Radiation response of hypoxic and generally heterogeneous tissues.
Biologically based treatment optimisation can be based on the local mean values of the number of clonogenic cells and the cellular radiation response taken over macroscopic tissue voxels. Steep oxygen gradients in tumours may often lead to microscopic distributions of radiation resistance at the cellular level, far beyond the geometrical resolution of current diagnostic and radiotherapeutic methods. The present work focuses on quantifying the radiobiological effect of such microscopic distributions through tissue-oxygenation modelling and on calculating the corresponding radiation response on both micro- and macroscopic scales. A simple model of tissue vasculature was developed with microvascular density and heterogeneity as its main parameters. New analytical expressions are presented for calculating the effective radiation response of tissues with generally heterogeneous radiation resistance and clonogen density. The oxygen distributions derived for different parameter sets agree very well with clinically measured oxygen distributions for both tumours and normal tissues. In addition to the vascular density, vascular heterogeneity is an important factor while estimating the hypoxic fraction in tissue. It is shown that both the local and global dose-response relation for tissues with heterogeneous radiation resistance can be accurately calculated from the effective initial clonogen number N(0,eff) and the effective radiation resistance D(0,eff). New equations are derived for calculating these quantities, for instance, from measured oxygen distributions. With the new methods presented here, existing techniques to measure the micro- and macroscopic oxygen distribution either using standard tumour-type or patient-specific oxygenation data can be used for biologically based treatment plan optimisation.


The human RAP1 and GFAPɛ proteins increase γ-secretase activity in a yeast model system.
Alzheimer's disease (AD) is an age-related disorder that results in progressive cognitive impairment and memory loss. Deposition of amyloid β (Aβ) peptides in senile plaques is a hallmark of AD. γ-secretase produces Aβ peptides, mostly as the soluble Aβ40 with fewer insoluble Aβ42 peptides. Rare, early-onset AD (EOAD) occurs in individuals under 60 years of age. Most EOAD cases are due to unknown genetic causes, but a subset is due to mutations in the genes encoding the amyloid precursor protein that is processed into Aβ peptides or the presenilins (PS1 and PS2) that process APP. PS1 interacts with the epsilon isoform of glial fibrillary acidic protein (GFAPɛ), a protein found in the subventricular zone of the brain. We have found that GFAPɛ interacts with the telomere protection factor RAP1 (TERF2IP). RAP1 can also interact with PS1 alone or with GFAPɛ in vitro. Our data show that the nuclear protein RAP1 has an extratelomeric role in the cytoplasm through its interactions with GFAPɛ and PS1. GFAPɛ coprecipitated with RAP1 from human cell extracts. RAP1, GFAPɛ, and PS1 all colocalized in human SH-SY5Y cells. Using a genetic model of the γ-secretase complex in Saccharomyces cerevisiae, RAP1 increased γ-secretase activity, and this was potentiated by GFAPɛ. Our studies are the first to connect RAP1 with an age-related disorder.


Heartfelt memories: Cardiac vagal tone correlates with increased memory for untrustworthy faces.
During social interactions, we rapidly judge others' trustworthiness on basis of their facial characteristics. Face-based trustworthiness judgments may not only affect our current but also our future interactions because we seem to be more inclined to remember untrustworthy than trustworthy faces. Memory formation of salient stimuli like untrustworthy faces may be modulated by the interplay between the autonomic and central nervous system, which can be indexed by changes in vagally mediated heart rate variability (HRV). To test this assumption, we investigated whether differences in HRV would be associated with differences in memory formation of untrustworthy faces in a sample of healthy participants (n = 34, all female). Untrustworthy faces were remembered more accurately than trustworthy faces, albeit only by participants with high and not low HRV. Across participants, increased memory accuracy for untrustworthy faces was associated with increased HRV. We discuss these findings in the context of neurobiological theories regarding the interplay between the autonomic and central nervous system during the regulation of autonomic, emotional and cognitive processes. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Elicited upper limb motions through transcutaneous cervical spinal cord stimulation.
Transcutaneous cervical spinal cord stimulation (tsCSC) has been demonstrated to activate the dorsal root and activate targeted muscles. However, it is unclear whether tsCSC can elicit functionally relevant movements of the upper limb for assistive/rehabilitative purposes. The current study sought to elicit arm and hand movements by tsCSC by placing an electrode array near the cervical segments of the spinal cord. Anode stimulation current pulses were delivered to the dorsal side at 120 Hz and 30 Hz in separate trials. The elicited joint kinematics were captured using a motion tracking system. The results revealed that distal and proximal joint movements can be elicited either independently or synergistically. Specifically, different motions, including flexion and extension of the elbow, wrist, and five digits, can be selectively elicited by adjusting the stimulation parameters, such as stimulation location and stimulation intensity. The findings demonstrated the feasibility of the spinal cord stimulation technique in eliciting functional movements of the upper limb. The outcomes also revealed the potential of the tsCSC technique as a promising assistive or rehabilitative method for individuals with impaired function of the upper limb.


