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1.
Eur Rev Med Pharmacol Sci ; 27(22): 11143-11155, 2023 Nov.
Article in English | MEDLINE | ID: mdl-38039046

ABSTRACT

OBJECTIVE: This retrospective study employed a competing-risks analysis utilizing the Surveillance, Epidemiology, and End Results (SEER) database to identify precise prognostic factors associated with ovarian serous cystadenocarcinoma (OSCC) in patients. PATIENTS AND METHODS: Patients with OSCC during 2004-2015 were identified in the SEER database, and their clinicopathological, demographic, and survival data were examined. Univariate analysis using Gray's test and the cumulative incidence function was used to evaluate the prognoses of events of interest. The multivariate analysis involved several models, including the Cox proportional hazards, Fine-Gray, and cause-specific (CS) hazard function models, to estimate the hazard functions of competing risks. Hazard ratios were analyzed to identify the reliability of the prognostic factors. RESULTS: Among the 10,400 individuals diagnosed with OSCC, 5,713 died from the illness, and 1,125 died from other causes. The cumulative incidence rate of events of interest was found to be significant for ethnicity, age at diagnosis, histological grade, American Joint Committee on Cancer (AJCC) stage, chemotherapy and surgery status, tumor size, marital status, and local lymph node metastases (p<0.05). The multivariate analysis revealed that ethnicity, histological grade, surgery and chemotherapy status, age at diagnosis, AJCC stage, marital status, and distant metastases were independent prognostic factors in the Cox model (p<0.05). Finally, the Fine-Gray and CS models demonstrated that ethnicity, histological grade, surgery and chemotherapy status, age at diagnosis, AJCC stage, tumor size, marital status, and combination summary stage were all identified as independent prognostic factors (p<0.05). CONCLUSIONS: This study determined the risk factors for OSCC using a competing risk analysis model established by the SEER database. The findings can help clinicians understand OSCC better and provide more accurate medical support to affected patients.


Subject(s)
Cystadenocarcinoma, Serous , Ovarian Neoplasms , Female , Humans , Prognosis , Cause of Death , Retrospective Studies , Reproducibility of Results , Carcinoma, Ovarian Epithelial , Ovarian Neoplasms/epidemiology , Ovarian Neoplasms/pathology
2.
medRxiv ; 2023 May 10.
Article in English | MEDLINE | ID: mdl-37162985

ABSTRACT

Background: Congenital toxoplasmosis is a treatable, preventable disease, but untreated causes death, prematurity, loss of sight, cognition and motor function, and substantial costs worldwide. Methods/Findings: In our ongoing USA feasibility/efficacy clinical trial, data collated with other ongoing and earlier published results proved high performance of an Immunochromatographic-test(ICT) that enables accurate, rapid diagnosis/treatment, establishing new paradigms for care. Overall results from patient blood and/or serum samples tested with ICT compared with gold-standard-predicate-test results found ICT performance for 4606 sera/1876 blood, 99.3%/97.5% sensitive and 98.9%/99.7% specific. However, in the clinical trial the FDA-cleared-predicate test initially caused practical, costly problems due to false-positive-IgM results. For 58 persons, 3/43 seronegative and 2/15 chronically infected persons had false positive IgM predicate tests. This caused substantial anxiety, concerns, and required costly, delayed confirmation in reference centers. Absence of false positive ICT results contributes to solutions: Lyon and Paris France and USA Reference laboratories frequently receive sera with erroneously positive local laboratory IgM results impeding patient care. Therefore, thirty-two such sera referred to Lyon's Reference laboratory were ICT-tested. We collated these with other earlier/ongoing results: 132 of 137 USA or French persons had false positive local laboratory IgM results identified correctly as negative by ICT. Five false positive ICT results in Tunisia and Marseille, France, emphasize need to confirm positive ICT results with Sabin-Feldman-Dye-test or western blot. Separate studies demonstrated high performance in detecting acute infections, meeting FDA, CLIA, WHO ASSURED, CEMark criteria and patient and physician satisfaction with monthly-gestational-ICT-screening. Conclusions/Significance: This novel paradigm using ICT identifies likely false positives or raises suspicion that a result is truly positive, rapidly needing prompt follow up and treatment. Thus, ICT enables well-accepted gestational screening programs that facilitate rapid treatment saving lives, sight, cognition and motor function. This reduces anxiety, delays, work, and cost at point-of-care and clinical laboratories. Author's Summary: Toxoplasmosis is a major health burden for developed and developing countries, causing damage to eyes and brain, loss of life and substantial societal costs. Prompt diagnosis in gestational screening programs enables treatment, thereby relieving suffering, and leading to > 14-fold cost savings for care. Herein, we demonstrate that using an ICT that meets WHO ASSURED-criteria identifying persons with/without antibody to Toxoplasma gondii in sera and whole blood with high sensitivity and specificity, is feasible to use in USA clinical practice. We find this new approach can help to obviate the problem of detection of false positive anti- T.gondii IgM results for those without IgG antibodies to T.gondii when this occurs in present, standard of care, predicate USA FDA cleared available assays. Thus, this accurate test facilitates gestational screening programs and a global initiative to diagnose and thereby prevent and treat T.gondii infection. This minimizes likelihood of false positives (IgG and/or IgM) while maintaining maximum sensitivity. When isolated IgM antibodies are detected, it is necessary to confirm and when indicated continue follow up testing in ∼2 weeks to establish seroconversion. Presence of a positive ICT makes it likely that IgM is truly positive and a negative ICT makes it likely that IgM will be a false positive without infection. These results create a new, enthusiastically-accepted, precise paradigm for rapid diagnosis and validation of results with a second-line test. This helps eliminate alarm and anxiety about false-positive results, while expediting needed treatment for true positive results and providing back up distinguishing false positive tests.

