Brachial plexus injury: a descriptive study of American football.
A stinger is a common, yet understudied, injury that involves stretching or compression of the brachial plexus, often occurring during contact sports. Five football teams, including high school, collegiate, and professional teams, completed questionnaires. Questions were designed to obtain descriptive information regarding the nature and consequence of this injury and assess effectiveness of current preventive measures. Three hundred and four surveys were returned with 153 players reporting a stinger in their career (50.3%). The prevalence increased with years played and was most common in running backs (69%), defensive linemen (60%), linebackers (55%), and defensive secondary (54%). Current protective equipment and neck-strengthening programs did not provide protective benefits. Players at greatest risk of developing a stinger include those having played 3 or more years and players whose primary position is running back, defensive back, or defensive lineman. Further study is needed to better evaluate the effectiveness of current preventive measures.


Operative Versus Nonoperative Treatment of Acute Achilles Tendon Ruptures: A Pilot Economic Decision Analysis.
The operative treatment of Achilles tendon ruptures has been associated with lower rerupture rates and better function but also a risk of surgery-related complications compared with nonoperative treatment, which may provide improved outcomes with accelerated rehabilitation protocols. However, economic decision analyses integrating the updated costs of both treatment options are limited in the literature. To compare the cost-effectiveness of operative and nonoperative treatment of acute Achilles tendon tears. Economic and decision analysis; Level of evidence, 2. An economic decision model was built to assess the cost-utility ratio (CUR) of open primary repair versus nonoperative treatment for acute Achilles tendon ruptures, based on direct costs from the practices of sports medicine and foot and ankle surgeons at a single tertiary academic center, with published outcome probabilities and patient utility data. Multiway sensitivity analyses were performed to reflect the range of data. Nonoperative treatment was more cost-effective in the average scenario (nonoperative CUR, US$520; operative CUR, US$1995), but crossover occurred during the sensitivity analysis (nonoperative CUR range, US$224-US$2079; operative CUR range, US$789-US$8380). Operative treatment cost an extra average marginal CUR of US$1475 compared with nonoperative treatment, assuming uneventful healing in both treatment arms. The sensitivity analysis demonstrated a decreased marginal CUR of operative treatment when the outcome utility was maximized, and rerupture rates were minimized compared with nonoperative treatment. Nonoperative treatment was more cost-effective in average scenarios. Crossover indicated that open primary repair would be favorable for maximized outcome utility, such as that for young athletes or heavy laborers. The treatment decision for acute Achilles tendon ruptures should be individualized. These pilot results provide inferences for further longitudinal analyses incorporating future clinical evidence.


Clinics in diagnostic imaging (54).
A 29-year-old man sustained a pelvic fracture and haemorrhagic shock after a road traffic accident. He underwent an exploratory laparotomy open cystostomy, and iliac artery embolisation. Subsequent antegrade cystography and computed tomography showed a complete traumatic posterior urethral rupture with a "high riding" bladder. Delayed repair of the posterior urethra was performed 6 months later with good functional outcome. The risk of urethral injury in pelvic fractures, the mechanism of injury, and the role of imaging in the diagnosis of possible urethral injury in pelvic fractures are discussed.


Effects of Hct and norepinephrine on segmental vascular resistance distribution in isolated perfused rat livers.
We studied the effects of blood hematocrit (Hct), blood flow, or norepinephrine on segmental vascular resistances in isolated portally perfused rat livers. Total portal hepatic venous resistance (Rt) was assigned to the portal (Rpv), sinusoidal (Rsinus), and hepatic venous (Rhv) resistances using the portal occlusion (Ppo) and the hepatic venous occlusion (Phvo) pressures that were obtained during occlusion of the respective line. Four levels of Hct (30%, 20%, 10%, and 0%) were studied. Rpv comprises 44% of Rt, 37% of Rsinus, and 19% of Rhv in livers perfused at 30% Hct and portal venous pressure of 9.1 cmH2O. As Hct increased at a given blood flow, all three segmental vascular resistances of Rpv, Rsinus, and Rhv increased at flow >15 ml/min. As blood flow increased at a given Hct, only Rsinus increased without changes in Rpv or Rhv. Norepinephrine increased predominantly Rpv, and, to a smaller extent, Rsinus, but it did not affect Rhv. Finally, we estimated Ppo and Phvo from the double occlusion maneuver, which occluded simultaneously both the portal and hepatic venous lines. The regression line analysis revealed that Ppo and Phvo were identical with those measured by double occlusion. In conclusion, changes in blood Hct affect all three segmental vascular resistances, whereas changes in blood flow affect Rsinus, but not Rpv or Rhv. Norepinephrine increases mainly presinusoidal resistance. Ppo and Phvo can be obtained by the double occlusion method in isolated perfused rat livers.


Dosimetry auditing procedure with alanine dosimeters for light ion beam therapy.
In the next few years the number of facilities providing ion beam therapy with scanning beams will increase. An auditing process based on an end-to-end test (including CT imaging, planning and dose delivery) could help new ion therapy centres to validate their entire logistic chain of radiation delivery. An end-to-end procedure was designed and tested in both scanned proton and carbon ion beams, which may also serve as a dosimetric credentialing procedure for clinical trials in the future. The developed procedure is focused only on physical dose delivery and the validation of the biological dose is out of scope of the current work. The audit procedure was based on a homogeneous phantom that mimics the dimension of a head (20 × 20 × 21 cm(3)). The phantom can be loaded either with an ionisation chamber or 20 alanine dosimeters plus 2 radiochromic EBT films. Dose verification aimed at measuring a dose of 10Gy homogeneously delivered to a virtual-target volume of 8 × 8 × 12 cm(3). In order to interpret the readout of the irradiated alanine dosimeters additional Monte Carlo simulations were performed to calculate the energy dependent detector response of the particle fluence in the alanine detector. A pilot run was performed with protons and carbon ions at the Heidelberg Ion Therapy facility (HIT). The mean difference of the absolute physical dose measured with the alanine dosimeters compared with the expected dose from the treatment planning system was -2.4 ± 0.9% (1σ) for protons and -2.2 ± 1.1% (1σ) for carbon ions. The measurements performed with the ionisation chamber indicate this slight underdosage with a dose difference of -1.7% for protons and -1.0% for carbon ions. The profiles measured by radiochromic films showed an acceptable homogeneity of about 3%. Alanine dosimeters are suitable detectors for dosimetry audits in ion beam therapy and the presented end-to-end test is feasible. If further studies show similar results, this dosimetric audit could be implemented as a credentialing procedure for clinical proton and carbon beam delivery.


Neisseria gonorrhoeae bacterioferritin: structural heterogeneity, involvement in iron storage and protection against oxidative stress.
The iron-storage protein bacterioferritin (Bfr) from Neisseria gonorrhoeae strain F62 was identified in cell-free extracts and subsequently purified by column chromatography. Gonococcal Bfr had an estimated molecular mass of 400 kDa by gel filtration; however, analysis by SDS-PAGE revealed that it was composed of 18 kDa (BfrA) and 22 kDa (BfrB) subunits. DNA encoding BfrB was amplified by PCR using degenerate primers derived from the N-terminal amino acid sequence of BfrB and from a C-terminal amino acid sequence of Escherichia coli Bfr. The DNA sequence of bfrA was subsequently obtained by genome walking using single-specific-primer PCR. The two Bfr genes were located in tandem with an intervening gap of 27 bp. A potential Fur-binding sequence (12 of 19 bp identical to the consensus neisserial fur sequence) was located within the 5' flanking region of bfrA in front of a putative -35 hexamer. The homology between the DNA sequences of bfrA and bfrB was 55.7%; the deduced amino acid sequences of BfrA (154 residues) and BfrB (157 residues) showed 39.7% identity, and showed 41.3% and 56.1% identity, respectively, to E. coli Bfr. Expression of recombinant BfrA and BfrB in E. coli strain DH5alpha was detected on Western blots probed with polyclonal anti-E. coli Bfr antiserum. Most Bfrs are homopolymers with identical subunits; however, the evidence presented here suggests that gonococcal Bfr was composed of two similar but not identical subunits, both of which appear to be required for the formation of a functional Bfr. A Bfr-deficient mutant was constructed by inserting the omega fragment into the BfrB gene. The growth of the BfrB-deficient mutant in complex medium was reduced under iron-limited conditions. The BfrB-deficient mutant was also more sensitive to killing by H2O2 and paraquat than the isogenic parent strain. These results demonstrate that gonococcal Bfr plays an important role in iron storage and protection from iron-mediated oxidative stress.


Immunohistochemical p16INK4a analysis of archival tumors with deletion, hypermethylation, or mutation of the CDKN2/MTS1 gene. A comparison of four commercial antibodies.
The MTS1/CDKN2/p16 gene encoding the p16INK4a tumor-suppressor protein is commonly inactivated by homozygous deletion or hypermethylation of the promoter in a wide range of human malignancies. In select tumor types, including pancreatic adenocarcinomas, intragenic mutations are found in a significant percentage of cases. The immunoreactivity of mutant p16 proteins has not been comprehensively studied. Moreover, the immunohistochemical properties of commercially available antibodies have not been described in detail. We studied 35 pancreatic adenocarcinomas with a molecularly defined p16 status (16 homozygous deletions, 3 hypermethylated cases, and 16 tumors with an intragenic mutation in one allele associated with loss of the second allele). In addition, we studied nine cell lines (three homozygous deletions, three hypermethylated lines, and three intragenic mutations). Paraffin sections of the tumors and cell blocks were reacted with four different anti-p16 antibodies: polyclonal and monoclonal (clone G175-405) antibodies from PharMingen, monoclonal antibody DCS-50 from Oncogene Science, and monoclonal antibody ZJ11 from Neo-Markers. Optimal staining conditions were established for each antibody. The pancreatic carcinomas with homozygous p16 deletions were largely devoid of nuclear staining (admixed nonneoplastic cells served as internal positive controls); only one adenocarcinoma each reacted with DCS-50 and the polyclonal antibody, and five were positive with ZJ11, suggesting that nonspecific nuclear staining can occur under certain conditions. Antibody DCS-50 produced nuclear staining in all three hypermethylated carcinomas, whereas G175-405 stained none of them. Three of the four antibodies produced nuclear immunoreactivity in 7 to 14 of the 16 carcinomas carrying p16 mutations; G175-405 showed only weak reactivity in one case. Cytoplasmic staining was present in all carcinomas and cell lines and with all antibodies and therefore cannot be considered specific; it was strongest with G175-405. Thus, we found antibody G175-405 to be the most specific, and monoclonals DCS-50 and ZJ11 the least specific for wild-type p16. However, the former tends to give stronger cytoplasmic background staining. For tumor types in which p16 mutations are uncommon, the PharMingen polyclonal antibody may be a suitable alternative.


