A multi-exon deletion within WWOX is associated with a 46,XY disorder of sex development

Disorders of sex development (DSD) are congenital conditions where chromosomal, gonad or genital development is atypical. In a significant proportion of 46,XY DSD cases it is not possible to identify a causative mutation, making genetic counseling difficult and potentially hindering optimal treatment. Here, we describe the analysis of a 46,XY DSD patient that presented at birth with ambiguous genitalia. Histological analysis of the surgically removed gonads showed bilateral undifferentiated gonadal tissue and immature testis, both containing malignant germ cells. We screened genomic DNA from this patient for deletions and duplications using an Illumina whole-genome SNP microarray. This analysis revealed a heterozygous deletion within the WWOX gene on chromosome 16, removing exons 6-8. Analysis of parental DNA showed that the deletion was inherited from the mother. cDNA analysis confirmed that the deletion maintained the reading frame, with exon 5 being spliced directly onto exon 9. This deletion is the first description of a germline rearrangement affecting the coding sequence of WWOX in humans. Previously described Wwox knockout mouse models showed gonadal abnormalities, supporting a role for WWOX in human gonad development

A High Deuterium Abundance at z=0.7

Of the light elements, the primordial abundance of deuterium, (D/H)_p, provides the most sensitive diagnostic for the cosmological mass density parameter Omega_B. Recent high redshift (D/H) measurements are highly discrepant, although this may reflect observational uncertainties. The larger (D/H) values, which imply a low Omega_B and require the Universe to be dominated by non-baryonic matter (dynamical studies indicate a higher total density parameter), cause problems for galactic chemical evolution models since they have difficulty in reproducing the large decline down to the lower present-day (D/H). Conversely, low (D/H) values imply an Omega_B greater than derived from ^7Li and ^4He abundance measurements, and may require a deuterium abundance evolution that is too low to easily explain. Here we report the first measurement at intermediate redshift, where the observational difficulties are smaller, of a gas cloud with ideal characteristics for this experiment. Our analysis of the z = 0.7010 absorber toward 1718+4807 indicates (D/H) = 2.0 +/- 0.5 x 10^{-4} which is in the high range. This and other independent observations suggests there may be a cosmological inhomogeneity in (D/H)_p of at least a factor of ten.Comment: 6 pages, 1 figur

High NRF2 expression controls endoplasmic reticulum stress induced apoptosis in multiple myeloma

Multiple myeloma (MM) is an incurable disease characterized by clonal plasma cell proliferation. The stress response transcription factor Nuclear factor erythroid 2 [NF-E2]-related factor 2 (NRF2) is known to be activated in MM in response to proteasome inhibitors (PI). Here, we hypothesize that the transcription factor NRF2 whose physiological role is to protect cells from reactive oxygen species via the regulation of drug metabolism and antioxidant gene plays an important role in MM cells survival and proliferation. We report for the first time that NRF2 is constitutively activated in circa 50% of MM primary samples and all MM cell lines. Moreover, genetic inhibition of constitutively expressed NRF2 reduced MM cell viability. We confirm that PI induced further expression of NRF2 in MM cell lines and primary MM. Furthermore, genetic inhibition of NRF2 of PI treated MM cells increased ER-stress through the regulation of CCAAT-enhancer-binding protein homologous protein (CHOP). Finally, inhibition of NRF2 in combination with PI treatment significantly increased apoptosis in MM cells. Here we identify NRF2 as a key regulator of MM survival in treatment naive and PI treated cells

An integrated approach to diagnosis and management of severe haemoptysis in patients admitted to the intensive care unit: a case series from a referral centre

BACKGROUND: Limited data are available concerning patients admitted to the intensive care unit (ICU) for severe haemoptysis. We reviewed a large series of patients managed in a uniform way to describe the clinical spectrum and outcome of haemoptysis in this setting, and better define the indications for bronchial artery embolisation (BAE). METHODS: A retrospective chart review of 196 patients referred for severe haemoptysis to a respiratory intermediate care ward and ICU between January 1999 and December 2001. A follow-up by telephone interview or a visit. RESULTS: Patients (148 males) were aged 51 (± sd, 16) years, with a median cumulated amount of bleeding averaging 200 ml on admission. Bronchiectasis, lung cancer, tuberculosis and mycetoma were the main underlying causes. In 21 patients (11%), no cause was identified. A first-line bronchial arteriography was attempted in 147 patients (75%), whereas 46 (23%) received conservative treatment. Patients who underwent BAE had a higher respiratory rate, greater amount of bleeding, persistent bloody sputum and/or evidence of active bleeding on fiberoptic bronchoscopy. When completed (n = 131/147), BAE controlled haemoptysis in 80% of patients, both in the short and long (> 30 days) terms. Surgery was mostly performed when bronchial arteriography had failed and/or bleeding recurred early after completed BAE. Bleeding was controlled by conservative measures alone in 44 patients. The ICU mortality rate was low (4%). CONCLUSION: Patients with evidence of more severe or persistent haemoptysis were more likely to receive BAE rather than conservative management. The procedure was effective and safe in most patients with severe haemoptysis, and surgery was mostly reserved to failure of arteriography and/or early recurrences after BAE

