Remote identification of the invasive tunicate Didemnum vexillum using reflectance spectroscopy.
Benthic coverage of the invasive tunicate Didemnum vexillum on Georges Bank is largely unknown. Monitoring of D. vexillum coverage is vital to understanding the impact this invasive species will have on the productive fishing grounds of Georges Bank. Here we investigate using reflectance spectroscopy as a method for remote identification of D. vexillum. Using two different systems, a NightSea Dive-Spec and a combination of LED light sources with a hyperspectral radiometer, we collected in-situ measurements of reflectance from D. vexillum colonies. In comparison to reflectance spectra of other common benthic substrates, D. vexillum appears to have a unique spectral signature between 500 and 600 nm. Measuring the slope of the spectrum between these wavelengths appears to be the most robust method for spectral identification. Using derivative analysis or principal component analysis, the reflectance spectra of D. vexillum can be identified among numerous other spectra of common benthic substrates. An optical system consisting of a radiometer, light source, and camera was deployed on a remotely operated vehicle to test the feasibility of using reflectance to assess D. vexillum coverage. Preliminary results, analyzed here, prove the method to be successful for the areas we surveyed and open the way for its use on large-scale surveys.


Robust cullin-RING ligase function is established by a multiplicity of poly-ubiquitylation pathways.
The cullin-RING ligases (CRLs) form the major family of E3 ubiquitin ligases. The prototypic CRLs in yeast, called SCF enzymes, employ a single E2 enzyme, Cdc34, to build poly-ubiquitin chains required for degradation. In contrast, six different human E2 and E3 enzyme activities, including Cdc34 orthologs UBE2R1 and UBE2R2, appear to mediate SCF-catalyzed substrate polyubiquitylation in vitro. The combinatorial interplay of these enzymes raises questions about genetic buffering of SCFs in human cells and challenges the dogma that E3s alone determine substrate specificity. To enable the quantitative comparisons of SCF-dependent ubiquitylation reactions with physiological enzyme concentrations, mass spectrometry was employed to estimate E2 and E3 levels in cells. In combination with UBE2R1/2, the E2 UBE2D3 and the E3 ARIH1 both promoted SCF-mediated polyubiquitylation in a substrate-specific fashion. Unexpectedly, UBE2R2 alone had negligible ubiquitylation activity at physiological concentrations and the ablation of UBE2R1/2 had no effect on the stability of SCF substrates in cells. A genome-wide CRISPR screen revealed that an additional E2 enzyme, UBE2G1, buffers against the loss of UBE2R1/2. UBE2G1 had robust in vitro chain extension activity with SCF, and UBE2G1 knockdown in cells lacking UBE2R1/2 resulted in stabilization of the SCF substrates p27 and CYCLIN E as well as the CUL2-RING ligase substrate HIF1α. The results demonstrate the human SCF enzyme system is diversified by association with multiple catalytic enzyme partners.


Osteoclast progenitors reside in the peroxisome proliferator-activated receptor γ-expressing bone marrow cell population.
Osteoclasts are bone-resorbing cells essential for skeletal development, homeostasis, and regeneration. They derive from hematopoietic progenitors in the monocyte/macrophage lineage and differentiate in response to RANKL. However, the precise nature of osteoclast progenitors is a longstanding and important question. Using inducible peroxisome proliferator-activated receptor γ (PPARγ)-tTA TRE-GFP (green fluorescent protein) reporter mice, we show that osteoclast progenitors reside specifically in the PPARγ-expressing hematopoietic bone marrow population and identify the quiescent PPARγ(+) cells as osteoclast progenitors. Importantly, two PPARγ-tTA TRE-Cre-controlled genetic models provide compelling functional evidence. First, Notch activation in PPARγ(+) cells causes high bone mass due to impaired osteoclast precursor proliferation. Second, selective ablation of PPARγ(+) cells by diphtheria toxin also causes high bone mass due to decreased osteoclast numbers. Furthermore, PPARγ(+) cells respond to both pathological and pharmacological resorption-enhancing stimuli. Mechanistically, PPARγ promotes osteoclast progenitors by activating GATA2 transcription. These findings not only identify the long-sought-after osteoclast progenitors but also establish unprecedented tools for their visualization, isolation, characterization, and genetic manipulation.


Ketolysis is required for the proper development and function of the somatosensory nervous system.
Ketogenic diets are emerging as protective interventions in preclinical and clinical models of somatosensory nervous system disorders. Additionally, dysregulation of succinyl-CoA 3-oxoacid CoA-transferase 1 (SCOT, encoded by Oxct1), the fate-committing enzyme in mitochondrial ketolysis, has recently been described in Friedreich's ataxia and amyotrophic lateral sclerosis. However, the contribution of ketone metabolism in the normal development and function of the somatosensory nervous system remains poorly characterized. We generated sensory neuron-specific, Advillin-Cre knockout of SCOT (Adv-KO-SCOT) mice and characterized the structure and function of their somatosensory system. We used histological techniques to assess sensory neuronal populations, myelination, and skin and spinal dorsal horn innervation. We also examined cutaneous and proprioceptive sensory behaviors with the von Frey test, radiant heat assay, rotarod, and grid-walk tests. Adv-KO-SCOT mice exhibited myelination deficits, altered morphology of putative Aδ soma from the dorsal root ganglion, reduced cutaneous innervation, and abnormal innervation of the spinal dorsal horn compared to wildtype mice. Synapsin 1-Cre-driven knockout of Oxct1 confirmed deficits in epidermal innervation following a loss of ketone oxidation. Loss of peripheral axonal ketolysis was further associated with proprioceptive deficits, yet Adv-KO-SCOT mice did not exhibit drastically altered cutaneous mechanical and thermal thresholds. Knockout of Oxct1 in peripheral sensory neurons resulted in histological abnormalities and severe proprioceptive deficits in mice. We conclude that ketone metabolism is essential for the development of the somatosensory nervous system. These findings also suggest that decreased ketone oxidation in the somatosensory nervous system may explain the neurological symptoms of Friedreich's ataxia.


Treatment and challenges with antiepileptic drugs in patients with juvenile myoclonic epilepsy.
Patients with juvenile myoclonic epilepsy (JME) may have uncontrolled seizures. The purpose of this study was to investigate the use and challenges with antiepileptic drugs (AEDs) and the patients' view of these challenges. A questionnaire about the use of AEDs, adherence to therapy, and quality of life was given to patients with JME recruited from Drammen Hospital. Data regarding AEDs were confirmed from medical records at Drammen Hospital, Norway (2007-2018). Additional clinical interviews were performed, and a mixed method approach was applied. Ninety patients with defined JME diagnosis, 54/36 women/men aged 14-39 (mean: 25) years, were included. Only 29 (33%) were seizure-free. Within the last year, 21% experienced generalized tonic-clonic seizures (GTCS), and 68% had myoclonic jerks. Seventy-six (84%) used AEDs, 78% in monotherapy. A total of 10 AEDs were used;: most commonly valproate (n = 33), lamotrigine (n = 27), and levetiracetam (n = 21). Two-thirds of valproate users were men while all other AEDs were used more in females than in men. Valproate and levetiracetam displayed better efficacy against GTCS than lamotrigine. One-third often/sometimes forgot their medication nonintentionally while 14% had intentional poor adherence. The majority reported good quality of life (76%). No significant correlations between the use of AEDs, use of valproate, poor adherence, quality of life score, and seizure freedom were demonstrated. Half of the patients had serum concentrations measured every year, and two-thirds thought this was important. Qualitative interviews elucidated treatment challenges in JME;, adverse effect burden, adherence, and activities of daily life. Despite the use of AEDs in the majority of patients, only one-third were seizure-free. Other challenges included polypharmacy, the use of valproate in women, and variable adherence. This points to a need for closer follow-up in patients with JME.


Proportional Joint-Moment Control for Instantaneously Adaptive Ankle Exoskeleton Assistance.
Lower-limb exoskeletons used to improve free-living mobility for individuals with neuromuscular impairment must be controlled to prescribe assistance that adapts to the diverse locomotor conditions encountered during daily life, including walking at different speeds and across varied terrain. The goal of this paper is to design and establish clinical feasibility of an ankle exoskeleton control strategy that instantly and appropriately adjusts assistance to the changing biomechanical demand during variable walking. To accomplish this goal, we developed a proportional joint-moment control strategy that prescribes assistance as a function of the instantaneous estimate of the ankle joint moment and conducted a laboratory-based feasibility study. Four individuals with neuromotor impairment and one unimpaired individual completed exoskeleton-assisted slow and fast gait transition tasks that involved gait initiation and changing walking speed. We found that the controller was effective in instantaneously prescribing exoskeleton assistance that was proportional to the ankle moment with less than 14% root-mean-square error, on average. We also performed a three-subject pilot investigation to determine the ability of the proportional joint-moment controller to improve walking economy. Evaluated in two individuals with cerebral palsy and one unimpaired individual, metabolic cost of transport improved 17-27% during treadmill and over-ground walking with proportional control compared with wearing the exoskeleton unassisted. These preliminary findings support the continued investigation of proportional joint-moment control for assisting individuals with neuromuscular disabilities during walking in real-world settings.


Estimating the gains of early detection of hypertension over the marginal patient.
This study estimated the potential impact of early diagnosis programs on health outcomes in England. Specifically, if advising individuals to visit their family doctor due to a suspected case of mild hypertension would result in (i) an increase in the diagnosis and treatment of high blood pressure; (ii) an improved lifestyle reflected in objective measures such as the body-mass-index and blood pressure levels; (iii) a reduced probability of the onset of other cardiovascular diseases, such as diabetes. To address potential selection bias in screening, a feature of the English Longitudinal Study of Ageing is exploited, motivating a regression discontinuity design. If respondents' blood pressure measurements are above a standard clinical threshold, they are advised to visit their family doctor to confirm hypertension. Two years after the protocol, there is evidence of an increase in diagnosis (5.7 pp, p-val = 0.06) and medication use (6 pp, p-val = 0.007) for treating the condition. However, four years after the protocol, the difference in diagnosis and medication disappeared (4 pp, p-val = 0.384; 3.4 pp, p-val = 0.261). Moreover, there are no differences on observed blood pressure levels (systolic 0.026 mmHg, p-val = 0.815; diastolic -0.336 mmHg, p-val = 0.765), or Body-Mass-Index ((0.771, p-val = 0.154)). There are also no differences on diagnosis of diabetes (1.7 pp, p-val = 0.343) or heart related conditions (3.6 pp, p-value = 0.161). In conclusion, the nudge produces an earlier diagnosis of around two years, but there are no perceivable gains in health outcomes after four years.