3.
Haemophilia ; 22(6): e527-e536, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27704689

ABSTRACT

INTRODUCTION: Joint haemorrhage is the principal clinical manifestation of haemophilia frequently leading to advanced arthropathy and arthrofibrosis, resulting in severe disability. The degree and prevalence of arthrofibrosis in hemophilic arthropathy is more severe than in other forms of arthropathy. Expression of connective tissue growth factor (CTGF) has been linked to many fibrotic diseases, but has not been studied in the context of haemophilic arthropathy. AIM: We aim to compare synovial tissues histologically from haemophilia and osteoarthritis patients with advanced arthropathy in order to compare expression of proteins that are possibly aetiologic in the development of arthrofibrosis. METHODS: Human synovial tissues were obtained from 10 haemophilia and 10 osteoarthritis patients undergoing joint surgery and processed for histology and immunohistochemistry. RESULTS: All samples from haemophilia patients had synovitis with hypertrophy and hyperplasia of synovial villi. Histologically, synovial tissues contained hyperplastic villi with increased cellularity and abundant haemosiderin- and ferritin-pigmented macrophage-like cells (HMCs), with a perivascular localization in the sub-surface layer. CTGF staining was observed in the surface layer and sub-surface layer in all haemophilia patients, exclusively co-localizing with HMCs. Quantification showed that the extent of CTGF-positive areas was correlated with the degree of detection of HMCs. CTGF was not observed in any of the samples from osteoarthritis patients. CONCLUSION: Using histological analysis, we showed that CTGF expression is elevated in haemophilia patients with arthrofibrosis and absent in patients with osteoarthritis. Additionally, we found that CTGF is always associated with haemosiderin-pigmented macrophage-like cells, which suggests that CTGF is produced by synovial A cells following the uptake of blood breakdown products.


Subject(s)
Connective Tissue Growth Factor/metabolism , Hemarthrosis/metabolism , Hemophilia A/metabolism , Joint Diseases/metabolism , Adult , Female , Hemarthrosis/complications , Hemophilia A/complications , Humans , Joint Diseases/etiology , Male , Middle Aged , Young Adult
4.
J Periodontal Res ; 46(6): 730-41, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21848615

