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Biomedical subjects

I Smith

Publications and source records attributed to I Smith.

At least 109 records · Page 6Linked to original sources
PubMed1998

Extra and intracellular expression of Mycobacterium tuberculosis genes.

To understand how Mycobacterium tuberculosis survives and grows in an infected host, we are studying the mycobacterial transcriptional machinery and its response to stresses encountered in vitro and in vivo. Much has been learned about sigma factors and other transcriptional regulators concerning their roles in controlling mycobacterial gene expression. It has recently been shown that sigma A is the essential housekeeping sigma factor and the alternative sigma factor sigma B, not essential for growth in a laboratory setting, is required for a robust protective response to various environmental stresses. We are also studying the mechanism by which the R522H mutation in sigma A prevents the transcription of certain genes, including some that are believed necessary for virulence. Also under investigation is the mycobacterial iron acquisition apparatus and its regulation, as metabolism of this essential element plays a key role in microbial pathogenesis. We have identified and characterized the major mycobacterial iron regulator IdeR that blocks the synthesis of the iron uptake machinery and have identified target genes in M. smegmatis and M. tuberculosis that are directly repressed by IdeR. Recent studies have examined the control of M. tuberculosis gene expression in vivo. Among these new approaches are an in vivo expression technology system to identify M. tuberculosis genes that are induced in macrophages and mice and a novel RT-PCR method that allows an accurate comparison between the levels of specific mRNAs in M. tuberculosis grown in vitro with those found in bacteria growing in human macrophages.

Animals↗
PubMed1998

Protective role of the Mycobacterium smegmatis IdeR against reactive oxygen species and isoniazid toxicity.

OBJECTIVE: To understand the mechanism by which IdeR is necessary for maintaining wild type levels of KatG and SodA enzyme activity and normal isoniazid (INH) resistance. DESIGN: To identify the step(s) of SodA and KatG function that were affected by the ideR mutation, quantitative western immunoassays and ribonucleic acid (RNA) hybridizations were performed. To see if the increased INH sensitivity of the ideR mutant was caused by lower SodA activity, the Mycobacterium smegmatis sod gene was inactivated. RESULTS: The levels of KatG and SodA mRNA and protein in the M. smegmatis IdeR mutant are decreased to approximately 20-40% of those observed in the wild type parent strain. This is quantitatively similar to the decrease in KatG and SodA enzyme activities originally observed in the ideR strain. The M. smegmatis sodA mutant was slightly more sensitive to INH, compared to the wild type strain and was more resistant than the ideR mutant. CONCLUSION: IdeR is necessary for full expression of the M. smegmatis katG and sodA genes. It is not yet known whether this protein acts directly at the gene level. The lower levels of SodA contribute slightly to the increased susceptibility to INH of the ideR mutant, but cannot explain the magnitude of the INH sensitivity observed when IdeR is not present. These data suggest that IdeR is a regulator of the cellular stress response, as it has a protective role in cells facing environmental stresses, such as increased levels of reactive oxygen species and INH toxic intermediates. These conclusions do not necessarily apply to IdeR's role in M. tuberculosis physiology, since we have not inactivated its gene in this pathogen.

Antitubercular Agents↗
PubMed1998

Comparison of intubating conditions after rocuronium or vecuronium when the timing of intubation is judged by clinical criteria.

The onset of action and intubating conditions after rocuronium 0.6 mg kg-1 or vecuronium 0.1 mg kg-1 were compared in a randomized, double-blind study when the timing of tracheal intubation was determined by clinical judgment alone. Times to laryngoscopy and completion of intubation were mean 89 (SD 20) s and 119 (28) s, respectively, in the rocuronium group compared with 110 (26) s and 142 (32) s in the vecuronium group (P < 0.05 in both cases). Recuronium also resulted in significantly better intubating conditions compared with vecuronium but with no significant reduction in the haemodynamic response to intubation. We found that onset of satisfactory intubating conditions after rocuronium was detected clinically, although even earlier intubation should be possible by careful timing or by neuromuscular monitoring.

Adult↗
PubMed1998

Comparison of desflurane with isoflurane or propofol in spontaneously breathing ambulatory patients.