The innate antiretroviral factor APOBEC3G does not affect human LINE-1 retrotransposition in a cell culture assay.
APOBEC3G (apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G) is an innate intracellular antiretroviral factor that can inhibit viral retroelements such as retroviruses and hepadnaviruses. However, it is unknown whether it can act on non-viral substrates. Retrotransposons are transposable elements that cumulatively account for about one third of the human genome. They are commonly classified in long terminal repeat (LTR) retrotransposons, which are strongly homologous to retroviruses, and non-LTR retrotransposons also known as L1 elements or LINE-1 (long interspersed nucleotide element-1) elements. Most of the L1 elements are defective and only a small number are very active in vivo, but they are responsible for nearby all of the retrotransposition in the human population. The cloning of active human L1 elements has allowed the development of tissue culture-based assays for measuring their retrotransposition potential. We used such an assay to demonstrate that APOBEC3G, which impairs the replication of exogenous retroelements, does not affect the replication of endogenous L1 retrotransposons.


Creating and testing a deaf-friendly, stop-smoking web site intervention.
Deaf adults' access to smoking cessation programs is limited due to cultural, linguistic, and geographic barriers. Web-based stop-smoking interventions have demonstrated cessation rates comparable to other interventions. The Internet is widely used by Deaf adults, but difficulties with online English text remain. We found no published accounts of Internet interventions promoting smoking cessation among Deaf individuals. The purpose of our project was to create and pilot test a prototype interactive Web site that provides users with information in American Sign Language related to smoking cessation. We utilized web cams to create real-time "video chat rooms" for virtual support groups and had an "ask the experts" feature. Deaf community members participated in all phases of development and testing, and a Deaf former smoker served as the moderator for the site. Evaluations were positive, with emphasis on interactive and visual aspects of the site.


NLRP1 and NLRP3 polymorphisms in mesothelioma patients and asbestos exposed individuals a population-based autopsy study from North East Italy.
NRLP1 (rs12150220, rs9889625, rs9900356, rs6502867, rs2670660) and NLRP3 (rs35829419, rs10754558) polymorphisms have been analyzed in 69 subjects with documented asbestos exposure and death for malignant pleural mesothelioma and 59 patients with documented asbestos exposure but death for other causes, all from a North East Italy. No association was found between NLRP1 and NLRP3 polymorphisms and susceptibility to develop mesothelioma using the general, dominant or recessive models. Also haplotype analysis did not reveal any significant association with mesothelioma. Our findings, being controversial with respect to another study on Italian patients, do suggest the need of further studies to unravel the contribution of NLRP1 and NLRP3 in susceptibility to mesothelioma.


Midlife hypertension and 20-year cognitive change: the atherosclerosis risk in communities neurocognitive study.
Hypertension is a treatable potential cause of cognitive decline and dementia, but its greatest influence on cognition may occur in middle age. To evaluate the association between midlife (48-67 years of age) hypertension and the 20-year change in cognitive performance. The Atherosclerosis Risk in Communities cohort (1990-1992 through 2011-2013) underwent evaluation at field centers in Washington County, Maryland, Forsyth County, North Carolina, Jackson, Mississippi, and the Minneapolis, Minnesota, suburbs. Of 13 476 African American and white participants with baseline cognitive data, 58.0% of living participants completed the 20-year cognitive follow-up. Hypertension, prehypertension, or normal blood pressure (BP) at visit 2 (1990-1992) constituted the primary exposure. Systolic BP at visit 2 or 5 (2011-2013) and indication for treatment at visit 2 based on the Eighth Joint National Committee (JNC-8) hypertension guidelines constituted the secondary exposures. Prespecified outcomes included the 20-year change in scores on the Delayed Word Recall Test, Digit Symbol Substitution Test, and Word Fluency Test and in global cognition. During 20 years, baseline hypertension was associated with an additional decline of 0.056 global z score points (95% CI, -0.100 to -0.012) and prehypertension was associated nonsignificantly with 0.040 more global z score points of decline (95% CI, -0.085 to 0.005) compared with normal BP. Individuals with hypertension who used antihypertensives had less decline during the 20 years than untreated individuals with hypertension (-0.050 [95% CI, -0.003 to -0.097] vs -0.079 [95% CI, -0.156 to -0.002] global z score points). Having a JNC-8-specified indication for initiating antihypertensive treatment at baseline was associated with a greater 20-year decline (-0.044 [95% CI, -0.085 to -0.003] global z score points) than not having an indication. We observed effect modification by race for the continuous systolic BP analyses (P = .01), with each 20-mm Hg increment at baseline associated with an additional decline of 0.048 (95% CI, -0.074 to -0.022) points in global cognitive z score in whites but not in African Americans (decline, -0.020 [95% CI, -0.026 to 0.066] points). Systolic BP at the end of follow-up was not associated with the preceding 20 years of cognitive change in either group. Methods to account for bias owing to attrition strengthened the magnitude of some associations. Midlife hypertension and elevated midlife but not late-life systolic BP was associated with more cognitive decline during the 20 years of the study. Greater decline is found with higher midlife BP in whites than in African Americans.


Homer-1c/Vesl-1L modulates the cell surface targeting of metabotropic glutamate receptor type 1alpha: evidence for an anchoring function.
Homer-1c/Vesl-1L is a 48-kDa protein that forms part of a family of conserved Homer-related proteins that interact with the C-termini of the metabotropic glutamate receptors mGluR1alpha and mGluR5. In order to examine the function of Homer-1c, HEK-293 cells have been transfected with mGluR1alpha, Homer-1c, and both proteins together. When cells were transfected with both proteins, biotinylation of cell surface molecules revealed a significant increase in the amount of receptor and Homer-1c associated with the cell surface compared with cells transfected with mGluR1alpha alone. This finding was paralleled by a concomitant increase in the production of inositol after treatment of the doubly transfected cells with agonist. Cell surface immunostaining of mGluR1alpha showed that Homer-1c can induce clustering of the receptor in the plasma membrane of HEK-293 cells and suggested that the surface receptor was associated with Homer-1c in the plasma membrane. The presence of Homer-1c reduced the rate of loss from the cell surface of mGluR1alpha from 5 to 1%/min and increased the extent of dendritic trafficking of the receptor in rat primary cultured neurons. Our results suggest that Homer-1c increases the cell surface expression of the metabotropic glutamate receptor type 1alpha by increasing its retention in the plasma membrane.


The effect of pumpkin seeds on oxalcrystalluria and urinary compositions of children in hyperendemic area.
We investigated the effect of pumpkin-seed supplementation on oxalcrystalluria and urinary composition in 20 boys age 2-7 yr from a hyperendemic area of Ubol province in Thailand. The experiment had four periods: control (before treatment), oxalate supplementation 5mg X kg-1 body wt X day-1, pumpkin-seed or orthophosphate supplementation 60 mg X kg body wt-1 X day-1, and posttreatment. Causal morning and 24-h urines were collected analyzed for crystalluria, pH, calcium, phosphorous, oxalate, creatinine, sodium, potassium, citrate glycosaminoglycans, and pyrophosphate. The results demonstrated that the longer the supplementation period of pumpkin seeds, the better were the results. Pumpkin seeds lowered calcium-oxalate crystal occurrence and calcium level but increased phosphorus, pyrophosphate, glycosaminoglycans, and potassium values in urine as compared with orthophosphate supplementation. Pumpkin seeds provide high phosphorus levels and can be used as a potential agent in lowering the risk of bladder-stone disease.


Analysis of root growth from a phenotyping data set using a density-based model.
Major research efforts are targeting the improved performance of root systems for more efficient use of water and nutrients by crops. However, characterizing root system architecture (RSA) is challenging, because roots are difficult objects to observe and analyse. A model-based analysis of RSA traits from phenotyping image data is presented. The model can successfully back-calculate growth parameters without the need to measure individual roots. The mathematical model uses partial differential equations to describe root system development. Methods based on kernel estimators were used to quantify root density distributions from experimental image data, and different optimization approaches to parameterize the model were tested. The model was tested on root images of a set of 89 Brassica rapa L. individuals of the same genotype grown for 14 d after sowing on blue filter paper. Optimized root growth parameters enabled the final (modelled) length of the main root axes to be matched within 1% of their mean values observed in experiments. Parameterized values for elongation rates were within ±4% of the values measured directly on images. Future work should investigate the time dependency of growth parameters using time-lapse image data. The approach is a potentially powerful quantitative technique for identifying crop genotypes with more efficient root systems, using (even incomplete) data from high-throughput phenotyping systems.


[Vigilance for veterinary medicinal products: declarations of adverse reactions in the year 2010].
In 2010, we observed again an increase in the number of declarations reported to the vigilance system for veterinary medicinal products up to a total of 160. The species and drug classes reported remained the same as in previous years: the majority of adverse drug reactions (ADRs) concerned either dogs or cats and the most frequently involved drugs were either antiparasitic products or antiinfectives. Adverse reactions following reconversions and 8 cases of suspected allergic reactions following the use of amoxicillin-clavulanic acid combinations in dogs were reported. Additional enquiries were processed by the Swiss Toxicological Information Centre and transmitted to Swiss medic. 11 of these reported accidental ingestions of flavoured tablets in overdose by dogs and some cats. The vaccino vigilance program received 179 declarations following immunization against blue tongue disease as well as 82 declarations following the application of other vaccines. The vigilance system increases the chance to identify rare reactions or interactions and thereby contributes to the security of veterinary medicinal products.


