Early relationships and the development of aggression in children.
The development of abnormally aggressive human behavior is complex and multifactorial. Aggressive patterns of behavior often begin early in life and, once established, are notorious for their resistance to change, which has led some to believe that environmental interventions offer little hope for significant reductions in the prevalence of violent behavior in our society. Recent findings from research in the field of developmental psychopathology, however, have shed some new light on this very old problem. This paper specifically reviews the attachment literature and interprets it in the context of what has already been learned from research in epidemiology and behavioral genetics on environmental contributions to aggression over the life span. Environmental factors may influence the development of aggression by affecting children's early relationships with primary caregivers or by limiting opportunities for children to engage in positive relationships with caring adult figures. Longitudinal studies directly correlating early attachment relationships with levels of aggression in later childhood have been limited in number but suggest that insecure early attachment relationships may predispose children to the development of abnormally aggressive behavior, particularly when such relationships represent the entirety of their early social experience. Interventions aimed at either enhancing parent-child relationships or providing opportunities for alternative relationships with caring adult figures, particularly in high-risk settings, may help to prevent abnormally aggressive behavioral outcome.


Experiences and challenges in the management of pregnancy-associated breast cancer at the Korle Bu Teaching Hospital: a review of four cases.
Breast cancer is the commonest female cancer worldwide and the most common malignancy during pregnancy. The current management of breast cancer is based on patient and tumour characteristics, preferences and disease stage. In pregnancy-associated breast cancer, the gestational age influences treatment options. Sequencing of therapies is guided by safe imaging options, timing of delivery and prognosis. Systemic therapy options in the neoadjuvant, adjuvant and palliative settings are limited due to safety concerns of the unborn foetus. In resource-constrained regions, the application of safe options may be challenging. This paper reports four of such cases managed in Ghana using a multidisciplinary approach and local resource-appropriate evidence-based practices. Maternal and foetal outcomes were acceptable with none resulting in termination of pregnancy.


Phylogenetics and taxonomy of the fungal vascular wilt pathogen Verticillium, with the descriptions of five new species.
Knowledge of pathogen biology and genetic diversity is a cornerstone of effective disease management, and accurate identification of the pathogen is a foundation of pathogen biology. Species names provide an ideal framework for storage and retrieval of relevant information, a system that is contingent on a clear understanding of species boundaries and consistent species identification. Verticillium, a genus of ascomycete fungi, contains important plant pathogens whose species boundaries have been ill defined. Using phylogenetic analyses, morphological investigations and comparisons to herbarium material and the literature, we established a taxonomic framework for Verticillium comprising ten species, five of which are new to science. We used a collection of 74 isolates representing much of the diversity of Verticillium, and phylogenetic analyses based on the ribosomal internal transcribed spacer region (ITS), partial sequences of the protein coding genes actin (ACT), elongation factor 1-alpha (EF), glyceraldehyde-3-phosphate dehydrogenase (GPD) and tryptophan synthase (TS). Combined analyses of the ACT, EF, GPD and TS datasets recognized two major groups within Verticillium, Clade Flavexudans and Clade Flavnonexudans, reflecting the respective production and absence of yellow hyphal pigments. Clade Flavexudans comprised V. albo-atrum and V. tricorpus as well as the new species V. zaregamsianum, V. isaacii and V. klebahnii, of which the latter two were morphologically indistinguishable from V. tricorpus but may differ in pathogenicity. Clade Flavnonexudans comprised V. nubilum, V. dahliae and V. longisporum, as well as the two new species V. alfalfae and V. nonalfalfae, which resembled the distantly related V. albo-atrum in morphology. Apart from the diploid hybrid V. longisporum, each of the ten species corresponded to a single clade in the phylogenetic tree comprising just one ex-type strain, thereby establishing a direct link to a name tied to a herbarium specimen. A morphology-based key is provided for identification to species or species groups.


Optical coherence tomography in acute optic neuritis: A population-based study.
To measure early structural damage caused by autoimmune inflammatory optic neuritis (ON) by optical coherence tomography (OCT) in a population-based cohort. In a prospective population-based study over 24 months in Southern Denmark, patients diagnosed with acute ON and without prior diagnosis of a chronic neuroinflammatory disorder were included and examined with OCT, visual evoked potentials (VEP), visual fields, high contrast visual acuity (HCVA), and low contrast letter acuity (LCLA). Structural and functional outcomes were determined at 6-month follow-up based on interocular differences. The 50 included patients had on average 16.9 μm peripapillary retinal nerve fiber layer loss, 10.6 μm ganglion cell and inner plexiform layer (GCIP) loss, and an average HCVA decrease of 0.22 dec. Based on a linear regression model, average GCIP loss amounted to -0.2 μm per day and started 8 days after onset. OCT outcomes but not VEP correlated well with all visual function measurements at follow-up. Structural and functional damage in 20 patients (40%) diagnosed de novo with multiple sclerosis (MS) and in 2 patients (4%) with positive myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) test did not differ from patients with idiopathic ON. Optic neuritis causes substantial retinal damage and vision loss independent of the underlying disease. Our study supports that GCIP damage starts closely to clinical onset. Good structure-function correlations between OCT and vision support the importance of OCT in monitoring acute ON.


Virus-induced cytokines regulate circulating lymphocyte levels during primary SIV infections.
Decline in blood CD4+ lymphocytes during primary symptomatic infections with HIV is usually attributed to viral killing, and has not been considered in terms of altered lymphocyte migration and sequestration. We therefore sought to examine whether CD4+ cell loss from blood of macaques undergoing an acute primary SIV infection might be due to increased synthesis of cytokines, known to profoundly affect lymphocyte trafficking, rather than to direct lymphocyte destruction by virus. The findings indicate that rapid lymphocyte depletion following acute infection is not selective for CD4+ cells, correlates precisely with increased plasma IFN-gamma and tumor necrosis factor-alpha levels, and is reversible. CD4/CD8 ratios in lymph nodes with high viral burdens remain relatively unchanged despite lymphocyte loss from blood. Levels of cytokine mRNA measured in lymphoid organs reflect neither cytokine plasma levels nor their potential to induce sequestration. These results support a model of cytokine-induced lymphocyte extravasation to account for the acute HIV/SIV-induced CD4+ cell lymphopenia and raise questions regarding the extent to which altered lymphocyte migration plays a role in the gradual CD4+ cell depletion throughout infection.


[Tumor lysis syndrome. A life-threatening complication during cytostatic treatment of chemosensitive types of cancer].
Tumour lysis syndrome is characterized by hyperkalemia, hypermagnesemia, hyperphosphatemia, hyperuricemia and elevated levels of serum creatinine and urea, indicating renal dysfunction due to rapid lysis of a large number of tumour cells. Hypocalcemia is often found as well. Tumour lysis syndrome is most likely to occur after chemotherapy of cancers that are highly responsive to chemotherapeutic drugs, such as malignant lymphomas and acute leukemias, when there is a large burden of tumours. Another risk factor is impaired renal function before treatment. Tumour lysis syndrome is potentially life-threatening. During the first course of chemotherapy in particular, the patient should receive prophylactic treatment, and laboratory tests should be performed daily in order to avoid this serious complication.


Overcoming P-Glycoprotein-Mediated Drug Resistance with Noscapine Derivatives.
The antitussive agent noscapine has been shown to inhibit the proliferation of cancer cells by disruption of tubulin dynamic. However, the efficacy of several anticancer drugs that inhibit tublin dynamics (vinca alkaloids and taxanes) is reduced by the multidrug resistance phenotype. These compounds are substrates for P-glycoprotein (P-gp)-mediated extrusion from cells. Consequently, the antiproliferative activity of noscapine and a series of derivatives was measured in drug-sensitive and drug-resistant cells that overexpress P-gp. None of the noscapine derivatives displayed lower potency in cells overexpressing P-gp, thereby suggesting a lack of interaction with this pump. However, the cellular efflux of a fluorescent substrate by P-gp was potently inhibited by noscapine and most derivatives. Further investigation with purified, reconstituted P-gp demonstrated that inhibition of P-gp function was due to direct interaction of noscapine derivatives with the transporter. Moreover, coadministration of vinblastine with two of the noscapine derivatives displayed synergistic inhibition of proliferation, even in P-gp-expressing resistant cell lines. Therefore, noscapine derivatives offer a dual benefit of overcoming the significant impact of P-gp in conferring multidrug resistance and synergy with tubulin-disrupting anticancer drugs.


Interleukin-8 and procalcitonin in early diagnosis of early severe bacterial infection in critically ill neonates.
We studied the value of serum interleukin-8 (IL-8) and procalcitonin (PCT) in the early diagnosis of early severe bacterial infection in 58 critically ill ventilated neonates. ELISA was used for determining IL-8 and immunoluminometric assay for PCT. IL-8 and PCT were compared with routinely used serum C-reactive protein (CRP). Neonates were divided into four groups: Ia--proven severe bacterial infection (n = 9), Ib--clinical sepsis (n = 16), II--respiratory distress without bacterial infection (n = 12), and III--various types of neonatal distress (n = 21). Sera were collected on admission, at 24 h and 48 h after admission. There was no significant difference between groups Ia and Ib for either parameter at any time interval. Significant difference was found between group Ia+b (septic neonates) and group II for PCT and CRP at 24 and 48 h, but not for IL-8. There was no difference between group Ia+b and group III except for CRP at 24 h. Diagnostic accuracy was best for PCT on admission and for CRP at 24 h. Serum PCT and IL-8 are not specific markers for early severe bacterial infection in critically ill neonates and are not better than CRP.


Comparison of ternary crystal complexes of F31 variants of human dihydrofolate reductase with NADPH and a classical antitumor furopyrimidine.
The novel furopyrimidine, N-[4-[(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)-methyl]-methylamino] -benzoyl]-L-glutamate (MTXO), a classical antifolate with weak antitumor activity compared with methotrexate (MTX), has been studied as inhibitorcofactor ternary crystal complexes with recombinant Phe-31 to Ser (F31S) and Phe-31 to Gly (F31G) variant human dihydrofolate reductase (hDHFR). Kinetic data show that the binding affinity of MTXO is significantly weaker for the variant hDHFR enzyme than for the wild type enzyme. Structural data for the Phe-31 variants, along with wild type hDHFR, provide the first direct comparison of the binding interactions of a single antifolate in a family of variant hDHFR. These ternary hDHFR complexes crystallize in the rhombohedral space group R3, isomorphous to that reported for wild type hDHFR MTXO-NADPH ternary complex. MTXO binds with its 2,4-diaminofuropyrimidine ring interacting with Glu-30 in hDHFR. The greatest change on modification of the side chain at position 31 is loss of hydrophobic contacts to the inhibitor, which results in the significant decrease in binding affinity of MTXO for the Phe-31 variants. The presence of the 6-5 furopyrimidine ring instead of the 6-6 pteridine ring causes a different bridge conformation compared with MTX, and in the case of the wild type MTXO complex also results in weaker hydrophobic contacts to Phe-31 than observed for MTXT. For the design of antitumor agents related to MTXO, increasing the bridge of MTXO from two to three or four atoms should provide increased DHFR inhibitory potency and antitumor activity.