Acute Coronary Syndrome: Posthospital Outpatient Management.
When providing care for patients who are discharged from the hospital after experiencing acute coronary syndrome (ACS), several issues should be addressed. Drug regimens should be reviewed to ensure that patients are taking appropriate drugs, including antiplatelet agents, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, aldosterone antagonists, beta blockers/calcium channel blockers, cholesterol-lowering drugs, and nitroglycerin. The review also should confirm that patients understand when and how to take their drugs, and that there are no obstacles (eg, cost) that might result in nonadherence to drug regimens. Lifestyle modifications, including improvements in diet and exercise regimens, along with participation in a cardiac rehabilitation program, should be encouraged. Risk factor reduction measures include smoking cessation for smokers, weight management for patients who are overweight, and optimal control of blood pressure and blood glucose levels. Appropriate vaccinations should be administered; influenza and pneumococcal vaccines are indicated for all patients with ACS in the absence of contraindications. Patients requiring pain control should avoid use of nonsteroidal anti-inflammatory drugs because they increase the risk of cardiovascular events; acetaminophen or other drugs should be used. Finally, depression is common among patients with ACS. Screening for and management of depression are significant components of care.


Expanding the boolean logic of the prokaryotic transcription factor XylR by functionalization of permissive sites with a protease-target sequence.
The σ54-dependent prokaryotic regulator XylR implements a one-input/one-output actuator that transduces the presence of the aromatic effector m-xylene into transcriptional activation of the cognate promoter Pu. Such a signal conversion involves the effector-mediated release of the intramolecular repression of the N-terminal A domain on the central C module of XylR. On this background, we set out to endow this regulator with additional signal-sensing capabilities by inserting a target site of the viral protease NIa in permissive protein locations that once cleaved in vivo could either terminate XylR activity or generate an effector-independent, constitutive transcription factor. To find optimal protein positions to this end, we saturated the xylR gene DNA with a synthetic transposable element designed for randomly delivering in-frame polypeptides throughout the sequence of any given protein. This Tn5-based system supplies the target gene with insertions of a selectable marker that can later be excised, leaving behind the desired (poly) peptides grafted into the protein structure. Implementation of such knock-in-leave-behind (KILB) method to XylR was instrumental to produce a number of variants of this transcription factor (TF) that could compute in vivo two inputs (m-xylene and protease) into a single output following a logic that was dependent on the site of the insertion of the NIa target sequence in the TF. Such NIa-sensitive XylR specimens afforded the design of novel regulatory nodes that entered protease expression as one of the signals recognized in vivo for controlling Pu. This approach is bound to facilitate the functionalization of TFs and other proteins with new traits, especially when their forward engineering is made difficult by, for example, the absence of structural data.


Computational analysis of the stereochemical outcome in the imidazolidinone-catalyzed enantioselective (4 + 3)-cycloaddition reaction.
Computations show why the catalytic, asymmetric (4 + 3)-cycloaddition reaction developed in the Harmata laboratories proceeds with facial selectivity opposite to that for models proposed for related catalyzed Diels-Alder reactions. Computations with M06-2X/6-311+G(d,p)//B3LYP/6-31G(d) show that iminium ions derived from MacMillan's chiral 2-tert-butyl-5-benzylimidazolidinone and siloxypentadienals undergo (4 + 3)-cycloadditions with furans preferentially on the more crowded face. Conformational reorganization of the benzyl group, to avoid intramolecular interaction with the silyl group, is responsible for differentiating the activation barriers of top- and bottom-face attack.


Lasting mantle scars lead to perennial plate tectonics.
Mid-ocean ridges, transform faults, subduction and continental collisions form the conventional theory of plate tectonics to explain non-rigid behaviour at plate boundaries. However, the theory does not explain directly the processes involved in intraplate deformation and seismicity. Recently, damage structures in the lithosphere have been linked to the origin of plate tectonics. Despite seismological imaging suggesting that inherited mantle lithosphere heterogeneities are ubiquitous, their plate tectonic role is rarely considered. Here we show that deep lithospheric anomalies can dominate shallow geological features in activating tectonics in plate interiors. In numerical experiments, we found that structures frozen into the mantle lithosphere through plate tectonic processes can behave as quasi-plate boundaries reactivated under far-field compressional forcing. Intraplate locations where proto-lithospheric plates have been scarred by earlier suturing could be regions where latent plate boundaries remain, and where plate tectonics processes are expressed as a 'perennial' phenomenon.


Unusual pattern of bucket-handle, medial meniscal tear in magnetic resonance imaging.
We present an unusual case of a medial meniscal tear in which a large fragment of meniscus was displaced posteriorly, outside the intercondylar notch, posterior to the posterior cruciate ligament (PCL). The appearance mimicked a second PCL posteriorly. The extensive longitudinal ("bucket-handle") tear was detached from the anterior horn of the meniscus but remained in continuity with the posterior tibial attachment. The fragment was prevented from displacement into the intercondylar notch by its large size, the ligament of Humphrey, and the anatomic location of the PCL. This case highlights the value of thin-section, high-resolution, cartilage-sensitive imaging, not only in defining the extent, location, and source of displaced meniscal fragments but also in demonstrating associated chondral injuries.


Electron spin relaxation times and rapid scan EPR imaging of pH-sensitive amino-substituted trityl radicals.
Carboxy-substituted trityl (triarylmethyl) radicals are valuable in vivo probes because of their stability, narrow lines, and sensitivity of their spectroscopic properties to oxygen. Amino-substituted trityl radicals have the potential to monitor pH in vivo, and the suitability for this application depends on spectral properties. Electron spin relaxation times T1 and T2 were measured at X-band for the protonated and deprotonated forms of two amino-substituted triarylmethyl radicals. Comparison with relaxation times for carboxy-substituted triarylmethyl radicals shows that T1 exhibits little dependence on protonation or the nature of the substituent, which makes it useful for measuring O2 concentration, independent of pH. Insensitivity of T1 to changes in substituents is consistent with the assignment of the dominant contribution to spin lattice relaxation as a local mode that involves primarily atoms in the carbon and sulfur core. Values of T2 vary substantially with pH and the nature of the aryl group substituent, reflecting a range of dynamic processes. The narrow spectral widths for the amino-substituted triarylmethyl radicals facilitate spectral-spatial rapid scan electron paramagnetic resonance imaging, which was demonstrated with a phantom. The dependence of hyperfine splittings patterns on pH is revealed in spectral slices through the image.


