Risks of common complications in deep brain stimulation surgery: management and avoidance.
Deep brain stimulation (DBS) surgery is increasingly prominent in the treatment of various disorders refractory to medication. Despite the procedure's efficacy, the community at large continues to be hesitant about presumed associated risks. The main object of this study was to assess the incidence of various surgical complications occurring both during and after DBS device implantation in a large population of patients with movement disorders in an effort to better quantify patient risk, define management plans, and develop methods for risk avoidance. A second aim was to corroborate the low procedural complication risk of DBS reported by others, which in light of the procedure's efficacy is needed to promote its widespread acceptance. All patients who had undergone new DBS device implantation surgery between 2002 and 2010 by a single surgeon were entered into a database after being verified by cross-referencing manufacturer implantation records. All surgical records and charts were reviewed to identify intraoperative, perioperative, and long-term surgical complications, including any characteristics predictive of an adverse event. Seven hundred twenty-eight patients received 1333 new DBS electrodes and 1218 new internal pulse generators (IPGs) in a total of 1356 stereotactic procedures for the treatment of movement disorders. Seventy-eight percent of the patients had staged lead and IPG implantations. Of the 728 patients, 452 suffered from medically refractory Parkinson disease; in the other patients, essential tremor (144), dystonia (64), mixed disease (30), and other hyperkinetic movement disorders (38) were diagnosed. Severe intraoperative adverse events included vasovagal response in 6 patients (0.8%), hypotension in 2 (0.3%), and seizure in 2 (0.3%). Postoperative imaging confirmed asymptomatic intracerebral hemorrhage (ICH) in 4 patients (0.5%), asymptomatic intraventricular hemorrhage in 25 (3.4%), symptomatic ICH in 8 (1.1%), and ischemic infarction in 3 (0.4%), associated with hemiparesis and/or decreased consciousness in 13 (1.7%). Long-term complications of DBS device implantation not requiring additional surgery included hardware discomfort in 8 patients (1.1%) and loss of desired effect in 10 (1.4%). Hardware-related complications requiring surgical revision included wound infections in 13 patients (1.7%), lead malposition and/or migration in 13 (1.7%), component fracture in 10 (1.4%), component malfunction in 4 (0.5%), and loss of effect in 19 (2.6%). The authors confirmed that the overall risk of both procedure- and hardware-related adverse events is acceptably low. They offer advice on how to avoid the most common complications.


The level of audiovisual print-speech integration deficits in dyslexia.
The classical phonological deficit account of dyslexia is increasingly linked to impairments in grapho-phonological conversion, and to dysfunctions in superior temporal regions associated with audiovisual integration. The present study investigates mechanisms of audiovisual integration in typical and impaired readers at the critical developmental stage of adolescence. Congruent and incongruent audiovisual as well as unimodal (visual only and auditory only) material was presented. Audiovisual presentations were single letters and three-letter (consonant-vowel-consonant) stimuli accompanied by matching or mismatching speech sounds. Three-letter stimuli exhibited fast phonetic transitions as in real-life language processing and reading. Congruency effects, i.e. different brain responses to congruent and incongruent stimuli were taken as an indicator of audiovisual integration at a phonetic level (grapho-phonological conversion). Comparisons of unimodal and audiovisual stimuli revealed basic, more sensory aspects of audiovisual integration. By means of these two criteria of audiovisual integration, the generalizability of audiovisual deficits in dyslexia was tested. Moreover, it was expected that the more naturalistic three-letter stimuli are superior to single letters in revealing group differences. Electrophysiological and hemodynamic (EEG and fMRI) data were acquired simultaneously in a simple target detection task. Applying the same statistical models to event-related EEG potentials and fMRI responses allowed comparing the effects detected by the two techniques at a descriptive level. Group differences in congruency effects (congruent against incongruent) were observed in regions involved in grapho-phonological processing, including the left inferior frontal and angular gyri and the inferotemporal cortex. Importantly, such differences also emerged in superior temporal key regions. Three-letter stimuli revealed stronger group differences than single letters. No significant differences in basic measures of audiovisual integration emerged. Convergence of hemodynamic and electrophysiological signals appeared to be limited and mainly occurred for highly significant and large effects in visual cortices. The findings suggest efficient superior temporal tuning to audiovisual congruency in controls. In impaired readers, however, grapho-phonological conversion is effortful and inefficient, although basic audiovisual mechanisms seem intact. This unprecedented demonstration of audiovisual deficits in adolescent dyslexics provides critical evidence that the phonological deficit might be explained by impaired audiovisual integration at a phonetic level, especially for naturalistic and word-like stimulation.


Durability of Satisfactory Functional Outcomes Following Surgical Adult Spinal Deformity Correction: A 3-Year Survivorship Analysis.
Despite reports showing positive long-term functional outcomes following adult spinal deformity (ASD)-corrective surgery, it is unclear which factors affect the durability of these outcomes. To assess durability of functional gains following ASD-corrective surgery; determine predictors for postoperative loss of functionality. Surgical ASD patients > 18 yr with 3-yr Oswestry Disability Index (ODI) follow-up, and 1-yr postoperative (1Y) ODI scores reaching substantial clinical benefit (SCB) threshold (SCB < 31.3 points). Patients were grouped: those sustaining ODI at SCB threshold beyond 1Y (sustained functionality) and those not (functional decline). Kaplan-Meier survival analysis determined postoperative durability of functionality. Multivariate Cox regression assessed the relationship between patient/surgical factors and functional decline, accounting for age, sex, and levels fused. All 166 included patients showed baseline to 1Y functional improvement (mean ODI: 35.3 ± 16.5-13.6 ± 9.2, P < .001). Durability of satisfactory functional outcomes following the 1Y postoperative interval was 88.6% at 2-yr postoperative, and 71.1% at 3-yr postoperative (3Y). Those sustaining functionality after 1Y had lower baseline C2-S1 sagittal vertical axis (SVA) and T1 slope (both P < .05), and lower 1Y thoracic kyphosis (P = .035). From 1Y to 3Y, patients who sustained functionality showed smaller changes in alignment: pelvic incidence minus lumbar lordosis, SVA, T1 slope minus cervical lordosis, and C2-C7 SVA (all P < .05). Those sustaining functionality beyond 1Y were also younger, less frail at 1Y, and had lower rates of baseline osteoporosis, hypertension, and lung disease (all P < .05). Lung disease (Hazard Ratio:4.8 [1.4-16.4]), 1Y frailty (HR:1.4 [1.1-1.9]), and posterior approach (HR:2.6 [1.2-5.8]) were associated with more rapid decline. Seventy-one percent of ASD patients maintained satisfactory functional outcomes by 3Y. Of those who failed to sustain functionality, the largest functional decline occurred 3-yr postoperatively. Frailty, preoperative comorbidities, and surgical approach affected durability of functional gains following surgery.


Grating resonances in air-silica microstructured optical fibers.
We report what is believed to be the first demonstration of optical fiber gratings written in photonic crystal fibers. The fiber consists of a germanium-doped photosensitive core surrounded by a hexagonal periodic air-hole lattice in a silica matrix. The spectra of these gratings allow for a detailed characterization of the fiber. In particular, the gratings facilitate coupling to higher-order leaky modes. We show that the spatial distribution and the effective index of these modes are determined largely by the design of the lattice and that the grating spectra are unaffected by the refractive index surrounding the fiber. We describe these measurements and corresponding simulations and discuss their implications for the understanding of such air-hole structures.


Approaches using molecular imaging technology -- use of PET in clinical microdose studies.
Positron emission tomography (PET) imaging uses minute amounts of radiolabeled drug tracers and thereby meets the criteria for clinical microdose studies. The advantage of PET, when compared to other analytical methods used in microdose studies, is that the pharmacokinetics (PK) of a drug can be determined in the tissue targeted for drug treatment. PET microdosing already offers interesting applications in clinical oncology and in the development of central nervous system pharmaceuticals and is extending its range of application to many other fields of pharmaceutical medicine. Although requirements for preclinical safety testing for microdose studies have been cut down by regulatory authorities, radiopharmaceuticals increasingly need to be produced under good manufacturing practice (GMP) conditions, which increases the costs of PET microdosing studies. Further challenges in PET microdosing include combining PET with other ultrasensitive analytical methods, such as accelerator mass spectrometry (AMS), to gain plasma PK data of drugs, beyond the short PET examination periods. Finally, conducting clinical PET studies with radiolabeled drugs both at micro- and therapeutic doses is encouraged to answer the question of dose linearity in clinical microdosing.


An endocannabinoid-regulated basolateral amygdala-nucleus accumbens circuit modulates sociability.
Deficits in social interaction (SI) are a core symptom of autism spectrum disorders (ASDs); however, treatments for social deficits are notably lacking. Elucidating brain circuits and neuromodulatory signaling systems that regulate sociability could facilitate a deeper understanding of ASD pathophysiology and reveal novel treatments for ASDs. Here we found that in vivo optogenetic activation of the basolateral amygdala-nucleus accumbens (BLA-NAc) glutamatergic circuit reduced SI and increased social avoidance in mice. Furthermore, we found that 2-arachidonoylglycerol (2-AG) endocannabinoid signaling reduced BLA-NAc glutamatergic activity and that pharmacological 2-AG augmentation via administration of JZL184, a monoacylglycerol lipase inhibitor, blocked SI deficits associated with in vivo BLA-NAc stimulation. Additionally, optogenetic inhibition of the BLA-NAc circuit markedly increased SI in the Shank3B-/- mouse, an ASD model with substantial SI impairment, without affecting SI in WT mice. Finally, we demonstrated that JZL184 delivered systemically or directly to the NAc also normalized SI deficits in Shank3B-/- mice, while ex vivo JZL184 application corrected aberrant NAc excitatory and inhibitory neurotransmission and reduced BLA-NAc-elicited feed-forward inhibition of NAc neurons in Shank3B-/- mice. These data reveal circuit-level and neuromodulatory mechanisms regulating social function relevant to ASDs and suggest 2-AG augmentation could reduce social deficits via modulation of excitatory and inhibitory neurotransmission in the NAc.


