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Biomedical subjects

M Patel

Publications and source records attributed to M Patel.

At least 217 records · Page 12Linked to original sources
PubMed1997

Comparison of the protection of cells from antifolates by transduced human dihydrofolate reductase mutants.

Retroviral transduction of antifolate-resistant variants of human dihydrofolate reductase (hDHFR) into cells can increase their resistance to the cytotoxic effects of these drugs. We evaluated the ability of wild-type hDHFR and 20 mutant enzymes (13 with single-amino acid substitutions, 7 with two substitutions) to prevent growth inhibition in antifolate-treated CCRF-CEM cells. The wild-type enzyme and all of the variants significantly protected transduced cells from trimetrexate (TMTX)-induced growth inhibition. However, only half of the variants conferred more protection than does the wild-type enzyme. For the variants tested, the observed protective effect was higher for TMTX than for methotrexate (< or =7.5-fold increased resistance), piritrexim (< or =16-fold), and edatrexate (negligible). Transduction of the variants L22Y-F31S and L22Y-F31R led to the greatest protection against TMTX (approximately 200-fold). Protection from loss of cell viability was similar to protection from growth inhibition. The protection associated with a particular mutant hDHFR did not result from the level of expression: Efficient protection resulted from low affinity of the variant for antifolates, reasonable catalytic activity, and good thermal stability. Clones isolated from a polyclonal population of transduced cells varied by as much as 30-fold in their resistance to TMTX, the resistance differences depending on hDHFR expression levels.

Aminopterin↗
PubMed1997

Mechanisms of resistance in a human cell line exposed to sequential topoisomerase poisoning.

Camptothecins are a new class of anticancer drugs that target DNA topoisomerase I; current efforts are directed toward elucidating optimal combinations of these drugs with other antineoplastic agents. A rationale for the use of sequential therapy involving the combination of camptothecins with topoisomerase II-targeting drugs, such as etoposide, has arisen from observations of increased topoisomerase II protein levels in cell lines resistant to camptothecin. In an effort to understand potential mechanisms of resistance to this strategy, we developed a U-937 cell subline, denoted RERC, that is capable of surviving exposure to sequential topoisomerase poisoning. The RERC cells are 200-fold resistant to camptothecin, 8-fold resistant to etoposide, and 10-fold hypersensitive to cisplatin compared to the parental U-937 cells. Biochemical analyses indicate that the resistant phenotype involves alterations in both topoisomerase I and topoisomerase IIalpha. Topoisomerase I catalytic activity in the resistant cells is similar to that of the parental line but is resistant to camptothecin. Moreover, the resistant cells express a single mRNA species of topoisomerase I that codes for a mutation in codon 533. In addition, topoisomerase IIalpha protein levels are decreased 10-fold in the resistant line, coincident with a two-fold decrease in the expression of topoisomerase IIalpha mRNA. Collectively, these results indicate that resistance to sequential topoisomerase poisoning may involve a reduction in total cellular topoisomerase activity.

Antineoplastic Agents↗
PubMed1997

Meningococcal disease in Australia; looking at the past, thinking of the future.

In 1987 an unexpected change in the epidemiology of meningococcal disease began in Australia. The change was accompanied by an outbreak of serogroup A meningococcal disease among Aboriginal central Australians, and was followed by a progressive rise in notifications of disease caused by both serogroup B and C nationwide. Over the last 4 years, the notification rate has plateaued at 2.1-2.3 per 100,000 population. Virulent clonal groups of serogroup A and C meningococci that have caused outbreaks appear to be identical to strains that have caused large outbreaks in other countries. We cannot predict where and when the next outbreak will occur. However, we can plan to respond swiftly when it does. This report presents an overview of the observed trends, the association between the microbiology and epidemiology of meningococcal disease, and the relevance of this association to outbreaks, with recommendations for management.

Australia↗
PubMed1997

A classical enzyme active center motif lacks catalytic competence until modulated electrostatically.

