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A L Jones

Publications and source records attributed to A L Jones.

At least 91 records · Page 5Linked to original sources
PubMed1998

Mechanism of action and value of N-acetylcysteine in the treatment of early and late acetaminophen poisoning: a critical review.

INTRODUCTION: The mechanism of action of N-acetylcysteine in early acetaminophen poisoning is well understood, but much remains to be learned of the mechanism of its possible benefit in acetaminophen poisoning presenting beyond 15 hours. METHODS: Selective review of medical literature. N-acetylcysteine should be used in all cases of early acetaminophen poisoning where the plasma acetaminophen concentration lies "above the line;" which line is chosen depends on individual preference and whether enzyme induction is suspected. Particular care should be taken with the use of the nomogram for patients with chronic excess ingestion of acetaminophen or for those who have taken slow-release formulations. CONCLUSIONS: While there is a trend suggesting a beneficial effect of N-acetylcysteine in some patients presenting beyond 15 hours, further research is necessary to establish just how effective N-acetylcysteine is, particularly in patients presenting with fulminant hepatic failure. Candidate mechanisms for a beneficial effect in-clude improvement of liver blood flow, glutathione replenishment, modification of cytokine production, and free radical or oxygen scavenging. Hemody-namic and oxygen delivery and utilization parameters must be monitored carefully during delayed N-acetylcysteine treatment of patients with fulminant hepatic failure, as unwanted vasodilation may be deleterious to the maintenance of mean arterial blood pressure.

Acetaminophen↗
PubMed1997

The effect of chemotherapy on the uptake of technetium-99m sestamibi in breast cancer.

Technetium-99m sestamibi scintimammography has been used primarily in the diagnosis of breast cancer. It has also been suggested that this technique could be used to monitor response to chemotherapy and possibly to predict those patients in whom no response can be expected. An initial study was performed in nine patients with primary breast cancer. All patients underwent prone lateral and anterior 99mTc-sestamibi imaging at diagnosis and 4-7 months later, after they had received cytotoxic chemotherapy. The uptake of 99mTc-sestamibi in the breast was compared with that in normal surrounding breast tissue and this ratio was expressed as the target to background ratio. In all patients treated there was a reduction in uptake of 99mTc-sestamibi after treatment, such that whilst all the tumours could be seen before treatment, only three were visible following chemotherapy. There was a significant fall in the mean target to background ratio of the patients undergoing chemotherapy: the tumour to background ratio was 2.48 before chemotherapy and 1.40 after treatment (P<0.001, paired Student's t test). This fall in tumour activity was observed both in those patients in whom a clinical response was seen and in the two patients in whom the tumour enlarged despite chemotherapy. It appears that the reduced uptake of 99mTc-sestamibi seen after chemotherapy may be a non-specific change and therefore may not be predictive of the clinical response to treatment.

Adult↗
PubMed1997

Open pelvic fractures. A multicenter retrospective analysis.

A marked discrepancy exists in the reported mortality rates in patients with open pelvic fractures, ranging from 4.8% to 50%. A retrospective review of patients with open pelvic fractures was performed at three centers. Thirty-nine patients with open pelvic fractures were identified; the average age was 32. The average injury-severity score was 29 (13-75). There were 10 (26%) deaths. Factors that correlated with mortality and morbidity were instability of the pelvic fracture and the presence of a rectal injury. Delay in performing diverting colostomy correlated with a poor outcome. Previously described methods of treatment are still valid; however, there is a need for re-emphasis of early diverting colostomy in the patient with a rectal or perineal injury. A classification system for open pelvic fractures is proposed in this article.

Adult↗
PubMed1997

Huntington disease: advances in molecular and cell biology.

Huntington disease is an inherited neurodegeneration, for which the associated mutation was isolated in 1993. The mutation is an expansion of a CAG trinucleotide repeat, which translates to give a polyglutamine tract at the N-terminus of a large protein, huntingtin. Neither the normal nor the pathogenic functions of this protein have been identified, but it is clear that pathogenesis is mediated through the expanded polyglutamine tract within the protein, and that polyglutamine is toxic to cells. A number of proteins which interact with the N-terminal region of huntingtin have been isolated, but this has not, so far, yielded a rationale for pathogenesis. Huntingtin is found in areas of the brain that degenerate in this disease but is also associated with pathogenic inclusions in Alzheimer disease and Pick disease. It is possible that Huntington disease has pathogenic mechanisms in common with these other neurodegenerative diseases, and that the mechanism may relate to the formation of abnormal, cytoskeletal-associated, inclusions within cells.