FCRL3 -169CT functional polymorphism in type 1 diabetes and autoimmunity traits.
A functional variant located in the promoter region of the Fc receptor like 3 gene (FCRL3, -169CT variant) has been recently shown to be associated with several autoimmune diseases in the Japanese population. Following the concept of shared genetic determinants between autoimmune diseases, we tested this variant for association to Type 1 diabetes (T1D) and T1D-related phenotypes in two independent settings: a family-based association study (French and US families) and a case-control study (French population). We found suggestive evidence for association of the FCRL3 -169CC genotype, corresponding to the susceptibility genotype for rheumatoid arthritis, with an increased risk of additional autoimmunity markers (OR=1.97, P=0.01) and of other autoimmune diseases (OR=1.75, P=0.05). However, there was no evidence of association of this variant with T1D in these cohorts, separately and combined, nor in subgroups of patients defined based on their major T1D risk factors at HLA-DRB1, insulin and PTPN22. Hence, this variant may help define subgroups of T1D patients with contrasted risk of other autoimmune diseases.


Effects of aging on mechanics and composition of cerebral arterioles in rats.
The purpose of this study was to examine effects of aging on the mechanics and composition of cerebral arterioles. We measured pressure (servo-null) and diameter in pial arterioles in anesthetized adult (9-12 months old) and aged (24-27 months old) Fischer 344 rats. After deactivation of smooth muscle with EDTA, diameter of pial arterioles at 70 mm Hg pial arteriolar pressure was less in aged than in adult rats (67 +/- 4 vs. 81 +/- 4 microns [mean +/- SEM], p less than 0.05). The stress-strain relation and the slope of tangential elastic modulus versus stress (6.8 +/- 0.6 vs. 5.3 +/- 0.3, p less than 0.05) indicated that distensibility of pial arterioles was reduced in aged rats. Cross-sectional area of the vessel wall, measured histologically, was less in aged than adult rats (1,239 +/- 91 vs. 1,832 +/- 180 microns2, p less than 0.05). Point counting stereology was used to quantitate smooth muscle, elastin, collagen, and basement membrane in the arteriolar wall. Cross-sectional areas of smooth muscle and elastin were significantly less in aged than adult rats (744 +/- 57 vs. 1,291 +/- 119 microns2 for smooth muscle, 52 +/- 6 vs. 113 +/- 15 microns2 for elastin; p less than 0.05), whereas cross-sectional areas of collagen and basement membrane were not significantly different in aged and adult rats (4 +/- 1 vs. 3 +/- 1 microns2 for collagen, 236 +/- 17 vs. 258 +/- 31 microns2 for basement membrane). The ratio of nondistensible (collagen and basement membrane) to distensible (smooth muscle and elastin) components was greater in aged than adult rats (0.30 +/- 0.01 vs. 0.18 +/- 0.01, p less than 0.05). Thus, we conclude that, during aging, cerebral arterioles undergo atrophy, distensibility of cerebral arterioles is reduced, and the relative proportion of distensible elements, elastin and smooth muscle, is reduced in the arteriolar wall.


Risk stratification after acute myocardial infarction by amplitude-frequency mapping of cyclic variation of heart rate.
Blunted cyclic variation of heart rate (CVHR), measured as a decrease in CVHR amplitude (Acv), predicts mortality risk after acute myocardial infarction (AMI). However, Acv also can be reduced in mild sleep apnea with mild O2 desaturation. We investigated whether Acv's predictive power for post-AMI mortality could be improved by considering the effect of sleep apnea severity. In 24-hr ECG in 265,291 participants of the Allostatic State Mapping by Ambulatory ECG Repository project, sleep apnea severity was estimated by the frequency of CVHR (Fcv) measured by an automated algorithm for auto-correlated wave detection by adaptive threshold (ACAT). The distribution of Acv on the Acv-Fcv relation map was modeled by percentile regression, and a function converting Acv into percentile value was developed. In the retrospective cohort of the Enhancing Recovery in Coronary Heart Disease (ENRICHD) study, consisting of 673 survivors and 44 non-survivors after AMI, the mortality predictive power of percentile Acv calculated by the function was compared with that of unadjusted Acv. Among the ALLSTAR ECG data, low Acv values appeared more likely when Fcv was low. The logistic regression analysis for mortality in the ENRICHD cohort showed c-statistics of 0.667 (SE, 0.041), 0.817 (0.035), and 0.843 (0.030) for Fcv, unadjusted Acv, and the percentile Acv, respectively. Compared with unadjusted Acv, the percentile Acv showed a significant net reclassification improvement of 0.90 (95% CI, 0.51-1.42). The predictive power of Acv for post-AMI mortality is improved by considering its relation to sleep apnea severity estimated by Fcv.


BOBBER1 is a noncanonical Arabidopsis small heat shock protein required for both development and thermotolerance.
Plants have evolved a range of cellular responses to maintain developmental homeostasis and to survive over a range of temperatures. Here, we describe the in vivo and in vitro functions of BOBBER1 (BOB1), a NudC domain containing Arabidopsis (Arabidopsis thaliana) small heat shock protein. BOB1 is an essential gene required for the normal partitioning and patterning of the apical domain of the Arabidopsis embryo. Because BOB1 loss-of-function mutants are embryo lethal, we used a partial loss-of-function allele (bob1-3) to demonstrate that BOB1 is required for organismal thermotolerance and postembryonic development. Recombinant BOB1 protein functions as a molecular chaperone and prevents the aggregation of a model protein substrate in vitro. In plants, BOB1 is cytoplasmic at basal temperatures, but forms heat shock granules containing canonical small heat shock proteins at high temperatures. In addition to thermotolerance defects, bob1-3 exhibits pleiotropic development defects during all phases of development. bob1-3 phenotypes include decreased rates of shoot and root growth as well as patterning defects in leaves, flowers, and inflorescence meristems. Most eukaryotic chaperones play important roles in protein folding either during protein synthesis or during cellular responses to denaturing stress. Our results provide, to our knowledge, the first evidence of a plant small heat shock protein that has both developmental and thermotolerance functions and may play a role in both of these folding networks.


Using the OVAKO working posture analysis system in cleaning occupations.
Cleaning workers experience severe musculoskeletal symptoms. The objective of this paper was to examine musculoskeletal symptoms in cleaners of different heights to evaluate the effects of height on working postures in the work environment (schools). We used a three-stage method including using the Nordic Musculoskeletal Questionnaire (NMQ) to evaluate musculoskeletal symptoms, a task analysis to confirm typical cleaning tasks, and the OVAKO Working Posture Assessment System (OWAS) for posture analysis. Multinomial logistic regression was performed to evaluate the adjusted effects of individual characteristics on painful body regions, using individuals without any pain as the reference category. This study found that the prevalence of musculoskeletal symptoms is very high for cleaners, especially in the shoulders, elbows, and lower back. Odds ratios for the accumulation of two or more risk factors were higher among men and were inversely associated with national economic indicators. The relatively high prevalence of musculoskeletal symptoms may stem from the multiple operations involved in cleaning tasks, such as trash collecting, floor mopping, toilet cleaning, and mirror polishing. Workers of different heights had differential work loadings for different tasks. This paper proposes recommendations for job adaptations and occupational safety training. Cleaners of different heights execute the typical tasks via different postures, and awkward postures often result in musculoskeletal symptoms. Cleaners should be provided with specific tools and training regarding working postures on the basis of height. These findings can be used as a reference for related operation designs and task improvements to ensure correct tool usage and safer working postures during cleaning.


Bond strength for orthodontic brackets contaminated by blood: composite versus resin-modified glass ionomer cements.
The purpose of this study was to evaluate and compare the shear bond strengths of a self-cured glass ionomer versus composite cement for bonding of stainless steel buttons with various enamel surface and setting conditions. Stainless steel orthodontic buttons were bonded using composite material under 3 different enamel and setting conditions: 1) conditioned and dry enamel surface, 2) conditioned and precontamination of the enamel surface with blood before bonding, 3) conditioned and immediate blood contamination postbonding and were compared with 3 different enamel conditions and setting for bonding with the glass ionomer cement: 1) nonconditioned and wet enamel surfaces, 2) nonconditioned and blood contamination of enamel before bonding, and 3) nonconditioned and immediate blood contamination postbonding. The brackets were bonded to 109 recently extracted teeth and allowed to set in a moist plastic container for 24 hours. They were subsequently tested in shear mode with a universal testing machine. The maximum bond strength and the site of bond failure were recorded. In addition, the location of the bond failure was studied. Composite was capable of sustaining greater forces than the resin-modified glass ionomer materials. Hence, it took more force to debond a bracket cemented with composite than with resin-modified glass ionomer. The effect of contamination was similar in both of the materials, and the magnitude of the decrease in bond strength was nearly of the same proportion. The postcontamination values were not significantly different from the uncontaminated bond strength for either material. The type of bond failure was significantly different for the different materials, and there were significant differences among the treatment conditions. Composite resin had significantly greater shear strength than resin-reinforced glass ionomer cement. Both materials showed a significant decrease in bond strength when precontaminated with blood. The postcontamination values were not significantly different from the uncontaminated bond strength for either material.


Impact of FLT3 internal tandem duplication on the outcome of related and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first remission: a retrospective analysis.
Patients with acute myeloid leukemia (AML) and FLT3/internal tandem duplication (FLT3/ITD) have poor prognosis if treated with chemotherapy only. Whether this alteration also affects outcome after allogeneic hematopoietic stem-cell transplantation (HSCT) remains uncertain. We analyzed 206 patients who underwent HLA-identical sibling and matched unrelated HSCTs reported to the European Group for Blood and Marrow Transplantation with a diagnosis of AML with normal cytogenetics and data on FLT3/ITD (present: n = 120, 58%; absent: n = 86, 42%). Transplantations were performed in first complete remission (CR) after myeloablative conditioning. Compared with FLT3/ITD-negative patients, FLT3/ITD-positive patients had higher median leukocyte count at diagnosis (59 v 21 × 10(9)/L; P < .001) and shorter interval from CR to transplantation (87 v 99 days; P = .04). Other characteristics were similar in the two groups. At 2 years, relapse incidence (RI; ± standard deviation) was higher (30% ± 5% v 16% ± 5%; P = .006) and leukemia-free survival (LFS) lower (58% ± 5% v 71% ± 6%; P = .04) in FLT3/ITD-positive compared with FLT3/ITD-negative patients. In multivariate analyses, FLT3/ITD led to increased RI (hazard ratio [HR], 3.4; 95% CI, 1.46 to 7.94; P = .005), as did older age, female sex, shorter interval between CR and transplantation, and higher number of chemotherapy courses before achieving CR. FLT3/ITD positivity was associated with decreased LFS (HR, 0.37; 95% CI, 0.19 to 0.73; P = .002), along with older age and higher number of chemotherapy courses before achieving CR. FLT3/ITD adversely affected the outcome of HSCT in the same direction it does after chemotherapy; despite this, more than half of the patients harboring this mutation who received transplants were alive and leukemia free at 2 years. To further improve the results, use of FLT3 inhibitors before or after HSCT deserves investigation.


