ART in recurrent miscarriage: preimplantation genetic diagnosis/screening or surrogacy?

Recently, assisted reproductive techniques have been used to prevent further miscarriages in women with recurrent miscarriage. One approach uses either screening or diagnosis of embryonic chromosomes prior to embryo replacement [preimplantation genetic screening (PGS)/preimplantation genetic diagnosis (PGD)]. The second approach involves surrogacy. However, PGS/PGD assumes that the embryo is chromosomally abnormal, and that the mother should receive a chromosomally normal embryo. Surrogacy assumes that the embryo is normal and that the maternal environment needs to be substituted. This article examines the place of both techniques in different types of recurrent miscarriage, and tries to give guidelines as to which technique is preferable depending on the likelihood of an embryonic chromosome aberration. In repeated fetal aneuploidy or in the older patient, PGS or PGD are preferable. However, with high numbers of miscarriages, or in autoimmune pregnancy loss, surrogacy is preferable. In the light of recent work, it is uncertain which treatment mode is indicated in balanced parental chromosome aberrations. In conclusion, both techniques have a place, but probably only in those patients with a poor prognosis in whom assisted reproductive techniques will be shown to improve the subsequent live birth rate above the spontaneous rate.     

Can preimplantation genetic diagnosis improve success rates in recurrent aborters with translocations?

Preimplantation genetic diagnosis (PGD) for people suffering recurrent miscarriages is increasingly being performed worldwide. However, there is limited information on whether PGD can improve success rates in translocation carriers. We therefore compared pregnancy outcomes between PGD and natural pregnancy cases, reviewing the clinical research database. No improvement in the success rate at the first oocyte retrieval was evident in reciprocal translocation carriers. In the natural course of events, patients with translocations can hope for a baby in the long term. However, with PGD, rates can reach 68% after IVF failure and the duration to eventual birth may be shorter than with natural pregnancies. In the particular case of Robertsonian translocations, PGD may not be necessary because natural success rates are relatively good.     

High-risk consumers’ perceptions of preimplantation genetic diagnosis for hereditary cancers: a systematic review and meta-analysis

Individuals carrying deleterious germline mutations placing them at increased risk for hereditary cancer syndromes (high-risk consumers) often have a great deal of fear and concern over transmitting mutations to their offspring, particularly conditions which are autosomal dominant. Preimplantation genetic diagnosis (PGD) is a procedure that can detect certain germline cancer predisposing mutations present in embryos. The objective of this review was to assess high-risk consumers’ knowledge and perceptions of PGD for hereditary cancers. A systematic literature review was conducted through PubMed, Wiley Interscience, PsychInfo, and Cochrane Library databases to identify all articles assessing consumer knowledge and attitudes of PGD for hereditary cancer syndromes. We assessed heterogeneity and the robustness of findings through additional analyses according to study location, hereditary cancer type, and sample size. Thirteen articles remained eligible after the application of specific criteria. Results show a general low level of knowledge about PGD for hereditary cancers, moderate rates of acceptability among high-risk groups, and high levels of need for information about PGD. Individuals in specific risk groups such as those with a personal or family history of hereditary breast and ovarian cancer (HBOC) syndrome or familial adenomatous polyposis (FAP) may benefit from educational information from healthcare professionals about the use of PGD.Genet Med 2012:14(2):191–200     

What next for preimplantation genetic screening?

Preimplantation genetic diagnosis for aneuploidy screening (preimplantationgenetic screening—PGS) has been used to detect chromosomallynormal embryos from subfertile patients. The main indicationsare advanced maternal age (AMA), repeated implantation failure,repeated miscarriages and severe male factor infertility. Manynon-randomized PGS studies have been published and report anincrease in implantation rate, and/or a decrease in miscarriagerate. Recently, two randomized controlled trials have been conductedon patients with AMA as the only indication. Neither study showeda benefit in performing PGS using live birth rate as the measureof success. The debate on the usefulness of PGS is ongoing;the only effective way to resolve the debate is to perform morewell-designed and well-executed randomized clinical trials.     

