Suicide microbes on the loose.
Explore the source record for details and available documents.
Bacteria↗
Biomedical subjects
P Andersson
Publications and source records attributed to P Andersson.
Budesonide is metabolized by cytochrome P450 3A (CYP3A) enzymes in human liver.
Budesonide is a synthetic glucocorticosteroid that is commonly used in topical treatment of asthma and rhinitis. The main metabolites formed from budesonide in human liver microsomes have been identified as 16 alpha-hydroxyprednisolone and 6 beta-hydroxy-budesonide. Although it is apparent that the cytochrome P450 (CYP) system is involved, the actual subfamily has not been identified. In attempts to do this, budesonide was incubated with microsomes from ten different human liver samples where various CYP activities had been rank ordered. We found a strong correlation between formation of the two main metabolites and testosterone 6 beta-hydroxylation (correlation 0.98 and 0.95), a marker for CYP3A. When budesonide (10 microM) was incubated with human liver microsomes in the presence of compounds known to interact with different isoforms or subfamilies of CYP, ketoconazole was found to be the strongest inhibitor of budesonide metabolism (IC50: approximately 0.1 microM) followed by troleandomycin (IC50: approximately 1 microM), erythromycin, and cyclosporin, all substances known to interact with CYP3A isoenzymes. Substances known to interact with CYP2C (sulfaphenazole, mephenytoin, and tolbutamide) and with CYP2D6 (bufuralol and quinidine) did not specifically inhibit the metabolism of budesonide. In addition, formation of the budesonide metabolites (16 alpha-hydroxyprednisolone and 6 beta-hydroxybudesonide) was inhibited by antibodies against the CYP3A subfamily, but not by antibodies against the CYP1A subfamily or control immunoglobulin G. We conclude that the formation of 16 alpha-hydroxyprednisolone and 6 beta-hydroxybudesonide from budesonide is catalyzed by isoenzymes within the CYP3A subfamily.
Administration, Topical↗
Symptoms and immunologic markers induced by exposure to methyltetrahydrophthalic anhydride.
A study was performed in 43 workers exposed to methyltetrahydrophthalic anhydride (MTHPA) used as a hardener in an epoxy resin system. Ten workers sensitized to MTHPA (group SS; presence of serum IgE antibodies against a conjugate of MTHPA and human serum albumin (HSA) detected by RAST) had significantly higher levels of tryptase in nasal lavage fluid than 19 nonsensitized workers with work-related nasal symptoms (group NS) and 14 nonsensitized workers without nasal symptoms (group NN). This suggests an ongoing mast-cell-mediated reaction in the sensitized group. No statistically significant differences were found in the three groups concerning eosinophil cationic protein (ECP) and TAME-activity in lavage fluid. However, there was a significant increase in serum ECP in the SS group, as compared with a group of unexposed controls. Nasal challenge with MTHPA-HSA, performed in a subsequent study in seven workers from the SS group, six from the NS group, and seven from the NN, caused a larger increase of symptom score and a more pronounced decrease in nasal inspiratory peak flow in the SS group than in the other two groups. No significant rise was recorded for tryptase and ECP in lavage fluid in any of the three groups after challenge. The combined results of the two studies indicate that specific IgE antibodies play a pathogenetic role in at least some of the cases of work-related nasal symptoms associated with MTHPA exposure.
Blood Proteins↗
Pharmacokinetics and effects of mannitol on hemodynamics, blood and cerebrospinal fluid electrolytes, and osmolality during intracranial surgery.
Fifteen patients who underwent surgery for intracranial tumors under general anesthesia were given mannitol (1 g/kg of body weight) over 30 min. Measurements of mannitol concentration, osmolality, and electrolytes were determined in blood and cerebrospinal fluid (CSF) samples collected over an 8-h period. Seven sets of hemodynamic observations and four sets of intracranial pressure (ICP) measurements were also made. Mannitol disappeared from plasma in a biexponential manner. The mean maximal plasma concentration was 5.91 mg/ml at the end of mannitol infusion and decreased to 0.58 mg/ml after 8 h. The plasma half-life for the distribution phase was 0.16 h and for the elimination phase was 2.44 h. The distribution volume was 17.0 L and total plasma clearance 87.4 ml/min. There were marked interindividual variations of mannitol concentration in the CSF. The mean CSF concentration at 8 h was 97.1 micrograms/ml, started to decline earlier in 10 of 12 patients, and never exceeded 12% of that in plasma. Osmolality in serum increased with a maximum at the end of mannitol infusion (from 292 +/- 7 mOsmol/kg to 310 +/- 14 mOsmol/kg; p < 0.01), whereas CSF osmolality was unchanged, thus giving rise to a positive blood-CSF osmotic gradient of at least 10 mOsmol/kg for about 30 min. At the end of the mannitol infusion, cardiac output and pulmonary capillary wedge pressure increased significantly, whereas the hematocrit decreased. ICP was observed in five patients for 45 min, and mannitol induced a mean reduction from 11 +/- 4 to 4 +/- 2 mm Hg (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Oral availability of fluticasone propionate.
