Interprofessional differences in disposition decisions: results from a standardized web-based patient assessment.
This study examined differences in disposition decisions among mental health professionals using a standardized Web-based simulation. Using a Web-based simulation that described, across users, the same complex psychiatric patient, credentialed clinicians in a psychiatry department conducted a violence risk assessment and selected a level of follow-up care. Of 410 clinicians who completed the simulation, 60% of psychiatrists were more likely than other types of clinicians to select higher levels of care (inpatient or emergency services) for the standardized virtual patient (odds ratio=2.67, 95% confidence interval=1.67-4.25), even after adjustment for other factors. Virtual actions taken, such as contracting with the patient for safety and discussing hospitalization, elucidated these training differences. Training backgrounds were important determinants of clinicians' actions and the dispositions they recommended for a psychiatric patient at high risk of self-harm and harm to others in the educational setting and may suggest the need for further training to standardize and optimize care.


Fluorescence resonance energy transfer analysis of secretin docking to its receptor: mapping distances between residues distributed throughout the ligand pharmacophore and distinct receptor residues.
Full structural characterization of G protein-coupled receptors has been limited to rhodopsin, with its uniquely stable structure and ability to be crystallized. For other members of this important superfamily, direct structural insights have been limited to NMR structures of soluble domains. Two members of the Class II family have recently had the structures of their isolated amino-terminal regions solved by NMR, yet it remains unclear how that domain is aligned with the heptahelical transmembrane bundle domain of those receptors. Indeed, three distinct orientations have been suggested for different members of this family. In the current work, we have utilized fluorescence resonance energy transfer to establish the distances between four residues distributed throughout fully biologically active, high affinity analogues of secretin and distinct residues in each of four extracellular regions of the intact secretin receptor. These 16 distance constraints were utilized along with nine photoaffinity labeling spatial approximation constraints to study the three proposed orientations of the peptide-binding amino terminus and helical bundle domains of this receptor. In the best model, the carboxyl terminus of secretin was found to bind in a groove above the beta-hairpin region of the receptor amino terminus, with its amino-terminal end adjacent to the third extracellular loop and top of transmembrane segment VI. This refined model of the intact receptor was also fully consistent with the spatial approximation of the Trp(48)-Asp(49)-Asn(50) endogenous agonist segment with the third extracellular loop region that it has been shown to photolabel. This provides strong evidence for the orientation of peptide-binding and signaling domains of a prototypic Class II G protein-coupled receptor.


The hippocampus: anatomy, pathophysiology, and regenerative capacity.
Cognitive deficits following insults to the central nervous system-particularly those involving the hippocampus and related structures-are often persistent and severely debilitating. Progress has been made in establishing the role of the hippocampus in integrating information in the formation of memory necessary for subsequent recollection of information. The present article will review anatomic, physiological, and functional aspects of the hippocampus in reference to learning and memory. Both animal and human hippocampal pathophysiological processes will be explored. Adaptive and maladaptive central nervous system responses will be reviewed, with a special emphasis on neurogenesis. Ideally, physiological and cellular compensatory responses ought to parallel clinical observation. However, this association is not clearly established. Finally, the current understanding of neuromodulatory mechanisms (although quite preliminary) will also be discussed.


Biodiesel Exhaust Toxicity with and without Diethylene Glycol Dimethyl Ether Fuel Additive in Primary Airway Epithelial Cells Grown at the Air-Liquid Interface.
Biodiesel usage is increasing steadily worldwide as the push for renewable fuel sources increases. The increased oxygen content in biodiesel fuel is believed to cause decreased particulate matter (PM) and increased nitrous oxides within its exhaust. The addition of fuel additives to further increase the oxygen content may contribute to even further benefits in exhaust composition. The aim of this study was to assess the toxicity of 10% (v/v) diethylene glycol dimethyl ether (DGDME) added as a biodiesel fuel additive. Primary human airway epithelial cells were grown at the air-liquid interface and exposed to diluted exhaust from an engine running on either grapeseed, bran, or coconut biodiesel or the same three biodiesels with 10% (v/v) DGDME added to them; mineral diesel and air were used as controls. Exhaust properties, culture permeability, epithelial cell damage, and IL-6 and IL-8 release were measured postexposure. The fuel additive DGDME caused a decrease in PM and nitrous oxide concentrations. However, exhaust exposure with DGDME also caused decreased permeability, increased epithelial cell damage, and increased release of IL-6 and IL-8 (p < 0.05). Despite the fuel additive having beneficial effects on the exhaust properties of the biodiesel, it was found to be more toxic.


High-quality crystallinity controlled ALD TiO2 for waveguiding applications.
We demonstrate a novel atomic layer deposition (ALD) process to make high-quality nanocrystalline titanium dioxide (TiO(2)) with intermediate Al(2)O(3) layers to limit the crystal size. The process is based on titanium chloride (TiCl(4))+water and trimethyl aluminum (TMA)+ozone processes at 250°C deposition temperature. The waveguide losses measured using a prism coupling method for 633 and 1551 nm wavelengths are as low as 0.2±0.1 dB/mm with the smallest crystal size, with losses increasing with crystal size. In comparison, plain TiO(2) deposited at 250°C without the intermediate Al(2)O(3) layers shows high scattering losses and is not viable as waveguide material. The third-order optical nonlinearity decreases with smaller crystal size as verified by third-harmonic generation microscopy but still remains high for all samples. Crystallinity controlled ALD-grown TiO(2) is an excellent candidate for various optical applications, where good thermal stability and high third-order optical nonlinearity are needed.


Widespread periodic intrinsic connections in the tree shrew visual cortex.
Intrinsic connections within the tree shrew (Tupaia glis) visual cortex (area 17) are organized in periodic stripelike patterns within layers I, II, and III. This anatomical network resembles the regularly organized stripes of 2-deoxyglucose accumulation seen after stimulation of alert animals with uniformly oriented lines. Such connections imply that widespread lateral interactions are superimposed on the retinotopic organization of area 17 and suggest alternative interpretations of cortical columns.


The effect of antibiotic therapy for Clostridioides difficile infection on mortality and other patient-relevant outcomes: a systematic review and meta-analysis.
Current practice guidelines favour fidaxomicin over vancomycin and exclude metronidazole from the recommended standard regimen for Clostridioides difficile infection (CDI), based on lower recurrence rates with fidaxomicin, giving little weight to mortality or the clinical implications of recurrences. To compile the effects of metronidazole, glycopeptides (vancomycin or teicoplanin), and fidaxomicin for CDI on mortality and other patient-relevant outcomes. PubMed, the Cochrane Library, ClinicalTrials.gov, conference proceedings, and Google Scholar, until August 2023. Randomized controlled trials (RCTs). Adult patients experiencing primary or recurrent CDI. Glycopeptides versus fidaxomicin or metronidazole (comparators). We used the Risk of Bias 2 (RoB 2) tool for randomized trials, focusing on the outcome of all-cause mortality. Random effects meta-analyses were performed for dichotomous outcomes. Outcomes were summarized preferentially for all randomly assigned patients. Thirteen trials were included. There was no significant difference in all-cause mortality (risk ratio [RR] < 1 favouring the comparator) between vancomycin and fidaxomicin (RR 0.86, 95% CI 0.64-1.14, 8 RCTs, 1951 patients) or metronidazole (RR 0.78, 95% CI 0.46-1.32, 4 RCTs, 808 patients), with low and very low certainty of evidence, respectively. No significant difference in initial treatment failure between fidaxomicin and vancomycin was found, however, initial treatment failure was higher with metronidazole (RR 1.58, 95% CI 1.10-2.27, 5 RCTs, 843 patients). No study reported on symptomatic recurrence necessitating re-treatment among all randomly assigned patients. Among initially cured patients, symptomatic recurrence necessitating re-treatment was lower with fidaxomicin than with vancomycin (RR 0.54, 95% CI 0.42-0.71, 6 RCTs, 1617 patients). None of the studies reported on other CDI complications or the burden of infection on daily activities. Setting patient-relevant outcomes for CDI independently of the RCT definitions and results might lead to less confidence in the guidance for CDI management.


Postoperative MR findings of the healthy ACL grafts: correlation with second look arthroscopy.
To evaluate the postoperative MR findings of healthy anterior cruciate ligament (ACL) grafts, which were confirmed by second look arthroscopic examination. We evaluated 33 MR scans of 29 patients who underwent postoperative MR scans and second look arthroscopic examination (four patients underwent postoperative MRI twice) between June 1996 and January 2001. There were 18 male and 11 female patients, and their ages ranged from 16 to 59 years old (mean 29.7). There were 15 cases of autogenous bone-patellar tendon-bone (BPTB) grafts, 13 cases of autogenous double-loop hamstring grafts, and 1 case of allogenous BPTB graft. Thirty-three MRIs were divided into three groups according to the time interval between operation and postoperative MR examination: less than 6 months, 7-12 months, and 13 or more months. The following MR findings of ACL grafts--signal intensity, morphology, continuity, orientation, and diameter--were analyzed. Increased signal intensity was found in 29 ACL grafts (87.7%). The most common pattern of the graft morphology was a longitudinal streak-increased signal intensity band (27 cases, 81.8%). A partial rupture was seen in nine cases (27.3%) and lax orientation in four cases (12.1%). The signal intensity score of the ACL graft tended to decrease with time after operation, and the sagittal diameter of the graft tended to increase with time after operation. The main postoperative MR findings of the healthy ACL graft was a longitudinal streak-increased signal intensity band. The graft signal intensity seemed to decrease and the sagittal diameter of the graft seemed to increase as time passed after operation.


The nature and treatment of depression in bipolar disorder: a review and implications for future psychological investigation.
Bipolar depression is poorly understood and researched, yet it is has a huge impact on functioning in bipolar disorder. This review explores the current status of research regarding the phenomenology, natural history, neuropsychology, psychosocial predictors and cognitive style of bipolar depression. The current status of pharmacotherapy and psychological treatment of bipolar depression is also described. In particular, the manner in which cognitive behaviour therapy for bipolar depression has been adapted from CBT for unipolar depression is critically evaluated. It is concluded that there appears to be a considerable overlap between the features of unipolar and bipolar depression, yet there is also emerging evidence for specific elements. The ability of current psychological theories of bipolar disorder to account for the findings are compared, and as a consequence, a new preliminary integrative model is proposed to direct future hypothesis-led research, which will need to incorporate more suitable populations and utilise more objective methods of assessment.


