109 research outputs found
Expanding the genetics of microcephalic primordial dwarfism
Body mass varies considerably between different mammals and this variation is
largely accounted for by a difference in total cell number rather than individual cell
size. Insights into mechanisms regulating growth can therefore be gained by
understanding what governs total cell number at any one point. In addition, control
of cell proliferation and programmed cell death is fundamental to other areas of
research such as cancer and stem cell research. Microcephalic Primordial Dwarfism
(MPD) is a group of rare Mendelian human disorders in which there is an extreme
global failure of growth with affected individuals often only reaching a height of
around one metre in adulthood. To date, all identified disease genes follow an
autosomal recessive mode of inheritance and encode key regulators of the cell cycle,
where mutations impact on overall cell number and result in a substantially reduced
body size. MPD therefore provides a valuable model for examining genetic and
cellular mechanisms that impact on growth. The overall aims of this thesis were to
identify novel disease causing genes, as well as provide further characterisation of
known disease causing genes, through the analysis of whole exome sequencing
(WES) within a large cohort of MPD patients. Following the design and
implementation of an analytical bioinformatics pipeline, deleterious mutations were
identified in multiple disease genes including LIG4 and XRCC4. Both genes encode
components of the non-homologous end joining machinery, a DNA repair
mechanism not previously implicated in MPD. Additionally, the pathogenicity of
novel mutations in subunits of a protein complex involved in chromosome
segregation was assessed using patient-derived cells. These findings demonstrate
WES can be successfully implemented to identify known and novel disease causing
genes within a large heterogeneous cohort of patients, expanding the phenotype of
known disorders and improving diagnosis as well as providing novel insights into
intrinsic cellular mechanisms critical to growth
A novel nonsense CDK5RAP2 mutation in a Somali child with primary microcephaly and sensorineural hearing loss
Primary microcephaly is a genetically heterogeneous condition characterized by reduced head circumference (-3 SDS or more) and mild-to-moderate learning disability. Here, we describe clinical and molecular investigations of a microcephalic child with sensorineural hearing loss. Although consanguinity was unreported initially, detection of 13.7 Mb of copy neutral loss of heterozygosity (cnLOH) on chromosome 9 implicated the CDK5RAP2 gene. Targeted sequencing identified a homozygous E234X mutation, only the third mutation to be described in CDK5RAP2, the first in an individual of non-Pakistani descent. Sensorineural hearing loss is not generally considered to be consistent with autosomal recessive microcephaly and therefore it seems likely that the deafness in this individual is caused by the co-occurrence of a further gene mutation, independent of CDK5RAP2. Nevertheless, further detailed clinical descriptions of rare CDK5RAP2 patients, including hearing assessments will be needed to resolve fully the phenotypic range associated with mutations in this gene. This study also highlights the utility of SNP-array testing to guide disease gene identification where an autosomal recessive condition is plausible
Patient Outcomes at Twelve Months after Early Decompressive Craniectomy for Diffuse Traumatic Brain Injury in the Randomized DECRA Clinical Trial
Functional outcomes at 12 months were a secondary outcome of the randomized DECRA trial of early decompressive craniectomy for severe diffuse traumatic brain injury (TBI) and refractory intracranial hypertension. In the DECRA trial, patients were randomly allocated 1:1 to either early decompressive craniectomy or intensive medical therapies (standard care). We conducted planned secondary analyses of the DECRA trial outcomes at 6 and 12 months, including all 155 patients. We measured functional outcome using the Glasgow Outcome Scale-Extended (GOS-E). We used ordered logistic regression, and dichotomized the GOS-E using logistic regression, to assess outcomes in patients overall and in survivors. We adjusted analyses for injury severity using the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) model. At 12 months, the odds ratio (OR) for worse functional outcomes in the craniectomy group (OR 1.68; 95% confidence interval [CI]: 0.96-2.93; p = 0.07) was no longer significant. Unfavorable functional outcomes after craniectomy were 11% higher (59% compared with 48%), but were not significantly different from standard care (OR 1.58; 95% CI: 0.84-2.99; p = 0.16). Among survivors after craniectomy, there were fewer good (OR 0.33; 95% CI: 0.12-0.91; p = 0.03) and more vegetative (OR 5.12; 95% CI: 1.04-25.2; p = 0.04) outcomes. Similar outcomes in survivors were found at 6 months after injury. Vegetative (OR 5.85; 95% CI: 1.21-28.30; p = 0.03) and severely disabled outcomes (OR 2.49; 95% CI: 1.21-5.11; p = 0.01) were increased. Twelve months after severe diffuse TBI and early refractory intracranial hypertension, decompressive craniectomy did not improve outcomes and increased vegetative survivors
Superhumps in Cataclysmic Binaries. XXV. q_crit, epsilon(q), and Mass-Radius
We report on successes and failures in searching for positive superhumps in
cataclysmic variables, and show the superhumping fraction as a function of
orbital period. Basically, all short-period systems do, all long-period systems
don't, and a 50% success rate is found at P_orb=3.1+-0.2 hr. We can use this to
measure the critical mass ratio for the creation of superhumps. With a
mass-radius relation appropriate for cataclysmic variables, and an assumed mean
white-dwarf mass of 0.75 M_sol, we find a mass ratio q_crit=0.35+-0.02.