UNLABELLED: Desflurane is a potentially useful anesthetic for ambulatory surgery, but it has had limited evaluation in spontaneously breathing patients. After the induction of anesthesia with propofol and laryngeal mask insertion, 90 patients were randomized to receive isoflurane (0.25%-1%), propofol (50-200 microg x kg(-1) x min(-1)), or desflurane (1.4%-6%) for anesthetic maintenance. Respiratory complications were uncommon; only six patients coughed (three who received isoflurane, one who received propofol, and two who received desflurane), and no anesthetic produced significant respiratory depression. Purposeful movement was significantly more common with propofol (19 patients; 63%) compared with isoflurane (7 patients; 23%) or desflurane (2 patients; 6.7%), but no patient had recall. Emergence times were similar in the isoflurane, propofol, and desflurane groups (5.1 +/- 2.3, 5.6 +/- 3.1, and 4.4 +/- 1.4 min, respectively). Later recovery end points and pain and sedation visual analog scale scores did not differ among groups. Overall, 85 patients (94%) were free from postoperative nausea and vomiting. Desflurane produced few respiratory complications in spontaneously breathing ambulatory patients but offered no improvement in emergence or recovery compared with isoflurane. Propofol also did not reduce recovery times or side effects; however, it was more difficult to maintain an adequate depth of anesthesia. We conclude that neither desflurane nor propofol offered any major advantages over the older anesthetic, isoflurane, under the conditions of our study. IMPLICATIONS: The new inhaled anesthetic desflurane is acceptable in spontaneously breathing outpatients despite its known ability to irritate the airway. The i.v. anesthetic propofol was associated with more patient movement (without awareness) during surgery. Neither anesthetic conferred any clinically significant advantages over the older inhaled drug, isoflurane.

Adult↗
PubMed1998

Sequence and in vivo transcription of Lacanobia oleracea granulovirus egt.

We have determined the nucleotide sequence and located the major in vivo transcript termini of the Lacanobia oleracea granulovirus (LoGV) egt gene. The open reading frame encodes a 460-amino acid polypeptide having extensive sequence similarity to ten nucleopolyhedrovirus (NPV) ecdysteroid UDP-glucosyltransferase (EGT) proteins; the degree of similarity is particularly high within several previously identified EGT 'domains', and eight invariant amino acid residues are conserved. A phylogenetic tree, constructed by the neighbour joining method, showed LoGV EGT to be the most highly diverged of the eleven baculovirus sequences compared. Database searching revealed that part of a published DNA sequence from Cryptophlebia leucotreta granulovirus appears to encode the N-terminal region of EGT, and the relative genomic locations of the egt and granulin genes in that virus were compared with their positions in LoGV. In infected L. oleracea larvae, egt is transcribed predominantly as a 1.6 kb mRNA. Primer extension analysis suggested that the major egt 5' transcription terminus is located within a baculovirus late gene promoter motif (GTAAG), in contrast to the early gene promoter contexts determined by others for three NPV egt mRNA 5' ends. An early transcriptional start site is also used in LoGV egt expression, but at a much lower level. The 3' terminus of egt mRNA was identified by sequencing DNA fragments generated by rapid amplification of cDNA ends, and is located 58-62 nucleotides beyond the translation stop codon.

Amino Acid Sequence↗
PubMed1998

Haemorphin peptides may be endogenous ligands for brain angiotensin AT4 receptors.

1. Angiotensin IV (AngIV), the (3-8) fragment of AngII, was previously believed to be an inactive metabolite. However, specific binding sites, termed AT4 receptors, have been identified in the brain and peripheral organs and the peptide has been reported to enhance memory recall in passive avoidance studies and to dilate pial and renal cortical vessels. 2. AT4 receptors are distinct from AngII AT1 and AT2 receptors with respect to function, ligand specificity and distribution. 3. In the brain, AT4 receptors are abundant in cerebral and cerebellar cortex, hippocampal formation and cholinergic systems, as well as sensory and motor systems. However, the peptide AngIV is low or undetectable in the central nervous system. This led us to search for an alternative peptide ligand of the AT4 receptor. 4. The decapeptide LVVYPWTQRF was isolated from cerebral cortex and binds with high affinity to brain AT4 receptors. This peptide sequence corresponds to an internal sequence of beta-globin and has previously been named LVV-haemorphin 7. 5. Haemorphin may represent a new class of endogenous neuropeptides, some of which interact potently with the brain AT4 receptor to elicit a range of actions.

