DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer.
RRM1, the regulatory subunit of ribonucleotide reductase, is involved in carcinogenesis, tumor progression, and the response of non-small-cell lung cancer to treatment. We developed an automated quantitative determination of the RRM1 protein in routinely processed histologic specimens. In these specimens, we measured the expression of RRM1 and two other proteins that are relevant to non-small-cell lung cancer: the excision repair cross-complementation group 1 (ERCC1) protein and the phosphatase and tensin homologue (PTEN). We compared the results with the clinical outcomes in 187 patients with early-stage non-small-cell lung cancer who had received only surgical treatment. RRM1 expression correlated with the expression of ERCC1 (P<0.001) but not with the expression of PTEN (P=0.37). The median disease-free survival exceeded 120 months in the group of patients with tumors that had high expression of RRM1 and was 54.5 months in the group with low expression of RRM1 (hazard ratio for disease progression or death in the high-expression group, 0.46; P=0.004). The overall survival was more than 120 months for patients with tumors with high expression of RRM1 and 60.2 months for those with low expression of RRM1 (hazard ratio for death, 0.61; P=0.02). Among these 187 patients, the survival advantage was limited to the 30% of patients with tumors that had a high expression of both RRM1 and ERCC1. RRM1 and ERCC1 are determinants of survival after surgical treatment of early-stage, non-small-cell lung cancer.


Successful treatment of hemodynamic compromise caused by antibody-mediated and cellular rejection in a recipient 12 years after heart transplantation.
Heart transplantation (HTx) is an established therapy for stage D heart failure due to recent advances in immunosuppressive regimens. However, antibody-mediated rejection remains an unsolved problem because of its refractoriness to standard immunosuppressive therapy with high mortality and graft loss. We experienced a 16-year old patient with hemodynamic compromise caused by both cellular and antibody-mediated rejection 12 years after HTx. The rejection was refractory to repeated steroid pulse treatment, intravenous immunoglobulin administration, and intensifying immunosuppression including addition of everolimus. Eventually, she was successfully treated with repeated plasma exchange accompanied by a single administration of the anti-CD20 monoclonal antibody rituximab.


[Investigational new drugs among glycoprotein IIb/IIIa-receptor antagonists].
Glycoprotein IIb/IIIa receptors play an important role in platelet aggregation by binding fibrinogen. Drugs that antagonize this binding have been developed for the treatment of thrombotic diseases including acute coronary syndrome. These drugs are of four main types: [1] monoclonal antibody, [2] synthetized peptide, [3] non-peptide, and [4] oral antagonist. Since these drugs inhibit the final step in platelet aggregation, i.e., binding of fibrinogen to the platelet membrane, they were expected to 1) have high specificity for inhibiting platelet aggregation, 2) inhibit any kind of aggregation regardless of stimulation, 3) have high potency in aggregation suppression. As a result of large clinical trials, however, monoclonal antibody alone was revealed to be effective, but non-peptide and oral antagonists were ineffective. The possible mechanisms that lead to such inefficiency are: 1) difference in binding duration to platelets, 2) concomitant suppression of other adhesion molecules beside IIb/IIIa, 3) difference in binding site in the receptor and presence of a partial agonist effect, 4) aggregation promotion or induction of apoptosis via caspase-3 activation, 5) modified aggregation by gene polymorphism. New findings on platelet physiology through studying ways to overcome the above problems will lead to the development of new drugs and treatment.


Activation of β-catenin by oncogenic PIK3CA and EGFR promotes resistance to glucose deprivation by inducing a strong antioxidant response.
Glucose is an essential fuel for cell survival and its availability limits aberrant cellular proliferation. We have hypothesized that specific cancer mutations regulate metabolic response(s) to glucose deprivation (GD). By means of somatic knock-in cellular models, we have analyzed the response to glucose deprivation in cells carrying the frequent (delE746-A750)EGFR, (G13D)KRAS or (E545K)PIK3CA cancer alleles. We demonstrate that, in mammary epithelial cells, glucose has an essential antioxidant function and that these cells are very sensitive to GD. Conversely, isogenic cells carrying the (delE746-A750)EGFR or the (E545K)PIK3CA, but not the (G13D)KRAS allele, display high tolerance to GD by stimulating the expression of anti-oxidant genes (MnSOD and catalase). This adaptive transcriptional response is mediated by the activation of WNT/β-catenin and FOXO4 signalling. Our data highlights a new functional synergism between oncogenic EGFR and PIK3CA with WNT/β-catenin conferring high tolerance to oxidative stress generated by nutrient deprivation.


Species-dependent extracranial manifestations of a brain seeking breast cancer cell line.
Metastatic brain tumors pose a severe problem in the treatment of patients with breast carcinoma. Preclinical models have been shown to play an important role in unraveling the underlying mechanisms behind the metastatic process and evaluation of new therapeutic approaches. As the size of the rat brain allows improved in vivo imaging, we attempted to establish a rat model for breast cancer brain metastasis that allows follow-up by 7 tesla (7T) preclinical Magnetic Resonance Imaging (MRI). Green fluorescent protein-transduced (eGFP) MDA-MB-231br breast cancer cells were labeled with micron-sized particles of iron oxide (MPIOs) and intracardially injected in the left ventricle of female nude rats and mice. 7T preclinical MRI was performed to show the initial distribution of MPIO-labeled cancer cells and to visualize metastasis in the brain. Occurrence of potential metastasis outside the brain was evaluated by 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET)/computed tomography (CT) and potential bone lesions were assessed using [18F]sodium fluoride ([18F]NaF) PET/CT. The first signs of brain metastasis development were visible as hyperintensities on T2-weighted (T2w) MR images acquired 3 weeks after intracardiac injection in rats and mice. Early formation of unexpected bone metastasis in rats was clinically observed and assessed using PET/CT. Almost no bone metastasis development was observed in mice after PET/CT evaluation. Our results suggest that the metastatic propensity of the MDA-MB-231br/eGFP cancer cell line outside the brain is species-dependent. Because of early and abundant formation of bone metastasis with the MDA-MB-231br/eGFP cancer cell line, this rat model is currently not suitable for investigating brain metastasis as a single disease model nor for evaluation of novel brain metastasis treatment strategies.


Intrahepatic splenosis in a chronic hepatitis C patient with no history of splenic trauma mimicking hepatocellular carcinoma.
Intrahepatic splenosis (IHS) is the autotransplantation of splenic tissue that mostly develops after abdominal injury and is often misdiagnosed as hepatocellular carcinoma (HCC) because of similarities in radiological features. We had an opportunity to treat an extremely rare case of intrahepatic splenosis, which were found in a patient without any history of splenic injury. To the best of our knowledge, this is the first such case report in the world. A 58-year-old man with chronic hepatitis C was referred to our hospital for further examination of liver function abnormality. Abdominal ultrasonography incidentally revealed a low echoic tumor in the posterior segment of the liver, with high echoic capsule, which is possibly different from tumor capsule of HCC, known as halo. Abdominal contrast-enhanced computed tomography and gadoxetic acid-enhanced magnetic resonance imaging showed that the tumor had an inhomogeneous enhancement in the arterial phase and diminished enhancement in the equilibrium phase, diagnosed as HCC. The patient underwent right lateral segmentectomy of the liver, and histopathological study confirmed a diagnosis of intrahepatic splenosis. This case presents a new understanding of IHS in a patient without any splenic injury. We also focused on the differences in echo patterns of the tumor capsule between HCC and IHS, which can be used to efficiently diagnose IHS.


IL-36γ Is a Key Regulator of Neutrophil Infiltration in the Vaginal Microenvironment and Limits Neuroinvasion in Genital HSV-2 Infection.
HSV-2 is a neurotropic virus that causes a persistent, lifelong infection that increases risk for other sexually transmitted infections. The vaginal epithelium is the first line of defense against HSV-2 and coordinates the immune response through the secretion of immune mediators, including the proinflammatory cytokine IL-36γ. Previously, we showed that IL-36γ treatment promoted transient polymorphonuclear cell infiltration to the vaginal cavity and protected against lethal HSV-2 challenge. In this report, we reveal that IL-36γ specifically induces transient neutrophil infiltration but does not impact monocyte and macrophage recruitment. Using IL-36γ-/- mice in a lethal HSV-2 challenge model, we show that neutrophil counts are significantly reduced at 1 and 2 d postinfection and that KC-mediated mature neutrophil recruitment is impaired in IL-36γ-/- mice. Additionally, IL-36γ-/- mice develop genital disease more rapidly, have significantly reduced survival time, and exhibit an increased incidence of hind limb paralysis that is linked to productive HSV-2 infection in the brain stem. IL-36γ-/- mice also exhibit a significant delay in clearance of the virus from the vaginal epithelium and a more rapid spread of HSV-2 to the spinal cord, bladder, and colon. We further show that the decreased survival time and increased virus spread observed in IL-36γ-/- mice are not neutrophil-dependent, suggesting that IL-36γ may function to limit HSV-2 spread in the nervous system. Ultimately, we demonstrate that IL-36γ is a key regulator of neutrophil recruitment in the vaginal microenvironment and may function to limit HSV-2 neuroinvasion.


[Comparative analysis of the treatment of inpatients with community-acquired pneumonia and its different outcomes].
The aim of the work was to compare the quality of medical care provided to patients with severe community-acquired pneumonia (CAP) and its different outcomes. (complete recovery, or death--25 patients in either group). In the latter group, the patients did not undergo adequate clinical and instrumental examination at the pre-hospital stage). Most recovered patients were given high doses of ceftriaxone, clarithromycin and ambroxol or low doses of systemic glucocorticoids. A pulmonologist participated in the treatment of these patients twice as frequently as in the treatment of the patients of the latter group. Effects of high doses of systemic glucocorticoids remains debatable.


