selective antagonist of the CCK type B receptor, applied alone or in combination with intrathecal (i.t.) morphine, on the self-mutilating behavior of rats (autotomy) after axotomy, a sign of neuropathic pain and/or dysesthesia. There was a dramatic increase in the number of neurons in dorsal root ganglia synthesizing the peptide cholecystokinin (CCK) after sciatic nerve section. Furthermore, the autotomy behavior of rats was significantly inhibited by chronic i.t. administration of morphine in conjunction with subcutaneous (s.c.) injection of CI 988. Neither i.t. morphine nor s.c. CI 988 alone produced a comparable effect on autotomy. Our results suggested that up-regulation of the mRNA for CCK in primary afferents after nerve injury may be related to the clinical phenomenon of opioid insensitivity. Thus, coadministration of CCK antagonists in combination with opioids may offer a new approach in treating neuropathic pain.
Animals↗
Cholecystokinin dipeptoid antagonists: design, synthesis, and anxiolytic profile of some novel CCK-A and CCK-B selective and "mixed" CCK-A/CCK-B antagonists.
The design, synthesis, and structure-activity relationships (SAR) for the development of selective dipeptoid ligands for both of the cholecystokinin (CCK) receptor subtypes CCK-A and CCK-B are described. The SAR developed is used to design a ligand with equal nanomolar binding affinity for both the CCK-A and CCK-B receptors. Example compounds such as [1R-[1 alpha[R*(R*)],2 beta]]-4-[[2-[[3-(1H-indol-3-yl)- 2-methyl-2-[[[(2-methylcyclohexyl)oxy]carbonyl]amino]-1- oxopropyl]-amino]-1-phenylethyl]amino]-4-oxo-butanoic acid (24c), (1R-trans)-N-[alpha-methyl-N-[[(2-methylcyclohexyl)oxy] carbonyl]-D-tryptophyl]-L-3-(phenylmethyl)-beta-alanine (28i), and N-[alpha-methyl-N-[(tricyclo[3.3.1.1]dec-2-yloxy) carbonyl]-D-tryptophanyl]-L-3-(phenylmethyl)-beta-alanine (30m) are CCK-B selective compounds having CCK-B binding affinities of IC50 = 3.9, 0.34, and 0.15 nM with a CCK-A/CCK-B ratio of 464, 53, and 170, respectively. Other compounds such as (1R-trans)-N-[alpha-methyl-N-[[(2-methylcyclohexyl)oxy]carbonyl]- L-tryptophyl]-D-3-(phenylmethyl)-beta-alanine (281) and N-(alpha-methyl-N-[(tricyclo[3.3.1.1]dec-2-yloxy)carbonyl]-L - tryptophyl]-D-3-(phenylmethyl)-beta-alanine (30p) are CCK-A-selective compounds having CCK-A binding affinities of IC50 = 7.9 and 2.82 nM with a CCK-A/CCK-B ratio of 0.007 and 0.01, respectively. Further to these, (1S-trans)-N-[alpha-methyl-N-[[(2-methylcyclohexyl)oxy] carbonyl]-D-tryptophyl]-L-3-(phenylmethyl)-beta-alanine (28h) is a mixed CCK-A/CCK-B ligand with a CCK-A binding affinity of IC50 = 3.9 nM and a CCK-B binding affinity of IC50 = 4.2, producing a CCK-A/CCK-B ratio of unity. The CCK-B selective compounds are shown to be antagonists in electrophysiological tests on the rat ventromedial nucleus of the hypothalamus with an equilibrium constant (Ke) value of 2.8 nM for 30m and are also shown to be anxiolytic in the mouse ligh/dark box test with a minimum effective dose of 0.01 mg/kg, sc, for 30m. The CCK-A selective compounds are also shown to be competitive antagonists by the inhibition of CCK-8S-evoked amylase secretion from pancreatic acinar cells with a Ke value of 16 nM for 30p. In electrophysiological tests on the rat dorsal raphé (an area rich in CCK-A receptors) 30p had a Ke value of 12.8 nM. The mixed CCK-A/CCK-B compound 28h showed antagonistic properties in both CCK-A and CCK-B models; thus it inhibited CCK-8S-evoked amylase secretion from pancreatic acinar cells and is anxiolytic in the light/dark box paradigm.(ABSTRACT TRUNCATED AT 400 WORDS)
Amino Acid Sequence↗
The effect of dizocilpine and enadoline on immediate early gene expression in the gerbil global ischaemia model.