Supporting the use of research evidence in the Canadian health sector.
Interventions to support evidence-informed decision making have increased in recent years, but they are often fragmented across different clinical, management and policy environments. Many of these efforts also place varying emphasis on supporting the use of research evidence, with some choosing to focus more on expert knowledge and/or media coverage and others focusing on supporting the use of actionable messages arising from high-quality, relevant and optimally packaged research evidence. In this paper, we profile five Canadian contributions--EvidenceUpdates, Rx for Change, Health-Evidence.ca, Health Systems Evidence and the McMaster Health Forum--that allow providers, managers and policy makers to efficiently find and use research evidence when they need it. These contributions are critical for supporting both local and global efforts to provide optimal and cost-effective care, improving the quality of care and strengthening health systems.


Characterizing the outcomes of metastatic papillary renal cell carcinoma.
Outcomes of metastatic papillary renal cell carcinoma (pRCC) patients are poorly characterized in the era of targeted therapy. A total of 5474 patients with metastatic renal cell carcinoma (mRCC) in the International mRCC Database Consortium (IMDC) were retrospectively analyzed. Outcomes were compared between clear cell (ccRCC; n = 5008) and papillary patients (n = 466), and recorded type I and type II papillary patients (n = 30 and n = 165, respectively). Overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) favored ccRCC over pRCC. OS was 8 months longer in ccRCC patients and the hazard ratio of death was 0.71 for ccRCC patients. No differences in PFS or ORR were detected between type I and II PRCC in this limited dataset. The median OS for type I pRCC was 20.0 months while the median OS for type II was 12.6 months (P = 0.096). The IMDC prognostic model was able to stratify pRCC patients into favorable risk (OS = 34.1 months), intermediate risk (OS = 17.0 months), and poor-risk groups (OS = 6.0 months). pRCC patient outcomes were inferior to ccRCC, even after controlling for IMDC prognostic factors. The IMDC prognostic model was able to effectively stratify pRCC patients.


Influence of exposure time and pressure amplitude on blood-brain-barrier opening using transcranial ultrasound exposures.
Pulsed ultrasound exposures of brain tissue in the presence of micro-bubble contrast agents have been shown to achieve transient focal disruption of the blood brain barrier without significant damage to surrounding brain tissue. The effects of overall exposure duration on the extent of blood brain barrier disruption was studied in these experiments to determine operating conditions for increasing the amount of therapeutic agents delivered to the brain. Exposures at 1.08 MHz ranging from 0.2 to 0.8 MPa in amplitude were delivered transcranially to the brains of rabbits and rats for durations ranging from 30 to 1200 seconds. The amount of signal enhancement on contrast-enhanced T1-weighted MR images were used to quantify the extent of blood brain barrier disruption and histological evaluation of the exposed regions was performed to evaluate the impact on brain tissue. A subset of four rats underwent weekly exposures for 3 weeks to evaluate the feasibility of repeat sonications to the brain. The results suggest that exposures less than 180 seconds in duration are associated with a low probability of irreversible damage to brain tissue at pressure amplitudes of 0.38 MPa. Although exposures greater than 300 seconds were associated with an increase in the proportion of irreversible damage, this may be acceptable for chemotherapy delivery, where the therapeutic goal is tissue destruction. Repeat exposures to the brain were feasible, but resulted in evidence of focal brain damage in 50% of animals.


Combining experiment and energy landscapes to explore anaerobic heme breakdown in multifunctional hemoproteins.
To survive, many pathogens extract heme from their host organism and break down the porphyrin scaffold to sequester the Fe2+ ion via a heme oxygenase. Recent studies have revealed that certain pathogens can anaerobically degrade heme. Our own research has shown that one such pathway proceeds via NADH-dependent heme degradation, which has been identified in a family of hemoproteins from a range of bacteria. HemS, from Yersinia enterocolitica, is the main focus of this work, along with HmuS (Yersinia pestis), ChuS (Escherichia coli) and ShuS (Shigella dysenteriae). We combine experiments, Energy Landscape Theory, and a bioinformatic investigation to place these homologues within a wider phylogenetic context. A subset of these hemoproteins are known to bind certain DNA promoter regions, suggesting not only that they can catalytically degrade heme, but that they are also involved in transcriptional modulation responding to heme flux. Many of the bacterial species responsible for these hemoproteins (including those that produce HemS, ChuS and ShuS) are known to specifically target oxygen-depleted regions of the gastrointestinal tract. A deeper understanding of anaerobic heme breakdown processes exploited by these pathogens could therefore prove useful in the development of future strategies for disease prevention.


Prognostic factors for successful recovery after arthroscopic rotator cuff repair: a systematic literature review.
Systematic literature review. To perform a systematic review of the literature on prognostic factors for successful recovery after arthroscopic rotator cuff repair. Rotator cuff lesion is a common shoulder disorder, with a prevalence ranging from 13% in people over 50 years of age to more than 50% in people over 80 years of age. Several factors can affect the extent to which a person will recover after the surgical repair of a rotator cuff tear. More knowledge about these prognostic factors may lead to a better understanding of why the recovery process is successful in some patients but not in others. A systematic literature search from 1995 to November 2013 was performed to identify studies reporting prognostic factors for successful recovery after arthroscopic rotator cuff repair. A total of 455 studies were initially identified, 10 of which were included in the review. For all included studies, the percentage of patients with complete tendon healing at final assessment ranged from 60% to 88%. Twelve prognostic factors, which could be divided into 4 categories, were identified as being associated with better recovery: demographic factors (younger age, male gender), clinical factors (higher bone mineral density, absence of diabetes mellitus, higher level of sports activity, greater preoperative range of motion, absence of obesity), factors related to cuff integrity (smaller sagittal size of the cuff lesion, less retraction of the cuff, less fatty infiltration, no multiple tendon involvement), and factors related to the surgical procedure (no concomitant biceps or acromioclavicular joint procedures). Knowledge and understanding of prognostic factors should be used in the decision-making process concerning arthroscopic rotator cuff repair to offer better care to patients. Prognosis, level 2a-.


Consistent platelet inhibition during long-term maintenance-dose clopidogrel therapy among 359 compliant outpatients with documented vascular disease.
Numerous reports have dichotomized responses after clopidogrel therapy using varying definitions and platelet tests in patients immediately after acute vascular events; however, no large study has assessed platelet characteristics in outpatients receiving long-term treatment for more than 30 days with the maintenance dose (75 mg/d) of clopidogrel. The aim of this study was to describe the responses of ex vivo measures of platelet aggregation and activation to long-term clopidogrel therapy in a large population of outpatients after coronary stenting or ischemic stroke. We conducted a secondary post hoc analysis of a data set represented by presumably compliant patients after coronary stenting (n = 237) or a documented ischemic stroke (n = 122) treated with clopidogrel-and-aspirin combination antiplatelet therapy. The mean duration of treatment was 5.8 months (range 1-21 months). Every patient exhibited a significant inhibition of adenosine diphosphate-induced platelet aggregation (mean 52.9%, range 36%-70%) as compared with the preclopidogrel measures. Inhibition of aggregation strongly correlated with a diminished expression of PECAM-1 (platelet/endothelial cell adhesion molecule 1, r = 0.75), glycoprotein IIb/IIIa (r = 0.62), and PAR-1 (protease-activated receptor 1, r = 0.71). None of the patients developed hyporesponsiveness (reduction from the baseline <15%) or profound inhibition (residual platelet activity <10%). In contrast to the wide variability of responses that exists in the acute setting, long-term therapy with clopidogrel leads to consistent and much less variable platelet inhibition. Lack of nonresponse and profound inhibition with clopidogrel allow for the maintenance of a delicate balance between proven efficacy and acceptable bleeding risks for long-term secondary prevention in outpatients after acute vascular events.


Hospitalizations for suspected dengue in Puerto Rico, 1991-1995: estimation by capture-recapture methods. The Puerto Rico Association of Epidemiologists.
Capture-recapture estimations compare the results of 2 or more independent surveillance systems for the same event, and by measuring the degree of overlap between them, provide an estimate of the total number of events, and therefore the completeness of ascertainment in each system. The Puerto Rico Department of Health and the Dengue Branch of the Centers for Disease Control and Prevention (CDC) monitor dengue activity in Puerto Rico through 2 distinct surveillance systems: diagnostic specimens from patients with suspected dengue and infection control nurses' reports on patients hospitalized for suspected dengue. The patient listings from these systems were used in a 2-sample, capture-recapture calculation to estimate the total number of persons with suspected dengue hospitalized from 1991 to 1995. The laboratory positivity rate for suspected dengue cases who submitted appropriately timed serum samples in those years ranged from 72.1% to 81.2%. The laboratory-based (diagnostic sample) surveillance system (routinely used to monitor hospitalizations for suspected dengue) detected an average of 1,197 hospitalized cases during non-epidemic years, and 4,329 cases during the epidemic year of 1994. The detection rate of this system averaged 42% of the numbers derived by the capture-recapture method. In non-epidemic years, an estimated average of 2,791 patients (range = 1,553-3,481) was estimated to have been hospitalized with a clinical diagnosis of dengue, compared with 9,479 during 1994. These results demonstrate the under-detection inherent in passive surveillance systems for hospitalized cases of suspected dengue, and illustrate the value of capture-recapture techniques to better estimate the true incidence of hospitalizations for this disease.


Novel role of miR-29a in pancreatic cancer autophagy and its therapeutic potential.
Pancreatic Ductal Adenocarcinoma (PDAC) is a highly lethal malignancy that responds poorly to current therapeutic modalities. In an effort to develop novel therapeutic strategies, we found downregulation of miR-29 in pancreatic cancer cells, and overexpression of miR-29a sensitized chemotherapeutic resistant pancreatic cancer cells to gemcitabine, reduced cancer cell viability, and increased cytotoxicity. Furthermore, miR-29a blocked autophagy flux, as evidenced by an accumulation of autophagosomes and autophagy markers, LC3B and p62, and a decrease in autophagosome-lysosome fusion. In addition, miR-29a decreased the expression of autophagy proteins, TFEB and ATG9A, which are critical for lysosomal function and autophagosome trafficking respectively. Knockdown of TFEB or ATG9A inhibited autophagy similar to miR-29a overexpression. Finally, miR-29a reduced cancer cell migration, invasion, and anchorage independent growth. Collectively, our findings indicate that miR-29a functions as a potent autophagy inhibitor, sensitizes cancer cells to gemcitabine, and decreases their invasive potential. Our data provides evidence for the use of miR-29a as a novel therapeutic agent to target PDAC.