Detection of Spatially Localized Sounds Is Robust to Saccades and Concurrent Eye Movement-Related Eardrum Oscillations (EMREOs).
Hearing is an active process, and recent studies show that even the ear is affected by cognitive states or motor actions. One example are movements of the eardrum induced by saccadic eye movements, known as "eye movement-related eardrum oscillations" (EMREOs). While these are systematically shaped by the direction and size of saccades, the consequences of saccadic eye movements and their resulting EMREOs for hearing remain unclear. We here studied their implications for the detection of near-threshold clicks in human participants. Across three experiments, sound detection was not affected by their time of presentation relative to saccade onset, by saccade amplitude or direction. While the EMREOs were shaped by the direction and amplitude of the saccadic movement, inducing covert shifts in spatial attention did not affect the EMREO, suggesting that this signature of active sensing is restricted to overt changes in visual focus. Importantly, in our experiments, fluctuations in the EMREO amplitude were not related to detection performance, at least when monaural cues are sufficient. Hence, while eye movements may shape the transduction of acoustic information, the behavioral implications remain to be understood.SIGNIFICANCE STATEMENT Previous studies suggest that oculomotor behavior may influence how we perceive spatially localized sounds. Recent work has introduced a new perspective on this question by showing that eye movements can directly modulate the eardrum. Yet, it remains unclear whether this signature of active hearing accounts for behavioral effects. We here show that overt but not covert changes in visual attention modulate the eardrum, but these modulations do not interfere with the detection of sounds. Our results provide a starting point to obtain a deeper understanding about the interplay of oculomotor behavior and the active ear.


Suicide and sleep: Is it a bad thing to be awake when reason sleeps?
Suicide is the second leading cause of death, worldwide, for those between the ages of 24 and 44 y old. In 2013, more than 41,000 suicides occurred in the United States. These statistics underscore the need to 1) understand why people die by suicide and 2) identify risk factors that are potentially modifiable. While it has been posited that sleep disturbance may represent one such factor, systematic research in this arena did not begin until the 2000s. Since that time, sleep disturbance has been reliably identified as a risk factor for suicidal ideation, suicide attempts, and suicide. While insomnia, nightmares, and other sleep disorders have each been found to contribute to the risk for suicidal ideation and behavior, it is also possible that these factors share some common variance. One possibility is that sleep disturbance results in being awake at night, and being awake at night also confers risk. The hypothesis proffered here is that being awake when one is not biologically prepared to be so results in "hypofrontality" and diminished executive function, and that this represents a common pathway to suicidal ideation and behavior. Such a proposition is highly testable under a variety of possible protocols. The current review summarizes the extant literature on suicide rates by time-of-day, and discusses circadian, psychosocial, and neurocognitive explanations of risk. Such a focus promises to enhance our understanding of how sleep disturbance may confer risk, allows for the identification of future lines of research, and further justifies the need for interventions that promote good sleep continuity among at-risk individuals.


Discordance at human leukocyte antigen-DRB3 and protection from human immunodeficiency virus type 1 transmission.
Host human leukocyte antigens (HLAs) integrated into the human immunodeficiency virus (HIV) type 1 envelope could theoretically determine, as in tissue transplants, whether HIV-1 is "rejected" by exposed susceptible persons, preventing transmission. HLA discordance (mismatch) was examined among 45 heterosexual partner pairs in which at least 1 partner was HIV-1 infected and exposure or transmission between partners had occurred. Immunologic discordance at class II HLA-DRB3 (present in the HIV donor partner but absent in the recipient partner) was associated with lack of transmission of HIV-1. Eight (35%) of 23 partner pairs in which HIV-1 transmission did not occur were immunologically discordant at HLA-DRB3, compared with 0 of 11 partner pairs in which HIV-1 transmission did occur (P=.027). Further investigation of the roles of class II HLAs in HIV-1 transmission and as possible components of HIV-1 vaccines should be pursued.


Topography and Permeability Analyses of Vasculature-on-a-Chip Using Scanning Probe Microscopies.
Microphysiological systems (MPS) or organs-on-chips (OoC) can emulate the physiological functions of organs in vitro and are effective tools for determining human drug responses in preclinical studies. However, the analysis of MPS has relied heavily on optical tools, resulting in difficulties in real-time and high spatial resolution imaging of the target cell functions. In this study, the role of scanning probe microscopy (SPM) as an analytical tool for MPS is evaluated. An access hole is made in a typical MPS system with stacked microchannels to insert SPM probes into the system. For the first study, a simple vascular model composed of only endothelial cells is prepared for SPM analysis. Changes in permeability and local chemical flux are quantitatively evaluated during the construction of the vascular system. The morphological changes in the endothelial cells after flow stimulation are imaged at the single-cell level for topographical analysis. Finally, the possibility of adapting the permeability and topographical analysis using SPM for the intestinal vascular system is further evaluated. It is believed that this study will pave the way for an in situ permeability assay and structural analysis of MPS using SPM.


Corticotropin and beta-endorphin-like materials are native to unicellular organisms.
Multiple molecular forms of immunoreactive corticotropin (ACTH) and beta-endorphin were present in extracts of a unicellular eukaryote (Tetrahymena pyriformis). One form of immunoreactive ACTH reacted similarly with two different ACTH antisera (one specific for the 11-24 sequence and the other with determinants within sequences 1-14 and 17-39) and migrated with synthetic hACTH-(1-39) in a gel filtration system. This form also exhibited ACTH bioactivity in a dispersed rat adrenal cell bioassay system, with a mean immunoassay/bioassay ratio of 1.5. Gel filtration revealed multiple size classes of immunoreactive beta-endorphin; a major peak of radioreceptor activity was detected which exhibited a K(av) similar to that of authentic beta-endorphin. A major portion of immunoreactive beta-endorphin-sized material exhibited retention times similar to those of synthetic human and camel beta-endorphin upon reverse-phase high-pressure liquid chromatography. These distinctive properties and specificities would seem to exclude the presence of limited homologies with sequences present in other proteins. High molecular weight material containing both ACTH and beta-endorphin antigenic determinants was also demonstrated, suggesting, but not proving, the presence of a common precursor molecule.


Evaluation of outcomes from a national patient-initiated second-opinion program.
We examined outcomes of patient-initiated second opinions provided by a national second-opinion program. We independently examined data collected from January 1, 2011 to December 31, 2012 from a second-opinion program (Best Doctors, Inc.) that allows employee-beneficiaries to request free second opinions. Clinical intake included ascertaining why patients sought second opinions and acquiring patients' complete medical records. Trained physicians summarized the cases; identified key, unresolved clinical questions; and forwarded the cases to expert specialists who provided independent assessments and recommendations. Second opinions were discussed with and returned to patients for review with their physicians. Nurses determined whether second opinions confirmed, clarified, or changed initial diagnoses and treatments, and physicians estimated their clinical impact. Patient satisfaction also was surveyed. A total of 6791 patient-initiated second opinions were completed across medical specialties. Patients primarily sought second opinions for help choosing treatment options (41.3%) and for diagnostic concerns (34.8%). Second opinions often resulted in changes in diagnosis (14.8%), treatment (37.4%), or changes in both (10.6%). Clinical impact was estimated as moderate/major in 20.9% of cases for diagnosis and 30.7% of cases for treatment. Changes in diagnoses and/or treatments and clinical impact varied across medical specialties. In patients surveyed (n = 2683), most (94.7%) were satisfied with the experience, but fewer (61.2%) planned to follow the recommendations. Patient-initiated second opinions led to recommended changes in diagnosis for about 15% and in treatment for about 37% of participants. Further evaluation is needed to determine whether this impacts clinical outcomes, such as the reduction of diagnosis and treatment errors.


A measure of internal noise based on sample discrimination.
Internal noise is often inferred from the difference between observed performance and optimum performance in detection and discrimination tasks. It can be measured directly in some cases by observing the extent to which a change in external variability impacts performance. In the studies reported here, external variability was added to an intensity discrimination task by adding a Gaussian random variable with zero mean to the overall level presented in each interval of a two-interval forced-choice task. The standard deviation of the random variable was set to half the mean difference between the levels in the two intervals, resulting in d'(ideal) = 2. As the mean difference and the corresponding standard deviation of the random variable decreased in size, performance was increasingly limited by internal noise, permitting a reliable estimate of internal noise to be obtained. This can be viewed as a sample discrimination task, with one component per sample. In the first study, performance was measured using 2-kHz tones presented at an average level of 70 dB SPL, with mean differences between distributions ranging from 0.1 to 2.2 dB in steps of 0.3 dB. The distributions were either Gaussian in level or in power. Conditions with no external variability were used to obtain a psychometric function. In the second study, performance was measured using 2-kHz tones presented at average levels of 50 and 90 dB SPL, with mean differences ranging from 0.4 to 2.2 dB in steps of 0.6 dB. In both studies, the measure of internal noise was highly reliable and in good agreement with the intensity difference limen (DL) estimated from the psychometric function. Analyses suggest that this measure could be used to estimate the mean difference between the decision distributions as well as the amount of internal noise in cases where the mean difference between the distributions is unknown.


Evaluative conditioning and conscious knowledge of contingencies: a correlational investigation with large samples.
Evaluative conditioning (EC) is a change in the valence of a stimulus that results from pairing the stimulus with an affective stimulus. Two high-powered studies (total N = 1,161) investigated the nature of the relationship between EC and contingency awareness measured as contingency memory. Stronger EC occurred among people with more accurate and more confident memory of the pairings. Awareness was a necessary condition for EC, but EC was not necessary for awareness. Supporting a propositional account of EC, we found evidence for intentional reliance on the contingency for the evaluation of stimuli. We also found evidence that contingency memory was based both on the actual contingency and on preexisting attitudes.


