Showing papers by "Sunnybrook Health Sciences Centre published in 2001"

Clinical Utility of an Instrument Assessing Migraine Disability: The Migraine Disability Assessment (MIDAS) Questionnaire

Abstract: Objective.—We evaluated the agreement between Migraine Disability Assessment (MIDAS) scores and independent physician judgments about pain, disability, and treatment needs based on patient medical histories. Background.—The MIDAS questionnaire measures headache-related disability as lost time due to headache from paid work or school, household work, and nonwork activities. Methods.—Twelve histories from patients with migraine were presented to 49 primary and specialty care physicians unaware of the MIDAS scores. Physicians graded each patient for pain level (mild, moderate, or severe), level of disability (none, mild, moderate, or severe), and need for medical care (from 0 [lowest] to 100 [highest]). Physicians also identified MIDAS scores they associated with different degrees of disability and with the urgency to prescribe an effective treatment during the first consultation. Results.—The physicians' perceptions of the need for medical care based on medical histories correlated with the MIDAS score (r = .69). Estimates of pain and disability by physicians were directly correlated with increasing MIDAS scores. Using the physicians' clinical judgments, the overall MIDAS score was categorized into four grades of increasing severity. Conclusions.—Scores on the MIDAS are highly correlated with physician judgments regarding patients' pain, disability, and need for medical care. These findings support the potential utility of the MIDAS questionnaire in clinical practice.

Exercise for osteoarthritis of the hip or knee.

Abstract: Background Biomechanical factors, such as reduced muscle strength and joint mal-alignment, have an important role in the initiation and progression of osteoarthritis (OA) of the hip or knee. Currently, there is no known cure for OA, however, disease-related factors, such as impaired muscle function and reduced fitness, are potentially amenable to therapeutic exercise. Objectives To determine whether land-based therapeutic exercise is beneficial for people with OA of the hip or knee in terms of reduced joint pain, improved physical function and/or the patient's global assessment of therapeutic effectiveness. Search strategy Five databases (the Cochrane Controlled Trials Register, the Cochrane Musculoskeletal Group Trials Register, MEDLINE, CINAHL, PEDro) were searched up until November 2002. Selection criteria All randomized controlled trials comparing some form of land-based therapeutic exercise (as opposed to exercises conducted in the water) with a non-exercise group. Data collection and analysis Two reviewers independently extracted data and assessed methodological quality. All analyses were conducted on continuous outcomes. Main results Only 2 studies totaling about 100 participants, could potentially provide data on people with OA of the hip. However, for OA of the knee, 17 included studies provided data on 2562 participants. For pain, combining the results revealed a beneficial treatment effect (standardised mean difference) of .39 (95% confidence interval (CI) .30 - .47) while for self-reported physical function a beneficial treatment effect of .31 (95% CI .23 - .39). Group format programs appeared to be as effective as treatments provided on a one-to-one basis. The results were sensitive to various aspects of study design methodology. Authors' conclusions Land-based therapeutic exercise was shown to reduce pain and improve physical function for people with OA of the knee. There were insufficient data to provide useful guidelines on optimal exercise type or dosage. Supervised exercise classes appeared to be as beneficial as treatments provided on a one-to-one basis.

Hospitalization for ambulatory care-sensitive conditions: a method for comparative access and quality studies using routinely collected statistics.