The University College Hospital/Royal National Institute for the Deaf cochlear implant programme.
The rationale for developing a single channel, round window, cochlear implant at University College Hospital, London is described. There are advantages to both extra and intra cochlear implants. Surgeons and patients should have a choice. The benefits of implants are now abundantly clear and an implant programme should be funded through the National Health Service.


Ionizing radiation mediates expression of cell adhesion molecules in distinct histological patterns within the lung.
Inflammatory cell infiltration of the lung is a predominant histopathological change that occurs during radiation pneumonitis. Emigration of inflammatory cells from the circulation requires the interaction between cell adhesion molecules on the vascular endothelium and molecules on the surface of leukocytes. We studied the immunohistochemical pattern of expression of cell adhesion molecules in lungs from mice treated with thoracic irradiation. After X-irradiation, the endothelial leukocyte adhesion molecule 1 (ELAM-1; E-selectin) was primarily expressed in the pulmonary endothelium of larger vessels and minimally in the microvascular endothelium. Conversely, the intercellular adhesion molecule 1 (ICAM-1; CD54) was expressed in the pulmonary capillary endothelium and minimally in the endothelium of larger vessels. Radiation-mediated E-selectin expression was first observed at 6 h, whereas ICAM-1 expression initially increased at 24 h after irradiation. ICAM-1 and E-selectin expression persisted for several days. P-selectin is constitutively expressed in Weibel-Palade bodies in the endothelium, which moved to the vascular lumen within 30 min after irradiation. P-selectin was not detected in the pulmonary endothelium at 6 h after irradiation. The radiation dose required for increased cell adhesion molecule expression within the pulmonary vascular endothelium was 2 Gy, and expression increased in a dose-dependent manner. These data demonstrate that ICAM-1 and E-selectin expression is increased in the pulmonary endothelium following thoracic irradiation. The pattern of expression of E-selectin, P-selectin, and ICAM-1 is distinct from one another.


[Sevoflurane-N2O inhalation anaesthesia with laryngeal mask airway and propofol-ketamine intravenous anaesthesia in strabismus surgery].
To investigate the advantages and disadvantages of sevoflurane-N2O inhalation anesthesia with laryngeal mask airway (LMA) and propofolketamine total intravenous anaesthesia in children undertaking strabismus surgery. Eighty children undertaking strabismus surgery were randomly divided into sevoflurane-N2O inhalation anaesthesia group with LMA (volatile group, n=40) and propofol-ketamine total intravenous anesthesia group (TIVA group, n=40). LMA was used to secure respiratory airway in the volatile group, but LMA or endotracheal intubation was not used in the TIVA group. All children breathed spontaneously during operative period. The anesthesia was maintained with 2%-3% sevoflurane-50% N2O-50% O2 in the volatile group, and continuous intravenous infusion with propofol 5-10 mg/(kg x h) plus ketamine 1-2 mg/(kg x h) in the TIVA group. The incidence of SpO2 less than 95% and the movement of the limbs and head induced by operative stimulation, oculocardiac reflex (OCR) and postoperative vomiting (POV) were recorded in all children. The incidence of limbs and head movement, the incidence of SpO2 less than 95% and OCR were significantly lower in the volatile group than those in the TIVA group (P < 0.01); but the incidence of POV was significantly higher in the volatile group than that in the TIVA group (P < 0.01). Sevoflurane-N2O-O2 anesthesia with LMA can secure respiratory airway of patients, avoid hypoxemia, and have good anesthetic quality and low OCR incidence. It is a new anesthesia method with more advantages in children undertaking strabismus surgery, but the prevention and treatment of POV must be noticed.


Comparative ontogenetic shape changes in the skull of Caiman species (Crocodylia, Alligatoridae).
Ontogenetic shape changes in the skull of three species of the genus Caiman (C. latirostris, C. sclerops, and C. yacare) are compared by geometric morphometrics for three-dimensional configurations (the least-squares analysis). The technique for obtaining the landmark coordinates is a simplification of the algorithm for multidimensional scaling. The ontogenetic nonlinear shape changes are similar in the three species but occur in a lesser extent in C. latirostris. These seem to be correlated with functional changes in the skull. The uniform shape change corresponds to an elongation of the skull, dorsoventral flattening, and lateral compression in C. sclerops and C. yacare. There is some lateral broadening in C. latirostris. Differences in the ontogenetic processes probably cause the differences in diet observed between C. latirostris and the other two species. Neotenic evolution seems to have acted in the skull of C. latirostris, and a posterior amplification of the early divergence led to a repatterning of the shape ontogenetic trajectory in this species. J. Morphol. 231:53-62, 1997. © 1997 Wiley-Liss, Inc.


Longitudinal integrated rural placements: a social learning systems perspective.
There is currently little theoretically informed exploration of how non-traditional clinical placement programmes that are longitudinal, immersive, based on community-engaged education principles and located in rural and remote settings may contribute to medical student learning. This paper aims to theoretically illustrate the pedagogical and socio-cultural underpinnings of student learning within a longitudinal, integrated, community-engaged rural placement. Data collected using semi-structured interviews with medical students, their supervisors and other health clinicians participating in a longitudinal rural placement programme were analysed using framework analysis. Data interpretation was informed by the theory of social learning systems (SLSs). In a longitudinal, rural clinical placement students participate in an SLS with distinct yet interrelated learning spaces that contain embedded communities of practice (CoPs). These spaces are characterised by varying degrees of formality, membership and interaction, and different learning opportunities and experiences. They are situated within and shaped by a unique geography of place comprising the physical and social features of the placement setting. Within these learning spaces, students acquire clinical knowledge, skills and competencies, professional attitudes, behaviours and professional values. The process of connectivity helps explain how students access and cross the boundaries between these learning spaces and develop a more complex sense of professional identity. Longitudinal, integrated clinical placement models can be understood as SLSs comprising synergistic and complementary learning spaces, in which students engage and participate in multiple CoPs. This occurs in a context shaped by unique influences of the geography of place. This engagement provides for a range of student learning experiences, which contribute to clinical learning and the development of a more sophisticated professional identity. A range of pedagogical and practical strategies can be embedded within this SLS to enhance student learning.


Resistance to radiation-induced apoptosis in Burkitt's lymphoma cells is associated with defective ceramide signaling.
Increased sensitivity to ionizing radiation has been shown to be due to defects in double-strand break repair and mutations in the proteins that detect DNA damage. However, it is now recognized that the cellular radiation response is complex and that radioresistance/radiosensitivity may also be regulated at different levels in the radiation signal transduction pathway. Here, we describe a direct relationship between resistance to radiation-induced apoptosis and defective ceramide signaling. Radiation sensitivity in human tumor cells correlated with the immediate accumulation of the second messenger ceramide. In the BL30A Burkitt's lymphoma line, ceramide increased 4-fold by 10 min postirradiation (10 Gy), and in the moderately sensitive HL-60 leukemia cells, ceramide accumulated 2.5-fold above basal levels. In contrast, in all radioresistant tumor cells examined, including several Burkitt's lymphoma lines (BL30K, BL29, and BL36) and the MO59K glioma cell line, ceramide did not accumulate postirradiation. The ability to abrogate ceramide production by pretreatment with the tumor promoter, 12-O-tetradecanoylphorbol 13-acetate, conferred resistance to radiation-induced apoptosis in the sensitive BL30A cells. An isogenic subline of BL30A, BL30K, was resistant to both C8-ceramide (20 microM) and ionizing radiation-induced apoptosis. Bypassing the block in radiation-induced ceramide production by the addition of exogenous ceramide was not sufficient to induce apoptosis; this suggests the existence of a second ceramide-associated signaling defect in these radioresistant cells that confers resistance to ceramide-induced apoptosis. Thus, these results provide compelling evidence that ceramide is an essential mediator of radiation-induced apoptosis and that defective ceramide signaling confers an apoptosis-resistant phenotype in tumor cells.


Conversion of carbonyl compounds to alkynes: general overview and recent developments.
The preparation of alkynes from carbonyl compounds via a one-carbon homologation has become a very useful pathway for the synthesis of acetylenic compounds, both internal and terminal. This tutorial review provides an overview of the different methods available for this transformation, including their scope and limitations, recent developments and applications in total syntheses.


Highly Efficient Visible Colloidal Lead-Halide Perovskite Nanocrystal Light-Emitting Diodes.
Lead-halide perovskites have been attracting attention for potential use in solid-state lighting. Following the footsteps of solar cells, the field of perovskite light-emitting diodes (PeLEDs) has been growing rapidly. Their application prospects in lighting, however, remain still uncertain due to a variety of shortcomings in device performance including their limited levels of luminous efficiency achievable thus far. Here we show high-efficiency PeLEDs based on colloidal perovskite nanocrystals (PeNCs) synthesized at room temperature possessing dominant first-order excitonic radiation (enabling a photoluminescence quantum yield of 71% in solid film), unlike in the case of bulk perovskites with slow electron-hole bimolecular radiative recombination (a second-order process). In these PeLEDs, by reaching charge balance in the recombination zone, we find that the Auger nonradiative recombination, with its significant role in emission quenching, is effectively suppressed in low driving current density range. In consequence, these devices reach a maximum external quantum efficiency of 12.9% and a power efficiency of 30.3 lm W-1 at luminance levels above 1000 cd m-2 as required for various applications. These findings suggest that, with feasible levels of device performance, the PeNCs hold great promise for their use in LED lighting and displays.


Sex and HIV education programs: their impact on sexual behaviors of young people throughout the world.
This paper reviews 83 studies that measure the impact of curriculum-based sex and HIV education programs on sexual behavior and mediating factors among youth under 25 years anywhere in the world. Two thirds of the programs significantly improved one or more sexual behaviors. The evidence is strong that programs do not hasten or increase sexual behavior but, instead, some programs delay or decrease sexual behaviors or increase condom or contraceptive use. Effective curricula commonly incorporated 17 characteristics that describe the curricula development; the goals, objectives, and teaching strategies of the curricula themselves; and their implementation. Programs were effective across a wide variety of countries, cultures, and groups of youth. Replications of studies also indicate that programs remain effective when implemented by others in different communities, provided all the activities are implemented as intended in similar settings.