ABSTRACT

BACKGROUND AND OBJECTIVE: Adaptive properties of the bone-periodontal ligament-tooth complex have been identified by changing the magnitude of functional loads using small-scale animal models, such as rodents. Reported adaptive responses as a result of lower loads due to softer diet include decreased muscle development, change in structure-function relationship of the cranium, narrowed periodontal ligament space, and changes in the mineral level of the cortical bone and alveolar jaw bone and in the glycosaminoglycans of the alveolar bone. However, the adaptive role of the dynamic bone-periodontal ligament-cementum complex to prolonged reduced loads has not been fully explained to date, especially with regard to concurrent adaptations of bone, periodontal ligament and cementum. Therefore, in the present study, using a rat model, the temporal effect of reduced functional loads on physical characteristics, such as morphology and mechanical properties and the mineral profiles of the bone-periodontal ligament-cementum complex was investigated. MATERIAL AND METHODS: Two groups of 6-wk-old male Sprague-Dawley rats were fed nutritionally identical food with a stiffness range of 127-158 N/mm for hard pellet or 0.3-0.5 N/mm for soft powder forms. Spatio-temporal adaptation of the bone-periodontal ligament-cementum complex was identified by mapping changes in the following: (i) periodontal ligament collagen orientation and birefringence using polarized light microscopy, bone and cementum adaptation using histochemistry, and bone and cementum morphology using micro-X-ray computed tomography; (ii) mineral profiles of the periodontal ligament-cementum and periodontal ligament-bone interfaces by X-ray attenuation; and (iii) microhardness of bone and cementum by microindentation of specimens at ages 6, 8, 12 and 15 wk. RESULTS: Reduced functional loads over prolonged time resulted in the following adaptations: (i) altered periodontal ligament orientation and decreased periodontal ligament collagen birefringence, indicating decreased periodontal ligament turnover rate and decreased apical cementum resorption; (ii) a gradual increase in X-ray attenuation, owing to mineral differences, at the periodontal ligament-bone and periodontal ligament-cementum interfaces, without significant differences in the gradients for either group; (iii) significantly (p < 0.05) lower microhardness of alveolar bone (0.93 ± 0.16 GPa) and secondary cementum (0.803 ± 0.13 GPa) compared with the higher load group insert bone = (1.10 ± 0.17 and cementum = 0.940 ± 0.15 GPa, respectively) at 15 wk, indicating a temporal effect of loads on the local mineralization of bone and cementum. CONCLUSION: Based on the results from this study, the effect of reduced functional loads for a prolonged time could differentially affect morphology, mechanical properties and mineral variations of the local load-bearing sites in the bone-periodontal ligament-cementum complex. These observed local changes in turn could help to explain the overall biomechanical function and adaptations of the tooth-bone joint. From a clinical translation perspective, our study provides an insight into modulation of load on the complex for improved tooth function during periodontal disease and/or orthodontic and prosthodontic treatments.


Subject(s)
Adaptation, Physiological , Alveolar Process/physiology , Dental Cementum/physiology , Dental Stress Analysis , Periodontal Ligament/physiology , Alveolar Process/anatomy & histology , Alveolar Process/chemistry , Alveolar Process/diagnostic imaging , Animals , Birefringence , Bone Density , Collagen/ultrastructure , Compressive Strength , Dental Cementum/anatomy & histology , Dental Cementum/chemistry , Dental Cementum/diagnostic imaging , Food , Hardness , Hardness Tests , Male , Periodontal Ligament/anatomy & histology , Periodontal Ligament/chemistry , Periodontal Ligament/diagnostic imaging , Rats , Rats, Sprague-Dawley , Weight-Bearing , X-Ray Microtomography
5.
Osteoarthritis Cartilage ; 16(1): 70-82, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17644010

ABSTRACT

OBJECTIVE: Articular cartilage is separated from subchondral bone by the tidemark and a calcified cartilage zone. Advancement of the calcified region and tidemark duplication are both hallmarks of osteoarthritis (OA). Currently the mechanisms controlling post-natal articular cartilage mineralization are poorly understood. The objective of this study is to test the hypothesis that cellular communication between different cartilage layers regulates articular chondrocyte mineralization. DESIGN: Co-culture models were established to evaluate the interaction of chondrocytes derived from the surface, middle and deep zones of articular cartilage. The cultures were stimulated with triiodothyronine (T3) to promote chondrocyte hypertrophy. The effects of zonal chondrocyte interactions on chondrocyte mineralization were examined over time. RESULTS: Co-culture of deep zone chondrocytes (DZCs) with surface zone chondrocytes (SZCs) suppressed the T3-induced increase in alkaline phosphatase (ALP) activity and related mineralization. Moreover, SZC-DZC co-culture was associated with a significantly higher parathyroid hormone-related peptide (PTHrP) expression when compared to controls. When PTHrP(1-40) was added to the DZC-only culture, it suppressed DZC ALP activity similar to the inhibition observed in co-culture with SZC. In addition, treatment with PTHrP reversed the effect of T3 stimulation on the expression of hypertrophic markers (Indian hedgehog, ALP, matrix metalloproteinases-13, Type X collagen) in the DZC cultures. Moreover, blocking the action of PTHrP significantly increased ALP activity in SZC+DZC co-culture. CONCLUSION: Our findings demonstrate the role of zonal chondrocyte interactions in regulating cell mineralization and provide a plausible mechanism for the post-natal regulation of articular cartilage matrix organization. These findings also have significant implications in understanding the pathology of articular cartilage as well as devising strategies for functional cartilage repair.