Ecological selectivity and the evolution of mammalian substrate preference across the K-Pg boundary.
The Cretaceous-Paleogene (K-Pg) mass extinction 66 million years ago was characterized by a worldwide ecological catastrophe and rapid species turnover. Large-scale devastation of forested environments resulting from the Chicxulub asteroid impact likely influenced the evolutionary trajectories of multiple clades in terrestrial environments, and it has been hypothesized to have biased survivorship in favour of nonarboreal lineages across the K-Pg boundary. Here, we evaluate patterns of substrate preferences across the K-Pg boundary among crown group mammals, a group that underwent rapid diversification following the mass extinction. Using Bayesian, likelihood, and parsimony reconstructions, we identify patterns of mammalian ecological selectivity that are broadly similar to those previously hypothesized for birds. Models based on extant taxa indicate predominant K-Pg survivorship among semi- or nonarboreal taxa, followed by numerous independent transitions to arboreality in the early Cenozoic. However, contrary to the predominant signal, some or all members of total-clade Euarchonta (Primates + Dermoptera + Scandentia) appear to have maintained arboreal habits across the K-Pg boundary, suggesting ecological flexibility during an interval of global habitat instability. We further observe a pronounced shift in character state transitions away from plesiomorphic arboreality associated with the K-Pg transition. Our findings are consistent with the hypothesis that predominantly nonarboreal taxa preferentially survived the end-Cretaceous mass extinction, and emphasize the pivotal influence of the K-Pg transition in shaping the early evolutionary trajectories of extant terrestrial vertebrates.


Pro and anti-inflammatory cytokine levels (TNF-α, IL-1β, IL-6 and IL-10) in rat model of neuroma.
Traumatic neuroma is neuronal tissue proliferation developed in a nerve injury site, often associated with increased sensitivity and spontaneous or evoked neuropathic pain. The mechanisms leading to the disorganized nerve proliferation are not completely understood, though inflammation in the injured nerve vicinity most likely has a role in the process. Inflammatory cytokines are also known to be involved in the maintenance and development of post-traumatic and neuropathic pain. The goal of this study was to quantify and compare pro and anti-inflammatory cytokines (TNF-α, IL-1β, IL-6 and IL-10) levels in nerves that formed neuromas and nerves that did not, following sciatic nerve transection. A total of 30 rats were used in this study. Twenty rats underwent sciatic nerve transection and 10 underwent sham surgery. Six weeks post-surgery nerve sections were collected and histologically evaluated for neuroma formation. The samples were then classified as neuroma, non-neuroma and sham groups. TNF-α, IL-1β, IL-6 and IL-10 levels were measured in the nerves employing ELISA. TNF-α levels were significantly higher in both neuroma and non-neuroma-forming injured nerves compared to the sham group. IL-1β and IL-6 levels were significantly higher in the neuroma-forming nerves compared to the sham group. IL-10 levels were significantly higher in the non-neuroma group compared to the sham group. In conclusion IL-6, and IL-1 β may have a role in the formation of traumatic neuroma while IL-10 may inhibit neuroma formation.


[Costs of chronic obstructive pulmonary disease in patients treated in ambulatory care in Poland].
Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. A cost-of-illness study aims to determine the total economic impact of a disease or health condition on society through the identification, measurement, and valuation of all direct and indirect costs. Exacerbations are believed to be a major cost driver in COPD. The aim of this study was to examine direct, mean costs of COPD in Poland under usual clinical practice form societal perspective. It was an observational bottom-up-cost-of-illness study, based on a retrospective sample of patients presenting with COPD in pulmonary ambulatory care facilities in Poland. Total medical resources consumption of a sample were collected in 2007/2008 year by physician - lung specialists. Direct costs of COPD were evaluated based on data from different populations of five clinical hospitals and eight out-patient clinics. Resources utilisation and cost data are summarised as mean values per patient per year. 95% confidence intervals were derived using percentile bootstrapping. Total medicals resources consumption of a COPD patient per year was 1007 EURO (EUR 1 = PLN 4.0; year 2008). Among this cost 606 EURO was directly related to COPD follow up, 105 EURO was related to ambulatory exacerbation, and 296 EURO was related to exacerbation treated in hospital. The burden of COPD itself appeared to be considerable magnitude for society in Poland.


Milrinone therapy in catecholamine-dependent critically ill patients with heart failure.
Treatment with the PDE-III inhibitor milrinone improves hemodynamics in patients with heart failure. We examined whether therapy with milrinone is safe and effective in critically ill patients with catecholamine-dependent heart failure and whether treatment with milrinone facilitates weaning from prolonged catecholamine therapy. Twenty adult patients with reduced left ventricular function and prolonged (7+/-4 days) catecholamine therapy in whom attempts at catecholamine weaning had failed were examined. Patients were prospectively randomised either to group A (addition of a fixed dose of 0.5 microg x kg(-1) x min(-1) milrinone to catecholamine therapy) or to group B (continued catecholamine therapy without milrinone). Dobutamine and norepinephrine treatment and fluid intake were titrated according to predefined hemodynamic goals. Hemodynamic parameters, fluid requirements and catecholamine dose were monitored. After 24 h of study treatment goup A showed a significant increase in cardiac index (2.2+/-0.4 1 min(-1) x m(-2) to 2.7+/-0.51 min(-1) x m(-2); P<0.005), a decrease in systemic vascular resistance (1,427+/-609 dyn x s x cm(-5) to 951+/-184 dyn x s x cm(-5); P<0.005), required lower doses of dobutamine (5.9+/-4.2 microg x kg(-1) x min(-1) to 2.2+/-3.3 microg x kg(-1) x min(-1); P<0.02), but showed a tendency for higher vasoconstrictor (0.14+/-0.16 microg x kg(-1) x min(-1) to 0.29+/-0.43 microg x kg(-1) x min(-1); P=n.s.) and fluid requirements (+1,404+/-2,257 ml/24 h to +2,508+/-1,873 ml/ 24 h; P=n.s.). No significant changes occurred in group B. Weaning from catecholamine therapy was more often achieved in group A and more milrinone treated patients were discharged alive from the ICU (80% vs. 30%; P<0.05). Milrinone improves central hemodynamics and may facilitate weaning from prolonged catecholamine support in critically ill patients with heart failure. Its administration in this subset of critically ill patients is safe, but eventually is associated with additional vasoconstrictor and fluid requirements.


Latent infection of human bocavirus accompanied by flare of chronic cough, fatigue and episodes of viral replication in an immunocompetent adult patient, Cologne, Germany.
The human bocavirus (HBoV) is a parvovirus and is associated with mild to life-threatening acute or persisting respiratory infections, frequently accompanied by further pathogens. So far, there is limited knowledge on the mechanisms of persistence, and no reports on chronic infections or latency have been published so far. An immunocompetent male patient suffers from a chronic HBoV1 infection, i.e. viral DNA was detected in both serum and bronchoalveolar lavage (BAL) for >5 months without co-infections and with respiratory symptoms resolved spontaneously while receiving symptomatic treatment with montelukast and corticosteroids. Following the symptomatic medication of a chronic infection with HBoV1 viraemia indicating active viral replication lasting over 5 months, the patient cleared the viraemia and no further viral DNA was detectable in the BAL. However, by fluorescence in situ hybridization analyses of mucosal biopsies, it was shown that the virus genome still persisted in the absence of viral shedding but in a more compact manner possibly representing a supercoiled episomal form of this otherwise linear single-stranded DNA genome. This indicated the entry into a latency phase. Moreover, the cytokine profile and the IP-10/TARC ratio, a marker for fibrotization, seem to have been altered by HBoV1 replication. Although specific IgG antibodies were detectable during the whole observation period, they showed an apparently insufficient neutralising activity. On the one hand, these findings suggest that the symptomatic medication may have led to clearance of the virus from blood and airways and, moreover, that the viral DNA persists in the tissue as an altered episomal form favoured by lacking neutralising antibodies. This appears to be important in order to reduce possible long-term effects such as lung fibrosis.


Molecular and cellular mechanisms of bone morphogenetic proteins and activins in the skin: potential benefits for wound healing.
Bone morphogenetic proteins (BMPs) and activins are phylogenetically conserved proteins, belonging to the transforming growth factor-β superfamily, that signal through the phosphorylation of receptor-regulated Smad proteins, activating different cell responses. They are involved in various steps of skin morphogenesis and wound repair, as can be evidenced by the fact that their expression is increased in skin injuries. BMPs play not only a role in bone regeneration but are also involved in cartilage, tendon-like tissue and epithelial regeneration, maintain vascular integrity, capillary sprouting, proliferation/migration of endothelial cells and angiogenesis, promote neuron and dendrite formation, alter neuropeptide levels and are involved in immune response modulation, at least in animal models. On the other hand, activins are involved in wound repair through the regulation of skin and immune cell migration and differentiation, re-epithelialization and granulation tissue formation, and also promote the expression of collagens by fibroblasts and modulate scar formation. This review aims at enunciating the effects of BMPs and activins in the skin, namely in skin development, as well as in crucial phases of skin wound healing, such as inflammation, angiogenesis and repair, and will focus on the effects of these proteins on skin cells and their signaling pathways, exploring the potential therapeutic approach of the application of BMP-2, BMP-6 and activin A in chronic wounds, particularly diabetic foot ulcerations.


Evaluation of candidate DNA barcoding loci for economically important timber species of the mahogany family (Meliaceae).
There has been considerable debate regarding locus choice for DNA barcoding land plants. This is partly attributable to a shortage of comparable data from proposed candidate loci on a common set of samples. In this study, we evaluated main candidate plastid regions (rpoC1, rpoB, accD) and additional plastid markers (psbB, psbN, psbT exons and the trnS-trnG spacer) as well as the nuclear ribosomal spacer region (ITS1-5.8S-ITS2) in a group of land plants belonging to the mahogany family, Meliaceae. Across these samples, only ITS showed high levels of resolvability. Interspecific sharing of sequences from individual plastid loci was common. The combination of multiple loci did not improve performance. DNA barcoding with ITS alone revealed cryptic species and proved useful in identifying species listed in Convention on International Trade of Endangered Species appendixes.