GPML: an XML-based standard for the interchange of genetic programming trees

We propose a Genetic Programming Markup Language (GPML), an XML based standard for the interchange of genetic programming trees, and outline the benefits such a format would bring in allowing the deployment of trained genetic programming (GP) models in applications as well as the subsidiary benefit of allowing GP researchers to directly share trained trees. We present a formal definition of this standard and describe details of an implementation. In addition, we present a case study where GPML is used to implement a model predictive controller for the control of a building heating plant

Dental management considerations for the patient with an acquired coagulopathy. Part 1: Coagulopathies from systemic disease

Current teaching suggests that many patients are at risk for prolonged bleeding during and following invasive dental procedures, due to an acquired coagulopathy from systemic disease and/or from medications. However, treatment standards for these patients often are the result of long-standing dogma with little or no scientific basis. The medical history is critical for the identification of patients potentially at risk for prolonged bleeding from dental treatment. Some time-honoured laboratory tests have little or no use in community dental practice. Loss of functioning hepatic, renal, or bone marrow tissue predisposes to acquired coagulopathies through different mechanisms, but the relationship to oral haemostasis is poorly understood. Given the lack of established, science-based standards, proper dental management requires an understanding of certain principles of pathophysiology for these medical conditions and a few standard laboratory tests. Making changes in anticoagulant drug regimens are often unwarranted and/or expensive, and can put patients at far greater risk for morbidity and mortality than the unlikely outcome of postoperative bleeding. It should be recognised that prolonged bleeding is a rare event following invasive dental procedures, and therefore the vast majority of patients with suspected acquired coagulopathies are best managed in the community practice setting

Two Major Medicinal Honeys Have Different Mechanisms of Bactericidal Activity

Honey is increasingly valued for its antibacterial activity, but knowledge regarding the mechanism of action is still incomplete. We assessed the bactericidal activity and mechanism of action of Revamil® source (RS) honey and manuka honey, the sources of two major medical-grade honeys. RS honey killed Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa within 2 hours, whereas manuka honey had such rapid activity only against B. subtilis. After 24 hours of incubation, both honeys killed all tested bacteria, including methicillin-resistant Staphylococcus aureus, but manuka honey retained activity up to higher dilutions than RS honey. Bee defensin-1 and H2O2 were the major factors involved in rapid bactericidal activity of RS honey. These factors were absent in manuka honey, but this honey contained 44-fold higher concentrations of methylglyoxal than RS honey. Methylglyoxal was a major bactericidal factor in manuka honey, but after neutralization of this compound manuka honey retained bactericidal activity due to several unknown factors. RS and manuka honey have highly distinct compositions of bactericidal factors, resulting in large differences in bactericidal activity

A high-velocity black hole on a Galactic-halo orbit in the solar neighborhood

Only a few of the dozen or so stellar-mass black holes have been observed away from the plane of the Galaxy$^1$. Those few could have been ejected from the plane as a result of a ``kick'' received during a supernova explosion, or they could be remnants of the population of massive stars formed in the early stages of evolution of the Galaxy. Determining their orbital motion should help to distinguish between these options. Here we report the transverse motion (in the plane of the sky) for the black hole X-ray nova XTE J1118+480 (refs 2-5), from which we derive a large space velocity. This X-ray binary has an eccentric orbit around the Galactic Centre, like most objects in the halo of the Galaxy, such as ancient stars and globular clusters. The properties of the system suggest that its age is comparable to or greater than the age of the Galactic disk. Only an extraordinary ``kick'' from a supernova could have launched the black hole into an orbit like this from a birth place in the disk of the Galaxy.Comment: 8 pages including 2 color figures. Additional figures and animation in http://www.iafe.uba.ar/astronomia/FM/mirabel.htm

Care of older people and people requiring palliative care with COVID-19: guidance from the Australian National COVID-19 Clinical Evidence Taskforce.

INTRODUCTION: Older people living with frailty and/or cognitive impairment who have coronavirus disease 2019 (COVID-19) experience higher rates of critical illness. There are also people who become critically ill with COVID-19 for whom a decision is made to take a palliative approach to their care. The need for clinical guidance in these two populations resulted in the formation of the Care of Older People and Palliative Care Panel of the National COVID-19 Clinical Evidence Taskforce in June 2020. This specialist panel consists of nursing, medical, pharmacy and allied health experts in geriatrics and palliative care from across Australia. MAIN RECOMMENDATIONS: The panel was tasked with developing two clinical flow charts for the management of people with COVID-19 who are i) older and living with frailty and/or cognitive impairment, and ii) receiving palliative care for COVID-19 or other underlying illnesses. The flow charts focus on goals of care, communication, medication management, escalation of care, active disease-directed care, and managing symptoms such as delirium, anxiety, agitation, breathlessness or cough. The Taskforce also developed living guideline recommendations for the care of adults with COVID-19, including a commentary to discuss special considerations when caring for older people and those requiring palliative care. CHANGES IN MANAGEMENT AS RESULT OF THE GUIDELINE: The practice points in the flow charts emphasise quality clinical care, with a focus on addressing the most important challenges when caring for older individuals and people with COVID-19 requiring palliative care. The adult recommendations contain additional considerations for the care of older people and those requiring palliative care