Same but Different: Dipole-Stabilized Shape Resonances in CuF(-) and AgF(.).
Electron attachment to closed-shell molecules is a gateway to various important processes in the gas and condensed phases. The properties of an electron-attached state, such as its energy and lifetime as well as the character of the molecular orbital to which the electron is attached, determine the fate of the anion. In this experimental and theoretical study of copper and silver fluoride anions, we introduce a new type of metastable anionic state. Abrupt changes in photoelectron angular distributions point to the existence of autodetaching states. Equation-of-motion coupled-cluster singles and doubles calculations augmented by a complex absorbing potential identify some of these states as Σ and Π dipole-stabilized resonances, a new type of shape resonance. In addition, these molecules support valence and dipole-bound states and a Σ resonance of charge-transfer character. By featuring five different types of anionic states, they provide a vehicle for studying fundamental properties of anions and for validating new theoretical approaches for metastable states.


Pharmacologic Neuroprotection for Functional Outcomes After Traumatic Brain Injury: A Systematic Review of the Clinical Literature.
Traumatic brain injury (TBI) is a major cause of death and disability worldwide. The deleterious effects of secondary brain injury may be attenuated by early pharmacological therapy in the emergency room and intensive care unit (ICU). Current medical management of acute TBI is primarily supportive, aimed at reducing intracranial pressure (ICP) and optimizing cerebral perfusion. There are no pharmacological therapies to date that have been unequivocally demonstrated to improve neurological outcomes after TBI. The purpose of this systematic review was to evaluate the recent clinical studies from January 2013 through November 2015 that investigated neuroprotective functional outcomes of pharmacological agents after TBI. The following databases were searched for relevant studies: MEDLINE (OvidSP January Week 1, 2013-November Week 2 2015), Embase (OvidSP 2013 January 1-2015 November 24), and the unindexed material in PubMed (National Library of Medicine/National Institutes of Health [NLM/NIH]). This systematic review included only full-length clinical studies and case series that included at least five patients and were published in the English language. Only studies that examined functional clinical outcomes were included. Twenty-five of 527 studies met our inclusion criteria, which investigated 15 independent pharmacological therapies. Eight of these therapies demonstrated possible neuroprotective properties and improved functional outcomes, of which five were investigated with randomized clinical trials: statins, N-acetyl cysteine (NAC), Enzogenol, Cerebrolysin, and nitric oxide synthase inhibitor (VAS203). Three pharmacological agents did not demonstrate neuroprotective effects, and four agents had mixed results. While there is currently no single pharmacological therapy that will unequivocally improve clinical outcomes after TBI, several agents have demonstrated promising clinical benefits for specific TBI patients and should be investigated further.


Ingenol mebutate: induced cell death patterns in normal and cancer epithelial cells.
We investigated the proposed necrotic mechanism of ingenol mebutate, a natural compound with anti-cancer properties in human keratinocytes, the human squamous cell carcinoma cell line HSC-5, and HeLa cervix carcinoma cells. Topical application of a clinical dose of ingenol mebutate 0.05% (1.15 mM) gel to human reconstituted full-thickness skin equivalents strongly reduced epidermal, but not dermal viability. Ingenol mebutate showed cytotoxic potency between 200-300 M on normal and cancer cells. When keratinocytes were induced to differentiate, they became significantly less sensitive to ingenol mebutate and half-maximal induction of cell death required more than 300 M ingenol mebutate. Cytotoxic concentrations of ingenol mebutate caused rupture of the mitochondrial network within minutes paralleled by cytosolic calcium release in all cells. Subsequently, plasma membrane integrity was lost as seen by propidium uptake into the cells. This was in sharp contrast to lysis of cells with low concentrations of the detergent Triton X-100 that permeabilized the plasma membrane within minutes without affecting organelle morphology. Buffering of intracellular calcium and inhibition of the mitochondrial permeability transition pore reduced the cytotoxic effect of ingenol mebutate in cancer cells, but not in normal keratinocytes. However, these inhibitors could not prevent cell death subsequent to prolonged incubation. Our findings reveal that ingenol mebutate does not mediate cytotoxicity by a simple lytic, necrotic mechanism, but activates distinct processes involving multiple cell organelles in a cell-type and differentiation-dependent manner. These data improve our understanding of ingenol mebutate-target cell interactions and offer new insights relevant to the removal of aberrant cells in human skin.


Proline bulky substituents consecutively act as steric hindrances and directing groups in a Michael/Conia-ene cascade reaction under synergistic catalysis.
In this study, we report a highly stereoselective and versatile synthesis of spiro pyrazolones, promising motifs that are being employed as pharmacophores. The new synthetic strategy merges organocatalysis and metal catalysis to create a synergistic catalysis using proline derivatives and Pd catalysts. This protocol is suitable for late-stage functionalization, which is very important in drug discovery. Additionally, a thorough computational study proved to be very useful to elucidate the function of the different catalysts along the reaction, showing a peculiar feature: the -CPh2OSiMe3 group of the proline catalyst switches its role during the reaction. In the initial Michael reaction, this group plays its commonly-assumed role of bulky blocking group, but the same group generates π-Pd interactions and acts as a directing group in the subsequent Pd-catalyzed Conia-ene reaction. This finding might be very relevant especially for processes with many steps, such as cascade reactions, in which functional groups are assumed to play the same role during all reaction steps.


Patients' expectations before and satisfaction after ultrasound guided foam sclerotherapy for varicose veins.
Ultrasound guided foam sclerotherapy (UGFS) is a minimally invasive treatment for varicose veins (VV) whose clinical and cost-effectiveness remains incompletely defined. The aim of the current study was to examine patients' expectations before and satisfaction after UGFS for VV in terms of relief of lower limb symptoms, improvement in appearance, and beneficial effect on life-style. A consecutive series of 351 patients (464 limbs) undergoing UGFS for VV completed questionnaires one week prior to and six months after treatment. Pre and post-treatment response rates were 80%; 60% returned both questionnaires. Virtually all patients were expecting improvement in lower limb symptoms; these were exceeded in a third. Most patients expected cosmetic improvement and these were largely met. Two-thirds of patients expected significant life-style (clothes, work, social) benefits and outcomes were slightly less than expected. A quarter expected improvement in their interpersonal relationships. This benefit was greater than expected occurring in one-third of patients. Overall, a quarter of patients had their expectations exceeded and 10% (appearance and relationships) to 25% (clothing, work and social and leisure activities) were left with unmet expectations. When specifically asked most patients admit to having a wide range of expectations in relation to their VV treatment, many of them probably unanticipated by the clinician. However, present data indicate that UGFS is usually able to meet, and often exceeds, these physical and psychosocial needs and expectations. UGFS is, therefore, a highly effective treatment for VV from the patients' perspective.


Effects of Hydrolyzable Tannins on In Vitro Growth of Armillaria calvescens and A. gallica.
We hypothesized that Armillaria gallica, which is abundant in oak-dominated forests, is more successful at oxidizing and metabolizing polyphenols than A. calvescens, which is mostly restricted to maple-dominated forests. Isolates were challenged with up to seven concentrations of tannic acid (TA), gallic acid (GA), and black oak root bark extracts (RBE). Six concentrations of glucose and ethanol were also tested to determine the influence of available carbon on growth. Colony area and biomass values were analyzed using a GLM and Tukey's HSD test. When challenged with 0.12% concentrations of TA, GA, and RBE, A. gallica produced a significantly larger biomass in all treatments and larger colony areas in four of the five treatments compared to control values. A. gallica also produced a significantly larger number of rhizomorphs than A. calvescens on RBE medium. In contrast, A. calvescens generated significantly larger biomass over control treatments only when RBE was added, and values were substantially less compared to A. gallica. Growth of both species was significantly greater when ethanol was added, especially on GA medium, while glucose had little effect. Results from this study suggest that A. gallica is better at oxidizing and metabolizing polyphenols than A. calvescens.


Expression of adrenomedullin and proadrenomedullin N-terminal 20 peptide in human and rat prostate.
Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are two recently discovered hypotensive peptides translated from the same message transcript (preproAM mRNA). In this article we report the presence of AM, PAMP, and their mRNA in human and rat prostate and of AM receptor mRNA in rat prostate. PreproAM mRNA was found in the epithelium of normal human and rat prostate glands by in situ hybridization. In humans, it was mainly expressed in the basal cells. In rat, its expression was higher in the ducts than in the acini of all the prostate lobes. Immunocytochemistry identified a similar distribution pattern for AM compared with its mRNA but showed different locations for AM and PAMP immunoreactivity. The former was widespread in the epithelia, whereas the latter was almost exclusively found in neuroendocrine cells. In rat, Western blot analysis confirmed the presence of high levels of AM peptide in the ventral lobe and of its precursor in the ventral and dorsolateral lobes. Immunoreactivity for serotonin, chromogranin A, PAMP, and AM defined four subpopulations of prostate neuroendocrine-like cells in rat, a cell type that has not been previously described.


Antitumor effect of hydrolyzed anthocyanin from grape rinds and red rice.
When Balb/C mice that were fed with red glutinous rice, white ordinary rice, or commercially available standard food were inoculated with syngeneic Meth/A lymphoma cells i.p., the group fed the red rice survived longer than the other two groups. In order to determine if the anthocyanins contained in red-coloured seeds and fruit rinds were responsible for the tumor suppressive effect, we added anthocyanins extracted from grape rinds and glutinous red rice to petri dishes that had been seeded with HCT-15 cells. After 4 days of culture, cell counts were made. These anthocyanins were not effective in suppressing the tumor growth. However, anthocyanidins, which were generated by keeping anthocyanins in 5 to 6% HC1 methanol for 5 to 6 hours, were effective in the suppression of tumor growth. Flowcytometric histograms were made after 2 days of culture with these bioflavonoids. The histogram of cells treated with crude anthocyanin was similar to that of the control. Hydrolyzed anthocyanidins gave the elevation of S phase, suggesting a block in the step from S-phase to G2-phase. It seemed that the anthocyanidins contained in the grape rinds and red rice were effective on the suppression of cell growth as observed previously for anthocyanins extracted from the petals of higher plants.