Monitoring adequacy of alpha-adrenoceptor blockade following systemic phentolamine administration.
Systemic phentolamine administration has been suggested as a diagnostic tool for identifying patients with sympathetically maintained pain (SMP) (Raja et al. 1991). The dose of phentolamine to produce adequate blockade of peripheral alpha-adrenoceptor function has, however, not been previously determined. In this study, the effects of two different doses of phentolamine on peripheral sympathetic vasoconstrictor function were investigated. One-hundred and seventeen (117) patients with chronic extremity pain underwent 130 phentolamine diagnostic tests using two different doses of phentolamine (0.5 mg/kg over 20 min (n = 60) and 1 mg/kg over 10 min (n = 59)). Eleven (11) patients did not receive phentolamine during the test. Cutaneous temperature was measured in the distal extremity before and after administration of phentolamine. In a subset of patients, baseline blood flow and sympathetically mediated vasoconstrictor response (SMR) to deep inhalation were measured on glabrous skin using laser Doppler flowmetry. SMR was elicited with a 5-sec maximal inspiratory gasp. A dose-related increase in cutaneous temperature was observed. In addition, baseline blood flow increased and SMR was attenuated after both doses of phentolamine, but to a greater degree after the 1 mg/kg dose. However, SMR was not completely attenuated, even after administration of the higher phentolamine dose. These results indicate that a phentolamine dose of 1 mg/kg over 10 min more completely blocks alpha-adrenoceptor function than a dose of 0.5 mg/kg over 20 min. We therefore recommend that to ensure adequate alpha-adrenoceptor blockade the higher phentolamine dose be used in the phentolamine diagnostic test for SMP.


CT scan modification in the treatment of mediastinal Hodgkin's disease.
Seventy-one patients with Hodgkin's disease who were initially treated at Johns Hopkins with radiation or radiation-chemotherapy from 1975--1980 had a five-year cumulative disease-free survival of I-A--100% (12 patients); II-A--85% (33 patients); II-B--83% (seven patients); III-A--75% (ten patients); and III-B--66% (nine patients). Fifty patients with mediastinal masses at the time of treatment demonstrated no marginal misses, two mediastinal recurrences (96% local control), and three lung disseminations. CT scan data yielded stage and treatment modification in 60% (9/15) of recent patients with mediastinal Hodgkin's disease. This demonstrates the need for routine thoracic scans and individual treatment planning in all mediastinal cases. Recommendations for combination treatment in early stage disease are made only for pericardial or extrathoracic chest wall extension based on CT scan findings, our low failure rates, radiation organ tolerances, and available relapse data in the literature, not arbitrary size designations from upright chest radiographs. It can be concluded that patients with mediastinal Hodgkin's disease require CT scan analysis to identify unusual patterns of presentations, sites at risk, and to allow for proper application of radiation portals and/or chemotherapeutic management.


Genetic rescue of glycosylation-deficient Fgf23 in the Galnt3 knockout mouse.
Fibroblast growth factor 23 (FGF23) is a hormone that inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D biosynthesis. The FGF23 subtilisin-like proprotein convertase recognition sequence ((176)RHTR(179)↓) is protected by O-glycosylation through ppGalNAc-T3 (GALNT3) activity. Thus, inactivating GALNT3 mutations render FGF23 susceptible to proteolysis, thereby reducing circulating intact hormone levels and leading to hyperphosphatemic familial tumoral calcinosis. To further delineate the role of glycosylation in the Fgf23 function, we generated an inducible FGF23 transgenic mouse expressing human mutant FGF23 (R176Q and R179Q) found in patients with autosomal dominant hypophosphatemic rickets (ADHR) and bred this animal to Galnt3 knockout mice, a model of familial tumoral calcinosis. Due to the low intact Fgf23 level, Galnt3 knockout mice with wild-type Fgf23 alleles were hyperphosphatemic. In contrast, carriers of the mutant FGF23 transgene, regardless of Galnt3 mutation status, had significantly higher serum intact FGF23, resulting in severe hypophosphatemia. Importantly, serum phosphorus and FGF23 were comparable between transgenic mice with or without normal Galnt3 alleles. To determine whether the presence of the ADHR mutation could improve biochemical and skeletal abnormalities in Galnt3-null mice, these mice were also mated to Fgf23 knock-in mice, carrying heterozygous or homozygous R176Q ADHR Fgf23 mutations. The knock-in mice with functional Galnt3 had normal Fgf23 but were slightly hypophosphatemic. The stabilized Fgf23 ADHR allele reversed the Galnt3-null phenotype and normalized total Fgf23, serum phosphorus, and bone Fgf23 mRNA. However, the skeletal phenotype was unaffected. In summary, these data demonstrate that O-glycosylation by ppGaINAc-T3 is only necessary for proper secretion of intact Fgf23 and, once secreted, does not affect Fgf23 function. Furthermore, the more stable Fgf23 ADHR mutant protein could normalize serum phosphorus in Galnt3 knockout mice.


CO2 Cycloaddition to Epoxides by using M-DABCO Metal-Organic Frameworks and the Influence of the Synthetic Method on Catalytic Reactivity.
A series of high-quality M2(BDC)2(DABCO) metal-organic frameworks (abbreviated as M-DABCO; M=Zn, Co, Ni, Cu; BDC=1,4-benzene dicarboxylate; DABCO=1,4-diazabicyclo[2.2.2]octane), were synthesized by using a solvothermal (SV) method, and their catalytic activity for the cycloaddition of CO2 to epoxides in the absence of a co-catalyst or solvent was demonstrated. Of these metal-organic frameworks (MOFs), Zn-DABCO exhibited very high activity and nearly complete selectivity under moderate reaction conditions. The other members of this MOF series (Co-DABCO, Ni-DABCO, and Cu-DABCO) displayed lower activity in the given sequence. Samples of Zn-DABCO, Co-DABCO, and Ni-DABCO were recycled at least three times without a noticeable loss in catalytic activity. The reaction mechanism can be attributed to structural defects along with the acid-base bifunctional characteristics of these MOFs. Moreover, we illustrate that the synthetic method of M-DABCO influences the yield of the reaction. In addition to the SV method, Zn-DABCO was synthesized by using spray drying due to its industrial attractiveness. It was found that the synthesis procedure clearly influenced the crystal growth and thus the physicochemical properties, such as surface area, pore volume, and gas adsorption, which in turn affected the catalytic performance. The results clarified that although different synthetic methods can produce isostructural MOFs, the application of MOFs, especially as catalysts, strongly depends on the crystal morphology and textural properties and, therefore, on the synthesis method.


Proteomic landscape of liver tissue in old male mice that are long-term treated with polysaccharides from Sargassum fusiforme.
Sargassum fusiforme is a type of brown algae and well known as a longevity promoting vegetable in Northeastern Asia. The polysaccharides derived from Sargassum fusiforme (SFPs) have been suggested as an antioxidant component for anti-aging function. However, global molecular changes in vivo by SFPs have not been fully elucidated. Here, we present a proteomics study using liver tissues of aged male mice that were fed with SFPs. Of forty-nine protein spots, thirty-eight were up-regulated and eleven were down-regulated, showing significant changes in abundance by two-dimensional gel electrophoresis. These differentially expressed proteins were mainly involved in oxidation-reduction, amino acid metabolism, and energy metabolism. Forty-six proteins were integrated into a unified network, with catalase (Cat) at the center. Intriguingly, most of the proteins were speculated as mitochondrial-located proteins. Our findings suggested that SFPs modulated antioxidant enzymes to scavenge redundant free radicals, thus preventing oxidative damage. In conclusion, our study provides a proteomic view on how SFPs have beneficial effects on the aspects of antioxidant and energy metabolism during the aging process. This study facilitates the understanding of anti-aging molecular mechanisms in polysaccharides derived from Sargassum fusiforme.


Global exponential stability of neural networks with non-smooth and impact activations.
In this paper, we consider a model of impulsive recurrent neural networks with piecewise constant argument. The dynamics are presented by differential equations with discontinuities such as impulses at fixed moments and piecewise constant argument of generalized type. Sufficient conditions ensuring the existence, uniqueness and global exponential stability of the equilibrium point are obtained. By employing Green's function we derive new result of existence of the periodic solution. The global exponential stability of the solution is investigated. Examples with numerical simulations are given to validate the theoretical results.


Evaluation of the impacts of biodiesel and second generation biofuels on NO(x) emissions for CARB diesel fuels.
The impact of biodiesel and second generation biofuels on nitrogen oxides (NO(x)) emissions from heavy-duty engines was investigated using a California Air Resources Board (CARB) certified diesel fuel. Two heavy-duty engines, a 2006 engine with no exhaust aftertreatment, and a 2007 engine with a diesel particle filter (DPF), were tested on an engine dynamometer over four different test cycles. Emissions from soy- and animal-based biodiesels, a hydrotreated renewable diesel, and a gas to liquid (GTL) fuel were evaluated at blend levels from 5 to 100%. NO(x) emissions consistently increased with increasing biodiesel blend level, while increasing renewable diesel and GTL blends showed NO(x) emissions reductions with blend level. NO(x) increases ranged from 1.5% to 6.9% for B20, 6.4% to 18.2% for B50, and 14.1% to 47.1% for B100. The soy-biodiesel showed higher NO(x) emissions increases compared to the animal-biodiesel. NO(x) emissions neutrality with the CARB diesel was achieved by blending GTL or renewable diesel fuels with various levels of biodiesel or by using di-tert-butyl peroxide (DTBP). It appears that the impact of biodiesel on NO(x) emissions might be a more important consideration when blended with CARB diesel or similar fuels, and that some form of NO(x) mitigation might be needed for biodiesel blends with such fuels.


Achillea spp.: A comprehensive review on its ethnobotany, phytochemistry, phytopharmacology and industrial applications.
The genus Achillea genus houses more than 100 species, a number of them are popularly used in traditional medicine for spasmodic gastrointestinal, gynecological and hepatobiliary disorders, hemorrhages, pneumonia, rheumatic pain, inflammation, wounds healing etc. Members of the genus contain a wide variety of volatile and non-volatile secondary metabolites, including terpenes, polyphenols, flavonoids and others. Multiple studies have assessed the biological effects and other aspects of Achillea spp. In a number of preclinical studies, Achillea plants and their essential oils have demonstrated promising antibacterial properties against a number of human and plant pathogens. Besides, the plants have displayed strong antioxidative and potent anti-proliferative and anticancer properties in various cellular and animal models. Achillea plants have widely been used as food preservative in food industry. Clinical studies have indicated its potential against multiple sclerosis (MS), irritable bowel syndrome (IBS), ulcerative colitis, episiotomy wound, primary dysmenorrhea, oral mucositis etc. The present work focuses to provide a brief overview on folk knowledge, phytochemistry, biological activity and applications of Achillea plants. There is a close relationship between the traditional ethnobotanical usage and pharmacological and clinical data from different Achillea spp. The application of Achillea plants and their extracts seems to be a promising alternative for antimicrobial and antioxidant purposes in food, pharmaceutical and cosmetic industries.


