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1.  Histamine release by Western red cedar (Thuja plicata) from lung tissue in vitro 
Evans, Elizabeth and Nicholls, P. J. (1974).British Journal of Industrial Medicine,31, 28-30. Histamine release by Western red cedar(Thuja plicata)from lung tissue in vitro. Various respiratory symptoms have previously been observed in workers exposed to dust from Western red cedar (Thuja plicata). Although an allergic basis for these effects has been proposed, the possibility that the dust may contain a pharmacologically active agent was investigated. Aqueous extracts of two samples of red cedar released significant amounts of histamine from pig and human lung in vitro. For one of these samples, using pig lung, a dose-response relation was found over a narrow range of concentrations. These dusts possessed the same order of histamine-releasing activity as a sample of cotton dust. Potassium cyanide reduced the release of histamine caused by low concentrations of Western red cedar. Similar effects of cyanide on the histamine-releasing activity of cotton dust and compound 48/80 were observed. It is possible that release of histamine in the lungs and upper respiratory tract occurs on inhalation of dust from Western red cedar and this may be a contributory factor to the development of respiratory symptoms in workers exposed to the dust of this wood.
PMCID: PMC1009539  PMID: 4132384
2.  Histamine-releasing activity and bronchoconstricting effects of sisal 
Nicholls, P. J., Evans, E., Valić, F., and Žuškin, E. (1973).British Journal of Industrial Medicine,30, 142-145. Histamine-releasing activity and bronchoconstricting effects of sisal. Extracts of dry and oiled sisal released histamine from pig and human but not from rat lung tissue. A suspension in Tyrode solution of the oil used for softening the sisal fibres had a pH of 8·1 and also released histamine from pig and human lung. The releasing activity was abolished when the pH of this suspension was adjusted to pH 7·4. As all the sisal extracts were adjusted to pH 7·4 for incubation with lung tissue, the histamine-releasing activity of sisal in vitro is unrelated to the presence of the oil.
Significant (P < 0·01) mean reductions over the work shift of ventilatory capacity (PEF and FEV1·0) were recorded in all the workers exposed to airborne sisal dust. These reductions were greater in combers than in drawers and spinners. Sisal collected from combing machines possessed more histamine-releasing activity than material from drawing and spinning machines.
These results indicate that histamine release by sisal may be the cause of acute ventilatory capacity changes in sisal exposure.
PMCID: PMC1009496  PMID: 4122162
3.  Histamine in cereal dusts 
Nicholls, P. J. (1970).Brit. J. industr. Med.,27, 179-180. Histamine in cereal dusts. It has been found that workers exposed to cereal grain dusts may experience acute mild respiratory distress. An attempt has been made to explain this observation by examining the pharmacological activity of aqueous extracts of several cereal dusts from the holds of cargo ships. Histamine, but no other active agent, was found in the samples. It is unlikely that the concentration of histamine in these dusts is sufficient to cause respiratory distress in dockers unloading cereal grain cargoes.
PMCID: PMC1009095  PMID: 5428638
4.  Comparative study of the smooth muscle contractor activity of airborne dusts and of dustiness in cotton, flax, and jute mills. 
A bioassay technique using isolated guinea-pig ileum was employed to compare the smooth muscle contractor activity of various dusts from mills in which the prevalence of byssinosis was known. The activity of dust from a mill spinning a coarse grade of cotton was several times greater than that in dust from a mill processing a fine grade of cotton. There was a similar order in the difference of the prevalence of byssinosis in these mills. However, the activities of fine cotton, flax, and jute dusts were very similar to each other, in spite of marked differences in the prevalence of byssinosis in these mills. For cotton dust, smooth muscle contractor activity was associated with all particle sizes, although the lowest level of activity was found in the largest sized fraction (less than 2 mm). Activity in the cotton dust extracts was not correlated with nitrogen, carbohydrate, or potassium content. However, about one-fifth of the activity of a cotton dust extract was associated with an insoluble particulate fraction. The possible chemical nature of the water-soluble contractor agent is discussed. It is concluded that, until the role of this agent in the pathogenesis of byssinosis has been established, the bioassay technique cannot be employed as a means of assessing the byssinogenic potential of cotton dust.
PMCID: PMC1008078  PMID: 1201255
6.  Pharmacokinetic Studies in Animals and Humans of a New Cephalosporin, the Sodium Salt of 7-Cyanacetamidocephalosporanic Acid 
The sodium salt of 7-cyanacetamidocephalosporanic acid (CAA) had a relatively short serum half-life in rabbits (21 min by intravenous and 30 min by intramuscular administration) and in humans (33 min by intravenous injection). The drug was not extensively bound (about 35%) to serum in either species. Even after large doses (500 mg/kg), CAA was not well absorbed from the gastrointestinal tract of rabbits. Urinary excretion of antibacterial activity was rapid after intravenous and intramuscular administration in rabbits and after intravenous administration in men. Expressed as unchanged CAA, antibacterial activity appeared in the urine to the extent of 84% for humans, 35% for rabbits and 32% for rats. Excretion proceeded partly by active renal tubular secretion in rabbits. In this latter species, low concentrations of the active drug were detected in cerebrospinal fluid and bile after an intravenous dose of 25 mg/kg. CAA was well tolerated after intravenous administration of a single dose in both rabbits and humans.
PMCID: PMC444479  PMID: 4208297
7.  A functional alternative splicing mutation in human tryptophan hydroxylase-2 
Molecular Psychiatry  2010;16(12):1169-1176.