WOX gene phylogeny in Poaceae: a comparative approach addressing leaf and embryo development.
The phylogeny based on the homeodomain (HD) amino acid sequence of the WOX (WUSCHEL-related homeobox gene family) was established in the 3 major radiations of the Poaceae family: Pooideae (Brachypodium distachyon), Bambusoideae (Oryza sativa), and Panicoideae (Zea mays). The genomes of all 3 grasses contain an ancient duplication in the WOX3 branch, and the cellular expression patterns in maize and rice indicate subfunctionalization of paralogues during leaf development, which may relate to the architecture of the grass leaf and the encircling of the stem. The use of maize WOX gene family members as molecular markers in maize embryo development for the first time allowed us to visualize cellular decisions in the maize proembryo, including specification of the shoot/root axis at an oblique angle to the apical-basal polarity of the zygote. All molecular marker data are compatible with the conclusion that the embryonic shoot/root axis comprises a discrete domain from early proembryo stages onward. Novel cell fates of the shoot and the root are acquired within this distinct morphogenic axis domain, which elongates and thus separates the shoot apical meristem and root apical meristem (RAM) anlagen in the maize embryo.


110 km transmission of 160 Gbit/s RZ-DQPSK signals by midspan polarization-insensitive optical phase conjugation in a Ti:PPLN waveguide.
We demonstrate 160 Gbit/s return-to-zero (RZ) differential quarternary phase-shift keying (DQPSK) signal transmission over a 110 km single-mode fiber by taking advantage of mid-span optical phase conjugation (OPC). The technique is based on nonlinear wavelength conversion by cascaded second harmonic and difference frequency generation in a Ti:PPLN waveguide. Error-free operation with a negligible optical signal-to-noise ratio penalty for the signal after the OPC transmission without and with polarization scrambling was achieved. The results also show the polarization insensitivity of the OPC system using a polarization diversity scheme.


Triplet-triplet annihilation photon upconversion from diphenylhexatriene and ring-substituted derivatives in solution.
We report that diphenylhexatriene (DPH) and its ring-substituted derivatives act as emitter molecules in triplet-triplet annihilation photon upconversion (TTA-UC). A palladium porphyrin derivative, meso-tetraphenyl-tetrabenzoporphine palladium complex (PdTPBP), which acts as a sensitiser in TTA-UC, and DPH derivatives were dissolved in tetrahydrofuran (THF). The solution showed blue-green to green UC emission under photoexcitation at 640 nm in a nitrogen atmosphere. The UC quantum efficiency (ηUC) values of the DPHs were estimated, with (E,E,E)-1,6-bis[4-(di-2-picolylamino)phenyl]hexa-1,3,5-triene (pico DPH) showing the highest. In addition, the quantum yields of triplet energy transfer (TET) and triplet-triplet annihilation (TTA), which are elementary processes in TTA-UC, were estimated, as well as the triplet lifetimes of each DPH derivative. The results indicate that the TTA process governs the value of ηUC.


Transmural eosinophilic gastroenteritis with ascites.
An atopic patient with recurrent abdominal pain, diarrhea, and ascites was shown to have eosinophilic gastroenteritis. Transmural involvement was inferred from the findings of dense eosinophilic infiltrates in the jejunal mucosa and eosinophilia in the ascitic fluid. An impressive response to steroid treatment occurred. The reported cases of eosinophilic gastroenteritis with ascites are reviewed.


Ride-Hailing Services and Alcohol Consumption: Longitudinal Analysis.
Alcohol consumption is associated with a wide range of adverse health consequences and a leading cause of preventable deaths. Ride-hailing services such as Uber have been found to prevent alcohol-related motor vehicle fatalities. These services may, however, facilitate alcohol consumption generally and binge drinking in particular. The goal of the research is to measure the impact of ride-hailing services on the extent and intensity of alcohol consumption. We allow these associations to depend on population density as the use of ride-hailing services varies across markets. We exploit the phased rollout of the ride-hailing platform Uber using a difference-in-differences approach. We use this variation to measure changes in alcohol consumption among a local population following Uber's entry. Data are drawn from Uber press releases to capture platform entry and the Behavioral Risk Factor Surveillance Systems (BRFSS) Annual Survey to measure alcohol consumption in 113 metropolitan areas. Models are estimated using fixed-effects Poisson regression. Pre- and postentry trends are used to validate this approach. Ride-hailing has no association with the extent of alcohol consumption in high (0.61 [95% CI -0.05% to 1.28%]) or low (0.61 [95% CI -0.05% to 1.28%]) density markets, but is associated with increases in the binge drinking rate in high-density markets (0.71 [95% CI 0.13% to 1.29%]). This corresponds to a 4% increase in binge drinking within a Metropolitan Statistical Area. Ride-hailing services are associated with an increase in binge drinking, which has been associated with a wide array of adverse health outcomes. Drunk driving rates have fallen for more than a decade, while binge drinking continues to climb. Both trends may be accelerated by ride-hailing services. This suggests that health information messaging should increase emphasis on the direct dangers of alcohol consumption and binge drinking.


Distinct spatial and temporal expression patterns of K+ channel mRNAs from different subfamilies.
Different types of K+ channels play important roles in many aspects of excitability. The isolation of cDNA clones from Drosophila, Aplysia, Xenopus, and mammals points to a large multigene family with several distinct members encoding K+ channels with unique electrophysiological and pharmacological properties. Given the pivotal role K+ channels play in the fine tuning of electrical properties of excitable tissues, we studied the spatial and temporal basis of K+ channel diversity. We report the isolation of two putative K+ channels that define two new subfamilies based upon amino acid sequence similarities with other known K+ channels. Northern blot and in situ hybridization studies revealed differences in the spatial and temporal expression patterns for these two new clones along with mRNAs from other K+ channel subfamilies. Two of the K+ channels studied are predominantly expressed in the brain. One of the "brain-specific" K+ channels is first expressed after about 2 weeks of postnatal cerebellar development and remains at levels about 10-fold higher in the cerebellum than in the rest of the brain.


Gastric partition after reversal of jejunoileal bypass for morbid obesity: three-year follow-up.
The jejunoileal bypass (JIB) has met with increasing disfavor as a result of its unacceptably high complication rate. JIB reversal was done in 54 patients at the University of Florida, with a gastric partition done concomitantly to avoid regaining weight. Weight control was generally adequate up to six months after conversion to gastric partition. However, mean weight gain progressed steadily afterward to a mean increase of 40% at three years. Six months after conversion to gastric partition, 55% of the patients (15/27) had gained weight, contrasted with 3% of 100 patients who had a gastric partition as a primary procedure. The percentage of patients gaining weight progressed until at three-year follow-up 30 of the 38 patients (79%) in this subpopulation showed a failure to control weight. It is apparent from these data that jejunoileal bypass has created a nutritional life-style that predisposes patients to hyperphagia. Conversion to a gastric partition has a much higher incidence of failure than gastric partition done de novo.


The role of frontal sinus drillouts in nasal polyposis.
Historically, the common frontal sinusotomy has been reserved only for salvage frontal sinus surgery in patients with severely recalcitrant inflammatory sinus disease. By understanding the pathophysiology of inflammatory sinus disease and the long-term role of topical medication in their treatment, the indications for Draf3 have expanded. A major therapeutic impact from endoscopic sinus surgery for inflammatory sinus disease is imparted by allowing sinus access to topical therapies to work. Although traditionally, the Draf3 frontal sinus procedure has been reserved for revision surgery in severe cases, advancements in technology, instrumentation, and techniques has allowed the Draf3 to evolve to efficient and safe procedure, often applied primarily in select patients. There is evidence to support the indication for Draf3 in primary surgery for severe cases. In inflammatory sinus disease, the goal of endoscopic sinus surgery is to convert the complex and limited frontal sinus outflow tracts into a simple common cavity. This allows for local, topical anti-inflammatory treatments to control the disease. When patients have broader inflammatory airway disease and asthma, the Draf3, as part of a neo-sinus cavity, is commonly applied early in surgical care.


Rapid corticosteroid tapering: Important risk factor for type 1 autoimmune hepatitis relapse in Japan.
Patients with autoimmune hepatitis (AIH) sometimes relapse after immunosuppressive therapies are discontinued or sometimes even while they are still being administrated. Furthermore, relapse often occurs in the absence of AIH relapse risk factors. This study aimed to identify the frequency of relapse and to analyze the risk factors associated with relapse in type 1 AIH patients. Clinical characteristics and therapeutic processes were assessed in 129 type 1 AIH patients. Relapse was identified in 39 (30.2%) type 1 AIH patients after alanine aminotransferase (ALT) level normalization. ALT levels significantly increased when corticosteroid treatment was initiated in relapsed patients compared with that in patients with sustained remission. The reduction dose and rate of corticosteroid taper were significantly increased in relapsed patients compared with those in sustained remission patients. Moreover, positive correlations were identified between the reduction dose/taper rate and initial corticosteroid dose, and ALT levels, total bilirubin levels and hepatitis activity. Multivariate logistic regression analysis identified the corticosteroid reduction rate as significantly associated with AIH relapse. Corticosteroid reduction taper rate until ALT normalization is an important AIH relapse risk factor.


Regular articles: conditional disruption of hedgehog signaling pathway defines its critical role in hair development and regeneration.
Members of the vertebrate hedgehog family (Sonic, Indian, and Desert) have been shown to be essential for the development of various organ systems, including neural, somite, limb, skeletal, and for male gonad morphogenesis. Sonic hedgehog and its cognate receptor Patched are expressed in the epithelial and/or mesenchymal cell components of the hair follicle. Recent studies have demonstrated an essential role for this pathway in hair development in the skin of Sonic hedgehog null embryos. We have further explored the role of the hedgehog pathway using anti-hedgehog blocking monoclonal antibodies to treat pregnant mice at different stages of gestation and have generated viable offspring that lack body coat hair. Histologic analysis revealed the presence of ectodermal placode and primodium of dermal papilla in these mice, yet the subsequent hair shaft formation was inhibited. In contrast, the vibrissae (whisker) development appears to be unaffected upon anti-hedgehog blocking monoclonal antibody treatment. Strikingly, inhibition of body coat hair morphogenesis also was observed in mice treated postnatally with anti-hedgehog monoclonal antibody during the growing (anagen) phase of the hair cycle. The hairless phenotype was reversible upon suspension of monoclonal antibody treatment. Taken together, our results underscore a direct role of the Sonic hedgehog signaling pathway in embryonic hair follicle development as well as in subsequent hair cycles in young and adult mice. Our system of generating an inducible and reversible hairless phenotype by anti-hedgehog monoclonal antibody treatment will be valuable for studying the regulation and mechanism of hair regeneration.