Subject(s)
Alkaline Phosphatase/metabolism , Cartilage, Articular/drug effects , Chondrocytes/drug effects , Parathyroid Hormone-Related Protein/pharmacology , Triiodothyronine/pharmacology , Animals , Cartilage, Articular/metabolism , Cattle , Chondrocytes/metabolism , Coculture Techniques , Collagen Type X/metabolism , Hedgehog Proteins/metabolism , Matrix Metalloproteinase 13/metabolism , Parathyroid Hormone-Related Protein/metabolism
6.
Singapore Med J ; 41(3): 111-3, 2000 Mar.
Article in English | MEDLINE | ID: mdl-11063193

ABSTRACT

UNLABELLED: Genital Chlamydia trachomatis infection has long been recognised as the major cause of pelvic disease and subsequently infertility. The diagnosis of this infection has traditionally relied on tissue culture. The availability of DNA amplification methods like ligase chain reaction promises faster and more sensitive results. This study was conducted to evaluate the prevalence of chlamydial infection in a subfertile population subgroup. AIM: A case control longitudinal study of 100 subfertile women in a tertiary teaching hospital were analyzed for the prevalence of genital Chlamydia trachomatis infection using ligase chain reaction test kit. RESULTS: A prevalence rate of 8% was detected, the majority being 25 years old or less (33.3%), p = 0.007. All patients gave no prior history of abnormal PAP smears, hospitalisation for pelvic inflammatory disease or abnormal vaginal discharge at the time of investigation. CONCLUSION: Our infertile group of patients has a relatively high incidence of silent genital Chlamydia trachomatis infection. This being highest in the below 25 years old age group. This finding indicates that screening for chlamydia may be necessary for the subfertile couple presenting to clinic. This is especially so if the patient is of the younger age group.


Subject(s)
Chlamydia Infections/diagnosis , Chlamydia trachomatis/isolation & purification , Genital Diseases, Female/diagnosis , Infertility, Female/complications , Adult , Chlamydia Infections/complications , Female , Genital Diseases, Female/complications , Humans , Ligase Chain Reaction , Pregnancy
7.
Singapore Med J ; 41(1): 29-31, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10783677

ABSTRACT

AIM OF STUDY: The aim was to analyse the pregnancy outcome among girls, aged 17 and below, at KK Hospital. METHODOLOGY: This is a retrospective study. A total of 108 adolescent pregnancies were analysed with regards to pregnancy order, antenatal complications, mode of delivery and pregnancy outcome. RESULTS: The 2 most common antenatal complications were anaemia and preterm labour. The repeat pregnancy rate was 15.7%. Vaginal delivery was achieved in 7.2%; 21.2% of babies born weighed less than 2.5 kg. CONCLUSIONS: Adolescent pregnancies accounted for only a small proportion of all deliveries in our hospital. Late or non-existent antenatal care was a feature in most pregnancies. The incidence of repeat pregnancies reflects the need for a more effective counselling on contraception.