Personality traits and common psychiatric conditions in adult patients with acne vulgaris.
We believe that instances of neuroticism and common psychiatric disorders are higher in adults with acne vulgaris than the normal population. Instances of acne in adults have been increasing in frequency in recent years. The aim of this study was to investigate personality traits and common psychiatric conditions in patients with adult acne vulgaris. Patients who visited the dermatology outpatient clinic at Bozok University Medical School with a complaint of acne and who volunteered for this study were included. The Symptom Checklist 90-Revised (SCL 90-R) Global Symptom Index (GSI), somatization, depression, and anxiety subscales and the Eysenck Personality Questionnaire-Revised Short Form (EPQ-RSF) were administered to 40 patients who fulfilled the inclusion criteria before treatment. The results were compared with those of a control group. Of the 40 patients included in this study, 34 were female and 6 were male. The GSI and the somatization, depression, and anxiety subscales of the SCL 90-R were evaluated. Patients with adult acne had statistically significant higher scores than the control group on all of these subscales. In addition, patients with adult acne had statistically significantly higher scores on the neuroticism subscale of the EPQ-RSF. Our results show that common psychiatric conditions are frequent in adult patients with acne. More importantly, neurotic personality characteristics are observed more frequently in these patients. These findings suggest that acne in adults is a disorder that has both medical and psychosomatic characteristics and requires a multi-disciplinary approach.


Capping of complement receptors on human neutrophils induced by group A streptococcal cell walls.
Peptidoglycan-polysaccharide polymers derived from group A streptococcal cell walls (PG-PS) were opsonized with either purified C3 or normal human serum and were used as a probe to investigate the mobility of CR1 and CR3, the C3b and iC3b receptors, respectively, on human neutrophils. Incubation of monolayers or cell suspensions of neutrophils with PG-PS opsonized with C3b or serum resulted in capping of PG-PS, as detected by fluorescein-labeled antibody to PS. No binding of PG-PS to neutrophils was observed with heat-inactivated serum. By 30 min the cell walls were internalized and observed in one to three vacuoles. Capping was totally inhibited when PG-PS opsonized with C3b or serum was preincubated with Fab'-anti-C3b. Similar inhibition was observed when C3b-opsonized PG-PS was incubated with neutrophils that were preincubated with anti-CR1 or fluid-phase C3b; only partial inhibition of neutrophil capping was observed by using serum-opsonized PG-PS. Because anti-CR1 blocks only the C3b receptor, the cap formation observed with serum-opsonized PG-PS is probably due to CR3. These results suggest that both CR1 and CR3 on neutrophils cap after stimulation by group A streptococcal cell wall fragments.


Mouse minor satellite DNA genetically maps to the centromere and is physically linked to the proximal telomere.
As an adjunct to attempts to define functionally important sequences at human centromeres, we have undertaken a long-range physical analysis of these regions in the mouse. Mouse centromeres are usually situated very close to the chromosome ends and are closely associated with minor satellite sequences on the basis of cytological observations. Using pulsed-field gel electrophoresis we find that this satellite DNA is arranged as tandem arrays, predominantly uninterrupted by nonsatellite sequences. These arrays can be released largely intact by digestion with a range of enzymes that generally cleave frequently in non-satellite DNA. The restriction fragments carrying these arrays are polymorphic in size between inbred strains and provide direct markers for mouse centromeres. To illustrate the possible use of these polymorphic markers we have mapped a 1.3-Mb PvuII variant in a set of RI strains to the centromere of Chromosome 7. The minor satellite arrays are very close to the centromeric telomere and physical linkage with terminal repeat sequences can readily be detected, placing many minor satellite arrays on terminal restriction fragments smaller than 1 Mb. The apparent lack of any sizable amount of nonsatellite DNA between the minor satellite and the terminal repeat arrays indicates that many mouse chromosomes are truly telocentric.


Partial reversal of ethanol-induced male reproductive pathology following abstinence.
To date, no longitudinal studies have been carried out to determine the recovery of ethanol-related reproductive failure subsequent to moderate periods of abstinence. An animal model (C57B1 mouse) was utilized to examine the effectiveness of abstinence for reversal of ethanol-induced reproductive failure. After treatment with either a 5% (v/v) ethanol diet (10 weeks) or a 6% (v/v) ethanol diet (5 weeks), ethanol-treated animals and their pair-fed controls were electroejaculated and hemicastrated (right testis and accessory organs); their reproductive tracts and epididymal spermatozoa were examined. Ingestion of the 5% and 6% ethanol diets resulted in significantly (P less than 0.05) decreased weights of testes (24% and 28%, respectively) and seminal vesicles/prostate (20%, 6% diet only), increased frequencies of germ cell desquamation (480% and 400%), inactive seminiferous tubules (186% and 567%), sperm dysmorphology (31% and 119%) and inhibition of in vitro fertilization of mouse oocytes by epididymal spermatozoa (26% and 62%), as compared to their respective pair-fed control values. Also observed were significant decreases in epididymal sperm content (72%, 6% diet only), total motile spermatozoa (85%, 6% diet only) and seminal vesicles epithelial cell height (13% and 29%). No abnormal semen parameters were observed after treatment with the 5% ethanol diet; however, in animals treated with the 6% diet, significant decreases were noted in coagulum weight (50%), sperm count (85%) and acid phosphatase content (53%). Improvement in all parameters was observed in the contralateral half of the reproductive tract subsequent to 10 weeks abstinence. Only germ cell desquamation remained significantly elevated (100% as compared to control) in animals that ingested the 5% diet. In contrast, significant abnormalities persisting 10 weeks after treatment with the 6% ethanol diet included increased germ cell desquamation (200%), inactive seminiferous tubules (157%) and sperm dysmorphology (39%) and decreased forward progression (17%) of epididymal sperm, as compared to values. These findings are discussed in relation to the influence of alcohol consumption on male reproductive function in man.


Graduate program in biomedical communication.
The need for harnessing the achievements of communication technology to the burgeoning mass of biomedical information is critical. Recognizing this problem and aware of the short supply of professionals with the skills necessary for the job, a group of leaders from the fields of medicine and communications formed a consortium in 1967 and have developed a twelve month graduate program in biomedical communication. Designed to ground the advanced student in the development and administration of biomedical communication programs, the curriculum focuses on the principles and practice of communication and the development of communications media. Courses are given in the control and communication of information; the printed and spoken word; visual media of photographic arts, television, and motion pictures; computer science; and administration and systems analysis.


Prospective, comparative effectiveness trial of cow's milk elimination and swallowed fluticasone for pediatric eosinophilic esophagitis.
Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease in which food antigens play a key role. Current therapeutic options are limited to long-term steroid medication and dietary elimination of multiple foods, each of which is challenging. Our objective was to compare single food elimination of cow's milk to swallowed fluticasone in pediatric EoE patients. This is a prospective, comparative effectiveness trial of newly diagnosed EoE patients (ages 2-18 years) treated with swallowed fluticasone (n = 24) or elimination of cow's milk (n = 20). The dual outcome measures of repeat esophageal biopsy (6-8 weeks) and change in Pediatric Quality of Life Inventor (PedsQL) EoE Module and Symptoms Scales were used to assess response to treatment. After 6-8 weeks of treatment, peak esophageal eosinophil counts decreased to below the threshold of 15 eosinophils/high-power field in 64% of patients treated with cow's milk elimination and 80% of patients treated with swallowed fluticasone (P = 0.4). Mean PedsQL EoE Module total scores (69 vs. 82; P < 0.005) and Total Symptoms scores (58 vs. 75; P = 0.001) showed significant improvement with cow's milk elimination. Among children treated with swallowed fluticasone, mean PedsQL EoE Module total scores (64 vs. 75; P < 0.05) and Total Symptoms scores (58 vs. 69; P < 0.01) were also significantly improved after 6-8 weeks of therapy. Removal of cow's milk from the diet is an effective single food elimination treatment for pediatric patients with EoE as assessed by statistically significant histologic and symptomatic improvement. Cow's milk elimination may be more desirable for EoE patients who do not want to take chronic, long-term steroid medications.


Methodology for concurrent determination of urea kinetics and the capture of recycled urea nitrogen by ruminal microbes in cattle.
We measured the incorporation of recycled urea-nitrogen (N) by ruminal microbes, using five ruminally and duodenally fistulated steers (237 kg) fed low-quality grass hay (47 g crude protein/kg dry matter (DM)). Three received 1 kg/day of soybean meal (SBM) and two received no supplemental protein (control). The experiment was 15 days long. Background enrichments of 15N were measured on day 9 and continuous jugular infusion of 0.12 g/day [15N15N]urea began on day 10. Daily samples of urine, feces, ruminal bacteria and duodenal digesta from days 10 through 14 were used to determine plateaus in 15N enrichment. Duodenal and bacterial samples collected on day 15 were used to measure duodenal N flows. Bacterial N flow was calculated as duodenal N flow multiplied by duodenal 15N enrichment divided by bacterial 15N enrichment. Bacterial N from recycled urea-N was calculated as bacterial N flow multiplied by bacterial 15N enrichment divided by urinary urea 15N enrichment. Urinary enrichment of [15N15N]urea plateaued within 24 h, whereas 14N15N urea plateaued within 48 h of [15N15N]urea infusion. Bacteria reached a plateau in 15N enrichment within 24 h and duodenal samples within 48 h. Urea production was 17.6 g of urea-N/day for control and 78.0 g/day for SBM. Gut entry was 0.99 g of urea-N/g of urea-N produced for control and 0.87 g/g for SBM. Incorporation of recycled N into microbial N was 9.0 g of N/day for control and 23.0 g/day for SBM. Recycled urea-N accounted for 0.33 g of N/g of microbial N at the duodenum for control and 0.27 g/g for SBM. Our methods allowed measurement of incorporation of recycled urea-N into ruminal microbial N.


A correlative study of the clinical and radiographic signs of periodontal disease in dogs.
Twenty-four dogs admitted for routine teeth cleaning were selected arbitrarily to undergo a periodontal examination and a dental radiographic examination before the dental procedure. Data pertaining to the physical and radiographic manifestations of periodontal disease of 783 teeth were collected. All dogs had lesions consistent with periodontal disease, ranging from mild gingivitis and minimal plaque accumulation to severely inflamed gingiva, exuberant calculus formation, and root exposure. Of the 783 teeth examined, 153 (20%) had a pocket depth greater than or equal to 4 mm and less than or equal to 9 mm. Data regarding these teeth were subjected to statistical analysis. The clinical signs of plaque, calculus, mobility, pocket depth, and furcation were positively associated with radiographic signs of periodonta disease. The association between grossly evident gingivitis and radiographic signs of periodontal disease was not significant. Conditional probability analysis was applied to determine confidence intervals for the probability of a radiographic sign of periodontal disease occurring given that a clinical sign of periodontal disease occurs.


