The association between circulating CD34+CD133+ endothelial progenitor cells and reduced risk of Alzheimer's disease in the Framingham Heart Study.

Aim: Endothelial dysfunction has been associated with both cerebrovascular pathology and Alzheimer's disease (AD). However, the connection between circulating endothelial cells and the risk of AD remains uncertain. The objective was to leverage data from the Framingham Heart Study to investigate various circulating endothelial subtypes and their potential correlations with the risk of AD. Methods: The study conducted data analyses using Cox proportional hazard regression and linear regression methods. Additionally, genome-wide association study (GWAS) was carried out to further explore the data. Results: Among the eleven distinct circulating endothelial subtypes, only circulating endothelial progenitor cells (EPCs) expressing CD34+CD133+ were found to be negatively and dose-dependently associated with reduced AD risk. This association persisted even after adjusting for age, sex, years of education, apolipoprotein E (APOE) ε4 status, and various vascular diseases. Particularly noteworthy was the significant association observed in individuals with hypertension and cerebral microbleeds. Consistently, positive associations were identified between CD34+CD133+ EPCs and specific brain regions, such as higher proportions of circulating CD34+CD133+ cells correlating with increased volumes of white matter and the hippocampus. Additionally, a GWAS study unveiled that CD34+CD133+ cells influenced AD risk specifically in individuals with homozygous genotypes for variants in two stem cell-related genes: kirre like nephrin family adhesion molecule 3 (KIRREL3, rs580382 CC and rs4144611 TT) and exocyst complex component 6B (EXOC6B, rs61619102 CC). Conclusions: The findings suggest that circulating CD34+CD133+ EPCs possess a protective effect and may offer a new therapeutic avenue for AD, especially in individuals with vascular pathology and those carrying specific genotypes of KIRREL3 and EXOC6B genes.

Scapulothoracic tenodesis using hamstring tendon graft for treatment of problematic scapula winging: A new surgical technique.

Introduction: Winging of the scapula occurs due to dysfunction of its stabilising muscles, most commonly serratus anterior and/or trapezius, for example in facioscapulohumeral muscular dystrophy. Resultant loss of scapular control and abnormal kinematics can decrease shoulder function due to glenohumeral joint instability, loss of range of motion and pain. Previously described treatment for cases resistant to physiotherapy includes scapulothoracic arthrodesis which involves risk of non-union and metalwork failure, as well as reduced respiratory function due to immobilisation of a segment of the adjacent chest wall. Technique: We present a novel surgical approach to the management of problematic scapular winging by using hamstring graft to achieve a scapulothoracic tenodesis. Discussion: We believe this technique provides an adequately stable scapula for improved shoulder movement and function, a sufficiently mobile chest wall for improved lung function and avoidance of complications specifically associated with arthrodesis.

Mitigation of Fetal Irradiation Injury from Mid-Gestation Total Body Radiation with Mitochondrial-Targeted GS-Nitroxide JP4-039.

Victims of a radiation terrorist event will include pregnant women and unborn fetuses. Mitochondrial dysfunction and oxidative stress are key pathogenic factors of fetal irradiation injury. The goal of this preclinical study is to investigate the efficacy of mitigating fetal irradiation injury by maternal administration of the mitochondrial-targeted gramicidin S (GS)- nitroxide radiation mitigator, JP4-039. Pregnant female C57BL/6NTac mice received 3 Gy total body ionizing irradiation (TBI) at mid-gestation embryonic day 13.5 (E13.5). Using novel time- and-motion-resolved 4D in utero magnetic resonance imaging (4D-uMRI), we found TBI caused extensive injury to the fetal brain that included cerebral hemorrhage, loss of cerebral tissue, and hydrocephalus with excessive accumulation of cerebrospinal fluid (CSF). Histopathology of the fetal mouse brain showed broken cerebral vessels and elevated apoptosis. Further use of novel 4D Oxy-wavelet MRI capable of probing in vivo mitochondrial function in intact brain revealed significant reduction of mitochondrial function in the fetal brain after 3Gy TBI. This was validated by ex vivo Oroboros mitochondrial respirometry. Maternal administration JP4-039 one day after TBI (E14.5), which can pass through the placental barrier, significantly reduced fetal brain radiation injury and improved fetal brain mitochondrial respiration. This also preserved cerebral brain tissue integrity and reduced cerebral hemorrhage and cell death. As JP4-039 administration did not change litter sizes or fetus viability, together these findings indicate JP4-039 can be deployed as a safe and effective mitigator of fetal radiation injury from mid-gestational in utero ionizing radiation exposure. One Sentence Summary: Mitochondrial-targeted gramicidin S (GS)-nitroxide JP4-039 is safe and effective radiation mitigator for mid-gestational fetal irradiation injury.