Abstract: Access to health care may be defined as the ability to obtain and benefit from care. Universal access to necessary care remains one of the chief goals of the health-care system in Canada. 1 Ambulatory care- sensitive conditions (ACSC) are a new neg- ative indicator of access. The rate of hospi- talization for ACSC is higher in communi- ties with poor access to ambulatory care. This paper describes the development, using consensus panels, of a Canadian set of ACSC and compares them to similar categories of care developed elsewhere. 2-4 ABSTRACT Background: Appropriate and timely provi- sion of ambulatory care is an important factor in maintaining population health and in avoid- ing unnecessary hospital use. This article describes conditions for which hospitalization rates have a strong and inverse relationship to access to high-quality ambulatory care. Methods: Three panels of Canadian physi- cians following different consensus techniques selected conditions for which the relative risk of hospitalization is inversely related to ambu- latory care access. Principal Findings: All panels identified asth- ma, angina pectoris, congestive heart failure, otitis media, gastric ulcer, pelvic inflammatory disease, malignant hypertension, and immunization- preventable infections as ambulatory care- sensitive admissions. These conditions strongly overlap with lists developed for similar purpos- es in the U.S. and England. Interpretation: Ambulatory care-sensitive conditions represent an intermediate health outcome. They are distinct from inappropriate hospitalizations. They may be useful for mea- suring the impact of health care policy, and for performance measurement or audit.

Efficacy and safety of desensitization to allopurinol following cutaneous reactions

Abstract: Objective. To evaluate the long-term efficacy and safety of slow oral desensitization in the management of patients with hyperuricemia and allopurinol-induced maculopapular eruptions. Methods. A retrospective evaluation of an oral desensitization regimen using gradual dosage-escalation of allopurinol in 32 patients (30 with gout and 2 with chronic lymphocytic leukemia) whose therapy was interrupted because of a pruritic cutaneous reaction to the drug. Results. Twenty-one men and 11 women with a mean age of 63 years (range 17-83 years), a mean serum urate level of 618 μmoles/liter (range 495-750) (or, mean 10.4 mg/dl [range 8.3-12.6]), and a mean serum creatinine level of 249 μmoles/liter (range 75-753) (or, mean 2.8 mg/dl [range 0.8-8.5]) were studied. Desensitization failed in 4 patients because of unmanageable recurrent rash. Twenty-eight patients completed the desensitization procedure to a target allopurinol dosage of 50-100 mg/day, 21 without deviation from the protocol for a mean of 30.5 days (range 21-56 days) and 7 requiring dosage adjustments because of a recurrent rash over 53.8 days (range 40-189 days). Seven of these 28 patients developed late cutaneous reactions 1-20 months postdesensitization, 4 responding to dosage modification and 3 discontinuing the drug. Twenty-five of the 32 patients (78%) continued to take allopurinol; their mean duration of followup was 32.6 months (range 3-92 months) and the mean postdesensitization serum urate level was 318 μmoles/liter (range 187-452) (or, mean 5.3 mg/dl [range 3.0-7.5]). Conclusion. The study confirms the long-term efficacy and safety of slow oral desensitization to allopurinol in patients with maculopapular eruptions, particularly in those with gout, who cannot be treated with uricosurics or other urate-lowering drugs. Although pruritic skin eruptions may recur both during and after desensitization, most of these cutaneous reactions can be managed by temporary withdrawal of allopurinol and dosage adjustment.

Problems for clinical judgement: introducing cognitive psychology as one more basic science

Abstract: Medical practice is not easy because of its inherent widespread uncertainty. Some questions are settled eventually through clinical trials, whereas others are impossible to resolve. Between these 2 extremes rests a large grey area where physicians must exercise their judgement. Good clinical

Effects of characteristic x rays on the noise power spectra and detective quantum efficiency of photoconductive x-ray detectors.

Abstract: The effects of K fluorescence on the imaging performance of photoconductor-based x-ray imaging systems are investigated A cascaded linear systems model was developed, where a parallel cascaded process was implemented to take into account the effect of K-fluorescence reabsorption on the modulation transfer function (MTF), noise power spectrum (NPS), and the spatial frequency dependent detective quantum efficiency [DQE(f)] of an imaging system The investigation was focused on amorphous selenium (a-Se), which is the most highly developed photoconductor material for x-ray imaging The results were compared to those obtained with Monte Carlo simulation using the same imaging condition and detector parameters, so that the validity of the cascaded linear system model could be confirmed Our results revealed that K-fluorescence reabsorption in a-Se is responsible for a 18% drop in NPS at high spatial frequencies with an incident x-ray photon energy of E=20 keV (which is just above the K edge of 125 keV) When E increases to 60 keV, the effects of K-fluorescence reabsorption on NPS decrease to approximately 12% at high spatial frequencies Because the high frequency drop is present in both MTF and NPS, the effect of K fluorescence on DQE(f) is minimal, especially for E that is much higher than the K edge We also applied the cascaded linear system model to a newly developed compound photoconductor, lead iodide (PbI2), and found that at 60 keV there is a high frequency drop in NPS of 19% The calculated NPS were compared to previously published measurements of PbI2 detectors