[Management of the nodal disease in vulvar cancers. The ESGO guidelines].
The European Society of Gynaecologic Oncology (ESGO) guidelines cover the whole field of common clinical situations in gynecologic oncology. Their elaboration follows a strict process including a systematic review of the literature, the setting up of a group of expert on the basis of scientific production, geographical balance, and multidisciplinarity, and an external review by users and patients. The recommendations for the management of vulvar cancer were elaborated in 2015 and published in 2017. They are available in open access on the ESGO website, and can be incorporated in clinical practice using the free ESGO guidelines smartphone application. This review is a selection of the sections addressing the diagnostic and strategical aspects of the management of lymph nodal disease in vulvar cancer. An additional review of the recent literature published since 2015 has been carried out. The management of nodal disease in vulvar cancer encompasses a diagnostic and a therapeutic component. Clinical and imaging assessment still play a major role, whilst the identification of the sentinel node is currently a mainstay of assessment of the nodal status in early vulvar cancer. The therapeutic component is based on the rational use of full lymph node dissection and (chemo)radiation.


Significance of the percentage of prostate needle biopsy cores with cancer as a predictor of disease extension in radical prostatectomy specimens in Japanese men.
To evaluate the significance of the percent of positive biopsy cores (PPBC) with cancer, which has been shown to be one of the most useful predictors of prostate cancer extension in patients undergoing radical prostatectomy. This study included 120 patients who underwent radical prostatectomy for prostate cancer without any neoadjuvant therapies. All of these patients were diagnosed by random prostate biopsy targeting 8 cores; that is, standard sextant cores and 2 additional cores from the bilateral anterior lateral horns. We evaluated the appropriate cut-off points of PPBC for predicting disease extension according to the number of biopsy cores. Based on these criteria, multivariate analysis was then performed to determine whether PPBC could be an independent factor differentiating organ-confined disease from extraprostatic disease. The most suitable PPBC cut-off value using findings targeting 8 cores for predicting disease extension was 37.5%. If PPBC was calculated based on the outcome of standard sextant cores alone, it is most appropriate to use 33.3% as the cut-off point. Multivariate analysis showed that PPBC calculated based on the standard sextant cores and percent of cancer in the biopsy set could be used as independent factors predicting disease extension irrespective of other biopsy-associated factors. For predicting disease extension, it may be useful to calculate PPBC based on the outcomes of standard sextant biopsy cores alone even if additional cores were taken, and that PPBC calculated in such a way may be the strongest preoperative predictor of prostate cancer extension in Japanese men scheduled for radical prostatectomy.


Cognitive Flexibility and Social Responsiveness in Children and Adolescents with Tourette Syndrome.
This study examined cognitive flexibility and social responsiveness in children and adolescents with Tourette Syndrome (TS). Thirty one subjects with TS were compared to 32 age-matched healthy controls. Assessments included semi-structured interviews to assess psychopathology, parent-rated Social Responsiveness Scale (SRS) and a brief neuropsychological battery selected as measures of cognitive flexibility. Completion time for both Trail Making Tests (TMT-A and TMT-B) were significantly longer for TS group than controls, however the difference in perseverative errors on Wisconsin Card Sorting Test (WCST) was not significant. SRS total score was significantly higher in the TS group compared to controls, indicating greater impairment in social responsiveness. Group difference for TMTs and SRS failed to reach significance after controlling for co-occurring conditions. Clinicians might consider social impairment in the evaluation plan of children and adolescents with Tourette syndrome.


Targeting prostate cancer with HTI-286, a synthetic analog of the marine sponge product hemiasterlin.
Therapeutic resistance is the underlying cause for most cancer deaths and a major problem associated with treatment of metastatic prostate cancer. HTI-286, a fully synthetic analog of the natural tripeptide hemiasterlin, inhibits tubulin polymerization and circumvents transport-based resistance to taxanes. In our study, we evaluated its inhibitory effects on human prostate cancer growth in vitro and in different in vivo models. Androgen-dependent and androgen-independent prostate cancer cell lines including a docetaxel-refractory PC-3 subline (PC-3dR) were treated with HTI-286. Transcriptional profiling was carried out to screen for changes in gene expression induced by HTI-286 and compared to docetaxel. In vivo, nude mice with established PC-3 or PC-3dR xenografts were given HTI-286 intravenously. Additionally, mice bearing hormone-sensitive LNCaP tumors were treated with castration in combination with early or delayed HTI-286 therapy. In all cell lines tested, HTI-286 was a potent inhibitor of proliferation and induced marked increases in apoptosis. Despite similar transcriptomic changes regarding cell death and cell cycle regulating genes after exposure to HTI-286 or docetaxel, array analysis revealed distinct molecular signatures for both compounds. Invivo, HTI-286 significantly inhibited growth of PC-3 and LNCaP xenografts and retained potency in PC-3dR tumors. Simultaneous castration plus HTI-286 therapy was superior to sequential treatment in the LNCaP model. In conclusion, HTI-286 showed strong antitumor activity both in androgen-dependent and androgen- independent tumors and may be a promising agent in second- line treatment strategies for patients suffering from docetaxel- refractory prostate cancer.


Hash Bit Selection for Nearest Neighbor Search.
To overcome the barrier of storage and computation when dealing with gigantic-scale data sets, compact hashing has been studied extensively to approximate the nearest neighbor search. Despite the recent advances, critical design issues remain open in how to select the right features, hashing algorithms, and/or parameter settings. In this paper, we address these by posing an optimal hash bit selection problem, in which an optimal subset of hash bits are selected from a pool of candidate bits generated by different features, algorithms, or parameters. Inspired by the optimization criteria used in existing hashing algorithms, we adopt the bit reliability and their complementarity as the selection criteria that can be carefully tailored for hashing performance in different tasks. Then, the bit selection solution is discovered by finding the best tradeoff between search accuracy and time using a modified dynamic programming method. To further reduce the computational complexity, we employ the pairwise relationship among hash bits to approximate the high-order independence property, and formulate it as an efficient quadratic programming method that is theoretically equivalent to the normalized dominant set problem in a vertex- and edge-weighted graph. Extensive large-scale experiments have been conducted under several important application scenarios of hash techniques, where our bit selection framework can achieve superior performance over both the naive selection methods and the state-of-the-art hashing algorithms, with significant accuracy gains ranging from 10% to 50%, relatively.


Genetic analysis of components involved in vitamin B12 uptake in Escherichia coli.
The products of three genes are involved in cyanocobalamin (B(12)) uptake in Escherichia coli. btuB (formerly bfe), located at min 88 on the Escherichia coli linkage map, codes for a protein component of the outer membrane which serves as receptor for B(12), the E colicins, and bacteriophage BF23. Four phenotypic classes of mutants varying in response to these agents were found to carry mutations that, based on complementation and reversion analyses, reside in the single btuB cistron. In one mutant class, ligand binding to the receptor appeared to be normal, but subsequent B(12) uptake was defective. The level of receptor and rate of uptake were responsive to btuB gene dosage. Previous studies showed that the tonB product was necessary for energy-dependent B(12) uptake but not for its binding. Other than those in tonB, no mutations that conferred insensitivity to group B colicins affected B(12) utilization. The requirement for the btuB and tonB products could be bypassed by elevated levels of B(12) (>1 muM) or by mutations compromising the integrity of the outer membrane as a permeability barrier. Utilization of elevated B(12) concentrations in strains lacking the btuB-tonB uptake system was dependent on the function of the btuC product. This gene was located at 37.7 min on the linkage map, with the order pps-btuC-pheS. Strains altered in btuC but with an intact btuB-tonB system were only slightly impaired in B(12) utilization, being defective in its accumulation. This defect was manifested as inability to retain B(12), such that intracellular label was almost completely lost by exchange or efflux. It is proposed that btuC encodes a transport system for B(12) in the periplasm.


Penalized weighted least-squares image reconstruction for dual energy X-ray transmission tomography.
We present a dual-energy (DE) transmission computed tomography (CT) reconstruction method. It is statistically motivated and features nonnegativity constraints in the density domain. A penalized weighted least squares (PWLS) objective function has been chosen to handle the non-Poisson noise added by amorphous silicon (aSi:H) detectors. A Gauss-Seidel algorithm has been used to minimize the objective function. The behavior of the method in terms of bias/standard deviation tradeoff has been compared to that of a DE method that is based on filtered back projection (FBP). The advantages of the DE PWLS method are largest for high noise and/or low flux cases. Qualitative results suggest this as well. Also, the reconstructed images of an object with opaque regions are presented. Possible applications of the method are: attenuation correction for positron emission tomography (PET) images, various quantitative computed tomography (QCT) methods such as bone mineral densitometry (BMD), and the removal of metal streak artifacts.


Efficiently Improving the Stability of Inverted Perovskite Solar Cells by Employing Polyethylenimine-Modified Carbon Nanotubes as Electrodes.
Inverted perovskite solar cells (PSCs) have been becoming more and more attractive, owing to their easy-fabrication and suppressed hysteresis, while the ion diffusion between metallic electrode and perovskite layer limit the long-term stability of devices. In this work, we employed a novel polyethylenimine (PEI) modified cross-stacked superaligned carbon nanotube (CSCNT) film in the inverted planar PSCs configurated FTO/NiO x/methylammonium lead tri-iodide (MAPbI3)/6, 6-phenyl C61-butyric acid methyl ester (PCBM)/CSCNT:PEI. By modifying CSCNT with a certain concentration of PEI (0.5 wt %), suitable energy level alignment and promoted interfacial charge transfer have been achieved, leading to a significant enhancement in the photovoltaic performance. As a result, a champion power conversion efficiency (PCE) of ∼11% was obtained with a Voc of 0.95 V, a Jsc of 18.7 mA cm-2, a FF of 0.61 as well as negligible hysteresis. Moreover, CSCNT:PEI based inverted PSCs show superior durability in comparison to the standard silver based devices, remaining over 85% of the initial PCE after 500 h aging under various conditions, including long-term air exposure, thermal, and humid treatment. This work opens up a new avenue of facile modified carbon electrodes for highly stable and hysteresis suppressed PSCs.