The striatal efferents in the globus pallidus and in the substantia nigra.
The radial fibers in the globus pallidus are the striatal efferents. Evidence now indicates that they arise from medium-sized neurons in the striatum. During their transit of the globus pallidus, they give off collaterals in both segments of the globus pallidus and undergo reduction in caliber. It has not been possible to observe the same radial fiber emitting collaterals in both segments of the globus pallidus, and the prospects of ever doing so are not good. The radial fibers in the medial segment of the globus pallidus continue into the substantia nigra by way of the "comb" bundle. The divergence and convergence in the striatal efferent systems is considerable. The afferent plexuses of fine fibers bearing bouton en passant endings, which completely ensheath the long dendrites in the globus pallidus and the substantia nigra and make "longitudinal axodendritic connections," are derived from the convergence of branches off the collaterals of a number of different radial fibers in the globus pallidus and the convergence of "comb" bundle fibers in the substantia nigra. The synaptic endings on these fibers constitute most of the endings in the globus pallidus. They are the endings with large, egg-shaped, synaptic vesicles and form symmetrical synapses.


How does academic achievement relate to cardiorespiratory fitness, self-reported physical activity and objectively reported physical activity: a systematic review in children and adolescents aged 6-18 years.
This report aimed to systematically review the evidence for a differential association between objective and self-reported physical activity and cardiorespiratory fitness on academic achievement. Systematic review. Studies were identified from searches in Embase, Education Resources Information Center, PubMed, PsycINFO, SPORTdiscus and Web of Science databases from January 2000 to December 2016. Eligibility criteria included cross-sectional, longitudinal and interventional study designs. Outcomes included students' school grade or a standardised test or measure of academic achievement. Explanatory variables were cardiorespiratory fitness and objective and self-reported physical activity. Inclusion criteria included school-aged children and adolescents aged-18 years (or students from primary to secondary school when student's participants age was not described) and articles published in English, Portuguese or Spanish. A total of 51 articles met inclusion criteria: 41 cross-sectional, 2 intervention and 8 longitudinal studies. Results from 11 studies were inconsistent regarding the relationship between objectively measured physical activity and academic achievement. Ten of the 16 articles reported positive associations between self-reported physical activity and academic achievement. From the 22 studies that analysed the relationship between cardiorespiratory fitness and academic achievement, it was verified that they all generally support the beneficial effect of cardiorespiratory fitness on students' academic achievement. Higher cardiorespiratory fitness may be important to enhance children and adolescents' health and, additionally, academic achievement. Due to a lack of consensus across studies, methodological issues associated with the assessment of physical activity should be considered when investigating physical activity and academic achievement.


Bayesian ensemble methods for survival prediction in gene expression data.
We propose a Bayesian ensemble method for survival prediction in high-dimensional gene expression data. We specify a fully Bayesian hierarchical approach based on an ensemble 'sum-of-trees' model and illustrate our method using three popular survival models. Our non-parametric method incorporates both additive and interaction effects between genes, which results in high predictive accuracy compared with other methods. In addition, our method provides model-free variable selection of important prognostic markers based on controlling the false discovery rates; thus providing a unified procedure to select relevant genes and predict survivor functions. We assess the performance of our method several simulated and real microarray datasets. We show that our method selects genes potentially related to the development of the disease as well as yields predictive performance that is very competitive to many other existing methods. http://works.bepress.com/veera/1/.


An Implementation Guide to Promote Sleep and Reduce Sedative-Hypnotic Initiation for Noncritically Ill Inpatients.
Sedative-hypnotic medications are frequently prescribed for hospitalized patients with insomnia, but they can result in preventable harm such as delirium, falls, hip fractures, and increased morbidity. Furthermore, sedative-hypnotic initiation while in the hospital carries a risk of chronic use after discharge. Disrupted sleep is a major contributor to sedative-hypnotic use among patients in the hospital and other institutional settings. Numerous multicomponent studies on improving sleep quality in these settings have been described, some demonstrating an associated reduction of sedative-hypnotic prescriptions. This selected review summarizes effective interventions aimed at promoting sleep and reducing inappropriate sedative-hypnotic initiation and proposes an implementation strategy to guide quality improvement teams.


Three New Bat Ectoparasite Species of the Genus Macronyssus from Western Siberia (with an Identification Key for Females of the Genus Macronyssus from the Palearctic Boreal Zone).
Three new gamasid mite species belonging to the genus Macronyssus Kolenati, 1858 (Acari: Macronyssidae), namely, Macronyssus sibiricus n. sp., Macronyssus stanyukovichi n. sp., and Macronyssus tigirecus n. sp., are described (females only; males, protonymphs, and larvae remain unknown). All species are known from Western Siberia and belong to the Siberian-Far Eastern bat ectoparasite fauna complex. The parasite hosts are the eastern water bat Myotis petax Hollister, 1912, and Hilgendorf's tube-nosed bat Murina hilgendorfi Peters, 1880 (Chiroptera: Vespertilionidae). An identification key for females of the genus Macronyssus Kolenati, 1858, in the boreal Palearctic region is presented.


Identification of kinetic order parameters for non-equilibrium dynamics.
A popular approach to analyze the dynamics of high-dimensional many-body systems, such as macromolecules, is to project the trajectories onto a space of slowly varying collective variables, where subsequent analyses are made, such as clustering or estimation of free energy profiles or Markov state models. However, existing "dynamical" dimension reduction methods, such as the time-lagged independent component analysis (TICA), are only valid if the dynamics obeys detailed balance (microscopic reversibility) and typically require long, equilibrated simulation trajectories. Here, we develop a dimension reduction method for non-equilibrium dynamics based on the recently developed Variational Approach for Markov Processes (VAMP) by Wu and Noé. VAMP is illustrated by obtaining a low-dimensional description of a single file ion diffusion model and by identifying long-lived states from molecular dynamics simulations of the KcsA channel protein in an external electrochemical potential. This analysis provides detailed insights into the coupling of conformational dynamics, the configuration of the selectivity filter, and the conductance of the channel. We recommend VAMP as a replacement for the less general TICA method.


Survival as medical registrar on call: remember the doughnut.
Life as a medical registrar presents many challenges and concern is growing that a downwards trend in recruitment to General Medicine is the direct result of a perception by junior doctors that the role of the medical registrar is excessively demanding and results in poor work-life balance. A solution-focused approach (SFA) can be used successfully to find a satisfying outcome for both registrar and patient in many of the situations encountered during an on-call, as well as carrying over benefits into life outside of work. We explore the origins of SFA and the ways in which it can be successfully applied to clinical medicine, providing case studies from the author's own experience to illustrate the principles of this way of thinking.


Effects of the accreditation council for graduate medical education duty hour limits on sleep, work hours, and safety.
To mitigate the risks of fatigue-related medical errors, the Accreditation Council for Graduate Medical Education introduced work hour limits for resident physicians in 2003. Our goal was to determine whether work hours, sleep, and safety changed after implementation of the Accreditation Council for Graduate Medical Education standards. We conducted a prospective cohort study in which residents from 3 large pediatric training programs provided daily reports of work hours and sleep. In addition, they completed reports of near-miss and actual motor vehicle crashes, occupational exposures, self-reported medical errors, and ratings of educational experience. They were screened for depression and burnout. Concurrently, at 2 of the centers, data on medication errors were collected prospectively by using an established active surveillance method. A total of 220 residents provided 6007 daily reports of their work hours and sleep, and 16 158 medication orders were reviewed. Although scheduling changes were made in each program to accommodate the standards, 24- to 30-hour shifts remained common, and the frequency of residents' call remained largely unchanged. There was no change in residents' measured total work hours or sleep hours. There was no change in the overall rate of medication errors, and there was a borderline increase in the rate of resident physician ordering errors, from 1.06 to 1.38 errors per 100 patient-days. Rates of motor vehicle crashes, occupational exposures, depression, and self-reported medical errors and overall ratings of work and educational experiences did not change. The mean length of extended-duration (on-call) shifts decreased 2.7% to 28.5 hours, and rates of resident burnout decreased significantly (from 75.4% to 57.0%). Total hours of work and sleep did not change after implementation of the duty hour standards. Although fewer residents were burned out, rates of medication errors, resident depression, and resident injuries and educational ratings did not improve.


Identification of small molecule inhibitors of RANKL and TNF signalling as anti-inflammatory and antiresorptive agents in mice.
Inflammatory joint diseases such as rheumatoid arthritis are associated with local bone erosions and systemic bone loss, mediated by increased osteoclastic activity. The receptor activator of nuclear factor (NF) κB ligand (RANKL) plays a key role in mediating inflammation-induced bone loss, whereas tumour necrosis factor (TNF) plays a central role in the inflammatory process. Here we tested whether a recently identified class of small molecule inhibitors of RANKL signalling (ABD compounds) also affect TNF signalling and whether these compounds inhibit inflammation in an animal model of rheumatoid arthritis. The inhibitory effects of the ABD compounds on TNF-induced signalling were tested in mouse macrophage cultures by western blotting and in an NFκB luciferase-reporter cell line. The anti-inflammatory effects of the compounds were tested in the mouse collagen-induced arthritis model of rheumatoid arthritis. The ABD compounds ABD328 and ABD345 both inhibited TNF-induced activation of the NFκB pathway and the extracellular signal-regulated kinase (ERK) and Jun kinase (JNK) mitogen activated protein kinases (MAPKs). When tested in the mouse collagen-induced arthritis model of rheumatoid arthritis, the compounds suppressed inflammatory arthritis, inhibited joint destruction and prevented systemic bone loss. Furthermore, one of the compounds (ABD328) showed oral activity. Here we describe a novel class of small molecule compounds that inhibit both RANKL- and TNF-induced NFκB and MAPK signalling in osteoclasts and macrophages, and inflammation and bone destruction in a mouse model of rheumatoid arthritis. These novel compounds therefore represent a promising new class of treatments for inflammatory diseases, such as rheumatoid arthritis.