Subject(s)
Pregnancy Outcome , Pregnancy in Adolescence/statistics & numerical data , Adolescent , Birth Weight , Female , Humans , Pregnancy , Pregnancy Complications/epidemiology , Retrospective Studies , Singapore/epidemiology
8.
Ann Acad Med Singap ; 28(2): 260-5, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10497679

ABSTRACT

Embryo cryopreservation is a vital part of any assisted conception programme. We analysed our experience with respect to various clinical factors which may influence success and help modify our own practice. Factors studied were endometrial preparation, number of embryos transferred, woman's age at embryo freezing and endometrial thickness. The 212 cycles analysed represented all our frozen embryo-transfers from 1994 to 1996. Four cycles were excluded because of incomplete data. Statistical analysis was done with Student's t-test, Fisher's exact test and chi-square test for trend. The clinical pregnancy rate rose yearly and it was 12.3% per transfer in 1996. The most important clinical factor appeared to be the type of endometrial preparation. Natural cycles resulted in a pregnancy rate of 17.7%, almost twice hormone-replacement cycles. When transfer was on days 14 to 16 of the natural cycle, the pregnancy rate reached 33%. Other factors that were suggestive of success were younger age at embryo freezing, transferring at least 2 embryos and endometrium thickness > or = 11 mm. The natural cycle gave the best pregnancy rate in our hands and is our method of choice for ovulatory women with normal cycle lengths. For all other women, hormonal preparation is needed but our protocols need refinement. Our initial performance is encouraging and embryo cryopreservation has certainly enhanced our overall success rate.


Subject(s)
Cryopreservation , Embryo, Mammalian , Reproductive Techniques , Adult , Age Factors , Chi-Square Distribution , Embryo Transfer , Endometrium/anatomy & histology , Endometrium/drug effects , Estradiol/analogs & derivatives , Estradiol/therapeutic use , Estrogen Replacement Therapy , Estrogens, Conjugated (USP)/therapeutic use , Female , Humans , Luteal Phase/drug effects , Menstrual Cycle/drug effects , Ovulation , Ovulation Induction , Pregnancy , Progesterone/therapeutic use , Retrospective Studies , Treatment Outcome
9.
Singapore Med J ; 40(12): 752-5, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10709427

ABSTRACT

AIM OF STUDY: The aim of this prospective clinical trial was to determine if intranasal nafarelin acetate (NA) is as effective as leuprolide (LA), our standard GnRHa, in IVF cycles. In addition, we believe that this may be the first report of such a trial in an Asian IVF population. METHOD: Midluteal GnRHa administration (LA = 0.5 mg/d; NA = 800 micrograms/d) was used with a standardised hMG ovarian stimulation protocol for all 88 consecutive cycles, randomised at recruitment. RESULTS: There were no significant differences between LA and NA in terms of the mean duration of agonist to reach pituitary suppression, total hMG dosage, number of embryos produced or frozen and the clinical pregnancy rate (LA = 21.4% and NA = 16.3% per cycle). CONCLUSION: Intranasal nafarelin acetate was as effective as leuprolide acetate in our series of IVF patients of Asian origin, and may be offered as an alternative choice for pituitary suppression.


Subject(s)
Fertilization in Vitro , Hormones/pharmacology , Nafarelin/pharmacology , Pituitary Gland/drug effects , Administration, Intranasal , Adult , Female , Fertility Agents, Female/therapeutic use , Hormones/therapeutic use , Humans , Leuprolide/therapeutic use , Nafarelin/therapeutic use , Ovulation , Pituitary Gland/physiology , Pregnancy , Pregnancy Rate , Prospective Studies , Singapore
10.
Singapore Med J ; 37(1): 66-8, 1996 Feb.
Article in English | MEDLINE | ID: mdl-8783917

ABSTRACT

The next step in the treatment of infertility after ovulation induction is usually in vitro fertilization (IVF) or some other sophisticated and expensive assisted reproductive technique. This study looks at the method of superovulation-intrauterine insemination (SO-IUI) as an alternative before IVF in the treatment of infertility. The first 7 months of this programme were reviewed. There was a clinical pregnancy rate of 20.5% per patient. Ninety-six percent of the pregnancies occurred in the first two cycles. The cycle-cancellation rate was 5.1%. The highest success was in couples with ovulatory disorders, endometriosis and cervical factor infertility. The study suggested that SO-IUI is a cheaper and effective additional tool in the treatment of some infertility disorders before proceeding to IVF or other sophisticated techniques.