Ras regulation of vascular endothelial growth factor and angiogenesis.

Abstract: Given the multifaceted role of Ras in tumor angiogenesis, pharmacologic targeting of such proteins may bring about at least three important consequences: (1) partial obliteration of the angiogenic competence of tumor cells, (2) an increase in vascular dependence and sensitization to apoptosis, and (3) a direct inhibition of endothelial cell responses to proangiogenic stimuli. Exploration of some of these possibilities, using various pharmacological compounds and antibodies, has already begun. An intriguing possibility is that Ras antagonists and signal transduction inhibitors may synergize with a number of other antiangiogenic modalities such as direct acting antiangiogenic agents (e.g., endostatin) or antivascular regimens involving low-dose continuous chemotherapy as a vasculature-targeting strategy.

Targeted Disruption of the Ceacam1(MHVR) Gene Leads to Reduced Susceptibility of Mice to Mouse Hepatitis Virus Infection

Abstract: The CEACAM1 glycoproteins, formerly called biliary glycoproteins (BGP, Bgp, mmCGM1, C-CAM, CD66a, or MHVR), are members of the carcinoembryonic antigen (CEA) family in the immunoglobulin (Ig) superfamily (4, 22, 44, 51, 70). The nomenclature for the CEA gene family has recently been unified (9), and seven genes are now referred to as the CEACAM genes. CEACAM1, the most conserved gene of the CEA gene family, is found as a single copy on human chromosome 19q13.2 (30) and in the rat genome (24). However, mouse chromosome 7, in the 7A2-A3 region near the centromere, a region syntenic to the region encoding CEACAM1 on human chromosome 19q, contains two highly related Ceacam genes, called Ceacam1 and Ceacam2 (formerly called Bgp1 and Bgp2, respectively) (48, 49, 58). The human, rat, and mouse CEACAM1 genes have highly conserved structures (4, 24, 49), 66% identity between their respective promoters, similar but not identical patterns of mRNA splicing, and similar patterns of expression in different tissues (27, 32, 44, 49, 52, 53). Mouse CEACAM1 isoforms are transmembrane glycoproteins that have either two or four Ig domains produced by alternative splicing of the primary transcript (Fig. ​(Fig.1A1A and B) (43, 44). CEACAM1 isoforms with four Ig domains, denoted CEACAM1/D1-4, include the N domain (D1) attached to three constant Ig domains (D2, D3, and D4). Splice isoforms with two Ig domains (CEACAM1/D1,4) link D1 to D4. The exodomains are linked via a transmembrane domain to either of two cytoplasmic tails. The short cytoplasmic tail (CEACAM1-S) contains 10 amino acids (aa) rich in Ser and Gly residues. The long cytoplasmic tail (CEACAM1-L) results from inclusion of 53-bp Ceacam1 exon 7, which shifts the open reading frame (ORF) for the tail at aa 453 to yield a 73-aa tail (Fig. ​(Fig.1A)1A) (43, 49). FIG. 1 Targeting of the Ceacam1 gene. (A) The mouse Ceacam1 gene encodes nine exons. The ATG initiation codon is located in the first exon, whereas two stop codons can be alternatively used, one in exon 8 [TGA(S), used in the translation of isoforms ... The CEACAM1 glycoproteins are abundantly expressed on apical membranes of epithelial cells in the gastrointestinal and respiratory tracts, in bile canaliculi, and on the proximal tubules of the kidneys (44, 50, 71). They are also found on small vascular endothelial cells, in hemopoietic cells (B cells, neutrophils, macrophages, monocytes, platelets, and activated T cells), and in thymic stromal cells (17, 27, 46, 47). CEACAM1 isoforms are also expressed at the apical surfaces of epithelial cells in the reproductive tissues (uterus, ovary, breast, and prostate) (34, 68, 71) and at low levels on glial cells in the nervous system (27, 62). CEACAM1 is abundantly expressed in endodermal and mesenchymal derivatives during early mouse embryonic development (19). CEACAM1 performs many important cellular functions. It is a cell adhesion molecule (44, 52, 59) and a signaling molecule (10, 31, 51) that regulates the growth of tumor cells (34, 40). Recently, CEACAM1 was shown to be a potent angiogenic factor (25). In addition, CEACAM1 is a receptor for bacterial and viral pathogens. The opa surface proteins of pathogenic strains of Neisseria gonorrhoeae and Neisseria meningitidis and membrane proteins of Haemophilus influenzae bind specifically to the human CEACAM1 protein and several other human CEA-related glycoproteins (29, 72–74). In this study, we explored the role in viral pathogenesis of murine CEACAM1a, a receptor for mouse hepatitis virus (MHV). MHV strains are murine coronaviruses that cause respiratory and enteric infections, hepatitis, splenolysis, immune dysfunction, acute encephalitis, and chronic demyelinating disease of the brain and spinal cord (5, 16). MHV infection of mice varies from inapparent and self-limited infection to