Eremohadena afzalipouri sp. nov. from Iran.
A new species of the genus Eremohadena Ronkay, Varga and Fabian, Eremohadena afzalipouri Shirvani sp. nov., is described from southeastern Iran. Holotype and female paratype and genitalia of both sexes are illustrated for the new species. A checklist of Iranian species of Eremohadena including nine species and subspecies is provided.


Pollen Allergy Screening with Allergen-Specific and Total Immunoglobulin E Titers.
Allergic rhinitis is a typical type I hypersensitivity reaction, commonly caused by inhalant allergens. Accurate identification of the causative antigen is important for rapid diagnosis and treatment initiation. This study examined the efficiency of serum-based allergen-specific immunoglobulin E and total immunoglobulin E antibody titers in screening for pollen allergy. We also examined the effect of cross-reactive carbohydrate determinants on specific immunoglobulin E titers in screening for pollen allergy, one of the causes of false positivity in specific immunoglobulin E measurements. A questionnaire was used to evaluate the symptoms of pollinosis among participants who underwent a medical examination. One hundred and thirty-two participants reported pollen allergy symptoms and 127 reported an absence of symptoms. Specific immunoglobulin E levels were measured using the AlaSTAT 3g Allergy method. Seventeen components, including four types of cross-reactive carbohydrate determinant-specific immunoglobulin E antibodies, were measured and evaluated comparatively. The sensitivity and specificity of the tests in predicting the presence or absence of pollen allergy were analyzed. The values of the areas under the curves for immunoglobulin E antibody levels against cedar, cypress, orchard grass, and ragweed pollen were 0.87, 0.82, 0.63, and 0.56, respectively. A cross-reactive carbohydrate determinant-related false-positive effect on the pollen specific immunoglobulin E titer was noted in pollen screening. Cedar pollen-specific immunoglobulin E titers showed sufficient accuracy for use in pollen allergy screening. The study of cross-reactive carbohydrate determinants suggested that subjects who tested positive for pollen often had false-positive results due to the impact of cross-reactive carbohydrate determinants.


Diffusion in the presence of a local attracting factor: Theory and interdisciplinary applications.
In many complex diffusion processes the drift of random walkers is not caused by an external force, as in the case of Brownian motion, but by local variations of fitness perceived by the random walkers. In this paper, a simple but general framework is presented that describes such a type of random motion and may be of relevance in different problems, such as opinion dynamics, cultural spreading, and animal movement. To this aim, we study the problem of a random walker in d dimensions moving in the presence of a local heterogeneous attracting factor expressed in terms of an assigned position-dependent "attractiveness function." At variance with standard Brownian motion, the attractiveness function introduced here regulates both the advection and diffusion of the random walker, thus providing testable predictions for a specific form of fluctuation-relations. We discuss the relation between the drift-diffusion equation based on the attractiveness function and that describing standard Brownian motion, and we provide some explicit examples illustrating its relevance in different fields, such as animal movement, chemotactic diffusion, and social dynamics.


Cardiac arrest in pregnancy and somatic support after brain death.
To review the important causes of cardiopulmonary arrest during pregnancy and the recommended modifications to resuscitation protocols when applied to pregnant patients, including the indications for perimortem cesarean section and the expected fetal outcomes, and to review the literature regarding extended somatic support after brain death during pregnancy. MEDLINE review of publications relating to cardiac arrest and resuscitation in pregnancy, physiologic changes after brain death, and attempted somatic support of brain-dead pregnant women. Cardiac arrest during pregnancy is rare, but it is important to recognize the causes, which may be either unrelated to pregnancy or unique to the pregnant woman. For the most part, the resuscitation protocol is the same as for nonpregnant victims of cardiac arrest, with a few important modifications, including especially the need for relieving aortocaval compression by the gravid uterus, the need for rapid intubation, and the importance of rapid perimortem cesarean delivery when indicated. In those rare cases of brain death occurring in a pregnant patient, continued somatic support of the mother may be possible, even for prolonged periods, to extend the pregnancy and further fetal maturation. The expected physiologic changes after brain death, challenges to successful somatic support, and specific recommendations regarding organ support of the brain-dead pregnant woman are reviewed.


Hand-held metal detector identification of ingested foreign bodies.
The study purpose was to determine the ability of hand-held metal detectors (HHMDs) to identify the presence of ingested metallic foreign bodies (MFBs). Twenty-three children presenting to the emergency department with a complaint of MFBs ingested were enrolled. Sixteen of 23 patients had radiographically proven foreign bodies. The MFBs comprised coins (n = 11), a button battery (n = 1), a medallion (n = 1), a token (n = 1), a needle (n = 1), and a marble (leaded glass) (n = 1). The HHMD correctly detected 15 of 16 radiographically positive MFBs (93%) and correctly excluded a potential MFB in six of six radiographically negative cases. The only foreign body not detected was an ingested needle. One radiograph was equivocal. Radiographic localization of the ingested objects was as follows: esophagus, n = 4; stomach, n = 9; and intestines, n = 3. The HHMD correctly localized all detected MFBs. The HHMD had a sensitivity of 94%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 86%. HHMDs are effective screening devices for possible ingested MFBs. Positive studies localized to the stomach and lower gastrointestinal tract do not require confirmatory radiographic studies.