We also report superhump studies of several stars of independently known mass
ratio: OU Virginis, XZ Eridani, UU Aquarii, and KV UMa (= XTE J1118+480). The
latter two are of special interest, because they represent the most extreme
mass ratios for which accurate superhump measurements have been made. We use
these to improve the epsilon(q) calibration, by which we can infer the elusive
q from the easy-to-measure epsilon (the fractional period excess of P_superhump
over P_orb). This relation allows mass and radius estimates for the secondary
star in any CV showing superhumps. The consequent mass-radius law shows an
apparent discontinuity in radius near 0.2 M_sol, as predicted by the disrupted
magnetic braking model for the 2.1-2.7 hour period gap. This is effectively the
"empirical main sequence" for CV secondaries.Comment: PDF, 45 pages, 9 tables, 12 figures; accepted, in press, to appear
November 2005, PASP; more info at http://cba.phys.columbia.edu
Early detection and intervention evaluation for people at risk of psychosis: multisite randomised controlled trial
Objective To determine whether cognitive therapy is effective in preventing the worsening of emerging psychotic symptoms experienced by help seeking young people deemed to be at risk for serious conditions such as schizophrenia
Embedding Physical Activity into Community-Based Peer Support Groups for those Severely Affected by Mental Illness
Despite a growing evidence base on the effectiveness of community-based physical activity interventions for mental health, there is a lack of studies that focus on those affected by severe mental illness (SMI), who often experience poorer physical health, and are less physically active than the wider population. The use of peer support groups in this context is also understudied, despite benefits being documented in other contexts. This study examined the impact and process of a nationwide project to embed physical activity into peer support groups for those affected by SMI. Following the embedding of physical activity within peer support groups, interviews and focus groups were conducted to explore the experiences of those involved with the project and analysed using reflexive thematic analysis. The key findings related to: 1) the social aspects of embedding physical activity in the groups; 2) the focus on peer support and informal physical activity (rather than organised sport) being beneficial; 3) doing things differently and lessons to learn; and 4) the impact of the COVID-19 pandemic. Overall, we found that peer support is an important feature to include in projects encouraging those severely affected by mental illness to become more physically active
Clinical practice guidelines for the diagnosis and surveillance of BAP1 tumour predisposition syndrome
BRCA1-associated protein-1 (BAP1) is a recognised tumour suppressor gene. Germline BAP1 pathogenic/likely pathogenic variants are associated with predisposition to multiple tumours, including uveal melanoma, malignant pleural and peritoneal mesothelioma, renal cell carcinoma and specific non-malignant neoplasms of the skin, as part of the autosomal dominant BAP1-tumour predisposition syndrome. The overall lifetime risk for BAP1 carriers to develop at least one BAP1-associated tumour is up to 85%, although due to ascertainment bias, current estimates of risk are likely to be overestimated. As for many rare cancer predisposition syndromes, there is limited scientific evidence to support the utility of surveillance and, therefore, management recommendations for BAP1 carriers are based on expert opinion. To date, European recommendations for BAP1 carriers have not been published but are necessary due to the emerging phenotype of this recently described syndrome and increased identification of BAP1 carriers via large gene panels or tumour sequencing. To address this, the Clinical Guideline Working Group of the CanGene-CanVar project in the United Kingdom invited European collaborators to collaborate to develop guidelines to harmonize surveillance programmes within Europe. Recommendations with respect to BAP1 testing and surveillance were achieved following literature review and Delphi survey completed by a core group and an extended expert group of 34 European specialists including Geneticists, Ophthalmologists, Oncologists, Dermatologists and Pathologists. It is recognised that these largely evidence-based but pragmatic recommendations will evolve over time as further data from research collaborations informs the phenotypic spectrum and surveillance outcomes.</p
How has the OSD affected our state hospitals?
The long-awaited occupation-specific dispensation (OSD) process for state-employed doctors has now been concluded. The final offer, signed and accepted in the bargaining chamber despite being rejected by 92% of doctors in a SAMA survey, has not received much attention or fanfare. At the conclusion of this process, which has been drawn out over several years, many points have emerged that are extremely worrying for the future of health care in this country
DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency.
During genome replication, polymerase epsilon (Pol Δ) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol Δ catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol Δ and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins
- âŠ