Isolated amyloidosis of the colon.
A 46-year-old man was seen with a 2-month history of crampy abdominal pain and recent onset of hematochezia. Colonoscopic examination revealed a semiannular mass lesion in the descending colon which was thought to represent a near-obstructing neoplasm. A partial colon resection was performed. Gross inspection revealed a segment of bowel with focally necrotic mucosa but no mass lesion. Microscopic examination revealed deposits of amyloid infiltrating the muscularis propria, submucosal vessel walls, and lamina propria, with focal ischemic necrosis of mucosa. Special stains were positive for light chains, indicating primary amyloidosis. Follow-up studies for multiple myeloma and inflammatory disorders gave negative results. A diagnosis of isolated amyloidosis of the colon was rendered. Two months after surgery, the patient had a recurrence of symptoms and colon biopsy specimens revealed amyloidosis. The patient was given colchicine, with subjective and objective improvement. The various types of amyloidosis are discussed.


A-kinase anchoring proteins 10 expression in relation to 2073A/G polymorphism and tumor progression in patients with colorectal cancer.
The cAMP/PKA signalling events regulated by A-kinase anchoring proteins 10 (AKAP10) is involved in tumorigenesis. Previous study showed that AKAP10 polymorphism (2073 A/G, I646V) was associated with colorectal cancer risk. However, there was no literature reporting the role of AKAP10 in the pathogenesis of colorectal cancer. The aim of the study was to investigate the clinicopathologic significance of A-kinase anchoring proteins 10 (AKAP 10) expression and the relationship with its polymorphism in colorectal cancer. The expression of AKAP10 was determined by immunohistochemical staining (IHC) and western blot assay on colorectal cancer (n = 176), adenoma (n = 87) and distant normal mucosa (n = 72). 176 patients with colorectal cancer were genotyped for AKAP10 2073A/G polymorphism by TaqMan RT-PCR. We found that the positive expression rate of AKAP10 in colorectal cancer (59 %) was significantly higher than those in adenoma (39 %) and distant normal mucosa (42 %) (P = 0.004). There was no significant difference between adenoma and distant normal mucosa (P = 0.741). Positive AKAP10 staining was correlated with deeper tumor invasion (P < 0.001), lymph nodes metastasis (P = 0.022), advanced tumor stage (P < 0.001) and poorly differentiated degree (P = 0.003). Compared with AA genotype (52 %), positive expression of AKAP10 was significantly increased in colorectal cancer patients with the variant (AG+GG) genotypes (68 %, P = 0.033). It was concluded that AKAP10 may play an important role in the development and progression of colorectal cancer.


Leveraging human genomic information to identify nonhuman primate sequences for expression array development.
Nonhuman primates (NHPs) are essential for biomedical research due to their similarities to humans. The utility of NHPs will be greatly increased by the application of genomics-based approaches such as gene expression profiling. Sequence information from the 3' end of genes is the key resource needed to create oligonucleotide expression arrays. We have developed the algorithms and procedures necessary to quickly acquire sequence information from the 3' end of nonhuman primate orthologs of human genes. To accomplish this, we identified terminal exons of over 15,000 human genes by aligning mRNA sequences with genomic sequence. We found the mean length of complete last exons to be approximately 1,400 bp, significantly longer than previous estimates. We designed primers to amplify genomic DNA, which included at least 300 bp of the terminal exon. We cloned and sequenced the PCR products representing over 5,500 Macaca mulatta (rhesus monkey) orthologs of human genes. This sequence information has been used to select probes for rhesus gene expression profiling. We have also tested 10 sets of primers with genomic DNA from Macaca fascicularis (Cynomolgus monkey), Papio hamadryas (Baboon), and Chlorocebus aethiops (African green monkey, vervet). The results indicate that the primers developed for this study will be useful for acquiring sequence from the 3' end of genes for other nonhuman primate species. This study demonstrates that human genomic DNA sequence can be leveraged to obtain sequence from the 3' end of NHP orthologs and that this sequence can then be used to generate NHP oligonucleotide microarrays. Affymetrix and Agilent used sequences obtained with this approach in the design of their rhesus macaque oligonucleotide microarrays.


Qualitative and quantitative comparison of the proteome of erythroid cells differentiated from human iPSCs and adult erythroid cells by multiplex TMT labelling and nanoLC-MS/MS.
Induced pluripotent stem cells (iPSC) are an attractive progenitor source for the generation of in vitro blood products. However, before iPSC-derived erythroid cells can be considered for therapeutic use their similarity to adult erythroid cells must be confirmed. We have analysed the proteome of erythroid cells differentiated from the iPSC fibroblast derived line (C19) and showed they express hallmark RBC proteins, including all those of the ankyrin and 4.1R complex. We next compared the proteome of erythroid cells differentiated from three iPSC lines (C19, OCE1, OPM2) with that of adult and cord blood progenitors. Of the 1989 proteins quantified <3% differed in level by 2-fold or more between the different iPSC-derived erythroid cells. When compared to adult cells, 11% of proteins differed in level by 2-fold or more, falling to 1.9% if a 5-fold threshold was imposed to accommodate slight inter-cell line erythropoietic developmental variation. Notably, the level of >30 hallmark erythroid proteins was consistent between the iPSC lines and adult cells. In addition, a sub-population (10-15%) of iPSC erythroid cells in each of the iPSC lines completed enucleation. Aberrant expression of some cytoskeleton proteins may contribute to the failure of the majority of the cells to enucleate since we detected some alterations in cytoskeletal protein abundance. In conclusion, the proteome of erythroid cells differentiated from iPSC lines is very similar to that of normal adult erythroid cells, but further work to improve the induction of erythroid cells in existing iPSC lines or to generate novel erythroid cell lines is required before iPSC-derived red cells can be considered suitable for transfusion therapy.


Thyroid incidentalomas identified by 18F-FDG PET: sonographic correlation.
The purpose of this study was to evaluate the risk of malignancy of thyroid incidentalomas detected on (18)F-FDG PET and the diagnostic accuracy of sonography for differentiating benign from malignant focal thyroid incidentalomas that were detected on FDG PET. Retrospective review was performed of a database of 87 focal thyroid lesions seen on FDG PET and sonography. Forty-two focal lesions were malignant. We compared the accuracy of the maximum standard uptake value (SUV) to differentiate benign from malignant thyroid lesions. We classified the thyroid nodules as probably benign or suspicious for malignancy by the sonographic features. Statistical analyses compared two subgroups by sonographic classifications between benign and malignant thyroid lesions. The maximum SUV of the malignant nodules was not significantly higher than that of benign lesions. Thirty-seven (75.5%) of 49 lesions with suspicious sonographic findings revealed malignancy on cytopathology, compared with five (13.2%) of 38 lesions that showed probably benign sonographic findings. These differences were statistically significant using a kappa test (kappa = 0.675, p = 0.001) and logistic regression (odds ratio = 26.2, p = 0.001). The probability (48.3%) of malignancy of focal thyroid incidentalomas seen on FDG PET is high. The maximum SUV of thyroid cancer is not significantly higher than that of benign lesions. The probability (13.2%) of malignancy is much lower when the sonographic findings appear benign, as compared with a significantly higher probability (75.5%) of malignancy when the sonographic findings are suspicious for malignancy.


Monocyte-derived HLA-G acts as a strong inhibitor of autologous CD4 T cell activation and is upregulated by interferon-beta in vitro and in vivo: rationale for the therapy of multiple sclerosis.
Peripheral antigen presenting cells (APCs) contribute to the maintenance of immune tolerance and are considered to play a critical role in promoting the (re)activation of autoreactive T cells in multiple sclerosis (MS). Interferon-beta (IFN-beta) is the principle immune-modulatory agent used in the treatment of MS, but its mechanism of action remains elusive. HLA-G is a non-classical MHC molecule (MHC class Ib) attributed chiefly immune-regulatory functions. We here investigated the role of monocyte-derived HLA-G in the immune-regulatory processes of MS and its implications for current immune-modulatory therapies. Monocytes constitutively express cell surface HLA-G1 and soluble HLA-G5. Comparison of monocytic HLA-G expression between patients with relapsing-remitting MS (n=17) and healthy donors (n=20) revealed significantly lower levels of HLA-G1 protein in MS patients. However, both groups showed a significant upregulation of HLA-G in response to IFN-beta in vitro. Serial measurements of HLA-G mRNA levels in MS patients before and during IFN-beta therapy corroborated the relevance of these results in vivo: 1 month after initiation of IFN-beta1b therapy (n=9), HLA-G1 and HLA-G5 were significantly increased compared to baseline levels and remained elevated during treatment for 6 months (n=3). Importantly, functional experiments demonstrated that monocyte-derived HLA-G inhibits both Th1 (IFN-gamma, IL-2) and Th2 (IL-10) cytokine production by antigen-stimulated autologous CD4 T cells. Soluble HLA-G added to antigen-specific T cell lines (TCLs) has similar effects on the release of cytokines and reduces T cell proliferation. Although both IFN-beta and IFN-gamma strongly enhance HLA-G1 and HLA-G5 expression by monocytes in vitro, IFN-beta leads to a stronger relative upregulation of HLA-G compared to classical MHC class I molecules than stimulation with IFN-gamma. Taken together, monocyte-derived HLA-G mediates the inhibition of autologous CD4 T cell activation and might be involved in immune-regulatory pathways in the pathogenesis of MS. We conclude that some desirable immune-modulatory effects of INF-beta might be accomplished via the upregulation of the immune-tolerogenic molecule HLA-G.


Confirmatory Factor Analysis of the Finnish Job Content Questionnaire (JCQ) in 590 Professional Musicians.
Poorly functioning work environments may lead to dissatisfaction for the employees and financial loss for the employers. The Job Content Questionnaire (JCQ) was designed to measure social and psychological characteristics of work environments. To investigate the factor construct of the Finnish 14-item version of JCQ when applied to professional orchestra musicians. In a cross-sectional survey, the questionnaire was sent by mail to 1550 orchestra musicians and students. 630 responses were received. Full data were available for 590 respondents (response rate 38%).The questionnaire also contained questions on demographics, job satisfaction, health status, health behaviors, and intensity of playing music. Confirmatory factor analysis of the 2-factor model of JCQ was conducted. Of the 5 estimates, JCQ items in the "job demand" construct, the "conflicting demands" (question 5) explained most of the total variance in this construct (79%) demonstrating almost perfect correlation of 0.63. In the construct of "job control," "opinions influential" (question 10) demonstrated a perfect correlation index of 0.84 and the items "little decision freedom" (question 14) and "allows own decisions" (question 6) showed substantial correlations of 0.77 and 0.65. The 2-factor model of the Finnish 14-item version of JCQ proposed in this study fitted well into the observed data. The "conflicting demands," "opinions influential," "little decision freedom," and "allows own decisions" items demonstrated the strongest correlations with latent factors suggesting that in a population similar to the studied one, especially these items should be taken into account when observed in the response of a population.


