The impact of the Rouge-Cloître as seen by a geneticist.
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Animals↗
Biomedical subjects
R Thomas
Publications and source records attributed to R Thomas.
Fractional retention of technetium-99m-sestamibi as an index of P-glycoprotein expression in untreated breast cancer patients.
UNLABELLED: The multidrug-resistant phenotype is characterized by the reduced intracellular retention of several structurally and functionally unrelated cytotoxic compounds due to the energy-dependent pump activity of P-glycoprotein (Pgp). Because 99mTc-sestamibi is a suitable transport substrate of Pgp, we tested whether the time-dependent fractional retention of this tracer could be used as an index of Pgp expression in untreated breast carcinomas. METHODS: Twenty-seven patients with histologically confirmed breast carcinoma were intravenously injected with 740 MBq (20 mCi) of 99mTc-sestamibi, and static planar images of the breast were obtained at 10, 60 and 240 min. The fractional retention of 99mTc-sestamibi was then calculated as the ratios between 60 and 10 min (R60/10) and between 240 and 10 min (R240/10) of decay-corrected counts/pixel registered in the region of interest drawn around the tumor. Surgically excised tumors were then obtained from each patient, and Pgp levels were determined using 125I-labeled MRK16 monoclonal antibody and in vitro quantitative autoradiography. RESULTS: The fractional retention of 99mTc-sestamibi at 60 and 240 min was significantly higher in tumors with low Pgp levels (Group I, n = 18) as compared to that measured in tumors with high Pgp expression (Group II, n = 9) (p < 0.001). In particular, R60/10 values were 0.86 and 0.59 in breast carcinomas of Groups I and II, respectively, whereas the values of R240/10 were 0.56 and 0.25 in low- and high-Pgp-expressing tumors, respectively. CONCLUSION: The determination of fractional retention of 99mTc-sestamibi may be used as a simple functional test for Pgp expression in untreated breast cancer. A preliminary estimate of the sensitivity and the specificity of the test indicates its potential use in clinical practice to identify patients with a high probability of developing multidrug resistance.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
A survey of the training of Canadian health professionals to counsel against smoking.
Canadian schools that train health professionals were asked to evaluate the amount of teaching of counselling skills to prevent clients from starting smoking or to help them quit, the topics covered, the knowledge and counselling skill level of their graduates and whether an integrated smoking counselling program was needed for their school. Responses to a questionnaire were received from the Assistant Dean of Undergraduate Studies, the Assistant Dean of Postgraduate Studies and/or the Postgraduate Program Director of 165 professional schools or departments of 283 contacted (58% response rate). For those schools that replied that they taught counselling about smoking, they devoted more hours in the curriculum (range 1-11 hours) to education about the diseases caused by smoking than to counselling children or adults against smoking or helping smokers to quit. Nursing schools tended to have integrated health education curricula, and it was therefore difficult for them to identify the hours devoted exclusively to counselling about tobacco. Few of the deans or program directors of any of the professional schools estimated the knowledge and counselling skills of their graduates as superior, and a majority felt that an integrated smoking counselling curriculum was needed for their school.
Adult↗
Unilateral multicystic dysplastic kidney.
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England↗
Releasable suture technique for trabeculectomy.
A retrospective review of 154 trabeculectomies with releasable sutures was performed to assess the effect of suture release on intraocular pressure (IOP) at various postoperative periods. Release of the suture was necessary in 38% of cases. The immediate reduction in IOP was significant (p < 0.01) when the suture was released during the first three postoperative weeks. Seventy percent of eyes had a reduction in IOP more than 5 mmHg if released within the first week compared to 20% after the third week. With suture release after the third postoperative week, there was no clinically significant decrease in IOP. The decrease in IOP was similar in eyes undergoing trabeculectomy alone or when cataract extraction through a separate corneal incision was undertaken simultaneously. The period during which release of suture was effective was not prolonged by use of antimetabolites. Complications included a typical windshield-wiper keratopathy (18 eyes), failure to release the suture (13 eyes), epithelial abrasion (6 eyes) and a sub-conjunctival bleed (1 eye).
