A review of trisomy X (47,XXX)

Trisomy X is a sex chromosome anomaly with a variable phenotype caused by the presence of an extra X chromosome in females (47,XXX instead of 46,XX). It is the most common female chromosomal abnormality, occurring in approximately 1 in 1,000 female births. As some individuals are only mildly affected or asymptomatic, it is estimated that only 10% of individuals with trisomy X are actually diagnosed. The most common physical features include tall stature, epicanthal folds, hypotonia and clinodactyly. Seizures, renal and genitourinary abnormalities, and premature ovarian failure (POF) can also be associated findings. Children with trisomy X have higher rates of motor and speech delays, with an increased risk of cognitive deficits and learning disabilities in the school-age years. Psychological features including attention deficits, mood disorders (anxiety and depression), and other psychological disorders are also more common than in the general population. Trisomy X most commonly occurs as a result of nondisjunction during meiosis, although postzygotic nondisjunction occurs in approximately 20% of cases. The risk of trisomy X increases with advanced maternal age. The phenotype in trisomy X is hypothesized to result from overexpression of genes that escape X-inactivation, but genotype-phenotype relationships remain to be defined. Diagnosis during the prenatal period by amniocentesis or chorionic villi sampling is common. Indications for postnatal diagnoses most commonly include developmental delays or hypotonia, learning disabilities, emotional or behavioral difficulties, or POF. Differential diagnosis prior to definitive karyotype results includes fragile X, tetrasomy X, pentasomy X, and Turner syndrome mosaicism. Genetic counseling is recommended. Patients diagnosed in the prenatal period should be followed closely for developmental delays so that early intervention therapies can be implemented as needed. School-age children and adolescents benefit from a psychological evaluation with an emphasis on identifying and developing an intervention plan for problems in cognitive/academic skills, language, and/or social-emotional development. Adolescents and adult women presenting with late menarche, menstrual irregularities, or fertility problems should be evaluated for POF. Patients should be referred to support organizations to receive individual and family support. The prognosis is variable, depending on the severity of the manifestations and on the quality and timing of treatment

Hodgkin's lymphoma masquerading as vertebral osteomyelitis in a man with diabetes: a case report

<p>Abstract</p> <p>Introduction</p> <p>Infection and malignancy often have common characteristics which render the differential diagnosis for a prolonged fever difficult. Imaging and tissue biopsy are crucial in making a correct diagnosis, though differentiating between chronic osteomyelitis and malignancy is not always straightforward as they possess many overlapping features.</p> <p>Case Presentation</p> <p>A 52-year-old Caucasian man was treated with antibiotics for his diabetic foot infection after a superficial culture showed <it>Staphylococcus aureus</it>. He had persistent fevers for several weeks and later developed acute onset of back pain which was treated with several courses of antibiotics. Radiographic and pathological findings were atypical, and a diagnosis of Hodgkin's lymphoma was made 12 weeks later.</p> <p>Conclusion</p> <p>Clinicians should maintain a suspicion for Hodgkin's lymphoma or other occult malignancy when features of presumed osteomyelitis are atypical. Chronic vertebral osteomyelitis in particular often lacks features common to acute infectious disease processes, and the chronic lymphocytic infiltrates seen on histopathology have very similar features to Hodgkin's lymphoma, highlighting a similar inflammatory microenvironment sustained by both processes.</p

Confronting chemobrain: an in-depth look at survivors’ reports of impact on work, social networks, and health care response

Mild cognitive impairment following chemotherapy is one of the most commonly reported post treatment symptoms by breast cancer survivors. This deterioration in cognitive function, commonly referred to as “chemobrain” or “chemofog,” was largely unacknowledged by the medical community until recent years. Although chemobrain has now become the subject of more vigorous exploration, little is known about this specific phenomenon’s psychosocial impact on breast cancer survivors. This research documents in-depth the effects that cognitive impairment has on women’s personal and professional lives, and our data suggest that greater attention needs to be focused on this arena of survivorship. The results are based on an in-depth qualitative study of 74 white and African American breast cancer survivors in California who experience post-treatment side effects. The data reported herein were obtained through the use of focus groups and in-depth interviews. Our data indicate that cognitive impairment can be problematic for survivors, with many asserting that it is their most troublesome post treatment symptom. Survivors report diminished quality of life and daily functioning as a result of chemobrain. Respondents detail a range of coping strategies that they are forced to employ in order to manage their social and professional lives. Chemobrain significantly impairs a proportion of cancer survivors, at great cost to them economically, emotionally, and interpersonally. This suggests that more research needs to be conducted on the psychosocial ramifications of post treatment symptoms in order to inform the efforts of the medical and mental health communities as well as the support networks of survivors. A better and broader understanding of the effects of cognitive impairment both in the medical community and among lay people could pave the way for improved social and psychological services for this population