Animals↗
PubMed1997

Pharmacokinetics of N-acetylcysteine are altered in patients with chronic liver disease.

BACKGROUND: The threshold plasma paracetamol concentration at which N-acetylcysteine (NAC) treatment is recommended to treat paracetamol poisoning in a patient with induced liver enzymes (for example, with chronic liver disease or taking anticonvulsant drugs) is 50% lower than in a patient without induced liver enzymes. More patients with chronic liver disease might therefore be expected to be exposed to NAC treatment than previously. In addition, there is increasing use of NAC in patients with chronic liver disease for multiorgan failure or hepatorenal syndrome. Little is known of NAC's pharmacokinetic properties in patients with cirrhosis. AIM: The aim was to determine if the pharmacokinetics of NAC are altered by chronic liver disease. SUBJECTS AND METHODS: NAC was given intravenously in a dose of 600 mg over 3 min to nine patients with biopsy-proven cirrhosis (Child's grade; 1 A, 4 B, 4 C: aetiology: 7 alcohol-related, 1 primary biliary cirrhosis, 1 secondary biliary stenosis) and six healthy matched controls. Venous blood was taken at 20, 40, 60 and 90 min then at 2, 3, 4, 6, 8 and 10 h after NAC administration. Serum NAC was estimated by HPLC. The data were normalized to a standard body weight of 70 kg. RESULTS: The area under the serum concentration-time curve was increased (152.34 mg/L.h +/- 50.38 s.d.) in cirrhotics compared with normal controls (93.86 mg/L.h +/- 9.60 s.d.) (P < 0.05). The clearance of NAC was reduced in patients with chronic liver disease (4.52 L/h +/- 1.87 s.d.) compared with controls (6.47 L/h +/- 0.78: P < 0.01). CONCLUSIONS: Increased vigilance for untoward anaphylactoid reactions is necessary in cirrhotics as they may have higher plasma NAC concentrations. Further studies to determine the optimum dosage regimen in such patients are required.

Acetylcysteine↗
PubMed1997

Protein involvement in thermally induced structural transitions of pig erythrocyte ghosts.

Thermal transitions in pig erythrocyte ghosts were studied by differential scanning calorimetry and thermal gel analysis (TGA). Heating of the suspension of pig erythrocyte ghosts induced at least six thermodynamically irreversible transitions. Each of these transitions is believed to be due to a localized structural transition induced by thermal stress. Using TGA and covalent attachment of the anionic transport inhibitor regions in the thermograms corresponding to the heat sorption of some proteins of the pig erythrocyte ghosts were identified.

Animals↗
PubMed1997

Immunocytochemical detection of breast cancer cells: a comparison of three attachment factors.

The evaluation of contaminating breast cancer cells in hematopoietic grafts is of considerable importance for monitoring the efficiency of purging procedures. We report a comparison of three systems for the in vitro detection and enumeration of metastatic breast cancer cells. Breast cancer cells from established cell lines were mixed with Daudi cells at dilutions ranging from 1:10 to 1:1,000,000, and a predetermined number were fixed in defined areas on microscope slides coated with one of the following attachment factors: (i) Cell-Tak Cell and Tissue Adhesive, (ii) 0.1% solution of Poly-L-Lysine, or (iii) Cel-Line HTC Super Cured slides. We employed a specificity-proven pancytokeratin antibody (A45-B/B3) and the alkaline phosphatase-antialkaline phosphatase (APAAP) staining technique. In multiple experiments, one breast cancer cell in 1,000,000 Daudi cells could reliably be detected in the Cell-Tak and Cel-Line systems and 1 in 100,000, with the Poly-L-Lysine system. The observed number of seeded cells showed a highly significant correlation with the number of cells seeded (p < 0.0001 in all cases). Finally, we used the Cell-Tak method to evaluate clinical material from various sources: from patients with primary carcinomas of the breast, prechemotherapy, and during various chemotherapeutic regimens, as well as from patients with metastatic disease. The system consistently detected tumor cells in bone marrow samples from these patients. All peripheral blood samples from patients with metastatic disease tested positive at incidences ranging from 5 to 19/10(6) peripheral blood mononuclear cells. This is a simple and reliable technique that allows rapid screening of large cell numbers with high resolution of positive cells.

Alkaline Phosphatase↗
PubMed1997

A relative of the broad-host-range plasmid RSF1010 detected in Erwinia amylovora.

Streptomycin- and sulfonamide-resistant Erwinia amylovora CA3R from California contained an 8.7-kb plasmid, pEa8.7, with a sulII-strA-strB resistance region; furthermore, PCR, sequencing, hybridization, and restriction analyses showed that pEa8.7 was closely related or identical to broad-host-range plasmid RSF1010. Although RSF1010 has been found in a variety of bacteria, this is the first report of its presence in plant pathogenic bacteria.