Antagonism of regulatory ISGs enhances the anti-melanoma efficacy of STING agonists.

Background: Stimulator of Interferon Genes (STING) is a dsDNA sensor that triggers type I inflammatory responses. Recent data from our group and others support the therapeutic efficacy of STING agonists applied intratumorally or systemically in a range of murine tumor models, with treatment benefits associated with tumor vascular normalization and improved immune cell recruitment and function within the tumor microenvironment (TME). However, such interventions are rarely curative and STING agonism coordinately upregulates expression of immunoregulatory interferon-stimulated genes (ISGs) including Arg2, Cox2, Isg15, Nos2, and Pdl1 that may limit treatment benefits. We hypothesized that combined treatment of melanoma-bearing mice with STING agonist ADU-S100 together with antagonists of regulatory ISGs would result in improved control of tumor growth vs. treatment with ADU-S100 alone. Methods: Mice bearing either B16 (BRAFWTPTENWT) or BPR20 (BRAFV600EPTEN-/-) melanomas were treated with STING agonist ADU-S100 plus various inhibitors of ARG2, COX2, NOS2, PD-L1, or ISG15. Tumor growth control and changes in the TME were evaluated for combination treatment vs ADU-S100 monotherapy by tumor area measurements and flow cytometry/transcriptional profiling, respectively. Results: In the B16 melanoma model, we noted improved antitumor efficacy only when ADU-S100 was combined with neutralizing/blocking antibodies against PD-L1 or ISG15, but not inhibitors of ARG2, COX2, or NOS2. Conversely, in the BPR20 melanoma model, improved tumor growth control vs. ADU-S100 monotherapy was only observed when combining ADU-S100 with ARG2i, COX2i, and NOS2i, but not anti-PD-L1 or anti-ISG15. Immune changes in the TME associated with improved treatment outcomes were subtle but included increases in proinflammatory innate immune cells and activated CD8+CD69+ T cells and varied between the two tumor models. Conclusions: These data suggest contextual differences in the relative contributions of individual regulatory ISGs that serve to operationally limit the anti-tumor efficacy of STING agonists which should be considered in future design of novel combination protocols for optimal treatment benefit.

Analysis of the interplay between MeCP2 and histone H1 during in vitro differentiation of human ReNCell neural progenitor cells.