Quasi-Normal Modes of Stars and Black Holes

Perturbations of stars and black holes have been one of the main topics of relativistic astrophysics for the last few decades. They are of particular importance today, because of their relevance to gravitational wave astronomy. In this review we present the theory of quasi-normal modes of compact objects from both the mathematical and astrophysical points of view. The discussion includes perturbations of black holes (Schwarzschild, Reissner-Nordstr\"om, Kerr and Kerr-Newman) and relativistic stars (non-rotating and slowly-rotating). The properties of the various families of quasi-normal modes are described, and numerical techniques for calculating quasi-normal modes reviewed. The successes, as well as the limits, of perturbation theory are presented, and its role in the emerging era of numerical relativity and supercomputers is discussed.Comment: 74 pages, 7 figures, Review article for "Living Reviews in Relativity

Physics, Astrophysics and Cosmology with Gravitational Waves

Gravitational wave detectors are already operating at interesting sensitivity levels, and they have an upgrade path that should result in secure detections by 2014. We review the physics of gravitational waves, how they interact with detectors (bars and interferometers), and how these detectors operate. We study the most likely sources of gravitational waves and review the data analysis methods that are used to extract their signals from detector noise. Then we consider the consequences of gravitational wave detections and observations for physics, astrophysics, and cosmology.Comment: 137 pages, 16 figures, Published version <http://www.livingreviews.org/lrr-2009-2

Statistical power considerations in genotype-based recall randomized controlled trials

Randomized controlled trials (RCT) are often underpowered for validating gene-treatment interactions. Using published data from the Diabetes Prevention Program (DPP), we examined power in conventional and genotype-based recall (GBR) trials. We calculated sample size and statistical power for genemetformin interactions (vs. placebo) using incidence rates, gene-drug interaction effect estimates and allele frequencies reported in the DPP for the rs8065082 SLC47A1 variant, a metformin transported encoding locus. We then calculated statistical power for interactions between genetic risk scores (GRS), metformin treatment and intensive lifestyle intervention (ILI) given a range of sampling frames, clinical trial sample sizes, interaction effect estimates, and allele frequencies; outcomes were type 2 diabetes incidence (time-to-event) and change in small LDL particles (continuous outcome). Thereafter, we compared two recruitment frameworks: GBR (participants recruited from the extremes of a GRS distribution) and conventional sampling (participants recruited without explicit emphasis on genetic characteristics). We further examined the influence of outcome measurement error on statistical power. Under most simulated scenarios, GBR trials have substantially higher power to observe gene-drug and gene-lifestyle interactions than same-sized conventional RCTs. GBR trials are becoming popular for validation of gene-treatment interactions; our analyses illustrate the strengths and weaknesses of this design

Quality of life and cost-effectiveness of interferon-alpha in malignant melanoma: results from randomised trial

A definitive conclusion regarding the value of low-dose extended duration adjuvant interferon-alpha therapy in the treatment of malignant melanoma is only possible once data on health-related quality of life (HRQoL) and costs have been considered. This trial randomised 674 patients to interferon alpha-2a (3 megaunits three times per week for 2 years or until recurrence) or placebo. Health-related quality of life (QoL) was to be assessed up to 60 months using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30. Data for the economic analysis, including cost information and the EQ-5D were also collected. Patients in the observation (OBS) group had significantly better mean follow-up quality of on five dimensions of the EORTC QLQ-C30 functional scales: role functioning (P=0.033), emotional functioning (P=0.003), cognitive functioning (P=0.001), social functioning (P=0.003) and global health status (P=0.001). Patients in the OBS group had significantly better mean follow-up symptom scores on seven dimensions of the EORTC QLQ-C30 V1 symptom scales. Economic data showed that costs were £3066 higher in the interferon group and produces an incremental cost per quality-adjusted life year of £41 432 at 5 years. The results show that interferon has significant effects on QoL and symptomatology and is unlikely to be cost-effective in this patient group in the UK

Cellular Radiosensitivity: How much better do we understand it?

