Biomedical subjects
Publications and source records attributed to G Sher.
HLA-G is believed to play a pivotal role in the immunoprotection of the semiallogenic embryo. Its expression during pre- and early implantation is correlated with the cleavage rate of the embryo. Studies in congenic mice have revealed that mRNA of both the maternal and paternal haplotypes are present in zygotes and in embryos at all stages of development.
BACKGROUND: We have previously reported the retrospective observation that when at least one embryo, transferred on day 3, expressed sHLA-G above the geometric mean (sHLA-G+) 46 h post-ICSI, there was a marked improvement in both pregnancy (PR) and implantation (IR) rates. METHODS: The media surrounding individual embryos derived from ICSI performed on oocytes from 482 women < or =43 years of age were tested for sHLA-G expression by specific ELISA. RESULTS: We report here prospective results showing improved IVF results following the transfer of 'good quality' embryos (7-9 cells with <20% fragmentation) by preferentially including at least one sHLA-G+ embryos. PR and IR for women < or =38 years were 63% and 32% when one transferred embryo was sHLA-G+, and 69% and 36% when at least two embryos were sHLA-G+. When none of the embryos transferred was sHLA-G+, PR and IR were 25% and 13%, respectively. Comparable PR and IR for women 39-43 years were 29% and 11% when none of the transferred embryos were sHLA-G+; 38% and 15% when at least one sHLA-G+ embryo was transferred; and 61% and 26% when at least two 2 sHLA-G+ embryos were transferred. The data were stratified by patient age. CONCLUSIONS: PR and IR increased with the addition of each sHLA-G+ embryo, regardless of age. While there are significant barriers to routine embryo sHLA-G testing, we believe that if implemented, this would provide a mechanism for optimizing IVF PR while minimizing the risk of multiple pregnancies.
Three cases of transfusion-transmitted malaria in Canada are described. Although very rare, this diagnosis should be considered in transfusion recipients who have undiagnosed symptoms consistent with malaria. Thick and thin blood smears should be urgently examined to exclude this possibility.
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BACKGROUND: Embryo morphology and cleavage rates alone do not consistently identify embryos with high implantation potential following IVF. Blastocyst transfer has been reported to improve success rates by identifying potentially superior quality embryos. Algorithms for predicting IVF outcomes based on the presence of early developmental milestones have been proposed. Here we introduce the Graduated Embryo Score (GES). METHODS: Nucleolar alignment along the pronuclear axis, regular cleavage and degree of fragmentation at the first cell division, and cell number and morphology on day 3 were weighted to create a possible GES of 100 for each of 1245 fertilized embryos derived from 109 patients aged <40 years. The GES was correlated with IVF outcome. RESULTS: Of 983 embryos for extended culture, 349 (36%) developed to blastocyst and 180 (18%) were good quality (grade I-II). When ranked by cell number and morphology alone, 34% of embryos with > or =7 cells and <20% fragmentation formed good quality blastocysts. Using GES, embryos scoring 90-100 had 64% blastocyst formation compared with 31% scoring 70-85 and with 11% scoring 30-65. Embryos scoring 70-100 had 44% blastocyst development compared with 9% scoring 0-65. Fifty-six patients (51%) conceived on-going gestations from 294 transferred embryos. In patients with at least one transferred embryo scoring > or =70, the pregnancy rate was 59% compared with 34% if all embryos scored <70. The overall implantation rate was 28%. Among embryos scoring 70-100, an implantation rate of 39% was seen, compared with 24% among embryos scoring 0-65. CONCLUSIONS: Predicting which cleaved embryos will form blastocysts could permit the high success rates associated with blastocyst transfer to be achieved from day 3 embryo transfer.
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Platelet transfusion reactions were prospectively studied in haematology/oncology patients at five university teaching hospitals over three consecutive summers. The initial summer study provided baseline information on the use of premedications and the rate of platelet transfusion reactions (fever, chills, rigors and hives). Most (73%) platelet recipients were premedicated and 30% (95% CI 28-33%) of transfusions were complicated by reactions. The second study followed implementation of guidelines for premedicating platelet transfusions. Despite a marked reduction in premedication (50%), there was little change in the platelet transfusion reaction rate, 26% (95% CI 24-29%), or the type of reactions. The third study followed implementation of prestorage platelet leukoreduction while maintaining the premedication guidelines. The reaction rate decreased to 19% (95% CI 17-22%). For nonleukoreduced platelets, there was a statistically significant association between the platelet age and reaction rate (P = 0.04). For leukoreduced platelets, there was no statistically significant association between platelet age and reaction rate (P = 0.5). Plasma reduction of nonleukoreduced platelet products also reduced the reaction rate. These prospective studies document a high rate of platelet transfusion reactions in haematology/oncology patients and indicate premedication use can be reduced without increasing the reaction rate. Prestorage leukoreduction and/or plasma reduction of platelet products reduces but does not eliminate febrile nonhemolytic platelet transfusion reactions.