Assessing the saturation of Krylov complexity as a measure of chaos.
Krylov complexity is a novel approach to study how an operator spreads over a specific basis. Recently, it has been stated that this quantity has a long-time saturation that depends on the amount of chaos in the system. Since this quantity not only depends on the Hamiltonian but also on the chosen operator, in this work we study the level of generality of this hypothesis by studying how the saturation value varies in the integrability to chaos transition when different operators are expanded. To do this, we work with an Ising chain with a longitudinal-transverse magnetic field and compare the saturation of the Krylov complexity with the standard spectral measure of quantum chaos. Our numerical results show that the usefulness of this quantity as a predictor of the chaoticity is strongly dependent on the chosen operator.


Human T cell leukemia virus-1 antibodies not detected in AIDS.
A collaborative study of sera from men in New York City with AIDS and at risk for AIDS, by investigators in Omaha, Cambridge and Kyoto, has failed to identify antibodies to human T cell leukemia virus I (HTLV-I).


Observations of the Nighttime Abundance of OClO in the Winter Stratosphere Above Thule, Greenland.
Observations at Thule, Greenland, that made use of direct light from the moon on 2,3, 4,5, and 7 February 1988 revealed nighttime chlorine dioxide (OClO) abundances that were less than those obtained in Antarctica by about a factor of 5, but that exceeded model predictions based on homogeneous (gas-phase) photochemistry by about a factor of 10. The observed time scale for the formation of OClO after sunset strongly supports the current understanding of the diurnal chemistry of OClO. These data suggest that heterogeneous (surface) reactions due to polar stratospheric clouds can occur in the Arctic, providing a mechanism for possible Arctic ozone depletion.


Identification of Early Represented Gluten Proteins during Durum Wheat Grain Development.
The time course of biosynthesis and accumulation of storage proteins in developing grains of durum wheat (Triticum turgidum ssp. durum (Desf.) Husn.) pasta-quality reference cv. Svevo was investigated at the protein level for the first time. Seeds were harvested at key kernel developmental stages, namely, 3 (seed increase 3-fold in size), 5 (kernel development, water-ripe stage), 11 (kernel development, water-ripe stage), 16 (kernel full development, water-ripe stage), 21 (milk-ripe stage), and 30 (dough stage) days postanthesis (dpa). Gliadins and glutenins were fractionated according to their different solubility and individually analyzed after fractionation by reversed-phase high performance liquid chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Proteins were identified by liquid chromatography-tandem mass spectrometry of proteolytic peptides. The α- and γ-gliadin were already detected at 3 dpa. The biosynthesis of high molecular mass glutenin Bx7 was slightly delayed (11 dpa). Most of the gluten proteins accumulated rapidly between 11 and 21 dpa, with a minor further increase up to 30 dpa. The expression pattern of gluten proteins in Triticum durum at the early stages of synthesis provides reference data sets for future applications in crop breeding and growth monitoring.


[Drug therapy of lymphomas].
The therapy of lymphomas has undergone a major expansion during the last decade. Novel therapeutic targets have appeared beyond classical chemotherapeutic combinations. These novel drugs have very pronounced action across lymphoma types, and their toxicity profile is usually better tolerable compared to standard chemotherapies. These new therapies are enabling us to offer treatment to those patients who have refractory disease, and we had no option to treat them before these drugs. The author describes several new therapeutic options. New chemotherapeutic drugs are pixantrone and bendamustin. Monoclonal antibodies, like rituximab, ofatumumab, obinotuzumab are described, and conjugated antibodies like brentuximab vedotin and inotuzumab ozogamicin are also discussed. The bispecific antibody blinatumomab can modulate the immune response, and the new class of immune checkpoint inhibitors (pembrolizumab, nivolumab) is also discussed. Therapies targeting the epigenetic regulatory network are also important. Several studies reported promising results of abexinostat, vorinostat, belinostat and panobinostat. The new class of immunomodulatory drugs (imids) is also growing, results with thalidomid and lenalidomid are discussed. The proteasome inhibitors are offering new combinations, with the use of bortezomid, carfilzomib, ixazomib. All these new drugs described above offer to the physician several therapeutic options to better treat patients with lymphoma.


Medical evacuation management and clinical characteristics of 3,255 inpatients after the 2010 Yushu earthquake in China.
A catastrophic earthquake struck the Yushu prefecture of China's Qinghai province on April 14, 2010. Supported by the China National Ministry of Health, this study performed a detailed medical analysis of injuries and diseases, based on comprehensive medical data of hospitalized patients to share the experiences and lessons learned from emergency medical aid operations in high-altitude regions. To survey the management of medical relief, more than 10 interviews with rescuers were held and more than 100 documents were reviewed. Medical records of 3,255 patients from 57 hospitals were analyzed retrospectively. Patient demographic data, complaints, diagnoses, prognoses, injury types, dispositions, and means of transportation were all reviewed. A total of 3,255 patients were admitted to hospitals. Of these, 1,426 (43.8%) were middle-aged (31-50 years), 2,574 (79.07%) were transported by plane, and the first 3 days were the peak period for air transportation. The records of 2,622 patients with earthquake-related injuries were analyzed, and 1,775 (68.32%) of them were admitted to hospital within the first 3 days. Bone fractures were diagnosed in 1,431 (55.08%) patients and crush syndrome was observed in 23 (0.89%). Illnesses accounted for 657 patients who were admitted to surveyed hospitals. Of these, 143 (20.63%) suffered from respiratory diseases and 259 (39.97%) from acute high-altitude sickness. Of the latter, 224 (86.49%) were rescuers. The overall mortality rate was 0.2% (7 of 3,255). Four patients died from earthquake-related injuries and three from other illnesses. A devastating earthquake occurring in a remote, high-altitude region presented a variety of challenges for external medical aid. Air transportation for those with severe injuries and diseases played a crucial role in decreasing the mortality and morbidity. It is necessary for hospitals to initiate effective emergency measures while facing the peak admission flow within the initial 72-hour period. Characteristic factors such as high altitude, low-oxygen content, local construction features, and lifestyle may contribute to complex injuries and illnesses. More attention should be paid to medical aid training for rescuers, and effective measures should be developed to deal with destructive natural disasters occurring in special geographical environments. Epidemiological study, level III.