Improved harmonization of critical characterization assays across cell therapies.
The field of cell therapy has blossomed, providing exciting new options for treating a variety of diseases. While few cell therapy products have US FDA approval, there are thousands of cell treatments at various stages of development, pointing to a potential revolutionary shift in patient care. The expanding number and nature of cellular therapies necessitate greater standardization. Several international organizations are collaborating to pursue some level of global standardization, especially concerning cell banking. However, less harmonization surrounds assays used for critical quality characterization including: identity, purity, safety and potency. Frequently, there is divergence regarding the terms describing the characterization assays across regulatory authorities and guidances. This review summarizes the critical quality assays currently used for different categories of cell therapies. Areas of harmonization and an absence of standardization are highlighted. We propose potential solutions to facilitate harmonization of critical quality characterization assays and the language used to describe them.


Retreatment of children after surgery for acquired esotropia: reoperation versus botulinum injection.
Two viable options were compared, reoperation and botulinum toxin injection, in the management of children who need retreatment after surgery for acquired esotropia. 47 strabismic children previously operated to correct an acquired esotropia were randomised to reoperation or botulinum toxin injection. Reoperation was undertaken in 24 of these patients and botulinum toxin injection in 23 of them. The percentage net change in distance deviation, the percentage of patients with successful motor outcome, detectable fusion, and stereopsis were compared 1 year after retreatment and at last visit (average follow up: 2.9 years in reoperation group, and 2.7 years in botulinum group). The motor success rate relative to time elapsed from initial surgery was evaluated. There was no significant difference in the motor and sensory outcomes between patients reoperated and treated with botulinum injection. The frequency of correction to within 8 prism dioptres of orthotropia was, respectively: 75% versus 69.56% at 1 year; 70.83% versus 60.86% at last visit. Botulinum injection could be more effective when performed within 3 months of initial surgery. Botulinum injection is a rapid and safe procedure that may be as effective as reoperation in the management of children who need a secondary procedure after surgery for acquired esotropia.


Refixation patterns of mind-wandering during real-world scene perception.
Recent studies have shown that mind-wandering (MW) is associated with changes in eye movement parameters, but have not explored how MW affects the sequential pattern of eye movements involved in making sense of complex visual information. Eye movements naturally unfold over time and this process may reveal novel information about cognitive processing during MW. The current study used Recurrence Quantification Analysis (Anderson, Bischof, Laidlaw, Risko, & Kingstone, 2013) to describe the pattern of refixations (fixations directed to previously inspected regions) during MW. Participants completed a real-world scene encoding task and responded to thought probes assessing intentional and unintentional MW. Both types of MW were associated with worse memory of the scenes. More important, RQA showed that scanpaths during unintentional MW were more repetitive than during on-task episodes, as indicated by a higher recurrence rate and more stereotypical fixation sequences. This increased repetitiveness suggests an adaptive response to processing failures through reexamining previous locations. Moreover, this increased repetitiveness contributed to fixations focusing on a smaller spatial scale of the stimuli. Finally, we were also able to validate several traditional measures: both intentional and unintentional MW were associated with fewer and longer fixations; eye-blinking increased numerically during both types of MW but the difference was only significant for unintentional MW. Overall, the results advanced our understanding of how visual processing is affected during MW by highlighting the sequential aspect of eye movements. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


A Smartphone Application as a Telemedicine Tool for Stroke Care Management.
Since smartphone applications are revolutionizing telemedicine, a new application specifically for stroke care (JOIN) was designed. Addition of the JOIN smartphone application to the stroke treatment workflow in our hospital was assessed. JOIN has key functions that may improve the care of stroke patients, including the ability to (1) exchange information such as patient data and medical images in real-time throughout the entire process of patient management; (2) track each step of the protocol from door to discharge; and (3) facilitate real-time interaction of all team members via text, audio, and a video chat system. Two periods, 2.7 years before the implementation of JOIN (Pre-JOIN) with 37 patients and 2.2 years after (Post-JOIN) with 54 patients, were compared, and the workflow for all 91 patients who had a cerebral infarction and were treated with tissue plasminogen activator (tPA) and/or thrombectomy between October 2012 and July 2017 was reviewed. There were noticeable reductions in overall patient management time, including times for door-to-imaging, starting tPA treatment, and endovascular intervention with JOIN. Staff members were unanimously satisfied with JOIN, due to the increased efficiency of information exchange and the ability for real-time discussions with different professionals when needed. No significant changes in patient outcomes (as assessed by modified Rankin Scale [mRS] scores) at 3 months and in the total cost for the treatment were observed. A smartphone-based application with the capability of sharing information instantaneously among healthcare professionals facilitated time-sensitive, acute care of ischemic stroke patients.


Cognitive Training Enhances Auditory Attention Efficiency in Older Adults.
Auditory cognitive training (ACT) improves attention in older adults; however, the underlying neurophysiological mechanisms are still unknown. The present study examined the effects of ACT on the P3b event-related potential reflecting attention allocation (amplitude) and speed of processing (latency) during stimulus categorization and the P1-N1-P2 complex reflecting perceptual processing (amplitude and latency). Participants completed an auditory oddball task before and after 10 weeks of ACT (n = 9) or a no contact control period (n = 15). Parietal P3b amplitudes to oddball stimuli decreased at post-test in the trained group as compared to those in the control group, and frontal P3b amplitudes show a similar trend, potentially reflecting more efficient attentional allocation after ACT. No advantages for the ACT group were evident for auditory perceptual processing or speed of processing in this small sample. Our results provide preliminary evidence that ACT may enhance the efficiency of attention allocation, which may account for the positive impact of ACT on the everyday functioning of older adults.


Stimulated monocyte IL-6 secretion predicts survival of patients with head and neck squamous cell carcinoma.
This study was performed in order to determine whether monocyte in vitro function is associated with presence, stage and prognosis of head and neck squamous cell carcinoma (HNSCC) disease. Prospective study describing outcome, after at least five years observation, of patients treated for HNSCC disease in relation to their monocyte function. Sixty-five patients with newly diagnosed HNSCC and eighteen control patients were studied. Monocyte responsiveness was assessed by measuring levels of monocyte in vitro interleukin (IL)-6 and monocyte chemotactic peptide (MCP)-1 secretion after 24 hours of endotoxin stimulation in cultures supplied either with 20% autologous serum (AS) or serum free medium (SFM). Survival, and if relevant, cause of death, was determined at least 5 years following primary diagnosis. All patients, as a group, had higher in vitro monocyte responsiveness in terms of IL-6 (AS) (t = 2.03; p < 0.05) and MCP-1 (SFM) (t = 2.49; p < 0.05) compared to controls. Increased in vitro monocyte IL-6 endotoxin responsiveness under the SFM condition was associated with decreased survival rate (Hazard ratio (HR) = 2.27; Confidence interval (CI) = 1.05-4.88; p < 0.05). The predictive value of monocyte responsiveness, as measured by IL-6, was also retained when adjusted for age, gender and disease stage of patients (HR = 2.67; CI = 1.03-6.92; p < 0.05). With respect to MCP-1, low endotoxin-stimulated responsiveness (AS), analysed by Kaplan-Meier method, predicted decreased survival (chi = 4.0; p < 0.05). In HNSCC patients, changed monocyte in vitro response to endotoxin, as measured by increased IL-6 (SFM) and decreased MCP-1 (AS) responsiveness, are negative prognostic factors.


Low-moderate urine arsenic and biomarkers of thrombosis and inflammation in the Strong Heart Study.
The underlying pathology of arsenic-related cardiovascular disease (CVD) is unknown. Few studies have evaluated pathways through thrombosis and inflammation for arsenic-related CVD, especially at low-moderate arsenic exposure levels (<100 μg/L in drinking water). We evaluated the association of chronic low-moderate arsenic exposure, measured as the sum of inorganic and methylated arsenic species in urine (ΣAs), with plasma biomarkers of thrombosis and inflammation in American Indian adults (45-74 years) in the Strong Heart Study. We evaluated the cross-sectional and longitudinal associations between baseline ΣAs with fibrinogen at three visits (baseline, 1989-91; Visit 2, 1993-95, Visit 3, 1998-99) using mixed models and the associations between baseline ΣAs and Visit 2 plasminogen activator inhibitor-1 (PAI-1) and high sensitivity C-reactive protein (hsCRP) using linear regression. Median (interquartile range) concentrations of baseline ΣAs and fibrinogen, and Visit 2 hsCRP and PAI-1 were 8.4 (5.1, 14.3) μg/g creatinine, 346 (304, 393) mg/dL, 44 (30, 67) mg/L, and 3.8 (2.0, 7.0) ng/mL, respectively. Comparing the difference between the 75th and the 25th percentile of ΣAs (14.3 vs. 5.1 μg/g creatinine), ΣAs was positively associated with baseline fibrinogen among those with diabetes (adjusted geometric mean ratio (GMR): 1.05, 95% CI: 1.02, 1.07) not associated among those without diabetes (GMR: 1.01, 95% CI: 0.99, 1.02) (p-interaction for diabetes = 0.014), inversely associated with PAI-1 (GMR: 0.94, 95% CI: 0.90, 0.99), and not associated with hsCRP (GMR: 1.00, 95% CI: 0.93, 1.08). We found no evidence for an association between baseline ΣAs and annual change in fibrinogen over follow-up (p-interaction = 0.28 and 0.12 for diabetes and non-diabetes, respectively). Low-moderate arsenic exposure was positively associated with baseline fibrinogen in participants with diabetes and unexpectedly inversely associated with PAI-1. Further research should evaluate the role of prothrombotic factors in arsenic-related cardiovascular disease.