What next for preimplantation genetic screening? A clinician's perspective

Preimplantation genetic screening (PGS) is a technique that has been introduced into clinical practice to screen and eliminate aneuploid embryos from transfer with the intention to improve implantation rates and decrease pregnancy wastage. Although practiced widely throughout the world, PGS unfortunately has been adopted without being subjected to rigorous scientific validation. Data from recent randomized trials have shed doubt on the efficacy of the procedure when used in women with advanced age, one of the target populations for PGS. Other purported indications for the application of this complicated technique such as recurrent implantation failure and recurrent spontaneous abortion have not been subjected to randomized controlled trials. For the best interest of patients, we feel it is timely for a debate regarding the efficacy and safety of PGS.     

preimplantation genetics diagnosis译为“植入前遗传诊断”为妥

1.implantation按1993年《全国自然科学名词审定委员会公布、胚胎学名》第126页,审定“implantation”译为“植入”(胚泡进入子宫内膜的过程)编号为02.078。 2.人民卫生出版社出版的《英汉医学词汇》第706页和《汉英医学词汇》均将implantation译为“植入”(胚泡在子宫内)。     

What next for preimplantation genetic screening? More randomized controlled trials needed?

The recent debate on preimplantation genetic screening (PGS) has raised questions about its routine use in clinical practice. It has been suggested that the most effective way to resolve the debate about the usefulness of PGS is to perform more well-designed and well-executed randomized controlled trials (RCTs). However, in view of the lack of evidence for the effectiveness of PGS and the accumulating evidence for its harmfulness, it is our opinion that it is unethical to perform additional RCTs for the indication advanced maternal age using cleavage stage biopsy.     

The diagnosis of pertussis: which method to choose?

Despite the introduction of routine vaccination against pertussis for more than a half century, leading to a drastic decline in the number of reported cases, pertussis continues to be an important respiratory disease afflicting unvaccinated infants and previously vaccinated children as well as adults in whom immunity has waned. The diagnosis of pertussis is challenging and accurate laboratory identification of Bordetella infections remains problematic. Common laboratory diagnostic methods used for pertussis diagnosis include culture, direct-fluorescent-antibody testing (DFA), serology and polymerase chain reaction (PCR). Culture of Bordetella pertussis is highly specific but fastidious and has limited sensitivity. DFA provides a much more rapid result, but has the disadvantage of poor sensitivity and specificity. Serology is not useful in infants. In older persons, it is hampered by the limitations of paired sera and it provides mainly a retrospective diagnosis. Such limitations of conventional diagnosis testing have led to the development of PCR assays. Notwithstanding its lack of standardization, PCR has been found to be more sensitive and more specific than other methods. In this report, we aimed to review current knowledge about the available diagnostic methods and tests that accurately diagnose pertussis.     

Analysis of genetic markers of N. Gonorrhoeae resistance to β-lactam antibiotics

A complex method for detection of genetic markers of N. gonorrhoeae resistance to penicillin was developed. Mutations in penA and ponA genes were detected by minisequencing reaction with subsequent detection of reaction products by MALDI-TOF mass spectrometry. This approach was tested on 31 clinical strains of N. gonorrhoeae with minimum inhibitory concentration of penicillin from 0.03 to 8 μg/ml and higher. Mutations in penA and ponA genes in moderately resistant strains were shown (minimum inhibitory concentration up to 0.5 μg/ml) and mutations in penA, ponA, and penB genes in resistant strains (minimum inhibitory concentration more than 1.0 μg/ml). β-Lactamase genes were detected in 4 strains with high resistance (minimum inhibitory concentration 4–8 and more μg/ml). Correlation between microbiological resistance and presence of respective mutations in the studied locuses was detected. __________ Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 141, No. 5, pp. 549–554, May, 2006     

Primary immunodeficiencies and Bruton's disease genetic analysis: which prospects offers this genetic diagnosis?

Bruton's disease is the most frequently primary X-linked immunodeficiency. Bruton's tyrosine kinase (Btk) is encoded by the XLA gene that when mutated causes bruton's disease. This protein acts in multiple intracellular signaling pathways where the BCR (B-cell receptor) pathway is the most elucidated. Moreover 400 mutations were found and identified as responsible for B-cells differentiation block; consequences are a lack of B-cells in peripheral blood and hypo/agammaglobulinemia. Thus, patients are more susceptible to early and recurring infections occurring before the age of one year. Laboratory testing allow differential diagnosis among primary immunodeficiencies in which others hypogammaglobulinemia. Genetic analyses help physicians for clinical and biological diagnosis, and allow prenatal diagnosis for patient's family. Patient's management is based upon polyclonal immunoglobulin supplementation, infectious diseases prevention and genetic advice.     

What improves the likelihood of people receiving genetic test results communicating to their families about genetic risk?