Explore the source record for details and available documents.
Administration, Oral↗
Analysis of an Escherichia coli mutant strain resistant to the cell-killing function encoded by the gef gene family.
The chromosomal genes gef and relF from Escherichia coli and the plasmid-encoded genes hok, flmA, srnB, and pndA constitute the gef gene family, which encodes a cell-killing function. In order to investigate the mechanism of cell killing we have isolated an E. coli mutant strain that is resistant to the overexpression of the toxic proteins encoded by the gef gene family. This phenotype requires at least two mutations, one of which has been mapped to 55.2 minutes. This mutation was sequenced and shown to represent a single base substitution in an open reading frame (ORF178) encoding a putative membrane protein having a molecular mass of 20.1 kDa. ORF178 and an upstream frame, ORF190, probably constitute an operon.
Amino Acid Sequence↗
Absence of interaction between oxcarbazepine and erythromycin.
When erythromycin (ERY) is co-administrated with the antiepileptic carbamazepine (CBZ), a drug interaction may cause an increase in CBZ plasma concentrations, which can result in CBZ related toxic symptoms. This cross-over study was designated to investigate whether ERY influences the pharmacokinetics of the new antiepileptic oxcarbazepine (OXC) and its metabolites. In 8 healthy volunteers there were no significant differences in AUC, peak plasma concentrations or time to peak concentration when OXC was administered either with or without ERY. The results of this study suggest that OXC may offer an important advantage over CBZ especially when concomitant therapy with ERY is required.
Adult↗
Preventive effects of inhaled formoterol and salbutamol on histamine-induced bronchoconstriction--a placebo-controlled study.
The preventive effects of inhaled formoterol (a new beta 2-agonist) and salbutamol aerosols on histamine-induced bronchoconstriction were studied in 12 patients with mild or moderate asthma in a placebo-controlled, double-blind study. Three hours after the administration of 12 micrograms formoterol, 200 micrograms salbutamol (doses with equal bronchodilator effects) or placebo via aerosol, histamine challenge was undertaken, using a dosimetric jet nebulizer with controlled tidal breathing. The noncumulative dose of histamine diphosphate aerosol provoking a 15% fall in FEV1 (PD15) was calculated. The PD15 after inhalation of 12 micrograms formoterol was significantly higher than that after 200 micrograms salbutamol (median values 640 and 310 micrograms, respectively; p < 0.01). For both treatments, the PD15 was significantly higher than that after placebo (median 185 micrograms). The results indicate that the preventive effect against histamine-induced bronchoconstriction at 3 h after drug is significantly better with formoterol than with salbutamol when using inhaled doses with an equal acute bronchodilator effect.
Administration, Inhalation↗
Topographic analysis of the toxic Gef protein from Escherichia coli.
The chromosomal gef gene of Escherichia coli is a member of the gef gene family which encodes strongly toxic proteins of about 50 amino acids. We demonstrate here that the Gef protein is detectable by anti-peptide antibodies. Furthermore, we show that Gef is anchored in the cytoplasmic membrane by the N-terminal part of the protein, and that the C-terminal part is localized in the periplasm in a dimeric form with at least one disulphide bond. By mutagenesis of gef it is shown that the periplasmic portion of Gef encodes the toxic domain and that the dimerization of Gef is not essential for the toxic effect.
Amino Acid Sequence↗
The gef gene from Escherichia coli is regulated at the level of translation.
We describe post-transcriptional regulation of the chromosomal gene, gef, from Escherichia coli. The gef gene is a member of a gene family consisting of the chromosomal gef and relF genes from Escherichia coli and the hok, flmA, srnB, and pndA genes, which are situated on conjugative plasmids. All the genes encode small, toxic proteins of approximately 50 amino acids which are functionally and structurally homologous. Furthermore, the gene family shares post-transcriptional regulation of expression, albeit by different mechanisms. We demonstrate here that translation of gef is coupled to an upstream open reading frame which, in turn, is regulated by a transacting factor, probably an antisense RNA.
Amino Acid Sequence↗
Persistence of Escherichia coli bacteriuria is not determined by bacterial adherence.