An immortalized neural cell line derived from the human ventral mesencephalon, called ReNCell, and its MeCP2 knock out were used. With it, we characterized the chromatin compositional transitions undergone during differentiation, with special emphasis on linker histones. While the WT cells displayed the development of dendrites and axons the KO cells did not, despite undergoing differentiation as monitored by NeuN. ReNCell expressed minimal amounts of histone H1.0 and their linker histone complement consisted mainly of histone H1.2, H1.4 and H1.5. The overall level of histone H1 exhibited a trend to increase during the differentiation of MeCP2 KO cells. The phosphorylation levels of histone H1 proteins decreased dramatically during ReNCell's cell differentiation independently of the presence of MeCP2. Immunofluorescence analysis showed that MeCP2 exhibits an extensive co-localization with linker histones. Interestingly, the average size of the nucleus decreased during differentiation but in the MeCP2 KO cells, the smaller size of the nuclei at the start of differentiation increased by almost 40% after differentiation by 8 days (8 DIV). In summary, our data provide a compelling perspective on the dynamic changes of H1 histones during neural differentiation, coupled with the intricate interplay between H1 variants and MeCP2.Abbreviations: ACN, acetonitrile; A230, absorbance at 230 nm; bFGF, basic fibroblast growth factor; CM, chicken erythrocyte histone marker; CNS, central nervous system; CRISPR, clustered regulated interspaced short palindromic repeatsDAPI, 4,'6-diaminidino-2-phenylindole; DIV, days in vitro (days after differentiation is induced); DMEM, Dulbecco's modified Eagle medium; EGF, epidermal growth factor; ESC, embryonic stem cell; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFAP, glial fibrillary acidic proteinHPLC, high-performance liquid chromatography; IF, immunofluorescence; iPSCs, induced pluripotent stem cells; MAP2, microtubule-associated protein 2; MBD, methyl-binding domain; MeCP2, methyl-CpG binding protein 2; MS, mass spectrometry; NCP, nucleosome core particle; NeuN, neuron nuclear antigen; NPC, neural progenitor cellPAGE, polyacrylamide gel electrophoresis; PBS, phosphate buffered saline; PFA, paraformaldehyde; PTM, posttranslational modification; RP-HPLC, reversed phase HPLC; ReNCells, ReNCells VM; RPLP0, ribosomal protein lateral stalk subunit P0; RT-qPCR, reverse transcription quantitative polymerase-chain reaction; RTT, Rett Syndrome; SDS, sodium dodecyl sulphate; TAD, topologically associating domain; Triple KO, triple knockout.

Phosphorylation Promotes DELLA Activity by Enhancing Its Binding to Histone H2A at Target Chromatin in Arabidopsis.

DELLA proteins are conserved master growth regulators that play a central role in controlling plant development in response to internal and environmental cues. DELLAs function as transcription regulators, which are recruited to target promoters by binding to transcription factors (TFs) and histone H2A via its GRAS domain. Recent studies showed that DELLA stability is regulated post-translationally via two mechanisms, phytohormone gibberellin-induced polyubiquitination for its rapid degradation, and Small Ubiquitin-like Modifier (SUMO)- conjugation to alter its accumulation. Moreover, DELLA activity is dynamically modulated by two distinct glycosylations: DELLA-TF interactions are enhanced by O -fucosylation, but inhibited by O -linked N -acetylglucosamine ( O -GlcNAc) modification. However, the role of DELLA phosphorylation remains unclear. Here, we identified phosphorylation sites in REPRESSOR OF ga1-3 (RGA, an AtDELLA) purified from Arabidopsis by tandem mass spectrometry analysis, and showed that phosphorylation of the RGA LKS-peptide in the poly- S/T region enhances RGA-H2A interaction and RGA association with target promoters. Interestingly, phosphorylation does not affect RGA-TF interactions. Our study has uncovered that phosphorylation is a new regulatory mechanism of DELLA activity.

Patient-Reported Outcomes Improve after Hypothenar Fat Flap for the Treatment of Recurrent Carpal Tunnel Syndrome.

Background: Recalcitrant carpal tunnel syndrome (CTS) can present with persistent or recurrent symptoms after carpal tunnel release (CTR). A common aetiology for recurrent CTS is the development of perineural adhesions due to excess scarring. The hypothenar fat pad flap (HFPF) has been described to decrease the amount of scarring formed after revision CTR. Herein, we present a prospective evaluation of these patients. Methods: A prospective series of consecutive patients by a single surgeon with recurrent CTS was conducted. All patients had at least 3 months follow-up. Patients received a revision open CTR with HFPF. The primary outcome was the Boston Carpal Tunnel Questionnaire (BCTQ). Secondary outcomes included pain and satisfaction on visual analogue scale, range of motion, grip strength, patient-reported outcomes and complications. Clinical outcomes were compared between preoperative and postoperative intervals using paired t-tests, with significance defined as p < 0.05. Results: Fifteen wrists (14 patients) were recruited for the study. Patients were predominantly male (n = 9; 66%). Revision open CTR with HFPF was performed a median of 42 months (range: 4-300 months) post primary CTR. Patients demonstrated improved patient-reported outcomes with significantly improved BCTQ pain score (p < 0.01), Patient-Rated Wrist and Hand Evaluation (p < 0.01) and QuickDASH (p < 0.001). Two patients in the series reported postoperative complications; however, there was no incidence of donor site morbidity recorded. Conclusions: Revision open CTR with hypothenar fat pad flap is associated with decreased pain, high patient satisfaction and improved functional measures compared to pre-operative status. Level of Evidence: Level IV (Therapeutic).