Crystal structure of ferrochelatase: the terminal enzyme in heme biosynthesis.
The metallation of closed ring tetrapyrroles resulting in the formation of hemes, chlorophylls and vitamin B12 is catalyzed by specific enzymes called chelatases. Ferrochelatase catalyzes the terminal step in heme biosynthesis by inserting ferrous ion into protoporphyrin IX by a mechanism that is poorly understood. Mutations in the human gene for ferrochelatase can result in the disease erythropoietic protoporphyria, and a further understanding of the mechanism of this enzyme is therefore of clinical interest. No three-dimensional structure of a tetrapyrrole metallation enzyme has been available until now. The three-dimensional structure of Bacillus subtilis ferrochelatase has been determined at 1.9 A resolution by the method of multiple isomorphous replacement. The structural model contains 308 of the 310 amino acid residues of the protein and 198 solvent molecules. The polypeptide is folded into two similar domains each with a four-stranded parallel beta sheet flanked by alpha helices. Structural elements from both domains build up a cleft, which contains several amino acid residues that are invariant in ferrochelatases from different organisms. In crystals soaked with gold and cadmium salt solutions, the metal ion was found to be coordinated to the conserved residue His 183, which is located in the cleft. This histidine residue has previously been suggested to be involved in ferrous ion binding. Ferrochelatase seems to have a structurally conserved core region that is common to the enzyme from bacteria, plants and mammals. We propose that porphyrin binds in the identified cleft; this cleft also includes the metal-binding site of the enzyme. It is likely that the structure of the cleft region will have different conformations upon substrate binding and release.


Temozolomide in newly diagnosed malignant gliomas: administered concomitantly with radiotherapy, and thereafter as consolidation treatment.
Surgical resection followed by radiotherapy used to be the standard treatment in malignant gliomas. Recently, temozolomide has become a cornerstone in the treatment of these patients. We evaluated retrospectively the efficacy and the toxicity of temozolomide which was administered concomitantly with radiotherapy, and thereafter as consolidation treatment. Medical records of 64 patients with malignant glioma were reviewed. Postoperatively, temozolomide was given at a dose of 75 mg/m(2)/day concomitantly with cranial radiotherapy. After 4 weeks of rest, patients were treated with temozolomide 200 mg/m(2) on days 1-5 every 28 days for 6 cycles. 62 patients were evaluable for response and toxicity. Objective response rate was 38.7% including 7 (11.3%) complete responses, and 17 (27.4%) partial responses. Median progression-free survival, and overall survival have not yet been reached in the grade III astrocytoma group at a median follow-up of 19 months. In the glioblastoma multiforme group, median progression-free survival, and median overall survival were 10 and 19 months, respectively. 2-year survival rates were 80% and 19% for the grade III astrocytoma, and for the glioblastoma multiforme groups, respectively. Toxicity was mild to moderate with rare grade 4 toxicities. Our data suggest that temozolomide is an active regimen for malignant gliomas. It was more effective in younger patients with better performance status.


Effect of the surface roughness on X-ray absorption by mirrors operating at extremely small grazing angles.
This study theoretically analyzes an increase in X-ray absorption by a grazing incidence mirror due to its surface roughness. We demonstrate that the increase in absorption can be several hundred times larger than predicted by the Nevot-Croce formula. As a result, absorption enhances by several times compared to a perfectly smooth mirror despite the extremely small grazing angle of an incident X-ray beam (a fraction of the critical angle of the total external reflection) and the high quality of the reflecting surface (the roughness height was 0.5 nm in modeling). The main contribution to the absorption increase was dictated by the mid-scale roughness (waviness) of the virgin substrate surface, whose quality thus defines an absorption enhancement. The approach was applied to the analysis of two real mirrors used in a synchrotron (BESSY-I) and a European X-ray free-electron laser (XFEL) beamline. The modern surface finishing technology of elastic emission machining provides extremely low substrate waviness, guaranteeing the negligible effect of the surface roughness on the absorption increase.


The Caenorhabditis elegans orthologue of mammalian puromycin-sensitive aminopeptidase has roles in embryogenesis and reproduction.
Mammals possess membrane-associated and cytosolic forms of the puromycin-sensitive aminopeptidase (PSA; EC 18.104.22.168). Increasing evidence suggests the membrane PSA is involved in neuromodulation within the central nervous system and in reproductive biology. The functional roles of the cytosolic PSA are less clear. The genome of the nematode Caenorhabditis elegans encodes an aminopeptidase, F49E8.3 (PAM-1), that is orthologous to PSA, and sequence analysis predicts it to be cytosolic. We have determined the spatio/temporal gene expression pattern of pam-1 by using the promoter region of F49E8.3 to control expression in the nematode of a second exon translational fusion of the aminopeptidase to green fluorescent protein. Cytosolic fluorescence was observed throughout development in the intestine and nerve cells of the head. Neuronal expression was also observed in the tail of adult males. Recombinant PAM-1, expressed and purified from Escherichia coli, hydrolyzed the N-terminal amino acid from peptide substrates. Favored substrates had positively charged or small neutral amino acids in the N-terminal position. Peptide hydrolysis was inhibited by the metal-chelating agent 1,10-phenanthroline and by the aminopeptidase inhibitors actinonin, amastatin, and leuhistin. However, the enzyme was approximately 100-fold less sensitive toward puromycin (IC50, 135 mum) than other PSA homologues. Following inactivation of the enzyme, aminopeptidase activity was recovered with Zn2+, Co2+, and Ni2+. Silencing expression of pam-1 by RNA interference resulted in 30% embryonic lethality. Surviving adult hermaphrodites deposited large numbers of oocytes throughout the self-fertile period. The overall brood size was, however, unaffected. We conclude that pam-1 encodes an aminopeptidase that clusters phylogenetically with the PSAs, despite attenuated sensitivity toward puromycin, and that it functions in embryo development and reproduction of the nematode.


Penicillium brocae, a new species associated with the coffee berry borer in Chiapas, Mexico.
Penicillium brocae is a new monoverticillate species isolated from coffee berry borers collected at coffee plantations in Mexico near Cacahoatán, Chiapas, and from borers reared on artificial diets at ECOSUR laboratory facilities in Tapachula, Chiapas. Phenotypically, it is in Penicillium series Implicatum, but because it does not conform to known species we have described it as new. ITS and large subunit rDNA were sequenced and compared to determine the phylogenetic position of this species. It is most closely related to Penicillium adametzii. Penicillium brocae has only been found in association with the coffee berry borer and is one of several fungi that grow in coffee berry borer galleries. Penicillium brocae may provide the exogenous sterols necessary for the coffee berry borer's development and thus be mutualistically associated with the insect.


Integrating quality, safety, and environment management systems.
Internationally consistent ISO standards are in use, or are being developed, for quality systems, environmental management, and occupational health and safety. These standards outline a model for the management of quality, environment or safety. In many respects the process of developing management systems for these matters contains a number of common elements, including obtaining commitment from senior management; instituting consultative mechanisms; developing a policy; identifying components of the management program; resourcing, implementing, and reviewing the program; and integrating the program into the organization's strategic plan. The necessity of developing separate management systems for different organizational aspects is wasteful and inefficient. Better management systems will be developed if they are integrated into a single management structure.


The antigen-bearing eye and the spleen are indispensable in maintaining anterior chamber-associated immune deviation.
To investigate the role of the eye and the spleen in maintaining suppression of delayed-type hypersensitivity (DTH) after anterior chamber (AC) inoculation of allogeneic splenocytes. Suppression of DTH response was tested in BALB/c mice after AC inoculation of allogeneic B10.D2 splenocytes. Seven days after AC injection, the antigen-inoculated eyes were enucleated or the spleens were removed. After enculeation or splenectomy at different time intervals, DTH responses in groups of the BALB/c mice were examined. Spleen components obtained from BALB/c mice that had been primed by B10.D2 splenocytes in the AC 7 days earlier were transferred intravenously to groups of naive syngeneic acceptors. At various intervals after adoptive transfer, variations of DTH responses were tested. Inoculation of B10.D2 splenocytes to the AC of BALB/c mice induced antigen-specific suppression of DTH. Either enucleation of the antigen-inoculated eyes or splenectomy weakened the DTH-suppressive effect within 5 weeks and abolished it within 9 weeks, whereas the mice retaining both antigen-inoculated eyes and spleens maintained longstanding DTH suppression. Adoptive transfer of spleen components to syngeneic acceptors demonstrated DTH suppression for only 3 weeks. The antigen-inoculated eye and spleen are required for long-standing suppression of DTH after AC inoculation of allogeneic splenocytes.


Intraspecific variation in retinal cone distribution in the bluefin killifish, Lucania goodei.
Studies of visual ecology have typically focused on differences among species while paying less attention to variation among populations and/or individuals. Here, we show that the relative abundance of UV, violet, yellow, and red cones varies between two populations of bluefin killifish, Lucania goodei. Animals from a spring population (high-transmission UV/blue light) have a higher frequency of UV and violet cones and a lower frequency of yellow and red cones than animals from a swamp population (low-transmission UV/blue light). Visual sensitivity does not vary significantly between the populations, but spring animals tend to be more sensitive in the UV/blue wavelengths (360-440 nm) and less sensitive in longer wavelengths (560-600 nm) than swamp animals. The results have two important implications. First, the tight conservation of functional regions of opsin genes across taxa does not imply that visual systems are constrained in their evolution; differential sensitivity can arise through differential expression of cone classes within the retina. Second, intraspecific visual signals in this species may evolve to maximize contrast between the signaler and the background (as opposed to brightness); males with blue anal fins are most abundant in swamp habitats where animals express fewer UV and violet cones.


Association between combined lifestyle factors and non-restorative sleep in Japan: a cross-sectional study based on a Japanese health database.
Although lifestyle factors such as cigarette smoking, excessive drinking, obesity, low or no exercise, and unhealthy dietary habits have each been associated with inadequate sleep, little is known about their combined effect. The aim of this study was to quantify the overall impact of lifestyle-related factors on non-restorative sleep in the general Japanese population. A cross-sectional study of 243,767 participants (men, 39.8%) was performed using the Specific Health Check and Guidance System in Japan. A healthy lifestyle score was calculated by adding up the number of low-risk lifestyle factors for each participant. Low risk was defined as (1) not smoking, (2) body mass index<25 kg/m², (3) moderate or less alcohol consumption, (4) regular exercise, and (5) better eating patterns. Logistic regression analysis was used to examine the relationship between the score and the prevalence of non-restorative sleep, which was determined from questionnaire responses. Among 97,062 men (mean age, 63.9 years) and 146,705 women (mean age, 63.7 years), 18,678 (19.2%) and 38,539 (26.3%) reported non-restorative sleep, respectively. The prevalence of non-restorative sleep decreased with age for both sexes. Compared to participants with a healthy lifestyle score of 5 (most healthy), those with a score of 0 (least healthy) had a higher prevalence of non-restorative sleep (odds ratio, 1.59 [95% confidence interval, 1.29-1.97] for men and 2.88 [1.74-4.76] for women), independently of hypertension, hypercholesterolemia, diabetes, and chronic kidney disease. The main limitation of the study was the cross-sectional design, which limited causal inferences for the identified associations. A combination of several unhealthy lifestyle factors was associated with non-restorative sleep among the general Japanese population. Further studies are needed to establish whether general lifestyle modification improves restorative sleep.