Subject(s)
Infertility/therapy , Insemination, Artificial , Superovulation , Adult , Cost-Benefit Analysis , Female , Humans , Male , Pregnancy , Pregnancy Outcome , Retrospective Studies
11.
Surgery ; 118(2): 212-9, 1995 Aug.
Article in English | MEDLINE | ID: mdl-7638736

ABSTRACT

BACKGROUND: The induction of specific tolerance could prevent acute and chronic rejection, as well as immunosuppressive complications, in recipients of vascularized organ allografts. Mixed hematopoietic chimerism is one approach to allogeneic tolerance. In these studies we examined whether mixed chimerism can confer tolerance to heart allografts across major and minor histocompatiblity barriers. We also examined the transcription of cytokine genes within the allografts of tolerance animals and in cell culture. METHODS: Adult Lewis rats were lethally irradiated and reconstituted with a mixture of 50 x 10(6) T-cell depleted bone marrow cells. Chimeric animals received heterotopic donor strain and third-party heart allografts and were assessed daily for rejection. Another set of chimeras received heart allografts that were examined at varying time points for transcription of cytokine genes by reverse-transcriptase polymerase chain reaction. RESULTS: Median graft survival in control animals was 6 days. Graft survival in 11 mixed chimeras ranged from more than 165 to more than 274 days (p < 0.001), and no episode of rejection or graft-versus-host disease was observed. Examination of cytokine transcriptions revealed dramatic alterations in interleukin-4 transcription in vivo and in vitro. CONCLUSIONS: Alterations in cytokine gene transcription are descriptive of tolerance in this model. Mixed chimerism confers long-term unresponsiveness to heart allografts across major and minor histocompatibility barriers with desirable features for clinical application.


Subject(s)
Chimera , Hematopoiesis , Immune Tolerance , Interleukin-4/metabolism , Animals , Bone Marrow Transplantation , Cytokines/genetics , Graft Survival , Interleukin-4/genetics , Male , Rats , Rats, Inbred BN , Rats, Inbred Lew , Rats, Sprague-Dawley , Transcription, Genetic
12.
Singapore Med J ; 36(1): 63-7, 1995 Feb.
Article in English | MEDLINE | ID: mdl-7570139

ABSTRACT

OBJECTIVE: The purpose of this study was to determine the incidence, presentation, management and outcome of uterine perforation during elective first trimester abortions. METHODS: We conducted a retrospective study of 40 patients, including 2 transferred patients, who sustained uterine perforation during elective abortions from January 1980 to December 1992. RESULTS: The incidence of uterine perforation was 0.8 per 1,000 procedures (0.08%). There were 8 (20%) nulliparae and 3 (7.5%) grand multigravidae. 82.5% of the cases occurred when the abortion was performed by medical officers or junior registrars under training. The commonest perforating instrument was the suction cannula (25%) followed by the uterine sound (22.5%) and the dilator (20%). Three (7.5%) cases were treated conservatively, 33 (82.5%) cases underwent emergency operation, 2 (5%) cases were discovered during subsequent sterilisation, and 2 (5%) cases suffered undiagnosed perforation and were re-admitted for emergency surgery. Morbidity included post operative fever (12.5%), bowel injury (7.5%), retained conceptus (5%) and wound breakdown (2.5%). There was no mortality. CONCLUSION: A careful assessment of the uterine size and position, vigilance in the use of uterine sound and dilators, greater care in the use of suction cannula, and experience in vacuum aspiration will decrease the incidence of uterine perforation during elective abortions. A high degree of suspicion, early diagnosis and treatment will prevent the potential complications that may arise from uterine perforation.


Subject(s)
Abortion, Induced/adverse effects , Uterine Perforation/etiology , Abortion, Induced/methods , Adult , Female , Humans , Incidence , Middle Aged , Morbidity , Pregnancy , Pregnancy Trimester, First , Retrospective Studies , Singapore/epidemiology , Uterine Perforation/epidemiology , Uterine Perforation/therapy
13.
Transplantation ; 59(2): 282-8, 1995 Jan 27.
Article in English | MEDLINE | ID: mdl-7839452