Endometrial growth is thought to depend on uterine artery blood flow and the importance of endometrial development on in-vitro fertilization (IVF) outcome has been previously reported. Nitric oxide (NO) relaxes vascular smooth muscle through a cGMP-mediated pathway and NO synthase isoforms have been identified in the uterus. Sildenafil citrate (Viagra), a type 5-specific phosphodiesterase inhibitor, augments the vasodilatory effects of NO by preventing the degradation of cGMP. In this preliminary report we describe the use of vaginal sildenafil to improve uterine artery blood flow and sonographic endometrial appearance in four patients with prior failed assisted reproductive cycles due to poor endometrial response. The uterine artery pulsatility index (PI) was measured in a mock cycle after pituitary down-regulation with Lupron. The PI was decreased after 7 days of sildenafil (indicating increased blood flow) and returned to baseline following treatment with placebo. The combination of sildenafil and oestradiol valerate improved blood flow and endometrial thickness in all patients. These findings were reproduced in an ensuing gonadotrophin-stimulated cycle. Three of the four patients conceived. Although greater numbers of patients and randomized evaluation are needed to validate this treatment, vaginal sildenafil may be effective for improving uterine artery blood flow and endometrial development in IVF patients with prior poor endometrial response.
Antiphospholipid antibodies (APA) have been identified in patients with recurrent pregnancy loss and IVF failure. Of these, antiphosphatidylethanolamine (aPE) and antiphosphatidylserine (aPS) may have special significance. A link between increased natural killer cell activity (NKa+) and trophoblast cell apoptosis has also been reported. This study was undertaken to determine how the APA profile was associated with peripheral NK cell activity. We evaluated 197 female IVF candidates for APA and NKa. Eighty-nine patients (45%) were APA+ and of these, 51 (57%) were aPE/aPS+. Fifty-four patients (27%) had increased NK cell activity. Some 51% of APA+ and 78% of aPE/aPS+ patients had increased NK cell activity compared with 8% and 13% when APA and aPE/aPS tested negative respectively (P: < 0.0001). Non-male factor infertility patients were APA+ and NKa+ in 57% and 34% of cases respectively, compared with 19% and 13% if a pure male factor was present. Some 88% of aPE/aPS+, non-male factor patients had increased NK cell activity, compared with 12% who tested aPE/aPS negative (P: < 0.0001) and 25% of aPE/aPS+, isolated male factor patients (P: < 0.0001). These findings establish a direct relationship between APA (specifically aPE/aPS) and increased peripheral NK cell activity among non-male factor infertility patients. It is possible that APA do not directly cause reproductive failure but rather function as markers or intermediaries for an underlying, abnormal activation of cellular immunity.
To date the true prevalence of hepatitis C virus (HCV) mixed-genotype infections has not been established mainly because currently available methods are not suitable for the detection of mixed genotypes in a viral population. A novel semiautomated genotyping method, primer-specific and mispair extension analysis (S-PSMEA), which is more reliable than other genotyping assays was developed for detection of HCV mixed-genotype infections. A genotype present at levels as low as 0.8% in a defined mix of HCV genotypes was detected, showing a 20-fold increase in sensitivity over that of direct DNA sequencing. A total of 434 HCV isolates were genotyped and analyzed for a comparative study of the accuracy between S-PSMEA and four current genotyping methods. The results showed that viruses in approximately 40% of the samples from this group determined to be infected with mixed genotypes by S-PSMEA were undetected by direct DNA sequencing due to its low sensitivity. Type-specific PCR, line probe assay, and restriction fragment length polymorphism analysis performed poorly, being able to identify only 38.5, 16.1, and 15.4% of mixed-genotype infections, respectively, that were detected by direct DNA sequencing. The prevalence of mixed-genotype infections detected by S-PSMEA was 7.9% (12 of 152 donors) among HCV-infected blood donors, 14.3% (15 of 105) among patients with chronic hepatitis C, and 17.1% (6 of 36) among thalassemia patients who had received multiple transfusions. The data lead us to conclude that HCV mixed-genotype infections are more common than previously estimated and that S-PSMEA may be the method of choice when detection of genotypes present at low levels in mixed-genotype infections is required due to its higher level of sensitivity.