Arthroscopic acetabuloplasty and labral refixation without labral detachment.
Arthroscopic acetabuloplasty was initially described with detachment of the labrum to access the acetabular rim for resection, followed by labral refixation. Recent technical improvements have made it possible to perform acetabuloplasty and labral refixation without labral detachment when the chondrolabral junction is intact. To compare outcomes for patients undergoing arthroscopic acetabuloplasty and labral refixation without labral detachment (study group), as well as compare this with a group of patients who underwent acetabuloplasty with labral refixation and labral detachment (control group) with a minimum 2-year follow-up. Cohort study; Level of evidence, 3. During the study period, data were prospectively collected on all patients treated with hip arthroscopy. Inclusion criteria for the study group were acetabuloplasty and labral refixation without detachment, performed in cases with an intact chondrolabral junction. Patients were then compared with a control group of patients who had acetabuloplasty with labral detachment and refixation. All patients were assessed pre- and postoperatively using 4 patient-reported outcome (PRO) measures and a visual analog scale (VAS) for pain, as well as monitored for revision surgery. In the study group, the preoperative to postoperative score changed from 64.2 to 86.6 for modified Harris Hip Score (mHHS), 60.5 to 83.8 for Nonarthritic Hip Score (NAHS), 65.3 to 87.3 for Hip Outcome Score-Activity of Daily Living (HOS-ADL), 45 to 75.1 for Hip Outcome Score-Sport-Specific Subscale (HOS-SSS), and 5.7 to 2.6 for VAS. In the control group, the preoperative to postoperative score changed from 61.2 to 84.4 for mHHS, 59 to 84 for NAHS, 62.7 to 86.2 for HOS-ADL, 40.1 to 74.1 for HOS-SSS, and 6.3 to 2.8 for VAS. There was no difference between preoperative and postoperative PRO scores. The preoperative VAS score was lower in the study group than in the control group (P=.04). The control group demonstrated larger mean preoperative anterior center edge angles (ACEA) (33.8° vs 29.5°) and mean alpha angles (60.5° vs 53.5°) than the study group (P<.05). There was no statistically significant difference in the change in PRO or VAS scores between groups. Both groups demonstrated significant improvement from preoperative to 2-year follow-up for all 4 PRO scores (P<.05) and decrease in VAS (P<.05). One patient in the study group converted to total hip arthroplasty. Seven patients underwent revision hip arthroscopy in the study group, and 8 patients in the control group underwent revision hip arthroscopy. There was no difference in revision rates between groups. Treatment of pincer- and combined-type impingement with arthroscopic acetabuloplasty and labral refixation without detachment, when possible, resulted in similar patient outcomes compared with acetabuloplasty with labral detachment. We may conclude that in cases where the chondrolabral junction remains intact, acetabuloplasty and labral refixation without detachment is a viable option.


Endogenous interleukin 6 can function as an in vivo growth- stimulatory factor for advanced-stage human melanoma cells.
We have previously shown that a majority of human melanoma cell lines derived from early-stage lesions were growth inhibited by exogenous interleukin 6 (IL-6) in vitro, whereas cell lines from advanced-stage lesions were resistant to such IL-6-induced growth inhibition. Among the resistant melanoma cell lines, 50-60% constitutively produced IL-6, which appeared to function as a growth stimulator in vitro, based on the growth-suppressive effects of antisense oligonucleotides to the IL-6 gene. The present study was primarily aimed at evaluating whether endogenous IL-6 also functions in vivo as a growth modulator for IL-6-producing and -nonproducing melanoma cells. To do so, we first introduced an IL-6 expression vector into IL-6-nonproducing human melanoma cells using WM35, an early-stage (radial growth phase) cell line, the growth of which is normally inhibited by IL-6, and WM983A, an advanced-stage cell line, the growth of which in vitro is not affected by exogenous IL-6. None of the IL-6-producing transfectants showed a significant alteration in tumor growth in nude mice. Next, two IL-6-producing melanoma cell lines, both of which were derived from metastases, MeWo and WM9, and which are growth resistant to exogenously added IL-6, were transfected with an antisense IL-6 expression vector. Several transfectant clones manifested a constitutive decrease in IL-6 gene expression and protein production, and they also gave rise to much smaller tumors with slower growth rates and longer latency periods. However, these IL-6 antisense transfectants were not growth suppressed in in vitro cell cultures, relative to their respective parental controls. Taken together, the results demonstrate that endogenous IL-6 can indeed function as a growth stimulator for human cutaneous melanomas in vivo. This growth-stimulatory or survival mechanism remains to be clarified but may be paracrine rather than autocrine in nature.


Allogeneic stem cell transplantation in adult patients with acute myeloid leukaemia and 17p abnormalities in first complete remission: a study from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT).
Acute myeloid leukaemia (AML) with 17p abnormalities (abn(17p)) carries a very poor prognosis due to high refractoriness to conventional chemotherapy, and allogeneic stem cell transplantation (allo-SCT) appears as the only potential curative option. To address outcomes after allo-SCT in patients with abn(17p), we retrospectively analysed de novo or secondary AML undergoing SCT between 2000 and 2013 from the EBMT registry. One hundred thirty-nine patients with confirmed abn(17p) have been selected. At the time of transplant, one hundred twenty-five were in first remission (CR1). Median age was 54 years old. Abn(17p) was associated with a monosomal karyotype in 83% of patients, complex karyotype in 91%, monosomy 5 or 5q deletion (-5/5q-) in 55%, monosomy 7 (-7) in 39% and both -5/5q and -7 in 27%. Seventy-three patients (59%) had a reduced-intensity conditioning regimen. The 2-year overall survival (OS) and leukaemia-free survival (LFS) were 28 and 24%, respectively. The 2-year non-relapse mortality (NRM) was 15%, and 2-year relapse incidence (RI) was 61%. The cumulative incidence of grade II to IV acute graft-versus-host disease (GvHD) was 24% and that of chronic GvHD was 21%. In multivariate analysis, the presence of a -5/5q- in addition to abn(17p) was significantly and independently associated with worse OS, LFS and higher RI. Age and donor types did not correlate with outcome. Conditioning intensity was not statistically associated with OS, LFS and NRM when adjusted for patients' age. In contrast to the dismal prognosis reported for AML patients harbouring abn(17p) undergoing conventional chemotherapy, allogeneic SCT provides responses in about 25% of those patients transplanted in CR1.


Global features of functional brain networks change with contextual disorder.
It is known that features of stimuli in the environment affect the strength of functional connectivity in the human brain. However, investigations to date have not converged in determining whether these also impact functional networks' global features, such as modularity strength, number of modules, partition structure, or degree distributions. We hypothesized that one environmental attribute that may strongly impact global features is the temporal regularity of the environment, as prior work indicates that differences in regularity impact regions involved in sensory, attentional and memory processes. We examined this with an fMRI study, in which participants passively listened to tonal series that had identical physical features and differed only in their regularity, as defined by the strength of transition structure between tones. We found that series-regularity induced systematic changes to global features of functional networks, including modularity strength, number of modules, partition structure, and degree distributions. In tandem, we used a novel node-level analysis to determine the extent to which brain regions maintained their within-module connectivity across experimental conditions. This analysis showed that primary sensory regions and those associated with default-mode processes are most likely to maintain their within-module connectivity across conditions, whereas prefrontal regions are least likely to do so. Our work documents a significant capacity for global-level brain network reorganization as a function of context. These findings suggest that modularity and other core, global features, while likely constrained by white-matter structural brain connections, are not completely determined by them.


Inhibition of osteoclast differentiation and bone resorption by N-methylpyrrolidone.
Regulation of RANKL (receptor activator of nuclear factor κB ligand)-induced osteoclast differentiation is of current interest in the development of antiresorptive agents. Osteoclasts are multinucleated cells that play a crucial role in bone resorption. In this study, we investigated the effects of N-methylpyrrolidone (NMP) on the regulation of RANKL-induced osteoclastogenesis. NMP inhibited RANKL-induced tartrate-resistant acid phosphatase activity and the formation of tartrate-resistant acid phosphatase-positive multinucleated cells. The RANKL-induced expression of NFATc1 (nuclear factor of activated T cells, cytoplasmic 1) and c-Fos, which are key transcription factors for osteoclastogenesis, was also reduced by treatment with NMP. Furthermore, NMP induced disruption of the actin rings and decreased the mRNAs of cathepsin K and MMP-9 (matrix metalloproteinase-9), both involved in bone resorption. Taken together, these results suggest that NMP inhibits osteoclast differentiation and attenuates bone resorption. Therefore, NMP could prove useful for the treatment of osteoporosis or other bone diseases associated with excessive bone resorption.


A designer hyper interleukin 11 (H11) is a biologically active cytokine.
Interleukin 11 (IL-11) is a pleiotropic cytokine with anti-apoptotic, anti-inflammatory and hematopoietic potential. The IL-11 activity is determined by the expression of the IL-11R receptor alpha (IL-11Rα) and the signal transducing subunit β (gp130) on the cell membrane. A recombinant soluble form of the IL-11Rα (sIL-11Rα) in combination with IL-11 acts as an agonist on cells expressing the gp130 molecule. We constructed a designer cytokine Hyper IL-11 (H11), which is exclusively composed of naturally existing components. It contains the full length sIL-11Rα connected with the mature IL-11 protein using their natural sequences only. Such a construct has two major advantages: (i) its components are as close as possible to the natural forms of both proteins and (ii) it lacks an artificial linker what should avoid induction of antibody production. The H11 construct was generated, the protein was produced in a baculovirus expression system and was then purified by using ion exchange chromatography. The H11 protein displayed activity in three independent bioassays, (i) it induced acute phase proteins production in HepG2 cells expressing IL-11, IL-11Rα and gp130, (ii) it stimulated the proliferation of B9 cells (cells expressing IL-11Rα and gp130) and (iii) proliferation of Baf/3-gp130 cells (cells not expressing IL-11 and IL-11Rα but gp130). Moreover, the preliminary data indicated that H11 was functionally distinct from Hyper-IL-6, a molecule which utilizes the same homodimer of signal transducing receptor (gp130). The biologically active H11 may be potentially useful for treatment of thrombocytopenia, infertility, multiple sclerosis, cardiovascular diseases or inflammatory disorders.


Suppression of growth and death of meristematic tissues in Abies sachalinensis under strong shading: comparisons between the terminal bud, the terminally lateral bud and the stem cambium.
The suppression of apical growth and radial trunk growth in trees under shade is a key factor in the competition mechanism among individuals in natural and artificial forests. However, the timing of apical and radial growth suppression after shading and the physiological processes involved have not been evaluated precisely. Twenty-one Abies sachalinensis seedlings of 5-years-old were shaded artificially under a relative light intensity of 5% for 70 days from August 1, and the histological changes of the terminal bud and terminally lateral bud of terminal leader and the cambial zone of the trunk base were analyzed periodically. In shade-grown trees, cell death of the leaf primordia in a terminal bud of terminal leader was observed in one of the three samples after 56 and 70 days of shading, whereas the leaf primordia in a terminal bud of terminal leader in all open-grown trees survived until the end of the experiment. In addition, the leaf primordia of the terminally lateral buds of terminal leader retained their cell nuclei until the end of the experiment. No histological changes were observed in the cambial cells after shading, but the shade-grown trees had less cambial activity than the open-grown trees through the experiment. Strong shading appeared to inhibit the formation and survival of cells in the terminal bud of terminal leader rather than the terminally lateral buds of terminal leader and the cambium. The suppression of the terminal bud growth and elongation of the surviving lateral buds would result in an umbrella-shaped crown under shade.