MR cholangiopancreatographic differentiation of benign and malignant intraductal mucin-producing tumors of the pancreas.
The purpose of this study was to establish MR cholangiopancreatographic criteria for discriminating benign from malignant intraductal mucin-producing tumors of the pancreas. Thirty-one patients with 34 intraductal mucin-producing tumors underwent MR cholangiopancreatography. Tumors were classified as either main duct type (n = 10) or branch duct type (n = 24). In patients with the main duct type, the maximum diameter and the location of the main pancreatic duct, the extent of main pancreatic duct dilatation, and the presence of a filling defect were evaluated. For branch duct type, the location and maximum diameter of the cystic lesion, the presence of a filling defect, and the presence of associated main pancreatic duct dilatation were evaluated. In patients with the main duct type, the main pancreatic duct was significantly narrower when associated with benign rather than malignant tumors. All malignant tumors showed diffuse main pancreatic duct dilatation, whereas all benign tumors showed segmental dilatation. Among patients with branch duct type, the cyst was smaller when it was a benign rather than malignant tumor. All but one malignant tumor showed mild associated main pancreatic duct dilatation, whereas benign tumors were not associated with main pancreatic duct dilatation. Filling defects suggested malignancy, although half of the malignant tumors had no filling defects. In patients with intraductal mucin-producing tumors of the pancreas, filling defects are indicative of malignancy. Diffuse main pancreatic duct dilatation greater than 15 mm (main duct type), or any main pancreatic duct dilatation (branch duct type), is strongly associated with malignancy.


Methionine-restricted C57BL/6J mice are resistant to diet-induced obesity and insulin resistance but have low bone density.
Dietary methionine restriction (MR) extends lifespan, an effect associated with reduction of body weight gain, and improvement of insulin sensitivity in mice and rats as a result of metabolic adaptations in liver, adipose tissue and skeletal muscle. To test whether MR confers resistance to adiposity and insulin resistance, C57BL/6J mice were fed a high fat diet (HFD) containing either 0.86% methionine (control fed; CF) or 0.12% methionine (methionine-restricted; MR). MR mice on HFD had lower body weight gain despite increased food intake and absorption efficiency compared to their CF counterparts. MR mice on HFD were more glucose tolerant and insulin sensitive with reduced accumulation of hepatic triglycerides. In plasma, MR mice on HFD had higher levels of adiponectin and FGF21 while leptin and IGF-1 levels were reduced. Hepatic gene expression showed the downregulation of Scd1 while Pparg, Atgl, Cd36, Jak2 and Fgf21 were upregulated in MR mice on HFD. Restriction of growth rate in MR mice on HFD was also associated with lower bone mass and increased plasma levels of the collagen degradation marker C-terminal telopeptide of type 1 collagen (CTX-1). It is concluded that MR mice on HFD are metabolically healthy compared to CF mice on HFD but have decreased bone mass. These effects could be associated with the observed increase in FGF21 levels.


Acute effects of trauma-focused research procedures on participant safety and distress.
The ethical conduct of research on posttraumatic stress disorder (PTSD) requires assessing the risks to study participants. Some previous findings suggest that patients with PTSD report higher distress compared to non-PTSD participants after trauma-focused research. However, the impact of study participation on participant risk, such as suicidal/homicidal ideation and increased desire to use drugs or alcohol, has not been adequately investigated. Furthermore, systematic evaluation of distress using pre- and post-study assessments, and the effects of study procedures involving exposure to aversive stimuli, are lacking. Individuals with a history of PTSD (n=68) and trauma-exposed non-PTSD controls (n=68) responded to five questions about risk and distress before and after participating in research procedures including a PTSD diagnostic interview and a behavioral task with aversive stimuli consisting of mild electrical shock. The desire to use alcohol or drugs increased modestly with study participation among the subgroup (n=48) of participants with current PTSD. Participation in these research procedures was not associated with increased distress or participant risk, nor did study participation interact with lifetime PTSD diagnosis. These results suggest some increase in distress with active PTSD but a participant risk profile that supports a favorable risk-benefit ratio for conducting research in individuals with PTSD.


Spontaneous adverse event reports of serious ventricular arrhythmias, QT prolongation, syncope, and sudden death in patients treated with cisapride.
Adverse cardiac events, typically long QT syndrome, have been reported in patients treated with the gastrointestinal prokinetic agent cisapride. To analyze cases of cisapride-associated long QT syndrome and ascertain the degree of confidence in the diagnosis of long QT syndrome and the presence of risk factors. Review of all cases reported to the manufacturer, health authorities, or in the medical literature as of October 1999. Before review, specific definitions and a classification scheme were agreed upon. Each case was classified by confidence in the long QT syndrome diagnosis and the presence of recognized risk factors (cofactors) or other medical conditions that were listed as contraindications in the June 1998 United States labeling (labeled conditions). Of 574 cases reviewed, 391 cases of long QT syndrome or isolated QT prolongation were confirmed. Most of these were classified as long QT syndrome with high (145, 37%) or medium (92, 23.5%) confidence in the diagnosis. Recognized cofactors were present in 262 (67%) cases. The proportion of cases with recognized cofactors rose with confidence in the diagnosis (P < 0.001) from 42.2% in the low-confidence group to 68.5% and 82.1% in the medium- and high-confidence groups, respectively. Conversely, the proportion of cases with other labeled conditions decreased with confidence in the diagnosis, from 33.3% for low confidence to 13% and 8.3% for medium and high confidence, respectively. Analysis of cases and prescribing data showed reporting rates decreased in studied months in 1999 compared with the average study period. In most cases with high or medium confidence in the diagnosis of cisapride-associated long QT syndrome, recognized cofactors for long QT syndrome were present. The risk of cisapride-related long QT syndrome may be minimized by avoiding cofactors.


[Movement of the ear ossicles by middle ear muscle contraction].
Up to now, the function of the middle ear muscles has mainly been investigated from an acoustical point of view. However, the primary function of the middle-ear muscles, namely the induction of ossicular movements, has never been investigated systematically. For this purpose, the displacements of the ossicles, as induced by simulated muscle contractions, were measured microscopically in 13 fresh temporal bone preparations. Both muscles move all ossicles. The tensor tympani muscle pulls the umbo inwards about 100 microns. Due to the gliding motion in the malleus-incus joint, the stapes is thus pushed inwards by at the most 10 microns and, additionally, displaced anteriorly, antagonistic to the pull of the stapedius muscle. This muscle pulls the stapes backwards, lifting the anterior crus outwards and pushing the posterior crus inwards. This reduces the pressure on the cochlear fluids significantly as compared to our former concepts of the movement of the footplate, tilting outwards as a whole around an axis at the posterior pole. Furthermore, this outward displacement of the stapes is not prerequisite for the outward movement of the malleus-drumhead complex, which typically appears at the contraction of the stapedius muscle. The basic motion of the stapes is the movement backwards, which is 5 times greater and which matches the anatomic direction of the pull of the stapedius muscle. This explains the otherwise unlogical position of the stapedius muscle parallel to the footplate. Due to the gliding movement in the malleus-incus joint, this motion changes at the umbo into outward rotation, counteracting the tensor tympani muscle.(ABSTRACT TRUNCATED AT 250 WORDS)


Musculoskeletal Injuries Associated With Hoverboard Use in Children.
Hoverboards burst onto the scene with wide popularity only to be quickly deemed unsafe and banned in many arenas. We conducted a retrospective cohort study of 35 patients seen in our outpatient pediatric orthopedic office over a 1-year period. The mean age of injured patients was 11.14 years; 18 patients were male (51.4%), and 17 were female (48.5%). The highest number of injuries occurred in children 10 to 14 years old who had 57.1% of the injuries. There were a total of 31 fractures in 27 patients. Most of the fractures were in the upper extremities (93.6 %). Also, 9 soft-tissue injuries were found in 8 patients; 88.9 % of injuries occurred in the upper extremities. Most of the injuries were secondary to a fall (94.3%). We found that the most common injury was upper-extremity fracture. We suggest restricting riding <16 years and encourage protective equipment, especially elbow and wrist guards.


CNV Radar: an improved method for somatic copy number alteration characterization in oncology.
Cancer associated copy number variation (CNV) events provide important information for identifying patient subgroups and suggesting treatment strategies. Technical and logistical issues, however, make it challenging to accurately detect abnormal copy number events in a cost-effective manner in clinical studies. Here we present CNV Radar, a software tool that utilizes next-generation sequencing read depth information and variant allele frequency patterns, to infer the true copy number status of genes and genomic regions from whole exome sequencing data. Evaluation of CNV Radar in a public multiple myeloma dataset demonstrated that CNV Radar was able to detect a variety of CNVs associated with risk of progression, and we observed > 70% concordance with fluorescence in situ hybridization (FISH) results. Compared to other CNV callers, CNV Radar showed high sensitivity and specificity. Similar results were observed when comparing CNV Radar calls to single nucleotide polymorphism array results from acute myeloid leukemia and prostate cancer datasets available on TCGA. More importantly, CNV Radar demonstrated its utility in the clinical trial setting: in POLLUX and CASTOR, two phase 3 studies in patients with relapsed or refractory multiple myeloma, we observed a high concordance rate with FISH for del17p, a risk defining CNV event (88% in POLLUX and 90% in CASTOR), therefore allowing for efficacy assessments in clinically relevant disease subgroups. Our case studies also showed that CNV Radar is capable of detecting abnormalities such as copy-neutral loss of heterozygosity that elude other approaches. We demonstrated that CNV Radar is more sensitive than other CNV detection methods, accurately detects clinically important cytogenetic events, and allows for further interrogation of novel disease biology. Overall, CNV Radar exhibited high concordance with standard methods such as FISH, and its success in the POLLUX and CASTOR clinical trials demonstrated its potential utility for informing clinical and therapeutic decisions.