Electronic engineering of a tetrathiafulvalene charge-transfer salt via reduced symmetry induced by combined substituents.
A 1 : 1 metallic charge-transfer salt is obtained by cosublimation of (Z,E)-(SMe)2Me2TTF and TCNQ. X-ray diffraction studies confirm the formation of segregated stacks comprising donor and acceptor molecules in [(E)-(SMe)2Me2TTF](TCNQ). The crystal packing features lateral SS interactions between TTF stacks, which is in sharp contrast to that in (TTF)(TCNQ). Structural analysis and theoretical studies afford a partial charge-transfer (ρ ≈ 0.52), leading to a system with the electronic structure close to quarter-filled. Resistivity measurements reveal that this material behaves as a metal down to 56 K and 22 K at 1 bar and 14.9 kbar, respectively. The thermopower is negative in the metallic regime, indicating the dominant role of the acceptor stacks for the observed conducting behavior. Analysis of single-crystal EPR spectra shows the remaining spin susceptibility at 4.3 K, suggesting the importance of the Hubbard U correction. These results highlight the judicious engineering of electronic and geometrical effects on the TTF core; the combined use of methyl and thiomethyl groups has decreased the TCNQ bandwidth while maintaining the segregated stacks, converting the metal to insulator (M-I) transition to more 4kF like. In addition, the enhanced SS contacts between the TTF stacks lead to more rapidly decreasing M-I transition temperature under various pressures.


Practical applications of physical activity for successful cognitive aging.
As patients lose cognitive function, they lose autonomy and increasingly use fiscal, social, and medical resources. Healthcare costs for Americans older than age 65 years are three to five times higher than for the remaining population, and dementia is the third most costly disease in the United States. Interventions that promote successful aging can help patients and reduce the financial, workforce, and treatment resource burdens on the population. Because a relationship between physical activity, particularly aerobic exercise, and cognitive decline has been established, physical activity interventions may prove practical, affordable, and effective. Attention to empiric research and knowledge of evidence-based strategies for prescribing physical activity are critical for PAs to embrace.


Long-term nitrogen and phosphorus enrichment alters vegetation species composition and reduces carbon storage in upland soil.
Reactive nitrogen (N) deposition can affect ecosystem processes, particularly in oligotrophic upland habitats. Phosphorus (P) addition has been proposed to reduce the effects of N enrichment on N leaching and acidification, since P limitation can reduce biomass production and consequent sequestration of reactive N. However, biodiversity is often reduced in more productive ecosystems and P limitation may protect against this effect. Responses to P availability in instances of high N deposition are poorly understood. This study investigated the ecosystem response to alleviation of P limitation, using a long-term nutrient addition experiment (1996-2012) three years after ceasing N inputs and 15years after a single P application. Substantial differences were observed in the structure and composition of vegetation species and above-ground vegetation biomass. Vegetation height was greater in the N+P addition treatments (+38% cf. control), with increased cryptogam cover (+47%), whereas N addition increased graminoid species cover (+68%). Vegetation diversity was significantly reduced by the addition of P (-21%), indicating that P limitation is likely to be an important mechanism that limits biodiversity loss in upland habitats exposed to chronic N deposition. Significant differences in soil C and N contents were also observed between treatments. Relative to control, the addition of N increased soil C (+11%) and N (+11%) pool sizes, whereas the addition of N and P reduced soil C (-12%) and N (-13%) pool sizes. This demonstrated the importance of P availability for upland ecosystem processes, and highlights the long-term effects of P addition on vegetation species composition and C storage. Thus, the addition of P cannot be endorsed as a method for reducing impacts of N deposition. Capsule: Phosphorus limitation is a major mechanism governing ecosystem processes in situations of high atmospheric nitrogen deposition.


Corticosterone slowly enhances miniature excitatory postsynaptic current amplitude in mice CA1 hippocampal cells.
Corticosteroid hormones are released in high amounts after stress and bind to intracellular receptors in the brain, which in activated form function as transcription factors. We here tested the effect of a high dose of corticosterone on AMPA-receptor-mediated transmission in the CA1 hippocampal area, which is enriched in corticosteroid receptors. To focus on slow gene-mediated effects of the hormone, excitatory postsynaptic currents were measured at least 1 h after a brief application of 100 nM corticosterone to slices from adrenally intact adult mice. The amplitude but not frequency of miniature postsynaptic excitatory currents was found to be significantly enhanced. These effects were mimicked by 100 nM RU 28362, a selective agonist for intracellular glucocorticoid receptors. Evoked AMPA responses at the single cell were significantly enhanced when measured 2-4 h after application of 100 nM corticosterone, but not at earlier moments nor with a longer delay. In summary, the present results show that activation of hippocampal glucocorticoid receptors induces a slow enhancement of AMPA-receptor-mediated responses, at the single-cell level.


Tuning the Chemical Environment within the UiO-66-NH2 Nanocages for Charge-Dependent Contaminant Uptake and Selectivity.
The remarkable water stability of Zr-carboxylate-based metal-organic frameworks (MOFs) stimulated considerable interest toward their utilization in aqueous phase applications. The origin of such stability is probed here through pH titration and pKa modeling. A unique feature of the Zr6(μ3-OH)4(μ3-O)4(RCO2)12 cluster is the Zr-bridging oxo/hydroxyl groups, demonstrating several pKa values that appear to provide for the water stability at a wide range of pH. Accordingly, the tunability of the cage/surface charge of the MOF can feasibly be controlled through careful adjustment of solution pH. Such high stability, and facile control over cage/surface charge, can additionally be augmented through introducing chemical functionalities lining the cages of the MOF, specifically amine groups in the UiO-66-NH2 presented herein. The variable protonation states of the Zr cluster and the pendant amino groups, their H-bond donor/acceptor characteristics, and their electrostatic interactions with guest molecules were effectively utilized in controlled experiments to demonstrate high uptake of model guest molecules (137 mg/g for Cr(VI), 1275 mg/g for methylene blue, and 909 mg/g for methyl orange). Additionally, a practical form of the silica-supported MOF, UiO-66-NH2@SiO2, constructed in under 2 h reaction time, is described, generating a true platform microporous sorbent for practical use in demanding applications.


[High-risk situation - which is the best chemotherapy?].
High-risk situations in early breast cancer concern patients with less than 3 involved lymph nodes but additional risk factors as well as patients with more than 3 involved lymph nodes. For the first group, new risk assessment methods to better identify the need for chemotherapy with or without a taxane or with a taxane instead of an anthracycline are needed. For the second group, further improvement of anthracycline- or taxane-containing chemotherapy regimens is warranted. Current approaches include the sequential or simultaneous use of these groups of agents, the combination with antimetabolites, antibodies or small molecules, the neoadjuvant use of chemotherapy as well as dose-dense and dose-escalated chemotherapy regimens.


The influence of viewing eye on pseudoneglect magnitude.
Various factors influence the degree of leftward error (pseudoneglect) that typifies the performance of normal individuals in line bisection tasks. This experiment reveals that the eye through which stimuli are viewed also exerts a modulating influence on spatial attention, as indexed by significant alterations in the magnitude of pseudoneglect. Using a forced-choice tachistoscopic line bisection protocol, 24 participants (12 male; 12 female) bisected horizontally oriented lines (22.6 degrees w x 0.39 degrees h) presented to central vision in 3 conditions: left uniocular viewing (L), right uniocular viewing (R), and binocular viewing (B). Perceived line midpoint, a measure of bisection accuracy, deviated significantly leftward of veridical (p < .05) in all viewing conditions, confirming a tonic asymmetry of visuospatial attention in normal young observers. In addition, a significant influence of viewing condition was found (p < .05) where pseudoneglect was greatest in the L condition, followed by the B and R conditions, respectively. Analysis of the slopes of the psychometric functions revealed significantly greater bisection precision in the binocular versus uniocular viewing conditions (p < .05). The results are interpreted to suggest that phasic effects on spatial attention can be produced by uniocular viewing via asymmetric retinotectal projections. The results are consistent with activation-orientation theories of attentional asymmetry.


(Correcting) misdiagnoses of asthma: a cost effectiveness analysis.
The prevalence of physician-diagnosed-asthma has risen over the past three decades and misdiagnosis of asthma is potentially common. to determine whether a secondary-screening-program to establish a correct diagnosis of asthma in those who report a physician diagnosis of asthma is cost effective. Randomly selected physician-diagnosed-asthmatic subjects from 8 Canadian cities were studied with an extensive diagnostic algorithm to rule-in, or rule-out, a correct diagnosis of asthma. Subjects in whom the diagnosis of asthma was excluded were followed up for 6-months and data on asthma medications and heath care utilization was obtained. Economic analysis was performed to estimate the incremental lifetime costs associated with secondary screening of previously diagnosed asthmatic subjects. Analysis was from the perspective of the Canadian healthcare system and is reported in Canadian dollars. Of 540 randomly selected patients with physician diagnosed asthma 150 (28%; 95%CI 19-37%) did not have asthma when objectively studied. 71% of these misdiagnosed patients were on some asthma medications. Incorporating the incremental cost of secondary-screening for the diagnosis of asthma, we found that the average cost savings per 100 individuals screened was $35,141 (95%CI $4,588-$69,278). Cost savings primarily resulted from lifetime costs of medication use averted in those who had been misdiagnosed.


Predictors of Driving Cessation in Dementia: Baseline Characteristics and Trajectories of Disease Progression.
A diagnosis of dementia implies the eventual need to relinquish driving. This is associated with significant morbidity and anticipating when it will need to occur can be important for planning. Patients, however, vary in the course of their disease. We sought to identify predictors of driving cessation in patients with dementia, including both baseline characteristics and changes in cognition and function over time as indicators of disease trajectory. A total of 779 patients with dementia were recruited from 9 memory clinics around Australia. Patients and their carers reported their driving status and completed measures of dementia severity, cognition, function, neuropsychiatric symptoms, and medication use at regular intervals over a 3-year period. Of the 247 patients still driving at baseline, 147 (59.5%) stopped driving during the study. Variables that predicted driving cessation included older age; female sex; greater dementia severity and cognitive and functional impairments at baseline; and greater increases in dementia severity and cognitive and functional impairments over 3 and 6 month periods. The findings confirm that easily assessable characteristics, including changes over time, predict future driving status. The findings underscore the value of regularly assessing patients with standardized measures to determine disease trajectory and likely prognosis.