Increases in mRNA levels for c-fos, c-jun, junB, hsp70 and NGFI-A were observed in the dentate gyrus of the hippocampus following 7 min ischaemia in the Mongolian gerbil. The response was rapid and transient (30 min to 4 hr) for NGFI-A, junB and c-fos mRNA. In contrast c-jun mRNA remained increased for several hours. Hsp70 increased in the dentate gyrus 1 hr after the insult, returned to control values at 4 hr and showed a secondary increase at 24 hr. At 24 hr increased hsp70 mRNA was observed in other regions of the CNS, i.e. CA1, CA2, CA3 and cortex. The non-competitive NMDA receptor antagonist, dizocilpine, attenuated the increases in IEG expression and was neuroprotective. In contrast the kappa opiate receptor agonist, enadoline, protected the CA1 neurones from degeneration but did not inhibit the increased levels of IEG mRNA. Increases in hsp70 mRNA were reduced to baseline by both enadoline and dizocilpine. These results suggest that inhibition of IEG expression is not a prerequisite for neuroprotection. However, hsp70 was predictive of neuronal protection and may be a useful assay in this and related models.
Animals↗
A virulent Salmonella expressing hybrid hepatitis B virus core/pre-S genes for oral vaccination.
This report reviews and extends data on the use of hepatitis B virus (HBV) core (HBcAg) particles as a carrier moiety for B-cell epitopes of the HBV envelope proteins. Virus-neutralizing epitopes of the HBV pre-S region were inserted at the N-terminus, the N-terminus through a precore linker sequence, the C-terminus and an internal position of HBcAg by genetic engineering in Escherichia coli. The hybrid HBc/pre-S proteins were purified and their antigenicity and immunogenicity analysed. All purified HBc/pre-S particles were particulate. Pre-S epitopes inserted at the N-terminus through a precore polylinker, the truncated C-terminus and at the internal position between HBcAg amino acids 75 and 81 were accessible on the particle surface. N-terminal fusions required the presence of the linker sequence to become surface accessible and immunogenic. Fusions to the N- and C-termini of HBcAg did not interfere with HBcAg antigenicity and immunogenicity. In contrast, insertion at the internal site abrogated recognition of HBcAg by five out of six monoclonal antibodies and diminished recognition by human polyclonal anti-HBc antibodies as well as HBcAg immunogenicity. A pre-S(2) sequence fused to the C-terminus of HBcAg was surface accessible and weakly immunogenic. Pre-S(1) sequences fused to the N-terminus through a precore linker were surface accessible and highly immunogenic. The same sequence fused to the core methionine was not surface accessible or immunogenic. Insertion of the same pre-S(1) sequence at an internal position of HBcAg resulted in the most efficient anti-pre-S(1) antibody response.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Anticonvulsant agents, dizocilpine maleate, enadoline and HA 966 have different effects on N-methyl-DL-aspartate-induced immediate early gene induction in mice.
Administration of N-methyl-DL-aspartate (85 mg/ml) was given by infusion (0.14 ml/min) until a clonic seizure was elicited. In situ hybridization was used to assess regional levels of four immediate early gene messenger RNA levels (c-fos, c-jun, junB, and a nerve growth factor induced gene, NGFI-A). Messenger RNA levels were highest at 25 min following infusion of N-methyl-DL-aspartate. c-jun messenger RNA levels remained elevated for over 2 h; however, c-fos, junB and, NGFI-A messenger RNA levels had returned to control levels by this time. Expression was detected in the hippocampus, hypothalamus and piriform cortex. Pre-treatment (30 min prior to N-methyl-DL-aspartate) with the anticonvulsant drugs dizocilpine maleate (1 mg/kg) and HA 966 (200 micrograms, i.c.v.) resulted in significantly reduced immediate early gene messenger RNA levels in the hypothalamus and piriform cortex, and attenuated levels in the hippocampus. Pre-treatment with the anticonvulsant agent enadoline (3 mg/kg), given at an anticonvulsant dose, did not result in reduced immediate early gene messenger RNA levels. These results suggest that monitoring immediate early gene expression may lead to advances in the understanding of the mechanism of action of many pharmacological agents, such as the kappa-opioid agonist enadoline.
Animals↗
Hypertonic saline infusion increases plasma norepinephrine concentrations in normal men.