Hippocampal pyramidal cell orientation in schizophrenia. A controlled neurohistologic study of the Yakovlev collection.
The finding of marked disorganization of the hippocampal pyramidal cell layer in the brains of schizophrenic patients has recently been reported. The present study was undertaken to determine whether similar abnormalities could be found in the brains of a population of schizophrenic patients, most of whom were never exposed to neuroleptics. Though statistical analysis of 2808 pyramidal cells failed to reveal significantly greater disorganization in a group of seven alleged schizophrenic brains than in brains of age-matched, nonpsychotic controls, the data suggest a relationship between the degree of pyramidal cell disarray and the severity of behavioral impairment due to psychosis. The implications and pitfalls in interpreting these findings are discussed.


The implementation of a surgeon-directed quality improvement strategy in breast cancer surgery.
The investigators designed a sustained, surgeon-directed, iterative project to improve the quality of breast cancer surgery in south central Ontario. The strategy included audit and feedback of surgeon-selected quality indicators, workshops, and tailoring interviews. Workshops were held to discuss quality improvement strategies, select quality indicators, review audited results, and select interventions for subsequent implementation. Semistructured tailoring interviews were conducted to identify facilitators and barriers to improved quality. All presentations and results were disseminated to all surgeons performing breast surgery in the study region. Forty-four surgeons performing breast surgery across 12 hospitals are involved in the project. Five workshops have been held since 2005. Surgeons' enthusiasm and involvement in the project have been positive. Interim results demonstrated that over 4 audit cycles (2006-2010), the preoperative core biopsy rate increased from 73% to 92%. The tailoring interviews indicated that 18 of 21 surgeons performed preoperative core biopsies. This project highlights the feasibility of a surgeon-directed, iterative quality improvement strategy in breast cancer surgery. Interim results demonstrate consistent improvements in a key selected quality indicator.


Developmental study of Müller cells in the rat retina using a new monoclonal antibody, RT10F7.
We produced the monoclonal antibody RT10F7, characterized its antigenic specificity and expression in the adult and developing retina, in cultured retinal cells and in other parts of the central nervous system. In metabolically-labelled retinal cultures RT10F7 immunoprecipitated a protein of approximately 36,000 mol. wt. In the adult, RT10F7 stained endfeet of Müller cells in the ganglion cell layer, four horizontal bands in the inner plexiform layer, and radial fibres in the outer plexiform layer which terminated at the outer limiting membrane. In the inner nuclear layer, most somata were underlined by Müller processes that wrapped around them, but some cell bodies were immunoreactive for RT10F7 in the cytoplasm. During development, postnatal day 21 was the first age at which the adult pattern of immunoreactivity was present, although a fourth band in the inner plexiform layer was less clear than for the adult. By 14 and eight days after birth, the pattern of RT10F7 immunoreactivity approximated that of the adult; however, only three bands and one band were present, respectively, in the inner plexiform layer. At earlier ages, postnatal days 4, 1 and embryonic ages 19 and 15, the monoclonal antibody stained Müller cell endfeet and radial fibres, from the inner plexiform layer through the neuroblastic layer to the outer limiting membrane. At these ages, the immunoreactivity was more prominent at the level of Müller cell endfeet. The monoclonal antibody stained glia in preparations of dissociated retinal cells maintained in culture but not astrocytes or oligodendrocytes from optic nerve cultures. In brain sections, tanycytes exhibited RT10F7 immunoreactivity. The monoclonal antibody RT10F7 recognized a specific cell type in the retina, the Müller cell. In the adult and developing retina, RT10F7 recognized an antigen that is present primarily in Müller cell processes. This feature allowed us to follow the maturation of the Müller cell and correlate it with developmental events in the retina. RT10F7 is a specific marker for Müller cells in vivo and in vitro and may be useful for studies of function of Müller cells after ablation or after injuries that are known to activate Müller cells.


A FRET-based approach for quantitative evaluation of forskolin-induced pendrin trafficking at the plasma membrane in bronchial NCI H292 cells.
Human pendrin (SLC26A4, PDS) is an integral membrane protein acting as an electroneutral anion exchanger. Loss of function mutations in pendrin protein cause Pendred syndrome, a disorder characterized by sensorineural deafness and a partial iodide organification defect that may lead to thyroid goiter. Additionally, pendrin up-regulation could play a role in the pathogenesis of several diseases including bronchial asthma and chronic obstructive pulmonary disease (COPD). Therefore, monitoring the plasma membrane abundance and trafficking of pendrin in the context of a living cell is crucially important. Trafficking of pendrin to the plasma membrane was monitored by fluorescence resonance energy transfer (FRET), a physical phenomenon occurring between two fluorophores (the FRET donor and acceptor) located in close spatial proximity. Because the efficiency of the energy transfer is inversely proportional to the sixth power of the distance between donor and acceptor, FRET is extremely sensitive to small changes in distance between the donor and acceptor and is therefore a powerful tool to determine protein-protein interactions. FRET studies revealed that forskolin-induced cAMP production is associated with a significant increase of pendrin expression at plasma membrane, which is paralleled by a decrease in intracellular pH. Pendrin transposition to the membrane is accompanied with a partial depolymerization of actin cytoskeleton via Rho-GTPase inhibition. Trafficking to the plasma membrane is critical in the regulation of pendrin activity. Therefore, reliable tools for monitoring and quantifying this phenomenon are highly desirable.


Cell counting.
This unit presents protocols for counting cells using either a hemacytometer or electronically using a Coulter counter. Cell counting with a hemacytometer permits effective discrimination of live from dead cells using trypan blue exclusion. In addition, the procedure is less subject to errors arising from cell clumping or size heterogeneity. Counting cells is more quickly and easily performed using an electronic counter, but live-dead discrimination is unreliable. Cell populations containing large numbers of dead cells and/or cell clumps are difficult to count accurately. In addition, electronic counting requires resetting of the instrument for cell populations of different sizes; heterogeneous populations can give rise to inaccurate counts, and resting and activated cells may require counting at separate settings. In general, electronic cell counting is best performed on fresh peripheral blood cells.


Secretory leukoprotease inhibitor and pulmonary surfactant serve as principal defenses against influenza A virus infection in the airway and chemical agents up-regulating their levels may have therapeutic potential.
Influenza A virus (IAV) is one of the most common infectious pathogens in humans. Entry of this virus into cells is primarily determined by host cellular trypsin-type processing proteases, which proteolytically activate viral membrane fusion glycoprotein precursors. Human IAV and murine parainfluenza virus type 1 Sendai virus are exclusively pneumotropic, and the infectious organ tropism of these viruses is determined by the susceptibility of the viral envelope glycoprotein to cleavage by proteases in the airway. Proteases in the upper respiratory tract are suppressed by secretory leukoprotease inhibitor, and those in the lower respiratory tract are suppressed by pulmonary surfactant, which by adsorption inhibits the interaction between the proteases and viral membrane proteins. Although the protease activities are predominant over the activities of inhibitory compounds under normal airway conditions, intranasal administration of inhibitors was able to significantly suppress multi-cycles of viral replication in the airway. In addition, we identified chemical agents that could act as defensive factors by up-regulating the levels of the natural inhibitors and immunoglobulin A (IgA) in airway fluids. One of these compounds, ambroxol, is a mucolytic and anti-oxidant agent that stimulates the release of secretory leukoprotease inhibitor and pulmonary surfactant in the early phase, and IgA in the late phase of infection at an optimal dose, i.e. a dose sufficient to inhibit virus proliferation and increase the survival rate of animals after treatment with a lethal dose of IAV. Another agent, clarithromycin, is a macrolide antibiotic that increases IgA levels through augmentation of interleukin-12 levels and mucosal immunization in the airway. In addition to the sialidase inhibitors, which prevent the release of IAV from infected cells, inhibitors of the processing proteases and chemical agents that augment mucosal immunity and/or levels of the relevant defensive compounds may also ultimately prove to be useful as new anti-influenza agents.