1H NMR and CD secondary structure analysis of cell adhesion promoting peptide F-9 from laminin.
A heparin binding, cell adhesion promoting domain, termed peptide F-9, from the B1 chain of human laminin, residues 641 to 660, i.e. RYVVLPRPVCFEKGMNYTVR, has been investigated by 1H NMR (500 MHz) spectroscopy and CD spectropolarimetry. While small linear peptides in water solution normally exist in a number of fluctuating conformational states, CD data analysis of peptide F9 indicates the existence of some preferred average structural populations consisting of about 30% beta-sheet, 22% beta-turn, and 6% alpha-helix. NMR structural analysis supports this observation and indicates specific sequences of preferred structural populations. Evidence for these is indicated by the presence of dNN nuclear Overhauser effect (NOE) populations and attenuated or absent d alpha N NOEs at short mixing times (0.1 s), 3J alpha N coupling constants of 5 and 10 Hz, and chemical shifts significantly removed from random coil positions. The NH2-terminal VVL sequence primarily exists in an extended chain conformation by virtue of large d alpha N NOEs and 9-10 Hz 3J alpha N coupling constants. Residues C10-N16 have turn-like or helix character with a run of dNN and d beta N NOEs and attenuated d alpha N NOEs. These midchain reversals include the lysine and asparagine residues proposed to be involved in heparin binding and N-glycosylation, respectively, to laminin peptide F-9.


Management of Major Bleeding in Patients With Atrial Fibrillation Treated With Non-Vitamin K Antagonist Oral Anticoagulants Compared With Warfarin in Clinical Practice (from Phase II of the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation [ORBIT-AF II]).
Non-vitamin K antagonist oral anticoagulants (NOACs) are effective at preventing stroke in patients with atrial fibrillation (AF). However, little is known about the management of bleeding in contemporary, clinical use of NOACs. We aimed to assess the frequency, management, and outcomes of major bleeding in the setting of community use of NOACs. Using the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II registry, we analyzed rates of International Society on Thrombosis and Haemostasis major bleeding and subsequent outcomes in patients treated with NOACs versus warfarin. Outcomes of interest included acute and chronic bleeding management, recurrent bleeding, thromboembolic events, and death. In total, 344 patients with atrial fibrillation experienced major bleeding events over a median follow-up of 360 days follow-up: n = 273 on NOAC (3.3 per 100 patient-years) and n = 71 on warfarin (3.5 per 100 patient-years). Intracranial bleeding was uncommon but similar (0.34 per 100 patient-years for NOAC vs 0.44 for warfarin, p = 0.5), as was gastrointestinal bleeding (1.8 for NOAC vs 1.3 for warfarin, p = 0.1). Blood products and correction agents were less commonly used in NOAC patients with major bleeds compared with warfarin-treated patients (53% vs 76%, p = 0.0004 for blood products; 0% vs 1.5% for recombinant factor; p = 0.0499); no patients received pharmacologic hemostatic agents (aminocaproic acid, tranexamic acid, desmopressin, aprotinin). Within 30 days, 23 NOAC-treated patients (8.4%) died versus 5 (7.0%) on warfarin (p = 0.7). At follow-up, 126 NOAC-treated (46%) and 29 warfarin-treated patients (41%) were not receiving any anticoagulation. In conclusion, rates of major bleeding are similar in warfarin and NOAC-treated patients in clinical practice. However, NOAC-related bleeds require less blood product administration and rarely require factor replacement.


Cytoskeleton-dependent tyrosine phosphorylation of the p130(Cas) family member HEF1 downstream of the G protein-coupled calcitonin receptor. Calcitonin induces the association of HEF1, paxillin, and focal adhesion kinase.
HEF1 is a recently described p130(Cas)-like docking protein that contains one SH3 domain and multiple SH2 binding motifs. In B cells, HEF1 is phosphorylated by a cytoskeleton-dependent mechanism that is triggered by integrin ligation. However, the induction of HEF1 phosphorylation by G protein-coupled receptors has not been reported. We found that HEF1, but not p130(Cas), is tyrosine-phosphorylated following stimulation of the rabbit C1a calcitonin receptor stably expressed in HEK-293 cells. The calcitonin-induced tyrosine phosphorylation of HEF1 increased in a time- and dose-dependent manner. Dibutyryl cAMP and forskolin had little or no effect on HEF1 phosphorylation, and the protein kinase A inhibitor H89 failed to detectably inhibit the response to calcitonin, indicating that the G(s)/cAMP/protein kinase A pathway does not mediate the calcitonin effect. Pertussis toxin, which selectively blocks G(i/o) signaling, also had no effect. Increasing cytosolic Ca(2+) with ionomycin stimulated HEF1 phosphorylation and preventing any calcitonin-induced change in cytosolic calcium by a combination of BAPTA and extracellular EGTA completely blocked the calcitonin-induced tyrosine phosphorylation of HEF1. Phorbol 12-myristate 13-acetate also induced HEF1 tyrosine phosphorylation, and the protein kinase C inhibitor calphostin C completely inhibited both calcitonin- and phorbol 12-myristate 13-acetate-stimulated HEF1 phosphorylation. Calcitonin also induced the tyrosine phosphorylation of paxillin and focal adhesion kinase, and the association of these two proteins with HEF1. Pretreatment with cytochalasin D, which disrupts actin microfilaments, prevented the calcitonin-induced HEF1 and paxillin phosphorylation. In conclusion, the calcitonin-stimulated tyrosine phosphorylation of HEF1 is mediated by calcium- and protein kinase C-dependent mechanisms and requires the integrity of the actin cytoskeleton.


Histamine Intolerance: The Current State of the Art.
Histamine intolerance, also referred to as enteral histaminosis or sensitivity to dietary histamine, is a disorder associated with an impaired ability to metabolize ingested histamine that was described at the beginning of the 21st century. Although interest in histamine intolerance has considerably grown in recent years, more scientific evidence is still required to help define, diagnose and clinically manage this condition. This article will provide an updated review on histamine intolerance, mainly focusing on its etiology and the existing diagnostic and treatment strategies. In this work, a glance on histamine intoxication will also be provided, as well as the analysis of some uncertainties historically associated to histamine intoxication outbreaks that may be better explained by the existence of interindividual susceptibility to ingested histamine.


Effective Treatment with Cabozantinib in an Advanced Non-Small-Cell Lung Cancer Patient Harboring a CD74-ROS1 Fusion: A Case Report.
Cabozantinib has been shown to have potent anti-ROS1 activity in many solid malignancies, particularly against those with solvent-front resistance mutations following crizotinib therapy. With regard to the most common CD74-ROS1 fusion, the efficacy of cabozantinib has only been demonstrated in vitro. Therefore, we evaluate the efficacy of cabozantinib in a patient with advanced non-small-cell lung cancer (NSCLC) harboring a CD74-ROS1 fusion in the present study. A 40-year-old female patient presented with 1-month history of cough, white sputum and chest pain. Chest CT scan revealed a consolidation in the middle lobe of the right lung together with multiple cavity lesions spreading in both lungs. Histopathological analysis of biopsy samples from the lesion in the middle lobe of the right lung suggested lung adenocarcinoma. After two lines of chemotherapy and EGFR-TKI therapy, a CD74-ROS1 rearrangement was detected and the patient was administered with cabozantinib for 1.5 years. Since cabozantinib resistance developed, crizotinib therapy was applied and demonstrated clinical effectiveness until now. Together, we report the first case of cabozantinib effectiveness in treating a CD74-ROS1-positive advanced NSCLC patient. Crizotinib remained as an effective therapeutic option following the acquisition of cabozantinib resistance.


[Food risk factors and arterial hypertension in a rural population of Chernigov Province].
The prevalence of consumption of foodstuffs in the rural population of Chernigov Province was studied as were aspects of diet among the population depending on the presence of arterial hypertension (AH), for which purpose a special questionnaire was used permitting the objective assessment to be carried out of the character of nutrition. Most prevalent among the rural population is consumption of predominantly animal fat, eggs, sour-milk foodstuffs, sugar, and legumina. In AH patients, a not-rational diet is manifested by a high consumption of saturated fats and inadequate intake of polyunsaturated fatty acids, vitamines, and mineral substance.


Viewpoint: linking professionalism to humanism: what it means, why it matters.
The terms professionalism and humanism are sometimes confused as being synonymous; even more confusing, each is sometimes regarded as a component feature of the other. The author argues that, in the context of medicine, the two terms describe distinctly different, albeit intimately linked attributes of the good doctor. Professionalism denotes a way of behaving in accordance with certain normative values, whereas humanism denotes an intrinsic set of deep-seated convictions about one's obligations toward others. Viewed in this way, humanism is seen as the passion that animates professionalism. Nurturing the humanistic predispositions of entering medical students is key to ensuring that future physicians manifest the attributes of professionalism. Medical educators are encouraged to recognize the role of humanism in professional development and to incorporate into their curricula and learning environments explicit means to reinforce whatever inclinations their students have to be caring human beings. Chief among those means are respected role models who unfailingly provide humanistic care, ceremonies that celebrate the attributes of humanism, awards that honor exemplars of the caring physician, and serious engagement with the medical humanities to provide vivid insights into what a humanistic professional is.


Right aortic arch with mirror-image branching and coarctation of the aorta.
We report a case of right aortic arch with mirror-image branching and coarctation of the aorta and left ductus arteriosus in a 6-year-old boy. He was referred to Chang Gung Children's Hospital with suspected left ventricular failure. Physical examination revealed hypertension and a pulse discrepancy between the upper and lower extremities. Echocardiography and magnetic resonance imaging revealed a right aortic arch, a long segmental aortic coarctation, and a patent ductus arteriosus. In addition, mirror-image branching of the brachiocephalic vessels was found. The coarctation was resected and the ductus arteriosus was ligated. The postoperative recovery was uneventful and the blood pressure returned to normal. He remained normotensive and had no symptoms of heart failure within the 2 years of follow-up.