[New paradigm of host defense against intracellular pathogens by nitric oxide].
Nitric oxide (NO) produced by inducible NO synthase (iNOS) during infection plays a crucial role in host defense mechanisms, via its antimicrobial and cytoprotective activities. Infection of Salmonella typhimurium in mice induces excessive production of NO, as a host defense response. We found much greater bacterial growth and apoptotic changes in iNOS-deficient (iNOS-/-) mice than in wild-type mice. However, the mechanism of NO-mediated cytoprotection during Salmonella infection remained unclear. An important signaling mechanism induced by NO is heme oxygenase (HO)-1, a significant cytoprotective molecule produced by oxidative stress. Thus, we sought to clarify NO-dependent cytoprotective and antimicrobial host defense, with a particular focus on the signaling mechanism of HO-1 induction. We recently discovered a nitrated cyclic nucleotide, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), which is formed via NO possibly with reactive oxygen species. We observed strong immunoreactivity for 8-nitro-cGMP in Salmonella-infected wild-type mouse liver and peritoneal macrophages in culture but not in iNOS-/- mouse liver and macrophages. Moreover, a higher apoptosis was observed in iNOS-/- macrophages compared with wild-type macrophages after Salmonella infection, but the difference was nullified when iNOS-/- cells were treated with 8-nitro-cGMP. Finally, authentic 8-nitro-cGMP induced HO-1 in cultured macrophages infected with Salmonella. The signaling function of 8-nitro-cGMP appears to be mediated by its unique reaction with the sulfhydryl group of cysteine, thus forming a proteinS-cGMP adduct, which is an important mechanism of post-translational modification of proteins called protein S-guanylation. More importantly, we found 8-nitro-cGMP-dependent S-guanylation of Keap1, a regulatory protein of transcription factor Nrf2, which regulates the transcription of HO-1. In this review, we focus on a unique mechanism of NO-mediated host defense via formation of a novel signaling molecule, 8-nitro-cGMP in microbial infections.


HOTAIR: an oncogenic long non-coding RNA in different cancers.
Long non-coding RNAs (lncRNAs) refer to a group of RNAs that are usually more than 200 nucleotides and are not involved in protein generation. Instead, lncRNAs are involved in different regulatory processes, such as regulation of gene expression. Different lncRNAs exist throughout the genome. LncRNAs are also known for their roles in different human diseases such as cancer. HOTAIR is an lncRNA that plays a role as an oncogenic molecule in different cancer cells, such as breast, gastric, colorectal, and cervical cancer cells. Therefore, HOTAIR expression level is a potential biomarker for diagnostic and therapeutic purposes in several cancers. This RNA takes part in epigenetic regulation of genes and plays an important role in different cellular pathways by interacting with Polycomb Repressive Complex 2 (PRC2). In this review, we describe the molecular function and regulation of HOTAIR and its role in different types of cancers.


Office-based deep sedation for pediatric ophthalmologic procedures using a sedation service model.
Aims. (1) To assess the efficacy and safety of pediatric office-based sedation for ophthalmologic procedures using a pediatric sedation service model. (2) To assess the reduction in hospital charges of this model of care delivery compared to the operating room (OR) setting for similar procedures. Background. Sedation is used to facilitate pediatric procedures and to immobilize patients for imaging and examination. We believe that the pediatric sedation service model can be used to facilitate office-based deep sedation for brief ophthalmologic procedures and examinations. Methods. After IRB approval, all children who underwent office-based ophthalmologic procedures at our institution between January 1, 2000 and July 31, 2008 were identified using the sedation service database and the electronic health record. A comparison of hospital charges between similar procedures in the operating room was performed. Results. A total of 855 procedures were reviewed. Procedure completion rate was 100% (C.I. 99.62-100). There were no serious complications or unanticipated admissions. Our analysis showed a significant reduction in hospital charges (average of $1287 per patient) as a result of absent OR and recovery unit charges. Conclusions. Pediatric ophthalmologic minor procedures can be performed using a sedation service model with significant reductions in hospital charges.


Significance of Staphylococcus lugdunensis bacteremia: report of 28 cases and review of the literature.
Staphylococcus lugdunensis endocarditis has been associated with an aggressive course. The aim of this study was to determine factors associated with the development of endocarditis in patients with S. lugdunensis bacteremia. A retrospective analysis of all patients with S. lugdunensis bacteremia in three tertiary care centers in Switzerland was performed. Data regarding medical history, symptoms, and susceptibility of S. lugdunensis isolates were collected. Our results were reviewed in the context of the current literature. A total of 28 patients with S. lugdunensis bacteremia were identified. Of the 13 patients with endocarditis, all were community acquired. Cardiac surgery was performed in 85% of these patients; mortality was 23%, reflecting the aggressive course of this disease. In contrast, in the 15 patients without endocarditis, no complications associated with S. lugdunensis bacteremia were observed. In 73%, a probable source was identified in the form of a venous catheter or other foreign device. Only three of these episodes were community acquired. No difference was observed in susceptibility of the S. lugdunensis isolates to penicillin, which was 77% in endocarditis isolates, and 87% in isolates of bacteremia without endocarditis, respectively. S. lugdunensis bacteremia is associated with endocarditis in up to 50% of patients. Every patient with community-acquired S. lugdunensis bacteremia should be carefully examined for signs of endocarditis. Once S. lugdunensis endocarditis is diagnosed, close monitoring is essential and surgical treatment should be considered early. In the nosocomial setting, endocarditis is far less frequent, and S. lugdunensis bacteremia is usually associated with a catheter or other foreign materials.


Antibodies of the IgA type in intestinal plasma cells of germfree mice after oral or parenteral immunization with ferritin.
In adult germfree C(3)H mice immunized with horse spleen ferritin, either subcutaneously or intraperitoneally, plasma cells containing specific antibodies were found in lymph nodes and spleen and, in smaller numbers, also in the lamina propria of the intestine. In extraintestinal sites, these antiferritin-containing plasma cells were mainly of the IgM class after a single stimulation, and of the IgG(1) class after repeated stimulation. In the intestine, all the anti-ferritin-containing cells appeared to be of the IgA class. Circulating antibodies, after repeated stimulation, were for the major part IgG(1) and IgG(2). In germfree mice given ferritin in their drinking water, antiferritin-containing cells were abundant in the intestinal mucosa, much less numerous in the mesenteric lymph nodes, and extremely scarce in other lymphoid tissues. All these cells, whatever their location, appeared to belong exclusively to the IgA class. Similarly, all the circulating antibody in these animals was found to be IgA. These findings illustrate the role of the gut as a site of antibody synthesis, as well as its selective commitment to the production of antibodies of the IgA class.


Resilience as an Incomplete Strategy for Coping With Moral Distress in Critical Care Nurses.
Moral distress is receiving increasing attention in health care. The theoretical value of resilience as a strategy for coping with moral distress is prominent in the literature. The potential negative consequences of moral distress for nurses are indisputable, driving a push to identify interventions to help nurses deal with the experience. The evidence that resilience is an important quality and skill for maintaining wellness is equally clear. To review moral distress and resilience and examine the evidence for the new focus on resilience. The complexity of both moral distress and resilience suggests that resilience by itself is an incomplete strategy for coping with and addressing moral distress.


Optimizing observer performance of clinic blood pressure measurement: a position statement from the Lancet Commission on Hypertension Group.
: High blood pressure (BP) is a highly prevalent modifiable cause of cardiovascular disease, stroke, and death. Accurate BP measurement is critical, given that a 5-mmHg measurement error may lead to incorrect hypertension status classification in 84 million individuals worldwide. This position statement summarizes procedures for optimizing observer performance in clinic BP measurement, with special attention given to low-to-middle-income settings, where resource limitations, heavy workloads, time constraints, and lack of electrical power make measurement more challenging. Many measurement errors can be minimized by appropriate patient preparation and standardized techniques. Validated semi-automated/automated upper arm cuff devices should be used instead of auscultation to simplify measurement and prevent observer error. Task sharing, creating a dedicated measurement workstation, and using semi-automated or solar-charged devices may help. Ensuring observer training, and periodic re-training, is critical. Low-cost, easily accessible certification programs should be considered to facilitate best BP measurement practice.


Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors.
The implantation of a blastocyst into a receptive uterus is associated with a series of events, namely the attachment reaction followed by decidualization of the stroma. Previous studies established that the gene encoding heparin-binding EGF-like growth factor (HB-EGF) is expressed in the luminal epithelium solely at the site of blastocyst apposition preceding the attachment reaction. We report here the expression during implantation of 21 genes encoding other signaling proteins, including those belonging to the Bone morphogenetic protein (BMP), fibroblast growth factor (FGF), WNT, and Hedgehog (HH) pathways. We find that the attachment reaction is associated with a localized stromal induction of genes encoding BMP-2, FGF-2, and WNT-4. Despite efforts by many investigators, a simple in vitro model of implantation is not yet available to study either the hierarchy of the events triggered in the uterus by the embryo or the function of individual signaling proteins. We have therefore approached these questions by introducing beads loaded with purified factors into the receptive uterus. We show that beads soaked in HB-EGF or insulin-like growth factor-1 (IGF-1), but not other proteins, induce many of the same discrete local responses elicited by the blastocyst, including increased localized vascular permeability, decidualization, and expression of Bmp2 at the sites of the beads. By contrast, the expression domains of Indian hedgehog (Ihh), patched, and noggin become restricted as decidualization proceeds. Significantly, beads containing BMP-2 do not themselves elicit an implantation response but affect the spacing of implantation sites induced by blastocysts cotransferred with the beads.


