An aggregated mitochondrial distribution in preimplantation embryos disrupts nuclear morphology, function, and developmental potential.

A dispersed cytoplasmic distribution of mitochondria is a hallmark of normal cellular organization. Here, we have utilized the expression of exogenous Trak2 in mouse oocytes and embryos to disrupt the dispersed distribution of mitochondria by driving them into a large cytoplasmic aggregate. Our findings reveal that aggregated mitochondria have minimal impact on asymmetric meiotic cell divisions of the oocyte. In contrast, aggregated mitochondria during the first mitotic division result in daughter cells with unequal sizes and increased micronuclei. Further, in two-cell embryos, microtubule-mediated centering properties of the mitochondrial aggregate prevent nuclear centration, distort nuclear shape, and inhibit DNA synthesis and the onset of embryonic transcription. These findings demonstrate the motor protein-mediated distribution of mitochondria throughout the cytoplasm is highly regulated and is an essential feature of cytoplasmic organization to ensure optimal cell function.

Comparison of Low-Value Care Among Commercial and Medicaid Enrollees.

BACKGROUND: Low-value healthcare is costly and inefficient and may adversely affect patient outcomes. Despite increases in low-value service use, little is known about how the receipt of low-value care differs across payers. OBJECTIVE: To evaluate differences in the use of low-value care between patients with commercial versus Medicaid coverage. DESIGN: Retrospective observational analysis of the 2017 Rhode Island All-payer Claims Database, estimating the probability of receiving each of 14 low-value services between commercial and Medicaid enrollees, adjusting for patient sociodemographic and clinical characteristics. Ensemble machine learning minimized the possibility of model misspecification. PARTICIPANTS: Medicaid and commercial enrollees aged 18-64 with continuous coverage and an encounter at which they were at risk of receiving a low-value service. INTERVENTION: Enrollment in Medicaid or Commercial insurance. MAIN MEASURES: Use of one of 14 validated measures of low-value care. KEY RESULTS: Among 110,609 patients, Medicaid enrollees were younger, had more comorbidities, and were more likely to be female than commercial enrollees. Medicaid enrollees had higher rates of use for 7 low-value care measures, and those with commercial coverage had higher rates for 5 measures. Across all measures of low-value care, commercial enrollees received more (risk difference [RD] 6.8 percentage points; CI: 6.6 to 7.0) low-value services than their counterparts with Medicaid. Commercial enrollees were also more likely to receive low-value services typically performed in the emergency room (RD 11.4 percentage points; CI: 10.7 to 12.2) and services that were less expensive (RD 15.3 percentage points; CI 14.6 to 16.0). CONCLUSION: Differences in the provision of low-value care varied across measures, though average use was slightly higher among commercial than Medicaid enrollees. This difference was more pronounced for less expensive services indicating that financial incentives may not be the sole driver of low-value care.

Oocyte mitochondria-key regulators of oocyte function and potential therapeutic targets for improving fertility.

The development of oocytes and early embryos is dependent on mitochondrial ATP production. This reliance on mitochondrial activity, together with the exclusively maternal inheritance of mitochondria in development, places mitochondria as central regulators of both fertility and transgenerational inheritance mechanisms. Mitochondrial mass and mtDNA content massively increase during oocyte growth. They are highly dynamic organelles and oocyte maturation is accompanied by mitochondrial trafficking around subcellular compartments. Due to their key roles in generation of ATP and reactive oxygen species (ROS), oocyte mitochondrial defects have largely been linked with energy deficiency and oxidative stress. Pharmacological treatments and mitochondrial supplementation have been proposed to improve oocyte quality and fertility by enhancing ATP generation and reducing ROS levels. More recently, the role of mitochondria-derived metabolites in controlling epigenetic modifiers has provided a mechanistic basis for mitochondria-nuclear crosstalk, allowing adaptation of gene expression to specific metabolic states. Here, we discuss the multi-faceted mechanisms by which mitochondrial function influence oocyte quality, as well as longer-term developmental events within and across generations.

Early-Stage Alzheimer's Disease Categorization Using PET Neuroimaging Modality and Convolutional Neural Networks in the 2D and 3D Domains.