The cysteine proteinase superfamily is a source of natural structural variants of value in the investigation of mechanism. It has long been considered axiomatic that catalytic competence of these enzymes mirrors the generation of the ubiquitous catalytic site imidazolium-thiolate ion pair. We here report definitive evidence from kinetic studies supported by electrostatic potential calculations, however, that at least for some of these enzymes the ion pair state which provides the nucleophilic and acid-base chemistry is essentially fully developed at low pH where the enzymes are inactive. Catalytic competence requires an additional protonic dissociation with a common pKa value close to 4 possibly from the Glu50 cluster to control ion pair geometry. The pH dependence of the second-order rate constant (k) for the reactions of the catalytic site thiol groups with 4,4'-dipyrimidyl disulfide is shown to provide the pKa values for the formation and deprotonation of the (Cys)-S-/(His)-Im+H ion pair state. Analogous study of the reactions with 2,2'-dipyridyl disulfide reveals other kinetically influential ionizations, and all of these pKa values are compared with those observed in the pH dependence of kcat/Km for the catalyzed hydrolysis of N-acetylphenylalanylglycine 4-nitroanilide. The discrepancy between the pKa value for ion pair formation and the common pKa value close to 4 related to generation of catalytic activity is particularly marked for ficin (pKa 2.49 +/- 0.02) and caricain (pKa 2.88 +/- 0.02) but exists also for papain (pKa 3.32 +/- 0.01).

Binding Sites↗
PubMed1997

Subdural empyema resulting from displacement of a root into the maxillary antrum.

Subdural empyema is a rare but serious complication of paranasal sinusitis which may result in death or permanent disability in a significant proportion of cases. A case is presented in which displacement of a premolar root in the maxillary sinus led to a subdural empyema and a resultant left-sided hemiplegia. This case illustrates the necessity of early surgical intervention to remove displaced roots in the maxillary antrum in order to prevent the serious complications of paranasal sinusitis.

Adult↗
PubMed1997

Q fever vaccination in Queensland abattoirs.

Outbreaks of Q fever continue to be recorded in abattoirs despite a protective vaccine being available. All accredited abattoirs in Queensland were surveyed to ascertain the number that conducted Q fever vaccination programs. Only ten of the 30 abattoirs had vaccination programs. Vaccination programs were present at all abattoirs with more than 360 employees. Thirty-seven per cent of abattoir employees worked at abattoirs that did not have vaccination programs. Research is required into the attitudes and barriers to vaccination at smaller abattoirs so that vaccination coverage can be increased. Economic data, including litigation costs, should be considered in a cost-effectiveness study so that smaller abattoirs appreciate the benefits of implementing vaccination programs. The protocols for vaccination of new employees should be analysed for their capacity to provide appropriate worker coverage. Abattoir workers are a readily identifiable at-risk group who should be fully protected from this occupational disease. It is the responsibility of industry and health authorities to ensure all workers are appropriately protected.

Abattoirs↗
PubMed1997

Catheter-induced acute aortic insufficiency with hemodynamic collapse during PTCA: an unreported complication.

Primary PTCA as a means of reestablishing coronary blood flow in the infarct related artery is preferable in certain subgroups of patients with acute myocardial infarction. While the success rate of primary PTCA is very high, the procedure is not without risk. We report a case of hemodynamic collapse during PTCA due to an Amplatz guide catheter-induced, acute, and reversible aortic insufficiency. With the increasing use of the left Amplatz catheter for better guide support during PTCA, this unusual and previously unreported complication should be borne in mind.

Acute Disease↗
PubMed1997

The tethered spinal cord in patients with anorectal malformations.