Catecholamine sensitivity in brown fat cells from cold-acclimated hamsters and rats.
Brown fat cells, freshly isolated from cold-acclimated hamsters and rats, did not respond to norepinephrine addition with the characteristic increase in oxygen consumption (heat production) seen in cells from control animals. However, incubation of these cells for 1 h in a Krebs-Ringer bicarbonate buffer, in the presence of 10 mM pyruvate, fully restored norepinephrine responsiveness. Cells treated in this way from cold-acclimated hamsters (a hibernator) increased the rate of oxygen consumption after maximal norepinephrine stimulation as much as cells from control hamsters; also norepinephrine-stimulated fatty acid release was unaltered, indicating that brown fat cells may partly be responsible for the increase in serum fatty acid level seen during arousal from hibernation. Similarly, preincubated cells from cold-acclimated rats (a nonhibernator) increased oxygen consumption and fatty acid release as much as cells from control rats; this suggests that also in cold-acclimated rats brown fat may supply the circulation with fatty acids during cold stress. Cells from cold-acclimated animals were, however, about 10 times less sensitive to norepinephrine than cells from control animals; this desensitization may be the result of a stimulated phosphodiesterase.


Delivering Integrative Restoration-Yoga Nidra Meditation (iRest®) to Women with Sexual Trauma at a Veteran's Medical Center: A Pilot Study.
This pilot study examines iRest, a form of guided mindfulness meditation, and its ability to reduce symptoms associated with sexual trauma, including military sexual trauma (MST), in a sample of women seeking psychotherapy services at a Department of Veterans Affairs (VA) medical center. 90-minute sessions were held 19 times, twice a week for 10 weeks, except for the week with a holiday. Participants completed self-report measures Brief Symptom Inventory-18 (BSI), Posttraumatic Cognitions Inventory (PTCI), and the Post-traumatic Stress Disorder Check List (PCL) pre- and post-treatment. Sixteen women were recruited: 15 enrolled, 5 dropped due to transportation issues, and 10 completed the protocol. Completers reported significant decreases in symptoms of posttraumatic stress disorder (PCL, t (9) = 3.17, p < 0.01, d = 0.66), negative thoughts of self-blame (PTCI t (9) = 2.96, p < 0.05, d = 0.52), and depression (BSI, t (9) = 2.33, p < 0.05, d = 0.64). Participants also offered verbal reports of decreased body tension, improved quality of sleep, improved ability to handle intrusive thoughts, improved ability to manage stress, and an increased feeling of joy. Participants also enthusiastically endorsed the class and stated they would take it again and recommend it to others. This small pilot study showed promising results for delivering iRest to women with sexual trauma in a VA medical center. Further research is warranted.


Pulmonary valve restitution following transannular patch repair of tetralogy of Fallot.
Chronic pulmonary insufficiency following transannular patch repair of tetralogy of Fallot may mandate restoration of a competent pulmonary valve. Pulmonary valve leaflets that are preserved at initial surgery may grow and develop normal morphology and subsequent valve repair may be possible. We reviewed our experience with native pulmonary valve restitution following transannular patch repair (2001-15). The cohort included 9 patients with a median age of 18.7 (range 10.6-31.3) years. Operative technique involved reapproximation of the anterior commissure of the pulmonary valve. Median length of stay was 3 days, and there were no deaths. At median follow-up of 2.0 (0.4-13.5) years, pulmonary insufficiency was graded as ≤mild (n = 4), mild-moderate or moderate (n = 4) and moderate-severe (n = 1); pulmonary stenosis was ≤mild (n = 8) and moderate (n = 1), with median peak gradient of 21 (16-64) mmHg. No patient required reintervention. At reoperation to treat pulmonary insufficiency in repaired TOF, if residual leaflets are found with favourable anatomy, restitution of the native valve should be considered. This valve-preserving technique avoids the certain failure of a bioprosthesis and is associated with favourable early outcomes. The viability of this option may influence surgeons to leave the pulmonary leaflets in situ at the time of initial repair.


Enzymatic PET Degradation.
Plastic, in the form of packaging material, disposables, clothing and other articles with a short lifespan, has become an indispensable part of our everyday life. The increased production and use of plastic, however, accelerates the accumulation of plastic waste and poses an increasing burden on the environment with negative effects on biodiversity and human health. PET, a common thermoplastic, is recycled in many countries via thermal, mechanical and chemical means. Recently, several enzymes have been identified capable of degrading this recalcitrant plastic, opening possibilities for the biological recycling of the omnipresent material. In this review, we analyze the current knowledge of enzymatic PET degradation and discuss advances in improving the involved enzymes via protein engineering. Looking forward, the use of plastic degrading enzymes may facilitate sustainable plastic waste management and become an important tool for the realization of a circular plastic economy.


Small cell osteosarcoma: cytopathologic characteristics and differential diagnosis.
Small cell osteosarcoma may present a challenging primary diagnosis on cytologic assessment owing to its rarity and its morphologic similarity to other small round blue cell tumors. Five cases of small cell osteosarcoma from our cytopathology archives were identified and reviewed and cytologic features elaborated. Three cases were fine-needle aspirations from bony lesions in the classic location for osteosarcoma (2 distal femur and 1 proximal tibia), and 2 aspirations were from metastases. Common cytomorphologic features included relatively small to intermediate cell size, high nuclear/cytoplasmic ratios, round nuclei, minimal anisonucleosis, finely granular nuclear chromatin, fine cytoplasmic vacuoles, and only rare osteoid. Small cell osteosarcoma shares many of the well-described cytomorphologic features of classic osteosarcoma, but the relatively small cells, round hyperchromatic nuclei, and scant osteoid constitute the common denominator. Correlation with radiographic findings and ancillary tests can aid in definitive diagnosis.


The incidence of radiation necrosis following stereotactic radiotherapy for melanoma brain metastases: the potential impact of immunotherapy.
Stereotactic radiotherapy (SRT) is the standard treatment for patients with limited number of brain metastases. In the past few years, newer immunotherapies (immune checkpoint inhibitors) have been proven to prolong survival in patients with metastatic melanoma. The safety of the combination of SRT and immunotherapy for brain metastases is unknown. We retrospectively identified patients with melanoma brain metastases treated with SRT between 2007 and 2015. Patients who did not have at least 3 months of follow-up with imaging after SRT were excluded from the analysis. Outcomes were compared between patients who were treated with or without immunotherapy. A total of 58 patients were included; of these, 29 were treated with SRT and immunotherapy. MAPK inhibitors (BRAF, MEK inhibitors) were used more often in the immunotherapy group (nine vs. two patients). There was a higher incidence of intracranial complications in patients treated with immunotherapy and SRT. Eight patients had radiation necrosis; all occurred in patients who were treated with immunotherapy. Nine patients had hemorrhage, of which seven occurred in patients who were treated with immunotherapy (P=0.08). However, patients treated with immunotherapy and SRT had a significant overall survival advantage compared with SRT without immunotherapy (15 vs. 6 months, P=0.0013). Patients treated with SRT and immunotherapy have a higher incidence/risk of intracranial complications, but a longer overall survival.


Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer.
Numerous studies have established a causal link between aberrant mammalian target of rapamycin (mTOR) activation and tumorigenesis, indicating that mTOR inhibition may have therapeutic potential. In this study, we show that rapamycin and its analogs activate the MAPK pathway in human cancer, in what represents a novel mTORC1-MAPK feedback loop. We found that tumor samples from patients with biopsy-accessible solid tumors of advanced disease treated with RAD001, a rapamycin derivative, showed an administration schedule-dependent increase in activation of the MAPK pathway. RAD001 treatment also led to MAPK activation in a mouse model of prostate cancer. We further show that rapamycin-induced MAPK activation occurs in both normal cells and cancer cells lines and that this feedback loop depends on an S6K-PI3K-Ras pathway. Significantly, pharmacological inhibition of the MAPK pathway enhanced the antitumoral effect of mTORC1 inhibition by rapamycin in cancer cells in vitro and in a xenograft mouse model. Taken together, our findings identify MAPK activation as a consequence of mTORC1 inhibition and underscore the potential of a combined therapeutic approach with mTORC1 and MAPK inhibitors, currently employed as single agents in the clinic, for the treatment of human cancers.


How do impulsivity traits influence problem gambling through gambling motives? The role of perceived gambling risk/benefits.
Although substantial research suggests that motivations have been found to mediate the relationships between impulsivity traits and various forms of substance use, no studies have examined how gambling motives may mediate the relationships between impulsivity traits and problem gambling. The primary purpose of this study was to test an integrative model linking impulsivity traits and gambling problems, evaluating the mediating effects of gambling motives. Participants were 594 students (73% male; age, M = 19.92 years; SD = 2.91) enrolled in public high schools or universities. Young people who tend to act rashly in response to extremely positive moods showed higher enhancement and coping motives, which in turn were positively related to gambling problems. Individuals with higher levels of sensation seeking were more likely to have higher levels of enhancement motives, which in turn were also positively related to gambling problems. The model was examined in several groups, separately for the level of perceived gambling risk/benefits (lower perceived gambling risk, higher perceived gambling risk, lower perceived gambling benefits, and higher perceived gambling benefits). There were significant differences between these groups for this division. These findings suggest that prevention and/or treatment strategies might need to consider the model's variables, including impulsivity traits and gambling motives, in accordance with individual levels of perceived gambling risk/benefits.