Longitudinal 3-D Visualization of Microvascular Disruption and Perfusion Changes in Mice During the Evolution of Glioblastoma Using Super-Resolution Ultrasound.

Glioblastoma is an aggressive brain cancer with a very poor prognosis in which less than 6% of patients survive more than five-year post-diagnosis. The outcome of this disease for many patients may be improved by early detection. This could provide clinicians with the information needed to take early action for treatment. In this work, we present the utilization of a non-invasive, fully volumetric ultrasonic imaging method to assess microvascular change during the evolution of glioblastoma in mice. Volumetric ultrasound localization microscopy (ULM) was used to observe statistically significant ( ) reduction in the appearance of functional vasculature over the course of three weeks. We also demonstrate evidence suggesting the reduction of vascular flow for vessels peripheral to the tumor. With an 82.5% consistency rate in acquiring high-quality vascular images, we demonstrate the possibility of volumetric ULM as a longitudinal method for microvascular characterization of neurological disease.

Shoulder joint arthroplasty in young patients: Analysis of 8742 patients from the Australian Orthopaedic Association National Joint Replacement Registry.

Background: Shoulder replacement is a reliable treatment for the relief of pain and improvement of function in patients with glenohumeral arthritis, rotator cuff arthropathy, osteonecrosis and fracture. Limited data is available comparing revision rates for the different types of shoulder replacement when used in younger patients. This study aims to compare the survivorship of hemi resurfacing, stemmed hemiarthroplasty, total shoulder arthroplasty and reverse total shoulder arthroplasty in younger patients using data from a large national arthroplasty registry. Methods: Data from the Australian Orthopaedic Association National Joint Replacement Registry was obtained for the period 16 April 2004-31 December 2018. The study population included all shoulder arthroplasty patients aged <65 years. These were stratified into two groups: <55 years and 55-64 years. A total of 8742 primary shoulder arthroplasty procedures were analysed (1936 procedures in the <55 years and 6806 in the 55-64 years age group). Results: In the <55 years age group, there was no difference in revision rate for total shoulder arthroplasty versus reverse total shoulder arthroplasty at any time point. Reverse total shoulder arthroplasty had a lower revision rate after six months when compared to hemi resurfacing (HRA) (p = 0.031). Also, reverse total shoulder arthroplasty had a higher early rate of revision in the first 12 months compared to hemiarthroplasty (p = 0.018). However, from 2 years reverse total shoulder arthroplasty had a lower revision rate overall (p = 0.029).In the 55-64 years patient age group, reverse total shoulder arthroplasty had a lower earlier revision rate. This was statistically significant compared to hemi resurfacing (HRA) (p = 0.028), hemiarthroplasty (p = 0.049) and total shoulder arthroplasty (p < 0.001). Conclusion: This study demonstrated that for patients aged <55 years there was no significant difference in the rate of revision when total shoulder arthroplasty and reverse total shoulder arthroplasty were compared. reverse total shoulder arthroplasty had a lower rate of revision when compared to hemi resurfacing and hemiarthroplasty after 2 years. reverse total shoulder arthroplasty had the lowest comparative revision rate in patients aged 55-64 years overall.

Whole-Genome Sequencing Can Identify Clinically Relevant Variants from a Single Sub-Punch of a Dried Blood Spot Specimen.