The brain serotonergic system has an essential role in the physiological functions of the central nervous system and dysregulation of serotonin (5-HT) homeostasis has been implicated in many neuropsychiatric disorders. The tryptophan hydroxylase-2 (TPH2) gene is the rate-limiting enzyme in brain 5-HT synthesis, and thus is an ideal candidate gene for understanding the role of dysregulation of brain serotonergic homeostasis. Here, we characterized a common, but functional single-nucleotide polymorphism (SNP rs1386493) in the TPH2 gene, which decreases efficiency of normal RNA splicing, resulting in a truncated TPH2 protein (TPH2-TR) by alternative splicing. TPH2-TR, which lacks TPH2 enzyme activity, dominant-negatively affects full-length TPH2 function, causing reduced 5-HT production. The predicted mRNA for TPH2-TR is present in postmortem brain of rs1386493 carriers. The rs13864923 variant does not appear to be overrepresented in either global or multiplex depression cohorts. However, in combination with other gene variants linked to 5-HT homeostasis, this variant may exhibit important epistatic influences.
doi:10.1038/mp.2010.99
PMCID: PMC3021090  PMID: 20856248
TPH2; serotonin (5-HT); SNP; alternative splicing
8.  Some Pharmacological Actions of Cotton Dust and Other Vegetable Dusts 
Aqueous extracts of cotton and other vegetable dusts cause contraction of the isolated ileum and tracheal muscle of the guinea-pig, and of isolated human bronchial muscle. The levels of this contractor activity place the dusts of cotton, flax, and jute in the order of the probable incidence of byssinosis occurring in the mills spinning these fibres.
Extracts of cotton dust possess a histamine-liberating activity and contain a permeability-increasing component. These actions are of plant origin and are found in the pericarp and bracts of the cotton boll. Histamine and 5-hydroxytryptamine have also been found in some cotton dust samples. The formation of histamine by bacterial action in cotton dust does not take place under conditions found in cotton mills. The smooth muscle contractor substance is organic in nature, relatively heat-stable, and dialysable. The relevance of these results to the symptoms of byssinosis is discussed.
PMCID: PMC1038128  PMID: 14479451
9.  Internalization of a Bacillus anthracis protective antigen-c-Myc fusion protein mediated by cell surface anti-c-Myc antibodies. 
Molecular Medicine  1998;4(2):87-95.
BACKGROUND: Anthrax toxin, secreted by Bacillus anthracis, consists of protective antigen (PA) and either lethal factor (LF) or edema factor (EF). PA, the receptor-binding component of the toxin, translocates LF or EF into the cytosol, where the latter proteins exert their toxic effects. We hypothesized that anthrax toxin fusion proteins could be used to kill virus-infected cells and tumor cells, if PA could be redirected to unique receptors found only on these cells. MATERIALS AND METHODS: To test this hypothesis in a model system, amino acids 410-419 of the human p62(c-myc) epitope were fused to the C-terminus of PA to redirect PA to the c-Myc-specific hybridoma cell line 9E10. RESULTS: The PA-c-Myc fusion protein killed both mouse macrophages and 9E10 hybridoma cells when administered with LF or an LF fusion protein (FP59), respectively. Similar results were obtained with PA, which suggests that PA-c-Myc used the endogenous PA receptor to enter the cells. By blocking the endogenous PA receptors on 9E10 cells with the competitive inhibitor PA SNKEDeltaFF, the PA-c-Myc was directed to an alternate receptor, i.e., the anti-c-Myc antibodies presented on the cell surface. The c-Myc IgG were proven to act as receptors because the addition of a synthetic peptide containing the c-Myc epitope along with PA SNKEDeltaFF further reduced the toxicity of PA-c-Myc + FP59. CONCLUSION: This study shows that PA can be redirected to alternate receptors by adding novel epitopes to the C-terminus of PA, enabling the creation of cell-directed toxins for therapeutic purposes.
PMCID: PMC2230306  PMID: 9508786
10.  Identification of a single amino acid substitution in the diphtheria toxin A chain of CRM 228 responsible for the loss of enzymatic activity. 
Journal of Bacteriology  1994;176(15):4766-4769.
CRM 228 (T. Uchida, A. M. Pappenheimer, and R. Greany, J. Biol. Chem. 248:3838-3844, 1973), a mutant form of diphtheria toxin which completely lacks ADP-ribosyltransferase activity, contains five amino acid substitutions. The two amino acid changes that fall within the A chain of the toxin (G79D and E162K) were separately analyzed by substituting a variety of other amino acids at these sites. The substitution at position 79 (G79D) singularly appears to account for the loss of enzymatic activity found in CRM 228.
PMCID: PMC196302  PMID: 8045910
11.  In vitro release of arachidonic acid and in vivo responses to respirable fractions of cotton dust. 
It was considered that the fall in lung function seen after exposure to cotton dust may be attributable in part to the activity of arachidonic acid metabolites, such as leucotrienes as well as to the more established release of histamine by cotton dust. However, we found that cotton and barley dusts elicited poor release of arachidonic acid from an established macrophage like cell line compared with that observed with other organic dusts. In the experimental animal, pulmonary cellular responses to both cotton and barley dust were similar to those evoked by moldy hay and pigeon dropping dusts, although after multiple doses a more severe response was seen to cotton and barley. Since both moldy hay and pigeon droppings elicit a greater arachidonic acid release than cotton or barley, a role for arachidonic acid in inducing the cellular response is less likely than other factors. There are limitations to our conclusions using this system, i.e., the arachidonic acid may be released in a nonmetabolized form, although it is noted that the two dusts with the greatest arachidonic acid release produce their clinical responses in humans largely by hypersensitivity mechanisms.
PMCID: PMC1474386  PMID: 3086080
12.  Splints in severe osteogenesis imperfecta. 
British Medical Journal  1978;1(6113):620-621.
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PMCID: PMC1603404  PMID: 630260

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