severe disease and death, depending on the age, immune status, strain, and route of inoculation of the mouse and on the dose and strain of the virus. In some mouse strains, inapparent MHV infection disrupts normal patterns of cytokine expression for 5 months after infection (18). Many, but not all, of the murine tissues that express CEACAM1 are natural targets for MHV infection. Williams (76), Williams et al. (77), and Dveksler et al. (22) identified and cloned the cDNA encoding the CEACAM1/D1-4 MHV receptor. When this murine Ceacam1a cDNA was transfected into hamster cell lines, which are not susceptible to MHV, expression of the mouse CEACAM1a glycoprotein rendered the hamster cells susceptible to MHV (22). The sequence of the virus receptor was found to be identical to that of the biliary glycoprotein identified as a CEA-related cell adhesion glycoprotein (44). Adult SJL mice, which are highly resistant to MHV infection (7, 39, 67), are homozygous for CEACAM1b, an allele of CEACAM1a that differs by 27 of 108 aa in the N domain (D1) (21, 78). The spike (S) glycoprotein of MHV attaches to the N domain (D1) of CEACAM1a (23). Most inbred strains of mice (BALB/c, C57BL/6, C3H, 129Sv, and so forth) are susceptible to MHV infection and are homozygous for the CEACAM1a allele, whereas outbred CD1 mice express both CEACAM1a and CEACAM1b and are susceptible to infection. All MHV strains tested to date utilize the murine CEACAM1a proteins as receptors (15, 21). Mutational analyses showed that the virus binds to the B-C-C′ region of domain 1 of the CEACAM1a protein (57, 75). A monoclonal antibody (CC1) directed against D1 of CEACAM1a blocks virus attachment and prevents infection in vitro and in vivo (23, 65). All four isoforms of murine CEACAM1a serve as receptors for MHV A59 when expressed at high levels in hamster cells (21). Interestingly, the expression of high levels of murine CEACAM1b in hamster cells also makes the cells susceptible to MHV-A59 infection (21). When expressed at high levels in BHK cells, murine CEACAM2 also serves as an MHV receptor, although it is a markedly less efficient MHV A59 receptor than CEACAM1a (48). Soluble CEACAM2 also has much less virus neutralization activity than soluble CEACAM1a (80). The surface density of CEACAM1a/D1,4 with the short cytoplasmic tail affects the susceptibility of cells to infection with the MHV JHM strain. HeLa cells that expressed low levels of recombinant murine CEACAM1a/D1,4 were susceptible to infection with MHV JHM but did not exhibit cytopathic effects, such as cell fusion and death (55). In contrast, HeLa cells that expressed high levels of murine CEACAM1a/D1,4 with the short tail on the cell surface were killed within 14 h of infection with MHV JHM. Complexes formed between the CEACAM1a receptor protein and the viral S glycoprotein in the endoplasmic reticulum and Golgi apparatus (56). MHV infection or expression of the viral S glycoprotein on murine cells rapidly led to the selection of cells that expressed reduced levels of CEACAM1a (14, 55, 63). Persistent infection of murine cells in vitro with MHV A59 leads to the selection of cells resistant to wild-type virus and to the selection of small-plaque viral mutants that have mutations in the receptor-binding N-terminal domain of the viral S glycoprotein, and some of these small-plaque mutants have an extended host range (2, 3, 28, 63, 64). The goal of this research was to derive Ceacam1 knockout mice for the study of CEACAM1 functions in normal and infected animals. We therefore disrupted the mouse Ceacam1a gene in 129Sv mouse embryonic stem (ES) cells in order to generate knockout animals and examined the genotypes and phenotypes of the resulting heterozygous and homozygous mice. Normally this technique completely abrogates or knocks out the expression of the targeted gene in homozygous mice. The only line of mice that resulted from this knockout strategy showed only partial, incomplete reduction in CEACAM1a expression; expressed markedly altered ratios of CEACAM1a isoforms in different murine tissues; but had normal phenotype, fertility, and life span. Expression of the CEACAM1a/D1-4 isoforms was reduced by 90 to 95% in these mice, whereas the CEACAM1a/D1,4 isoforms were expressed at levels higher than normal. Following intranasal inoculation with MHV A59, homozygous (p/p) Ceacam1a-targeted mice failed to develop clinical signs of viral infection, developed fewer and smaller lesions in the liver, and produced less virus in the liver than wild-type (+/+) mice. Thus, reducing the level of expression of CEACAM1a/D1-4 proteins and altering the ratios of two- and four-domain CEACAM1a isoforms in vivo resulted in mice with significantly decreased susceptibility to MHV infection. These results also suggest that the four-domain CEACAM1a isoforms are the principal MHV receptors in vivo.

