A campaign for success.
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Education, Medical, Graduate↗
Biomedical subjects
D Lewis
Publications and source records attributed to D Lewis.
Longterm methotrexate use in rheumatoid arthritis: 12 year followup of 460 patients treated in community practice.
OBJECTIVE: To extend our observations on the longterm tolerability of methotrexate (MTX) and reasons for discontinuation in a cohort of 460 patients with rheumatoid arthritis (RA). METHODS: We studied all patients with RA who started MTX before June 1986 and attended the community based private practices of 6 rheumatologists in Melbourne. Information to at least April 1, 1995, or within one year of death was updated from the patient's medical records to include MTX discontinuation and reasons for discontinuation. Addition of disease modifying antirheumatic drugs (DMARD) concomitant with MTX was noted. Survival analyses based upon life table methods were used with MTX discontinuation as the observable endpoint. Three different definitions of MTX discontinuation were used (1) according to whether the patient was taking the drug at last followup irrespective of any periods of temporary discontinuation; (2) MTX discontinuation for > 3 months considered to be a treatment endpoint; and (3) addition of concomitant DMARD considered to be only partial success of MTX (as a need for additional therapy to meet treatment goals). RESULTS: At 12 years, 53% of patients were continuing to take MTX (irrespective of any periods of temporary discontinuation). If discontinuation of the drug for 3 or more months was considered a treatment termination then 38% were still taking the drug at 12 years, and if addition of concomitant DMARD was regarded as a treatment endpoint only 17% of patients were continuing MTX at 12 years. Withdrawal for gastrointestinal toxicity declined over time but the risk of other adverse effects appeared to persist over time. CONCLUSION: MTX in RA is well tolerated over the longer term, with > 50% of patients starting MTX in a community based rheumatology private practice continuing to take it 12 years later. However, a substantial number of patients had 2nd line therapies added over this time. Monitoring for toxicity should continue throughout the course of therapy.
Antirheumatic Agents↗
Midwifery in Trinidad and Tobago.
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Female↗
Trinidad and Tobago Association of Midwives.
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Female↗
Direct to consumer.
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Access to Information↗
Modulation of aerosol clouds produced by pressurised inhalation aerosols.
The inclusion of non-volatile components such as glycerol or polyethylene glycol in hydrofluoralkane (HFA) solution formulations for pressurised metered dose inhalers (pMDIs), greatly increases the particle size of the aerosol. Cloud characteristics can be further modulated by permuting this factor with the choice of propellant and the dimensions of the actuator, to give a chosen fine particle dose and particle diameter. This principle has been used to design solutions which closely match the performance of chlorofluorocarbon based suspension formulations containing beclomethasone dipropionate, budesonide and ipratropium bromide as assessed for pharmaceutical equivalence using the Andersen Cascade impactor.
Aerosols↗
The detection of cotinine in hydrolyzed meconium samples.
To date, the screening of meconium for the determination of tobacco exposure in newborns has proven difficult. It was hypothesized that cotinine forms reversible Schiff base bonds with free amino functions on proteins, therefore, hydrolysis of meconium would be necessary for the detection of 'free' cotinine. One-hundred-and-two (102) meconium samples received into our laboratory were extracted using a routine non-hydrolysis screening procedure for drugs of abuse. Separate aliquots of the specimens were hydrolyzed and re-extracted according to the same procedure. The results of the two methods were compared using a highly specific cotinine micro-plate enzyme immunoassay procedure (EIA). Of the non-hydrolyzed samples, 33% were positive for cotinine, while 79% of the hydrolyzed samples were cotinine-positive. Common drugs of abuse did not interfere with the analysis. Micro-plate EIA provides a rapid, simple and reliable screening method for the determination of cotinine in meconium following hydrolysis and extraction. In general, the meconium specimens received into our laboratory are from newborns considered to be at risk for post-natal problems due to suspected drug and/or alcohol abuse during pregnancy.
Cotinine↗
Bone marrow NK1.1(-) and NK1.1(+) T cells reciprocally regulate acute graft versus host disease.