Association between gastric reflux, obesity and erosive tooth wear among psychiatric patients.
The prevalence of erosive tooth wear and obesity are high in psychiatric patients and soft drink consumption is a common risk factor associated with both diseases. This study aimed to assess the association between soft drink consumption, gastric reflux, erosive tooth wear, and obesity among resident patients at the Psychiatric Hospital, Taif, Saudi Arabia.This descriptive, cross-sectional study included 223 adult psychiatric inpatients (126 male, 97 female) with a mean age of 42.3 years (± 2.2). Dental erosion detection was performed according to World Health Organization criteria. The medical evaluation included assessment of the body mass index (BMI). With appropriate sample weighting, relationships between erosive tooth wear, gastric reflux, and obesity were assessed using multivariable logistic regression.Ninety eight patients (43.9%) presented with erosive tooth wear. The mean BMI for the entire study population was 27.7 ± 6.3 kg/m2. Regression analysis showed a strong association between erosive tooth wear and chronic vomiting or bulimia (adjusted odds ratio = 2.11; 95% confidence interval [CI] = 1.98-5.07, P < .001), gastric reflux (adjusted odds ratio = 2.13; 95% CI = 1.34-6.23, P < .001), consumption of soft drinks (adjusted odds ratio = 2.14; 95% CI = 1.03-6.08, P < .001), and schizophrenia and delusional disorders (adjusted odds ratio = 2.07; 95% CI = 1.98-5.08, P < .001).This study demonstrates a significant association between erosive tooth wear prevalence and chronic vomiting or bulimia, consumption of soft drinks, and gastric reflux among resident patients at psychiatric hospital.


Metabolism of the active metabolite of quetiapine, N-desalkylquetiapine in vitro.
The antipsychotic drug quetiapine has been approved for the treatment of unipolar and bipolar depression. The antidepressant activity is considered to be mediated by the active metabolite N-desalkylquetiapine, which is mainly formed by CYP3A4. Little is known about the subsequent elimination of this metabolite. Therefore, this study investigated the possible involvement of cytochrome P450 (P450) enzymes in the metabolism of N-desalkylquetiapine. Screening for and interpretation of metabolites were performed by incubating N-desalkylquetiapine in human liver microsomes (HLM) followed by liquid chromatography-tandem mass spectrometry. The possible involvement of P450 enzymes in N-desalkylquetiapine metabolism was evaluated by coincubation of selective P450 inhibitors in HLM and subsequent experiments with recombinant human P450 enzymes. In HLM experiments, three chromatographic peaks were interpreted as possible metabolites of N-desalkylquetiapine, namely, N-desalkylquetiapine sulfoxide, 7-hydroxy-N-desalkylquetiapine, and an unrecognized metabolite (denoted M3). Inhibition of CYP2D6 (by quinidine) reduced formation of 7-hydroxy-N-desalkylquetiapine by 81%, whereas the CYP3A4 inhibitor ketoconazole inhibited formation of N-desalkylquetiapine sulfoxide and M3 by 65 and 34%, respectively. Inhibitors of CYP1A2, CYP2C9, and CYP2C19 showed only limited changes in metabolite formation. In recombinant systems, 7-hydroxy-N-desalkylquetiapine was exclusively formed by CYP2D6, whereas N-desalkylquetiapine sulfoxide and M3 were formed by both CYP3A4 and CYP2D6. Overall, intrinsic clearance of N-desalkylquetiapine was 12-fold higher by recombinant CYP2D6 relative to CYP3A4. In conclusion, N-desalkylquetiapine is metabolized by both CYP2D6 and CYP3A4 in vitro with preference for the former enzyme. The pharmacologically active metabolite, 7-hydroxy-N-desalkylquetiapine, was exclusively formed by CYP2D6, whereas the two other metabolites were mainly formed by CYP3A4.


Simultaneous determination of diethylene glycol and propylene glycol in pharmaceutical products by HPLC after precolumn derivatization with p-toluenesulfonyl isocyanate.
A simple and reliable HPLC method was developed for the simultaneous quantitative analysis of diethylene glycol (DEG) and propylene glycol (PG) in pharmaceutical products by precolumn derivatization. The derivatization reagent p-toluenesulfonyl isocyanate (TSIC, 10 microL, 20% in ACN v/v) was added to 100 microL of the sample, and then 10 muL of water was added. The resulting derivatives were separated using a C(18)analytical column and a mobile phase composed of 0.01 M KH(2)PO(4)buffer (adjusted to pH 2.5 with phosphoric acid) and ACN (47:53 v/v) at 1 mL/min and 25 degrees C. For detection, UV light at 227 nm was used. The derivatization conditions including reaction time, temperature, and concentration of TSIC were optimized. The calibration curves were linear from 0.062 to 18.6 microg/mL (r(2)= 0.9999) and from 0.071 to 21.3 microg/mL (r(2) = 0.9999) for DEG and PG, respectively. The RSD values of intra- and interday assays were all below 4% for DEG and PG. The proposed method was then successfully applied to analyze two Armillarisin A injection samples and two spiked syrup samples.