Cataract Extraction↗
VISTECH contrast sensitivity testing in primary open angle glaucoma.
Contrast sensitivity has been recommended as a screening and diagnostic test in primary open angle glaucoma (POAG). We tested contrast sensitivity (CS) using Vistech charts in 184 eyes of 95 patients. Three groups were examined--established primary open angle glaucoma, glaucoma suspects and age matched controls. The distribution of contrast sensitivities amongst the three groups were similar. The median contrast sensitivity of glaucoma suspects and controls were well within normal limits while that of the POAG group fell along the lower limit of normal. In all three groups the younger subjects scored better than the older, indicating a depression of contrast sensitivity with increasing age. Even if depression of any one spatial frequency was considered abnormal, the test yielded a sensitivity of 55.4% and specificity of 69.5%. Similarly contrast sensitivity testing was found to be of little use in detecting field defects a maximum sensitivity of 47.3% and specificity of 73.3%. Vistech contrast sensitivity testing is not a useful test in POAG screening or diagnosis.
Adult↗
Confidence with confidence intervals.
When considering the results of a study that reports one treatment to be better than another, what the practicing ophthalmologist really wants to know is the magnitude of the difference between treatment groups. If this difference is large enough, we may wish to offer the new treatment to our own patients. Even in well executed studies, differences between the groups (the sample) may be due to chance alone. The "p" value is the probability that the difference observed between the groups could have occurred purely due to chance. For many ophthalmologists assessing this difference means a simple look this "p" value to convince ourselves that a statistically significant result has indeed been obtained. Unfortunately traditional interpretation of a study based on the "p" value at an arbitrary cut-off (of 0.05 or any other value) limits our ability to fully appreciate the clinical implications of the results. In this article we use simple examples to illustrate the use of "confidence intervals" in examining precision and the applicability of study results (means, proportions and their comparisons). An attempt is made to demonstrate that the use of "confidence intervals" enables more complete evaluation of study results than with the "p" value.
Clinical Trials as Topic↗
Evaluation of the role of syringing prior to cataract surgery.
Patients for cataract surgery in India routinely undergo preoperative syringing to rule out chronic dacryocystitis. We determined the sensitivity and specificity of the clinical test of regurgitation on pressure over the lacrimal sac (ROPLAS) as a screening test for chronic dacryocystitis and compared it to syringing. 621 consecutive outpatients who needed syringing for various reasons (including 318 who had routine syringing prior to cataract surgery) were examined in a masked manner for regurgitation on pressure over the lacrimal sac. They then underwent syringing by a trained (masked) observer. The sensitivity and specificity of ROPLAS were 93.2% and 99.3%, respectively. Using a 6.6% prevalence of chronic dacryocystitis (the prevalence in our cataract population), the negative predictive value of the test was 99.5%. In the presence of regurgitation of pressure over the sac, the high specificity of ROPLAS confirms chronic dacryocystitis. In view of the opportunity costs, when ROPLAS is negative, preoperative syringing in cataract is perhaps unnecessary, unless the findings are equivocal or the index of suspicion for chronic dacryocystitis is very high.
Cataract↗
Visual outcome and complications of residents learning phacoemulsification.
The increasing popularity of phacoemulsification in our country raises important training issues. We prospectively analyzed the incidence of complications and visual outcomes in the initial 70 phacoemulsifications (70 patients) performed by the first two residents learning phacoemulsification in our training programme. Both were experienced in standard (manual) extracapsular cataract extraction. Postoperative follow up of 6 weeks or longer was available in 59 eyes. The 11 patients (11 eyes) lost to follow up did not have any intra-operative complications. The overall incidence of vitreous loss was 10%, similar to the frequency of this complication (determined retrospectively) in the first 70 standard extracapsular cataract extractions performed by the same residents. Intraocular lenses (IOL) were successfully implanted in 62 eyes, as planned. One IOL dislocated into the vitreous was successfully repositioned. Other complications encountered included superior corneal edema (3 eyes), iris damage inferiorly (7 eyes) and clinical cystoid macular edema (5 eyes). A best corrected visual acuity of 6/12 or better was obtained in 56 (94.8%) of the 59 eyes available for the six week follow up. In the eyes with vitreous loss, 6 out of 7 had visual acuity better than 6/12. No nuclei were lost into the vitreous. The rate of surgical complications for residents learning phacoemulsification in a supervised manner can be acceptably low.