The pallidopyramidal syndromes: nosology, aetiology and pathogenesis.
The aims of this review is to suggest a new nomenclature and classification system for the diseases currently categorized as neurodegeneration with brain iron accumulation (NBIA) or dystonia-parkinsonism, and to discuss the mechanisms implicated in the pathogenesis of these diseases. NBIA is a disease category encompassing syndromes with iron accumulation and prominent dystonia-parkinsonism. However, as there are many diseases with similar clinical presentations but without iron accumulation and/or known genetic cause, the current classification system and nomenclature remain confusing. The pathogenetic mechanisms of these diseases and the causes of gross iron accumulation and significant burden of neuroaxonal spheroids are also elusive. Recent genetic and functional studies have identified surprising links between NBIA, Parkinson's disease and lysosomal storage disorders (LSD) with the common theme being a combined lysosomal-mitochondrial dysfunction. We hypothesize that mitochondria and lysosomes form a functional continuum with a predominance of mitochondrial and lysosomal pathways in NBIA and LSD, respectively, and with Parkinson's disease representing an intermediate form of disease. During the past 18 months, important advances have been made towards understanding the genetic and pathological underpinnings of the pallidopyramidal syndromes with important implications for clinical practice and future treatment developments.


Advancements in radiation techniques for gastric cancer.
All but the earliest cases of nonmetastatic gastric cancer represent a therapeutic challenge given the high propensity of these patients to develop locoregional and distant relapse. Neoadjuvant or adjuvant strategies that include chemoradiotherapy or chemotherapy have been associated with significant toxicity, but also improvement in patient survival. Technologic advances in the planning and delivery of radiotherapy (RT) have enabled significant progress in the accuracy and conformality of radiation treatment. Four-dimensional CT and image-guided RT improve the accuracy of radiation treatment. Three-dimensional RT and intensity-modulated RT allow increased conformality of radiation dose distribution, sparing of normal organs, and providing opportunity for dose escalation. Initial clinical experience with these technologies shows favorable tolerance and outcomes.


Combined gamma-irradiation and subsequent cisplatin treatment in human squamous carcinoma cell lines sensitive and resistant to cisplatin.
To investigate the effects of combined radiation and subsequent cisplatin treatment on the human squamous carcinoma cell line SCC-25 and its cisplatin-resistant derivative SCC-25/CP. SCC-25 and SCC-25/CP cells were treated with various gamma-ray doses (5 cGy-7 Gy) followed 60 min later by cisplatin treatment and subsequently assayed for survival using a conventional colony assay. For SCC-25, the subsequent cisplatin treatment was 0.1, 1, 10 and 20 microM for 1 h. For the more cisplatin-resistant SCC-25/CP cells, the subsequent cisplatin treatment was 10 and 50 microM for 1 h. The cisplatin-resistant SCC-25/CP cells were not cross-resistant to gamma-irradiation. Subsequent treatment with an LD50 concentration of cisplatin (10 and 50 microM for SCC-25 and SCC-25/CP, respectively) resulted in radiosensitization for SCC-25/CP but not for SCC-25 cells. Gamma-irradiation of SCC-25/CP cells followed by treatment with 10 and 50 microM cisplatin for 1 h resulted in radiation survival curves displaying a significant low-dose hypersensitive region followed by increased radioresistance at higher doses. A total of 10 microM cisplatin resulted in radiosensitization confined to the low-dose region (0.05 and 0.25 Gy), whereas the higher cisplatin treatment of 50 microM resulted in the appearance of a hypersensitive region together with a reduction of the increased radioresistance region. In contrast, cisplatin treatment (0.1, 1, 10 and 20 microM for 1 h) of SCC-25 cells had no significant effect on survival following 2.5 or 7.0 Gy and actually resulted in an increased low-dose radiation survival (0.05, 0.25 and 1 Gy) when survival was corrected for cisplatin treatment (p<0.01 for all cisplatin concentrations tested). The significant radiosensitization for SCC-25/CP given subsequent treatment with 50 microM cisplatin indicates cisplatin can inhibit the increased radioresistance response in SCC-25/CP cells. In contrast, the subsequent cisplatin treatment of SCC-25 cells can enhance their survival following low radiation doses.


KCl evokes contraction of airway smooth muscle via activation of RhoA and Rho-kinase.
Airway smooth muscle (ASM) cells express voltage-dependent Ca2+ channels, primarily of the L-subtype. These may play a role in excitation-contraction coupling of ASM, although other signaling pathways may also contribute: one of these includes Rho and its downstream effector molecule Rho-associated kinase (ROCK). Although voltage-dependent Ca2+ influx and Rho/ROCK signaling have traditionally been viewed as entirely separate pathways, recent evidence in vascular smooth muscle suggest differently. In this study, we monitored contractile activity (muscle baths) in bronchial and/or tracheal preparations from the pig, cow, and human, and further examined Rho and ROCK activities (Western blots and kinase assays) and cytosolic levels of Ca2+ (fluo 4-based fluorimetry) in porcine tracheal myocytes. KCl evoked substantial contractions that were suppressed in tracheal preparations by removal of external Ca2+ or using the selective L-type Ca2+ channel blocker nifedipine; porcine bronchial preparations were much less sensitive, and bovine bronchi were essentially unaffected by 1 microM nifedipine. Surprisingly, KCl-evoked contractions were also highly sensitive to two structurally different ROCK inhibitors: Y-27632 and HA-1077. Furthermore, the inhibitory effects of nifedipine and of the ROCK inhibitors were not additive. KCl also caused marked stimulation of Rho and ROCK activities, and both these changes were suppressed by nifedipine or by removal of external Ca2+. KCl-induced elevation of [Ca2+]i was not affected by Y-27632 but was reversed by NiCl2 or by BAPTA-AM. We conclude that KCl acts in part through stimulation of Rho and ROCK, possibly secondary to voltage-dependent Ca2+ influx.


Progenitor Cells and Clinical Outcomes in Patients With Acute Coronary Syndromes.
Circulating progenitor cells (CPCs) mobilize in response to ischemic injury, but their predictive value remains unknown in acute coronary syndrome (ACS). We aimed to investigate the number of CPCs in ACS compared with those with stable coronary artery disease (CAD), relationship between bone marrow PCs and CPCs, and whether CPC counts predict mortality in patients with ACS. In 2028 patients, 346 had unstable angina, 183 had an acute myocardial infarction (AMI), and the remaining 1499 patients had stable CAD. Patients with ACS were followed for the primary end point of all-cause death. CPCs were enumerated by flow cytometry as mononuclear cells expressing a combination of CD34+, CD133+, vascular endothelial growth factor receptor 2+, or chemokine (C-X-C motif) receptor 4+. CPC counts were higher in subjects with AMI compared those with stable CAD even after adjustment for age, sex, race, body mass index, renal function, hypertension, diabetes mellitus, hyperlipidemia, and smoking; CD34+, CD34+/CD133+, CD34+/CXCR4+, and CD34+/VEGFR2+ CPC counts were 19%, 25%, 28%, and 142% higher in those with AMI, respectively, compared with stable CAD. There were strong correlations between the concentrations of CPCs and the PC counts in bone marrow aspirates in 20 patients with AMI. During a 2 (interquartile range, 1.31-2.86)-year follow-up period of 529 patients with ACS, 12.4% died. In Cox regression models adjusted for age, sex, body mass index, heart failure history, estimated glomerular filtration rate, and AMI, subjects with low CD34+ cell counts had a 2.46-fold (95% confidence interval, 1.18-5.13) increase in all-cause mortality, P=0.01. CD34+/CD133+ and CD34+/CXCR4+, but not CD34+/VEGFR2+ PC counts, had similar associations with mortality. Results were validated in a separate cohort of 238 patients with ACS. CPC levels are significantly higher in patients after an AMI compared with those with stable CAD and reflect bone marrow PC content. Among patients with ACS, a lower number of hematopoietic-enriched CPCs are associated with a higher mortality.


Strategies for surgical treatment of gallbladder carcinoma based on information available before resection.
Precise preoperative staging for gallbladder carcinoma is difficult, despite recent advances in hepatobiliary imaging. However, the most accurate preoperative staging may be possible by integrating preoperative key data. To establish useful strategies for the surgical treatment of gallbladder cancer based on information available before resection. Retrospective review. University hospital and tertiary referral cancer center. From January 1, 1978, through March 31, 2001, 152 patients with gallbladder cancer underwent surgical resection with curative intent. Preoperative diagnoses of the T factor (image-T) and N factor (image-N) in the TNM classification were determined by evaluating all findings of diagnostic imaging, including ultrasonography, enhanced computed tomography, endoscopic ultrasonography, and angiography. The distribution of lymph node metastasis and prognostic factors were also analyzed. The overall diagnostic accuracy for image-T was 52.6% (95% confidence interval, 44.7%-60.6%) and was lower in patients with pT1 and pT2 disease (37.2% and 33.9%, respectively). However, image-T was a significant predictor of lymph node metastasis and patient outcome. Preoperative staging for N was more difficult, with only 24.5% (95% confidence interval, 12.4%-36.5%) of the node-positive patients being correctly diagnosed. An analysis of harvested lymph nodes showed that the cystic, pericholedochal, and posterosuperior peripancreatic nodes were the most prevalent sites of metastasis, and these were considered key nodes for the lymphatic spread of gallbladder cancer. By combining data on image-T and positivity of these key nodes, more accurate TNM staging was possible. Although an extended lymph node dissection provided significantly better survival in patients with pN2 disease, there was no survival advantage to more radical operations, including bile duct resection or pancreaticoduodenectomy. Although precise preoperative TNM staging for gallbladder carcinoma was difficult, the most accurate staging before resection was possible by integrating image-T classification and data from the intraoperative histopathologic examination of key lymph nodes. Based on this staging, we propose algorithms for the surgical treatment of gallbladder carcinoma.