Randomized phase II study of fludarabine + cytosine arabinoside + idarubicin +/- all-trans retinoic acid +/- granulocyte colony-stimulating factor in poor prognosis newly diagnosed acute myeloid leukemia and myelodysplastic syndrome.
Preclinical data suggest that retinoids, eg, all-trans retinoic acid (ATRA), lower concentrations of antiapoptotic proteins such as bcl-2, possibly thereby improving the outcome of anti-acute myeloid leukemia (AML) chemotherapy. Granulocyte colony-stimulating factor (G-CSF) has been considered to be potentially synergistic with ATRA in this regard. Accordingly, we randomized 215 patients with newly diagnosed AML (153 patients) or high-risk myelodysplastic syndrome (MDS) (refractory anemia with excess blasts [RAEB] or RAEB-t, 62 patients) to receive fludarabine + ara-C + idarubicin (FAI) alone, FAI + ATRA, FAI + G-CSF, or FAI + ATRA + G-CSF. Eligibility required one of the following: age over 71 years, a history of abnormal blood counts before M.D. Anderson (MDA) presentation, secondary AML/MDS, failure to respond to one prior course of chemotherapy given outside MDA, or abnormal renal or hepatic function. For the two treatment arms containing ATRA, ATRA was given 2 days (day-2) before beginning and continued for 3 days after completion of FAI. For the two treatment arms including G-CSF, G-CSF began on day-1 and continued until neutrophil recovery. Patients with white blood cell (WBC) counts >50,000/microL began ATRA on day 1 and G-CSF on day 2. Events (death, failure to achieve complete remission [CR], or relapse from CR) have occurred in 77% of the 215 patients. Reflecting the poor prognosis of the patients entered, the CR rate was only 51%, median event-free survival (EFS) time once in CR was 36 weeks, and median survival time was 28 weeks. A Cox regression analysis indicated that, after accounting for patient prognostic variables, none of the three adjuvant treatment combinations (FAI + ATRA, FAI + G, FAI + ATRA + G) affected survival, EFS, or EFS once in CR compared with FAI. Similarly, there were no significant effects of either ATRA ignoring G-CSF, or of G-CSF ignoring ATRA. As previously found, a diagnosis of RAEB or RAEB-t rather than AML was insignificant. There were no indications that the effect of ATRA differed according to cytogenetic group, diagnosis (AML or MDS), or treatment schedule. Logistic regression analysis indicated that, after accounting for prognosis, addition of G-CSF +/- ATRA to FAI improved CR rate versus either FAI or FAI + ATRA, but G-CSF had no effect on the other outcomes. We conclude that addition of ATRA +/- G-CSF to FAI had no effect on CR rate, survival, EFS, or EFS in CR in poor prognosis, newly diagnosed AML or high-risk MDS.


Warfare in an evolutionary perspective.
The importance of warfare for human evolution is hotly debated in anthropology. Some authors hypothesize that warfare emerged at least 200,000-100,000 years BP, was frequent, and significantly shaped human social evolution. Other authors claim that warfare is a recent phenomenon, linked to the emergence of agriculture, and mostly explained by cultural rather than evolutionary forces. Here I highlight and critically evaluate six controversial points on the evolutionary bases of warfare. I argue that cultural and evolutionary explanations on the emergence of warfare are not alternative but analyze biological diversity at two distinct levels. An evolved propensity to act aggressively toward outgroup individuals may emerge irrespective of whether warfare appeared early/late during human evolution. Finally, I argue that lethal violence and aggression toward outgroup individuals are two linked but distinct phenomena, and that war and peace are complementary and should not always be treated as two mutually exclusive behavioral responses.


Granule cells in the CA3 area.
A fundamental property of neuronal networks in Ammon's horn is that each area comprises a single glutamatergic cell population and various types of GABAergic neurons. Here we describe an exception to this rule, in the form of granule cells that reside within the CA3 area and function as glutamatergic nonprincipal cells with distinct properties. CA3 granule cells in normal, healthy rats, similarly to dentate gyrus granule cells, coexpressed calbindin and the homeobox protein Prox1. However, CA3 granule cells were located outside of the dentate gyrus, often hundreds of micrometers from the hilar border, in the lucidum and radiatum layers. CA3 granule cells were present in numbers that were comparable to the rarer GABAergic neuronal subtypes, and their somato-dendritic morphology, intrinsic properties, and perforant path inputs were similar to those of dentate gyrus granule cells. CA3 granule cell axons displayed giant mossy fiber terminals with filopodial extensions, demonstrating that not all mossy fibers originate from the dentate gyrus. Somatic paired recordings revealed that CA3 granule cells innervated CA3 pyramidal and GABAergic cells similarly to conventional mossy fiber synapses. However, CA3 granule cells were distinct in the specific organization of their GABAergic inputs. They received GABAergic synapses from cholecystokinin-expressing mossy fiber-associated cells that did not innervate the dentate granule cell layer, and these synapses demonstrated unusually strong activity-dependent endocannabinoid-mediated inhibition of GABA release. These results indicate that granule cells in the CA3 constitute a glutamatergic, nonprincipal neuronal subtype that is integrated into the CA3 synaptic network.


Evaluation of neurofeedback in ADHD: the long and winding road.
Among the clinical applications of neurofeedback, most research has been conducted in ADHD. As an introduction a short overview of the general history of neurofeedback will be given, while the main part of the paper deals with a review of the current state of neurofeedback in ADHD. A meta-analysis on neurofeedback from 2009 found large effect sizes for inattention and impulsivity and medium effects sizes for hyperactivity. Since 2009 several new studies, including 4 placebo-controlled studies, have been published. These latest studies are reviewed and discussed in more detail. The review focuses on studies employing (1) semi-active, (2) active, and (3) placebo-control groups. The assessment of specificity of neurofeedback treatment in ADHD is discussed and it is concluded that standard protocols such as theta/beta, SMR and slow cortical potentials neurofeedback are well investigated and have demonstrated specificity. The paper ends with an outlook on future questions and tasks. It is concluded that future controlled clinical trials should, in a next step, focus on such known protocols, and be designed along the lines of learning theory.


Matrix-assisted laser desorption/ionization mass spectrometric analysis of poly(3,4-ethylenedioxythiophene) in solid-state dye-sensitized solar cells: comparison of in situ photoelectrochemical polymerization in aqueous micellar and organic media.
Solid-state dye-sensitized solar cells (sDSCs) are devoid of such issues as electrolyte evaporation or leakage and electrode corrosion, which are typical for traditional liquid electrolyte-based DSCs. Poly(3,4-ethylenedioxythiophene) (PEDOT) is one of the most popular and efficient p-type conducting polymers that are used in sDSCs as a solid-state hole-transporting material. The most convenient way to deposit this insoluble polymer into the dye-sensitized mesoporous working electrode is in situ photoelectrochemical polymerization. Apparently, the structure and the physicochemical properties of the generated conducting polymer, which determine the photovoltaic performance of the corresponding solar cell, can be significantly affected by the preparation conditions. Therefore, a simple and fast analytical method that can reveal information on polymer chain length, possible chemical modifications, and impurities is strongly required for the rapid development of efficient solar energy-converting devices. In this contribution, we applied matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) for the analysis of PEDOT directly on sDSCs. It was found that the PEDOT generated in aqueous micellar medium possesses relatively shorter polymeric chains than the PEDOT deposited from an organic medium. Furthermore, the micellar electrolyte promotes a transformation of one of the thiophene terminal units to thiophenone. The introduction of a carbonyl group into the PEDOT molecule impedes the growth of the polymer chain and reduces the conductivity of the final polymer film. Both the simplicity of sample preparation (only application of the organic matrix onto the solar cell is needed) and the rapidity of analysis hold the promise of making MALDI MS an essential tool for the physicochemical characterization of conducting polymer-based sDSCs.


Antioxidant activity of various solvent fractions from edible brown alga, Eisenia bicyclis and its active compounds.
In this study, we aimed to elucidate the antioxidant capacity of Eisenia bicyclis and evaluated its antioxidant activity using various assay systems such as 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, 2,2-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical scavenging, reducing power ability, and content of total polyphenol. Among all the performed experiments, the ethyl acetate fraction of E. bicyclis exhibited higher antioxidant activities. From this finding, isolation and purification were performed on the ethyl acetate fraction and identified dieckol and phlorofucofureoeckol-A by spectroscopic analyses including FAB-mass in the negative mode, (1) H NMR, (13) C NMR, (1) H-(1) H COSY, HMQC, and HMBC spectra. Interestingly, ABTS radical scavenging activities of dieckol and phlorofucofuroeckol showed strong effects of 65.36% and 70.38% at a concentration of 50 μg/mL, respectively. DPPH radical scavenging and reducing power abilities were increased in a dose-dependent manner at various concentrations. These results suggest that dieckol and phlorofucofuroeckol-A of E. bicyclis may play an important role in protection from oxidative stress involving reactive oxygen species and may contribute to the development of new bio products, for example, a useful preservative to improve food quality and a drug for various oxidative damage-associated diseases. Practical Application: The results suggest that dieckol and phlorofucofuroeckol-A can be utilized as a natural source for potential application of antioxidant in food industry and drug for oxidative damage-associated diseases.


[Evaluation of the cost of treating pressure ulcers in hospitalized patients using industrialized dressings].
This work evaluated wound dresses used in the Neurosurgery Department of Restauração Hospital: polyurethane, hydrogel and activated carbon wound dresses and hydrogel with alginate used for pressure ulcer care. This work aimed to identify a critical factor that increases demand and cost of wound dresses. The evaluation conducted at the Neurosurgery Department identified individuals at risk of pressure ulcer development. Sixty-two patients were evaluated and the prevalence of pressure ulcer was 22.6% according to the Braden scale. Comparative evaluation between patients that didn't receive preventive measures and others that received, showed that the average daily cost of hospitalization for the first group was 45% higher than the mean for the second group. The Wilcoxon-Mann-Withiney test compared the population at risk to develop pressure ulcer and population at low risk showing that the evaluation of Braden Scale scores between the groups presents statistically significant differences and confidence limits of 95%. Pressure ulcer is a key quality indicator in health services.It is possible to reduce costs and offer higher quality public health services by implementing a training program of nursing staff using a preventive measure protocol based on a test to evaluate risk as Braden Scale.