Sorted CD4(+) and CD8(+) T cells from the peripheral blood or bone marrow of donor C57BL/6 (H-2(b)) mice were tested for their capacity to induce graft-versus-host disease (GVHD) by injecting the cells, along with stringently T cell-depleted donor marrow cells, into lethally irradiated BALB/c (H-2(d)) host mice. The peripheral blood T cells were at least 30 times more potent than the marrow T cells in inducing lethal GVHD. As NK1.1(+) T cells represented <1% of all T cells in the blood and approximately 30% of T cells in the marrow, the capacity of sorted marrow NK1.1(-) CD4(+) and CD8(+) T cells to induce GVHD was tested. The latter cells had markedly increased potency, and adding back marrow NK1.1(+) T cells suppressed GVHD. The marrow NK1.1(+) T cells secreted high levels of both interferon gamma (IFN-gamma) and interleukin 4 (IL-4), and the NK1.1(-) T cells secreted high levels of IFN-gamma with little IL-4. Marrow NK1.1(+) T cells obtained from IL-4(-/-) rather than wild-type C57BL/6 donors not only failed to prevent GVHD but actually increased its severity. Together, these results demonstrate that GVHD is reciprocally regulated by the NK1.1(-) and NK1.1(+) T cell subsets via their differential production of cytokines.
Animals↗
Proteoglycans on normal and migrating human corneal endothelium.
Proteoglycans are of fundamental importance to the normal functioning of the cornea. They consist of a core protein to which one or more glycosaminoglycan chains are attached. Cell surface proteoglycans are known to mediate many aspects of cell behaviour including cell adhesion, control of extracellular matrix deposition, cell proliferation, cell migration, leukocyte adhesion and modulation of growth factor activity. This paper describes the first investigation into the distribution and function of the three main classes of proteoglycans on human corneal endothelium. Immuno-gold labelling techniques were used at the light, scanning and transmission electron microscope level to localise heparan sulphate, chondroitin sulphate and keratan sulphate proteoglycans on human corneal endothelium. Human corneas were freeze-wounded and kept in organ culture for 3 days in order to study the distribution of proteoglycans on migrating corneal endothelium. An Optimas image analysis system was used to quantify the change in proteoglycan labelling during cell migration. Labelling for chondroitin sulphate and heparan sulphate was at very low levels on normal corneal endothelium while keratan sulphate labelling was at high levels. The wound healing experiments showed that migrating cells had increased labelling for heparan sulphate and chondroitin sulphate with greatly decreased labelling for keratan sulphate. Statistical analysis showed these changes were highly significant (P<0.001). Transmission electron microscopy revealed that chondroitin sulphate and keratan sulphate were present throughout Descemet's membrane while heparan sulphate was concentrated at the interface of Descemet's membrane and the migrating corneal endothelial cells. The pattern of occurrence of chondroitin sulphate, heparan sulphate and keratan sulphate on the human endothelium in normal and wounded cornea suggests that these proteoglycans are linked to the process of cell migration.
Cell Movement↗
EUS features of duodenal invasion secondary to hepatocellular carcinoma: case report.
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Carcinoma, Hepatocellular↗
Kaposi's sarcoma-associated herpesvirus-positive primary effusion lymphoma arising in the subarachnoid space.
Primary effusion lymphoma (PEL) is a rare and distinctive type of B-cell non-Hodgkin's lymphoma (NHL) that occurs primarily, although not exclusively, in patients with AIDS. It usually develops as a lymphomatous effusion in the absence of a tumor mass, characteristically contains the Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV-8), usually also contains the Epstein-Barr virus (EBV), displays a characteristic cytomorphology bridging immunoblastic and anaplastic large cell lymphoma, often expresses an indeterminate immunophenotype, and a B-cell genotype. Thus far, PEL has been limited almost entirely to the pleural, peritoneal, and pericardial cavities. We describe a NHL occurring in a gay man with AIDS that is typical of PEL in that it arose in a body cavity or space without an associated tumor mass, displays the cytomorphology typical of PEL, is a clonal B-cell neoplasm, and contains KSHV as well as EBV. This case is singularly distinctive in that it is the first case of PEL reported to arise in the subarachnoid space. This unique case further supports the strong association between KSHV and malignant lymphoma arising in body cavities and growing as an effusion.
Adult↗
A multicenter, randomized trial of percutaneous coronary intervention versus bypass surgery in high-risk unstable angina patients. The AWESOME (Veterans Affairs Cooperative Study #385, angina with extremely serious operative mortality evaluation) investigators from the Cooperative Studies Program of the Department of Veterans Affairs.
This multicenter, prospective randomized trial was designed to test the hypotheses that percutaneous coronary intervention (PCI) is a safe and effective alternative to coronary artery bypass grafting (CABG) for patients with refractory ischemia and high risk of adverse outcomes. As a comparison of revascularization strategies, the trial specifically allows surgeons and interventionists to use new techniques as they become clinically available. After 42 months of this 72-month trial, 17,624 patients have been screened and 2022 met eligibility requirements: 341 have been randomized to either CABG or PCI, and the remaining 1681 are being prospectively followed in a registry. The 3-year overall survival of patients in the registry and randomized trial is comparable. To enhance accrual into the randomized trial, site visits were conducted, a few low-accruing hospitals were put on probation and/or replaced, eligibility criteria were reviewed at annual meetings of investigators, and the accrual period was extended by 1 year. These data demonstrate that a prospective randomized trial and registry of coronary revascularization for medically refractory high-risk patients is feasible.