The role of bacterial adherence in the persistence of bacteria in the human urinary tract was analyzed. Women with chronic symptomatic urinary tract infections were subjected to deliberate colonization with nonvirulent Escherichia coli, after eradication of their current infections. E. coli organisms were instilled into the bladder through a catheter. The strain used for colonization, E. coli 83972, was isolated from a patient with stable bacteriuria. It lacked expressed adherence factors and did not belong to the uropathogenic O:K:H serotypes. Strain 83972 was transformed with the pap and pil DNA sequences encoding Gal alpha 1-4Gal beta- and mannose-specific (type 1) adhesins. Patients were colonized with a mixture of the wild-type and the transformed strains. E. coli 83972 caused stable bacteriuria for greater than 30 days in 7 of 12 individuals. In contrast, the Gal alpha 1-4 Gal beta-recognizing or mannose-binding transformants were eliminated within 48 h. The consistent superiority of the wild-type strain in establishing stable bacteriuria when compared with the adhesive transformants did not appear to be due to differences in growth rates or to plasmid segregation. Rather, the transformants expressing the adhesin determinants were selectively eliminated by the host. This suggested that the acquisition of adherence factors is not sufficient to increase the fitness of E. coli for survival in the urinary tract of humans.
Adult↗
High incidence of hepatitis B infection and evolution of chronic hepatitis B infection in patients with advanced HIV infection.
Two hundred eleven HIV-seropositive patients with AIDS, AIDS-related complex, or a CD4+ cell count less than 200 x 10(6) were examined for the presence of hepatitis B virus markers during the course of their HIV infection (median follow-up of 18 months; range of 1 to 107 months). Anti-HBs was detected initially in 138 patients (65%). Sixteen patients (8%) were HBsAg positive at entry. Fourteen had chronic HBV infection of whom 12 initially were positive for HBeAg and HBV DNA; 11 remained positive during follow-up, whereas one seroconverted to anti-HBe and lost HBV DNA. Two patients with chronic HBV infection were initially negative for HBeAg and HBV DNA: one later had reactivated HBV replication and one cleared HBeAg following onset of hepatitis D infection. The last two HBsAg-positive patients had resolving acute HBV infection. Six of the 57 patients who initially were negative for HBV markers acquired HBV infection during follow-up. Four of these six patients developed chronic infection whereas two patients had acute subclinical resolving hepatitis. In addition, four patients became HBsAg positive with their last serum samples, possibly indicating reactivation of HBV infection following progressive immunological and clinical deterioration. None of the patients developed clinical symptoms that could be ascribed to HBV infection, and transaminase elevations were only sporadically recorded. It is concluded that acquisition of HBV infections is not infrequent in HIV-seropositive patients with immune deficiency. Furthermore, the course of both previously established chronic HBV infection and newly acquired HBV infection is modified in such patients, whereas reactivation of past HBV infection seems to be a rare event.
Adult↗
Double blind comparison of transdermal hyoscine and placebo for the prevention of postoperative nausea.
Transdermal hyoscine (Scopoderm, Ciba-Geigy) has been compared with placebo in 283 female patients. The hyoscine patch had no significant effect on postoperative nausea or vomiting. In contrast with earlier studies, there was no correlation between previous experiences of nausea (motion, pregnancy or surgery related) and nausea caused by the surgery or anaesthetic in this study. No correlation was found between nausea or vomiting and the type of operation.
Administration, Cutaneous↗
Reactivation of viral replication in anti-HBe positive chronic HBsAg carriers.
Reactivation of hepatitis B virus replication was investigated in an unselected group of 44 HBV DNA negative, anti-HBe positive chronic HBsAg carriers. Twenty-five patients (54%) were intravenous drug addicts and 7 (16%) were male homosexuals. Sixteen patients had evidence of delta infection and five of the seven male homosexuals had human immunodeficiency virus infection. The patients were followed for 1 to 180 months (median, 24 months) while HBV DNA negative, anti-HBe positive. Reactivation, defined as reappearance of HBV DNA or HBeAg, or both, was detected in six patients corresponding to an annual reactivation rate of 5%. Reactivation in four patients was detected by reversion to HBV DNA positivity only, whereas HBeAg/anti-HBe status remained unchanged. Two patients became both HBV DNA and HBeAg positive. None of the patients developed hepatitis-like symptoms and transaminase elevation was only observed in two patients. Reactivation in two patients was ascribed to human immunodeficiency virus infection and in one patient to chronic lymphatic leukaemia. It is concluded that HBV DNA seems to be superior to HBeAg in the detection of reactivation of HBV replication and that reactivation associated with clinical symptoms leading to progression in chronic liver disease is a rare event in the population studied.
