Fragile X Syndrome: A Family Study

A research report submitted to the Faculty of Medicine, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the Degree of Master of Science in Medicine. Johannesburg October, 1997Fragile X syndrome is, second to Down syndrome, the commonest form of genetic mental retardation. The aim of this research project was to investigate the impact of having a child with this syndrome on the family relationships. The subjects were 21 mothers and 9 fathers of affected children. The data were collected by means of specially constructed questionnaires in interviews with 19 mothers and 8 fathers and completed by post in three cases. A control group of parents with a normal child, matched for sex and age of the affected child, family size and ethnic groups, was interviewed. The data were computerised and analyzed. The results showed that more experimental parents than controls enjoyed their child’s nature, but disliked the behavioural problems. About half of the experimental parents tended not to reward good behaviour physically. However, although most of the affected children were accepted by their siblings, they had fewer friends and more problems with their peers. Some parents thought that their relationship with their spouse had improved and others thought that it had deteriorated after the affected child’s birth. Most parents in both study groups would request prenatal diagnosis in subsequent pregnancies and significantly more experimental parents than controls would request a termination of pregnancy for an affected fetus. Most parents were satisfied with the health service they received. These results show that family dynamics are disturbed by the presence of a child with FMR. Counsellors and therapists working with these families should be aware of the effects of the syndrome on the familyIT201

"There is a chance for me" - Risk communication in advanced maternal age genetic counseling sessions in South Africa

Providing risk information is central to genetic counseling. Many studies have examined risk communication, but the focus has been on professional and patient perspectives. Less information is available on risk communication in interactions. This study aimed to examine genetic counselors' (GCs) risks communication in multicultural genetic counseling sessions with women of advanced maternal age (AMA). Six GCs (2–20 years' experience) conducted AMA sessions in English (women's second language). The sessions were video and voice recorded and transcribed verbatim. Data were analysed using conversation analysis (CA). CA examines discourse as a topic, i.e. describing the turns, its functions and how these functions are accomplished. Analysis revealed that the GCs presented the risk of having a baby with a chromosome abnormality in several ways and that they invite the women to reflect on the risk information. This discussion was found to be a five step process and showed that the women responded to the invitation to reflect rather than the risk information itself by providing additional information. The counselors in the majority of the sessions responded to this additional information the women provided. It therefore seems that the way in which risks are presented are less important than the meaning of the risks for the women. The research showed the power of interactional research such as CA methodology to gain new insights into old problems. Importantly, the study revealed some on the nuances of risk communication in genetic counseling and has implications for practice