[Changes in the alpha-macroglobulins during evolution].
It has been demonstrated that antigenic properties of alpha-macroglobulins from 6 species of vertebrate and invertebrate animals are rather similar. All proteins consist of identical subunits which are associated by covalent and noncovalent bonds. All of them are presented by glycoproteins and exhibit the capacity to bind proteinases, as well as the capacity to inhibit the latter with respect to protein and low-molecular synthetic substrates.


Differential impact on motor unit characteristics across severities of adult spinal muscular atrophy.
To test the hypotheses that decomposition electromyography (dEMG) motor unit action potential (MUAP) amplitude and firing rate are altered in SMA; dEMG parameters are associated with strength and function; dEMG parameters are correlated with traditional electrophysiological assessments. Ambulatory and non-ambulatory adults with SMA on nusinersen and healthy controls were enrolled. MUAPs were decomposed from multielectrode surface recordings during 30-s maximum contraction of the abductor digiti minimi (ADM). Isometric strength, upper limb function, patient-reported function, and standard electrophysiologic measures of the ADM (compound muscle action potential [CMAP], single motor unit potential [SMUP], motor unit number estimation [MUNE]) were collected. dEMG MUAP amplitudes were higher in ambulatory versus control and non-ambulatory groups and were higher in controls versus non-ambulatory SMA. In contrast, dEMG firing rates were higher in ambulatory versus non-ambulatory and control groups but similar between non-ambulatory and control. dEMG parameters showed moderate to strong positive correlation with strength and function whereas CMAP and MUNE better correlated with function than strength. SMUP did not correlate with strength, function, or dEMG MUAP amplitude. dEMG parameters show overall good test-retest reliability. dEMG provided reliable, noninvasive measure of MUAP amplitude size and firing rate and revealed divergent patterns across disease severity in adults with SMA. Firing rate enhancement, as seen in milder SMA, may provide a therapeutic avenue for improving function in more severe SMA, where firing rates appear preserved. MUAP amplitude size and firing rate, quantified with dEMG, may be promising monitoring biomarker candidates for noninvasive assessment of SMA.


Metabolic control of potassium permeability in pancreatic islet cells.
The K(+) permeability of pancreatic islet cells was studied by monitoring the efflux of (86)Rb(+) (used as tracer for K(+)) from perifused rat islets and measuring the uptake of (42)K(+). Glucose markedly and reversibly decreased (86)Rb(+) efflux from islet cells and this effect was antagonized by inhibitors of the metabolic degradation of the sugar, i.e. mannoheptulose, iodoacetate, glucosamine and 2-deoxyglucose. Among glucose metabolites, glyceraldehyde reduced the K(+) permeability even more potently than did glucose itself; pyruvate and lactate alone exhibited only a small effect, but potentiated that of glucose. Other metabolized sugars, like mannose, glucosamine and N-acetylglucosamine, also decreased (86)Rb(+) efflux from islet cells. Fructose was effective only in the presence of glucose. Non-metabolized sugars like galactose, 2-deoxyglucose and 3-O-methylglucose had no effect. The changes in K(+) permeability by agents known to modify the concentrations of nicotinamide nucleotides, glutathione or ATP in islet cells were also studied. Increasing NAD(P)H concentrations in islet cells by pentobarbital rapidly and reversibly reduced (86)Rb(+) efflux; exogenous reduced glutathione produced a similar though weaker effect. By contrast, oxidizing nicotinamide nucleotides with phenazine methosulphate or Methylene Blue, or oxidizing glutathione by t-butyl hydroperoxide increased the K(+) permeability of islet cells. Uncoupling the oxidative phosphorylations with dicumarol also augmented (86)Rb(+) efflux markedly. In the absence of glucose, but not in its presence, methylxanthines reduced (86)Rb(+) efflux from the islets; such was not the case for cholera toxin or dibutyryl cyclic AMP. Glucose and glyceraldehyde had no effect on (42)K(+) uptake after a short incubation (10min), but augmented it after 60min; the effect of glucose was suppressed by mannoheptulose and not mimicked by 3-O-methylglucose. The results clearly establish the importance of the metabolic degradation of glucose and other substrates for the control of the K(+) permeability in pancreatic islet cells and support the concept that a decrease in the K(+) permeability represents a major step of the B-cell response to physiological stimulation.


Differential regulation of DC function by Siphonodiol.
Siphonodiol is a polyacetylene diol isolated from marine sponges Callyspongia sp. We demonstrate that the effect of Siphonodiol on the phenotypic and functional maturation of human monocyte derived DC in vitro. Human monocytes were exposed to Siphonodiol alone, or in combination with LPS and thereafter co-cultured with naïve T cells. The expression levels of CD1a, CD80, CD83, CD86 and HLA-DR on LPS-primed DC were partially enhanced by Siphonodiol. Siphonodiol augmented the T cell stimulatory capacity in an allo MLR to LPS-primed DC. Siphonodiol dose-dependently enhanced the production of IL-12p70 by LPS-primed DC and this cytokine production was inhibited by anti-TLR4 mAb. IFN-gamma secretion from naive T cells co-cultured with DC differentiated with LPS was augmented by Siphonodiol. These results suggest that the enhancement of Th1 cells polarization to LPS-primed DC induced by Siphonodiol depends on TLR4 and via the activation of IL-12p70.


Pilot Test of the Maximizing Adolescent Post-Secondary Success (MAPSS) Intervention: Supporting Parents of Autistic Youth.
Parents play an essential role in the transition to adulthood for autistic youth, yet often feel they do not have adequate training and resources. To evaluate data on the preliminary efficacy of and collect participant feedback about the Maximizing Adolescent Post-Secondary Success (MAPSS) intervention. Single-group, pretest-posttest pilot study. Clinic. Twenty-two families of autistic youth (ages 13-19 yr, 72.7% male). MAPSS is a group intervention for parent-youth dyads that is designed to guide parents in facilitating the development of independent skills for adulthood. Outcomes and Measures: Measures included the Transition Preparation Activities Measure (T-PAM), Family Empowerment Scale (FES), 10-item Perceived Stress Scale (PSS-10), Adulthood Expectations Questionnaire (AEQ), Adaptive Behavior Assessment System-Third Edition (ABAS-3), and a study-specific participant feedback survey. Frequency of transition preparation activities (T-PAM) significantly increased from before to after the intervention, and although the frequency of preparation activities decreased by 1-mo follow-up, it remained significantly higher than at baseline. Parent self-efficacy (FES), parent expectations (AEQ), and parent sense of control over outcomes (AEQ) also significantly increased from preintervention to follow-up; however, parent coping (PSS-10) was unchanged. Youth self-care skills (ABAS-3) demonstrated improvements 6 mo after the completion of the intervention, although other areas of adaptive behavior did not significantly change. Feedback from parents suggested they had positive experiences and felt the intervention was beneficial. Our data suggest that the MAPSS intervention is an appropriate candidate for larger, controlled clinical trials. What This Article Adds: With additional evidence, this intervention can offer guidelines for occupational therapists to work with autistic youth and their parents to prepare for adulthood.


[A neurophysiological analysis of the sensory disorders in trigeminal nerve neuropathy].
52 patients with various types of trigeminal nerve neuropathy were examined in terms of trigeminal somatosensory evoked potentials (TSEP). The increase of latent periods and the decrease of N5-N33 amplitude components as well as disappearance of some separate components of this period were observed in patients with moderate facial pain and hypersthesia when sore side was stimulated. Meanwhile the alterations level of TSEP correlated with trigeminal hypesthesia severity. In a course of such stimulation all TSEP components disappeared in patients with severe sensory deficit and this turned out to be unfavourable prognostic sign pointing out the small perspectivity of conservative antianalgesic therapy. TSEP investigation in patients with trigeminal nerve neuropathy promoted objectivity of face and oral cavity sensory insufficiency that permitted to estimate both the alteration degree and algesic syndrome severity.


Cobalt(I)-Catalyzed (3 + 2 + 2) Cycloaddition between Alkylidenecyclopropanes, Alkynes, and Alkenes.
Cobalt(I) catalysts equipped with bisphosphine ligands can be used to promote formal (3 + 2 + 2) intramolecular cycloadditions of enynylidenecyclopropanes of type 1. The method provides synthetically appealing 5,7,5-fused tricyclic systems in good yields and with complete diastereo- and chemoselectivity. Interestingly, its scope differs from that of previously reported annulations based on precious metal catalysts, specifically rhodium and palladium. Noticeably, density functional theory calculations confirm that the mechanism of the reaction is also different from those proposed for these other catalysts.


Diastereoselective cyclization of an aminobenzoic acid derivative and chiroptical properties of triple-stranded helical bis(phenylethynyl)benzene.
The diastereoselective cyclization of 2,5-dibromo-4-hexylaminobenzoic acid was achieved by the microwave-assisted condensation using SiCl4. Moreover, the triple-stranded helical structure of bis(phenylethynyl)benzene units embedded in the cyclic tri(benzamide) scaffold was obtained by a Sonogashira-Hagihara coupling reaction. Two optically active enantiomers that do not racemize even at the elevated temperature were separated by chiral HPLC. The chiral helical topology was revealed by the spectroscopic data and theoretical calculation.


Safety and feasibility of iliac endovascular interventions with a radial approach. Results from a multicenter study coordinated by the Italian Radial Force.
Percutaneous angioplasty of lower limb disease is commonly performed with a transfemoral access. In the coronary field, a transradial approach has shown to reduce access-site bleeding and adverse clinical events. This route has not yet been well studied for the majority of peripheral interventions, like those involving the iliac arteries. In this study we sought to evaluate the feasibility and safety of this approach for iliac interventions. Multicenter study was performed at high-volume centers with experience in transradial percutaneous interventions. Primary endpoint of the study was procedural success; secondary endpoints included in-hospital bleeding, 1-month freedom from adverse events and the rate of radial occlusion. Feasibility of this technique was evaluated by recording procedural and fluoroscopy time and contrast load. A total of 149 patients from 5 centers were enrolled. The population had a medium risk profile, with 48% of patients having TASC 2 or 3 lesions. Procedural success was achieved in 98.7% of the population, and we did not register in-hospital complications, including both vascular access site and procedural-related complications. An ancillary transfemoral approach was used in 13% of patients. One-month freedom from symptoms was achieved in 97.3% of patients, and the rate of radial occlusion was 2.7%. Major determinants of an unsuccessful procedure were the use of normal 6 or 7-Fr introducer with guiding catheter, TASC D lesion attempt, lesion length>30 mm and total occlusion. A transradial approach for iliac disease may be a feasible and safe alternative to the transfemoral route in experienced hands, in the light of significant technical improvements and dedicated devices.