Clinical relevance of contemporary cultural psychiatry.
In recent years, the field of cultural psychiatry has gained recognition and accumulated evidence of its clinical relevance. This article examines the intersections of culture and psychopathology and describes five independent but interrelated clinical dimensions that identify and define culture as: a) an interpretive/explanatory tool, b) a pathogenic/pathoplastic agent, c) a diagnostic/nosological factor, d) a therapeutic/protective element, and e) a service/management instrument. Along these lines, conceptual boundaries, clinical findings, specific applications, and research implications for each of the five dimensions are systematically reviewed. Cultural psychiatry adds significantly to the comprehensiveness of psychiatric evaluation and management and addresses prominent issues regarding understanding, classification, diagnosis, and competent treatment of most psychiatric disorders in every society and region of the world. Based on the strength of these clinical dimensions, and on the related educational and research efforts, cultural psychiatry can also contribute decisively to the design of comprehensive mental health policies.


Assessing infestation risk by vectors. Spatial and temporal distribution of African ticks at the scale of a landscape.
Control of major livestock diseases in the tropics, such as theileriosis or trypanosomosis, is still largely based on the control of their vectors. Understanding the distribution of vectors, such as ticks and tsetse flies, is needed in order to improve the efficiency and economical viability of control operations. Technical improvements such as remote sensing and global information systems have allowed valuable improvements for the prediction of large-scale vector distribution (continental to national), but trying to make these predictions at the scale of a landscape is facing other challenges. At this scale, an analysis of host/vector interactions with an evolutionary point of view is useful. A study was undertaken on a mixed game/cattle ranch in Zimbabwe during which we monitored variations in the abundance and spatial distribution of the immature free stages of Rhipicephalus appendiculatus/R. zambeziensis and R. e. evertsi, two major groups of tick species in Southern Africa. We found two contrasting distributions in relation to contact between tick larvae. The ungulate-host R. e. evertsi appeared to be unpredictable, whereas R. appendiculatus/R. zambeziensis were predictable in time and space, but associated with key-resources for ungulates (water and forage resources). The consequences of such distributions are discussed in terms of vector control.


HIV and cancer registry linkage identifies a substantial burden of cancers in persons with HIV in India.
We utilized computerized record-linkage methods to link HIV and cancer databases with limited unique identifiers in Pune, India, to determine feasibility of linkage and obtain preliminary estimates of cancer risk in persons living with HIV (PLHIV) as compared with the general population.Records of 32,575 PLHIV were linked to 31,754 Pune Cancer Registry records (1996-2008) using a probabilistic-matching algorithm. Cancer risk was estimated by calculating standardized incidence ratios (SIRs) in the early (4-27 months after HIV registration), late (28-60 months), and overall (4-60 months) incidence periods. Cancers diagnosed prior to or within 3 months of HIV registration were considered prevalent.Of 613 linked cancers to PLHIV, 188 were prevalent, 106 early incident, and 319 late incident. Incident cancers comprised 11.5% AIDS-defining cancers (ADCs), including cervical cancer and non-Hodgkin lymphoma (NHL), but not Kaposi sarcoma (KS), and 88.5% non-AIDS-defining cancers (NADCs). Risk for any incident cancer diagnosis in early, late, and combined periods was significantly elevated among PLHIV (SIRs: 5.6 [95% CI 4.6-6.8], 17.7 [95% CI 15.8-19.8], and 11.5 [95% CI 10-12.6], respectively). Cervical cancer risk was elevated in both incidence periods (SIRs: 9.6 [95% CI 4.8-17.2] and 22.6 [95% CI 14.3-33.9], respectively), while NHL risk was elevated only in the late incidence period (SIR: 18.0 [95% CI 9.8-30.20]). Risks for NADCs were dramatically elevated (SIR > 100) for eye-orbit, substantially (SIR > 20) for all-mouth, esophagus, breast, unspecified-leukemia, colon-rectum-anus, and other/unspecified cancers; moderately elevated (SIR > 10) for salivary gland, penis, nasopharynx, and brain-nervous system, and mildly elevated (SIR > 5) for stomach. Risks for 6 NADCs (small intestine, testis, lymphocytic leukemia, prostate, ovary, and melanoma) were not elevated and 5 cancers, including multiple myeloma not seen.Our study demonstrates the feasibility of using probabilistic record-linkage to study cancer/other comorbidities among PLHIV in India and provides preliminary population-based estimates of cancer risks in PLHIV in India. Our results, suggesting a potentially substantial burden and slightly different spectrum of cancers among PLHIV in India, support efforts to conduct multicenter linkage studies to obtain precise estimates and to monitor cancer risk in PLHIV in India.


User involvement in a Danish project on the empowerment of cancer patients - experiences and early recommendations for further practice.
This paper reports on the process of involving former and current cancer patients and carers as co-researchers in a Danish mixed methods research project on patient empowerment of cancer patients in follow up (The Empowerment study 2015-2019). User-Involvement in health care research is a relatively new practice in Denmark and the Empowerment project was one of the first to systematically involve patients and carers in its research design, conduct and reporting. The paper has two aims: first, it provides a detailed account of the process of involving co-researchers in the Empowerment project and second, it presents findings from a workshop held with academic researchers and co-researchers on the project to discuss their experiences and recommendations for user-involvement in the Danish context. The Empowerment project adopted a consultative and collaborative approach to user involvement and co-researchers were involved from the early stages and all through the project. Users gave feedback on the proposal, helped develop project documents and research tools, acted as peer interviewers in qualitative interviews, participated in data analysis and development of questionnaires, and co-authored journal articles. The workshop held with the academic researchers and co-researchers consisted of two parallel focus groups and a joint group discussion, following an interactive and informal format to facilitate discussion and exchange of ideas. The focus group resulted in eleven recommendations for the further development of user-involvement in Denmark. Key issues encountered were the general lack of guidelines on user-involvement in the Danish context and the need for more organisational support. Particular issues, such as payment, recruitment and training, need to be carefully considered within individual projects and within the national context in which projects are carried out. The paper adds to the current very limited knowledge base on user-involvement in the Danish context and provides a set of early recommendations for the further development of the practice in Danish Health Research. User-involvement needs to be developed with consideration to the local context, but common challenges also emphasise the usefulness of cross-country comparisons and knowledge exchange.


Perioperative practice: time to throttle back.
The United States spends more on health care than other nations, yet our health outcomes remain inferior to those of many countries. Change is therefore necessary. One approach to health care reform is to identify and eliminate practices associated with high cost and limited benefit. Recent research has shown that many perioperative practices meet this definition. An opportunity thus exists for rational reduction of perioperative expenditure. Perioperative tests and treatments improve outcomes only when targeted at specific patient subsets. For example, routine perioperative stress testing provides no incremental diagnostic yield in patients at low risk for cardiac events, and indiscriminate perioperative therapy with beta-blockers can increase mortality in otherwise stable patients. Thus, many "accepted" perioperative practices conflict with the evidence and can be safely discontinued while preserving outcomes and reducing costs. Implementation of the American College of Cardiology/American Heart Association perioperative guidelines ensures cost-effective management and promises the greatest benefit for our patients. Our society demands better care at lower cost; in perioperative medicine, it is time for us to throttle back.


Electrochemical detection of exogenously administered melatonin in the brain.
Melatonin (MT) is an important electroactive hormone that regulates different physiological actions in the brain, ranging from circadian clock to neurodegeneration. An impressive number of publications have highlighted the effectiveness of MT treatments in different types of sleep and neurological disorders, including Alzheimer's and Parkinson's disease. The ability to detect MT in different regions of the brain would provide further insights into the physiological roles and therapeutic effects of MT. While multiple electrochemical methods have been used to detect MT in biological samples, monitoring MT in the brain of live animals has not been demonstrated. Here, we optimized a square wave voltammetry (SWV) electroanalytical method to evaluate the MT detection performance at CFEs in vitro and in vivo. SWV was able to sensitively detect the MT oxidation peak at 0.7 V, and discriminate MT from most common interferents in vitro. More importantly, using the optimized SWV, CFEs successfully detected and reliably quantified MT concentrations in the visual cortex of anesthetized mice after intraperitoneal injections of different MT doses, offering stable MT signals for up to 40 minutes. To the best of our knowledge, this is the first electrochemical measurement of exogenously administered MT in vivo. This electrochemical MT sensing technique will provide a powerful tool for further understanding MT's action in the brain.


Pharmacological blocking agents for treating substance abuse.
Pharmacological blocking agents are an important treatment approach for the current epidemic of drug abuse. This approach is multidisciplinary, ranging from molecular neuroscience for developing these blocking agents to behavioral therapies for establishing treatment delivery systems. This paper outlines the biological, behavioral, and clinical components of the pharmacological blocking agent approach. Clinical results using two blocking agents, naltrexone for opioid abuse and disulfiram for alcohol abuse, are reviewed as a source of leads in developing potential agents for treating sedative and stimulant abuse. While specific pharmacological antagonists have been developed for benzodiazepines, such agents are not yet available for stimulants. Furthermore, the clinical utility of stimulant antagonists may depend on the development of multisite agents that partially block several neurotransmitter systems rather than target a single-system brain receptor.


Nanoemulsion: A Novel Eon in Cancer Chemotherapy.
Cancer refers to an assemblage of lethal diseases characterized by abnormal growth of cells. The most celebrated adverse effects accredited to the cytotoxic class of anticancer agents are constructed owing to their inability to differentiate between the abnormally multiplying cancerous cell mass and the rapidly dividing healthy cells of the human body. Consequently, unknown targets chemotherapy for cancer play host to a multitude of adverse effects ranging from nausea, alopecia to torturous ages associated with the current treatment etiquette. Nano-pharmaceuticals constitute the advanced scale drug targeting technologies. Nanoemulsion is an important tool in the nano-technological arena designed for clinical and therapeutic application. Currently among different nano-carriers, nanoemulsions are extensively envisaged as efficient drug delivery systems for the targeted delivery of lipophilic cytotoxic antineoplastic agents. Beauties of nanoemulsion include optical clarity, biocompatibility, non-immunogenic, biodegradable, drug encapsulation, sustained and controlled release, nanometric size, large surface area, ease of preparation and thermodynamic stability. After excessive delving, the research fraternity has acknowledged nanoemulsions as proficient nanocarriers capable of effectively addressing the low bioavailability and noncompliance issues associated with the conventional anticancerous chemotherapeutic dosage forms. This review attempts to shed new light on the current status of nanoemulsion in the cancer therapeutics, and commercial field on the basis of morphology, formulation, characteristics and characterization parameters.