Alzheimer's Disease (AD) is a health apprehension of significant proportions that is negatively impacting the ageing population globally. It is characterized by neuronal loss and the formation of structures such as neurofibrillary tangles and amyloid plaques in the early as well as later stages of the disease. Neuroimaging modalities are routinely used in clinical practice to capture brain alterations associated with AD. On the other hand, deep learning methods are routinely used to recognize patterns in underlying data distributions effectively. This work uses Convolutional Neural Network (CNN) architectures in both 2D and 3D domains to classify the initial stages of AD into AD, Mild Cognitive Impairment (MCI) and Normal Control (NC) classes using the positron emission tomography neuroimaging modality deploying data augmentation in a random zoomed in/out scheme. We used novel concepts such as the blurring before subsampling principle and distant domain transfer learning to build 2D CNN architectures. We performed three binaries, that is, AD/NC, AD/MCI, MCI/NC and one multiclass classification task AD/NC/MCI. The statistical comparison revealed that 3D-CNN architecture performed the best achieving an accuracy of 89.21% on AD/NC, 71.70% on AD/MCI, 62.25% on NC/MCI and 59.73% on AD/NC/MCI classification tasks using a five-fold cross-validation hyperparameter selection approach. Data augmentation helps in achieving superior performance on the multiclass classification task. The obtained results support the application of deep learning models towards early recognition of AD.

HENMT1 is involved in the maintenance of normal female fertility in the mouse.

PIWI-interacting small RNAs (piRNAs) maintain genome stability in animal germ cells, with a predominant role in silencing transposable elements. Mutations in the piRNA pathway in the mouse uniformly lead to failed spermatogenesis and male sterility. By contrast, mutant females are fertile. In keeping with this paradigm, we previously reported male sterility and female fertility associated with loss of the enzyme HENMT1, which is responsible for stabilising piRNAs through the catalysation of 3'-terminal 2'-O-methylation. However, the Henmt1 mutant females were poor breeders, suggesting they could be subfertile. Therefore, we investigated oogenesis and female fertility in these mice in greater detail. Here, we show that mutant females indeed have a 3- to 4-fold reduction in follicle number and reduced litter sizes. In addition, meiosis-II mutant oocytes display various spindle abnormalities and have a dramatically altered transcriptome which includes a down-regulation of transcripts required for microtubule function. This down-regulation could explain the spindle defects observed with consequent reductions in litter size. We suggest these various effects on oogenesis could be exacerbated by asynapsis, an apparently universal feature of piRNA mutants of both sexes. Our findings reveal that loss of the piRNA pathway in females has significant functional consequences.

Mitochondria-targeted therapeutics, MitoQ and BGP-15, reverse aging-associated meiotic spindle defects in mouse and human oocytes.

STUDY QUESTION: Do mitochondria-targeted therapies reverse ageing- and oxidative stress-induced spindle defects in oocytes from mice and humans? SUMMARY ANSWER: Exposure to MitoQ or BGP-15 during IVM protected against spindle and chromosomal defects in mouse oocytes exposed to oxidative stress or derived from reproductively aged mice whilst MitoQ promoted nuclear maturation and protected against chromosomal misalignments in human oocytes. WHAT IS KNOWN ALREADY: Spindle and chromosomal abnormalities in oocytes are more prevalent with maternal aging, increasing the risk of aneuploidy, miscarriage and genetic disorders such as Down's syndrome. The origin of compromised oocyte function may be founded in mitochondrial dysfunction and increased reactive oxygen species (ROS). STUDY DESIGN, SIZE, DURATION: Oocytes from young and old mice were treated with MitoQ and/or BGP-15 during IVM. To directly induce mitochondrial dysfunction, oocytes were treated with H2O2, and then treated the MitoQ and/or BGP-15. Immature human oocytes were cultured with or without MitoQ. Each experiment was repeated at least three times, and data were analyzed by unpaired-sample t-test or chi-square test. PARTICIPANTS/MATERIALS, SETTING, METHODS: Immature germinal vesicle (GV) stage oocytes from 1-, 12- and 18-month-old mice were obtained from preovulatory ovarian follicles. Oocytes were treated with MitoQ and/or BGP-15 during IVM. GV-stage human oocytes were cultured with or without MitoQ. Mitochondrial membrane potential and mitochondrial ROS were measured by live-cell imaging. Meiotic spindle and chromosome alignments were visualized by immunofluorescent labeling of fixed oocytes and the 3-dimensional images were analyzed by Imaris. MAIN RESULTS AND THE ROLE OF CHANCE: MitoQ or BGP-15 during IVM protects against spindle and chromosomal defects in oocytes exposed to oxidative stress and in oocytes from aged mice (P < 0.001). In human oocytes, the presence of MitoQ during IVM promoted nuclear maturation and had a similar positive effect in protecting against chromosomal misalignments (P < 0.001). LIMITATIONS, REASONS FOR CAUTION: Our study identifies two excellent candidates that may help to improve fertility in older women. However, these potential therapies must be tested for efficacy in clinical IVM systems, and undergo thorough examination of resultant offspring in preclinical models before utilization. WIDER IMPLICATIONS OF THE FINDINGS: Our results using in-vitro systems for oocyte maturation in both mouse and human provide proof of principle that mitochondrially targeted molecules such as MitoQ and BGP-15 may represent a novel therapeutic approach against maternal aging-related spindle and chromosomal abnormalities. STUDY FUNDING/COMPETING INTEREST(S): The project was financially supported by the National Health and Medical Research Council and Australian Research Council, Australia. U.A.-Z. was supported by the Iraqi Higher Education and Scientific Research Ministry PhD scholarship and O.C. was supported by TUBITAK-1059B191601275. M.P.M. consults for MitoQ Inc. and holds patents in mitochondria-targeted therapies. R.L.R. is an inventor on patents relating to the use of BGP-15 to improve gamete quality. TRIAL REGISTRATION NUMBER: N/A.