Wirkmechanismen in der Behandlung und Prävention chronischer Rückenschmerzen

Ziel Rückenschmerzen verursachen hohe sozioökonomische Kosten. Dabei kommt der Gruppe mit chronischen Rückenschmerzen eine besondere Bedeutung zu, da 80% der Behandlungskosten durch diese Patienten verursacht werden. Dies macht Rückenschmerzen neben Erkältungskrankheiten zum teuersten medizinischen Problem, zur teuersten muskuloskeletalen Erkrankung und zur häufigsten Ursache von Arbeitsunfähigkeit unter 45 Jahren. Die Verhinderung der Chronifizierung ist deshalb aus sozioökonomischen, aber auch ethischen Gründen („burden of disease“), ein überaus wichtiges Ziel. Die vorliegende Arbeit beschäftigt sich deshalb mit Wirkmechanismen in der Behandlung von Rückenschmerzen, d.h. mit der Vorhersage des Behandlungserfolgs durch innerhalb eines Behandlungsprogramms erreichte Veränderungen. Zur Behandlung und Sekundärprävention von Rückenschmerzen existieren eine Reihe von Interventionen, deren Effektivität belegt ist. Weitgehend unklar sind jedoch die zugrunde liegenden Wirkmechanismen. Ein besseres Verständnis der Wirkmechanismen würde es ermöglichen, Interventionen effizienter und damit auch kostengünstiger zu gestalten. Teil 1 der Arbeit ist ein systematischer Review, welcher Wirkmechanismen nicht-operativer Behandlungen chronischer Rückenschmerzen analysiert. Teil 2 der Arbeit untersucht relevante Wirkmechanismen in einem trainingstherapeutischen und einem multimodalen Programm zur Sekundärprävention von Rückenschmerzen. Methoden Teil 1: Basierend auf einer systematischen Literatursuche in den Datenbanken Medline, Embase und PsycInfo wurde ein Review erstellt. Es wurden Studien ausgewählt, die u.a. die folgenden Einschlusskriterien erfüllen: (1) Behandlung chronischer Rückschmerzen mit Trainingstherapie, Verhaltenstherapie oder multimodalen Behandlungsansätzen, (2) Analyse von Veränderungen in Prädiktorvariablen und Anteil der aufgeklärten Varianz am Ergebnis mit multivariaten Verfahren, z.B. Regressionsanalysen. Aufgrund der Heterogenität der Daten hinsichtlich erhobener Variablen und eingesetzter statistischer Methoden wurden die Daten deskriptiv ausgewertet und zusammengefasst. Teil 2: Zur Identifizierung relevanter Wirkmechanismen in der Sekundärprävention von Rückenschmerzen wurden Daten einer randomisierten klinischen Studie zur Überprüfung der Effektivität eines Trainings- und eines multimodalen Programms mit multiplen Regressionsanalysen ausgewertet. Es sollten Prädiktorvariablen identifiziert werden, die das Erfolgskriterium „Reduzierung von Beeinträchtigung“ nach Beendigung des Präventionsprogramms am besten vorhersagen. Als potentielle Prädiktorvariablen wurden Veränderungen in psychologischen Variablen und körperlichen Leistungstests berücksichtigt, sowie Interaktionen zwischen dem jeweiligen Programm und den Prädiktorvariablen, um zu überprüfen, ob sich die Wirkmechanismen in beiden Programmen unterscheiden. Ergebnisse Teil 1: Es konnten 13 Studien in den Review eingeschlossen werden. Der Anteil der erklärten Varianz lag zwischen 5% und 71%. In den ausgewerteten Studien zeichnete sich - unabhängig von der Intervention - folgende Tendenz ab: Schmerzreduktion konnte am besten mit einer Abnahme von Beeinträchtigung und zu einem geringeren Teil mit der Verbesserung physischer Leistungsparameter erklärt werden. Abnahme von Beeinträchtigung wiederum wurde am besten sowohl mit Schmerzreduktion, als auch mit einer Zunahme aktiver Copingmechanismen und einer Reduzierung von Fear-avoidance Überzeugungen erklärt. Eine Rückkehr an den Arbeitplatz konnte vor allem durch eine Reduzierung der Beeinträchtigung und zu einem etwas geringeren Teil durch eine Zunahme aktiver Copingmechanismen sowie einer Reduzierung von Fear-avoidance Überzeugungen vorhergesagt werden. Teil 2: In beiden Programmen zur Sekundärprävention von Rückenschmerzen konnte Reduzierung von Beeinträchtigung am besten mit Reduzierung von Schmerzintensität und Katastrophisieren erklärt werden. Die Zunahme von Kraft und Ausdauer hatte keinen statistisch signifikanten Einfluss auf den Behandlungserfolg. Insgesamt konnte durch das finale Modell 68.7% der Varianz erklärt werden. Es wurden keine signifikanten Interaktionen zwischen Programm und Prozessvariablen gefunden. Diskussion und Schlussfolgerungen Die Ergebnisse der vorliegenden Arbeit zeigen, dass zur Vorhersage des Behandlungserfolgs bei chronischen Rückenschmerzen, sowie in der Sekundärprävention Veränderungen psychologischer, sowie schmerz- und funktionsbezogener Variablen eine größere Relevanz besitzen, als Verbesserungen körperlicher Leistungsparameter. Diese Ergebnisse stimmen mit den Aussagen bisher publizierter Reviews und anderer Studien überein: Dass nämlich psychologische Faktoren - insbesondere Tendenzen zum Katastrophisieren und fear-avoidance Überzeugungen - sowie Schmerzparameter Chronifizierung und Beeinträchtigung wesentlich besser vorhersagen, als körperliche Parameter. Von besonderer Bedeutung bei den vorliegenden Ergebnissen ist zudem, dass der Behandlungserfolg trainingstherapeutischer und multimodaler Verfahren vorrangig durch psychologische Wirkmechanismen, nämlich Veränderungen psychologischer Faktoren wie dysfunktionalen Überzeugungen, vermittelt wird. Dies ist umso interessanter, als trainingstherapeutische Programme keine direkten psychologischen oder kognitiv-behavioralen Interventionen beinhalten. Der Wert trainingstherapeutischer Interventionen scheint deshalb darin zu liegen, die Erfahrung zu vermitteln, dass Bewegung nicht schädlich ist, und hierdurch dysfunktionale Einstellungen und Bewältigungsstrategien zu verändern. Ob zur Erreichung dieses Ziels die Durchführung aufwändiger Trainingskonzepte an speziellen Geräten notwendig ist, gilt es zu überdenken. In Bezug auf multimodale Programme könnten die Ergebnisse bedeuten, den Schwerpunkt auf verhaltens- und erfahrungsorientierte - im Gegensatz zu edukativen und kognitiven Inhalten - zu legen