Insulin resistance in childhood obesity.
The prevalence of childhood obesity is on the rise in the USA. Approximately 20% of children and adolescents are overweight, as defined by a body mass index (BMI) greater than the 85th percentile. We describe a series of studies that has elucidated the impact of both childhood and adolescent obesity on glucose and lipid metabolism in vivo. We used magnetic resonance imaging to quantify the abdominal, visceral and subcutaneous fat depots, together with the insulin and glucose clamping techniques, to assess alterations in insulin action and secretion early in the course of obesity.


Interplane bulk motion analysis and removal based on normalized cross-correlation in optical coherence tomography angiography.
Bulk motion seriously degrades the image quality of optical coherence tomography angiography (OCTA). Conventional correction methods focus on in-plane displacement, while the bulk motion component perpendicular to B-scans also introduces noise. This work first presents an evaluation of this component using a specific scan protocol and an approximate expression derived from peak-normalized cross-correlation values, and then quantitatively assesses how interplane bulk motion noise reduce the sensitivity of cross-sectional angiograms. Finally, we developed a repetitive bulk motion correction method based on the estimated displacements and redundant volume scans. The correction does not require registration and angiogram reconstruction of low flow sensitivity frames, and the results of in vivo mice skin OCTA imaging experiments show that the proposed method can effectively reduce bulk motion noise caused by cardiac and respiratory motion and occasional shaking, and improve OCTA image quality, which has practical significance for clinical OCTA diagnosis and analysis.


Dr. Marjory Warren and the origin of British geriatrics.
The life and works of the pioneer British geriatrician, Marjory Warren, are worthy of closer examination. The transformation of a Public Assistance Institution into her unit at the West Middlesex Hospital in 1935 represented the first organized geriatric medicine service in the United Kingdom. She promoted multidisciplinary rehabilitation and holistic appreciation of elderly patients, and emphasized the economic, social, and moral problems associated with their care. She was particularly concerned with the rehabilitation of hemiplegics and amputees, preventive medicine, patient responsibility, and home nursing. She underscored the need for geriatrics to maintain a close link with general medicine and its training programs. Her innovative methods, influential writings, committee work, and personal force were instrumental in the evolution of modern British geriatrics and rehabilitation medicine.


Association between XRCC1 and ERCC1 single-nucleotide polymorphisms and the efficacy of concurrent radiochemotherapy in patients with esophageal squamous cell carcinoma.
The aim of the present study was to investigate the association between single-nucleotide polymorphisms (SNPs) in X-ray repair cross-complementing 1-399 (XRCC1-399) or excision repair cross-complementation group 1-118 (ERCC1-118) and the short-term efficacy of radiochemotherapy, tumor metastasis and relapse, as well as the survival time in patients with esophageal squamous cell carcinoma (ESCC). TaqMan probe-based quantitative polymerase chain reaction (qPCR) was conducted to examine the levels of XRCC1-399 and ERCC1-118 SNPs in the peripheral blood of 50 patients with pathologically confirmed ESCC. In addition, the associations between different genotypes and short-term therapeutic efficacy [the complete remission (CR) rate], tumor metastasis and relapse, as well as the survival time following concurrent radiochemotherapy, were determined. A total of 50 ESCC patients who received concurrent radiochemotherapy were enrolled. It was found that the short-term therapeutic efficacy (CR rate) was higher in the group of patients carrying the homozygous mutation of XRCC1-399 (A/A genotype) than in the group of patients without the XRCC1-399 mutation (G/G genotype). In addition, the CR rate was significantly increased in patients carrying one or two ERCC1-118 C alleles (C/C or C/T genotype) compared with patients lacking the C allele (T/T genotype). The differences were statistically significant (A/A vs. G/G, P=0.014; TT vs. C/T+C/C, P=0.040). During the follow-up period, the group of patients carrying the homozygous mutation of XRCC1-399 (A/A genotype) exhibited a markedly reduced risk of metastasis and relapse compared with the group of patients carrying non-mutated XRCC1-399 (G/G genotype; P=0.031). By contrast, ERCC1-118 SNP was not associated with the risk of metastasis and recurrence (P>0.05). The combined results of univariate and multivariate Cox regression analysis showed that the SNP in ERCC1-118 was closely associated with survival time. The mean survival time was significantly prolonged in patients carrying 1 or 2 C alleles (C/C or C/T genotype) compared with patients lacking the C allele (T/T genotype) [T/T vs. C/C, HR=12.96, 95% confidence interval (CI)=3.08-54.61, P<0.001; TT vs. C/T+C/C, HR=11.71, 95% CI=3.06-44.83, P<0.001]. However, XRCC1-399SNP had no effect on survival time (P>0.05). XRCCl-399 SNP was associated with the short-term therapeutic efficacy (the CR rate) and tumor metastasis/relapse in ESCC patients who received the docetaxel plus cisplatin (TP) regimen-based concurrent radiochemotherapy. By contrast, ERCC1-118 SNP was significantly associated with the short-term therapeutic efficacy (the CR rate) and survival time in ESCC patients who received TP regimen-based concurrent radiochemotherapy.