The spatio-temporal dynamics of mitochondrial membrane potential during oocyte maturation.

Mitochondria are highly dynamic organelles and their distribution, structure and activity affect a wide range of cellular functions. Mitochondrial membrane potential (∆Ψm) is an indicator of mitochondrial activity and plays a major role in ATP production, redox balance, signaling and metabolism. Despite the absolute reliance of oocyte and early embryo development on mitochondrial function, there is little known about the spatial and temporal aspects of ΔΨm during oocyte maturation. The one exception is that previous findings using a ΔΨm indicator, JC-1, report that mitochondria in the cortex show a preferentially increased ΔΨm, relative to the rest of the cytoplasm. Using live-cell imaging and a new ratiometric approach for measuring ΔΨm in mouse oocytes, we find that ΔΨm increases through the time course of oocyte maturation and that mitochondria in the vicinity of the first meiotic spindle show an increase in ΔΨm, compared to other regions of the cytoplasm. We find no evidence for an elevated ΔΨm in the oocyte cortex. These findings suggest that mitochondrial activity is adaptive and responsive to the events of oocyte maturation at both a global and local level. In conclusion, we have provided a new approach to reliably measure ΔΨm that has shed new light onto the spatio-temporal regulation of mitochondrial function in oocytes and early embryos.

Use of Hospital-Based Rehabilitation Services and Hospital Readmission Following Ischemic Stroke in the United States.

OBJECTIVE: To examine the association between hospital-based rehabilitation service use and all-cause 30-day hospital readmission among patients with ischemic stroke. DESIGN: Secondary analysis of inpatient Medicare claims data using Standard Analytical Files. SETTING: Acute hospitals across the United States. PARTICIPANTS: From nationwide data, Medicare fee-for-service beneficiaries (N=88,826) aged 66 years or older hospitalized for ischemic stroke between January to November 2010. INTERVENTIONS: Hospital-based rehabilitation services were quantified using Medicare inpatient claims revenue center codes for evaluation (occupational therapy [OT] and physical therapy [PT]), as well as the number of therapy units delivered. Therapy minutes for both OT and PT services were categorized into none, low, medium, and high. MAIN OUTCOME MEASURES: All-cause 30-day hospital readmission. A generalized linear mixed model was used to examine the effect of hospital-based rehabilitation services on 30-day hospital readmission, after adjusting for patient and hospital characteristics. RESULTS: In fully adjusted models, compared to patients who received no PT, we observed a monotonic inverse relationship between the amount of PT and hospital readmission. For low PT (30 minutes), the odds ratio (OR) was 0.90 (95% confidence interval [CI], 0.83-0.96). For medium PT (>30 to ≤75 minutes), the OR was 0.89 (95% CI, 0.82-0.95). For high PT (>75 minutes), the OR was 0.86 (95% CI, 0.80-0.93). CONCLUSION: Hospital-based PT services were associated with lower risk of 30-day hospital readmission in patients with ischemic stroke.