Ethical issues and Huntington's disease

The practice of genetic counselling gives rise to many ethical dilemmas, and counsellors need to be familiar with the principles of biomedical ethics. The primary principles include respect for autonomy, beneficence, non-maleficence and justice. A case of identical twins at 50% risk for Huntington’s disease, in which only one twin sought predictive testing for this dominantly inherited disease, created several ethical dilemmas. Another case where predictive testing was carried out on two young children, at high risk, by a laboratory at the request of an adoption agency and a doctor, with a view to giving information to the foster parents, also posed many ethical conundrums for the counsellor. The ethical issues that arose in these cases are discussed in this paper.

Efavirenz use during pregnancy and for women of child-bearing potential

BACKGROUND: Efavirenz is the preferred non-nucleoside reverse transcriptase inhibitor for first-line antiretroviral treatment in many countries. For women of childbearing potential, advantages of efavirenz are balanced by concerns that it is teratogenic. This paper reviews evidence of efavirenz teratogenicity and considers implications in common clinical scenarios. FINDINGS: Concerns of efavirenz-induced fetal effects stem from animal studies, although the predictive value of animal data for humans is unknown. Four retrospective cases of central nervous system birth defects in infants with first trimester exposure to efavirenz have been interpreted as being consistent with animal data. In a prospective pregnancy registry, which is subject to fewer potential biases, no increase was detected in overall risk of birth defects following exposure to efavirenz in the first-trimester. DISCUSSION: For women planning a pregnancy or not using contraception, efavirenz should be avoided if alternatives are available. According to WHO guidelines for resource-constrained settings, benefits of efavirenz are likely to outweigh risks for women using contraception. Women who become pregnant while receiving efavirenz often consider drug substitution or temporarily suspending treatment. Both options have substantial risks for maternal and fetal health which, we argue, appear unjustified after the critical period of organogenesis (3–8 weeks post-conception). Efavirenz-based triple regimens, initiated after the first trimester of pregnancy and discontinued after childbirth, are potentially an important alternative for reducing mother-to-child transmission in pregnant women who do not yet require antiretroviral treatment. CONCLUSION: Current recommendations for care for women who become pregnant while receiving efavirenz may need to be re-considered, particularly in settings with limited alternative drugs and laboratory monitoring. With current data limitations, additional adequately powered prospective studies are needed

A TNF-Regulated Recombinatorial Macrophage Immune Receptor Implicated in Granuloma Formation in Tuberculosis

Macrophages play a central role in host defense against mycobacterial infection and anti- TNF therapy is associated with granuloma disorganization and reactivation of tuberculosis in humans. Here, we provide evidence for the presence of a T cell receptor (TCR) αβ based recombinatorial immune receptor in subpopulations of human and mouse monocytes and macrophages. In vitro, we find that the macrophage-TCRαβ induces the release of CCL2 and modulates phagocytosis. TNF blockade suppresses macrophage-TCRαβ expression. Infection of macrophages from healthy individuals with mycobacteria triggers formation of clusters that express restricted TCR Vβ repertoires. In vivo, TCRαβ bearing macrophages abundantly accumulate at the inner host-pathogen contact zone of caseous granulomas from patients with lung tuberculosis. In chimeric mouse models, deletion of the variable macrophage-TCRαβ or TNF is associated with structurally compromised granulomas of pulmonary tuberculosis even in the presence of intact T cells. These results uncover a TNF-regulated recombinatorial immune receptor in monocytes/macrophages and demonstrate its implication in granuloma formation in tuberculosis

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility

Impact of infection on proteome-wide glycosylation revealed by distinct signatures for bacterial and viral pathogens

Mechanisms of infection and pathogenesis have predominantly been studied based on differential gene or protein expression. Less is known about posttranslational modifications, which are essential for protein functional diversity. We applied an innovative glycoproteomics method to study the systemic proteome-wide glycosylation in response to infection. The protein site-specific glycosylation was characterized in plasma derived from well-defined controls and patients. We found 3862 unique features, of which we identified 463 distinct intact glycopeptides, that could be mapped to more than 30 different proteins. Statistical analyses were used to derive a glycopeptide signature that enabled significant differentiation between patients with a bacterial or viral infection. Furthermore, supported by a machine learning algorithm, we demonstrated the ability to identify the causative pathogens based on the distinctive host blood plasma glycopeptide signatures. These results illustrate that glycoproteomics holds enormous potential as an innovative approach to improve the interpretation of relevant biological changes in response to infection