The aims of this study were to find the prevalence of tethered cord in patients with anorectal malformations; to determine if the presence of tethered cord relates to the severity of the anorectal defect, and to certain symptoms, signs, radiologic findings, and associated anomalies; and finally to determine whether tethered cord impacted on a patient's functional prognosis and whether surgical untethering improved the patient. The authors studied 934 patients with anorectal malformations, 111 of whom had magnetic resonance imaging (MRI) of the spine. We compared patients with and without tethered cord by using parametric and nonparametric statistical tests. Tethered cord occurred in 24% of the patients. The prevalence varied according to the type of anorectal defect from 43% in the complex group to 11% in patients with rectovestibular fistula. Patients with tethered cord had a lateral sacral ratio lower than that of patients without tethered cord (0.410 versus 0.702). Tethered cord was present in 90% of patients with myelodysplasia, 60% of patients with a presacral mass, 57% of patients with sacral hemivertebrae, and 56% of patients with a single kidney. The greater number of associated anomalies a patient had, the greater the risk of having tethered cord (P < .05 for all differences). The authors noted differences between patients with and without tethered cord in the presence of voluntary bowel movements (46% versus 70%), fecal soiling (91% versus 63%), constipation (21% versus 43%), and urinary incontinence (86% versus 42%). The data indicate that patients with tethered cord have a worse functional prognosis than patients without tethered cord. However, the incontinence in our patients was also predictable based on the type of anorectal defect and the character of the sacrum irrespective of the presence of tethered cord. Eighteen patients underwent surgical untethering of the cord, and none had any significant change in bowel or urinary function postoperatively. No patient with tethered cord experienced incontinence that could be attributed to the cord defect alone. This study suggests that tethered cord occurs more frequently in patients with severe anorectal defects, sacral hypodevelopment, myelodysplasia, presacral mass, sacral hemivertebrae, or a single kidney, or in those with an anorectal defect with poor functional prognosis. At present no solid evidence supports the concept that tethered cord by itself affects the functional prognosis of patients with anorectal malformations. Also, there is no good evidence demonstrating that surgical untethering improves the prognosis.

Abnormalities, Multiple↗
PubMed1997

Pediatric duodenal perforation missed on computed tomography.

We present the case of a 2-year-old child who sustained duodenal perforation after blunt abdominal trauma. The presentation of gastrointestinal perforation after blunt abdominal trauma in children can be subtle and at times delayed. A slight increase in the concentration of aspartate aminotransferase, alanine aminotransferase, or pancreatic enzymes may be the only indication of hollow viscus injury. Initial radiographic studies have a low yield in detecting such injuries. Computed tomography is also unreliable. Conservative management with serial examinations and serial laboratory studies may be required to identify gastrointestinal perforation.

Child, Preschool↗
PubMed1997

Qualitative magnetic resonance imaging findings in geriatric depression. Possible link between later-onset depression and Alzheimer's disease?

BACKGROUND: Several clinical and neuroimaging investigations support the notion that underlying brain changes may relate to depression in older patients, especially those with a later-age initial episode. However uncertainty still exists about diagnostic and pathogenic significance of structural brain abnormalities in aged depressives, in part because many studies lack all-elderly and age-similar normal comparison populations. METHODS: Brain morphology of elderly depressives (N = 30) and normal controls (N = 36) was compared by assessing magnetic resonance imaging (MRI) brain scans with qualitative criteria-based scales. Ratings included lateral and third ventricle enlargement, and cortical, medial temporal, and caudate atrophy. RESULTS: Significant differences between depressed and control groups were not demonstrated. Later-onset depressives had significantly more left medial temporal and left caudate atrophy than early-onset counterparts of similar age. Medial temporal atrophy significantly correlated with cognitive impairment and was not related to physical illness. Depressives with medial temporal atrophy (N = 7) were older and had later age at onset of depression than those without such changes. Cerebrovascular disease risk factors did not predict MRI abnormalities. CONCLUSIONS: Results indicate non-specificity and lack of homogeneity of qualitatively measured structural brain changes in geriatric depression, but suggest that pathology of specific, lateralized brain regions may be implicated in some later-onset patients. The relationship between medial temporal atrophy and late-onset depression raises the possibility that such patients may suffer from as-yet undeclared Alzheimer's disease. Lack of association between cerebrovascular disease risk factors and brain changes suggests other pathophysiological contributions.

Aged↗
PubMed1997

Sch 54445: a new polycyclic xanthone with highly potent antifungal activity produced by Actinoplanes sp.

A novel antifungal agent, Sch 54445, was isolated from the fermentation broth of an Actinoplanes species. Sch 54445 was identified as a polycyclic xanthone related to the albofungin family of compounds on the basis of analyses of spectroscopic data. As a broad-spectrum antifungal agent, Sch 54445 exhibits highly potent activities against various yeasts and dermatophytes with MIC values approximately 0.00038 microgram/mL.

Actinomycetales↗
PubMed1997

Impaired nitric oxide-mediated vasodilatation and total body nitric oxide production in healthy old age.