Identification of a premature stop codon mutation in the PHGDH gene in severe Neu-Laxova syndrome-evidence for phenotypic variability.
In some cases Neu-Laxova syndrome (NLS) is linked to serine deficiency due to mutations in the phosphoglycerate dehydrogenase (PHGDH) gene. We describe the prenatal and postnatal findings in a fetus with one of the most severe NLS phenotypes described so far, caused by a homozygous nonsense mutation of PHGDH. Serial ultrasound (US) and pre- and postnatal magnetic resonance imaging (MRI) evaluations were performed. Prenatally, serial US evaluations suggested symmetric growth restriction, microcephaly, hypoplasia of the cerebellar vermis, micrognathia, hydrops, shortened limbs, arthrogryposis, and talipes equinovarus. The prenatal MRI confirmed these findings prompting a diagnosis of NLS. After birth, radiological imaging did not detect any gross bone abnormalities. DNA was extracted from fetal and parental peripheral blood, all coding exons of PHGDH were PCR-amplified and subjected to Sanger sequencing. Sequencing of PHGDH identified a homozygous premature stop codon mutation (c.1297C>T; p.Gln433*) in fetal DNA, both parents (first-cousins) being heterozygotes. Based on previous associations of mutations in this gene with a milder NLS phenotype, as well as cases of serine deficiency, these observations lend further support to a genotype-phenotype correlation between the degree of PHGDH inactivation and disease severity.


A meta-analysis of B-mode ultrasound, Doppler ultrasound, and computed tomography to diagnose pediatric ovarian torsion.
Ovarian torsion (OT) is a true surgical emergency that requires prompt diagnosis and therapy. There are conflicting reports on the accuracy of different imaging modalities for OT. In this study, we performed a meta-analysis of all the published studies on B-mode ultrasound (US, morphological criteria), Doppler US (DUS, flow criteria), and computed tomography (CT) for the diagnosis of OT. Methods: The medical literature from 1987 to 2013 was searched for studies that evaluated US, DUS, CT, or combination of these techniques to diagnose OT in children using PubMed/MEDLINE database. The studies were screened and included if the quality criteria were met. Data were extracted using a standardized form. Reported sensitivities and specificities were pooled with 95% confidence intervals using a RevMan version 5.1 software (The Cochrane Collaboration, Oxford, United Kingdom). A total of 18 US studies with 716 combined patients were included, along with 15 DUS studies comprising of 1,021 patients, and 5 CT studies with a total of 107 patients. All studies reported sensitivities, while only few selected studies also reported specificities. Using morphological criteria on B-mode US (including absolute or relative ovarian size, echotexture, location, and configuration) yielded high sensitivity and specificity (average 92 and 96%, respectively); DUS was highly specific, but lacked sensitivity, while CT was the least sensitive test. CT specificities could not be calculated from the available data. This study found considerable variability of the reported sensitivities and specificities for the diagnosis of OT across all evaluated imaging modalities. Interestingly, B-mode US was the most sensitive and specific examination to detect OT. Some authors reported high diagnostic accuracy of DUS as well, but these findings have not been universally reproduced. CT had low overall sensitivity and is not recommended for the workup of suspected OT.


Effects of Holding Density on the Welfare of Zebrafish: A Systematic Review.
The zebrafish is becoming an increasingly popular research animal around the world. Its welfare is affected by an array of environmental factors, such as food access and water quality. Holding density is an important welfare aspect, not least due to its interaction with other housing conditions. Despite the extensive use of zebrafish in research, little is known of how densities affect its welfare. In this systematic review, we have performed a large literature search, compiled, and evaluated all publications regarding zebrafish holding density. We have analyzed how density effects growth, reproduction, and stress response, including behavior, water quality, and pathogenic outbreaks in young and adult fish. Our review shows that the holding densities tested vary largely depending on the research focus, for example, body growth or behavior. In fact, research indicates that future recommendations on holding density could depend on which welfare aspects are considered. Overall, there is a need for more studies investigating the interactive effects of density on welfare indicators, such as reproduction coupled with stress response. We stress the necessity of including holding density in universal housing guidelines and reporting information on holding conditions of larvae and adults when publishing zebrafish work.


Coexistence of Low Muscle Mass and Osteoporosis as a Predictor of Fragility Fractures in Long-Term Kidney Transplant Recipients.
Sarcopenia and osteoporosis are highly prevalent among kidney transplant recipients (KTRs). Although osteoporosis is known to increase fracture risk in KTRs, it is unclear whether sarcopenia or osteosarcopenia is associated with this increased risk. Thus, we aimed to investigate the association of the coexistence of low muscle mass (LMM) and osteoporosis with the risk of fracture in long-term KTRs. Exactly 342 stable KTRs underwent dual-energy X-ray absorptiometry and skeletal muscle mass index (SMI) measurement using bioelectrical impedance analysis. LMM and osteoporosis were observed in 109 (31.9%) and 93 patients (27.2%), respectively. During a follow-up period of 5.1 years, 48 (14.0%) fractures occurred. KTRs with LMM had a higher fracture risk, but this was not significant (adjusted hazard ratio [aHR] 1.82, 95% confidence interval [CI] 0.94-3.50, p = 0.073). Similar results were obtained in KTRs with osteoporosis (aHR 1.84, 95% CI 0.96-3.47, p = 0.063). We divided the KTRs into four groups according to the presence of LMM and/or osteoporosis. The cumulative incidence rates of fractures were 13.0%, 11.1%, 10.5%, and 31.3% in the KTRs without both LMM and osteoporosis, those with LMM alone, those with osteoporosis alone, and those with both, respectively. The KTRs with both LMM and osteoporosis had a 2.92fold higher risk of fractures (95% CI 1.29-6.49; p = 0.010) than those without both LMM and osteoporosis. Long-term KTRs with the coexistence of LMM and osteoporosis had an independently higher risk of fragility fractures than those without both LMM and osteoporosis. The combination of SMI and osteoporosis definitions can be used to identify KTRs with a high fracture risk.


Atherosclerosis and myocardial lesions in subjects dying from fresh cerebrovascular disease.
TAKING INTO ACCOUNT AGE, SEX, GEOGRAPHICAL DISTRIBUTION, OBESITY, AND ASSOCIATED CAUSE OF DEATH, IT WAS CONCLUDED THAT: (1) the extent of aortic calcification was much lower in cerebral haemorrhage than in cerebral infarct. In deaths due to cerebral haemorrhage aortic calcification was at about the same level as in those due to cancer of the stomach, while in deaths due to cerebral infarct it was at the same level as in those due to coronary heart disease; (2) the prevalence of large myocardial scar was low in deaths due to cerebral haemorrhage (at about the same level as in those due to prostatic cancer), while in deaths due to cerebral infarct it was more frequent (at the same level as in deaths due to diabetes); (3) the extent of coronary calcification and prevalence of coronary stenosis and fresh myocardial infarction were low in the cerebral haemorrhage and cerebral infarct deaths, but a little lower in the former; and (4) the extent of raised lesions of the aorta and coronary arteries was similar in the cerebral haemorrhage and cerebral infarct deaths, the level of aortic lesions being high and overlapping in level with those in the coronary heart disease and hypertensive deaths, and the levels of coronary lesions being much lower and well below those in the coronary and diabetic hypertensive deaths.


[Aspergillosis of maxillary sinus: a case report].
A case of semi-invasive maxillary aspergillosis that presented with epiphora and responded well to surgical treatment is reported. Sixteen percent of cases of chronic sinusitis are produced by mycosis (particularly aspergillosis). The infection may be limited to the affected sinus (non-invasive forms) or may destroy the sinus wall, without tissue invasion (semi-invasive forms) or with tissue invasion (invasive forms). The diagnosis is mainly histological. Cultures present a high percentage of false positives and negatives. Treatment consists of surgical debridement of the sinus. Systemic amphotericin B is reserved for invasive aspergillosis (particularly fulminant cases).


Effects of vitamin D and resveratrol on metabolic associated markers in liver and adipose tissue from SAMP8 mice.
SAMP8 mice exhibit multiple metabolic characteristics associated with age, and it is a suitable candidate for researching aging associated metabolic dysfunction. We aimed to 1) explore how key metabolic markers will be altered in both liver and adipose tissue with aging in SAMP8 mice; and 2) how the combination of vitamin D (VD) with resveratrol (RSV) will affect aging associated metabolic impairment in liver and adipose tissue from SAMP8 mice. SAMP8 mice and their control SAMR1 mice were divided into 5 groups, i.e. SAMR1, SAMP8, SAMP8 mice supplemented with VD, RSV and VD combined with RSV group, respectively. At the end of the intervention, glucose and insulin tolerance, p-AMP-activated protein kinase (AMPK) and amyloid precursor protein (APP), and endoplasmic reticulum (ER) stress markers in liver and adipose tissue, adiponectin secretion, p-NF-κBp65 and TNF-α protein expression in adipose tissue were determined. Compared to SAMR1 control, SAMP8 mice demonstrate impaired glucose tolerance and reduction in circulating adiponectin level; in the liver, SAMP8 mice have reduction in p-Aktser473, elevation in PTP1B and APP, p-eIF2α, GRP78 and p-JNK protein expression. In epididymal (EPI) fat, SAMP8 mice also have elevated p-Aktser473 and PTP1B compared to SAMR1 mice. In both epididymal (EPI) and subcutaneous (SC) fat, there were elevated ER stress markers, reduced p-AMPK and elevated APP, as well as elevated p-NF-κBp65 and TNF-α protein expression from SAMP8 compared to SAMR1 mice. In liver, the combined intervention significantly restored p-Aktser473, p-eIF2α and p-JNK protein expression. In both EPI and SC fat, the combined intervention is effective for reducing p-NF-κB p65 and TNF-α in both fat depot, while only partially reduced ER stress markers in SC fat. As for adiponectin, their combination is unable to reverse reduction in adiponectin level. Adiponectin secretion in SC fat from VD, RSV and VDRSV group were also significantly reduced compared to SAMR1. The combined intervention might exert greater beneficial effects for reversing aging associated metabolic dysfunction in liver and adipose tissue from SAMP8 mice.


Robotic mitral valve replacement; results from the world's largest series.
This study evaluates the clinical outcome of patients with robotic mitral valve replacement (MVR). Between January 2010 and April 2022, 117 consecutive patients underwent robotic MVR with or without additional cardiac procedures. All procedures were completed by a single surgical team with Da Vinci Robotic Systems. Perioperative variables and early clinical outcomes were recorded. Mean age and EuroScore II of the patients were 57.1±12.9 and 5.1±5.7, respectively. Isolated MVR was performed in 55 (47.0%) patients and combined cardiac procedures were performed in 62 (53.0%) patients. Additional procedures included: ablation for atrial fibrillation, tricuspid valve replacement, tricuspid valve repair, left atrial appendix ligation, patent foramen ovale closure, left atrial thrombectomy and septal myectomy for hypertrophic obstructive cardiomyopathy. Mean cardiopulmonary bypass time and cross clamp time were 143±54 and 93±37 minutes, respectively. Mean intensive care unit stay time was 26.5±26.0 hours. Postoperative stroke was observed in one (0.9%) patient and new onset renal failure was observed in two (1.7%) patients. Perioperative and postoperative early mortality was observed in three (2.6%) patients, which was lower than expected. Robotic MVR is feasible and can be performed with good early postoperative outcomes. A majority of the patients require additional cardiac procedures.