Antiviral, antibacterial and vitamin C-synergized radical-scavenging activity of Sasa senanensis Rehder extract.
Sasa senanensis Rehder extract (SE) showed slightly higher cytotoxicity against human squamous cell carcinoma cell lines and human glioblastoma cell lines, as compared with human oral normal cells (gingival fibroblast, pulp cell, periodontal ligament fibroblast), and was more cytotoxic to human myelogenous and T-cell leukemia cell lines. SE showed a bacteriostatic effect on Fusobacterium nucleatum and Prevotella intermedia, but almost completely eliminated hydrogen sulfide (H2S) and methyl mercaptan (CH3SH) produced by these bacteria. SE protected human T-cell leukemia MT-4 cells from the cytopathic effect of human immunodeficiency virus (HIV) infection, and its anti-HIV activity was much higher than that of tannins and flavonoids, comparable with that of natural and synthetic lignins. SE also protected the MDCK cells from the cytopathic effect of influenza virus infection. SE synergistically enhanced the superoxide anion and hydroxyl radical-scavenging activity of vitamin C. The present study suggests the functionality of SE as a complementary alternative medicine.


Neuroprotective role of fucoxanthin against cerebral ischemic/reperfusion injury through activation of Nrf2/HO-1 signaling.
In the present study, an attempt was made to determine whether administration of fucoxanthin could attenuate cerebral ischemic/reperfusion (I/R) injury and its possible mechanisms using an in vivo middle cerebral artery occlusion (MCAO) model and an in vitro oxygen-glucose deprivation and reoxygenation (OGD/R) model. Fucoxanthin was intragastrically administrated in different doses (30 mg/kg, 60 mg/kg, and 90 mg/kg, respectively) to the rats 1 h before MCAO induction. The neurological function, infarct area and brain water content of rats were then evaluated. Rat cortical neuron were pretreated with different doses of fucoxanthin (5 μM, 10 μM, and 20 μM) and then subjected to OGD/R. Expression levels of proteins in the brain tissues and cultured cells were determined by western blotting. Our results demonstrated that fucoxanthin pretreatment improved the neurologic deficit score, lowered the infarct volume and reduced the expression of apoptosis-associated proteins in brain tissues. In addition, fucoxanthin also suppresses OGD/R-induced apoptosis and ROS accumulation in cultured neurons. Furthermore, we found that fucoxanthin could significantly activate the Nrf2/HO-1 signaling through inducing Nrf2 nuclear translocation with enhanced HO-1 expression, and Nrf2 knockdown obviously abrogated the beneficial role of fucoxanthin in OGD/R-treated neurons. These findings suggested that fucoxanthin could be exploited as a therapeutic target for protecting neurons from cerebral I/R injury.


Probing the ionization state of substrate alpha-D-glucopyranosyl phosphate bound to glycogen phosphorylase b.
The ionization state of the substrate alpha-D-glucopyranosyl phosphate bound at the active site of glycogen phosphorylase has been probed by a number of techniques. Values of Ki determined for a series of substrate analogue inhibitors in which the phosphate moiety bears differing charges suggest that the enzyme will bind both the monoanionic and dianionic substrates with approximately equal affinity. These results are strongly supported by 31P- and 19F-NMR studies of the bound substrate analogues alpha-D-glucopyranosyl 1-methylenephosphonate and 2-deoxy-2-fluoro-alpha-D-glucopyranosyl phosphate, which also suggest that the substrate can be bound in either ionization state. The pH-dependences of the inhibition constants K1 for these two analogues, which have substantially different phosphate pK2 values (7.3 and 5.9 respectively), are found to be essentially identical with the pH-dependence of K(m) values for the substrate, inhibition decreasing according to an apparent pKa value of 7.2. This again indicates that there is no specificity for monoanion or dianion binding and also reveals that binding is associated with the uptake of a proton. As the bound substrate is not protonated, this proton must be taken up by the proton.


WRKY75 transcription factor is a modulator of phosphate acquisition and root development in Arabidopsis.
Phosphate (Pi) deficiency limits plant growth and development, resulting in adaptive stress responses. Among the molecular determinants of Pi stress responses, transcription factors play a critical role in regulating adaptive mechanisms. WRKY75 is one of several transcription factors induced during Pi deprivation. In this study, we evaluated the role of the WRKY75 transcription factor in regulating Pi starvation responses in Arabidopsis (Arabidopsis thaliana). WRKY75 was found to be nuclear localized and induced differentially in the plant during Pi deficiency. Suppression of WRKY75 expression through RNAi silencing resulted in early accumulation of anthocyanin, indicating that the RNAi plants were more susceptible to Pi stress. Further analysis revealed that the expression of several genes involved in Pi starvation responses, including phosphatases, Mt4/TPS1-like genes, and high-affinity Pi transporters, was decreased when WRKY75 was suppressed. Consequently, Pi uptake of the mutant plant was also decreased during Pi starvation. In addition, when WRKY75 expression was suppressed, lateral root length and number, as well as root hair number, were significantly increased. However, changes in the root architecture were obvious under both Pi-sufficient and Pi-deficient conditions. This indicates that the regulatory effect of WRKY75 on root architecture could be independent of the Pi status of the plant. Together, these results suggest that WRKY75 is a modulator of Pi starvation responses as well as root development. WRKY75 is the first member of the WRKY transcription factor family reported to be involved in regulating a nutrient starvation response and root development.


MUTYH: Not just polyposis.
MUTYH is a base excision repair enzyme, it plays a crucial role in the correction of DNA errors from guanine oxidation and may be considered a cell protective factor. In humans it is an adenine DNA glycosylase that removes adenine misincorporated in 7,8-dihydro-8-oxoguanine (8-oxoG) pairs, inducing G:C to T:A transversions. MUTYH functionally cooperates with OGG1 that eliminates 8-oxodG derived from excessive reactive oxygen species production. MUTYH mutations have been linked to MUTYH associated polyposis syndrome (MAP), an autosomal recessive disorder characterized by multiple colorectal adenomas. MAP patients show a greatly increased lifetime risk for gastrointestinal cancers. The cancer risk in mono-allelic carriers associated with one MUTYH mutant allele is controversial and it remains to be clarified whether the altered functions of this protein may have a pathophysiological involvement in other diseases besides familial gastrointestinal diseases. This review evaluates the role of MUTYH, focusing on current studies of human neoplastic and non-neoplastic diseases different to colon polyposis and colorectal cancer. This will provide novel insights into the understanding of the molecular basis underlying MUTYH-related pathogenesis. Furthermore, we describe the association between MUTYH single nucleotide polymorphisms (SNPs) and different cancer and non-cancer diseases. We address the utility to increase our knowledge regarding MUTYH in the light of recent advances in the literature with the aim of a better understanding of the potential for identifying new therapeutic targets. Considering the multiple functions and interactions of MUTYH protein, its involvement in pathologies based on oxidative stress damage could be hypothesized. Although the development of extraintestinal cancer in MUTYH heterozygotes is not completely defined, the risk for malignancies of the duodenum, ovary, and bladder is also increased as well as the onset of benign and malignant endocrine tumors. The presence of MUTYH pathogenic variants is an independent predictor of poor prognosis in sporadic gastric cancer and in salivary gland secretory carcinoma, while its inhibition has been shown to reduce the survival of pancreatic ductal adenocarcinoma cells. Furthermore, some MUTYH SNPs have been associated with lung, hepatocellular and cervical cancer risk. An additional role of MUTYH seems to contribute to the prevention of numerous other disorders with an inflammatory/degenerative basis, including neurological and ocular diseases. Finally, it is interesting to note that MUTYH could be a new therapeutic target and future studies will shed light on its specific functions in the prevention of diseases and in the improvement of the chemo-sensitivity of cancer cells.


Tocilizumab: The evidence for its place in the treatment of juvenile idiopathic arthritis.
Juvenile idiopathic arthritis (JIA) is one of the most common chronic diseases with childhood onset. It comprises different subtypes of which the systemic onset subtype is often resistant to treatment. With the advent of biological treatment with tumor necrosis factor-alpha (TNFalpha)-inhibitors, the clinical outcome of JIA has improved considerably, but only for subtypes other than systemic JIA. Substantial evidence shows that the proinflammatory cytokine interleukin-6 (IL-6) plays a pivotal role in systemic JIA. The blockage of IL-6 action by tocilizumab, a humanized anti-IL-6-receptor monoclonal antibody, could therefore be an effective treatment of systemic JIA. The purpose of this article was to review the clinical trials of tocilizumab and to discuss its place in the treatment of JIA with the focus on the systemic onset of disease. Two phase II studies and one phase III clinical trial of tocilizumab demonstrating the clinical efficacy and safety in systemic onset JIA have been published. Within those studies, sustained and high response rates of clinical improvement have been achieved with American College of Rheumatology Pediatric criteria (ACRPed) 30, 50, and 70 observed in 98%, 94%, and 90% of patients, respectively, after 48 weeks. One study regarding the clinical efficacy of tocilizumab for the treatment of oligo- and polyarticular JIA has been presented only as a conference abstract. The very promising results seen so far in patients with severe systemic JIA and acceptable tolerability gives tocilizumab a central role in the future therapy in controlling this disease. No other biological therapy has achieved similar high response rates when treating with tocilizumab 8 mg/kg every two weeks to patients with systemic onset JIA, but direct comparison of the efficacy of different biological agents are not yet available.


Foods prepared outside the home: association with selected nutrients and body mass index in adult Australians.
To determine the proportion of energy from foods prepared outside the home (FPOH) and the relationships with energy and nutrient intakes and body mass index (BMI). A nutrition survey of a representative sample of the Australian population aged 18 years and over Measure used was a 24-hour dietary recall. Underreporters (energy intake/estimated basal metabolic rate (EI/BMR) <0.9) were excluded from analysis. Daily energy and selected nutrient intakes were calculated using a 1996 nutrient composition database for all foods/beverages during the 24-hour period. On average FPOH contributed a significant 13% to total energy intake. About a third of the sample had consumed FPOH in the last 24 hours and on average this group consumed a third of their total energy as FPOH. The relative contributions of fat (for men and women) and alcohol (for women) were significantly higher for those in the top tertile of FPOH consumers. The intakes of fibre and selected micronutrients (calcium, iron, zinc, folate and vitamin C) were significantly lower in this group. After adjustment for age and income no relationship between FPOH and BMI was observed. FPOH make a significant contribution to the energy intake of a third of the Australian population. FPOH contribute to poor nutritional intakes. Altering the supply of FPOH may be an effective means of improving diets at a population level.