Purpose: Ionizing radiation exposure gives rise to a variety of lesions in DNA that result in genetic instability and potentially tumorigenesis or cell death. Radiation extends its effects on DNA by direct interaction or by radiolysis of H2O that generates free radicals or aqueous electrons capable of interacting with and causing indirect damage to DNA. While the various lesions arising in DNA after radiation exposure can contribute to the mutagenising effects of this agent, the potentially most damaging lesion is the DNA double strand break (DSB) that contributes to genome instability and/or cell death. Thus in many cases failure to recognise and/or repair this lesion determines the radiosensitivity status of the cell. DNA repair mechanisms including homologous recombination (HR) and non-homologous end-joining (NHEJ) have evolved to protect cells against DNA DSB. Mutations in proteins that constitute these repair pathways are characterised by radiosensitivity and genome instability. Defects in a number of these proteins also give rise to genetic disorders that feature not only genetic instability but also immunodeficiency, cancer predisposition, neurodegeneration and other pathologies. Conclusions: In the past fifty years our understanding of the cellular response to radiation damage has advanced enormously with insight being gained from a wide range of approaches extending from more basic early studies to the sophisticated approaches used today. In this review we discuss our current understanding of the impact of radiation on the cell and the organism gained from the array of past and present studies and attempt to provide an explanation for what it is that determines the response to radiation

Validation of the Spanish version of the borderline symptom list, short form (BSL-23)

Background: The Borderline Symptom List-23 (BSL-23) is a reliable and valid self-report instrument for assessing Borderline Personality Disorder (BPD) severity. The psychometric properties of the original version have proven to be adequate. The aim of the present study was to validate the Spanish language version of the BSL-23. Methods: The BSL-23 was administered to 240 subjects with BPD diagnosis. Factor structure, reliability, test-retest stability, convergent validity, and sensitivity to change were analyzed. Results: The Spanish version of the BSL-23 replicates the one-factor structure of the original version. The scale has high reliability (Cronbach's alpha=.949), as well as good test-retest stability, which was checked in a subsample (n=74; r=.734; p<.01). The Spanish BSL-23 shows moderate to high correlations with depressive symptomatology, state and trait anxiety, hostility and impulsivity scores and BPD measures. The Spanish BSL-23 is able to discriminate among different levels of BPD severity and shows satisfactory sensitivity to change after treatment, which was verified by assessing change before and after 12 group sessions of Dialectical Behavioral Therapy in a subgroup of 31 subjects. Conclusions: Similar to the original BSL-23, the Spanish BSL-23 is a reliable and valid instrument for assessing BPD severity and sensitivity to change

Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal

Mounting evidence suggests that there is frequently considerable variation in the risk of the outcome of interest in clinical trial populations. These differences in risk will often cause clinically important heterogeneity in treatment effects (HTE) across the trial population, such that the balance between treatment risks and benefits may differ substantially between large identifiable patient subgroups; the "average" benefit observed in the summary result may even be non-representative of the treatment effect for a typical patient in the trial. Conventional subgroup analyses, which examine whether specific patient characteristics modify the effects of treatment, are usually unable to detect even large variations in treatment benefit (and harm) across risk groups because they do not account for the fact that patients have multiple characteristics simultaneously that affect the likelihood of treatment benefit. Based upon recent evidence on optimal statistical approaches to assessing HTE, we propose a framework that prioritizes the analysis and reporting of multivariate risk-based HTE and suggests that other subgroup analyses should be explicitly labeled either as primary subgroup analyses (well-motivated by prior evidence and intended to produce clinically actionable results) or secondary (exploratory) subgroup analyses (performed to inform future research). A standardized and transparent approach to HTE assessment and reporting could substantially improve clinical trial utility and interpretability