Motor Vehicle Crashes, Medical Outcomes, and Hospital Charges Among Children Aged 1-12 Years - Crash Outcome Data Evaluation System, 11 States, 2005-2008.
Motor vehicle crashes are a leading cause of death among children. Age- and size-appropriate restraint use is an effective way to prevent motor vehicle-related injuries and deaths. However, children are not always properly restrained while riding in a motor vehicle, and some are not restrained at all, which increases their risk for injury and death in a crash. 2005-2008. The Crash Outcome Data Evaluation System (CODES) is a multistate program facilitated by the National Highway Traffic Safety Administration to probabilistically link police crash reports and hospital databases for traffic safety analyses. Eleven participating states (Connecticut, Georgia, Kentucky, Maryland, Minnesota, Missouri, Nebraska, New York, Ohio, South Carolina, and Utah) submitted data to CODES during the reporting period. Descriptive analysis was used to describe drivers and child passengers involved in motor vehicle crashes and to summarize crash and medical outcomes. Odds ratios and 95% confidence intervals were used to compare a child passenger's likelihood of sustaining specific types of injuries by restraint status (optimal, suboptimal, or unrestrained) and seating location (front or back seat). Because of data constraints, optimal restraint use was defined as a car seat or booster seat use for children aged 1-7 years and seat belt use for children aged 8-12 years. Suboptimal restraint use was defined as seat belt use for children aged 1-7 years. Unrestrained was defined as no use of car seat, booster seat, or seat belt for children aged 1-12 years. Optimal restraint use in the back seat declined with child's age (1 year: 95.9%, 5 years: 95.4%, 7 years: 94.7%, 8 years: 77.4%, 10 years: 67.5%, 12 years: 54.7%). Child restraint use was associated with driver restraint use; 41.3% of children riding with unrestrained drivers also were unrestrained compared with 2.2% of children riding with restrained drivers. Child restraint use also was associated with impaired driving due to alcohol or drug use; 16.4% children riding with drivers suspected of alcohol or drug use were unrestrained compared with 2.9% of children riding with drivers not suspected of such use. Optimally restrained and suboptimally restrained children were less likely to sustain a traumatic brain injury than unrestrained children. The 90th percentile hospital charges for children aged 4-7 years who were in motor vehicle crashes were $1,630.00 and $1,958.00 for those optimally restrained in a back seat and front seat, respectively; $2,035.91 and $3,696.00 for those suboptimally restrained in a back seat and front seat, respectively; and $9,956.60 and $11,143.85 for those unrestrained in a back seat and front seat, respectively. Proper car seat, booster seat, and seat belt use among children in the back seat prevents injuries and deaths, as well as averts hospital charges. However, the number, severity, and cost of injuries among children in crashes who were not optimally restrained or who were seated in a front seat indicates the need for improvements in proper use of age- and size-appropriate car seats, booster seats, and seat belts in the back seat. Effective interventions for increasing proper child restraint use could be universally implemented by states and communities to prevent motor vehicle-related injuries among children and their resulting costs.


Development and preliminary validation of a risk prediction model for chemotherapy-related nausea and vomiting.
A number of risk factors have been implicated in the development of chemotherapy-induced nausea/vomiting (CINV). Our aim was to develop a risk prediction model and identify patients at high risk for developing CINV before their chemotherapy treatment. A multisite, observational, prospective longitudinal design was used. Participants were 336 chemotherapy-naïve cancer patients providing 791 assessments. They completed measures to assess potential risk factors for CINV, including socio-demographic and clinical/treatment-related characteristics, symptom distress, expectations for CINV and state-trait anxiety. CINV was measured with the MASCC Antiemesis Tool. Participants were divided randomly to a training set (=286) and a test set (=50). Random-effects models were run to ascertain the contribution of risk factors in the development of CINV using the training sample. Specificity and sensitivity of the model were assessed in both sets of samples. Younger age, history of nausea/vomiting, trait anxiety and fatigue were linked with higher levels of CINV, and use of moderately and low emetogenic chemotherapy were linked with lower CINV. The model's specificity were 55.4 and 50.0 % and sensitivity were 80.3 and 79.0 % in the training and test sample, respectively. A dynamic web-based tool is freely available for use by clinicians. This model of risk prediction for CINV can be an aid to clinical decision-making and assist clinicians to rationalise antiemetic use with their patients.


H-NS binding and repression of the ctx promoter in Vibrio cholerae.
Expression of the ctx and tcp genes, which encode cholera toxin and the toxin coregulated pilus, the Vibrio cholerae O1 virulence determinants having the largest contribution to cholera disease, is repressed by the nucleoid-associated protein H-NS and activated by the AraC-like transcriptional regulator ToxT. To elucidate the molecular mechanism by which H-NS controls transcription of the ctxAB operon, H-NS repression and binding were characterized by using a promoter truncation series, gel mobility shift assays, and DNase I footprinting. Promoter regions found to be important for H-NS repression correlated with in vitro binding. Four main H-NS binding regions are present at ctx. One region overlaps the high-affinity ToxT binding site and extends upstream, another overlaps the ToxT low-affinity binding site around the -35 element, and the remaining two are located adjacent to one another downstream of the transcriptional start site. Competition for binding to the overlapping H-NS/ToxT binding sites was observed in gel mobility shift assays, where ToxT was found to displace H-NS from the ctx promoter region. In addition, regulatory differences between the ctx and tcpA promoters were examined. H-NS was found to have a higher relative binding affinity for the ctx promoter than for the tcpA promoter in vitro. In contrast to ToxT-dependent activation of the tcpA promoter, ToxT activation of ctx did not require the C-terminal domain of the α-subunit of RNA polymerase. These findings demonstrate that transcriptional regulation of ctx and tcpA by H-NS and ToxT is mechanistically distinct, and this may lead to important differences in the expression of these coregulated genes.


Gold-Catalyzed Hydrofluorination of Electron-Deficient Alkynes: Stereoselective Synthesis of β-Fluoro Michael Acceptors.
The gold(I)-catalyzed, stereoselective hydrofluorination of electron-deficient alkynes with triethylamine trihydrogen fluoride (Et3N·3HF) is described. Fluorinated α,β-unsaturated aldehydes, amides, esters, ketones, and nitriles were isolated in moderate to good yields as single diastereomers. In all but four cases, the (Z)-vinyl fluorides were initially formed in ≥97% diastereoselectivity. This work constitutes the first catalytic example of the diastereoselective preparation of a variety of β-alkyl, β-fluoro Michael acceptors from alkynes. Additionally, the described work expands access to β-aryl, β-fluoro Michael acceptors to the synthesis of β-fluoro-α,β-unsaturated amides and nitriles. The monofluoroalkenes formed through this strategy were readily transformed into other fluorine-containing compounds, and the developed method was applied to the synthesis of a fluorinated analogue of Exoderil, a topical antimycotic.


Differential patterns of infection and disease with P. falciparum and P. vivax in young Papua New Guinean children.
Where P. vivax and P. falciparum occur in the same population, the peak burden of P. vivax infection and illness is often concentrated in younger age groups. Experiences from malaria therapy patients indicate that immunity is acquired faster to P. vivax than to P. falciparum challenge. There is however little prospective data on the comparative risk of infection and disease from both species in young children living in co-endemic areas. A cohort of 264 Papua New Guinean children aged 1-3 years (at enrolment) were actively followed-up for Plasmodium infection and febrile illness for 16 months. Infection status was determined by light microscopy and PCR every 8 weeks and at each febrile episode. A generalised estimating equation (GEE) approach was used to analyse both prevalence of infection and incidence of clinical episodes. A more pronounced rise in prevalence of P. falciparum compared to P. vivax infection was evident with increasing age. Although the overall incidence of clinical episodes was comparable (P. falciparum: 2.56, P. vivax 2.46 episodes / child / yr), P. falciparum and P. vivax infectious episodes showed strong but opposing age trends: P. falciparum incidence increased until the age of 30 months with little change thereafter, but incidence of P. vivax decreased significantly with age throughout the entire age range. For P. falciparum, both prevalence and incidence of P. falciparum showed marked seasonality, whereas only P. vivax incidence but not prevalence decreased in the dry season. Under high, perennial exposure, children in PNG begin acquiring significant clinical immunity, characterized by an increasing ability to control parasite densities below the pyrogenic threshold to P. vivax, but not to P. falciparum, in the 2(nd) and 3(rd) year of life. The ability to relapse from long-lasting liver-stages restricts the seasonal variation in prevalence of P. vivax infections.


Dietary patterns and risk of colorectal cancer in Tehran Province: a case-control study.
Colorectal cancer is the third and fourth leading cause of cancer incidence and mortality among men and women, respectively in Iran. However, the role of dietary factors that could contribute to this high cancer incidence remains unclear. The aim of this study was to determine major dietary patterns and its relationship with colorectal cancer. This case-control study was conducted in four hospitals in Tehran city of Iran. A total of 71 patients (35 men and 36 women, aged 40-75 years) with incident clinically confirmed colorectal cancer (CRC) and 142 controls (70 men and 72 women, aged 40-75 years) admitted to hospital for acute, non-neoplastic diseases were recruited and interviewed. Dietary data were assessed by 125-item semi-quantitative food frequency questionnaire. Multivariate logistic regression was used to estimate the relationship between dietary patterns and risk of colorectal cancer. Two major dietary patterns (Healthy pattern and Western pattern) were derived using principal component analysis. Each dietary pattern explained 11.9% (Healthy pattern) and 10.3% (Western pattern) of the variation in food intake, respectively. After adjusting for confounding factors, the Healthy dietary pattern was significantly associated with a decreased risk of colorectal cancer (OR= 0.227; 95% CI=0.108-0.478) while an increased risk of colorectal cancer was observed with the Western dietary pattern (OR=2.616; 95% CI= 1.361-5.030). Specific dietary patterns, which include healthy and western patterns, may be associated with the risk of colorectal cancer. This diet-disease relationship can be used for developing interventions that aim to promote healthy eating for the prevention of chronic disease, particularly colorectal cancer in the Iranian population.


Supported community exercise in people with long-term neurological conditions: a phase II randomized controlled trial.
Adults with long-term neurological conditions have low levels of participation in physical activities and report many barriers to participation in exercise. This study examines the feasibility and safety of supporting community exercise for people with long-term neurological conditions using a physical activity support system. A phase II randomized controlled trial using computer-generated block randomization, allocation concealment and single blind outcome assessment. Oxfordshire and Birmingham community Inclusive Fitness Initiative gyms. Patients with a long-term neurological condition. The intervention group (n = 51) received a 12-week, supported exercise programme. The control group (n = 48) participants received standard care for 12 weeks and were then offered the intervention. Physical activity, adherence to exercise, measures of mobility, health and well-being. Forty-eight patients (n = 51) completed the intervention, achieving 14 gym attendances (range 0-39) over the 12 weeks. Overall activity did not increase as measured by the Physical Activity Scale for the Elderly (change score mean 14.31; 95% confidence interval (CI) −8.27 to 36.89) and there were no statistically significant changes in body function and health and well-being measures. People with long-term neurological conditions can safely exercise in community gyms when supported and achieve similar attendance to standard exercise referral schemes, but may reduce other life activities in order to participate at a gym.


