Hematological deficiencies increase with aging, including anemias, reduced responses to hematopoietic stress and myelodysplasias. This investigation tested the hypothesis that increased bone marrow ...(BM) fat content in humans with age was associated with decreased numbers of side population (SP) hematopoietic stem cells, and this decrease correlated with changes in cytokine levels. BM was obtained from the femoral head and trochanteric region of the femur removed at surgery for total hip replacement (N = 100 subjects). In addition, BM from cadavers (N = 36), with no evidence of hip disease, was evaluated for fat content. Whole trabecular marrow samples were ground in a sterile mortar and pestle, and cellularity and lipid content determined. Marrow cells were stained with Hoechst dye and SP profiles were acquired. Plasma levels of insulin‐like growth factor (IGF)‐1, stromal‐derived factor (SDF)‐1 and interleukin (IL)‐6 were measured using ELISA. Fat content in the BM of human subjects and cadavers increased with age. The numbers of SP stem cells in BM as well as plasma IGF‐1 and SDF‐1 levels decreased in correlation with increased BM fat. IL‐6 had no relationship to changes in marrow fat. These data suggest that increased BM fat may be associated with a decreased number of SP stem cells and IGF‐1 and SDF‐1 levels with aging. These data further raise a more general question as to the role of adipose cells in the regulation of tissue stem cells.
Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with ...reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and 'enhancer hijacking' events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.
This phase 3 trial of enzyme-replacement therapy in children and adults with lysosomal acid lipase deficiency, which causes cirrhosis and severe dyslipidemia, showed that enzyme replacement lessened ...multiple disease-related hepatic and lipid abnormalities.
Lysosomal acid lipase deficiency (Online Mendelian Inheritance in Man number, 278000)
1
is an autosomal recessive storage disease that is caused by mutations in the
LIPA
gene.
2
In infants, progression of the disease (historically known as Wolman’s disease) is very rapid, with death typically occurring by 6 months of age.
2
In older patients, progression of the disease (historically known as cholesteryl ester storage disease) leads to cirrhosis and other complications in childhood or later in life.
3
Common features in infants, children, and adults include elevated serum aminotransferase levels, dyslipidemia, hepatomegaly, liver fibrosis, and cirrhosis.
3
–
5
Awareness of the disease is low, . . .
Aim
To harmonize two ascertainment and severity rating instruments commonly used for the clinical high risk syndrome for psychosis (CHR‐P): the Structured Interview for Psychosis‐risk Syndromes ...(SIPS) and the Comprehensive Assessment of At‐Risk Mental States (CAARMS).
Methods
The initial workshop is described in the companion report from Addington et al. After the workshop, lead experts for each instrument continued harmonizing attenuated positive symptoms and criteria for psychosis and CHR‐P through an intensive series of joint videoconferences.
Results
Full harmonization was achieved for attenuated positive symptom ratings and psychosis criteria, and modest harmonization for CHR‐P criteria. The semi‐structured interview, named Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS (PSYCHS), generates CHR‐P criteria and severity scores for both CAARMS and SIPS.
Conclusions
Using the PSYCHS for CHR‐P ascertainment, conversion determination, and attenuated positive symptom severity rating will help in comparing findings across studies and in meta‐analyses.
Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare ...setting, are often disappointingly low, at 25-30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome.
We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants.
Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving.
Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing.
To evaluate hoof size, shape, and balance as risk factors for catastrophic musculoskeletal injuries (CMI), including suspensory apparatus failure (SAF) and cannon bone condylar fracture (CDY) in ...Thoroughbred racehorses.
95 Thoroughbred racehorses that died between 1994 and 1996.
38 quantitative measures of hoof size, shape, and balance were obtained from orthogonal digital images of the hoof and were compared between case horses with forelimb CMI (70), SAF (43), and CDY (10) injuries and control horses whose death was unrelated to the musculoskeletal system (non-CMI, 25). Comparison of group means between cases and controls was done using ANOVA, and multivariable logistic regression was used to estimate odds ratios.
Odds of CMI were 0.62 times lower for a 5mm increase in ground surface width difference and 0.49 times lower for a 100-mm2 increase in sole area difference. Odds of SAF were 6.75 times greater with a 10 degrees increase in toe-heel angle difference and 0.58 times lower with a 100-mm2 increase in sole area difference. Odds of CDY were 0.26 times lower with a 3 degrees increase in toe angle, 0.15 times lower with a 5-mm increase in lateral ground surface width, and 0.35 times lower with a 100-mm2 increase in sole area difference.
Decreasing the difference between toe and heel angles should decrease risk of SAF for Thoroughbred racehorses and should be considered in addition to increasing toe angle alone to help prevent catastrophic injury. Trimming the hoof to perfect mediolateral symmetry may not be a sound approach to avoiding injury.
There is promise in combining stem cells with allogeneic bone matrix to promote bone healing. Murine bone marrow, peripheral blood, and compact bone cells were transplanted ectopically under the ...kidney capsule in mice, alone or in combination with allogeneic matrix products: powder and putty to determine their bone forming potential in comparison to transplanted femoral bone fragments and long-term cultured bone marrow cells. The end point was the amount of bone formed as determined by quantitative histology. Mononuclear cells from marrow, peripheral blood, or bone alone transplanted under the kidney capsule did not form bone. Mononuclear cell populations did not combine readily with matrix products and there was in vivo migration of the transplanted combinations. Kidney subcapsular transplanted cultured bone marrow cells formed bone in proportion to the culture period, but after 9 weeks, the extent was only 20% by area of that of similarly transplanted femoral bone fragments. An inductive stimulus for bone formation seemed necessary. Osteoprogenitor cells were not detected in significant numbers in blood unless high doses of cytokines were administered. A better definition of the optimal cell populations and manipulations required for promotion of bone healing is needed along with new (transplant) models that allow for cell tracking. Much work remains to overcome current pitfalls in the use of stem cells to promote allograft integration and bone healing.
Therapeutic study, Level V (expert opinion). See the Guidelines for Authors for a complete description of levels of evidence.
This edited collection addresses the institutional context and social issues in which teaching the women's studies introductory course is embedded and provides readers with practical classroom ...strategies to meet the challenges raised. The collection serves as a resource and preparatory text for all teachers of the course including experienced teachers, less experienced teachers, new faculty, and graduate student teaching assistants. The collection will also be of interest to educational scholars of feminist and progressive pedagogies and all teachers interested in innovative practices.The contributors discuss the larger political context in which the course has become a central representative of women's studies to a growing, although less feminist-identified, population. Increased enrollments and changes in student population are noted as a result, in part, of the popularity of Introduction to Women's Studies courses in fulfilling GED and diversity requirements. New forms of student resistance in a climate of backlash and changes in course content in response to internal and external challenges are also discussed. Evidence is provided for an emerging paradigm in the conceptualization of the introductory course as a result of challenges to racism, heterosexism, and classism in women's studies voiced by women of color and others in the 1980s and 1990s. Sensationalist charges that women's studies teachers, including those who teach the Introduction to Women's Studies course, are the academic shock troops of a monolithic feminism are challenged and refuted by the collection's contributors who share their struggles to make possible classrooms in which informed dialogue and disagreement are valued.
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