The collection of dried blood spots (DBS) facilitates newborn screening for a variety of rare, but very serious conditions in healthcare systems around the world. Sub-punches of varying sizes (1.5-6 mm) can be taken from DBS specimens to use as inputs for a range of biochemical assays. Advances in DNA sequencing workflows allow whole-genome sequencing (WGS) libraries to be generated directly from inputs such as peripheral blood, saliva, and DBS. We compared WGS metrics obtained from libraries generated directly from DBS to those generated from DNA extracted from peripheral blood, the standard input for this type of assay. We explored the flexibility of DBS as an input for WGS by altering the punch number and size as inputs to the assay. We showed that WGS libraries can be successfully generated from a variety of DBS inputs, including a single 3 mm or 6 mm diameter punch, with equivalent data quality observed across a number of key metrics of importance in the detection of gene variants. We observed no difference in the performance of DBS and peripheral-blood-extracted DNA in the detection of likely pathogenic gene variants in samples taken from individuals with cystic fibrosis or phenylketonuria. WGS can be performed directly from DBS and is a powerful method for the rapid discovery of clinically relevant, disease-causing gene variants.

The exercise IL-6 enigma in cancer.

Interleukin (IL)-6 elicits both anticancer and procancer effects depending on the context, which we have termed the 'exercise IL-6 enigma'. IL-6 is released from skeletal muscles during exercise to regulate short-term energy availability. Exercise-induced IL-6 provokes biological effects that may protect against cancer by improving insulin sensitivity, stimulating the production of anti-inflammatory cytokines, mobilising immune cells, and reducing DNA damage in early malignant cells. By contrast, IL-6 continuously produced by leukocytes in inflammatory sites drives tumorigenesis by promoting chronic inflammation and activating tumour-promoting signalling pathways. How can a molecule have such opposing effects on cancer? Here, we review the roles of IL-6 in chronic inflammation, tumorigenesis, and exercise-associated cancer prevention and define the factors that underpin the exercise IL-6 enigma.

Predicting small molecule binding pockets on diacylglycerol kinases using chemoproteomics and AlphaFold.

Diacylglycerol kinases (DGKs) are metabolic kinases involved in regulating cellular levels of diacylglycerol and phosphatidic lipid messengers. The development of selective inhibitors for individual DGKs would benefit from discovery of protein pockets available for inhibitor binding in cellular environments. Here we utilized a sulfonyl-triazole probe (TH211) bearing a DGK fragment ligand for covalent binding to tyrosine and lysine sites on DGKs in cells that map to predicted small molecule binding pockets in AlphaFold structures. We apply this chemoproteomics-AlphaFold approach to evaluate probe binding of DGK chimera proteins engineered to exchange regulatory C1 domains between DGK subtypes (DGKα and DGKζ). Specifically, we discovered loss of TH211 binding to a predicted pocket in the catalytic domain when C1 domains on DGKα were exchanged that correlated with impaired biochemical activity as measured by a DAG phosphorylation assay. Collectively, we provide a family-wide assessment of accessible sites for covalent targeting that combined with AlphaFold revealed predicted small molecule binding pockets for guiding future inhibitor development of the DGK superfamily.

Clinical Outcomes of Arthroscopic Ligament-Sparing Dorsal Capsulodesis for Partial Scapholunate Ligament Tear.