ObjectiveWe currently rely on probands to communicate genetic testing results and health risks within a family to stimulate preventive behaviors, such as cascade testing. Rates of guidelines-based cascade testing are low, possibly due to low frequency or non-urgent communication of risk among family members. Understanding what is being communicated and why may help improve interventions that increase communication and rates of cascade testing.MethodsParticipants (n = 189) who were to receive both positive and negative colorectal cancer (CRC) sequencing results completed surveys on family communication, family functioning, impact of cancer in the family, and future communication of risk and were participants in eMERGE3. Questions were taken from existing surveys and administered electronically using email and a web driven tool.ResultsCommon family member targets of CRC risk communication, before results were received, were mothers and fathers, then sisters and grandchildren and finally, children and brothers. A communication impact score of 0.66 (sd = 0.83) indicated low-to-moderate communication impact. Age and education were significantly associated with frequency of familial communication, but not on the cancer-related impact of familial communication.ConclusionsThere is infrequent communication about cancer risk from probands to family members.Practice ImplicationsThese results demonstrate an opportunity to help families improve communication.     

Referral to cancer genetic counseling: are there stages of readiness?

As genetic awareness spreads among healthcare providers and the general public, and evidence mounts to show the efficacy of cancer control methods, referrals to cancer genetic counseling services for risk assessment are becoming more common. However, few studies have examined referral patterns to genetics and even less is known about referral uptake to clinical cancer genetic counseling. We investigated outcome of genetics referral in 43 affected women attending a breast cancer treatment program who were referred based on having BRCA mutation carrier risks > or =10%. Within 6 months, of the 36 women we were able to recontact, 13 (36%) came to an appointment at the cancer genetic counseling clinic (Acceptors), 10 (27%) said they intended to come in the future (Intenders), and 13 (36%) said they would not consider genetic counseling (Decliners). Referral uptake was framed by elements of the Transtheoretical model (TTM) to determine if decisional balance scores (DBSs), a summary of an individual's "Pro" and "Con" opinions related to genetic testing, correlated with their decision to follow through. Mean DBS's were strongly negative for the Decliner group (-7.4), weakly negative for the Intender group (-1.1), and positive for the Acceptor group (5.4). The difference in the DBS along the continuum was due more to the mean "Con" score decreasing, rather than the mean "Pro" score increasing. Theoretical frameworks are needed to study adherence to referral for cancer genetic counseling. Stage-based theories may have a role to play.     

Recent advances in the diagnosis of malignant hyperthermia susceptibility: how confident can we be of genetic testing?

Malignant hyperthermia (MH) is a condition that manifests in susceptible individuals only on exposure to certain anaesthetic agents. Although genetically heterogeneous, mutations in the RYR1 gene (19q13.1) are associated with the majority of reported MH cases. Guidelines for the genetic diagnosis for MH susceptibility have recently been introduced by the European MH Group (EMHG). These are designed to supplement the muscle biopsy testing procedure, the in vitro contracture test (IVCT), which has been the only means of patient screening for the last 30 years and which remains the method for definitive diagnosis in suspected probands. Discordance observed in some families between IVCT phenotype and susceptibility locus genotype could limit the confidence in genetic diagnosis. We have therefore assessed the prevalence of 15 RYR1 mutations currently used in the genetic diagnosis of MH in a sample of over 500 unrelated European MH susceptible individuals and have recorded the frequency of RYR1 genotype/IVCT phenotype discordance. RYR1 mutations were detected in up to approximately 30% of families investigated. Phenotype/genotype discordance in a single individual was observed in 10 out of 196 mutation-positive families. In five families a mutation-positive/IVCT-negative individual was observed, and in the other five families a mutation-negative/IVCT-positive individual was observed. These data represent the most comprehensive assessment of RYR1 mutation prevalence and genotype/phenotype correlation analysis and highlight the possible limitations of MH screening methods. The implications for genetic diagnosis are discussed.     

Hypoplastic myelodysplastic syndrome-a clinical,morphologic, or genetic diagnosis?

We report a middle-aged female with an 11-year history of nonprogressive pancytopenia and severely hypoplastic marrow with minimal morphologic dysplasia. A diagnosis of hypoplastic myelodysplastic syndrome (MDS) was made because of the finding of a persistent clonal abnormality, del(13)(q12q14), and the subsequent demonstration of a single Auer rod-containing blast in the peripheral blood smear. The case illustrates the problems in the differentiation between aplastic anemia and hypoplastic MDS.