ABSTRACT

Chronic rejection is a major cause of graft failure in solid organ transplants after the first year. A characteristic lesion in a variety of chronically rejecting organs is a fibrointimal proliferative arteriosclerosis. It has been speculated that approaches to tolerance induction may be effective in obviating not only acute, but also chronic, rejection. A picture of chronic rejection develops naturally in heart grafts transplanted from the Lewis-to-F-344 strain of rat. We examined whether tolerance induction by bone marrow transplantation and development of hematopoietic chimerism or tolerance induction by intrathymic inoculation of alloantigen could effectively prevent chronic rejection in an established model of chronic rejection. Bone marrow chimeras were developed in F-344 hosts by transplantation of T cell-depleted allogeneic marrow (TCD A BMT). Another set of F-344 hosts was inoculated with intrathymic allogeneic bone marrow cells. Heart grafts in these animals demonstrated tolerance for 120 days after transplantation. Control F-344 animals treated with a short course of cyclosporine consistently developed chronic rejection by 120 days following heart transplantation. Strikingly absent from the tolerant animals was any sign of graft arteriosclerosis, which was demonstrated in the vast majority of control animals. Analysis of cytokine mRNA profiles at 30 days following heart transplantation demonstrated differences between control and tolerant animals. These results suggest that tolerance induction can effectively prevent chronic rejection.


Subject(s)
Arteriosclerosis/prevention & control , Graft Rejection/prevention & control , Transplantation Chimera/immunology , Animals , Arteriosclerosis/etiology , Bone Marrow Transplantation/immunology , Chronic Disease , Coronary Vessels/physiology , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Graft Rejection/complications , Graft Rejection/immunology , Heart Transplantation/adverse effects , Heart Transplantation/immunology , Immune Tolerance , Isoantigens/immunology , Male , Myocardium/pathology , RNA, Messenger/metabolism , Rats , Rats, Inbred F344 , Rats, Inbred Lew , Rats, Sprague-Dawley , T-Lymphocytes/immunology
14.
Surgery ; 116(2): 222-8, 1994 Aug.
Article in English | MEDLINE | ID: mdl-8047988

ABSTRACT

BACKGROUND: The induction of specific tolerance would greatly improve survival and functional state of organ transplant recipients. One approach that has recently received attention is the creation of mixed hematopoietic chimerism through the transplantation of allogeneic and syngeneic T-cell-depleted (TCD) bone marrows. In these studies we examined whether tolerance to highly immunogenic small-bowel transplants could be induced by mixed allogeneic chimerism. Tolerance induction depends on the sharing of antigens between bone marrow cells and small-bowel tissue. METHODS: Adult Lewis rats were lethally irradiated and reconstituted with a mixture of 50 x 10(6) TCD bone marrow cells. Thirty days after reconstitution, animals were tested for chimerism by fluorescence-activated cell sorter analysis. Chimeric animals then received ACI heterotopic small-bowel allografts and were assessed daily for rejection. Small-bowel allograft survival was compared to three control groups: (1) untreated Lewis recipients, (2) irradiated TCD syngeneically reconstituted Lewis recipients, and (3) Lewis bone marrow recipients that did not develop chimerism. RESULTS: Median graft survival in control groups was 8 days. Graft survival in eight mixed chimeras ranged from more than 135 to more than 304 days (p < 0.0001), and no episode of rejection or graft-versus-host disease was observed. Mixed lymphocyte reactivity of chimeric lymphocytes confirmed in vivo observation of tolerance. CONCLUSIONS: Bone marrow cells share tissue-specific antigens with small-bowel cells to permit induction of tolerance.


Subject(s)
Immune Tolerance , Intestine, Small/transplantation , Animals , Chimera , Graft vs Host Disease/etiology , Intestine, Small/pathology , Lymphocyte Depletion , Male , Rats , Rats, Inbred ACI , Rats, Inbred BN , Rats, Sprague-Dawley , Transplantation, Homologous
15.
Bone Marrow Transplant ; 14(1): 137-45, 1994 Jul.
Article in English | MEDLINE | ID: mdl-7951101