Citrus junos Fruit Extract Facilitates Anti-Adipogenic Activity of Garcinia cambogia Extract in 3T3-L1 Adipocytes by Reducing Oxidative Stress.

Obesity is a metabolic disorder associated with chronic oxidative stress and inflammation. Recruitment of inflammatory cells to adipose tissue and subsequent production of a large amount of reactive oxygen species (ROS) facilitates adipocyte differentiation and promotes lipid accumulation. The removal of ROS with anti-oxidants appeared an effective strategy against lipid accumulation. Here, we chose Citrus junos, a good dietary source of anti-oxidants and tested the anti-adipogenic potential of Citrus junos extract (CE). CE effectively suppressed the ROS production and lipid accumulation in H2O2-stimulated 3T3-L1 cells. CE also inhibited the expression of CEBP-α and PPAR-γ, the transcription regulators of adipocyte differentiation. These data suggest that CE might suppress the adipocyte differentiation through ROS scavenging action. Also, CE and Garcinia cambogia extract (GE) appeared act additively in reducing ROS and in inhibiting lipid accumulation. It implied a potential usefulness of this combination in the management of obesity related disorders.

Adapting the Elixhauser comorbidity index for cancer patients.

BACKGROUND: This study was designed to adapt the Elixhauser comorbidity index for 4 cancer-specific populations (breast, prostate, lung, and colorectal) and compare 3 versions of the Elixhauser comorbidity score (individual comorbidities, summary comorbidity score, and cancer-specific summary comorbidity score) with 3 versions of the Charlson comorbidity score for predicting 2-year survival with 4 types of cancer. METHODS: This cohort study used Texas Cancer Registry-linked Medicare data from 2005 to 2011 for older patients diagnosed with breast (n = 19,082), prostate (n = 23,044), lung (n = 26,047), or colorectal cancer (n = 16,693). For each cancer cohort, the data were split into training and validation cohorts. In the training cohort, competing risk regression was used to model the association of Elixhauser comorbidities with 2-year noncancer mortality, and cancer-specific weights were derived for each comorbidity. In the validation cohort, competing risk regression was used to compare 3 versions of the Elixhauser comorbidity score with 3 versions of the Charlson comorbidity score. Model performance was evaluated with c statistics. RESULTS: The 2-year noncancer mortality rates were 14.5% (lung cancer), 11.5% (colorectal cancer), 5.7% (breast cancer), and 4.1% (prostate cancer). Cancer-specific Elixhauser comorbidity scores (c = 0.773 for breast cancer, c = 0.772 for prostate cancer, c = 0.579 for lung cancer, and c = 0.680 for colorectal cancer) performed slightly better than cancer-specific Charlson comorbidity scores (ie, the National Cancer Institute combined index; c = 0.762 for breast cancer, c = 0.767 for prostate cancer, c = 0.578 for lung cancer, and c = 0.674 for colorectal cancer). Individual Elixhauser comorbidities performed best (c = 0.779 for breast cancer, c = 0.783 for prostate cancer, c = 0.587 for lung cancer, and c = 0.687 for colorectal cancer). CONCLUSIONS: The cancer-specific Elixhauser comorbidity score performed as well as or slightly better than the cancer-specific Charlson comorbidity score in predicting 2-year survival. If the sample size permits, using individual Elixhauser comorbidities may be the best way to control for confounding in cancer outcomes research. Cancer 2018;124:2018-25. © 2018 American Cancer Society.

Processes and Outcomes of Congestive Heart Failure Care by Different Types of Primary Care Models.

BACKGROUND: Having nurse practitioners (NPs) as primary care providers for patients with congestive heart failure (CHF) is 1 way to address the growing shortage of primary care physicians (PCPs). METHODS AND RESULTS: We used inverse probability of treatment weighted with propensity score to examine the processes and outcomes of care for patients under 3 care models. Approximately 72.9%, 0.8%, and 26.3% of CHF patients received care under the PCP model, the NP model, and the shared care model, respectively. Patients under the NP or shared care models were more likely than those under the PCP model to be referred to cardiologists (odds ratio 1.35, 95% confidence interval 1.32-1.37; odds ratio 1.32, 95% confidence interval 1.30-1.35) and to get guideline-recommended medications. NPs and PCPs had similar rates of emergency room (ER) visits and Medicare spending after adjusting for processes of care. Patients under the shared care model had a higher burden of comorbidity and experienced a higher rate of ER visits and hospitalizations than those under the PCP model. CONCLUSION: The delivery of CHF care mirrors the severity of comorbidity in these patients. The high rate of hospitalization and ER visits in the shared care model underscores the need to design and implement more effective chronic disease management and integrated care programs.