Amino Acid Sequence↗
PubMed1997

Identification and characterization of a two-component regulatory system involved in invasion of eukaryotic cells and heavy-metal resistance in Burkholderia pseudomallei.

Burkholderia pseudomallei is the causative agent of melioidosis, a disease increasingly recognized as an important cause of morbidity and mortality in many regions of the world. B. pseudomallei is a facultative intracellular pathogen capable of invading eukaryotic cells. We used Tn5-OT182 mutagenesis to generate mutants deficient in the ability to invade a human type II pneumocyte cell line (A549 cells). One of these mutants, AJ1D8, exhibited approximately 10% of the ability of the parental strain, 1026b, to invade A549 cells. There was no difference in the abilities of 1026b and AJ1D8 to resist killing by RAW macrophages or the human defensin HNP-1. The nucleotide sequence flanking the Tn5-OT182 integration in AJ1D8 was determined, and two open reading frames were identified. The predicted proteins shared considerable homology with two-component regulatory systems involved in the regulation of heavy-metal resistance in other organisms. AJ1D8 was 16-fold more sensitive to Cd2+ and twofold more sensitive to Zn2+ than was 1026b but was not sensitive to any of the other heavy metals examined. The B. pseudomallei two-component regulatory system, termed irlRS, complemented the invasion-deficient and heavy-metal-sensitive phenotype of AJ1D8 in trans. There was no significant difference between the virulence of AJ1D8 and that of 1026b in infant diabetic rats and Syrian hamsters, suggesting that the irlRS locus is probably not a virulence determinant in these animal models of acute B. pseudomallei infection.

Amino Acid Sequence↗
PubMed1996

High-dose chemotherapy and autologous bone marrow transplant in relapsed Hodgkin's disease--a pragmatic prognostic index.

High-dose chemotherapy with autologous bone marrow transplantation is used in the treatment of relapsed or high-risk Hodgkin's disease. As prospective randomised studies have proved difficult to accrue to, current recommendations are based on the reports of large series of prospectively collected data. We have looked at the outcome of 89 patients treated in this way at a single institution and have developed an index to predict outcome. Of 89 patients, with a median age of 29 years (range 15-51 years), eight patients were in first complete remission/partial remission (CR/PR), 17 in second or later CR, 37 were responding relapses, 13 resistant relapses, 11 primary refractory and three untested relapses. Combinations of melphalan, BCNU and etoposide were given in all cases except in ten patients who received melphalan alone. The median follow-up was 43 months (range 6-77 months). A total of 24 patients were in CR at the time of autologous bone marrow transplantation (ABMT), 33 achieved CR with ABMT, 16 PR, to give a response rate to ABMT of 49/65 = 74% (95% CI 60-83%) with a CR rate of 51% (CI 36-62%). In a Cox's multivariate analysis the most important factors in predicting outcome after ABMT were response to treatment before entry, number of previous treatments and previous chemosensitivity. Using these factors we devised a prognostic index which reliably selects a group of patients (65%) with at least a 70% chance of being progression free from 1 year onwards. Patients who have never achieved a CR and have received three or more chemotherapy regimens do not benefit from high-dose chemotherapy as used in this study.

Adolescent↗
PubMed1996

Partial characterisation of murine huntingtin and apparent variations in the subcellular localisation of huntingtin in human, mouse and rat brain.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by the expansion of a CAG repeat in a gene coding for a protein of unknown function. We have raised a polyclonal antibody against a 12 amino acid peptide (residues 2110-2121 of human huntingtin) which specifically recognises huntingtin on Western blots of human, rat and mouse brain. We have characterised huntingtin expression in the mouse. The protein was detected on Western blots of all mouse tissues examined, with the highest expression seen in brain. Human, mouse and rat brain were fractionated by differential centrifugation and discontinuous Percoll gradients. The fractions were analysed by Western blotting for huntingtin and synaptophysin (a synaptic vesicle localised protein). In mouse brain, huntingtin was localised in the soluble S3 fraction; in rat brain it was localised in the soluble S3 fraction and also in the membrane P2 and P3 fractions; in both normal and HD-affected human brain, huntingtin was membrane bound with a distribution essentially the same as that of synaptophysin. These observed differences in the subcellular localisation of huntingtin between mouse and human brain are important in the context of mouse models for HD.

Adult↗
PubMed1996

Intracellular survival of Burkholderia pseudomallei.