Introduction Various wrist arthroscopy techniques can be used in the management of scapholunate ligament (SLL) partial tears but their success has not been proven. Arthroscopic techniques including thermal shrinkage are becoming more popular in the management of partial SLL injuries. We hypothesized that arthroscopic ligament-sparing capsular tightening yields reliable and satisfactory results for the management of partial SLL tears. Methods A prospective cohort study was conducted on adult (age ≥18 years) patients with chronic partial SLL tears. All patients failed a trial of conservative management consisting of scapholunate strengthening exercises. Patients underwent an arthroscopic dorsal capsular tightening of the radiocarpal joint capsule radial to the origin of the dorsal radiocarpal ligament and proximal to the dorsal intercarpal ligament by either thermal shrinkage or dorsal capsule abrasion. Demographic data, radiological outcomes, patient-rated outcome measures and objective measures of wrist range of motion (ROM), and grip and pinch strength were recorded. Postoperative outcome scores were collected at 3, 6, 12, and 24 months. Data are reported as median and interquartile range, and comparisons were drawn between baseline and last follow-up. Clinical outcome data were analyzed using a linear mixed model method, while radiographic outcomes were assessed with nonparametric analysis with p < 0.05 indicating statistical significance. Results Twenty-three wrists (22 patients) underwent SLL treatment by thermal capsular shrinkage (19 wrists) or dorsal capsular abrasion (4 wrists). Median age at surgery was 41 years (range: 32-48) and median follow-up time was 12 months (range: 3-24). Pain significantly decreased from 62 (45-76) to 18 (7-41) and satisfaction significantly increased from 2 (0-24) to 86 (52-92). Patient-Rated Wrist and Hand Evaluation and Quick Disabilities of the Arm, Shoulder, and Hand significantly improved from 68 (38-78) to 34 (13-49) and from 48 (27-55) to 36 (4-58), respectively. Median grip and tip pinch strength significantly increased at final review. Range of movement and lateral pinch strength were satisfactory and maintained. Four patients required further surgery for ongoing pain or reinjury. All were successfully managed with partial wrist fusion or wrist denervation. Conclusion Arthroscopic ligament-sparing dorsal capsular tightening is a safe and effective treatment for partial SLL tears. Dorsal capsular tightening demonstrates good pain relief and patient satisfaction while improving patient-reported outcomes, grip strength, and maintaining ROM. Longer term studies are required to determine the longevity of these results.

Survivorship of shoulder arthroplasty in young patients with osteoarthritis: an analysis of the Australian Orthopaedic Association National Joint Replacement Registry.

BACKGROUND: The treatment of shoulder osteoarthritis in the young patient remains challenging. The higher functional demands and higher expectations of the young patient cohort are often coupled with increased failure and revision rates. Consequently, shoulder surgeons are faced with a unique challenge with implant selection. The aim of this study was to compare the survivorship and reasons for revision of 5 classes of shoulder arthroplasty in patients aged <55 years with a primary diagnosis of osteoarthritis by use of data from a large national arthroplasty registry. METHODS: The study population included all primary shoulder arthroplasty procedures undertaken for osteoarthritis in patients aged <55 years and reported to the registry between September 1999 and December 2021. Procedures were grouped into the following classes: total shoulder arthroplasty (TSA), hemiarthroplasty resurfacing (HRA), hemiarthroplasty stemmed metallic head (HSMH), hemiarthroplasty stemmed pyrocarbon head (HSPH), and reverse total shoulder arthroplasty (RTSA). The outcome measure was the cumulative percent revision, which was defined using Kaplan-Meier estimates of survivorship to describe the time to the first revision. Hazard ratios (HRs) were calculated from Cox proportional hazards models, adjusting for age and sex, to compare revision rates among groups. RESULTS: There were 1564 shoulder arthroplasty procedures in patients aged <55 years, of which 361 (23.1%) were HRA, 70 (4.5%) were HSMH, 159 (10.2%) were HSPH, 714 (45.7%) were TSA, and 260 (16.6%) were RTSA. HRA had a higher rate of revision than RTSA after 1 year (HRA = 2.51 (95% CI 1.30, 4.83), P = .005), with no difference prior to that time. In addition, HSMH had a higher rate of revision than RTSA for the entire period (HR, 2.69 [95% confidence interval, 1.28-5.63], P = .008). There was no significant difference in the rate of revision for HSPH and TSA when they were compared with RTSA. Glenoid erosion was the most common cause of revision for HRA (28.6% of revisions) and HSMH (50%). Instability/dislocation was the leading cause of revision for RTSA (41.7%) and HSPH (28.6%), and for TSA, the majority of revisions were for either instability/dislocation (20.6%) or loosening (18.6%). CONCLUSION: These results should be interpreted within the context of the lack of availability of long-term data on RTSA and HSPH stems. RTSA outperforms all implants regarding revision rates at mid-term follow-up. The high early dislocation rate associated with RTSA, as well as the lack of revision options available to address this, indicates that careful selection of patients and a greater appreciation of anatomic risk factors are needed in the future.