Decline in opioid prescribing after federal rescheduling of hydrocodone products.

PURPOSE: To examine differences in opioid prescribing by patient characteristics and variation in hydrocodone combination product (HCP) prescribing attributed to states, before and after the 2014 Drug Enforcement Administration's reclassification of HCP from schedule III to the more restrictive schedule II. METHODS: We used 2013 to 2015 data for 9 202 958 patients aged 18 to 64 from a large nationally representative commercial health insurance program to assess the temporal trends in the monthly rate of opioid prescribing. RESULTS: HCP prescribing decreased by 26% from June 2013 to June 2015; the rate of prescriptions for any opioid decreased by 11%. Prescribing of non-hydrocodone schedule III opioids increased slightly while prescribing of non-hydrocodone schedule II opioids and tramadol was stable. Absolute decreases in HCP prescribing rates were larger in patients being treated for cancer (-2.26% vs -0.7% for non-cancer patients, P < 0.0001) and in those with high comorbidities (-2.13% vs -0.55% for those with no comorbidity, P < 0.0001). Differences in the absolute and relative changes in HCP prescribing rates among states were large; for example, a relative decrease of 46.7% in Texas and a 12.7% increase in South Dakota. The variation in HCP prescribing attributable to the state of residence increased from 6.6% in 2013 to 8.7% in 2015. CONCLUSIONS: The 2014 federal policy was associated with a decrease in rates of HCP and total opioid prescribing. The large decrease in the rates of HCP prescribing for patients with actively treated cancer may represent an unintended consequence.

Effects of Age and Sex on Hospital Readmission in Traumatic Brain Injury.

OBJECTIVE: To investigate the effects of age and sex on 30-, 60-, and 90-day hospital readmission after acute hospital discharge for individuals with traumatic brain injury (TBI). DESIGN: Retrospective cohort study. SETTING: Acute hospitals and postacute discharge settings. PARTICIPANTS: Individuals (N=52,877) with Diagnosis Related Group codes of TBI, who were divided into 4 age groups: 18 to 40, 41 to 65, 66 to 75, and ≥76 years. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: All-cause hospital readmission. RESULTS: Sex differences in 30-, 60-, and 90-day hospital readmission were found among all age groups (P<.05 for all). The largest sex differences in hospital readmission were in the 2 oldest groups (66-75 and ≥76y). For both sexes, the oldest group (≥76y) had the highest adjusted 90-day readmission risk (eg, 90-d readmission: odds ratio, 2.32 [95% confidence interval, 2.01-2.69] for men; odds ratio, 1.96 [95% confidence interval, 1.59-2.43] for women). Among those readmitted within 90 days, the youngest group (18-40y) had the highest cumulative readmission percentage (35% for both sexes) within the first week of hospital discharge. CONCLUSIONS: Age and sex were significantly associated with hospital readmission during the first 90 days postdischarge in our TBI sample. Specifically, those aged 66 to 75 or ≥76 years had the highest readmission risk over 90 days for both sexes. The findings suggest that clinicians should consider age and sex in discharge planning and for the entire episode of care for the population with TBI.

Safety of Continued Clopidogrel Use in the Preoperative Course of Gastrointestinal Surgery: A Retrospective Cohort Study.