Role of Functional Magnetic Resonance Imaging Derived Parameters as Imaging Biomarkers and Correlation with Clinicopathological Features in Carcinoma of Uterine Cervix.
Magnetic Resonance Imaging (MRI) is emerging as a powerful tool in the evaluation and management of cervical cancer. The role of Diffusion Weighted Imaging (DWI) with Apparent Diffusion Coefficient (ADC) as a non-invasive imaging biomarker is promising in characterization of the tumour and prediction of response. The aim of this study was to evaluate the role of conventional MRI and diffusion weighted MRI in predicting clinicopathological prognostic factors. This was a retrospective study. The data of 100 cervical cancer patients who had MRI with DWI was retrieved from the database and analysed. Clinico pathological details were collected from the computerized hospital information system. SPSS version 15.0 was used for statistical analysis. The mean tumour dimensions on MRI in x, y and z axes were 43.04 mm (±13.93, range: 17-85), 37.05mm (±11.83, range: 9-80) and 39.63 mm (±14.81, range: 14 -76). The mean T2W MRI based tumour volume (TV) was 48.18 (±34.3, range: 7-206) and on DWI images was 36.68(±33.72, range: 2.5-200). The mean ADC value in patients with squamous cell carcinoma was 0.694 (±0.125, n=88), adenocarcinoma was 0.989 (±0.309, n=6), adenosquamous was 0.894 (±0.324, n=4). There was statistical significant difference in mean ADC between squamous vs. non squamous histology (p = 0.02). The mean ADC values of well differentiated, moderately differentiated, and poorly differentiated tumours were 0.841(±0.227, n= 26), 0.729 (±0.125, n=28), 0.648 (±0.099, n=46) respectively. There was significant statistical difference of mean ADC between well differentiated, moderately differentiated (p=0.020) and poorly differentiated tumours (p=0.0001). Difference between the mean ADC values between the node positive and node negative disease was statistically significant (p=0.0001). There was no correlation between the tumour volumes on T2W and DWI images and ADC values. Sixteen patients had residual/recurrent disease at a median follow up of 12 months (range: 3-59 months). The mean ADC values in this group was 0.71 (n=16) and was not significantly different from the disease free group (mean ADC =0.72, n=74). Higher ADC values are associated with favourable histology and differentiation. Adenocarcinomas have higher ADC values followed by adenosquamous followed by squamous cell carcinomas. Well differentiated tumours had higher ADC values than moderately followed by poorly differentiated tumours. DWI with ADC have a potential role as an imaging biomarker for prognostication and needs further studies for routine clinical applications.


Utilizing Student Health and Academic Data: A County-Level Demonstration Project.
Students with chronic health conditions miss more school days than their peers and are at increased risk for performing worse on standardized tests and not completing a high school degree. University-based researchers, state government leaders, and a local county school system collaborated to use existing health and academic data to (1) evaluate the strength of the relationship between health status and school performance (absenteeism, grades) and (2) describe the health status of students who are chronically absent. Analyses included descriptive statistics, chi-square tests, negative binomial regression models, and estimated marginal means. The most common health conditions among the 3,663 kindergarten through Grade 12 students were ADD (attention deficit disorder)/ADHD (attention deficit hyperactivity disorder), asthma, migraine headaches, mental health conditions, and eczema/psoriasis/skin disorders. After controlling for covariates, having asthma or a mental health diagnosis was positively associated with absences; and having an ADD/ADHD or mental health diagnosis was negatively associated with GPA (grade point average). Chronically absent students had significantly lower GPAs, and a higher number of health conditions than other students. The success of this demonstration project encourages strengthening existing collaborations and establishing new multidisciplinary partnerships to analyze existing data sources to learn more about the relationship between student health and academic achievement. Moreover, connecting health status to academic achievement might be a chief tactic for advocating for additional resources to improve the care and management of chronic disease conditions among students.


Abi1 is essential for the formation and activation of a WAVE2 signalling complex.
WAVE2 belongs to a family of proteins that mediates actin reorganization by relaying signals from Rac to the Arp2/3 complex, resulting in lamellipodia protrusion. WAVE2 displays Arp2/3-dependent actin nucleation activity in vitro, and does not bind directly to Rac. Instead, it forms macromolecular complexes that have been reported to exert both positive and negative modes of regulation. How these complexes are assembled, localized and activated in vivo remains to be established. Here we use tandem mass spectrometry to identify an Abi1-based complex containing WAVE2, Nap1 (Nck-associated protein) and PIR121. Abi1 interacts directly with the WHD domain of WAVE2, increases WAVE2 actin polymerization activity and mediates the assembly of a WAVE2-Abi1-Nap1-PIR121 complex. The WAVE2-Abi1-Nap1-PIR121 complex is as active as the WAVE2-Abi1 sub-complex in stimulating Arp2/3, and after Rac activation it is re-localized to the leading edge of ruffles in vivo. Consistently, inhibition of Abi1 by RNA interference (RNAi) abrogates Rac-dependent lamellipodia protrusion. Thus, Abi1 orchestrates the proper assembly of the WAVE2 complex and mediates its activation at the leading edge in vivo.


Global and regional erosion of mammalian functional diversity across the diel cycle.
Biodiversity is declining worldwide. When species are physically active (i.e., their diel niche) may influence their risk of becoming functionally extinct. It may also affect how species losses affect ecosystems. For 5033 terrestrial mammals, we predict future changes to diel global and local functional diversity through a gradient of progressive functional extinction scenarios of threatened species. Across scenarios, diurnal species were at greater risk of becoming functionally extinct than nocturnal, crepuscular, and cathemeral species, resulting in deep functional losses in global diurnal trait space. Redundancy (species with similar roles) will buffer global nocturnal functional diversity; however, across the land surface, losses will mostly occur among functionally dispersed species (species with distinct roles). Functional extinctions will constrict boundaries of cathemeral trait space as megaherbivores, and arboreal foragers are lost. Variation in the erosion of functional diversity across the daily cycle will likely profoundly affect the partitioning of ecosystem functioning between night and day.


Agrobacterium-mediated floral dip transformation of the model polyploid species Arabidopsis kamchatica.
Polyploidization has played an important role in the speciation and diversification of plant species. However, genetic analyses of polyploids are challenging because the vast majority of the model species are diploids. The allotetraploid Arabidopsis kamchatica, which originated through the hybridization of the diploid Arabidopsis halleri and Arabidopsis lyrata, is an emerging model system for studying various aspects of polyploidy. However, a transgenic method that allows the insertion of a gene of interest into A. kamchatica is still lacking. In this study, we investigated the early development of pistils in A. kamchatica and confirmed the formation of open pistils in young flower buds (stages 8-9), which is important for allowing Agrobacterium to access female reproductive tissues. We established a simple Agrobacterium-mediated floral dip transformation method to transform a gene of interest into A. kamchatica by dipping A. kamchatica inflorescences bearing many young flower buds into a 5% sucrose solution containing 0.05% Silwet L-77 and Agrobacterium harboring the gene of interest. We showed that a screenable marker comprising fluorescence-accumulating seed technology with green fluorescent protein was useful for screening the transgenic seeds of two accessions of A. kamchatica subsp. kamchatica and an accession of A. kamchatica subsp. kawasakiana.


Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline.
To update the "Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline," published by the Endocrine Society in 2008. The participants include an Endocrine Society-appointed task force of seven medical experts and a methodologist. This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. Group meetings, conference calls, and e-mail communications facilitated consensus development. Endocrine Society committees, members, and cosponsoring organizations reviewed and commented on preliminary drafts of the guidelines. We suggest testing for elevated androgen levels in all women with an abnormal hirsutism score. We suggest against testing for elevated androgen levels in eumenorrheic women with unwanted local hair growth (i.e., in the absence of an abnormal hirsutism score). For most women with patient-important hirsutism despite cosmetic measures (shaving, plucking, waxing), we suggest starting with pharmacological therapy and adding direct hair removal methods (electrolysis, photoepilation) for those who desire additional cosmetic benefit. For women with mild hirsutism and no evidence of an endocrine disorder, we suggest either pharmacological therapy or direct hair removal methods. For pharmacological therapy, we suggest oral combined estrogen-progestin contraceptives for the majority of women, adding an antiandrogen after 6 months if the response is suboptimal. We recommend against antiandrogen monotherapy unless adequate contraception is used. We suggest against using insulin-lowering drugs. For most women who choose hair removal therapy, we suggest laser/photoepilation.


Thermodynamic Characterization of the Interaction of Biofunctionalized Gold Nanoclusters with Serum Albumin Using Two- and Three-Dimensional Methods.
Fluorescent gold nanoclusters have been successfully used as fluorescent markers for imaging of cells and tissues, and their potential role in drug delivery monitoring is coming to the fore. In addition, the development of biosensors using structure-tunable fluorescent nanoclusters is also a prominent research field. In the case of these sensor applications, the typical goal is the selective identification of, e.g., metal ions, small molecules having neuroactive or antioxidant effects, or proteins. During these application-oriented developments, in general, there is not enough time to systematically examine the interaction between nanoclusters and relevant biomolecules/proteins from a thermodynamic viewpoint. In this way, the primary motivation of this article is to carry out a series of tests to partially fill this scientific gap. Besides the well-known fluorescent probes, the mentioned interactions were investigated using such unique measurement methods as surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC). These two-dimensional (at the solid/liquid interface) and three-dimensional (in the bulk phase) measuring techniques provide a unique opportunity for the thermodynamic characterization of the interaction between different gold nanoclusters containing various surface functionalizing ligands and bovine serum albumin (BSA).