The neurosteroid pregnenolone sulfate infused into the nucleus basalis increases both acetylcholine release in the frontal cortex or amygdala and spatial memory.
The effects of an infusion (5 ng) of the neurosteroid pregnenolone sulfate into the nucleus basalis magnocellularis on acetylcholine release in the frontoparietal cortex and basolateral amygdala were evaluated during the 130 min post-injection in male Sprague-Dawley rats using in vivo microdialysis coupled "on line" with high performance liquid chromatography detection. One week later, the same animals were tested for spatial memory after another infusion of pregnenolone sulfate (5 ng) into the nucleus basalis. Results show that pregnenolone sulfate enhanced acetylcholine release by more than 50% of baseline concentrations in the two structures relative to a control injection. The duration of this effect was longer in cortex (130 min) than in amygdala (30 min). Furthermore, pregnenolone sulfate improved memory performance in a task based upon spatial recognition of a familiar environment. A significant positive correlation (r=0.49) was found between the recognition score in the spatial memory test and the levels of acetylcholine release in the frontoparietal cortex but not in the basolateral amygdala. Therefore, our results suggest that the nucleus basalis magnocellularis-cortical pathway could be in part responsible for the promnesic effect of pregnenolone sulfate. This neurosteroid acts as a negative modulator of the GABA(A) receptor complex and positively modulates the N-methyl-D-aspartate receptor, possibly resulting in a global stimulatory effect on central cholinergic neurotransmission.


Charge transfer quantification in a SnOx/CuPc semiconductor heterostructure: investigation of buried interface energy structure by photoelectron spectroscopies.
A tin oxide/copper phthalocyanine (CuPc) layer stack was investigated with two complementary photoemission methods. Non-destructive analysis of the electronic properties at the SnOx/CuPc interface was performed applying angle-dependent measurements with X-ray photoelectron spectroscopy (ADXPS) and energy-resolved photoemission yield spectroscopy (PYS). The different components (related to oxide layer and organic overlayer as well as to contamination features) observed in the spectra were assigned to a particular layer by relative depth plot analysis. ADXPS allowed determination of the chemical and electronic structure of the investigated samples. The addition of the organic ultra-thin film to the oxide layer caused a significant increase of the structure's photoemission yield. The combination of ADXPS and PYS allowed determination of the work function of constituent layers, and charge transfer phenomena at the SnOx/CuPc buried interface. An interface dipole of 0.23 eV was detected, assigned to charge transfer across the interface from the oxide layer towards the organic film. The energy level alignment at the SnOx/CuPc interface was determined, and presented in a band-like diagram, together with depth-dependent changes of the core energy levels of the structure's constituents. Finally the role of the oxide's defect-related energy levels in the charge transfer was discussed. The results obtained exhibit significance ranging from investigation, basic understanding and application of such hybrid films. Application of these results in hybrid electronic devices can help understanding and furthering this technology.


[Growth and development of children with low birth weight at their first birthday].
The aim of this prospective study was to evaluate the effect of low birthweight on growth and development at one year of age, in a cohort of infants born between March 1992 and March 1993 at Hospital de Famalicão. Information was obtained from 199 children, 89 low birthweight cases and 110 born with a normal (> or = 2500 g) weight. The infant mortality rate (56 vs 9 per 1000), the frequency of growth (32% vs 4%, p = 0.0000003) or developmental delay (30% vs 11%, p = 0.002) were significantly higher in low birthweight babies. However, all cases of developmental delay corresponded to minor impairments. At age one, children born with a normal weight presented mean higher values for weight (10.0 +/- 1.1 kg vs 9.2 +/- 1.2 kg; p = 0.000005), length (74.2 +/- 7.1 cm vs 72.9 +/- 3.1 cm, p = 0.0006) and head circumference (46.4 +/- 1.9 cm vs 45.8 +/- 1.6 cm; p = 0.004). Prenatal characteristics such as the planning of the pregnancy, gestational birth weight, diseases during the pregnancy, gestational age or twining, significantly affected development at one year of age, showing that delays can be prevented before a child is born. In addition, post-natal exposures, such as home conditions, energy and nutrient intake, or coping with vaccination schedules and the occurrence of diseases during the neonatal and post-neonatal periods were significantly associated to developmental delay.(ABSTRACT TRUNCATED AT 250 WORDS)


Truncated ErbB2 expressed in tumor cell nuclei contributes to acquired therapeutic resistance to ErbB2 kinase inhibitors.
ErbB2 tyrosine kinase inhibitors (TKI) block tyrosine autophosphorylation and activation of the full-length transmembrane ErbB2 receptor (p185(ErbB2)). In addition to p185(ErbB2), truncated forms of ErbB2 exist in breast cancer cell lines and clinical tumors. The contribution of these truncated forms, specifically those expressed in tumor cell nuclei, to the development of therapeutic resistance to ErbB2 TKIs has not been previously shown. Here, we show that expression of a 95-kDa tyrosine phosphorylated form of ErbB2, herein referred to as p95L (lapatinib-induced p95) was increased in ErbB2(+) breast cancer cells treated with potent ErbB2 TKIs (lapatinib, GW2974). Expressed in tumor cell nuclei, tyrosine phosphorylation of p95L was resistant to inhibition by ErbB2 TKIs. Furthermore, the expression of p95L was increased in ErbB2(+) breast cancer models of acquired therapeutic resistance to lapatinib that mimic the clinical setting. Pretreatment with proteasome inhibitors blocked p95L induction in response to ErbB2 TKIs, implicating the role of the proteasome in the regulation of p95L expression. In addition, tyrosine phosphorylated C-terminal fragments of ErbB2, generated by alternate initiation of translation and similar in molecular weight to p95L, were expressed in tumor cell nuclei, where they too were resistant to inhibition by ErbB2 TKIs. When expressed in the nuclei of lapatinib-sensitive ErbB2(+) breast cancer cells, truncated ErbB2 rendered cells resistant to lapatinib-induced apoptosis. Elucidating the function of nuclear, truncated forms of ErbB2, and developing therapeutic strategies to block their expression and/or activation may enhance the clinical efficacy of ErbB2 TKIs.


Current challenges in the management of sepsis in ICUs in resource-poor settings and suggestions for the future.
Sepsis is a major reason for intensive care unit (ICU) admission, also in resource-poor settings. ICUs in low- and middle-income countries (LMICs) face many challenges that could affect patient outcome. To describe differences between resource-poor and resource-rich settings regarding the epidemiology, pathophysiology, economics and research aspects of sepsis. We restricted this manuscript to the ICU setting even knowing that many sepsis patients in LMICs are treated outside an ICU. Although many bacterial pathogens causing sepsis in LMICs are similar to those in high-income countries, resistance patterns to antimicrobial drugs can be very different; in addition, causes of sepsis in LMICs often include tropical diseases in which direct damaging effects of pathogens and their products can sometimes be more important than the response of the host. There are substantial and persisting differences in ICU capacities around the world; not surprisingly the lowest capacities are found in LMICs, but with important heterogeneity within individual LMICs. Although many aspects of sepsis management developed in rich countries are applicable in LMICs, implementation requires strong consideration of cost implications and the important differences in resources. Addressing both disease-specific and setting-specific factors is important to improve performance of ICUs in LMICs. Although critical care for severe sepsis is likely cost-effective in LMIC setting, more detailed evaluation at both at a macro- and micro-economy level is necessary. Sepsis management in resource-limited settings is a largely unexplored frontier with important opportunities for research, training, and other initiatives for improvement.


Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies.
The coronavirus disease 2019 (COVID-19) virus is spreading rapidly, and scientists are endeavoring to discover drugs for its efficacious treatment in China. Chloroquine phosphate, an old drug for treatment of malaria, is shown to have apparent efficacy and acceptable safety against COVID-19 associated pneumonia in multicenter clinical trials conducted in China. The drug is recommended to be included in the next version of the Guidelines for the Prevention, Diagnosis, and Treatment of Pneumonia Caused by COVID-19 issued by the National Health Commission of the People's Republic of China for treatment of COVID-19 infection in larger populations in the future.


Streptomyces albus G mutants defective in the SalGI restriction-modification system.
Streptomyces albus G mutants (at least 12 of which were independent) defective in SalGI-mediated restriction (R-) were isolated after mutagenesis. Some of them lacked detectable SalGI activity in cell-free extracts. Some were also partially or completely defective in SalFI-associated modification (M-). Loss of restriction rendered S. albus G sensitive to many phages to which it was normally totally resistant. DNA from one such phage had many SalGI target sites (mean, one site per 1.35 kilobases). A mutant was isolated which was heat-sensitive for growth, apparently because it was restriction-proficient but temperature-sensitive for modification. At a rather high frequency, this mutant generated spontaneous heat-tolerant derivatives which were nearly all R-. Such R- mutants were always M- rather than being temperature-sensitive for modification. In a limited genetic analysis, the determinants of restriction and modification did not recombine with each other, and since there was no reassortment of these phenotypes among the parental output of crosses it appeared that the determinants were located close together on the chromosome.


Attribution of global foodborne disease to specific foods: Findings from a World Health Organization structured expert elicitation.
Recently the World Health Organization, Foodborne Disease Burden Epidemiology Reference Group (FERG) estimated that 31 foodborne diseases (FBDs) resulted in over 600 million illnesses and 420,000 deaths worldwide in 2010. Knowing the relative role importance of different foods as exposure routes for key hazards is critical to preventing illness. This study reports the findings of a structured expert elicitation providing globally comparable food source attribution estimates for 11 major FBDs in each of 14 world subregions. We used Cooke's Classical Model to elicit and aggregate judgments of 73 international experts. Judgments were elicited from each expert individually and aggregated using both equal and performance weights. Performance weighted results are reported as they increased the informativeness of estimates, while retaining accuracy. We report measures of central tendency and uncertainty bounds on food source attribution estimate. For some pathogens we see relatively consistent food source attribution estimates across subregions of the world; for others there is substantial regional variation. For example, for non-typhoidal salmonellosis, pork was of minor importance compared to eggs and poultry meat in the American and African subregions, whereas in the European and Western Pacific subregions the importance of these three food sources were quite similar. Our regional results broadly agree with estimates from earlier European and North American food source attribution research. As in prior food source attribution research, we find relatively wide uncertainty bounds around our median estimates. We present the first worldwide estimates of the proportion of specific foodborne diseases attributable to specific food exposure routes. While we find substantial uncertainty around central tendency estimates, we believe these estimates provide the best currently available basis on which to link FBDs and specific foods in many parts of the world, providing guidance for policy actions to control FBDs.