OBJECTIVE: Our study aimed to estimate postoperative bleeding risk in older adults taking clopidogrel before gastrointestinal (GI) surgery, to aid surgeons in decisions regarding clopigogrel cessation. SUMMARY BACKGROUND DATA: Balancing risks of postoperative bleeding associated with continued clopidogrel use and those associated with cessation is difficult for GI surgeons. METHODS: Using 100% Texas Medicare Claims Data from 2006 to 2011, we identified patients undergoing emergent GI surgery. We propensity score matched patients on clopidogrel before surgery to patients not on clopidogrel. Using conditional logistic regression, we compared risks of bleeding events at 1-month postdischarge between groups, adjusting for bleeding risk factors. RESULTS: In total, 1240 patients undergoing emergent GI surgery while treated with clopidogrel were matched to emergency GI surgery patients not treated with clopidogrel. The only significant preoperative differences between groups were higher percent of clopidogrel-treated patients with congestive heart failure, cholecystectomy, and lower percent of clopidogrel-treated patients with colectomy. Mean age was 76.91 (±7.06) and 76.70 (±7.05) years (P = 0.47), and 63.84% and 59.41% of operations were cholecystectomy, in the clopidogrel and nonclopidogrel groups (P = 0.18). In multivariable analyses adjusting for Elixhauser index, hyperlipidemia, confounding drugs, and surgery type, odds ratio for bleeding within 30 days of discharge in those exposed to clopidogrel compared with those not exposed was 1.60 (95% confidence interval, 1.08-2.38), with raw rates of bleeding 6.85% and 4.84%. CONCLUSIONS: Clopidogrel use in older adults through the preoperative period of GI surgery does not significantly increase bleeding events in the month after surgery.

Cdk2 catalytic activity is essential for meiotic cell division in vivo.

Cyclin-dependent kinases (Cdks) control the eukaryotic cell cycle by phosphorylating serine and threonine residues in key regulatory proteins, but some Cdk family members may exert kinase-independent functions that cannot easily be assessed using gene knockout approaches. While Cdk2-deficient mice display near-normal mitotic cell proliferation due to the compensatory activities of Cdk1 and Cdk4, they are unable to undergo meiotic generation of gametes and are consequently sterile. To investigate whether Cdk2 regulates meiosis via protein phosphorylation or by alternative kinase-independent mechanisms, we generated two different knockin mouse strains in which Cdk2 point mutations ablated enzyme activity without altering protein expression levels. Mice homozygous for the mutations Cdk2(D145N/D145N) or Cdk2(T160A/T160A) expressed only 'kinase-dead' variants of Cdk2 under the control of the endogenous promoter, and despite exhibiting normal expression of cell cycle regulatory proteins and complexes, both mutations rendered mice sterile. Mouse cells that expressed only 'kinase-dead' variants of Cdk2 displayed normal mitotic cell cycle progression and proliferation both in vitro and in vivo, indicating that loss of Cdk2 kinase activity exerted little effect on this mode of cell division. In contrast, the reproductive organs of Cdk2 mutant mice exhibited abnormal morphology and impaired function associated with defective meiotic cell division and inability to produce gametes. Cdk2 mutant animals were therefore comparable to gene knockout mice, which completely lack the Cdk2 protein. Together, our data indicate that the essential meiotic functions of Cdk2 depend on its kinase activity, without which the generation of haploid cells is disrupted, resulting in sterility of otherwise healthy animals.

A Comprehensive Review on Chemical Profiling of Nelumbo Nucifera: Potential for Drug Development.

Nelumbo nucifera, also known as sacred lotus, has primarily been used as food throughout the Asian continent, and its medicinal values have been described in Ayurvedic and Traditional Chinese Medicine. The purpose of this study is to systematically characterize the chemical profiling and pharmacological activities of N. nucifera. Herein, we critically reviewed and analysed the phytochemical and pharmacological reports of N. nucifera. Our search for the keyword 'Nelumbo nucifera pharmacology' in all databases reported in Web of Science yielded 373 results excluding reviews and abstracts in document types. Two hundred and forty-three spectrum natural compounds from different parts of N. nucifera belonging to diverse chemical groups, including alkaloids, flavonoids, glycosides, terpenoids, steroids, fatty acids, proteins, minerals, and vitamins have been reported. In addition, distinct pharmacological activities, mainly against cancer, microbial infection, diabetes, inflammation, atherosclerosis, and obesity, have been associated with crude extracts, fractions, and isolated compounds. This review highlights potential use of neferine, liensinine, isoliensinine, and nuciferine in clinical trials. In depth, mechanism of the potential chemical entities from N. nucifera via structure activity relationship needs to be explored to guarantee the stability and safety for the clinical use. Copyright © 2016 John Wiley & Sons, Ltd.

Preparation, Characterization, and Biological Activities of Topical Anti-Aging Ingredients in a Citrus junos Callus Extract.