Rigid head-neck responses to unpredictable perturbations in patients with long standing neck pain does not change with treatment.
In a previous study we have shown that patients with long standing non-specific neck-pain display more rigid neck movement behavior than controls in response to unpredictable perturbations. In the present study we investigated head/neck motor control in patients with neck-pain during a course of physiotherapy intervention and the associations with pain, neck disability and kinesiophobia. In this longitudinal observational study, 72 patients with non-specific neck-pain were exposed to unpredictable horizontal rotations by means of an actuated chair in three conditions; with a visual reference, and without vision with and without a cognitive task before first consultation with physiotherapist, after 2 weeks and 2 months of intervention. The neck movements were analyzed in the frequency domain to cover voluntarily and reflex controlled responses. Questionnaires encompassed Neck Disability Index, Tampa Scale of Kinesiophobia, and the Numerical Rating Scale for current pain. The results showed that the response pattern for the amplitudes of movement between head and trunk across frequencies did not change over time, whereas some changes in timing were found for some frequencies. Pain, neck disability, and kinesiophobia improved after intervention, but were not significantly associated with neck movement responses to perturbations across time or condition. Although physiotherapy intervention improved self-reported function, the rigid responses to unpredictable perturbations remained unchanged. This indicates altered function in reflex mediated control mechanisms, i.e., the vestibulocollic and the cervicocollic reflex systems that control the head in space and on the trunk. Future research should further investigate pain related changes in reflex systems and whether alterations in these systems are modifiable.


Ergonomic analysis of robot-assisted and traditional laparoscopic procedures.
Many laparoscopic surgeons report musculoskeletal symptoms that are thought to be related to the ergonomic stress of performing laparoscopy. Robotic surgical systems may address many of these limitations. To date, however, there have been no studies exploring the quantitative ergonomics of robotic surgery. In this study, we sought to compare the activation of bilateral biceps, triceps, deltoid, and trapezius muscle groups during traditional laparoscopic surgery (TLS) and robot-assisted laparoscopic surgery (RALS) procedures, as quantified by surface electromyography (sEMG). One surgeon with expertise in TLS and RALS performed 18 operative procedures (13 TLS, 5 RALS) while sEMG measurements were obtained from bilateral biceps, triceps, deltoid, and trapezius muscles. sEMG measurements were normalized to the maximum voluntary contraction of each muscle (%MVC). We compared mean %MVC values for each muscle group during TLS and RALS with unpaired t-tests and considered differences with a p value <0.05 to be statistically significant. Muscle activation was higher during TLS compared to RALS in bilateral biceps (L Biceps RALS:1.01%MVC, L Biceps TLS:3.14, p = 0.01; R Biceps RALS:1.81%MVC, R Biceps TLS:4.53, p = 0.0002). Muscle activation was higher during TLS compared to RALS in bilateral triceps (L Triceps RALS:1.73%MVC, L Triceps TLS:3.58, p = 0.04; R Triceps RALS:1.59%MVC, R Triceps TLS:5.11, p = 0.02). Muscle activation was higher during TLS compared to RALS in bilateral deltoids (L Deltoid RALS:1.50%MVC, L Deltoid TLS:3.68, p = 0.03; R Deltoid RALS:1.19%MVC, R Deltoid TLS:2.57, p = 0.01). Significant differences were not detected in the bilateral trapezius muscles (L Trapezius RALS:1.50 %MVC, L Trapezius TLS:3.68, p = 0.03; R Trapezius RALS:1.19%MVC, R Trapezius TLS:2.57, p = 0.01). We have quantitatively examined the ergonomics of TLS and RALS and shown that in a single surgeon, TLS procedures are associated with significantly elevated biceps, triceps, and deltoid activation bilaterally when compared to RALS procedures.


Science, dullness and truth: a rejoinder.
In a recent series of polemical editorials in this journal, a scathing and much needed criticism is made of many aspects of current scientific mores, detecting some worrying dysfunctions which threaten the integrity of the whole scientific enterprise. Although the tone is a bit hyperbolic, many important issues are addressed, such as honesty in research, the centrality of truth in science, the role of creativity, just to cite a few. Though agreeing with the overall diagnosis, the discussion still suffers from a lack of a clear and systemic view of science, from which a more precise analysis could be carried out. The presentation is also predicated on a too strong adherence to some popular notions of scientific progress and a somewhat romantic notion of genius. In this paper we address these shortcomings with the aim of contributing to a better understanding of this timely discussion. Though conceding that major structural, historical and cultural shifts might have caused irreversible changes on the way science now evolves, we make some suggestions to counter this trend. These include, among others, the need for an honest and careful dealing with the media and public, to prize and abide by the ethos of science and its underlying values, to cultivate an exact philosophy and to insist that disinterested curiosity and the desire to understand the world are the vital motivations of science.


Direct measurement of bone resorption and calcium conservation during vitamin D deficiency or hypervitaminosis D.
When bone is remodeled during the growth of a given size bone to a larger size, some bone is resorbed and some is deposited. Much of the resorbed bone mineral, calcium, can be reutilized during bone formation. The net and absolute effects of normal growth, vitamin D deficiency, or vitamin D excess were compared on bone resorption, bone formation, and calcium reutilization. Growing chicks were prelabeled extensively with three isotopes: (45)Ca, [(3)H]tetracycline, and [(3)H]proline. Data were obtained weekly during 3 weeks of control growth, vitamin D deficiency, or vitamin D overdosage while on a nonradioactive diet. Bone resorption as measured by increases in the marrow (inner) diameter of the midshaft of the femur and humerus and by the weekly losses of total [(3)H]tetracycline and [(3)H]collagen per whole bone was not significantly different among any of the groups studied. The data indicated that the high rate of cortical bone resorption in experimental chicks was not increased above that observed in experimental chicks was not increased above that observed in control chicks. Vitamin D deficiency had little effect on the total (45)Ca in whole bones, whereas vitamin D-treated chicks lost 40% of their (45)Ca. Thus, vitamin D overdosage resulted in a decrease of (45)Ca reutilization, whereas vitamin D deficiency resulted in an apparent increase of (45)Ca reutilization. Both vitamin D-deficient and vitamin D-treated chicks had a decreased accumulation of dietary calcium per whole bone. The insufficient mineral mass in vitamin D-deficient chicks resulted from the indirect inhibition of bone mineralization due to the low intestinal absorption of calcium rather than from a change in bone resorption. In vitamin D-treated chicks the apparent bone atrophy and net loss of (45)Ca from bone resulted from inhibiting bone matrix formation and mineralization instead of increasing bone resorption. The constancy of bone resorption under these experimental conditions suggests that bone mineralization is the major regulator of bone mass.


AbobotulinumtoxinA (Dysport®), OnabotulinumtoxinA (Botox®), and IncobotulinumtoxinA (Xeomin®) Neurotoxin Content and Potential Implications for Duration of Response in Patients.
Botulinum neurotoxin type-A (BoNT-A) blocks the release of acetylcholine from peripheral cholinergic nerve terminals and is an important option for the treatment of disorders characterised by excessive cholinergic neuronal activity. Several BoNT-A products are currently marketed, each with unique manufacturing processes, excipients, formulation, and non-interchangeable potency units. Nevertheless, the effects of all the products are mediated by the 150 kDa BoNT-A neurotoxin. We assessed the quantity and light chain (LC) activity of BoNT-A in three commercial BoNT-A products (Dysport®; Botox®; Xeomin®). We quantified 150 kDa BoNT-A by sandwich ELISA and assessed LC activity by EndoPep assay. In both assays, we assessed the results for the commercial products against recombinant 150 kDa BoNT-A. The mean 150 kDa BoNT-A content per vial measured by ELISA was 2.69 ng/500 U vial Dysport®, 0.90 ng/100 U vial Botox®, and 0.40 ng/100 U vial Xeomin®. To present clinically relevant results, we calculated the 150 kDa BoNT-A/US Food and Drug Administration (FDA)-approved dose in adult upper limb spasticity: 5.38 ng Dysport® (1000 U; 2 × 500 U vials), 3.60 ng Botox® (400 U; 4 × 100 U vials), and 1.61 ng Xeomin® (400 U; 4 × 100 U vials). EndoPep assay showed similar LC activity among BoNT-A products. Thus, greater amounts of active neurotoxin are injected with Dysport®, at FDA-approved doses, than with other products. This fact might explain the long duration of action reported across multiple indications, which benefits patients, caregivers, clinicians, and healthcare systems.


Effects of leukotrienes on phenotypic properties and growth of arterial smooth muscle cells in primary culture.
During the first few days in primary culture arterial smooth muscle cells (SMCs) go through a transition from a contractile to a synthetic phenotype. Morphologically, this process includes loss of myofilaments and formation of an extensive rough endoplasmic reticulum and a large Golgi complex. Functionally, it leads to the cells losing their contractility, beginning to secrete extracellular matrix components, and dividing in response to growth factor stimulation. Similar changes in the structure and function of the SMCs occur in the initial stages of atherogenesis. The object of the present investigation was to study the effects of leukotrienes on the differentiated properties and growth of rat aortic SMCs in primary culture. Enzymically isolated cells were seeded directly on a plastic surface in serum-containing medium or on a substratum of plasma fibronectin in serum-free medium. The change in cell morphology was followed by transmission electron microscopy, and the activation of cell growth by thymidine autoradiography and cell counting. The results demonstrate that 10 pM-LTB4, -LTC4, -LTD4 and -LTE4 all speeded up the shift of the SMCs into a synthetic phenotype, whereas 5S,12S-DHETE (an isomer of LTB4) lacked effect. Further, LTB4, LTC4 and LTD4 stimulated the SMCs to enter the cell cycle earlier than in the controls, enhanced the proliferative response to serum mitogens, and under serum-free conditions induced DNA synthesis by themselves. Indomethacin did not interfere with the effect of LTB4 on the structural transformation of the cells but blocked its effect on DNA replication, suggesting that only the latter involved endogenous production of a cyclo-oxygenase product.(ABSTRACT TRUNCATED AT 250 WORDS)


In vivo measurement of D2 receptor density and affinity for 18F-(3-N-methyl)benperidol in the rat striatum with a PET system for small laboratory animals.
A recent investigation showed that intracerebral radioactivity concentrations can reliably be quantified in vivo with a small-animal PET device. The purpose of the current study was to investigate the binding characteristics of the D(2) receptor radioligand (18)F-(3-N-methyl)benperidol ((18)FMB) in rat striatum by determining receptor density (B(max)) and affinity (K(d)) in vivo. For validation, K(d) and B(max) additionally were determined in vitro using storage phosphor autoradiography. Striatal radioactivity was measured with PET in 8 Sprague-Dawley rats after injection of (18)FMB in increasing specific activities. Free radioligand concentrations were estimated from cortical radioactivity concentrations and were subtracted from striatal radioactivity concentrations to obtain specific binding. In vitro saturation experiments were performed on 7 further rats according to the isotopic dilution method. Specific binding was determined by both subtraction of (18)FMB binding in the presence of raclopride and subtraction of cortical radioactivity concentrations from total radioligand binding. Saturation binding curves were obtained by plotting specifically bound radioligand concentrations against free radioligand concentrations and were evaluated with regression analysis. PET yielded a K(d) of 6.2 nmol/L and a B(max) of 16 fmol/mg for the striatal D(2) receptor. In vitro, K(d) and B(max) amounted to 4.4 nmol/L and 84.1 fmol/mg (subtraction of (18)FMB binding in the presence of raclopride), respectively, and 7.9 nmol/L and 70.1 fmol/mg (subtraction of cortical radioactivity concentrations), respectively. K(d) values measured with PET and autoradiography agreed and corresponded to inhibition constants obtained in previous in vitro studies. B(max) values lay within the same order of magnitude. The results of in vitro saturation binding analyses also agreed, irrespective of the mode of determination of free radioligand concentrations. Thus, B(max) and K(d) may be determined with PET in analogy to the evaluation of in vitro binding data by regression analysis of bound-versus-free ligand concentrations. Our results show that small-animal tomographs are valuable tools for the in vivo characterization of receptor radioligands as an alternative to autoradiography.