Age Factors↗
Congenital chylothorax in neonatal thyrotoxicosis.
We report a patient with congenital chylothorax who also had neonatal thyrotoxicosis secondary to maternal Graves' disease. Fetal tachycardia with hydrops was detected at 28 weeks' gestational age. The fetus responded to antithyroid medication in utero but had persistent bilateral pleural effusion. At birth, he had respiratory distress due to massive pleural effusion. Cytologic studies of pleural fluid were consistent with chylothorax. To the best of our knowledge, the association of congenital chylothorax with fetal (neonatal) thyrotoxicosis, has not been reported previously.
Adult↗
Highly sensitive micro-plate enzyme immunoassay screening and NCI-GC-MS confirmation of flunitrazepam and its major metabolite 7-aminoflunitrazepam in hair.
Flunitrazepam (Rohypnol) is a benzodiazepine used in the treatment of insomnia as a sedative hypnotic and as preanesthetic medication in European countries and Mexico. Although it has no medicinal purpose in the United States, the occurrence of its abuse is increasing. Sexual abuse of both men and women while under the influence of so-called "date-rape" drugs has been the focus of many investigations. Reported date-rape drugs include flunitrazepam (FN), clonazepam, diazepam, oxazepam, gamma-hydroxybutyrate, and many others. FN has been banned in the United States because of its alleged use in such situations. Unfortunately, the detection of FN or its metabolites 7-aminoflunitrazepam (7-AFN) and desmethylflunitrazepam in a single specimen such as urine or blood is difficult in criminal situations because of the likelihood of single-dose ingestion and the length of time since the alleged incident. Hair provides a solution to the second of these problems in that drugs tend to incorporate into hair and remain there for longer periods of time than either urine or blood. There are various techniques for the detection of FN in plasma, blood, and urine, but little work has been done with hair. Hair collection is a virtually noninvasive procedure that can supply information on drug use for several months preceding collection. The objective of this paper was to determine if a commercially available micro-plate enzyme immunoassay system was sufficiently sensitive for the routine screening of 7-AFN in hair by the development of extraction procedures and optimization of the immunoassay kit. Further, this study used the same solid-phase extraction to isolate FN and its major metabolite, 7-AFN, and gas chromatography-mass spectrometry with negative ion chemical ionization for confirmation. Two seven-point standard curves were established ranging from 0.5 pg/mg to 100 pg/mg for 7-AFN and 2.5 pg/mg to 200 pg/mg for FN with respective deuterated internal standards. A replicate analysis of controls was performed to establish inter- and intraday variabilities. Two suicide cases along with one alleged date-rape case and one case of an emergency room patient whose blood screened positive for benzodiazepines were analyzed. All the hair specimens screened positive for benzodiazepines using micro-plate enzyme immunoassay. Two cases, including the date-rape case, were negative for FN and 7-AFN, and two postmortem hair samples were confirmed positive for FN and its metabolite.
Anti-Anxiety Agents↗
Genetically detoxified mutants of heat-labile toxin from Escherichia coli are able to act as oral adjuvants.
Detoxified mutants of the Escherichia coli heat-labile toxin (LT) act as mucosal adjuvants to intranasally presented coadministered antigens. Here, we compare the adjuvant activity of a panel of detoxified derivatives of LT, using both intranasal (i.n.) and oral (p.o.) routes of administration. The mutants used as adjuvants varied in sensitivity to proteases and toxicity. With keyhole limpet hemocyanin (KLH) as the bystander antigen, the immune responses to i. n. immunizations were consistently higher than the equivalent p.o. -delivered proteins. LT-G192, a mutant which demonstrates a 10-fold reduction in toxicity in vitro, demonstrated wild-type adjuvant activity both i.n. and p.o., inducing similar titers of KLH specific antibody in the sera and immunoglobulin A in local mucosal secretions as wild-type LT. In line with previous data, the nontoxic holotoxoid LT-K63 induced intermediate immune responses in both the serum and mucosal secretions which were lower than those achieved with wild-type LT but at least 10-fold higher than those measured when the antigen was administered with LT-B. Although significant levels of local and systemic anti-KLH antibodies were induced following p.o. immunization with LT-K63, cellular proliferative responses to KLH was poor or undetectable. In contrast, LT and LT-G192 induced significant T-cell responses to KLH following p.o. immunization. These proliferating cells secreted both gamma interferon and interleukin-5, suggesting that the type of immune response induced following p.o. coimmunization with LT and purified protein is a mixed Th1/Th2 response.