The genomic landscape of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21.

Intrachromosomal amplification of chromosome 21 defines a subtype of high-risk childhood acute lymphoblastic leukemia (iAMP21-ALL) characterized by copy number changes and complex rearrangements of chromosome 21. The genomic basis of iAMP21-ALL and the pathogenic role of the region of amplification of chromosome 21 to leukemogenesis remains incompletely understood. In this study, using integrated whole genome and transcriptome sequencing of 124 patients with iAMP21-ALL, including rare cases arising in the context of constitutional chromosomal aberrations, we identified subgroups of iAMP21-ALL based on the patterns of copy number alteration and structural variation. This large data set enabled formal delineation of a 7.8 Mb common region of amplification harboring 71 genes, 43 of which were differentially expressed compared with non-iAMP21-ALL ones, including multiple genes implicated in the pathogenesis of acute leukemia (CHAF1B, DYRK1A, ERG, HMGN1, and RUNX1). Using multimodal single-cell genomic profiling, including single-cell whole genome sequencing of 2 cases, we documented clonal heterogeneity and genomic evolution, demonstrating that the acquisition of the iAMP21 chromosome is an early event that may undergo progressive amplification during disease ontogeny. We show that UV-mutational signatures and high mutation load are characteristic secondary genetic features. Although the genomic alterations of chromosome 21 are variable, these integrated genomic analyses and demonstration of an extended common minimal region of amplification broaden the definition of iAMP21-ALL for more precise diagnosis using cytogenetic or genomic methods to inform clinical management.

Practice Variation in Proximal Phalangeal Fracture Management.

Background: Practice variation may indicate a lack of evidence to guide management. This study investigated the preferences of operative management of proximal phalangeal fractures in Australian hand surgeons, as well as factors that may account for variations. Methods: An electronic survey of all members of the Australian Hand Surgery Society was performed. Surgeon demographic factors and surgical preferences were investigated. Three common proximal phalangeal fracture configurations were presented as cases. Potential predictors of management were explored. Results: A total of 51.9% of active hand surgeons responded. Orthopaedic surgeons were more comfortable with lateral plating and intramedullary screw fixation, while plastic surgeons preferred Kirschner wire (K-wire) fixation. Junior surgeons were more likely to believe that intramedullary screw fixation produced superior results. 53.0% of surgeons in a tertiary environment believed that adequate hand therapy was key (compared to 17.0% of clinicians in a secondary hospital). Conclusions: There is significant practice variation and a lack of standards in the management of a common clinical problem, as well as a lack of consensus on the evidence underpinning common fixation methods. Further research is needed. Level of Evidence: Level IV (Therapeutic).

Loss of DNA repair mechanisms in cardiac myocytes induce dilated cardiomyopathy.

Cardiomyopathy is a progressive disease of the myocardium leading to impaired contractility. Genotoxic cancer therapies are known to be potent drivers of cardiomyopathy, whereas causes of spontaneous disease remain unclear. To test the hypothesis that endogenous genotoxic stress contributes to cardiomyopathy, we deleted the DNA repair gene Ercc1 specifically in striated muscle using a floxed allele of Ercc1 and mice expressing Cre under control of the muscle-specific creatinine kinase (Ckmm) promoter or depleted systemically (Ercc1-/D mice). Ckmm-Cre+/- ;Ercc1-/fl mice expired suddenly of heart disease by 7 months of age. As young adults, the hearts of Ckmm-Cre+/- ;Ercc1-/fl mice were structurally and functionally normal, but by 6-months-of-age, there was significant ventricular dilation, wall thinning, interstitial fibrosis, and systolic dysfunction indicative of dilated cardiomyopathy. Cardiac tissue from the tissue-specific or systemic model showed increased apoptosis and cardiac myocytes from Ckmm-Cre+/- ;Ercc1-/fl mice were hypersensitive to genotoxins, resulting in apoptosis. p53 levels and target gene expression, including several antioxidants, were increased in cardiac tissue from Ckmm-Cre+/- ;Ercc1-/fl and Ercc1-/D mice. Despite this, cardiac tissue from older mutant mice showed evidence of increased oxidative stress. Genetic or pharmacologic inhibition of p53 attenuated apoptosis and improved disease markers. Similarly, overexpression of mitochondrial-targeted catalase improved disease markers. Together, these data support the conclusion that DNA damage produced endogenously can drive cardiac disease and does so mechanistically via chronic activation of p53 and increased oxidative stress, driving cardiac myocyte apoptosis, dilated cardiomyopathy, and sudden death.