BACKGROUND AND OBJECTIVES: GB virus C (GBV-C)/hepatitis G virus (HGV) is a recently recognized parenterally and sexually transmitted agent. The prevalence of GBV-C/HGV markers in Canadian blood donors has not been previously studied and was therefore determined. MATERIALS AND METHODS: Blood donors [identity unlinked (IU), short-term temporarily deferred (STTD) and autologous groups] and donor samples with antibodies to hepatitis C (anti-HCV) or hepatitis B core were tested for GBV-C/HGV RNA and for antibodies to E2 antigen (anti-E2). RESULTS: GBV-C/HGV RNA was found in 1.1% and anti-E2 in 7.3% of the combined IU/STTD donor group. Viremia was much more common in anti-HCV-positive samples (12.5%); anti-E2 was present in >50% of this group. In the STTD group, female gender was significantly associated with viremia. CONCLUSION: GBV-C/HGV infection is relatively common in Canadian donors, and a small proportion are viremic. The association of female gender and viremia was unexpected. Further study is needed to clarify the epidemiology and natural history of GBV-C/HGV infection.
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Platelet activation occurs during the collection, processing and storage of platelet concentrates. The effect of the platelet activation on the functional state of stored platelets remains however undefined. We employed flow cytometric analysis to evaluate the extent of platelet activation and the physiological response to thrombin stimulation of platelets stored for up to five days under routine blood bank conditions. Platelet surface expression of the activation markers CD62 and CD63 was examined, along with modulation of platelet membrane glycoproteins (GP) Ib and IIbIIIa. Platelet dense granule content was determined using a mepacrine uptake assay and the extent of platelet microparticle generation was quantified. Thirteen random-donor platelet concentrates prepared under routine conditions by a platelet-rich-plasma protocol were examined. Platelets were found to be activated following preparation on day 1. Although a gradual increase was seen with increasing storage time, this was not statistically significant for CD62 or CD63 expression, GPIIbIIIa or GPIb modulation or dense granule release; the generation of platelet microparticles did, however, increase with increasing storage time. The characteristic increase in surface expression of CD62, CD63 and GPIIbIIIa and decrease in GPIb and dense granule content in response to thrombin stimulation was observed with all concentrates, but these measures of platelet functional reserve showed decreasing platelet function with increasing storage time. The results indicate that platelets are activated by day 1, likely as a consequence of manipulation during collection and processing, but are not further progressively activated with increasing storage time; they do, however, become relatively hypofunctional with increasing storage.
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PROBLEM: To compare the effect of heparin/aspirin therapy alone vs. heparin/aspirin in combination with intravenous immuno-globulin (IVIg) immunotherapy on in vitro fertilization (IVF) outcome of patients who test positive for antithyroid antibodies (ATAs). METHOD OF STUDY: Eighty-two women younger than 40 years of age whose infertility was related exclusively to female causes were evaluated. All tested positive for organ-specific antithyroid antibodies (antimicrosomal and/or antithyroglobulin antibodies), but negative for antiphospholipid antibodies. Thirty-seven of these women (group A) received H/A alone, whereas 45 (group B) received heparin/aspirin in combination with IVIg. RESULTS: Ten (27%) of women in group A and 23 (51%) of women in group B achieved live births after completion of a single IVF/embryo transfer cycle (P = 0.027). CONCLUSION: We conclude that IVIg therapy significantly improves IVF success rates in ATA+ women.
PROBLEMS: 1) Does the administration of heparin and aspirin (H/A) in combination with intravenous immunoglobulin G (IVIG) improve in vitro fertilization (IVF) implantation and birth rates in patients with recurrent IVF failure? 2) Is the effect of such treatment related to the antiphospholipid antibody (APA) status of the patients concerned? METHOD OF STUDY: Subjects consisted of 89 women younger than 36 years of age whose infertility was a result of causes other than male infertility and who had experienced four or more failed IVF/embryo transfer procedures. Fifty-two women were APA+ (group A), and 37 were APA- (group B). All patients, regardless of their APA status, received H/A (5000 U sq bid), aspirin (81 mg po qd) from the inception of menotropin therapy along with IVIG (20 g) through a single infusion 3 to 10 days before egg retrieval. RESULTS: Twenty-two (42%) of group A and 7 (19%) of group B patients achieved live births (P = 0.020). CONCLUSIONS: IVF outcome is significantly improved when H/A and IVIG are administered to APA+ women with repeat IVF failures. APA- women do not seem to benefit from such treatment.