Targeting neural precursors in the adult brain rescues injured dopamine neurons.
In Parkinson's disease, multiple cell types in many brain regions are afflicted. As a consequence, a therapeutic strategy that activates a general neuroprotective response may be valuable. We have previously shown that Notch ligands support neural precursor cells in vitro and in vivo. Here we show that neural precursors express the angiopoietin receptor Tie2 and that injections of angiopoietin2 activate precursors in the adult brain. Signaling downstream of Tie2 and the Notch receptor regulate blood vessel formation. In the adult brain, angiopoietin2 and the Notch ligand Dll4 activate neural precursors with opposing effects on the density of blood vessels. A model of Parkinson's disease was used to show that angiopoietin2 and Dll4 rescue injured dopamine neurons with motor behavioral improvement. A combination of growth factors with little impact on the vasculature retains the ability to stimulate neural precursors and protect dopamine neurons. The cellular and pharmacological basis of the neuroprotective effects achieved by these single treatments merits further analysis.


Electronic origins of photocatalytic activity in d0 metal organic frameworks.
Metal-organic frameworks (MOFs) containing d(0) metals such as NH2-MIL-125(Ti), NH2-UiO-66(Zr) and NH2-UiO-66(Hf) are among the most studied MOFs for photocatalytic applications. Despite structural similarities, we demonstrate that the electronic properties of these MOFs are markedly different. As revealed by quantum chemistry, EPR measurements and transient absorption spectroscopy, the highest occupied and lowest unoccupied orbitals of NH2-MIL-125(Ti) promote a long lived ligand-to-metal charge transfer upon photoexcitation, making this material suitable for photocatalytic applications. In contrast, in case of UiO materials, the d-orbitals of Zr and Hf, are too low in binding energy and thus cannot overlap with the π* orbital of the ligand, making both frontier orbitals localized at the organic linker. This electronic reconfiguration results in short exciton lifetimes and diminishes photocatalytic performance. These results highlight the importance of orbital contributions at the band edges and delineate future directions in the development of photo-active hybrid solids.


Dissecting genetic networks underlying complex phenotypes: the theoretical framework.
Great progress has been made in genetic dissection of quantitative trait variation during the past two decades, but many studies still reveal only a small fraction of quantitative trait loci (QTLs), and epistasis remains elusive. We integrate contemporary knowledge of signal transduction pathways with principles of quantitative and population genetics to characterize genetic networks underlying complex traits, using a model founded upon one-way functional dependency of downstream genes on upstream regulators (the principle of hierarchy) and mutual functional dependency among related genes (functional genetic units, FGU). Both simulated and real data suggest that complementary epistasis contributes greatly to quantitative trait variation, and obscures the phenotypic effects of many 'downstream' loci in pathways. The mathematical relationships between the main effects and epistatic effects of genes acting at different levels of signaling pathways were established using the quantitative and population genetic parameters. Both loss of function and "co-adapted" gene complexes formed by multiple alleles with differentiated functions (effects) are predicted to be frequent types of allelic diversity at loci that contribute to the genetic variation of complex traits in populations. Downstream FGUs appear to be more vulnerable to loss of function than their upstream regulators, but this vulnerability is apparently compensated by different FGUs of similar functions. Other predictions from the model may account for puzzling results regarding responses to selection, genotype by environment interaction, and the genetic basis of heterosis.


Respiratory symptoms and bronchial responsiveness are related to dietary salt intake and urinary potassium excretion in male children.
To investigate whether dietary salt intake and urinary sodium and potassium levels are related to respiratory symptoms and bronchial responsiveness, a cross-sectional study among 2593 subjects aged 9 to 16 was conducted in four communities of the Latium region (Italy). Questionnaires were administered to the parents, urine samples were collected, lung function, methacholine challenge tests and prick tests were performed. Information about familial and personal dietary salt use and respiratory health was collected from the parents of 2439 (94%) subjects. A total of 2020 methacholine challenge tests and 916 urinary sodium and potassium levels were available for analysis. Personal table salt use was strongly related to cough and phlegm apart from colds (adjusted odds ratios, OR, 1.87, 95% confidence intervals, CI, 1.20-2.90), wheezing apart from colds (OR, 2.19, 95% CI, 1.27-3.77), wheezing with dyspnoea (OR, 1.45, 95% CI, 0.98-2.12) and wheezing after exercise (OR, 2.16, 95% CI, 1.35-3.44). These associations were mainly found in boys. Use of familial table salt and canned food showed no relation to respiratory symptoms. Increased bronchial responsiveness was associated with a higher urinary potassium excretion in boys, but not with urinary sodium. In conclusion, personal table salt use is related to an increased prevalence of bronchial symptoms; an increase in bronchial responsiveness among those with higher potassium excretion also seems to be implied. Although it is difficult to interpret the results of this study in causal terms, the findings might be relevant to the distribution of bronchial symptoms and diseases in the population.


Strong Correlation of Indoleamine 2,3-Dioxygenase 1 Expression with Basal-Like Phenotype and Increased Lymphocytic Infiltration in Triple-Negative Breast Cancer.
Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive enzyme involved in tumor immune escape. Blockade of the IDO1 pathway is an emerging modality of cancer immunotherapy. Triple-negative breast cancer (TNBC) lacks established therapeutic targets and may be a good candidate for this novel immunotherapeutic agent. The purpose of this study was to evaluate the clinicopathologic characteristics of the IDO1-expressing TNBC subset. A tissue microarray was constructed from 200 patients with TNBC. Immunohistochemistry (IHC) for IDO1 and TNBC molecular subtype-surrogate markers (AR, GCDFP-15, claudin-3, E-cadherin, CK5/6, and EGFR) was performed using this tissue microarray. Real-time polymerase chain reaction was performed to confirm the IDO1 mRNA expression level in 16 fresh-frozen TNBC samples. Two hundred TNBCs were classified into four subtypes based on surrogate IHC results: 22 luminal androgen receptor type (11.0%), 23 claudin-low type (11.4%), 103 basal-like type (51.5%), and 52 mixed type (26.0%). IDO1 positivity (defined as expression of >10% tumor cells) was observed in 37% of all TNBCs. IDO1 IHC expression was well correlated with mRNA expression. IDO1 positivity was significantly associated with smaller tumor size, dense stromal lymphocytic infiltration, and basal-like phenotype; however, it did not affect the patients' prognosis. IDO1 expression in basal-like TNBCs is considered an immune inhibitory signal that counterbalances active immunity and may reflect the high mutational load of these tumors. Our results suggest which patients with TNBC would be more efficaciously treated with IDO1 blockade.


Can Intensive Early Childhood Intervention Programs Eliminate Income-Based Cognitive and Achievement Gaps?
How much of the income-based gaps in cognitive ability and academic achievement could be closed by a two-year, center-based early childhood education intervention? Data from the Infant Health and Development Program (IHDP), which randomly assigned treatment to low-birth-weight children from both higher- and low-income families between ages one and three, shows much larger impacts among low-than higher-income children. Projecting IHDP impacts to the U.S. population's IQ and achievement trajectories suggests that such a program offered to low-income children would essentially eliminate the income-based gap at age three and between a third and three-quarters of the age five and age eight gaps.


A naturally occurring omega current in a Kv3 family potassium channel from a platyhelminth.
Voltage-gated ion channels are membrane proteins containing a selective pore that allows permeable ions to transit the membrane in response to a change in the transmembrane voltage. The typical selectivity filter in potassium channels is formed by a tetrameric arrangement of the carbonyl groups of the conserved amino-acid sequence Gly-Tyr-Gly. This canonical pore is opened or closed by conformational changes that originate in the voltage sensor (S4), a transmembrane helix with a series of positively charged amino acids. This sensor moves through a gating pore formed by elements of the S1, S2 and S3 helices, across the plane of the membrane, without allowing ions to pass through the membrane at that site. Recently, synthetic mutagenesis studies in the Drosophila melanogaster Shaker channel and analysis of human disease-causing mutations in sodium channels have identified amino acid residues that are integral parts of the gating-pore; when these residues are mutated the proteins allow a non-specific cation current, known as the omega current, to pass through the gating-pore with relatively low selectivity. The N.at-Kv3.2 potassium channel has an unusual weak inward rectifier phenotype. Several mutations of two amino acids in the voltage sensing (S4) transmembrane helix change the phenotype to a typical delayed rectifier. The inward rectifier channels (wild-type and mutant) are sensitive to 4-aminopyridine (4-AP) but not tetra-ethyl ammonium (TEA), whereas the delayed rectifier mutants are sensitive to TEA but not 4-AP. The inward rectifier channels also manifest low cation selectivity. The relative selectivity for different cations is sensitive to specific mutations in the S4 helix, N.at-Kv3.2, a naturally occurring potassium channel of the Kv3 sequence family, mediates ion permeation through a modified gating pore, not the canonical, highly selective pore typical of potassium channels. This channel has evolved to yield qualitatively different ion permeability when compared to all other members of this gene family.


Single-center experience with pediatric laparoscopic extravesical reimplantation: safe and effective in simple and complex anatomy.
Minimally invasive approaches to the surgical management of vesicoureteric reflux (VUR) have become more prominent over the last 10 years with progress in both endoscopic and laparoscopic/robotic surgery. We hypothesized that laparoscopic extravesical detrussoraphy (LED) for the management of VUR in children with complex bladders and/or bilateral VUR was safe and effective. Under institutional review board approval we evaluated the charts of all patients seen at our institution over the last 8 years who had undergone LED for the management of VUR. We evaluated demographic variables, surgical variables, and postoperative results. Postoperative bladder function was examined in the patients as well as need for secondary procedures. Patients with complex bladders included all patients who had previous surgery on the affected side, neurogenic bladders, and duplex or complex anatomy. Ninety-eight patients with 144 ureters were treated during this time period. The overall VUR resolution by voiding cystourethrogram was 95.2%. The average age was 6.74 years, with 13 children over the age of 12 years old. Average length of stay (LOS) was 1.7 days for children 5 years and older and 1.0 days for children less than 5 years old (P=.004). LOS was not affected by body mass index or complexity of the procedure. There were 46 bilateral procedures, and the incidence of urinary retention was 6.5% versus 0% in the unilateral group (P=.09). Of our patients, 27.6% had complex bladders, including 9 patients with complete ureteral duplications, 10 with periureteral diverticula, and 8 with prior surgery on the affected side. There were two complications requiring a second procedure in this group (7%). No patient with a complex bladder had persistent VUR. LED for the management of children with complex bladders and VUR is safe and effective. This technique is versatile and achieves high VUR resolution rates with minimal morbidity.