Clinical Competence↗
Estimating cataract blindness in India.
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Blindness↗
Antibody to CD18 reduces neutrophil and T lymphocyte infiltration and vascular cell adhesion molecule-1 expression in cardiac rejection.
Most antirejection therapies target immune activation but may not reduce leukocyte infiltration into the graft. The leukocyte integrin CD18 has been shown to be important for leukocyte migration in vitro. We postulated that antibody blockade of CD18 might reduce the migration of different leukocyte subpopulations into myocardium during rejection. Using a rabbit model, we evaluated the effect of a monoclonal antibody to CD18 on the infiltration of neutrophils (polymorphonuclear leukocytes [PMNs]), T lymphocytes, and macrophages into cardiac grafts. In addition, vascular cell adhesion molecule-1 (VCAM-1) expression was assessed to determine the relationship between leukocyte infiltration and VCAM-1 expression, an unblocked alternate adhesion pathway. Donor hearts from Stauffland rabbits were transplanted heterotopically into the cervical position of New Zealand White recipients. Recipient rabbits received either monoclonal antibody to CD18 daily without other immunosuppression (n=51), saline injections as placebo controls (n=52), or nonfunctional isotype-matched antibody (n=4). Recipient rabbits were killed at 1 hr, 6 hr, 24 hr, 3 days, and 7 days after transplantation (10-12 rabbits per group at each time point). PMNs, T lymphocytes, and macrophages were differentiated by routine staining and immunocytochemistry, respectively, and quantified as the number of cells per standardized field. VCAM-1 expression was examined immunocytochemically in 30 treated and 30 control transplanted hearts. Monoclonal antibody to CD18 significantly reduced the infiltration of PMNs and T lymphocytes into myocardium during rejection, but did not affect the infiltration of macrophages. Blocking the CD18/intercellular adhesion molecule-1 adhesion pathway also resulted in a decrease in VCAM-1 expression, which correlated in time with the reduction in T lymphocyte infiltration.
Animals↗
Alpha-melanocyte-stimulating hormone reduces endotoxin-induced liver inflammation.
Alpha-Melanocyte-stimulating hormone (MSH) is a potent anti-inflammatory agent in many models of inflammation, suggesting that it inhibits a critical step common to different forms of inflammation. We showed previously that alpha-MSH inhibits nitric oxide (NO) production in cultured macro-phages. To determine how alpha-MSH acts in vivo, we induced acute hepatic inflammation by administering endotoxin (LPS) to mice pretreated with Corynebacterium parvum, alpha-MSH prevented liver inflammation even when given 30 min after LPS administration. To determine the mechanisms of action of alpha-MSH, we tested its influence on NO, infiltrating inflammatory cells, cytokines, and chemokines. Alpha-MSH inhibited systemic NO production, hepatic neutrophil infiltration, and increased hepatic mRNA abundance for TNF alpha, and the neutrophil and monocyte chemokines (KC/IL-8 and MCP-1). We conclude that alpha-MSH prevents LPS-induced hepatic inflammation by inhibiting production of chemoattractant chemokines which then modulate infiltration of inflammatory cells. Thus, alpha-MSH has an effect very early in the inflammatory cascade.
Animals↗
Functional differentiation of dendritic cells in rheumatoid arthritis: role of CD86 in the synovium.