In this study, we prepared and characterized a callus extract from Citrus junos and assessed its utility as a source of topical anti-aging ingredients. Callus extract was produced by aqueous extraction from Citrus junos grown on Murashige and Skoog medium with picloram as a growth regulator. After measuring the total phenolic and flavonoid contents, the major phenolic compound in calli was identified as p-hydroxycinnamoylmalic acid (1) by spectroscopic analysis. The total phenol content in the extract was determined to be 24.50 ± 0.43 mg/g of gallic acid equivalents; however, the total flavonoid content of the extract was not determined. The biological activities of the callus extract, in terms of skin anti-aging, were assessed by measuring the anti-tyrosinase activity in, and melanogenesis by, melanoma cells; and proliferation of, and procollagen synthesis by, human fibroblasts. The callus extract was incorporated into nanoliposomes (NLs) to improve its percutaneous absorption. Addition of the callus extract resulted in a 1.85-fold decrease in the melanin content of melanocytes compared with that with arbutin. The extract (500 µg/mL) significantly promoted the proliferation of, and procollagen synthesis by, fibroblasts (by 154% and 176%, respectively). In addition, the flux through the human epidermis of Citrus junos callus extract incorporated into NLs was 17.67-fold higher than that of the callus extract alone. These findings suggest that Citrus junos callus extract-loaded NLs have promise as an anti-aging cosmetic, as well as having a skin-lightening effect.

Comparison of Comorbidity Scores in Predicting Surgical Outcomes.

INTRODUCTION: The optimal methodology for assessing comorbidity to predict various surgical outcomes such as mortality, readmissions, complications, and failure to rescue (FTR) using claims data has not been established. OBJECTIVE: Compare diagnosis-based and prescription-based comorbidity scores for predicting surgical outcomes. METHODS: We used 100% Texas Medicare data (2006-2011) and included patients undergoing coronary artery bypass grafting, pulmonary lobectomy, endovascular repair of abdominal aortic aneurysm, open repair of abdominal aortic aneurysm, colectomy, and hip replacement (N=39,616). The ability of diagnosis-based [Charlson comorbidity score, Elixhauser comorbidity score, Combined Comorbidity Score, Centers for Medicare and Medicaid Services-Hierarchical Condition Categories (CMS-HCC)] versus prescription-based Chronic disease score in predicting 30-day mortality, 1-year mortality, 30-day readmission, complications, and FTR were compared using c-statistics (c) and integrated discrimination improvement (IDI). RESULTS: The overall 30-day mortality was 5.8%, 1-year mortality was 17.7%, 30-day readmission was 14.1%, complication rate was 39.7%, and FTR was 14.5%. CMS-HCC performed the best in predicting surgical outcomes (30-d mortality, c=0.797, IDI=4.59%; 1-y mortality, c=0.798, IDI=9.60%; 30-d readmission, c=0.630, IDI=1.27%; complications, c=0.766, IDI=9.37%; FTR, c=0.811, IDI=5.24%) followed by Elixhauser comorbidity index/disease categories (30-d mortality, c=0.750, IDI=2.37%; 1-y mortality, c=0.755, IDI=5.82%; 30-d readmission, c=0.629, IDI=1.43%; complications, c=0.730, IDI=3.99%; FTR, c=0.749, IDI=2.17%). Addition of prescription-based scores to diagnosis-based scores did not improve performance. CONCLUSIONS: The CMS-HCC had superior performance in predicting surgical outcomes. Prescription-based scores, alone or in addition to diagnosis-based scores, were not better than any diagnosis-based scoring system.

Underwater flight by the planktonic sea butterfly.

In a remarkable example of convergent evolution, we show that the zooplanktonic sea butterfly Limacina helicina 'flies' underwater in the same way that very small insects fly in the air. Both sea butterflies and flying insects stroke their wings in a characteristic figure-of-eight pattern to produce lift, and both generate extra lift by peeling their wings apart at the beginning of the power stroke (the well-known Weis-Fogh 'clap-and-fling' mechanism). It is highly surprising to find a zooplankter 'mimicking' insect flight as almost all zooplankton swim in this intermediate Reynolds number range (Re=10-100) by using their appendages as paddles rather than wings. The sea butterfly is also unique in that it accomplishes its insect-like figure-of-eight wing stroke by extreme rotation of its body (what we call 'hyper-pitching'), a paradigm that has implications for micro aerial vehicle (MAV) design. No other animal, to our knowledge, pitches to this extent under normal locomotion.