Disparities in age-appropriate child passenger restraint use among children aged 1 to 12 years.
Observed racial disparities in child safety seat use have not accounted for socioeconomic factors. We hypothesized that racial differences in age-appropriate restraint use would be modified by socioeconomic status and child passenger safety information sources. A 2-site, cross-sectional tablet-based survey of parents seeking emergency care for their 1- to 12-year-old child was conducted between October 2011 and May 2012. Parents provided self-report of child passenger safety practices, demographic characteristics, and information sources. Direct observation of restraint use was conducted in a subset of children at emergency department discharge. Age-appropriate restraint use was defined by Michigan law. Of the 744 eligible parents, 669 agreed to participate and 601 provided complete responses to key variables. White parents reported higher use of car seats for 1- to 3-year-olds and booster seats for 4- to 7-year-olds compared with nonwhite parents. Regardless of race, <30% of 8- to 12-year-old children who were ≤4 feet, 9 inches tall used a booster seat. White parents had higher adjusted odds (3.86, 95% confidence interval 2.27-6.57) of reporting age-appropriate restraint use compared with nonwhite parents, controlling for education, income, information sources, and site. There was substantial agreement (82.6%, κ = 0.74) between parent report of their child's usual restraint and the observed restraint at emergency department discharge. Efforts should be directed at eliminating racial disparities in age-appropriate child passenger restraint use for children <8 years. Booster seat use, seat belt use, and rear seating represent opportunities to improve child passenger safety practices among older children.


Ischemic colitis after weight-loss medication.
Previous weight-loss medications have received cautious support due to their association with pulmonary hypertension and valvular heart disease. However, newer drugs are increasingly being recommended as potentially safer and more efficacious. We report a case of ischemic colitis possibly linked to the use of a weight-loss drug, and review the literature to highlight an important latent consequence of these medications. A 59-year-old obese woman presented to the emergency room with rectal bleeding and suprapubic abdominal pain. Her medical history was unremarkable for risk factors for bowel ischemia. An appetite suppressant, phentermine 15 mg daily, had been prescribed, and had resulted in a 12 kg weight loss over 10 weeks. Colonoscopy and biopsies both demonstrated findings typical of mild ischemia at the splenic flexure. Phentermine, an amphetamine-derived sympathomimetic, acts centrally to suppress appetite. While there are no published reports linking the use of phentermine as a single agent to ischemic colitis, phentermine alone has been associated with ischemic neurological events and, when used in combination with fenfluramine, has been implicated in a single case of acute ischemic colitis. Other sympathomimetics, such as cocaine, have been clearly linked with ischemic colitis. This report describes a temporal association with the use of phentermine and the development of ischemic colitis. Heightened awareness and appropriate surveillance is warranted to determine whether the use of weight-loss drugs, such as phentermine, can lead to ischemic colitis.


Prevalence and course of schizophrenia in a Chinese rural area.
To assess the characteristics and factors affecting course of schizophrenia in a Chinese rural area. An epidemiological investigation was conducted to identify all the patients with schizophrenia among 149 231 people in Xinjin County, Chengdu. The total prevalence of schizophrenia was 4.13 per 1000 population. Males had an earlier mean age of onset (29.6 years) than females (32.3 years). Duration of illness before treatment and the total duration of illness were found to be significantly associated with level of remission. The status of treatment, family economy, housing, and families' care of patients had a significant effect on the clinical course of the illness. Duration of illness before treatment may be an important predictor of course in schizophrenia. Early treatment for the patients may produce higher level of improvement in prognosis. Education intervention and community-based service are urgent priorities for these patients.


Effects of silica nanoparticles on electro-optical properties of polymer-stabilized liquid crystals.
We control the pretilt angle of liquid crystals (LCs) by simultaneously doping silica nanoparticles (SNs) and reactive monomers into the LC cell. Application of AC high voltage (ACHV) to the cell compels the lifting force and the facilitation of polar groups to move the SNs and monomers toward the substrate surface. Polymer networks and SNs are stabilized at the substrate surface after UV exposure, sustaining the LCs at high pretilt angles. The deposited SNs on the substrate surface increases the anchoring energy of the substrate; the dispersed SNs in the cell decrease the relaxation constant of LCs. Therefore, the response time of the high-pretilted-polymer-stabilized LC cell is decreased. The method enables the control of the LC pretilt angle over a broad range. The slow response time of the polymer-stabilized LC cell from high monomer dose can also be prevented following the addition of SNs.


Recurrent natural killer/T-cell lymphoma of the lacrimal sac and nasolacrimal duct in a 59-year-old Caucasian woman.
A 59-year-old Caucasian woman with past medical history significant for Natural Killer (NK)/T-cell lymphoma of the right nasal septum in remission for nine months presented after surveillance PET-CT imaging revealed increased metabolic activity in the right nasolacrimal duct. She also reported ipsilateral epiphora starting around this time. The lacrimal sac and nasolacrimal ductal mucosa were biopsied via an external approach. Pathologic evaluation revealed a proliferation of lymphoid cells with necrotic tissue. Immunohistochemical staining demonstrated predominantly CD3+, EBER+, and CD56+ cells indicating recurrent NK/T-cell lymphoma. This case describes an unusual presentation of recurrent NK/T-cell lymphoma involving the lacrimal excretory system in a Caucasian adult. Recurrent malignancy should be considered in the differential of any patient with a history of a lymphoproliferative disorder near the lacrimal drainage system who presents with new onset epiphora.


Dual-mode plasmonic nanorod type antenna based on the concept of a trapped dipole.
In this paper we theoretically investigate the feasibility of creating a dual-mode plasmonic nanorod antenna. The proposed design methodology relies on adapting to optical wavelengths the principles of operation of trapped dipole antennas, which have been widely used in the low MHz frequency range. This type of antenna typically employs parallel LC circuits, also referred to as "traps", which are connected along the two arms of the dipole. By judiciously choosing the resonant frequency of these traps, as well as their position along the arms of the dipole, it is feasible to excite the λ/2 resonance of both the original dipole as well as the shorter section defined by the length of wire between the two traps. This effectively enables the dipole antenna to have a dual-mode of operation. Our analysis reveals that the implementation of this concept at the nanoscale requires that two cylindrical pockets (i.e. loading volumes) be introduced along the length of the nanoantenna, inside which plasmonic core-shell particles are embedded. By properly selecting the geometry and constitution of the core-shell particle as well as the constitution of the host material of the two loading volumes and their position along the nanorod, the equivalent effect of a resonant parallel LC circuit can be realized. This effectively enables a dual-mode operation of the nanorod antenna. The proposed methodology introduces a compact approach for the realization of dual-mode optical sensors while at the same time it clearly illustrates the inherent tuning capabilities that core-shell particles can offer in a practical framework.


Reinforcing effects of nicotine microinjections into the ventral tegmental area of mice: dependence on cholinergic nicotinic and dopaminergic D1 receptors.
We used an intracranial self-administration (ICSA) procedure to assess the involvement of the ventral tegmental area (VTA) nicotinic receptors in the rewarding effects of nicotine. We then challenged intra-VTA nicotine self-administration via systemic or local injections of dopamine (DA)-D1 and nicotinic receptor antagonists. C57BL/6J mice were stereotaxically implanted unilaterally with a guide cannula above the VTA. After 1 week of recovery, mice were allowed to discriminate between two arms of a Y-maze over seven daily sessions, one arm being reinforced by intracranial nicotine microinjection. Mice exhibited nicotine self-administration at both doses tested, i.e. 10 ng (21.6 pmol) and 100 ng (216 pmol)/50-nl injection. In contrast, mice receiving a 216-pmol nicotine dose 0.8 mm above VTA performed at chance level. Once the ICSA response was acquired, systemic pretreatment with the DA-D1 receptor antagonist SCH 23390 (25 microg/kg i.p.) or co-infusion of the nAChR antagonist DHbetaE with nicotine disrupted ICSA. Replacement of SCH 23390 by vehicle, or withdrawal of DHbetaE from nicotine/DHbetaE mixed solutions led to recovery of intra-VTA nicotine self-administration. We conclude that nicotinic receptors in the VTA, presumably alpha4beta2 nAChRs are critically to mediate the rewarding effects of nicotine and that DA-D1 receptors are also directly implicated.


Cell death in health and disease.
Cell death is clearly an important factor in development, homeostasis, pathology, and in aging, but medical efforts based on controlling cell death have not become major aspects of medicine. There are several reasons why hopes have been slow to be fulfilled, and they present indications for new directions in research. Most effort has focused on the machinery of cell death, or the proximate effectors of apoptosis and their closely-associated and interacting proteins. But cells have many options other than apoptosis. These include autophagy, necrosis, atrophy, and stepwise or other alternate means of self-disassembly. The response of a cell to a noxious or otherwise intimidating signal will depend heavily on the history, lineage, and current status of the cell. Many metabolic and other processes adjust the sensitivity of cells to signals, and viruses aggressively attempt to regulate the death of their host cells. Another complicating factor is that many death-associated proteins may have functions totally unrelated to their role in cell death, generating the possibility of undesirable side effects if one interferes with them. In the future, the challenge will be more to understand the challenge to the cell from a more global standpoint, including many more aspects of metabolism, and work toward alleviating or provoking the challenge in a targeted fashion.


Interferometric phase reconstruction by nonuniform shifting of the reference beam.
A method for phase measurement in common-path interferometers, believed to be novel, is presented. We use the property of phase reconstruction algorithms, such as the Carré and Hariharan algorithms, that do not require uniform phase across the reference beam. Only the ratio of the phase steps must be the same at each pixel. We show phase measurement and reconstruction in a common-path interferometer by shifting either the tilt or the focus of the reference wave front. We present a theoretical explanation of phase measurement using this property. We also present results from a proof-of-principle experiment using a scatterplate interferometer, in conjunction with the tilt phase-shifting technique, to measure the reflected phase of a test optical element. Furthermore, we present a computer simulation to demonstrate the mathematical validity of this measurement technique using defocus shifting, rather than tilt shifting, in the reference wave front.