Dendritic cells (DC) are the major APC in human peripheral blood (PB) and rheumatoid synovium. We previously identified in PB a population of CD33dim-CD14dim DC precursors, as well as a smaller population of CD33bright CD14dim mature DC. Neither PB DC population expressed the CD28/CTLA4 ligands, suggesting that additional signals are required for full functional DC differentiation. Because rheumatoid synovium is characterized by an ongoing immune response, the expression and function of CD80, CD86, and other markers of DC differentiation by rheumatoid arthritis synovial APC were examined. The phenotype of a large subset of freshly isolated rheumatoid arthritis synovial fluid (SF) DC resembled that of the mature PB DC. These DC expressed CD45R0, CD11c, CMRF-44, and high levels of CD33. Whereas CD80 expression by rheumatoid SF DC and monocytes was minimal, CD86 was expressed by a subset of SF monocytes and by CMRF-44+SF DC. Furthermore, sorted CD86- SF DC spontaneously up-regulated CD86 in vitro. CD80 was expressed diffusely and at low levels by rheumatoid synovial tissue cells, whereas CD86 was expressed by perivascular HLA-DR+HLA-DQ+CD80+CMRF-44+ DC, and by some CD14+ monocytes. Anti-CD86 mAb and CTLA4 Ig, but not anti-CD80 mAb, inhibited the MLR stimulated by SF DC. Both CMRF-44+ and CMRF-44- SF DC were efficient stimulators of the allogeneic MLR, which was in each case blocked by CTLA4 Ig. The data indicate that rheumatoid synovial DC can undergo full functional differentiation, associated with CD86 expression, in vitro and in situ. Synovial DC expressing high levels of MHC molecules and CD86 are strategically located to present arthritogenic Ag to T cells after transendothelial migration.
Antigen-Presenting Cells↗
A cloud adult: the Staphylococcus aureus-virus interaction revisited.
BACKGROUND: Nasal carriage of Staphylococcus aureus is common among health care workers, but outbreaks caused by such carriers are relatively uncommon. We previously reported outbreaks of S. aureus skin infections that affected newborn infants and were attributed to an S. aureus nasal carrier who had had an associated upper respiratory tract infection (UR) during the outbreak period. OBJECTIVE: To investigate the contribution of a nasal methicillin-resistant S. aureus (MRSA) carrier (physician 4) who contracted a URI to an outbreak of MRSA infections that involved 8 of 43 patients in a surgical intensive care unit during a 3-week period. DESIGN: An epidemiologic study of an outbreak of MRSA infections and a quantitative investigation of airborne dispersal of S. aureus associated with an experimentally induced rhinoviral infection. SETTING: A university hospital. PARTICIPANTS: 43 patients in a surgical intensive care unit and 1 physician. MEASUREMENTS: Molecular typing was done, and risk factors for MRSA colonization were analyzed. Agar settle plates and volumeric air cultures were used to evaluate the airborne dispersal of S. aureus by physician 4 before and after a rhinoviral infection and with or without a surgical mask. RESULTS: A search for nasal carriers of MRSA identified a single physician (physician 4); molecular typing showed that the MRSA strain from physician 4 and those from the patients were identical. Multivariate logistic regression analysis identified exposure to physician 4 and duration of ventilation as independent risk factors for colonization with MRSA (P < or = 0.008). Air cultures showed that physician 4 dispersed little S. aureus in the absence of a URI. After experimental induction of a rhinovirus URI, physician 4's airborne dispersal of S. aureus without a surgical mask increased 40- fold; dispersal was significantly reduced when physician 4 wore a mask (P < or = 0.015). CONCLUSIONS: Physician 4 became a "cloud adult," analogous to the "cloud babies" described by Eichenwald and coworkers who shed S. aureus into the air in association with viral URIs. Airborne dispersal of S. aureus in association with a URI may be an important mechanism of transmission of S. aureus.
Adult↗
Hematopoietic defects in mice lacking the sialomucin CD34.