We recently demonstrated in patients with panic disorder that hypertonic saline infusion induces acute panic with the same frequency and intensity as the standard hypertonic sodium lactate infusion. We now report the effects in normal men of hypertonic saline infusion on neuroendocrine systems possibly relevant to panic and anxiety. We administered a 150-min infusion of hypertonic saline (5% sodium chloride) which increased plasma osmolality from 288 +/- 1 to 303 +/- 2 mOsm/kg and produced the appropriate increase of plasma arginine vasopressin (AVP). Plasma norepinephrine (NE) increased substantially during hypertonic saline infusion compared to a normal saline infusion of equal volume and duration. Mean arterial pressure (MAP) also increased and there were significant positive correlations between MAP and NE, but not between MAP and AVP during hypertonic saline infusion. Plasma epinephrine and cortisol did not differ between conditions. Although the pattern of plasma adrenocorticotrophic hormone (ACTH) response differed between hypertonic saline and normal saline conditions, ACTH concentrations did not increase compared to baseline in either condition. These data suggest that hypertonic saline infusion increases sympathetic nervous system activity in normal men.
Adrenocorticotropic Hormone↗
Premonitory symptoms in epilepsy.
We studied premonitory symptoms in 128 patients with partial and 20 patients with primary generalized epilepsy. Sixty symptoms were reported by 43 (29%) patients, all of whom had partial seizure disorders (P < .01). Symptoms began at least 30 minutes before seizure onset, lasted 10 minutes to 3 days, and were continuous. Irritability, depression, headache, 'funny feeling', and confusion were the most common symptoms. Premonitory symptoms are a warning system in some patients and may permit therapeutic interventions.
Adolescent↗
Effects of tobacco abstinence on food intake among cigarette smokers.
The total caloric and specific nutrient intakes of smokers who became abstinent were compared with those of a control group. Both groups were composed of volunteer inpatients housed in a research ward for 7 days. After smoking ad libitum for 3 days, the experimental group was required to abstain from tobacco for the next 4 days while the control group continued to smoke. Significant increases in total caloric intake and in grams of carbohydrates, protein, fat, and sucrose were observed in the experimental relative to the control group, whereas no significant differences were found in fructose intake. The increase in caloric intake was not specific to increases in snacking. Preliminary analyses showed gender differences in food intake as a result of tobacco abstinence.
Adult↗
Role of T-cell tolerance in the persistence of hepatitis B virus infection.
Infants born to hepatitis B e antigen (HBeAg)-positive hepatitis B virus (HBV) carrier mothers invariably become persistently infected. To investigate the role of immunologic tolerance mechanisms in chronic infection of the newborn, we have generated HBeAg-expressing transgenic mice (B10.S-Tg31e). These mice were tolerant to both HBeAg and the nonsecreted HBcAg at the T-cell level. Furthermore, nontransgenic littermates born to HBeAg-expressing mothers showed lowered T-cell responses to HBc/HBe antigens, suggesting that tolerogenic HBeAg may cross the placenta. Tg mice did not produce antibody to HBeAg but did produce immunoglobulin M (IgM) antibodies to HBcAg via a T cell-independent pathway. The coexistence of tolerance to HBc/HBe T-cell determinants and production of antibody to HBcAg in vivo parallels the immunologic status of neonates born to carrier mothers. These observations suggest that expression of HBeAg may represent a viral strategy to guarantee persistence after perinatal infection. Further studies in F1 hybrid Tg mice (B10 x B10.S-Tg31e) illustrated that "self" tolerance to HBeAg is variable, depending on the major histocompatibility complex (MHC) genotype. A proportion of T cells recognizing e129-140 in the context of I-Ab evade induction of tolerance, persist in the periphery, and can be activated in vivo by a single injection of the 12 residue T-cell self-peptide. Furthermore, the self-reactive T cells can cooperate with self-reactive, HBeAg-specific B cells to mediate in vivo production of autoantibody sufficient to neutralize detection of the autoantigen in serum.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Infectious mononucleosis presenting as erythema multiforme.
Infectious mononucleosis is rarely associated with skin lesions. A 23-year-old woman with acute infectious mononucleosis who presented with moderately severe erythema multiforme is reported. The role of steroids in the management of this condition is briefly discussed.
Adult↗
Hallucinations on withdrawal of isoflurane used as sedation.
Hallucinations on withdrawal of midazolam have been noted in intensive care patients. Isoflurane is increasingly used as an alternative drug for sedation. We report a seven-year-old child with 15% burns who, on withdrawal of isoflurane, suffered hallucinations, a generalized seizure and disorientation. The adverse symptoms occurred within hours of stopping the isoflurane and lasted for five days.
Child↗
Retropharyngeal infection with Staphylococcus aureus in a haemodialysis patient.
The case of a 55-year-old female Asian haemodialysis patient is described. She developed a septicaemic illness and retropharyngeal soft-tissue infection secondary to Staphylococcus aureus infection.
Bacteremia↗