Vertex epidural hematoma with bilateral abducent nerve palsy: case report and literature review.
Epidural hematomas which are located at the vertex are rarely seen and form a small percentage of total epidural hematomas. Tearing in the superior sagittal sinus is the usual cause of an epidural hematoma located in the vertex. The clinical features of this entity are non-specific; hence, localization of the lesion is difficult. We report an adult who was hit by a motorcycle and was initially discharged from the hospital as a case of concussional head injury. He returned back with raised intracranial pressure symptoms, so a CT scan was done but was misinterpreted, and he reported one week later with bilateral abducent nerve palsy. Magnetic resonance imaging confirmed vertex EDH for which he was operated.These hematomas are seen rarely and can be interpreted as an artifact. Its recognition is important because it has an excellent prognosis. We concluded that all head injury patients should get high axial cuts on the CT scan, and any degree of suspicion should prompt a neurosurgeon to investigate further with coronal CT scan or MRI.


Pain Assessment and Management for a Chemically Paralyzed Child Receiving Mechanical Ventilation.
Pain assessment in the pediatric intensive care unit (PICU) is complex, specifically for children receiving mechanical ventilation who require neuromuscular blockade (NMB). No valid pain assessment method exists for this population. Guidelines are limited to using physiologic variables; it remains unknown how nurses are assessing and managing pain for this population in practice. To describe how PICU nurses are assessing and managing pain for children who require NMB. A cross-sectional quantitative design was used with an electronic survey. Nurses were asked to respond to 4 written vignettes depicting a child who required NMB and had a painful procedure, physiologic cues, both, or neither. A total of 107 PICU nurses answered the survey. Nurses primarily used behavioral assessment scales (61.0%) to assess the child's pain. All nurses reported that physiologic variables are either moderately or extremely important, and 27.3% of nurses used the phrase "assume pain present" formally at their organization. When physiologic cues were present, the odds of a nurse intervening with a pain intervention were 23.3 times (95% CI, 11.39-53.92; P < .001) higher than when such cues were absent. These results demonstrate variation in how nurses assess pain for a child who requires NMB. The focus remains on behavioral assessment scales, which are not valid for this population. When intervening with a pain intervention, nurses relied on physiologic variables. Decision support tools to aid nurses in conducting an effective pain assessment and subsequent management need to be created.


The role of individual-, family-, and school-level resilience in the subjective well-being of children exposed to violence in Namibia.
Children exposed to violence are at risk of a range of adverse outcomes. Given the unique cultural and social context, understanding what fosters children's resilience in resource-limited areas such as sub-Saharan Africa, is vital. Using data from the International Survey of Children's Well-Being (ISCWeB), this paper explores individual-, family-, and school-level factors associated with positive outcomes for children who have experienced some form of violence in Khomas region, Namibia. Using a cross-sectional survey design, the ISCWeB questionnaire, assessing cognitive, affective, and psychological dimensions of well-being, child protection factors and violence exposure was administered to 2124 Grade four and six children. Our sample had a mean age of 11.2 years. Overall, 56.8 % of children reported at least one incident of violence from an adult caregiver at home and 86.0 % of children reported some form of peer violence at school. Materially deprived children experienced higher incidence of both family and peer violence. The quality of children's relationships at home (β = 0.17, p < 0.001), and school (β = 0.07, p < 0.001) emerged as important protective factors for children's well-being for both types of violence, suggesting that supportive family and school relationships may be more important to the subjective well-being of children who experienced violence than material wellbeing, violence severity, and individual child factors. Providing positive social interaction and emotional security in contextually and culturally appropriate ways within children's proximal systems should be prioritized while challenging norms that support violence in Namibian families and schools.


Miniaturized lead sensor based on lead-specific DNAzyme in a nanocapillary interconnected microfluidic device.
A miniaturized lead sensor has been developed by combining a lead-specific DNAzyme with a microfabricated device containing a network of microfluidic channels that are fluidically coupled via a nanocapillary array interconnect. A DNAzyme construct, selective for cleavage in the presence of Pb2+ and derivatized with fluorophore (quencher) at the 5' (3') end of the substrate and enzyme strands, respectively, forms a molecular beacon that is used as the recognition element. The nanocapillary array membrane interconnect is used to manipulate fluid flows and deliver the small-volume sample to the beacon in a spatially confined detection window where the DNAzyme is interrogated using laser-induced fluorescence detection. A transformed log plot of the fluorescent signal exhibits a linear response (r2 = 0.982) over a Pb2+ concentration range of 0.1 - 100 microM, and a detection limit of 11 nM. The sensor has been applied to the determination of Pb2+ in an electroplating sludge reference material, the result agreeing with the certified value within 4.9%. Quantitative measurement of Pb2+ in this complex sample demonstrates the selectivity of this sensor scheme and points favorably to the application of such technologies to analysis of environmental samples. The unique combination of a DNAzyme with a microfluidic-nanofluidic hybrid device makes it possible to change the DNAzyme to select for other compounds of interest, and to incorporate multiple sensing systems within a single device for greater flexibility. This work represents the initial steps toward creation of a robust field sensor for lead in groundwater or drinking water.


The broad orientation dependence of the motion streak aftereffect reveals interactions between form and motion neurons.
The extended integration time of visual neurons can lead to the production of the neural equivalent of an orientation cue along the axis of motion in response to fast-moving objects. The dominant model argues that these motion streaks resolve the inherent directional uncertainty arising from the small size of receptive fields in V1, by combining spatial orientation with motion signals in V1. This model was tested in humans using visual aftereffects, in which adapting to a static grating causes the perceived direction of a subsequently presented motion stimulus to be tilted away from the adapting orientation. We found that a much broader range of orientations produced aftereffects than predicted by the current model, suggesting that these orientation cues influence motion perception at a later stage than V1. We also found that varying the spatial frequency of the adaptor changed the aftereffect from repulsive to attractive for motion-test but not form-test stimuli. Finally, manipulations of V1 excitability, using transcranial stimulation, reduced the aftereffect, suggesting that the orientation cue is dependent on V1. These results can be accounted for if the orientation information from the motion streak, gathered in V1, enters the motion system at a later stage of motion processing, most likely V5. A computational model of motion direction is presented incorporating gain modifications of broadly tuned motion-selective neurons by narrowly tuned orientation-selective cells in V1, which successfully accounts for the extant data. These results reinforce the suggestion that orientation places strong constraints on motion processing but in a previously undescribed manner.


Trends in Renal Replacement Therapy in Bosnia and Herzegovina 2002-2008.
Renal Registry (RR) of Bosnia and Herzegovina was established in 2002, with aim to follow up the trends of Renal Replacement Therapy in Bosnia and Herzegovina. The prevalence of Renal Replacement Therapy (RRT) in Bosnia and Herzegovina is rising steadily. One reason for this is an increasing number of patients starting RRT. The aim is to present the epidemiology and treatment of all aspects of RRT in Bosnia and Herzegovina in period 2002-2008. Centre-related and patient-related questionnaires were sent to all 25 dialysis centres in Bosnia and Herzegovina. The demographic data, prevalence and incidence, type of renal replacement therapy, cause of ESRD, erythropoietin administration, cause of death, and type of vascular access were obtained from the questionnaires. Collected data were analysed using SPSS statistics. The number of patients treated by Renal Replacement Therapy (RRT) increased steadily from 1,531 patients in 2002 to the 2,206 at the 2008 (43%). The prevalence has increased from 399 pmp in 2002 to 696 pmp. in 2008. Incidence (new patients) in 2002 was 110 pmp and incidence rate in 2008 was 163, and there were 249 new patients (day 1). The mean age for new patients increased from 60 years in 2002 to 63.5 years in 2008 and the population over 75 years rate from 8.79% to 11.3%. Most ESRD patients in Bosnia and Herzegovina are undergoing intermittent hemodialysis (92%), while some patients (8%) are treated by peritoneal dialysis and transplantation. The most significant cause of ESRD in 2008 was chronic glomerulonephritis (421 patients, 19.2%), followed by pyelonephritis (414 patients, 18.9%), BEN (14.7%) and Diabetes mellitus (12.2%). Hepatitis B and C virus infections had 397 (16.3%) patients, out of them 22 had both type of infections and 98 patients had B type infection. Only 10.5% of patients were tested on MRSA and 3 patients were positive on MRSA. There were no HIV-positive patients on RRT. The most common type of vascular access was AV fistula in 85% patients, AV graft 2% and catheters in 13%. Out of hemodialysis patients, 85.7% received ESA almost s.c. The median weekly dose was 4,000 UI. Cardiovascular diseases were the leading cause of death, gross mortality rate of dialysis patients being 13.01% in 2008. The need for RRT in Bosnia and Herzegovina is increasing and the number of patients increased by 43% since 2002. Hemodialysis is still the most common modality of treatment (92%), while proportion of PD and transplantation is slowly increasing. The preventive measures are necessary to prevent ESRD and also to decrease the number of patients on dialysis.


Multi-organ localization combining global-to-local regression and confidence maps.
We propose a method for fast, accurate and robust localization of several organs in medical images. We generalize global-to-local cascades of regression forests [1] to multiple organs. A first regressor encodes global relationships between organs. Subsequent regressors refine the localization of each organ locally and independently for improved accuracy. We introduce confidence maps, which incorporate information about both the regression vote distribution and the organ shape through probabilistic atlases. They are used within the cascade itself, to better select the test voxels for the second set of regressors, and to provide richer information than the classical bounding boxes thanks to the shape prior. We demonstrate the robustness and accuracy of our approach through a quantitative evaluation on a large database of 130 CT volumes.