Adolescent↗
A family of genes encoding a cell-killing function may be conserved in all gram-negative bacteria.
The relF gene in Escherichia coli is related to the hok gene on plasmid R1. Both genes encode small proteins which, when overexpressed in E. coli lead to collapse of the membrane potential and cell death. A third gene, designated gef, which encodes a homologous cell-toxic protein, has been isolated from E. coli DNA. Both gef and relF are transcribed in E. coli and subject to post-transcriptional regulation which, in the case of gef, is coupled to translation of a leader sequence. The finding of homologous sequences in such distantly related bacteria as Agrobacterium and Rhizobium species suggests an important physiological role.
Amino Acid Sequence↗
Eosinophils and eosinophil cationic protein in nasal lavages in allergen-induced hyperresponsiveness: effects of topical glucocorticosteroid treatment.
Airway challenges with allergen are frequently followed by an increase in responsiveness to both specific and unspecific stimuli. This phenomenon in the lower airways has been linked to the presence of a late phase response to allergen challenge. One of the hallmarks of the late phase response is a tissue infiltration of granulocytes, specifically the eosinophils. A hypothesis for the increase in responsiveness has been that local activation of these eosinophils with subsequent release of the toxic granular constituents leads to a decrease in the barrier function of the airway epithelium. The aim of the present study was to further explore this hypothesis. Ten patients with previously demonstrated nasal allergen-induced hyperresponsiveness participated in a double-blind cross-over study involving pretreatment for various periods with topical glucocorticosteroids. The patients were challenged intranasally with allergen on one day, rechallenge 24 h later and the increase in responsiveness noted. In a nasal lavage performed immediately prior to challenge the number of eosinophilic granulocytes and the level of eosinophilic cationic protein (ECP) was determined. As expected, the placebo-treated patients demonstrated an increase in nasal responsiveness at rechallenge accompanied by a tendency for an increase in eosinophils as well as ECP in the lavage preceding the rechallenge compared with the initial allergen challenge 24 h previously. The amount of ECP found in the lavage on the second day correlated with the TAME-esterase activity, a marker of ongoing inflammatory activity (r = 0.64; P less than 0.05) in the same lavage, suggesting participation of the eosinophilic granulocyte in the inflammatory response to allergen.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Topical↗
Familial occurrence of neuroblastoma, von Recklinghausen's neurofibromatosis, Hirschsprung's agangliosis and jaw-winking syndrome.
A family is reported with ganglioneuromas in the mother and neuroblastomas in her two daughters co-existing with cases of von Recklinghausen's neurofibromatosis, Hirschsprung's agangliosis, and the jaw-winking syndrome in other family members. There were no detectable constitutional chromosomal defects in the family even when high resolution techniques were applied. Similarly, DNA-hybridization analysis did not reveal gross molecular rearrangements in the vicinity of the proto-oncogenes N-myc-, c-myc, neu, and N-ras. However, the aggregation of several rare, autosomal dominant diseases affecting tissue derived from the neural crest not only suggest a link between te pathogenesis of these disease, but also makes it highly likely that a single mutation segregating within the family is responsible for this association.
Adult↗
Objective monitoring of the allergic inflammatory response of the nasal mucosa in patients with hay fever during natural allergen exposure.
A method is presented for the objective monitoring of the inflammatory response of the nasal mucosa to natural allergen exposure through measurements of biochemical markers such as TAME-esterase activity in a daily nasal lavage. Nine patients with strictly seasonal allergic rhinitis caused by birch pollen and five healthy nonatopic control subjects participated in the present study, which started 1 wk before the birch pollen season and continued throughout the entire pollen season. A diary card was used to assess daily nasal symptoms, and a daily nasal lavage was performed once every afternoon. The degree of pollen exposure was assessed by daily pollen counts. The TAME-esterase activity in the lavage fluid from the allergic patients, but not in that from the nonallergic control subjects, increased significantly during pollen exposure despite low pollen counts and was found to correlate with daily nasal symptoms (r = 0.36; p less than 0.05) and the degree of pollen exposure (r = 0.45; p less than 0.01). The area under the curve for the daily TAME-esterase measurements thus differed significantly (p less than 0.02) between allergic patients (158 +/- 28) and control subjects (74 +/- 9). This approach for the monitoring of patients with hay fever during natural allergen exposure will make further objective studies on the pathophysiology and pharmacology of hay fever possible. We also provide support for the validity of previous findings obtained in allergen challenge situations utilizing the lavage approach.
Adult↗