Co-morbidities and mortality in patients with sickle cell disease in England: A 10-year cohort analysis using hospital episodes statistics (HES) data.

Patients with a primary diagnosis of sickle cell disease (SCD) with or without crisis during the 10-year period January 2009 to December 2018 were identified in the HES Admitted Patient Care (APC) dataset and matched with the Office for National Statistics (ONS) mortality dataset. Three sub-cohorts were defined: 'crises', 'transfusions' and 'other SCD'. APC records were examined for co-morbidities commonly associated with SCD and 10-year mortality rates compared with the general population. After data cleaning and exclusions, 9503 patients remained (entire cohort), with 1171, 201, and 8131 in crises, transfusions, and other SCD sub-cohorts, respectively. Median numbers of co-morbidities per patient were 2 (Interquartile range (IQR): 1-4), 2 (IQR: 1-3), and 1 (IQR: 0-2) in the crises, transfusions, and other SCD sub-cohorts, respectively. The majority of patients in the crises (63.2%) and transfusions (56.3%) cohorts had ≥2 co-morbidities, compared with 25.3% in the other SCD sub-cohort. Crude 10-year mortality rate was 5.3% (entire cohort), compared with 8.0% (crises) and 11.4% (transfusions) sub-cohorts; all rates were substantially higher than in age-sex matched general population. Our study adds further evidence that morbidity and mortality associated with SCD in England is high.

Calcineurin Links Mitochondrial Elongation with Energy Metabolism.

Canonical protein phosphatase 3/calcineurin signaling is central to numerous physiological processes. Here we provide evidence that calcineurin plays a pivotal role in controlling systemic energy and body weight homeostasis. Knockdown of calcineurin in Drosophila melanogaster led to a decrease in body weight and energy stores, and increased energy expenditure. In mice, global deficiency of catalytic subunit Ppp3cb, and tissue-specific ablation of regulatory subunit Ppp3r1 from skeletal muscle, but not adipose tissue or liver, led to protection from high-fat-diet-induced obesity and comorbid sequelæ. Ser637 hyperphosphorylation of dynamin-related protein 1 (Drp1) in skeletal muscle of calcineurin-deficient mice was associated with mitochondrial elongation into power-cable-shaped filaments and increased mitochondrial respiration, but also with attenuated exercise performance. Our data suggest that calcineurin acts as highly conserved pivot for the adaptive metabolic responses to environmental changes such as high-fat, high-sugar diets or exercise.

Feasibility of the Ultrasonic Bone Aspirator in Retrosigmoid Vestibular Schwannoma Removal.

OBJECTIVE: Postoperative headache is an undesirable consequence of retrosigmoid vestibular schwannoma (VS) removal. An ultrasonic bone aspirator (UBA) may reduce headache by minimizing subarachnoid bone dust dispersion. The feasibility of removing internal auditory canal (IAC) bone with a UBA is unknown. This study assessed volume and duration of IAC bone removal in clinical and laboratory settings. STUDY DESIGN: (1) Retrospective review of radiologic data and intraoperative videos. (2) Cadaveric temporal bone model. SETTING: (1) Tertiary care medical center. (2) Laboratory. SUBJECTS METHODS: We calculated the volume of IAC bone drilled during retrosigmoid VS removal using postoperative computed tomography scans. We then measured the time spent actively drilling IAC bone by analyzing operative videos. Finally, we measured bone ablation rates in a cadaveric temporal bone model using a drill and UBA. RESULTS: The mean ± SD volume of IAC bone removed during surgery was 0.32 ± 0.17 mL (n = 9). The time spent actively removing IAC bone with a drill was only 10.4 ± 3.5 minutes, less than a third of the total IAC opening time of 34.2 ± 13.1 minutes (n = 5). On cadaveric specimens, the UBA removed bone at 0.21 ± 0.03 or 0.35 ± 0.07 µL/s at 15% or 50% power, respectively (n = 4). This extrapolates to 15.0 ± 3.0 to 25.0 ± 3.9 minutes to remove the same 0.32 mL from surgery. CONCLUSIONS: The volume and duration of IAC bone removal during retrosigmoid VS surgery are small. Using a UBA at low power instead of a drill would extend the length of surgery by 5 to 15 minutes, with the theoretical potential for reducing headache.

Reduction of bone dust with ultrasonic bone aspiration: implications for retrosigmoid vestibular schwannoma removal.