Although the pluripotent hematopoietic stem cell can only be definitively identified by its ability to reconstitute the various mature blood lineages, a diversity of cell surface antigens have also been specifically recognized on this subset of hematopoietic progenitors. One such stem cell-associated antigen is the sialomucin CD34, a highly O-glycosylated cell surface glycoprotein that has also been shown to be expressed on all vascular endothelial cells throughout murine embryogenesis as well as in the adult. The functional significance of CD34 expression on hematopoietic progenitor cells and developing blood vessels is unknown. To analyze the involvement of CD34 in hematopoiesis, we have produced both embryonic stem (ES) cells and mice that are null for the expression of this mucin. Analysis of yolk saclike hematopoietic development in embryoid bodies derived from CD34-null ES cells showed a significant delay in both erythroid and myeloid differentiation that could be reversed by transfection of the mutant ES cells with CD34 constructs expressing either a complete or truncated cytoplasmic domain. Measurements of colony-forming activity of hematopoietic progenitor cells derived from yolk sacs or fetal livers isolated from CD34-null embryos also showed a decreased number of these precursor cells. In spite of these diminished embryonic hematopoietic progenitor numbers, the CD34-null mice developed normally, and the hematopoietic profile of adult blood appeared typical. However, the colony-forming activity of hematopoietic progenitors derived from both bone marrow and spleen is significantly reduced in adult CD34-deficient animals, and these CD34-deficient progenitors also appear to be unable to expand in liquid cultures in response to hematopoietic growth factors. Even with these apparent progenitor cell deficiencies, CD34-null animals showed kinetics of erythroid, myeloid, and platelet recovery after sublethal irradiation that are indistinguishable from wild-type mice. These data strongly suggest that CD34 plays an important role in the formation of progenitor cells during both embryonic and adult hematopoiesis. However, the hematopoietic sites of adult CD34-deficient mice may still have a significant reservoir of progenitor cells that allows for normal recovery after nonmyeloablative peripheral cell depletion.
Animals↗
Presentation of self peptides by dendritic cells: possible implications for the pathogenesis of rheumatoid arthritis.
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Antigen-Presenting Cells↗
Dendritic cells: origin and differentiation.
Dendritic cells (DC) are bone marrow-derived cells that are specialized to take up, process and present antigen, and have the capacity to stimulate resting T cells in the primary immune response. DC are a unique population that is likely to derive from a myeloid precursor cell. DC differentiation from bone marrow precursors in enhanced by the cytokines GM-CSF and tumor necrosis factor-alpha. In contrast, it has been proposed that thymic DC and T cells arise from a common stem cell, and that these DC play a specific role in the negative selection of thymic T cells. A number of post-bone marrow differentiation stages can be defined phenotypically and functionally. Undifferentiated DC have very active endocytic pathways, including receptor-mediated endocytosis involving a mannose/beta glucan receptor, and macropinocytosis of soluble antigen. In contrast, later stages of maturation are associated with a decreased ability to take up and process antigen, and increasing expression of major histocompatibility complex, adhesion and costimulatory molecules. Finally, activation of DC for full antigen-presenting cell function can be identified by the expression of CD28 ligands. The inflammatory site in rheumatoid arthritis is a human model of DC differentiation in response to a chronic antigenic stimulus. The features of this DC model are discussed.
Animals↗
Lymphoproliferative disorder involving the cervix in a patient being treated with FK-506.
FK-506 is an immunosuppressive agent used mainly to prevent allograft rejection in organ transplant patients. Recently, it has been applied as a treatment for patients with autoimmune disorders. An entity called posttransplant lymphoproliferative disorder (PTLD) is a well-recognized result of immunosuppression in transplant patients receiving long-term immunosuppression. This disorder is a complication of treatment with FK-506 in 0.7 to 1.6% of transplant patients and is usually of B-cell origin. A majority of patients have serologic evidence of EBV infection. We report a case of a patient receiving long-term FK-506 therapy for multiple sclerosis who developed lymphoproliferative disorder involving the cervix. We will discuss the possible role of FK-506 initiation of this tumor.
Adult↗