Aerobically trained older adults show impaired resting, but preserved exercise-induced circulating progenitor cell count, which was not improved by sprint interval training.

Older adults exhibit a reduced number and function of CD34 + circulating progenitor cells (CPC), a known risk factor for cardiovascular disease. Exercise promotes the mobilisation of CPCs from bone marrow, so whether ageing per se or physical inactivity in older age reduces CPCs is unknown. Thus, this study examined the effect of age on resting and exercise-induced changes in CPCs in aerobically trained adults and the effect of 8 weeks of sprint interval training (SIT) on resting and exercise-induced CPCs in older adults. Twelve young (22-34 years) and nine older (63-70 years) adults participated in the study. Blood was sampled pre and immediately post a graded exercise test to exhaustion in both groups. Older participants repeated the process after 8 weeks of SIT (3 × 20 s 'all-out' sprints, 2 × a week). Total CPCs (CD34+) and endothelial progenitor cells (EPCs: CD34+KDR+) were determined by flow cytometry. Older adults exhibited lower basal total CD34+ CPCs (828 ± 314 vs. 1186 ± 272 cells·mL-1, p = 0.0149) and CD34+KDR+ EPCs (177 ± 128 vs. 335 ± 92 cells·mL-1, p = 0.007) than younger adults. The maximal exercise test increased CPCs in young (CD34+: p = 0.004; CD34+KDR+: p = 0.017) and older adults (CD34+: p < 0.001; CD34+KDR+: p = 0.008), without difference between groups (p = 0.211). SIT did not alter resting or exercise-induced changes in CPCs in the older cohort (p > 0.232). This study suggests age per se does not impair exercise-induced CPC counts, but does lower resting CPC counts.

Ex Vivo treatment of coronary artery endothelial cells with serum post-exercise training offers limited protection against in vitro exposure to FEC-T chemotherapy.

Background: Chemotherapy treatment for breast cancer associates with well-documented cardiovascular detriments. Exercise has shown promise as a potentially protective intervention against cardiac toxicity. However, there is a paucity of evidence for the benefits of exercise on the vasculature. Objectives: This study aimed to determine the effects of chemotherapy on the vascular endothelium; and if there are protective effects of serological alterations elicited by an exercise training intervention. Methods and Results: 15 women participated in a 12-week home-based exercise intervention consisting of three high-intensity interval sessions per week. Human coronary artery endothelial cells (HCAEC) were exposed to physiological concentrations of 5-fluorouracil, epirubicin, cyclophosphamide (FEC) and docetaxel to determine a dose-response. Twenty-4 hours prior to FEC and docetaxel exposure, HCAECs were preconditioned with serum collected pre- and post-training. Annexin V binding and cleaved caspase-3 were assessed using flow cytometry and wound repair by scratch assays. Chemotherapy exposure increased HCAEC Annexin V binding, cleaved caspase-3 expression in a dose-dependent manner; and inhibited wound repair. Compared to pre-training serum, conditioning HCAECs with post-training serum, reduced Annexin V binding (42% vs. 30%, p = 0.01) when exposed to FEC. For docetaxel, there were no within-group differences (pre-vs post-exercise) for Annexin V binding or cleaved caspase-3 expression. There was a protective effect of post-training serum on wound repair for 5-flurouracil (p = 0.03) only. Conclusion: FEC-T chemotherapy drugs cause significant damage and dysfunction of endothelial cells. Preconditioning with serum collected after an exercise training intervention, elicited some protection against the usual toxicity of FEC-T, when compared to control serum.