Fibromyalgia in fragile X mental retardation 1 gene premutation carriers.
FM is a disorder of altered pain regulation and is characterized by pain, fatigue, poor sleep and psychological impairments; thus, it is classified as a central sensitivity syndrome. Female carriers of a premutation in the fragile X mental retardation 1 (FMR1) gene frequently have widespread musculoskeletal pain and sometimes have been diagnosed with FM, especially if they have the motor signs of fragile X-associated tremor ataxia syndrome (FXTAS). Studies suggest that FM occurs in persons with a genetic predisposition. We describe the clinical features of female FMR1 premutation carriers with symptoms of FM. A sample of patients was selected that participated in studies at two tertiary referral academic centres on the phenotype and therapy of FXTAS. This selected sample of patients, five female premutation carriers, has FM symptoms or diagnoses and other central sensitivity syndromes. Since FM affects 2-4% of the world's population and about 1 in 250 females are FMR1 carriers, a study screening females with FM for the presence of the FMR1 premutation is worthwhile. A finding of increased prevalence of FMR1 carriers among females with FM would impact the standard evaluation of FM. Presently, guidelines for FMR1 genetic testing includes early menopause, congenital intellectual disability, autism spectrum disorder, tremor or ataxia, and a family history of FXTAS or fragile X syndrome. The latter is a common cause of autism and developmental delay. Such testing is important because female carriers are at risk of having a child with fragile X syndrome.


Genetic analysis of the role of the asparaginyl hydroxylase factor inhibiting hypoxia-inducible factor (FIH) in regulating hypoxia-inducible factor (HIF) transcriptional target genes [corrected].
Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor that directs a broad range of cellular responses to hypoxia. Recent studies have defined a set of 2-oxoglutarate and Fe(II)-dependent dioxygenases that modify HIF-alpha subunits by prolyl and asparaginyl hydroxylation. These processes potentially provide a dual system of control, down-regulating both HIF-alpha stability and transcriptional activity. Although genetic analyses in both primitive organisms and mammalian cells have demonstrated a critical role for the prolyl hydroxylase pathway in the regulation of HIF, analogous studies have not been performed on the HIF asparaginyl hydroxylase pathway, and its role in directing the expression of endogenous HIF transcriptional targets has not yet been clearly defined. Here we demonstrate, using small interfering RNA-mediated FIH suppression and controlled overexpression by a doxycycline-inducible system, that alterations in FIH expression in both directions have reciprocal effects on the expression of a range of HIF target genes. These effects were observed in normoxic and severely hypoxic cells but not anoxic cells. Evidence for FIH activity in severely hypoxic cells contrasted with results for the prolyl hydroxylase PHD2, suggesting that these enzymes display different oxygen dependence in vivo, with PHD2 requiring higher levels of oxygen for biological activity. Our results demonstrate an important physiological role for FIH in regulating HIF-dependent target genes over a wide range of oxygen tensions and indicate that inhibition of FIH has the potential to augment HIF target gene expression even in severe hypoxia.


Short-Term Outcomes of Treatment of Hip Osteoarthritis With 4 Bone Marrow Concentrate Injections: A Case Series.
The use of mesenchymal stem cells from bone marrow concentrate (BMC) has become an increasingly popular option as an alternative to total joint replacement. Although there is evidence to support the use of BMC injections to improve quality of life for patients with knee osteoarthritis (OA), there is limited evidence to support its use in patients with hip OA. This case series provides the short-term outcomes of 4 hip OA patients who each underwent 4 BMC injections. On average, the last follow-up was administered 3.5 months after the first injection. The results show that patients experienced decreased resting and active pain compared with baseline and mean 72.4% total overall improvement. Patients also reported less difficulty in performing daily activities following the procedure. These encouraging results warrant further research to better understand the effects of BMC injections on hip OA.


Investigation of nanostructured hybrid organic/semiconductor quantum dots in thin film and spatial distribution of the emission.
The optical properties of core-shell quantum dots (QDs) are important for optoelectronic devices and biological applications. In this study, we investigate the optical properties of core-shell CdSe/ZnS QDs embedded in PMMA polymer thin films. The luminescence from QD emission would be more applicable if the spatial distribution of the emission was controllable. We propose a method to control the emission distribution by modifying the nanostructure. A bi-periodic nanostructure was fabricated and characterized in hybrid QD thin films by a nano-imprint technique. The finite difference time domain method was used to simulate the electric field distribution in the measured structure. It is shown that the far-field distribution of the QD emission is controllable by manipulating the nanostructure of the hybrid QD thin films.


Auxin and its transport play a role in plant tolerance to arsenite-induced oxidative stress in Arabidopsis thaliana.
The role of auxin in plant development is well known; however, its possible function in root response to abiotic stress is poorly understood. In this study, we demonstrate a novel role of auxin transport in plant tolerance to oxidative stress caused by arsenite. Plant response to arsenite [As(III)] was evaluated by measuring root growth and markers for stress on seedlings treated with control or As(III)-containing medium. Auxin transporter mutants aux1, pin1 and pin2 were significantly more sensitive to As(III) than the wild type (WT). Auxin transport inhibitors significantly reduced plant tolerance to As(III) in the WT, while exogenous supply of indole-3-acetic acid improved As(III) tolerance of aux1 and not that of WT. Uptake assays using H(3) -IAA showed As(III) affected auxin transport in WT roots. As(III) increased the levels of H2 O2 in WT but not in aux1, suggesting a positive role for auxin transport through AUX1 on plant tolerance to As(III) stress via reactive oxygen species (ROS)-mediated signalling. Compared to the WT, the mutant aux1 was significantly more sensitive to high-temperature stress and salinity, also suggesting auxin transport influences a common element shared by plant tolerance to arsenite, salinity and high-temperature stress.


CT in malignancy grading and prognostic prediction of non-Hodgkin's lymphoma.
The presence of tumor inhomogeneities in MR images of non-Hodgkin's lymphoma (NHL) provides information about malignancy grade and prognosis. The aim of this study was to determine whether CT images are also informative in these respects. Sixty-three CT examinations in patients with NHL (32 high-grade and 31 low-grade tumors) were reviewed retrospectively by two senior radiologists. The tumor patterns were classified subjectively as homogeneous, slightly inhomogeneous or severely inhomogeneous and their relations to malignancy grade, clinical characteristics and prognosis were determined. Sixteen out of 17 patients with a severely inhomogeneous tumor pattern had high-grade NHL tumors while 21 out of 29 patients with a homogeneous tumor appearance had low-grade NHL tumors. Among chemotherapy-treated patients, those with the highest degree of inhomogeneity had a significantly worse prognosis (9 out of 11 patients died). This relationship was not found in patients treated with radiotherapy. A severely inhomogeneous tumor pattern on CT images was found to be associated with a high malignancy grade in NHL. This CT pattern was also compatible with a poor prognosis in patients treated with chemotherapy.


Hemopoietic stem cells in human peripheral blood.
A population of lymphocytes, separable from the great majority by virtue of their larger size and their failure to exhibit the rosetting characteristics of thymus-dependent lymphocytes and bursa-equivalent cells, possess true pluripotentiality. On culture in vivo they proliferate and differentiate into erythrocytic, granulocytic, and megakaryocytic progeny. This may be the first clear demonstration of the primitive progenitor blood cell in man.


Pericellular oxygen depletion during ordinary tissue culturing, measured with oxygen microsensors.
Recent research has found important differences in oxygen tension in proximity to certain mammalian cells when grown in culture. Oxygen has a low diffusion rate through cell culture media, thus, as a result of normal respiration, a decrease in oxygen tension develops close to the cells. Therefore, for the purpose of standardization and optimization, it is important to monitor pericellular oxygen tension and cell oxygen consumption. Here, we describe an integrated oxygen microsensor and recording system that allows measurement of oxygen concentration profiles in vertical transects through a 1.6-mm deep, stagnant, medium layer covering a cell culture. The measurement set-up reveals that, when confluent, a conventional culture of adherent cells, although exposed to the constant oxygen tension of ambient air, may experience pericellular oxygen tensions below the level required to sustain full oxidative metabolism. Depletions reported are even more prominent and potentially aggravating when the cell culture is incubated at reduced oxygen tensions (down to around 4% oxygen). Our results demonstrate that, if the pericellular oxygen tension is not measured, it is impossible to relate in vitro culture results (for example, gene expression to the oxygen tension experienced by the cell), as this concentration may deviate very substantially from the oxygen concentration recorded in the gas phase.


Patient hand hygiene practices in surgical patients.
Little is known about the hand hygiene practices of surgical patients. Most of the research has been directed at the health care worker, and this may discount the role that hand hygiene of the surgical patient might play in surgical site infections. A quasiexperimental, pretest/post-test study was conducted in which patients (n = 72) and nurses (n = 42) were interviewed to examine perceptions and knowledge about patient hand hygiene. Concurrently, observations were conducted to determine whether surgical patients were offered assistance by the nursing staff. Following an initial observation period, nursing staff received an educational session regarding general hand hygiene information and observation results. One month after the education session, patient/nurse dyads were observed for an additional 6 weeks to determine the impact of the educational intervention. Eighty observations, 72 patient interviews, and 42 nurse interviews were completed preintervention, and 83 observations were completed postintervention. In response to the survey, more than half of patients (n = 41, 55%) reported that they were not offered the opportunity to clean their hands, but a majority of the nursing staff reported (n = 25, 60%) that they offered patients the opportunity to clean their hands. Prior to the educational intervention, nursing staff assisted patients in 14 of 81 hand hygiene opportunities. Following the intervention, nursing staff assisted patients 37 out of 83 opportunities (17.3% vs 44.6%, respectively, [χ(2)1 = 13.008, P = .0003]). This study suggests that efforts to increase hand hygiene should be directed toward patients as well as health care workers.