Clinical evaluation of the refined clothespin relocation test: A pilot study.
The refined clothespin relocation test is a test used to evaluate the performance of a prosthesis user by analysing the compensatory motions and time to complete a grasping and placement exercise. The test has been studied previously with a motion capture laboratory and has now been adapted for a clinical setting. A comparison of prosthesis user to an able-bodied group is needed to determine efficacy as an assessment tool. To modify the previous refined clothespin relocation test and assess whether it can distinguish between able-bodied and prosthesis users. Comparative analysis. Forty-two able-bodied subjects and three prosthesis users completed the adapted refined clothespin relocation test protocol. Average refined clothespin relocation test scores describing the degree of compensatory movements and the time to complete the protocol were compared using a Mann-Whitney U-test. A significant difference was found in the refined clothespin relocation test score between the able-bodied (Md = 65.32, n = 42) and prosthesis users (Md = 23.07, n = 3) with a medium effect size (p < 0.001, r = 0.43). Prosthesis users demonstrated larger compensations and longer completion times, as reflected in the refined clothespin relocation test final score. The refined clothespin relocation test has the potential to be a useful clinical tool to assess user performance on a functional task. This preliminary study demonstrates that the adapted protocol can distinguish between the two groups based on refined clothespin relocation test score. A future multi-centre study is required using multiple raters and comparing it with the existing outcome measures to validate the refined clothespin relocation test and determine inter-rater reliability.


Casein kinase 2 inhibits HomolD-directed transcription by Rrn7 in Schizosaccharomyces pombe.
In Schizosaccharomyces pombe, ribosomal protein gene (RPG) promoters contain a TATA analogue element called the HomolD box. The HomolD-binding protein Rrn7 forms a complex with the RNA polymerase II machinery. Despite the importance of ribosome biogenesis to cell survival, the mechanisms involved in the regulation of transcription of eukaryotic RPGs are unknown. In this study, we identified Rrn7 as a new substrate of the pleiotropic casein kinase 2 (CK2), which is a regulator of basal transcription. Recombinant Rrn7 from S. pombe, which is often used as a model organism for studying eukaryotic transcription, interacted with CK2 in vitro and in vivo. Furthermore, CK2-mediated phosphorylation of Rrn7 inhibited its HomolD-directed transcriptional activity and ability to bind to an oligonucleotide containing a HomolD box in vitro. Mutation of Rrn7 at Thr67 abolished these effects, indicating that this residue is a critical CK2 phosphorylation site. Finally, Rrn7 interacted with the regulatory subunit of CK2 in vivo, inhibition of CK2 in vivo potentiated ribosomal protein gene transcription, and chromatin immunoprecipitation analyses identified that the catalytic subunit of CK2 was associated with the rpk5 gene promoter in S. pombe. Taken together, these data suggest that CK2 inhibits ribosomal protein gene transcription in S. pombe via phosphorylation of Rrn7 at Thr67.


Multilayer flow modulator enhances vital organ perfusion in patients with type B aortic dissection.
Management of aortic dissections (AD) is still challenging, with no universally approved guideline among possible surgical, endovascular, or medical therapies. Approximately 25% of patients with AD suffer postintervention malperfusion syndrome or hemodynamic instability, with the risk of sudden death if left untreated. Part of the issue is that vascular implants may themselves induce flow disturbances that critically impact vital organs. A multilayer mesh construct might obviate the induced flow disturbances, and it is this concept we investigated. We used preintervention and post-multilayer flow modulator implantation (PM) geometries from clinical cases of type B AD. In-house semiautomatic segmentation routines were applied to computed tomography images to reconstruct the lumen. The device was numerically reconstructed and adapted to the PM geometry concentrically fit to the true lumen centerline. We also numerically designed a pseudohealthy case, where the geometry of the aorta was extracted interpolating geometric features of preintervention, postimplantation, and published representative healthy volunteers. Computational fluid dynamics methods were used to study the time-dependent flow patterns, shear stress metrics, and perfusion to vital organs. A three-element Windkessel lumped parameter module was coupled to a finite-volume solver to assign dynamic outlet boundary conditions. Multilayer flow modulator not only significantly reduced false lumen blood flow, eliminated local flow disturbances, and globally regulated wall shear stress distribution but also maintained physiological perfusion to peripheral vital organs. We propose further investigation to focus the management of AD on both modulation of blood flow and restoration of physiologic end-organ perfusion rather than mere restoration of vascular lamina morphology. NEW & NOTEWORTHY The majority of aortic dissection modeling efforts have focused on the maintenance of physiological flow using minimally invasive placed grafts. The multilayer flow modulator is a complex mesh construct of wires, designed to eliminate flow disruptions in the lumen, regulate the physiological wall stresses, and enhance endothelial function and offering the promise of improved perfusion of vital organs. This has never been fully proved or modeled, and these issues we confirmed using a dynamic framework of time-varying arterial waveforms.