Angiotensin II↗
PubMed1998

Obstacles to timely neonatal screening in North Thames.

OBJECTIVE: To assess the timeliness of neonatal (Guthrie card) screening in North Thames, and to identify the most effective ways of improving it. DESIGN: Analysis of information routinely collected in the course of neonatal screening; reanalysis of published data on blood phenylalanine concentration in phenylketonuria (PKU) over the first two weeks; simulation studies on the impact of different interventions. SUBJECTS: 100,690 infants born over one year and screened at Great Ormond Street Hospital NHS Trust. OUTCOME MEASURE: Interval between birth and reading PKU screen results. RESULTS: Although 75% of samples (district range 55-91%) were collected by day 7, only 81% had arrived in the laboratory seven days later (range 57-96%). The average interval between birth and reading results was 14.5 days, with only 9.7% read by day 10. Samples could be collected from day 4 without significant impact on false negative rates for PKU. If samples were collected from day 4 and posted promptly (second class), the average interval between birth and reading results could be reduced to 9.3 days. If first class mail were used and the laboratory operated on Saturdays, and used assays that could be read the same day rather than bacterial inhibition assays, the average would be 7.8 days, with 96% read by day 10. CONCLUSION: Timeliness of neonatal screening shows unacceptable variation between districts, and delays in dispatch of specimens to the laboratory. Same day, first class posting should be introduced, and samples could be collected between days 4 and 8.

Blood Specimen Collection↗
PubMed1998

Clinical prognostic and predictive factors for primary chemotherapy in operable breast cancer.

PURPOSE: This study aimed to identify clinical factors that are of prognostic significance or that predict for subsequent treatment outcome in patients with large operable breast cancer treated with primary chemotherapy (PCT) at our institution. METHODS: One hundred eighty-five patients received the following regimens: CMF or MMM (76 patients), ECF (75 patients), AC or FEC (34 patients), followed by surgery, with radiotherapy (RT) given to those with breast conservation. A number of common clinical variables were assessed in relation to local recurrence-free survival (LRFS), disease-free survival (DFS), and overall survival (OS). RESULTS: Clinical responders had improved DFS (P = .009) and OS (P = .08) compared with nonresponders. There was no association between clinical or pathologic complete remission (CR) and survival. Pretreatment clinical axillary node positivity was a significant predictor of worsened DFS (P = .0001), OS (P = .0001), and LRFS (P = .03). Patients remaining clinically node-positive postchemotherapy had an inferior outcome compared with those becoming node-negative (DFS, P = .03; OS, P = .03) but pathologic axillary node status was not shown to predict for survival. Twenty-nine patients in clinical CR following PCT who electively did not have surgery and were treated with RT alone had significantly increased local recurrence rate compared with partial responders having surgery and RT (P = .02). There were no differences in DFS or OS between these groups. On multivariate analysis, clinical axillary node status was the only independent predictor of OS and DFS, and LRFS. CONCLUSION: Pretreatment and posttreatment clinical axillary node status is a major predictor of outcome following PCT. Complete clinical response does not define a more favorable subgroup compared with those not obtaining CR.

Adult↗
PubMed1998

Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate.

PURPOSE: To compare two doses of letrozole and megestrol acetate (MA) as second-line therapy in postmenopausal women with advanced breast cancer previously treated with antiestrogens. PATIENTS AND METHODS: Five hundred fifty-one patients with locally advanced, locoregionally recurrent or metastatic breast cancer were randomly assigned to receive letrozole 2.5 mg (n = 174), letrozole 0.5 mg (n = 188), or MA 160 mg (n = 189) once daily in a double-blind, multicenter trial. Data were analyzed for tumor response and safety variables up to 33 months of follow-up evaluation and for survival up to 45 months. RESULTS: Letrozole 2.5 mg produced a significantly higher overall objective response rate (24%) compared with MA (16%; logistic regression, P = .04) or letrozole 0.5 mg (13%; P = .004). Duration of objective response was significantly longer for letrozole 2.5 mg compared with MA (Cox regression, P = .02). Letrozole 2.5 mg was significantly superior to MA and letrozole 0.5 mg in time to treatment failure (P = .04 and P = .002, respectively). For time to progression, letrozole 2.5 mg was superior to letrozole 0.5 mg (P = .02), but not to MA (P = .07). There was a significant dose effect in overall survival in favor of letrozole 2.5 mg (P = .03) compared with letrozole 0.5 mg. Letrozole was significantly better tolerated than MA with respect to serious adverse experiences, discontinuation due to poor tolerability, cardiovascular side effects, and weight gain. CONCLUSION: The data show letrozole 2.5 mg once daily to be more effective and better tolerated than MA in the treatment of postmenopausal women with advanced breast cancer previously treated with antiestrogens.