ACT and Recovery: What We Know About Their Compatibility.
While assertive community treatment (ACT) is a widely implemented evidence-based practice, the extent of its recovery orientation has been debated. A literature search identified 16 empirical articles studying recovery and ACT. These 16 studies were classified as involving stakeholder perceptions, interventions, or fidelity measurement. Stakeholders generally viewed ACT as being recovery oriented; research on both interventions and fidelity measurement showed promising approaches. Overall the literature yielded encouraging findings regarding ACT and recovery, though there remains a dearth of research on the topic. We discuss future directions for research and practice to ensure that ACT programs skillfully support recovery.


Isoflavonoids and chronic disease: mechanisms of action.
Soy and its isoflavones are associated with a reduced risk of chronic disease. The mechanisms of action of isoflavones include their roles as weak estrogens, inhibitors of tyrosine kinase-dependent signal transduction processes and as cellular antioxidants. Although estrogen receptor beta binds genistein with an affinity close to that of 17beta-estradiol, it remains to be determined whether it is a mediator of genistein's activity in vivo. Genistein's inhibition of protein tyrosine kinases is not limited to direct effect on these kinases, but may result from alteration in kinase expression. Genistein is not a particularly good scavanger of cellular oxidants; however, it reacts vigorously with the prooxidant hypochlorous acid, produced by neutrophils as part of the inflammatory response. The chlorinated isoflavones may have altered biochemical and biological effects compared to their parent compounds and may provide increased protection against inflammatory disease.


Developmental changes in the microgenesis of face perception revealed by effects of context and inversion.
Present studies on the development of face perception mechanisms are ambiguous about the question of whether holistic face vision arises early, or in the second decade of life (Crookes & McKone, 2009). Measuring the time course of face matching we assess effects of context and inversion as correlates of holistic processing in the microgenesis of face perception within the first 650 ms, and compare among 8- to 10-year-old children and adults. Results for adults indicate dominance of holistic viewing at brief timings, which is gradually replaced by feature selective strategies enabling them to selectively attend either internal or external features, as demanded by instruction. For children, however, effects of context and inversion are absent at brief timings, but gradually increase to strong levels with increasing viewing times. Moreover, we find a pronounced asymmetry in face matching performance with internal and external features. While face matching by attending external features is well developed and robust against variable facial contexts, face matching by attending internal features is generally poor, and strongly affected by interleaved congruent and incongruent contextual information. These results indicate that children and adults differ not only in the kind of featural information they preferentially encode in face perception, but also in the processing time they need to build holistic representations. While these are fast and automatic in adults' face vision, children's face representations are part based at brief timings, but develop to integrated wholes as more temporal resources are made available.


Development of a split G-quadruplex and DAPI-based fluorescent probe for Hg(II) and Pb(II) ions detection.
A novel thymine- and guanine-rich oligonucleotide (ODN-7) was engineered explicitly for the detection of Hg(II) and Pb(II) by a single intercalated dye 4',6-diamidinyl-2-phenylindole (DAPI). Upon the introduction of Hg(II), a rapid formation of T-Hg(II)-T base pairs takes place, triggering the assembly of a split G-quadruplex structure, resulting in a strong fluorescence signal due to DAPI intercalating into the T-Hg(II)-T mismatch. The introduction of Pb(II) initiates an interaction with the split G-quadruplex, causing a significant conformational change in its structure. Consequently, the altered split G-quadruplex structure fails to facilitate the insertion of DAPI into the T-Hg(II)-T complexes, leading to fluorescence quenching. This strategy offers a straightforward means of detecting Hg(II) and Pb(II). Leveraging the split G-quadruplex, the ODN-7 sensor enables the detection limits (3σ) for Hg(II) and Pb(II) to reach an impressive low of 0.39 nM and 4.98 nM, respectively. It exhibited a favorable linear range of 0.39-900 nM for Hg(II) detection (R2 = 0.9993) and 4.98 nM-5 μM for Pb(II) determination (R2 = 0.9953), respectively. Furthermore, the proposed sensor had excellent selectivity for detecting Hg(II) and Pb(II). It was used in milk samples containing mixed Hg(II) and Pb(II) solutions, yielding recovery rates of 99.3-103.8% for Hg(II) detection and 100.1-104.1% for Pb(II) detection.


Deaths Related to Tractor Accidents in Eskişehir, Turkey: A 25-Year Analysis.
This study aimed to analyze deaths related to tractor accidents in Eskişehir Province and characteristics of these cases to provide data and suggestions along with the literature. The cases involved individuals died due to tractor-related accidents were retrospectively examined between 1992 and 2016 (25-year period). Demographic data related to the cases and crime scenes, characteristics of events, and autopsy findings were evaluated. In the 25-year period, 61 individuals (88.5% males, average age: 48.7 years) died due to tractor accidents in Eskişehir Province, and approximately 45.9% of these accidents most commonly involved tractor rollover. Deaths due to tractor accidents will be decreased by raising awareness among tractor drivers, preventing young individuals from driving tractors, not allowing individuals to drive without license, making mechanical and physical features of tractors suitable for agricultural activity to be performed, ensuring their safety for travel and use, and avoiding carrying passengers on tractors.


The binding of L-[3H]nicotine to a single class of high affinity sites in rat brain membranes.
The binding of optically pure L-[3H]nicotine to rat brain membrane preparations was studied using a rapid filtration method. The binding properties observed depended on the method used for tissue isolation. The most consistent results were obtained with membranes prepared in the presence of protease inhibitors, without divalent cations. Binding was saturable, reversible, and stereospecific. Scatchard analysis revealed a single class of high affinity sites with an average KD of 2 nM and a Bmax of approximately 200 fmol/mg of protein. The Hill coefficient was near unity. The KD calculated from the kinetic rate constants for association (k1 = 0.012 min-1 nM-1) and dissociation (k-1 = 0.04 min-1) was around 3 nM, in good agreement with the dissociation constant determined from equilibrium binding. In competition studies, cholinergic agonists were generally the most effective in inhibiting L-[3H]nicotine binding, whereas antagonists were relatively ineffective. The D-isomer of nicotine was about 60-fold less potent than the L-isomer in inhibiting binding. The results were unaffected by temperature, with the exception that Bmax was somewhat lower at 37 degrees. The equilibrium binding properties of these sites were essentially identical in adult male and female brain. However, Bmax was lower in fetal brain tissue. The present findings are consistent with the idea that there is a single class of high affinity nicotinic binding sites in rat brain with cholinoceptive properties.


Characteristics of temper tantrums in preschoolers with disruptive behavior in a clinical setting.
The purpose of this study was to describe clinician-observed, naturally occurring temper tantrums in preschoolers ages 2 to 5.5 diagnosed with severe behavior problems. Participants were 24 mother-child dyads enrolled in an intensive outpatient treatment program. Clinicians timed and observed 330 temper tantrums, rated their intensity, and recorded occurrence of 16 behaviors, tantrum precipitants, and interventions; parents completed the Achenbach Child Behavior Checklist pre- and posttreatment. Data were analyzed using descriptive statistics, Pearson chi square, paired t tests, and generalized linear modeling. Mean tantrum duration was 3.4 minutes (range = 0.2 to 26.5 minutes); most tantrums were low in intensity. Noncompliance precipitated 52% of tantrums. Aggressive behaviors were more likely to occur early in tantrums, with distress behaviors occurring later. Parent surveys indicated perceptions of behavioral improvement but no change in tantrum behavior. Study findings corroborate those of previous studies using retrospective parent reports.


Combined hematopoietic and lentiviral gene-transfer therapies in newborn Twitcher mice reveal contemporaneous neurodegeneration and demyelination in Krabbe disease.
This study characterized the therapeutic benefits of combining hematogenous cell replacement with lentiviral-mediated gene transfer of galactosylceramidase (GALC) in Twitcher mice, a bona fide model for Krabbe disease. Bone marrow cells and GALC-lentiviral vectors were administered intravenously without any preconditioning to newborn Twitcher pups before postnatal day 2. Treated Twitchers survived up to 4 months of age. GALC activity remained less than 5% of normal values in the nervous system for the first 2 months after treatment and reached approximately 30% in long-term-surviving mice. Long-term reconstitution of GALC activity in the nervous system was provided primarily by infiltrating macrophages and to a lesser extent by direct lentiviral transduction of neural cells. Treated Twitchers had significant preservation of myelin, with a G-ratio (ratio of the axon diameter to the diameter of the myelinated fiber) in sciatic nerve myelin of 0.75 +/- 0.08 compared with 0.85 +/- 0.10 in untreated mutants. Although treated mutants had improved locomotor activities during their long-term survival, they died with symptoms of progressive neurological degeneration, indistinguishable from those seen in untreated Twitchers. Examination of long-lived Twitchers showed that treated mutants were not protected from developing degeneration of axons throughout the neuroaxis. These results suggest that GALC deficiency not only affects myelinating glia but also leads to neuronal dysfunction. The contemporaneous neuropathology might help to explain the limited efficacy of current gene and cell therapies.


Temperature-sensitive lethal pseudorevertants of ste mutations in Saccharomyces cerevisiae.
A procedure was devised to isolate mutations that could restore conjugational competence to temperature sensitive ste mutants and simultaneously confer temperature-sensitive lethal growth phenotypes. Three such mutations, falling into two complementation groups, were identified on the basis of suppression of ste5 alleles. These same mutations were later shown to be capable of suppressing ste4 and ste7 alleles. Five mutations in a single complementation group were isolated as suppressors of ste2 alleles. None of the mutations described in this study conferred a homogeneous cell cycle arrest phenotype, and all were shown to define complementation groups distinct from those previously identified in studies of cell division cycle (cdc) mutations. In no instance did pseudoreversion appear to be achieved by mutational G1 arrest of ste mutant cells. Instead, it is proposed that the mutations restore conjugation by reestablishing the normal pheromone response.


Photoredox Nickel-Catalysed Stille Cross-Coupling Reactions.
The Stille cross-coupling reaction is one of the most common strategies for the construction of C-C bonds. Despite notable strides in the advancement of the Stille reaction, persistent challenges persist in hindering its greener evolution. These challenges encompass multiple facets, such as the high cost of precious metals and ligands, the demand for various additives, and the slow reaction rate. In comparison to the dominant palladium-catalysed Stille reactions, cost-effective nickel-catalysed systems lag behind, and enantioconvergent Stille reactions of racemic stannanes remain undeveloped. Herein, we present a pioneering instance of nickel-catalysed enantioconvergent Stille cross-coupling reactions of racemic stannane reagents, resulting in the formation of C-C bonds in good to high yields with excellent stereoselectivity. This strategy provides a practical, scalable, and operationally straightforward method for the synthesis of C(sp3 )-C(sp3 ), C(sp3 )-C(sp2 ), and C(sp3 )-C(sp) bonds under exceptionally mild conditions (without additives and bases, ambient temperature). The innovative use of synergistic photoredox/nickel catalysis enables a novel single-electron transmetalation process of stannane reagents, providing a new research paradigm of Stille reactions.