[Status of cerebral ventricles and meninges in subarachnoid hemorrhage (clinico-pathomorphological studies)].
Long-term investigation of 64 patients with subarachnoidal hemorrhages (SH), 24 of which had subsequently died, and 2 series of experiments of animals with a single or repeated intracysternal infusion of various doses of autologous blood, yielded the description of the response of the meninges and ventricles at different terms after SH. The brain ventricles were measured by axial computer tomography and echoencephalography. A index of CSF resorption resistance and CSF pressure were determined. The cerebral meninges from experimental animals and autopsied human ones underwent the histological examination. The authors discuss the mechanisms of development of liquor dynamic disorders at different terms after SH.


Evolution of the volume-outcome relation for hospitals performing coronary angioplasty.
Hospitals performing more surgical procedures tend to yield better outcomes. This study examines the evolution of this volume-outcome relation over time. The relation between the number of percutaneous transluminal coronary angioplasty (PTCA) procedures performed at hospitals (volume) and in-hospital bypass surgery and death for 353 488 patients treated in California between 1984 and 1996 was examined. Descriptive statistics and logistic regression were used to compare outcomes for 3 periods: 1984 to 1987, 1988 to 1992, and 1993 to 1996. The in-hospital mortality rate was 2.5% for hospitals performing <200 PTCA procedures per year but only 1.3% for hospitals performing >400 procedures per year in 1984 to 1987. By 1993 to 1996, mortality rates in these 2 volume categories narrowed to 1.7% and 1.3%, respectively. Bypass surgery rates also narrowed and fell in low-volume (<200 procedures) versus high-volume (>400 procedures) hospitals from 12.4% versus 6.9% in 1984 to 1987 to 4.6% versus 3.3% in 1993 to 1996. In a logistic regression, PTCA procedures significantly predicted in-hospital mortality and bypass surgery rates in all 3 time periods. However, coefficient estimates indicate that improvements over time in outcomes for hospitals performing <200 procedures were comparable to the predicted benefits of increasing volume above 400 procedures within time periods. Over time, the disparity in outcomes between low- and high-volume hospitals has narrowed, and outcomes have improved significantly for all hospitals. Given these improvements, lower minimum volume standards may be advisable in less populated areas, where the alternative is no angioplasty at all.


Self-Control and Crime: Beyond Gottfredson and Hirschi's Theory.
Over the past several decades, Gottfredson & Hirschi's (1990) SCT has dominated research on self-control and crime. In this review, I assess the current state of self-control knowledge and encourage the field to move beyond SCT, as its peculiar conceptualization of self-control and causal model presents challenges for integrative scholarship. Drawing heavily on scholarship outside criminology, I clarify the definition of self-control; describe the malleable nature of trait self-control; highlight its situational variability as state self-control; and consider the multiplicity of contextual, situational, and individual factors that affect its operation in relation to crime. This specification of contingencies and the interplay between impulse strength and control efforts in the process of self-control is intended as a springboard for research moving beyond SCT and its key premise that self-control ability is sufficient for explanation. Finally, I address what I see as important areas for further study in light of current knowledge.


The distribution of anionic sites on the surface of the Golgi complex.
The distribution of anionic binding sites has been investigated in the isolated Golgi complex using cationic ferritin. The greatest density of anionic sites occurs on the tubular network and small vesicles, and this binding is accompanied by increased levels of galactosyltransferase activity. The density of anionic sites on the cisternae is less than on the tubules and shows anisotropic distribution, with higher density on the convex surface and lower density on the concave surface. The distribution of anionic sites may reflect the functional activity of the Golgi complex and possibly the interaction or cohesion between cisternae in this organelle.


Prefertilization Exposure of Rainbow Trout Eggs to Per- and Polyfluoroalkyl Substances to Simulate Accumulation During Oogenesis.
Aqueous film-forming foams (AFFFs) are used in firefighting and are sources of per- and polyfluoroalkyl substances (PFAS) to the environment through surface runoff and groundwater contamination at defense and transportation sites. Little is known regarding the toxicity and bioaccumulation of newer AFFF formulations containing novel PFAS. To mimic maternal transfer of PFAS, prefertilization rainbow trout eggs were exposed to three PFAS using novel methodologies. Batches of unfertilized oocytes were exposed for 3 h to 0, 0.01, 0.1, 1, or 10 µg/ml separately to perfluorooctanoic acid, perfluorohexanoic acid, or perfluorooctanesulfonic acid in either coelomic fluid or Cortland's solution. After exposure, the gametes were fertilized and rinsed with dechlorinated water. Egg yolk was aspirated from a subset of fertilized eggs for PFAS quantification. Each PFAS was detected in yolks of eggs exposed to the respective PFAS, and yolk concentrations were directly proportional to concentrations in aqueous media to which they were exposed. Exposure in coelomic fluid or Cortland's solution resulted in similar concentrations of PFAS in egg yolks. Ratios of PFAS concentrations in oocytes to concentrations in exposure media (oocyte fluid ratios) were <0.99 when exposed from 0.01 to 10 µg/ml and <0.45 when exposed from 0.1 to 10 µg/ml for both media and all three PFAS, demonstrating that the water solubility of the chemicals was relatively great. Prefertilization exposure of eggs effectively introduced PFAS into unfertilized egg yolk. This method provided a means of mimicking maternal transfer to evaluate toxicity to developing embryos from an early stage. This method is more rapid and efficient than injection of individual fertilized eggs and avoids trauma from inserting needles into eggs. Environ Toxicol Chem 2021;40:3159-3165. © 2021 SETAC.


(-)-Epigallocatechin-3-gallate blocks the induction of nitric oxide synthase by down-regulating lipopolysaccharide-induced activity of transcription factor nuclear factor-kappaB.
Nitric oxide (NO) plays an important role in inflammation and multiple stages of carcinogenesis. We investigated the effect of various tea polyphenols and caffeine on the induction of NO synthase (NOS) in thioglycollate-elicited and lipopolysaccharide (LPS)-activated peritoneal macrophages. Gallic acid (GA), (-)-epigallocatechin (EGC), and (-)-epigallocatechin-3-gallate (EGCG), the major tea catechin, were found to inhibit inducible NOS (iNOS) protein in activated macrophages. EGCG, a potent antitumor agent with anti-inflammatory and antioxidant properties, inhibited NO generation, as measured by the amount of nitrite released into the culture medium. Inhibition of NO production was observed when cells were cotreated with EGCG and LPS. iNOS activity in soluble extracts of lipopolysaccharide-activated macrophages treated with EGCG (5 and 10 microM) for 6-24 hr was significantly lower than that in macrophages without EGCG treatment. Western blot, reverse transcription-polymerase chain reaction, and Northern blot analyses demonstrated that significantly reduced 130-kDa protein and 4.5-kb mRNA levels of iNOS were expressed in lipopolysaccharide-activated macrophages with EGCG compared with those without EGCG. Electrophoretic mobility shift assay indicated that EGCG blocked the activation of nuclear factor-kappaB, a transcription factor necessary for iNOS induction. EGCG also blocked disappearance of inhibitor kappaB from cytosolic fraction. These results suggest that EGCG decreases the activity and protein levels of iNOS by reducing the expression of iNOS mRNA and the reduction could occur through prevention of the binding of nuclear factor-kappaB to the iNOS promoter, thereby inhibiting the induction of iNOS transcription.


Multi adducts of diphenylmethanofullerenes as electron acceptors for polymer solar cells: a quantum chemical study.
In the present study, quantum chemical methods were applied to investigate the energy levels of the frontier orbital of mono and multi adducts of diphenylmethanofullerenes (DPMs). Recently these molecules have been used as electron acceptors in polymer solar cells showing interesting properties compared to the widely used [6, 6]-phenyl-C61-butyric acid methyl ester (PCBM). The geometries of all the investigated compounds were optimized with the density functional theory at the B3LYP/3-21G level of calculation. We studied the effect of electron-donating (methoxy and methyl thioether) and electron-withdrawing (fluorine) substituents (placed on the diphenylmethano addend in ortho, meta and para position of the phenyl rings), on the lowest unoccupied molecular orbital (LUMO) level of DPM. Afterward, we analysed all the possible isomers arising from bis and tris additions to fullerene cage. The LUMO level is significantly raised compared to the mono adduct but different isomers have different LUMO levels. Since the open circuit voltage (V(oc)) for polymer solar cells with ohmic contacts is proportional to the difference between the highest occupied molecular orbital (HOMO) of the donor polymer and the LUMO of the acceptor (fullerene), these bisadducts have the potential to increase the V(oc) of the corresponding devices.


Estimating the effects of a calorie-based sugar-sweetened beverage tax on weight and obesity in New York City adults using dynamic loss models.
Sugar-sweetened beverages (SSBs) contribute to weight gain and increase the risk of obesity. In this article, we determine the effects of an innovative SSB tax on weight and obesity in New York City adults. Dynamic weight loss models were used to estimate the effects of an expected 5800-calorie reduction resulting from an SSB tax on weight and obesity. Baseline data were derived from the New York City Community Health Survey. One, five, and 10-year simulations of weight loss were performed. Calorie reductions resulted in a per-person weight loss of 0.46 kg in year 1 and 0.92 kg in year 10. A total of 5,531,059 kg was expected to be lost over 10 years when weighted to the full New York City adult population. Approximately 50% of overall bodyweight loss occurred within the first year, and 95% within 5 years. Results showed consistent but nonsignificant decreases in obesity prevalence. SSB taxes may be viable strategies to reduce obesity when combined with other interventions to maximize effects in the population.