Antimicrobial and Anti-Virulence Activity of Capsaicin Against Erythromycin-Resistant, Cell-Invasive Group A Streptococci.
Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is the active component of Capsicum plants (chili peppers), which are grown as food and for medicinal purposes since ancient times, and is responsible for the pungency of their fruit. Besides its multiple pharmacological and physiological properties (pain relief, cancer prevention, and beneficial cardiovascular, and gastrointestinal effects) capsaicin has recently attracted considerable attention because of its antimicrobial and anti-virulence activity. This is the first study of its in vitro antibacterial and anti-virulence activity against Streptococcus pyogenes (Group A streptococci, GAS), a major human pathogen. The test strains were previously characterized, erythromycin-susceptible (n = 5) and erythromycin-resistant (n = 27), cell-invasive pharyngeal isolates. The MICs of capsaicin were 64-128 μg/mL (the most common MIC was 128 μg/mL). The action of capsaicin was bactericidal, as suggested by MBC values that were equal or close to the MICs, and by early detection of dead cells in the live/dead assay. No capsaicin-resistant mutants were obtained in single-step resistance selection studies. Interestingly, growth in presence of sublethal capsaicin concentrations induced an increase in biofilm production (p ≤ 0.05) and in the number of bacteria adhering to A549 monolayers, and a reduction in cell-invasiveness and haemolytic activity (both p ≤ 0.05). Cell invasiveness fell so dramatically that a highly invasive strain became non-invasive. The dose-response relationship, characterized by opposite effects of low and high capsaicin doses, suggests a hormetic response. The present study documents that capsaicin has promising bactericidal activity against erythromycin-resistant, cell-invasive pharyngeal GAS isolates. The fact that sublethal concentrations inhibited cell invasion and reduced haemolytic activity, two important virulence traits of GAS, is also interesting, considering that cell-invasive, erythromycinresistant strains can evade β-lactams by virtue of intracellular location and macrolides by virtue of resistance, thus escaping antibiotic treatment. By inhibiting intracellular invasion and haemolytic activity, capsaicin could thus prevent both formation of a difficult to eradicate intracellular reservoir, and infection spread to deep tissues.


Substance use identification and follow-up rates among commercial and Medicare health insurance members in primary care and other settings.
The objective of this study was to investigate factors associated with substance use disorder identification and follow-up rates among samples of members of a private health insurance plan. In an observational study, samples of claims data for 2017 for Commercial and Medicare members from a private health insurer were accessed and analyzed using descriptive statistics, decision tree analysis, and linear regression models. Commercial and Medicare members differed in age. Medicare members had higher rates of inclusion in a measure of substance use disorder than Commercial members, lower rates of initial short term follow-up, more opioid prescriptions from primary care provides, fewer prescriptions for opioid treatment, and higher rates of selected comorbid conditions. Mental health diagnoses and substance use disorder co-occurred frequently and to a greater extent in the Medicare sample. Among commercial members, there were primarily alcohol problems that increased with age, while opioid problems at about 10% peaked in the mid-twenties. More males were included among all substance types. The overall rate for an initial short term follow-up visit indicating initiation of treatment was 30%. There were large differences in the follow-up rates across settings with a very low rate (4.6% for alcohol and 6.9% for opioid) in primary care settings. These results suggest that increased attention in primary care to young adult males and to older adults, may help to reduce substance use disorder rates, especially alcohol use disorders.


Genetic variation within and among lion tamarins.
The golden lion tamarin Leontopithecus rosalia rosalia, one of the rarest and most endangered of New World primates, has been the focus of an intensive research and conservation effort for two decades. During that period, managed breeding from 44 founders has brought the captive population to over 400 individuals, a number that equals or exceeds the estimated number of free-ranging golden lion tamarins. The extent of genetic variation among golden lion tamarins was estimated with an electrophoretic survey of 47 allozyme loci from 67 captive and 73 free-ranging individuals. The amount of variation was low, compared to 15 other primate species, with 4% of the loci being polymorphic (P), and with an average heterozygosity H estimate of 0.01 in these callitrichids. Electrophoretic analyses of captive and free-ranging animals (N = 31) of two allopatric morphotypes, Leontopithecus rosalia chrysopygus and L. r. chrysomelas, were similar to the L. r. rosalia findings insofar as they also revealed limited genetic polymorphism. Computation of the Nei-genetic distance measurements showed that the three morphotypes were genetically very similar, although discernible differentiation had occurred at two loci. These data are consistent with the occurrence of recent reproductive isolations of these subspecies.


Structural organization of the 19S proteasome lid: insights from MS of intact complexes.
The 26S proteasome contains a 19S regulatory particle that selects and unfolds ubiquitinated substrates for degradation in the 20S catalytic particle. To date there are no high-resolution structures of the 19S assembly, nor of the lid or base subcomplexes that constitute the 19S. Mass spectra of the intact lid complex from Saccharomyces cerevisiae show that eight of the nine subunits are present stoichiometrically and that a stable tetrameric subcomplex forms in solution. Application of tandem mass spectrometry to the intact lid complex reveals the subunit architecture, while the coupling of a cross-linking approach identifies further interaction partners. Taking together our results with previous analyses we are able to construct a comprehensive interaction map. In summary, our findings allow us to identify a scaffold for the assembly of the particle and to propose a regulatory mechanism that prevents exposure of the active site until assembly is complete. More generally, the results highlight the potential of mass spectrometry to add crucial insight into the structural organization of an endogenous, wild-type complex.


Adaptive Hierarchical Dual Consistency for Semi-Supervised Left Atrium Segmentation on Cross-Domain Data.
Semi-supervised learning provides great significance in left atrium (LA) segmentation model learning with insufficient labelled data. Generalising semi-supervised learning to cross-domain data is of high importance to further improve model robustness. However, the widely existing distribution difference and sample mismatch between different data domains hinder the generalisation of semi-supervised learning. In this study, we alleviate these problems by proposing an Adaptive Hierarchical Dual Consistency (AHDC) for the semi-supervised LA segmentation on cross-domain data. The AHDC mainly consists of a Bidirectional Adversarial Inference module (BAI) and a Hierarchical Dual Consistency learning module (HDC). The BAI overcomes the difference of distributions and the sample mismatch between two different domains. It mainly learns two mapping networks adversarially to obtain two matched domains through mutual adaptation. The HDC investigates a hierarchical dual learning paradigm for cross-domain semi-supervised segmentation based on the obtained matched domains. It mainly builds two dual-modelling networks for mining the complementary information in both intra-domain and inter-domain. For the intra-domain learning, a consistency constraint is applied to the dual-modelling targets to exploit the complementary modelling information. For the inter-domain learning, a consistency constraint is applied to the LAs modelled by two dual-modelling networks to exploit the complementary knowledge among different data domains. We demonstrated the performance of our proposed AHDC on four 3D late gadolinium enhancement cardiac MR (LGE-CMR) datasets from different centres and a 3D CT dataset. Compared to other state-of-the-art methods, our proposed AHDC achieved higher segmentation accuracy, which indicated its capability in the cross-domain semi-supervised LA segmentation.


The UCSC Genome Browser database: extensions and updates 2013.
The University of California Santa Cruz (UCSC) Genome Browser (http://genome.ucsc.edu) offers online public access to a growing database of genomic sequence and annotations for a wide variety of organisms. The Browser is an integrated tool set for visualizing, comparing, analysing and sharing both publicly available and user-generated genomic datasets. As of September 2012, genomic sequence and a basic set of annotation 'tracks' are provided for 63 organisms, including 26 mammals, 13 non-mammal vertebrates, 3 invertebrate deuterostomes, 13 insects, 6 worms, yeast and sea hare. In the past year 19 new genome assemblies have been added, and we anticipate releasing another 28 in early 2013. Further, a large number of annotation tracks have been either added, updated by contributors or remapped to the latest human reference genome. Among these are an updated UCSC Genes track for human and mouse assemblies. We have also introduced several features to improve usability, including new navigation menus. This article provides an update to the UCSC Genome Browser database, which has been previously featured in the Database issue of this journal.


Gastrointestinal Bleeding Secondary to Calciphylaxis.
BACKGROUND Calciphylaxis is associated with a high mortality that approaches 80%. The diagnosis is usually made when obvious skin lesions (painful violaceous mottling of the skin) are present. However, visceral involvement is rare. We present a case of calciphylaxis leading to lower gastrointestinal (GI) bleeding and rectal ulceration of the GI mucosa. CASE REPORT A 66-year-old woman with past medical history of diabetes mellitus, hypertension, end-stage renal disease (ESRD), recently diagnosed ovarian cancer, and on hemodialysis (HD) presented with painful black necrotic eschar on both legs. The radiograph of the legs demonstrated extensive calcification of the lower extremity arteries. The hospital course was complicated with lower GI bleeding. A CT scan of the abdomen revealed severe circumferential calcification of the abdominal aorta, celiac artery, and superior and inferior mesenteric arteries and their branches. Colonoscopy revealed severe rectal necrosis. She was deemed to be a poor surgical candidate due to comorbidities and presence of extensive vascular calcifications. Recurrent episodes of profuse GI bleeding were managed conservatively with blood transfusion as needed. Following her diagnosis of calciphylaxis, supplementation with vitamin D and calcium containing phosphate binders was stopped. She was started on daily hemodialysis with low calcium dialysate bath as well as intravenous sodium thiosulphate. The clinical condition of the patient deteriorated. The patient died secondary to multiorgan failure. CONCLUSIONS Calciphylaxis leading to intestinal ischemia/perforation should be considered in the differential diagnosis in ESRD on HD presenting with abdominal pain or GI bleeding.


Hybrid thoracic endovascular aortic repair via right anterior minithoracotomy.
Hybrid thoracic endovascular aortic repair (TEVAR) has expanded the surgical management of complex thoracic aneurysms. Aortic arch debranching generally requires a sternotomy. We describe our experience performing a right anterior minithoracotomy for hybrid TEVAR. During a 3-year period, 7 patients (aged 76 ± 15 years; 57% were male) with aortic arch aneurysms underwent hybrid TEVAR via a right anterior minithoracotomy. Of all with prior thoracic or abdominal aortic surgery, 4 had a prior sternotomy. All patients included in this series had an American Society of Anesthesiology score of 4 or greater. Repairs were performed via a 5-cm incision at the third to fourth intercostal space to access the ascending arch. A Satinsky clamp on the ascending aorta facilitated bypass with the 10-mm arm of a bifurcated 10/12-mm graft to the innominate artery or right common carotid artery (12-mm arm: endoprosthesis conduit). The remaining arch vessels were bypassed as needed; subsequently, a thoracic stent graft was deployed by the 12- or 14-mm arm. Primary technical success was 86% (6 patients); 1 patient required conversion to sternotomy secondary to bleeding. Complications included cerebrovascular accident in 2 patients (28%) and respiratory failure in 2 patients (28%). The average length of stay was 12 days with no wound infection. One death occurred during the 30-day period. Right anterior minithoracotomy is a compelling, less invasive technique for hybrid TEVAR. Further experience will be necessary to completely evaluate the merits of this approach.