Late renal transplant failure: an adverse prognostic factor at initiation of peritoneal dialysis.

Abstract: BackgroundEarly renal transplant failure necessitating a return to dialysis has been shown to be a poor prognostic factor for survival. Little is known about the outcome of patients with late trans...

T cells of multiple sclerosis patients target a common environmental peptide that causes encephalitis in mice.

Abstract: Multiple sclerosis (MS) is a chronic autoimmune disease triggered by unknown environmental factors in genetically susceptible hosts. MS risk was linked to high rates of cow milk protein (CMP) consumption, reminiscent of a similar association in autoimmune diabetes. A recent rodent study showed that immune responses to the CMP, butyrophilin, can lead to encephalitis through antigenic mimicry with myelin oligodendrocyte glycoprotein. In this study, we show abnormal T cell immunity to several other CMPs in MS patients comparable to that in diabetics. Limited epitope mapping with the milk protein BSA identified one specific epitope, BSA(193), which was targeted by most MS but not diabetes patients. BSA(193) was encephalitogenic in SJL/J mice subjected to a standard protocol for the induction of experimental autoimmune encephalitis. These data extend the possible, immunological basis for the association of MS risk, CMP, and CNS autoimmunity. To pinpoint the same peptide, BSA(193), in encephalitis-prone humans and rodents may imply a common endogenous ligand, targeted through antigenic mimicry.