Administration, Oral↗
PubMed1997

off absorption, pharmacodynamics, metabolism and excretion of 14C-sumatriptan following intranasal administration to the beagle dog.

The pharmacodynamics, pharmacokinetics, metabolism, and excretion of 14C-sumatriptan have been studied in the beagle dog following administration by the intranasal and other routes. The pharmacological response which was monitored, an increase in carotid arterial vascular resistance, correlated with the plasma levels of unchanged sumatriptan following intranasal, intravenous, or intraduodenal administration to the anaesthetised dog. The pharmacokinetics and metabolism of sumatriptan were then confirmed in conscious male and female dogs. Intranasal administration of 14C-sumatriptan resulted in rapid absorption of part of the dose. The overall bioavailability of sumatriptan was 40-50%. Sumatriptan was eliminated from plasma with a half-life of 1.5 or 1.9 h after intravenous or intranasal dosage respectively. Radioactivity was largely excreted in urine (up to 75% of the dose) with small amounts in the bile and faeces after intravenous and intranasal dosing, as sumatriptan and a major metabolite. The results from these studies suggest that intranasal administration provides a viable method for delivering sumatriptan to the systemic circulation.

Administration, Intranasal↗
PubMed1997

The management of patients with advanced cancer (II).

In this second article in the series, obstruction of hollow viscera in patients with advanced malignant disease is discussed. The obstruction of such structures can be associated with the development of painful and incapacitating symptoms, often in patients who have a limited life expectancy. This obstruction may be caused by the primary tumour, compression from adjacent tumour-draining lymph nodes, the presence of metastases distant from the site of the primary tumour or to adhesions within the abdominal compartment (usually as a result of previous surgery). The organs most often affected are the oesophagus, the intestine (small and large), the biliary tree and the genito-urinary tract. Obstruction of each of these organs and its management is discussed in more detail below.

Cholestasis↗
PubMed1997

A comparison of propofol and remifentanil during monitored anesthesia care.

STUDY OBJECTIVE: To compare remifentanil, an esterase-metabolized opioid, to a standard propofol-based sedation technique for monitored anesthesia care (MAC). DESIGN: Non-randomized, open label. SETTING: University hospital. PATIENTS: 44 healthy female outpatients undergoing breast biopsy procedures under local anesthesia. INTERVENTIONS: All patients received intravenous (IV) midazolam 2 mg, followed by a continuous infusion of either propofol 75 micrograms/kg/min, or remifentanil 0.1 microgram/kg/min, which was subsequently titrated to maintain optimal patient comfort without respiratory depression. Surgical-related pain was treated by injecting additional local anesthetic solution and "rescue" boluses of fentanyl 25 micrograms IV. MEASUREMENTS AND MAIN RESULTS: Sedation, pain, and discomfort were monitored using standardized rating scales at 1 to 5 minute intervals. Recovery times were measured from the end of the study drug infusions. Propofol resulted in significantly higher median sedation scores compared with remifentanil, with 73% of patients requiring a decrease in the propofol infusion rate because of "excessive" sedation. Local anesthetic requirements, pain, and discomfort scores during surgery were similar in both groups. Remifentanil resulted in greater respiratory depression compared with propofol, with decreases in the remifentanil infusion rate required by 41% of patients because of a slow respiratory rate (< 8 bpm) and/or oxygen desaturation measured by pulse oximetry (SpO2 < 90%). Median times to ambulation and to being judged "fit for discharge" were significantly shorter following propofol (40 and 47 minutes, respectively) compared with remifentanil (52 and 58 minutes, respectively). CONCLUSION: Remifentanil provided comparable intraoperative conditions and patient comfort at a lower sedation level compared with propofol. However, remifentanil was associated with greater respiratory depression and a longer time to home readiness.

Adolescent↗