Burkholderia pseudomallei is the causative agent of melioidosis, a disease being increasingly recognized as an important cause of morbidity and mortality in many regions of the world. Several features of melioidosis suggest that B. pseudomallei is a facultative intracellular pathogen. This study was designed to assess the ability of B. pseudomallei to invade and survive in eukaryotic cells. We have shown that B. pseudomallei has the capacity to invade cultured cell lines, including HeLa, CHO, A549, and Vero cells. We have demonstrated intracellular survival of B. pseudomallei in professional phagocytic cells, including rat alveolar macrophages. B pseudomallei was localized inside vacuoles in human monocyte-like U937 cells, a histiocytic lymphoma cell line with phagocytic properties. Additionally, electron microscopic visualization of B. pseudomallei-infected HeLa cells and polymorphonuclear leukocytes confirmed the presence of intracellular bacteria within membrane-bound vacuoles. B. pseudomallei was found to be resistant to the cationic peptide protamine and to purified human defensin HNP-1.

Animals↗
PubMed1996

VirB2 is a processed pilin-like protein encoded by the Agrobacterium tumefaciens Ti plasmid.

The mechanism of DNA transmission between distinct organisms has remained a subject of long-standing interest. Agrobacterium tumefaciens mediates the transfer of plant oncogenes in the form of a 25-kb T-DNA sector of a resident Ti plasmid. A growing body of evidence leading to the elucidation of the mechanism involved in T-DNA transfer comes from studies on the vir genes contained in six major operons that are required for the T-DNA transfer process. Recent comparative amino acid sequence studies of the products of these vir genes have revealed interesting similarities between Tra proteins of Escherichia coli F factor, which are involved in the biosynthesis and assembly of a conjugative pilus, and VirB proteins encoded by genes of the virB operon of A. tumefaciens pTiC58. We have previously identified VirB2 as a pilin-like protein with processing features similar to those of TraA of the F plasmid and have shown that VirB2 is required for the biosynthesis of pilin on a flagella-free Agrobacterium strain. In the present work, VirB2 is found to be processed and localized primarily to the cytoplasmic membrane in E. coli. Cleavage of VirB2 was predicted previously to occur between alanine and glutamine in the sequence -Pro-Ala-Ala-Ala-Glu-Ser-. This peptidase cleavage sequence was mutated by an amino acid substitution for one of the alanine residues (D for A at position 45 [A45D]), by deletion of the three adjacent alanines, and by a frameshift mutation 22 bp upstream of the predicted Ala-Glu cleavage site. With the exception of the frameshift mutation, the alanine mutations do not prevent VirB2 processing in E. coli, while in A. tumefaciens they result in VirB2 instability, since no holo- or processed protein is detectable. All of the above mutations abolish virulence. The frameshift mutation abolishes processing in both organisms. These results indicate that VirB2 is processed into a 7.2-kDa structural protein. The cleavage site in E. coli appears to differ from that predicted in A. tumefaciens. Yet, the cleavage sites are relatively close to each other since the final cleavage products are similar in size and are produced irrespective of the length of the amino-terminal portion of the holoprotein. As we observed previously, the similarity between the processing of VirB2 in A. tumefaciens and the processing of the propilin TraA of the F plasmid now extends to E. coli.

Agrobacterium tumefaciens↗
PubMed1996

Intestinal immunisation with Escherichia coli protects rats against Escherichia coli induced cholangitis.

BACKGROUND: Cholangitis, an infection of the biliary tract, is most commonly caused by Gram negative bacteria, particularly Escherichia coli. Factors governing the severity of cholangitis, including the role of biliary IgA, are poorly understood. AIMS: The aim of this work was to find out if biliary IgA directed against E coli protects rats against hepatobiliary infection with E coli. SUBJECTS: Male Sprague-Dawley rats weighing 270-350 grams were used in all of the experiments. METHODS: At laparotomy, rats were immunised by injecting killed E coli or normal saline (controls) into Peyer's patches. With or without subsequent antigenic boosting (by oral administration of killed E coli), bile was collected at a second laparotomy, and rats were infected by introducing viable E coli into the bile duct. Production of IgA anti-E coli antibody was measured by enzyme linked immunosorbent assay of bile, and the presence of hepatobiliary infection was determined by quantitative culture of liver homogenates. RESULTS: Systemic infection was present in six of 12 control rats and in one of 24 immunised rats (p = 0.005) after death. There was an inverse correlation between immunisation and E coli colony counts in cultured liver homogenates (p = 0.024). CONCLUSION: The findings suggest that biliary IgA directed against E coli protected rats against hepatobiliary E coli infection and systemic sepsis.

Animals↗