ABSTRACT

We describe the recipient of a marrow graft from an HLA-serologically identical unrelated donor from whom highly potent host-reactive CTL of donor origin were isolated in association with acute GVHD. Extensive sequence and biochemical analysis of the HLA complex of this donor and recipient revealed several disparities in class I and class II HLA with the potential to be recognized by T cells from the donor or the host. The donor-derived CTL exclusively recognized a class I HLA difference associated with HLA-B44. Nucleotide sequencing of donor and recipient cells revealed that the patient possessed the HLA-B*4402 allele recognized by IEF as B44.2 while the donor possessed HLA-B*4403 (IEF variant B44.1). These alleles differ at one amino acid residue located at position 156 in the alpha 2 domain. The donor-derived CTL were shown to be specific for B44.2 by blocking studies and by the lysis of five different B44.2+ unrelated cell lines, two of which were confirmed by sequencing to be homozygous for B*4402. A host-specific difference involving a HLA-DRB1 allele was not recognized by the CTL, neither did HLA differences unique to the donor HLA-B*4403 and HLA-DQ8 elicit a host response. These data show that certain HLA disparities may be tolerated at the same time that other disparities elicit a potent immunologic response. The chemical nature of the difference, its structural impact, as well as the conditions of transplant appear to influence the type of response which occurs.


Subject(s)
Bone Marrow Transplantation/adverse effects , Graft vs Host Disease/etiology , HLA-B Antigens , T-Lymphocytes, Cytotoxic/immunology , Acute Disease , Adult , Alleles , Base Sequence , Bone Marrow Transplantation/immunology , Cytotoxicity Tests, Immunologic , DNA Primers/genetics , Graft vs Host Disease/immunology , HLA-B Antigens/genetics , HLA-B44 Antigen , Histocompatibility Testing , Humans , Leukemia, Myeloid, Accelerated Phase/genetics , Leukemia, Myeloid, Accelerated Phase/immunology , Leukemia, Myeloid, Accelerated Phase/therapy , Male , Molecular Sequence Data , Tissue Donors , Transplantation, Homologous
17.
Bone Marrow Transplant ; 12(3): 289-95, 1993 Sep.
Article in English | MEDLINE | ID: mdl-8241989

ABSTRACT

The mechanism by which GVHD augments the graft-versus-leukemia (GVL) effect of marrow transplants has not been ascertained. One possibility involves the secondary activation of natural killer (NK) cells by cytokines released during the GVHD process. To evaluate this possibility we have compared NK activity and lymphokine-activated killer cell precursor (LAKp) frequencies in serially sampled PBMC from recipients of unmanipulated autologous or allogeneic marrow with and without active GVHD. NK activity recovered rapidly after BMT and was elevated during episodes of acute GVHD. However, NK activity did not differ between recipients of autologous or allogeneic marrow without GVHD nor was NK activity increased in association with chronic GVHD. Endogenously-activated NK cells were detected only in recipients of allogeneic marrow but this did not correlate with GVHD status. In contrast to NK activity, LAKp frequencies fell below the control range during the first 8 weeks after BMT. By 9-14 weeks the median LAKp frequency was normal and did not differ between the three groups then or later after transplant. We conclude that acute GVHD may serve to increase the lytic activity of NK cells but does not result in increased LAKp. LAKp frequencies are below normal during the first two months after BMT, a finding not previously recognized from bulk culture LAK studies. The role of LAK effectors in GVL may involve more the degree of cellular activation rather than the number of cells activated.


Subject(s)
Bone Marrow Transplantation/immunology , Graft vs Host Disease/immunology , Killer Cells, Lymphokine-Activated/immunology , Killer Cells, Natural/immunology , Acute Disease , Anemia, Aplastic/immunology , Anemia, Aplastic/surgery , Bone Marrow Transplantation/adverse effects , Humans , Leukemia/immunology , Leukemia/surgery , Lymphoma/immunology , Lymphoma/surgery , Multiple Myeloma/immunology , Multiple Myeloma/surgery , Recurrence
19.
J Singapore Paediatr Soc ; 31(1-2): 90-2, 1989.
Article in English | MEDLINE | ID: mdl-2528027

ABSTRACT

Hydrops fetalis is an unusual manifestation of Down's syndrome and diagnosis of Down's syndrome in the hydropic newborn can be difficult as the clinical signs are masked by severe oedema. The baby may also be seriously ill and die soon after birth, before any investigative procedures could be done. Down's syndrome should be considered in foetuses or babies presented with pleural effusion and/or ascites.


Subject(s)
Chylothorax/complications , Down Syndrome/complications , Hydrops Fetalis/complications , Female , Humans , Infant, Newborn , Pleural Effusion/etiology , Pregnancy
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