1. Basal release of nitric oxide from the vascular endothelium maintains a constant vasodilating tone. Impaired nitric oxide-mediated vasodilatation has been described in hypertension and atheromatous disease. Circulatory diseases account for considerable morbidity and almost half of all deaths in people over the age of 75 years. 2. We have therefore compared nitric oxide-dependent vasorelaxation in 12 healthy elderly subjects with 12 young volunteers matched for blood pressure, cholesterol and glucose, using forearm occlusion venous plethysmography combined with brachial artery infusions of the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA; 1, 2 and 4 mumol/min) with noradrenaline (60, 120 and 240 pmol/min) as a control vasoconstrictor. We also measured urinary nitrate excretion after a controlled 48 h low nitrate diet as an index of total body nitric oxide production and correlated these changes with forearm blood flow responses to L-NMMA and noradrenaline in both groups. 3. The mean age and blood pressure of the elderly subjects was 76 (range 66-82) years and 132/76 (SEM 4/3) mmHg respectively, while in the young these were 27 (20-35) years and 131/72 (4/3) mmHg respectively. L-NMMA and noradrenaline produced dose-dependent reductions in forearm blood flow in both groups. L-NMMA (4 mumol/min) produced less vasoconstriction in the elderly than in the young (-37.7 +/- 2.6 versus -48.3 +/- 4.2%; P = 0.017). The mean slope of the L-NMMA dose-response curves in the elderly was significantly less than the younger group (-35.2 +/- 3.1 versus -63.7 +/- 10.6; P = 0.041). Noradrenaline, 240 pmol/min, also produced less vasoconstriction in the elderly compared with the young (-22.8 +/- 2.9 versus -35.3 +/- 5.0%; P = 0.029) although the slopes of the dose-response curves did not differ significantly. 4. Urinary nitrate adjusted for creatinine clearance was also significantly higher in the younger group (460.6 +/- 97.7 versus 205.9 +/- 64.8 mumol/day; P = 0.042) and showed a significant correlation with the percentage change in forearm blood flow in response to the maximum dose of L-NMMA (r = 0.5, P = 0.046). 5. We conclude that nitric oxide-mediated vasodilatation in the forearm vascular bed is diminished in old age and this reflects a more generalized reduction in nitric oxide production (as measured by urinary nitrate) in the circulation of older people. The blunted response to noradrenaline points to a more generalized reduction in vascular reactivity in the elderly.

Adult↗
PubMed1997

The role of the Fgr tyrosine kinase in the control of the adhesive properties of U937 monoblastoid cells and their derivatives.

In humans, expression of the cellular proto-oncogene c-fgr is normally restricted to mature cells of the myeloid lineage, mantle zone B cells and various myeloid and B-cell lines. Previous studies of the monoblastoid cell line, U937, showed that c-fgr expression increased following differentiation, but its role in monocytes and related cells has not been defined in functional terms. We therefore investigated the role of c-fgr in U937 cells transfected with the c-fgr gene such that its expression could be manipulated independent of differentiation. Induction of the transfected c-fgr gene by cadmium ions did not affect cell proliferation, responses to phorbol 12-myristate 13-acetate (PMA), dihydroxycholecalciferol (DHCC), tumour necrosis factor-alpha (TNF-alpha) or retinoic acid, or phagocytosis of antibody-coated sheep red blood cells. However, there was increased surface expression of CD54 (intracellular adhesion molecule-1; ICAM-1) and CD102 (ICAM-2) and decreased surface expression of CD50 (ICAM-3) compared with cells that had been transfected with plasmid only and treated in the same way. These findings suggest that the product of the c-fgr gene may be important in control of relative adhesive properties of mature monocytic cells.

Antigens, CD↗
PubMed1997

SPECT and subtraction imaging of an ectopic parathyroid adenoma.

Primary hyperparathyroidism is a disease best managed surgically; resection of the lesion(s) is curative. Although the routine use of localizing procedures is controversial before surgery, it is generally agreed that these techniques are useful in cases of reexploration. The authors have recently studied a patient with long-standing hyperparathyroidism, in whom initial surgery was unsuccessful. Although planar imaging with Tc-99m sestamibi is usually sufficient for identification and localization of the lesion, both SPECT and subtraction imaging provided additional information that contributed to the success of the subsequent surgery. Single-proton emission computed tomography provided critical information about the position of the ectopic parathyroid adenoma in relation to the right submandibular salivary gland, whereas subtraction imaging confirmed that the focus was indeed a parathyroid lesion, and not merely an anatomic variant of a normal salivary gland.

Adenoma↗