A Prospective Study on the Effect of Sport Specialization on Lower Extremity Injury Rates in High School Athletes.
Sport specialization is associated with an increased risk of musculoskeletal lower extremity injuries (LEIs) in adolescent athletes presenting in clinical settings. However, sport specialization and the incidence of LEIs have not been investigated prospectively in a large population of adolescent athletes. To determine if sport specialization was associated with an increased risk of LEIs in high school athletes. Cohort study; Level of evidence, 2. Participants (interscholastic athletes in grades 9-12) were recruited from 29 Wisconsin high schools during the 2015-2016 school year. Participants completed a questionnaire identifying their sport participation and history of LEIs. Sport specialization of low, moderate, or high was determined using a previously published 3-point scale. Athletic trainers reported all LEIs that occurred during the school year. Analyses included group proportions, odds ratios (ORs) and 95% CIs, and days lost due to injury (median and interquartile range [IQR]). Multivariate Cox proportional hazard ratios (HRs) with 95% CIs were calculated to investigate the association between the incidence of LEIs and sport specialization level. A total of 1544 participants (50.5% female; mean age, 16.1 ± 1.1 years) enrolled in the study, competed in 2843 athletic seasons, and participated in 167,349 athlete-exposures. Sport specialization was classified as low (59.5%), moderate (27.1%), or high (13.4%). Two hundred thirty-five participants (15.2%) sustained a total of 276 LEIs that caused them to miss a median of 7.0 days (IQR, 2.0-22.8). Injuries occurred most often to the ankle (34.4%), knee (25.0%), and upper leg (12.7%) and included ligament sprains (40.9%), muscle/tendon strains (25.4%), and tendinitis/tenosynovitis (19.6%). The incidence of LEIs for moderate participants was higher than for low participants (HR, 1.51 [95% CI, 1.04-2.20]; P = .03). The incidence of LEIs for high participants was higher than for low participants (HR, 1.85 [95% CI, 1.12-3.06]; P = .02). Athletes with moderate or high sport specialization were more likely to sustain an LEI than athletes with low specialization. Sports medicine providers need to educate coaches, parents, and interscholastic athletes regarding the increased risk of LEIs for athletes who specialize in a single sport.


An intrinsic neural pathway for long intestino-intestinal inhibitory reflexes.
We studied the mechanisms of initiation and pathways for the propagation of intestino-intestinal inhibitory reflexes induced by close intraarterial injections of neostigmine in conscious dogs. Two or three T-shaped catheters were surgically implanted in the intestinal branches of the superior mesenteric artery to inject pharmacologic agents locally in 10-15-cm-long segments. Migrating myoelectric complexes were recorded by a set of 10 electrodes and strain-gauge transducers. Close intraarterial injection of neostigmine initiated strong contractions of long duration in the perfused segment that terminated phase III activity in progress 90-150 cm distal or proximal to the cannulated sites and stopped its further migration. Atropine or 4-diphenylmethoxy-N-methylpiperidine methiodide injected just before neostigmine administration through the same catheter blocked both the local contractile effects and the reflex inhibition of phase III activity. Pirenzepine or hexamethonium injected in a similar manner did not affect the local response to neostigmine but blocked the reflex inhibition of phase III activity. A transection and reanastomosis in the mid-small intestine blocked the reflex inhibition by close intraarterial injection of neostigmine beyond the transection site. Pirenzepine, atropine, or hexamethonium injected through a middle catheter also blocked the reflex inhibition of phase III activity beyond the site perfused with these cholinergic antagonists. Close intraarterial administration of 4-diphenylmethoxy-N-methylpiperidine methiodide at a middle site had no effect on reflex inhibition. We concluded that strong spasmodic contractions in the small intestine initiate an intestino-intestinal inhibitory reflex in both directions. This reflex is mediated through an intrinsic neural pathway involving nicotinic and M1 muscarinic receptors.


Influence of dietary carbohydrates and glycaemic response on subjective appetite and food intake in healthy elderly persons.
Increased satiety and decreased food intake are reported following the consumption of low glycaemic index (GI) foods, which gradually increase blood glucose. This observation, however, is not uniformly supported and few studies have examined the impact of different GI foods on satiety and intake in the elderly. After an overnight fast, 10 men and 10 women (aged 60-82 years) consumed similar amounts of available carbohydrate as high (glucose drink or potatoes) or low (barley) GI foods or a non-energy placebo drink on four mornings. Blood glucose and subjective appetite were measured throughout a 120 min post-ingestion period, followed by consumption of an ad libitum lunch. Differences in plasma glucose after test food ingestion (glucose > potatoes > barley > placebo; P < 0.03) did not predict subjective appetite or lunch intake. Potatoes increased subjective satiety the most, followed by barley, then glucose, which trended towards greater satiety than placebo. Potatoes led to less hunger than placebo (P = 0.0023) and less prospective consumption than the other three foods (P < 0.0083), and potatoes and barley led to greater fullness than glucose and placebo (P < 0.0001). Lunch intake was decreased, compared with placebo (502 +/- 47 kcal, P < 0.031), by potatoes (405 +/- 40 kcal) and barley (441 +/- 41 kcal); however, only potatoes (41.9 +/- 12.3%) led to greater compensation at lunch for test food ingestion compared with glucose (11.9 +/- 9.5%, P = 0.016). These results suggest that elderly subjects are sensitive to the effects of different foods on subjective appetite and food intake, and that the GI of the foods tested did not predict their effects on satiety and food intake.


Comparing policies to tackle ethnic inequalities in health: Belgium 1 Scotland 4.
Ethnic-minority health is a public health priority in Europe. This study compares strategies for tackling ethnic inequalities in health from two countries, Scotland and Belgium. We compared the countries using the Whitehead framework. Official policy documents were retrieved and reviewed and two databases related to immigrant health policies were also used. Ethnic inequalities in health were compared using the UK and Belgian Censuses of 2001. We analysed the recognition of the problem, the policies and the services and described ethnic health inequalities. Scotland has recognized the problem of ethnic inequalities in health, thanks to better data and the Scottish Government has come up with a bold strategy. Belgium is a later starter, unable to properly monitor ethnic inequalities. In addition, there is no clear government commitment to tackling either health inequalities or ethnic inequalities in health. Both countries provide health-care services to ethnic minority groups through the mainstream services, although ethnic minority groups have more choice in Belgium than in Scotland. Overall, ethnic heath inequalities are lower in Scotland than in Belgium. Scotland has provided a more advanced and comprehensive response to tackling ethnic inequalities in health than Belgium. It has acknowledged that discrimination exists and that ethnic minority groups may have different needs. Belgium still assumes non-discrimination in health care and effectively denies the need for policy to tailor services to meet these needs. In Scotland, public organizations have been made accountable for promoting equality in health. This is an important contribution to European health policy.


Assessment for bone health in patients with differentiated thyroid carcinoma after postoperative thyroid-stimulating hormone suppression therapy: a new fracture risk assessment algorithm.
The fracture risk assessment tool (FRAX) is used to assess the 10-year risk of major site and hip fractures; however, whether this tool can be applied to patients receiving levothyroxine-based thyroid-stimulating hormone (TSH) suppressive therapy for postoperative differentiated thyroid cancer (DTC) patients is yet to be clarified. A total of 64 patients with DTC following thyroidectomy and oral levothyroxine for TSH suppression therapy and 30 gender- and age-matched controls were collected. The fracture risk was compared between the affected groups with different TSH levels. FRAX was used to calculate the fracture risk with and without bone mineral density (BMD). The TSH level was converted to an age-weighted score to estimate the fracture risk of postoperatively differentiated thyroid cancer patients. The sensitivity, specificity, and area under the AUC curve of the traditional FRAX and the new algorithm for osteoporosis diagnosis were compared. The dual-energy X-ray bone mineral density measurement T score was used as the gold standard to diagnose osteoporosis. There were 24 patients in the T ≥ -1-2.5 group, 23 in the -2.5 < T < -1 group, and 17 in the T ≤ -2.5 group. The T score of BMD in the disease group was significantly lower than that in the control group (p < 0.05). The risk of MOF and hip fracture without a T score were significantly different under various TSH levels (p < 0.05). The area under the curve (AUC) of FRAX without BMD for predicting major osteoporotic fractures (PMOF) and major hip fractures (PHF) was 0.694 and 0.683, respectively. The cutoff values were 2.15% and 0.25%, respectively. The AUC of FRAX with BMD for PMOF and PHF was 0.976 and 0.989, respectively, and the cutoff values were 4.15% and 1.1%, respectively. The AUC of FRAX without BMD for PMOF and PHF was 0.708 and 0.72, respectively, and the cutoff values were 5.5% and 1.55%, respectively. FRAX is suitable for postoperative DTC patients after TSH suppressive therapy. In the absence of BMD, TSH weighted by age can improve the specificity of FRAX in the diagnosis of osteoporosis in this population.


Risk of cardiac rupture after acute myocardial infarction is related to a risk of hemorrhage.
Although cardiac rupture (CR) is a fatal mechanical complication of acute myocardial infarction (AMI), to date no predictive model for CR has been described. CR has common pathological characteristics with major bleeding. We aimed to investigate the relationship between the risk factors of major bleeding and CR. A total of 10202 consecutive AMI patients were recruited, and mechanical complications occurred in 72 patients. AMI patients without CR were chosen as control group. Clinical characteristics including bleeding-related factors were compared between the groups. The incidences of free wall rupture (FWR), ventricular septal rupture (VSR), and papillary muscle rupture (PMR) were 0.39%, 0.21%, and 0.09%, respectively, and the hospital mortalities were 92.5%, 45.5%, and 10.0%, respectively. Female proportion and average age were significantly higher in the groups of FWR and VSR than in the control group (P<0.01); higher white blood cell count and lower hemoglobin were found in all CR groups (P<0.01). Compared to the control group, patients with CR were more likely to receive an administration of thrombolysis [26.39% vs. 13.19%, P<0.05], and were less likely to be treated with primary percutaneous coronary intervention (PCI) [41.67% vs. 81.60%, P<0.05]. The major bleeding scores (integer scores) of FWR, VSR, and PMR were (17.70±7.24), (21.91±8.33), and (18.60±7.88), respectively, and were significantly higher than that of the control group (11.72±7.71) (P<0.05). A regression analysis identified age, increased heart rate, anemia, higher white blood cell count, and thrombolysis as independent risk factors of CR, most of which were major bleeding-related factors. The patients with CR have a significantly higher risk of hemorrhage compared to the group without CR. Risk of CR after AMI is related to the risk of hemorrhage.