OBJECTIVE: Postoperative headache is not uncommon after retrosigmoid vestibular schwannoma removal. Bone dust dispersed into the subarachnoid space during drilling may be responsible. If dispersion could be reduced, headache incidence might be decreased. An ultrasonic bone aspirator (UBA) containing an integrated suction at the tip may more effectively suction bone dust created during bone removal. The objective is to determine whether a UBA results in less bone dust dispersion than a standard otologic drill. STUDY DESIGN: Cadaveric temporal bone quantitative model. SETTING: Laboratory. SUBJECTS AND METHODS: Temporal bone blocks were placed in a watertight enclosure. Under irrigation, bone was removed by use of either a drill or a UBA. The settings of the UBA were varied. The irrigant containing bone dust was microfiltered, and bone dust was weighed. Differences were compared across groups (n = 2-9 per group). Ablation times were also recorded (n = 3 per group). RESULTS: Only 3% (SD = 1.6%, n = 7) of the drilled bone mass was re-collected as bone dust with the UBA under optimized settings (power = 15%, suction = 100%, irrigation = 15 mL/min) compared with 81% (SD = 10%, n = 4) with the drill and external suction (P < .001). Increasing UBA power and reducing suction led to significantly more bone dust dispersal than with optimized settings. Varying irrigation did not have a significant effect. Bone ablation time was 1.4 times longer with the UBA at 50% power compared with the drill at maximum power. CONCLUSIONS: The UBA resulted in approximately 25 times less bone dust dispersion than the otologic drill at optimized settings.

High-density lipoprotein maintains skeletal muscle function by modulating cellular respiration in mice.

BACKGROUND: Abnormal glucose metabolism is a central feature of disorders with increased rates of cardiovascular disease. Low levels of high-density lipoprotein (HDL) are a key predictor for cardiovascular disease. We used genetic mouse models with increased HDL levels (apolipoprotein A-I transgenic [apoA-I tg]) and reduced HDL levels (apoA-I-deficient [apoA-I ko]) to investigate whether HDL modulates mitochondrial bioenergetics in skeletal muscle. METHODS AND RESULTS: ApoA-I ko mice exhibited fasting hyperglycemia and impaired glucose tolerance test compared with wild-type mice. Mitochondria isolated from gastrocnemius muscle of apoA-I ko mice displayed markedly blunted ATP synthesis. Endurance capacity during exercise exhaustion test was impaired in apoA-I ko mice. HDL directly enhanced glucose oxidation by increasing glycolysis and mitochondrial respiration rate in C2C12 muscle cells. ApoA-I tg mice exhibited lower fasting glucose levels, improved glucose tolerance test, increased lactate levels, reduced fat mass, associated with protection against age-induced decline of endurance capacity compared with wild-type mice. Circulating levels of fibroblast growth factor 21, a novel biomarker for mitochondrial respiratory chain deficiencies and inhibitor of white adipose lipolysis, were significantly reduced in apoA-I tg mice. Consistent with an increase in glucose utilization of skeletal muscle, genetically increased HDL and apoA-I levels in mice prevented high-fat diet-induced impairment of glucose homeostasis. CONCLUSIONS: In view of impaired mitochondrial function and decreased HDL levels in type 2 diabetes mellitus, our findings indicate that HDL-raising therapies may preserve muscle mitochondrial function and address key aspects of type 2 diabetes mellitus beyond cardiovascular disease.

Exercise protects against high-fat diet-induced hypothalamic inflammation.

Hypothalamic inflammation is a potentially important process in the pathogenesis of high-fat diet-induced metabolic disorders that has recently received significant attention. Microglia are macrophage-like cells of the central nervous system which are activated by pro-inflammatory signals causing local production of specific interleukins and cytokines, and these in turn may further promote systemic metabolic disease. Whether or how this microglial activation can be averted or reversed is unknown. Since running exercise improves systemic metabolic health and has been found to promote neuronal survival as well as the recovery of brain functions after injury, we hypothesized that regular treadmill running may blunt the effect of western diet on hypothalamic inflammation. Using low-density lipoprotein receptor deficient (l dlr-/-) mice to better reflect human lipid metabolism, we first confirmed that microglial activation in the hypothalamus is severely increased upon exposure to a high-fat, or "western", diet. Moderate, but regular, treadmill running exercise markedly decreased hypothalamic inflammation in these mice. Furthermore, the observed decline in microglial activation was associated with an improvement of glucose tolerance. Our findings support the hypothesis that hypothalamic inflammation can be reversed by exercise and suggest that interventions to avert or reverse neuronal damage may offer relevant potential in obesity treatment and prevention.