Comparison of Salmeterol/Fluticasone Propionate Combination with Budesonide in Patients with Mild-to-Moderate Asthma

Abstract: To compare the efficacy and tolerability of a salmeterol/fluticasone propionate (FP) combination product (50/100μg twice daily) with budesonide (BUD) at a four-fold higher microgram dose (400μg twice daily) in patients with mild-to-moderate asthma uncontrolled on existing therapy. This was a multicentre, randomised, double-blind, double-dummy, parallel-group study consisting of a 2-week run-in and a 12-week treatment period. Symptomatic patients (n = 349) received either the salmeterol/FPcombination (50/100μg twice daily; Diskus™) or BUD (400μg twice daily; Turbuhaler™). The salmeterol/FP combination group showed a significantly greater increase in mean morning (p = 0.022) and evening (p = 0.008) peak expiratory flow (PEF) compared with the BUD group. After 12 weeks of treatment, patients in the combination group had a mean PEF of 426 L/min (am) and 435 L/min (pm) compared with 415 L/min (am) and 424 L/min (pm) in the BUD group. The significant benefit of the combination product was evident from day one for both morning (p < 0.001) and evening (p = 0.002) PEF. Both treatments were well tolerated, and no difference was observed between the groups in improved symptom scores, use of rescue medication, clinic spirometry and exacerbations. This study showed that the salmeterol/FP combination product was at least as effective as a four-fold higher microgram dose of BUD, with greater, and more rapid, improvement in morning and evening PEF. Therefore, in patients with mild-to-moderate asthma, symptomatic on existing therapy, the salmeterol/FP combination is an effective alternative to increasing the dose of inhaled corticosteroids, without the need for an additional inhaler.

Exposure of human oocytes to endometrioma fluid does not alter fertilization or early embryo development.

Abstract: Background: Extensive endometriosis causes a mechanical disturbance in the pelvis leading to obstructive-type infertility However, minimal or mild endometriosis is suspected to cause infertility, possibly through a humoral agent Previous studies reported the presence of a factor in the serum of patients with endometriosis which reduced fertilization and early embryo formation in a rat IVF model

Role of Th2 cytokines, RANTES and eotaxin in AIDS-associated eosinophilic folliculitis.

Abstract: The pathogenesis of AIDS-associated eosinophilic folliculitis is still unknown. The expression of chemokines and Th2-type cytokines is increased in other conditions associated with tissue eosinophilia and in allergic reactions. We evaluated the mRNA expression by reverse transcriptase polymerase chain reaction of two Th2 cytokines (interleukin-4 and interleukin-5) and of two chemokines (RANTES and eotaxin) in the skin of 6 patients with AIDS-associated eosinophilic folliculitis; the tissue localization of eotaxin was shown by immunohistochemistry. We demonstrated the increased expression of interleukin-4, interleukin-5, RANTES and eotaxin in lesional skin of the patients compared to normal skin of HIV+ individuals. We concluded that a Th2 pattern is present in AIDS-associated eosinophilic folliculitis. The cytokine milieu in this disease may favour a Th2 immune response to an unknown antigen, whereby RANTES and eotaxin act in synergy with interleukin-4 and interleukin-5 to mediate tissue inflammation.

Investigation of imaging performance of amorphous selenium flat-panel detectors for digital mammography

Abstract: Our work is to investigate and understand the factors affecting the imaging performance of amorphous selenium (a-Se) flat-panel detectors for digital mammography. Both theoretical and experimental methods were developed to investigate the spatial frequency dependent detective quantum efficiency [DQE(f)] of a-Se flat-panel detectors for digital mammography. Since the k-edge of a-Se is 12.66 keV and within the energy range of a mammographic spectrum, a cascaded linear system model was developed which takes into account the effect of k-fluorescence on the modulation transfer function (MTF), noise power spectrum (NPS) and DQE(f) of the detector. This model was used to understand the performance of a prototype detector with 85 mm pixel size. The presampling MTF, NPS and DQE(f) of the prototype were measured, and compared to the theoretical calculation by the model. The calculation showed that k-fluorescence reduces the MTF by 15% at the Nyquist frequency (fNY) of the prototype detector, and the NPS at fNY was reduced to 82% of that at zero spatial frequency. Because of the decrease in both MTF and NPS at high spatial frequencies, k-fluorescence only has a small degradation effect on DQE(f) for mammography. The measurement of presampling MTF of the prototype detector revealed an additional source of blurring, which was attributed to the blocking layer at the interface between a-Se and the active matrix. This introduced high frequency drop in both presampling MTF and NPS, and reduced aliasing in the NPS. As a result, the DQE(f) of the prototype detector at fNY approaches 50% of that at zero spatial frequency.