Low-symmetry spin hamiltonian and crystal field tensors analysis: Fe(3+) in natrolite.
Electron paramagnetic resonance study of a natural single crystal of natrolite was carried out at the frequency nu=36.772 GHz at room temperature. The angular dependence of the four symmetry-related spectra of Fe(3+) in the three crystallographic planes was fitted to a spin Hamiltonian (S=5/2) of symmetry C(i). The rank 4 crystal field tensors at tetrahedral sites were calculated using the point-charge model to determine the principal axes orientations of their cubic and trigonal components. The analysis of zero-field splitting tensors and comparison with crystal field ones suggests that Fe(3+) substitutes for Al(3+) with no significant distortion of the coordination tetrahedron in natrolite. Comparison of data for several natural and synthetic crystals reveals that the 4-rank zero-field splitting tensor invariants for Fe(3+) at the tetrahedral oxygen-coordinated sites are distinguishably smaller than those for Fe(3+) at octahedral sites. Such comparative analysis may help to determine the substitutional sites in other crystals.


Antigenic cross-reaction between mouse intestine and a member of the autochthonous microflora.
Antigenic cross-reaction has been demonstrated between homogenates of intestine taken from fetal mice and suspensions of a Bacteriodes species isolated from the large intestines of normal adult mice. This observation provides an explanation for the lack of immunological response observed in mice after antigenic stimulation with this member of the normal autochthonous intestinal flora of these animals.


Peroxiredoxin 3 Has Important Roles on Arsenic Trioxide Induced Apoptosis in Human Acute Promyelocytic Leukemia Cell Line via Hyperoxidation of Mitochondrial Specific Reactive Oxygen Species.
NB4 cell, the human acute promyelocytic leukemia (APL) cell line, was treated with various concentrations of arsenic trioxide (ATO) to induce apoptosis, measured by staining with 7-amino-actinomycin D (7-AAD) by flow cytometry. 2', 7'-dichlorodihydro-fluorescein-diacetate (DCF-DA) and MitoSOXTM Red mitochondrial superoxide indicator were used to detect intracellular and mitochondrial reactive oxygen species (ROS). The steady-state level of SO2 (Cysteine sulfinic acid, Cys-SO2H) form for peroxiredoxin 3 (PRX3) was measured by a western blot. To evaluate the effect of sulfiredoxin 1 depletion, NB4 cells were transfected with small interfering RNA and analyzed for their influence on ROS, redox enzymes, and apoptosis. The mitochondrial ROS of NB4 cells significantly increased after ATO treatment. NB4 cell apoptosis after ATO treatment increased in a time-dependent manner. Increased SO2 form and dimeric PRX3 were observed as a hyperoxidation reaction in NB4 cells post-ATO treatment, in concordance with mitochondrial ROS accumulation. Sulfiredoxin 1 expression is downregulated by small interfering RNA transfection, which potentiated mitochondrial ROS generation and cell growth arrest in ATO-treated NB4 cells. Our results indicate that ATO-induced ROS generation in APL cell mitochondria is attributable to PRX3 hyperoxidation as well as dimerized PRX3 accumulation, subsequently triggering apoptosis. The downregulation of sulfiredoxin 1 could amplify apoptosis in ATO-treated APL cells.


Serum biomarkers as predictors of long-term outcome in severe traumatic brain injury: analysis from a randomized placebo-controlled Phase II clinical trial.
OBJECTIVE There has been increased interest in the potential importance of biochemical parameters as predictors of outcome in severe traumatic brain injury (sTBI). METHODS Of 107 patients with sTBI (age 18-65 years with a Glasgow Coma Scale score of 4-8 presenting within 8 hours after injury) who were randomized for a placebo-controlled Phase II trial of progesterone with or without hypothermia, the authors serially analyzed serum biomarkers (S100-B, glial fibrillary acidic protein [GFAP], neuron-specific enolase [NSE], tumor necrosis factor-α, interleukin-6 [IL-6], estrogen [Eg], and progesterone [Pg]). This analysis was performed using the sandwich enzyme-linked immunosorbent assay technique at admission and 7 days later for 86 patients, irrespective of assigned group. The long-term predictive values of serum biomarkers for dichotomized Glasgow Outcome Scale (GOS) score, functional independence measure, and survival status at 6 and 12 months were analyzed using an adjusted binary logistic regression model and receiver operating characteristic curve. RESULTS A favorable GOS score (4-5) at 1 year was predicted by higher admission IL-6 (above 108.36 pg/ml; area under the curve [AUC] 0.69, sensitivity 52%, and specificity 78.6%) and Day 7 Pg levels (above 3.15 ng/ml; AUC 0.79, sensitivity 70%, and specificity 92.9%). An unfavorable GOS score (1-3) at 1 year was predicted by higher Day 7 GFAP levels (above 9.50 ng/ml; AUC 0.82, sensitivity 78.6%, and specificity 82.4%). Survivors at 1 year had significantly higher Day 7 Pg levels (above 3.15 ng/ml; AUC 0.78, sensitivity 66.7%, and specificity 90.9%). Nonsurvivors at 1 year had significantly higher Day 7 GFAP serum levels (above 11.14 ng/ml; AUC 0.81, sensitivity 81.8%, and specificity 88.9%) and Day 7 IL-6 serum levels (above 71.26 pg/ml; AUC 0.87, sensitivity 81.8%, and specificity 87%). In multivariate logistic regression analysis, independent predictors of outcome at 1 year were serum levels of Day 7 Pg (favorable GOS-OR 3.24, CI 1.5-7, p = 0.003; and favorable survival-OR 2, CI 1.2-3.5, p = 0.01); admission IL-6 (favorable GOS-OR 1.04, CI 1.00-1.08, p = 0.04); and Day 7 GFAP (unfavorable GOS-OR 0.79, CI 0.65-0.95, p = 0.01; and unfavorable survival-OR 0.80, CI 0.66-0.96, p = 0.01). CONCLUSIONS Serial Pg, GFAP, and IL-6 monitoring could aid in prognosticating outcomes in patients with acute sTBI. A cause and effect relationship or a mere association of these biomarkers to outcome needs to be further studied for better understanding of the pathophysiology of sTBI and for choosing potential therapeutic targets. Clinical trial registration no.: CTRI/2009/091/000893 ( http://www.ctri.nic.in ).


Lack of ataxia telangiectasia mutated kinase induces structural and functional changes in the heart: role in β-adrenergic receptor-stimulated apoptosis.
Ataxia telangiectasia mutated kinase (ATM) is involved in cell cycle checkpoints, DNA repair and apoptosis. β-Adrenergic receptor (β-AR) stimulation induces cardiac myocyte apoptosis. Here we analysed basal myocardial structure and function in ATM knockout (KO) mice and tested the hypothesis that ATM modulates β-AR-stimulated myocyte apoptosis. Left ventricular (LV) structure and function, myocyte apoptosis, fibrosis and expression of fibrosis-, hypertrophy- and apoptosis-related proteins were examined in wild-type (WT) and KO mice with or without l-isoprenaline treatment for 24 h. Body and heart weights were lower in KO mice. M-Mode echocardiography showed reduced septal wall thicknesses and LV diameters in KO mice. Doppler echocardiography showed an increased ratio of early peak velocity (E wave) to that of the late LV filling (A wave) in KO mice. Basal fibrosis and myocyte cross-sectional area were greater in KO hearts. Expression of fibrosis-related genes (connective tissue growth factor and plasminogen activator inhibitor-1) and hypertrophy-related gene (atrial natriuretic peptide) was higher in KO hearts. β-Adrenergic receptor stimulation increased myocyte apoptosis to a similar extent in both groups. Activation of c-Jun N-terminal kinases and expression and phosphorylation of p53 in response to β-AR stimulation were only observed in the WT group. Akt phosphorylation was lower in KO sham-treated animals and remained lower following β-AR stimulation in the KO group. β-Adrenergic receptor stimulation activated glycogen synthase kinase-3β to a similar extent in both groups. Thus, lack of ATM induces structural and functional changes in the heart, with enhanced myocardial fibrosis and myocyte hypertrophy. β-Adrenergic receptor-stimulated apoptosis in WT hearts is associated with a p53- and JNKs-dependent mechanism, while decreased Akt activity may play a role in increased myocyte apoptosis in the absence of ATM.


A roadmap to build a phenotypic metric of ageing: insights from the Baltimore Longitudinal Study of Aging.
Over the past three decades, considerable effort has been dedicated to quantifying the pace of ageing yet identifying the most essential metrics of ageing remains challenging due to lack of comprehensive measurements and heterogeneity of the ageing processes. Most of the previously proposed metrics of ageing have been emerged from cross-sectional associations with chronological age and predictive accuracy of mortality, thus lacking a conceptual model of functional or phenotypic domains. Further, such models may be biased by selective attrition and are unable to address underlying biological constructs contributing to functional markers of age-related decline. Using longitudinal data from the Baltimore Longitudinal Study of Aging (BLSA), we propose a conceptual framework to identify metrics of ageing that may capture the hierarchical and temporal relationships between functional ageing, phenotypic ageing and biological ageing based on four hypothesized domains: body composition, energy regulation, homeostatic mechanisms and neurodegeneration/neuroplasticity. We explored the longitudinal trajectories of key variables within these phenotypes using linear mixed-effects models and more than 10 years of data. Understanding the longitudinal trajectories across these domains in the BLSA provides a reference for researchers, informs future refinement of the phenotypic ageing framework and establishes a solid foundation for future models of biological ageing.


Chondroblastic osteosarcoma of the larynx.
Osteosarcoma of the larynx is a rare lesion. Acceptable cases in the literature are difficult to find. We report a case in which total laryngectomy was carried out for a large, obstructing mass that arose from the cricoid cartilage. We present the histologic criteria for the diagnosis of chondroblastic osteosarcoma.