Adjuvants, Immunologic↗
Comparison of SERCA1 and SERCA2a expressed in COS-1 cells and cardiac myocytes.
Cultured COS-1 cells, as well as chicken embryonic and neonatal rat cardiac myocytes, were infected with recombinant adenovirus vectors to define limiting factors in the expression and Ca2+ transport function of recombinant sarcoplasmic-endoplasmic reticulum Ca(2+) (SERCA) isoforms. Titration experiments showed that all COS-1 cells and myocytes in culture could be infected by an adenovirus titer of 10 plaque-forming units (pfu) per seeded cell. Raising the adenovirus titer further yielded higher protein expression up to an asymptotic limit for functional, membrane-bound SERCA protein. The asymptotic behavior of SERCA expression was not transcription related but was due to posttranscriptional events. The minimal (-268) cardiac troponin T (cTnT) promoter was a convenient size for adenovirus vector construction and manifested tight muscle specificity. However, its efficiency was lower than that of the nonspecific cytomegalovirus (CMV) promoter. At any rate, identical maximal levels of SERCA expression were obtained with the CMV and the cTnT promoter, as long as the viral titer was adjusted to compensate for transcription efficiency. A maximal threefold increase of total SERCA protein expression over the level of the endogenous SERCA of control myocytes was reached (a sevenfold increase compared with the endogenous SERCA of the same infected myocytes due to reduction of endogenous SERCA after infection). In contrast with previous reports [Ji et al. Am. J. Physiol. 276 (Heart Circ. Physiol. 45): H89-H97, 1999], a higher kinetic turnover was demonstrated for the SERCA1 compared with the SERCA2a isoform as shown by a 5.0- versus 2.6-fold increase in calcium uptake rate accompanying maximal expression of recombinant SERCA1 or SERCA2a, respectively. This information is deemed necessary for studies attempting to modify myocardial cell function by manipulation of SERCA expression.
Adenoviridae↗
Cats increase fatty acid oxidation when isocalorically fed meat-based diets with increasing fat content.
This study tested the hypothesis that sedentary cats have the ability to adapt to high-fat carnivore diets by increasing fat oxidation. Twenty-four hour indirect calorimetry was used to determine total energy expenditure (TEE) and macronutrient oxidation in six vasectomized male (VAS) and six ovariectomized female (OVX) cats isocalorically fed lower-fat (53% fat, 45% protein) and higher-fat (71% fat, 26% protein) meat-based diets at maintenance for 8 days. Fat oxidation increased linearly with fat intake with a mean slope of 0.91 g fat oxidized/g fat intake (P < 0.001), with no change in TEE. However, VAS male cats were able to more precisely match fat oxidation with fat intake than OVX female cats (P < 0.02). Body fat content did not significantly influence fat oxidation. These results demonstrate that cats maintain body weight during short-term isocaloric feeding of a high-fat carnivore-type diet in part by increasing fat oxidation commensurate with increases in fat intake. This ability may be an important mechanism underlying the resistance of cats to obesity, despite habitual consumption of high-fat diets.
Animals↗
Characterization of ionotropic glutamate receptors in rat hypothalamus, pituitary and immortalized gonadotropin-releasing hormone (GnRH) neurons (GT1-7 cells).
Evidence from various sources suggested that the Gonadotropin-Releasing Hormone (GnRH) neuron does not contain glutamate receptors. Northern analysis of the hypothalamus showed the presence of NMDAR1, GluR1, GluR4 and GluR6 mRNA, while the pituitary showed the presence of NMDAR1, GluR1 and GluR6 mRNA. Western blot analysis also showed the presence of NMDAR1 and GluR1 protein. Since there are relatively few GnRH neurons in the hypothalamus, and GT1-7 cells have been considered to be a GnRH neuronal cell line, GT1-7 cells were studied in detail. GT1-7 cells contained NMDAR1 mRNA levels as shown by Northern analysis but did not contain GluR1, GluR4, or GluR6 mRNA. They did not show the presence of NMDAR1 and GluR1 protein by Western analysis. In addition, GT1-7 cells showed no NMDA receptor binding using the competitive inhibitor CGP-39563 and the noncompetitive inhibitor MK-801. Likewise, no binding was detected for kainate receptors. However, a small amount of binding for AMPA receptors was found in GT1-7 cells. GT1-7 cells did not exhibit glutamate toxicity and NMDA failed to elicit inward currents using patch-clamp techniques, although GABA did induce currents in the cells. As a whole, these studies suggest that GT1-7 cells lack or possess only low levels of ionotropic glutamate receptors.
Animals↗