Establishment of a cytokine-producing anaplastic large-cell lymphoma cell line containing the t(2;5) translocation: potential role of cytokines in clinical manifestations.

Abstract: A permanent cell line, HSC-M1, was established from a child with advanced CD30 (Ki-1)+ anaplastic large-cell lymphoma (ALCL). Clinical features included irritability, fever, weight loss, tender lymphadenopathy, pneumonitis, neutrophilia, and bone marrow erythrophagocytosis. While HSC-M1 cells exhibited an immunophenotype characteristic of ALCL of T-cell lineage, the cell line also demonstrated features of monocyte-macrophage lineage. Cytogenetic and polymerase chain reaction (PCR) analysis of the HSC-M1 cell line and involved bone marrow demonstrated the characteristic non-random chromosomal translocation t(2;5)(p23;q35). Reverse transcriptase PCR for mRNA expression of cytokines and cytokine receptors showed that HSC-M1 cells expressed the message for multiple cytokines and their receptors. Measurement of cytokine levels in serum samples using enzyme-linked immunosorbent assays showed increased concentrations of several cytokines. The increased levels of some cytokines correlated with disease activity an...

Combination immunotherapy of cancer

Abstract: The interaction of cancer with the immune system has long been established. Modernapproaches to cancer immunotherapy concentrate on boosting host resistance by vaccines, killer cells or cytokines, such as interleukin-2 or interferons. Little attention has been paid to the possibility of sensitizing tumor cells to immune mediated attack. The non-steroidal antiestrogenic agents, tamoxifen (TX) and toremifene (TO) are widely used for the treatment of estrogen receptor positive mammary carcinomas and other sex hormone dependent tumors. We discovered that TX and TO sensitize tumor cells for killing by natural killer (NK), lymphokine activated killer (LAK) and cytotoxic T lymphocytes (CTL). We also demonstrated that TX and TO potentiated the immunotherapy of lethal cancer in syngeneic murine tumor-host system. DBA/2 and C3H mice were injected with lethal doses of tumor cells subcutaneously. Combination therapy with NK, LAK or CTL effector cells and antiestrogens could cure lethal cancer in up to 75% of mice. Lymphocytes freshly isolated from the ascites of patients with ovarian cancer had no lytic effect on autologous tumor cells. Activation of tumor associated lymphocytes (TAL) or tumor infiltrating lymphocytes (TIL) with hrIL-2 in the presence of autologous tumor cells induced detectable cytotoxicity in most of the cell cultures. A highly significant increase of tumor cell lysis was found when both target and effector cells were treated with antiestrogens. Additional treatment with interferon-alpha resulted in the further enhancement of cytotoxicity in a significant number of cases. It is clear from our results that TX and TO are capable of increasing the susceptibility ofhuman ovarian and lung cancer cells to autologous killer cells in about 60% of the cases so examined. Sensitization requires the active metabolic participation of the target cells suggesting the amplification of programmed cell death as the underlying mechanism. Both the Fas/Fas-L and perforin/granzyme pathways, which can trigger apoptosis, are affected by antiestrogens. This was further supported by the observations that Fas receptor expression on ovarian carcinoma cells and the Fas-antibody mediated killing of ovarian carcinomas were upregulated by antiestrogen treatment. In contrast, TX and TO did not stimulate the Fas-L expression on killer cells. The lack of correlation between Fas receptor expresion and drug induced increase of kille cell mediated cytolysis suggest the participation of the perforin/granzyme pathway. K562 cells are Fas negative and are not susceptible to anti-Fas mediated cytolysis. However, antiestrogen treatment significantly inceased the NK cell mediated cytotoxicity of K562 cells. The total abrogation of cell death by chelation of extracellular Ca++ indicates that NK cell mediated cytolysis of K562 cells was dependent on perforin/grenzyme pathway. Similar results were obtained with the Fas receptor positive ovarian carcinomas. It is clear from our results that antiestrogens reder the cancer cells more susceptible forkiller cell mediated destruction, and thereby potentiate immune defence against cancer. On the basis of our combination immunotherapy experiments in tumor bearing mice we now conduct feasibility trials for the development of treatment protocols for the combination immunotherapy of cancer in man.