Desulfotomaculum arcticum sp. nov., a novel spore-forming, moderately thermophilic, sulfate-reducing bacterium isolated from a permanently cold fjord sediment of Svalbard.
Strain 15T is a novel spore-forming, sulfate-reducing bacterium isolated from a permanently cold fjord sediment of Svalbard. Sulfate could be replaced by sulfite or thiosulfate. Hydrogen, formate, lactate, propionate, butyrate, hexanoate, methanol, ethanol, propanol, butanol, pyruvate, malate, succinate, fumarate, proline, alanine and glycine were used as electron donors in the presence of sulfate. Growth occurred with pyruvate as sole substrate. Optimal growth was observed at pH 7.1-7.5 and concentrations of 1-1.5 % NaCl and 0.4 % MgCl2. Strain 15T grew between 26 and 46.5 degrees C and optimal growth occurred at 44 degrees C. Therefore, strain 15T apparently cannot grow at in situ temperatures of Arctic sediments from where it was isolated, and it was proposed that it was present in the sediment in the form of spores. The DNA G+C content was 48.9 mol%. Strain 15T was most closely related to Desulfotomaculum thermosapovorans MLF(T) (93.5 % 16S rRNA gene sequence similarity). Strain 15T represents a novel species, for which the name Desulfotomaculum arcticum sp. nov. is proposed. The type strain is strain 15T (=DSM 17038T = JCM 12923T).


Outcome of neurolysis for failed tarsal tunnel surgery.
Revision tarsal tunnel surgery was performed on 44 patients (two bilaterally). The surgical procedure included a neurolysis of the tibial nerve in the tarsal tunnel, the medial plantar, lateral plantar, and calcaneal nerves in their respective tunnels, excision of the intertunnel septum, and neuroma resection as indicated. A painful tarsal tunnel scar or painful heel was treated, respectively, by resection of the distal saphenous nerve or a calcaneal nerve branch. Postoperative, immediate ambulation was permitted. Outcomes were assessed with a numerical grading scale that included neurosensory measurements. Outcomes were also assessed by patient satisfaction and their own estimate of residual pain and/or numbness. Mean follow-up time was 2.2 years. Outcomes in terms of patient satisfaction were 54% excellent, 24% good, 13% fair, and 9% poor results. The mean preoperative numerical score was 6.0 and the mean postoperative score was 2.7. There was a significant improvement seen, based on the median difference between scores (P<0.001). Prognostic indicators of poor results in our patient group were coexisting lumbosacral disc disease and/or neuropathy. An approach related to resecting painful cutaneous nerves and neurolysis of all tibial nerve branches at the ankle offers hope for relief of pain and recovery of sensation for the majority of patients with failed previous tarsal tunnel surgery.


Motor skill learning between selection and execution.
Learning motor skills evolves from the effortful selection of single movement elements to their combined fast and accurate production. We review recent trends in the study of skill learning which suggest a hierarchical organization of the representations that underlie such expert performance, with premotor areas encoding short sequential movement elements (chunks) or particular component features (timing/spatial organization). This hierarchical representation allows the system to utilize elements of well-learned skills in a flexible manner. One neural correlate of skill development is the emergence of specialized neural circuits that can produce the required elements in a stable and invariant fashion. We discuss the challenges in detecting these changes with fMRI.


Global analysis of the cortical neuron proteome.
In this study, a multidimensional fractionation approach was combined with MS/MS to increase the capability of characterizing complex protein profiles of mammalian neuronal cells. Proteins extracted from primary cultures of cortical neurons were digested with trypsin followed by fractionation using strong cation exchange chromatography. Each of these fractions was analyzed by microcapillary reversed-phase LC-MS/MS. The analysis of the MS/MS data resulted in the identification of over 15,000 unique peptides from which 3,590 unique proteins were identified based on protein-specific peptide tags that are unique to a single protein in the searched database. In addition, 952 protein clusters were identified using cluster analysis of the proteins identified by the peptides not unique to a single protein. This identification revealed that a minimum of 4,542 proteins could be identified from this experiment, representing approximately 16% of all known mouse proteins. An evaluation of the number of false-positive identifications was undertaken by searching the entire MS/MS dataset against a database containing the sequences of over 12,000 proteins from archaea. This analysis allowed a systematic determination of the level of confidence in the identification of peptides as a function of SEQUEST cross correlation (Xcorr) and delta correlation (DeltaCn) scores. Correlation charts were also constructed to show the number of unique peptides identified for proteins from specific classes. The results show that low-abundance proteins involved in signal transduction and transcription are generally identified by fewer peptides than high-abundance proteins that play a role in maintaining mammalian cellular structure and motility. The results presented here provide the broadest proteome coverage for a mammalian cell to date and show that MS-based proteomics has the potential to provide high coverage of the proteins expressed within a cell.


EARTH SCIENCE: Did Volcanoes Drive Ancient Extinctions?
With the publication in recent weeks of two papers on a mass extinction 183 million years ago, researchers can add five suggestive cases to the list of extinctions with known causes. These extinctions coincide with massive outpourings of lava, accompanied by signs that global warming threw the ocean-atmosphere system out of whack. Although no one can yet pin any of these mass extinctions with certainty on the volcanic eruptions, scientists say it's unlikely that they're all coincidences.


What is the impact of comorbid depression on adolescent substance abuse treatment?
Substance use disorders (SUDs) are among the most common psychiatric diagnoses in adolescents. Some research suggests that comorbid depression in adolescents with SUD is associated with increased likelihood of alcohol dependence, poorer social competence, and greater risk for suicide attempts. However, little is known about how depression influences adolescent substance abuse treatment retention and outcomes. This review aimed to summarize the effects of comorbid depression on treatment retention and outcomes across 13 adolescent SUD treatment studies. RESULTS indicated that depression has a mixed relationship with treatment retention and outcomes, exerting a negative, positive, or nonsignificant effect depending on aspects of the study. More research needs to be done, particularly addressing the potential mediators and moderators of the relationship between depression and SUD outcomes. Importantly, recognizing that the studies varied widely in hypotheses and research methods, the field needs to develop more standardized methods to allow for a clearer understanding of the role of comorbid depression.


Clinical implication of negative conversion of predicted circumferential resection margin status after preoperative chemoradiotherapy for locally advanced rectal cancer.
To evaluate the prognostic implication of the negative conversion of predicted circumferential resection margin status before surgery in patients with locally advanced rectal cancer with predicted circumferential resection margin involvement. Thirty-eight patients (28 men, 10 women; median age, 61 years; age range, 39-80 years) with locally advanced rectal cancer with predicted circumferential resection margin involvement who underwent preoperative chemoradiotherapy followed by radical surgery were analyzed. Involvement of the circumferential resection margin was predicted on the basis of pre- and post-chemoradiotherapy magnetic resonance imaging. The primary endpoints were 3-year local recurrence-free survival and overall survival. The median follow-up time was 41.1 months (range, 13.9-85.2 months). The negative conversion rate of predicted circumferential resection margin status after preoperative chemoradiotherapy was 65.8%. Patients who experienced negative conversion of predicted circumferential resection margin status had a significantly higher 3-year local recurrence-free survival rate (100.0% vs. 76.9%; P=0.013), disease-free survival rate (91.7% vs. 59.3%; P=0.023), and overall survival rate (96.0% vs. 73.8%; P=0.016) than those who had persistent circumferential resection margin involvement. The negative conversion of the predicted circumferential resection margin status as predicted by magnetic resonance imaging will assist in individual risk stratification as a predictive factor for treatment response and survival before surgery. These findings may help physicians determine whether to administer more intense adjuvant chemotherapy or change the surgical plan for patients displaying resistance to preoperative chemoradiotherapy.


Supramolecular Polymerization from Controllable Fabrication to Living Polymerization.
Supramolecular polymers have attracted plenty of interest in the scientific community; however, developing controllable methods of supramolecular polymerization remains a serious challenge. This article reviews some recent developments of methods for supramolecular polymerization from controllable fabrication to living polymerization. Three facile methods with general applicability for controllable fabrication of supramolecular polymers have been established recently: the first method is a self-sorting approach by manipulating ring-chain equilibrium based on noncovalent control over rigidity of monomers; the second is covalent polymerization from supramonomers formed by noncovalent interactions; and the third is supramolecular interfacial polymerization. More excitingly, living supramolecular polymerization has been achieved by two elegant strategies, including seeded supramolecular polymerization under pathway complexity control and chain-growth supramolecular polymerization by metastable monomers. It is anticipated that this review may provide some guidance for precise fabrication of supramolecular polymers, leading to the construction of supramolecular polymeric materials with controllable architectures and functions.


Evaluating the Impact of Genomic Data and Priors on Bayesian Estimates of the Angiosperm Evolutionary Timescale.
The evolutionary timescale of angiosperms has long been a key question in biology. Molecular estimates of this timescale have shown considerable variation, being influenced by differences in taxon sampling, gene sampling, fossil calibrations, evolutionary models, and choices of priors. Here, we analyze a data set comprising 76 protein-coding genes from the chloroplast genomes of 195 taxa spanning 86 families, including novel genome sequences for 11 taxa, to evaluate the impact of models, priors, and gene sampling on Bayesian estimates of the angiosperm evolutionary timescale. Using a Bayesian relaxed molecular-clock method, with a core set of 35 minimum and two maximum fossil constraints, we estimated that crown angiosperms arose 221 (251-192) Ma during the Triassic. Based on a range of additional sensitivity and subsampling analyses, we found that our date estimates were generally robust to large changes in the parameters of the birth-death tree prior and of the model of rate variation across branches. We found an exception to this when we implemented fossil calibrations in the form of highly informative gamma priors rather than as uniform priors on node ages. Under all other calibration schemes, including trials of seven maximum age constraints, we consistently found that the earliest divergences of angiosperm clades substantially predate the oldest fossils that can be assigned unequivocally to their crown group. Overall, our results and experiments with genome-scale data suggest that reliable estimates of the angiosperm crown age will require increased taxon sampling, significant methodological changes, and new information from the fossil record. [Angiospermae, chloroplast, genome, molecular dating, Triassic.].