Novel demonstration of a physiologic/pharmacologic role of insulin-like growth factor-1 in ovulation in rats and action on cumulus oophorus.

Abstract: Gonadotropins are well known to be the most important stimulus for ovarian follicular development. More recently, there is indirect evidence that insulin-like growth factor-1 (IGF-1) is also a very important autocrine/paracrine factor in folliculogenesis. We had access to an analog of IGF-1, LR3IGF-1, which binds very poorly to IGF-1 binding proteins and therefore was shown by previous investigators to have biologic effects. We studied rats that were superovulated with the use of gonadotropins. We showed that the addition of LR3IGF-1 by infusion further increased the ovulation rate (statistically significant) and increased the ovarian weight in two of three strains of rats. We demonstrated that infusion of LR3IGF-1 or injection of equine chorionic gonadotropin or a combination of these two were associated with oocytes with reduced number of cumulus cells (statistically significant). We conducted an experiment to determine whether in vitro culturing with varying dosage of IGF-1 may stimulate cumulus cell replication to improve the quality of oocyte cumulus complex. IGF-1 did not show any change in this respect. Through these physiologic (pharmacologic) studies, we have shown that IGF-1 (analog) can further increase the ovulation rate induced by gonadotropins.

Estimation of relaxation time distributions in magnetic resonance imaging

Abstract: Magnetic resonance imaging techniques can be used to measure some biophysical properties of tissue. In this context, the T2 relaxation time is an important parameter for soft-tissue contrast. The authors develop a new technique to estimate the integral of the distribution of T2 relaxation time without imposing any constraint other than the monotonicity of the underlying cumulative relaxation time distribution. They explore the properties of the estimation and its applications for the analysis of breast tissue data. As they show, an extension of linear discriminant analysis is found to distinguish well between two classes of breast tissue. Estimation de la loi du temps de decontraction en imagerie par resonance magnetique Les techniques d'imagerie par resonance magnetique permettent de mesurer certaines proprietes biophysiques des tissus. Dans ce contexte, le temps de decontraction T2 est un parametre important pour l'identification des tissus mous. Les auteurs proposent une nouvelle technique d'estimation de l'integrate de la loi du temps de decontraction T2 sans imposer d'autres contraintes que la monotonicite de la fonction de repartition de la variable sous-jacente. Ils explorent les proprietes de l'estimateur et montrent son utilite dans l'analyse de tissus mammaires. Comme ils le font valoir, une generalisation de l'analyse discriminante lineaire permet de distinguer nettement entre deux types de tissus mammaires.

Globalization and Health

Abstract: There are no precedents to follow to direct the increasing globalization of health as we enter the twenty-first century. As the global village expands we need to develop new blueprints for understanding, managing, and strengthening health care. Principles of multicultural, multidisciplinary, holistic, and family-centered care are required to supplement evidence-based use of appropriate technology in health care. Demedicalizing health care is a priority based not only on economic considerations but also, more importantly, on the effective and appropriate use of medical science.