Engineering a Biomimetic In Vitro Model of Bruch's Membrane Using Hagfish Slime Intermediate Filament Proteins.
Bruch's membrane resides in the subretinal tissue and regulates the flow of nutrients and waste between the retinal pigment epithelial (RPE) and vascular layers of the eye. With age, Bruch's membrane becomes thicker, stiffer, and less permeable, which impedes its function as a boundary layer in the subretina. These changes contribute to pathologies such as age-related macular degeneration (AMD). To better understand how aging in Bruch's membrane affects surrounding tissues and to determine the relationship between aging and disease, an in vitro model of Bruch's membrane is needed. An accurate model of Bruch's membrane must be a proteinaceous, semipermeable, and nonporous biomaterial with similar mechanical properties to in vivo conditions. Additionally, this model must support RPE cell growth. While models of subretinal tissue exist, they typically differ from in vivo Bruch's membrane in one or more of these properties. This study evaluates the capability of membranes created from recombinant hagfish intermediate filament (rHIF) proteins to accurately replicate Bruch's membrane in an in vitro model of the subretinal tissue. The physical characteristics of these rHIF membranes were evaluated using mechanical testing, permeability assays, brightfield microscopy, and scanning electron microscopy. The capacity of the membranes to support RPE cell culture was determined using brightfield and fluorescent microscopy, as well as immunocytochemical staining. This study demonstrates that rHIF protein membranes are an appropriate biomaterial to accurately mimic both healthy and aged Bruch's membrane for in vitro modeling of the subretinal tissue.


Identification of diagnostic biomarkers and immuno-infiltration analysis for rheumatoid arthritis based on biological information and WGCNA.
Rheumatoid arthritis (RA), as an autoimmune disease, poses a huge social and economic burden worldwide. Although the diagnosis of RA has been gradually improved, there is still a need to discover accurate and rapid biomarkers for diagnosis and therapy with a precise understanding of the disease. This study aimed to screen diagnostic biomarkers and analyze immune infiltration in RA based on weighted gene co-expression network analysis (WGCNA). Firstly, we screened the experimental and validation sets associated with RA from the GEO database. Crossover genes were obtained using differential genes (DEGs) and key modules in WGCNA. Subsequently, the crossover genes were constructed into protein-protein interaction (PPI) networks and screened to obtain hub genes. The receiver operating characteristic (ROC) curve assessment was performed to identify diagnostic biomarkers. In addition, we used the Cibersort algorithm for immuno-infiltration analysis and the DGidb database to search for drugs associated with diagnostic biomarkers. In the end, 377 DEGs were identified, and the enrichment analysis revealed significant associations with the immune system. Blue modules in the WGCNA analysis were positively associated with the disease and were identified as key modules. ROC curves evaluated the four hub genes, which significantly differentiated RA from healthy controls and could be used as diagnostic biomarkers. In further analysis, we found that RA is closely related to immunity, and the search identified multiple drugs that hold promise for treating RA. BCL2A1, PTGS2, FAS, and LY96 may be used as diagnostic biomarkers, which is significant for diagnosing and treating RA.


Uncommon Etiology for Seizure: Cerebral Hyperperfusion Syndrome.
Cerebral hyperperfusion syndrome (CHS) is a rare life-threatening complication of carotid endarterectomy (CEA) and carotid artery stenting (CAS) for carotid artery stenosis. The incidence varies between 0 and 3%, depending on the severity of the stenosis, perioperative hypertension, and contralateral carotid stenosis. This case report reports a 53-year-old female patient presenting with decreased alertness and multiple tonic-clonic seizures, in the background of bilateral CEA. She was found to have bilateral carotid stenosis. Her left CEA was performed three months prior and right CEA was four days prior to her current presentation with seizures. After bilateral CEA, the imaging showed extensive pathologic process involving primarily the subcortical white matter and overlying cortex, more on the right cerebral hemisphere. On follow-up six weeks later, she reported no recurrent seizures and imaging showed decrease in abnormal signal intensity of the grey and white matter. This was indicative of near complete resolution of hyperperfusion damage. CHS is a rare complication due to the loss of autoregulation of the cerebrovascular system and increased blood flow status after bilateral CEA. This case is reported because of a rare and unique presentation of seizures in the background of bilateral CEA.


Role of liver stem cells in hepatocarcinogenesis.
Liver cancer is an aggressive disease with a high mortality rate. Management of liver cancer is strongly dependent on the tumor stage and underlying liver disease. Unfortunately, most cases are discovered when the cancer is already advanced, missing the opportunity for surgical resection. Thus, an improved understanding of the mechanisms responsible for liver cancer initiation and progression will facilitate the detection of more reliable tumor markers and the development of new small molecules for targeted therapy of liver cancer. Recently, there is increasing evidence for the "cancer stem cell hypothesis", which postulates that liver cancer originates from the malignant transformation of liver stem/progenitor cells (liver cancer stem cells). This cancer stem cell model has important significance for understanding the basic biology of liver cancer and has profound importance for the development of new strategies for cancer prevention and treatment. In this review, we highlight recent advances in the role of liver stem cells in hepatocarcinogenesis. Our review of the literature shows that identification of the cellular origin and the signaling pathways involved is challenging issues in liver cancer with pivotal implications in therapeutic perspectives. Although the dedifferentiation of mature hepatocytes/cholangiocytes in hepatocarcinogenesis cannot be excluded, neoplastic transformation of a stem cell subpopulation more easily explains hepatocarcinogenesis. Elimination of liver cancer stem cells in liver cancer could result in the degeneration of downstream cells, which makes them potential targets for liver cancer therapies. Therefore, liver stem cells could represent a new target for therapeutic approaches to liver cancer in the near future.


Functional assessment of the right ventricle in patients with bronchial asthma of various severity.
Pulmonary artery hypertension and its consequences still constitutes an underestimated clinical problem in asthma patients and its non-invasive early detection may influence proper treatment. To non-invasively examine the pulmonary artery flow parameters and right ventricular function in patients with asthma of various severity. The analysis of parameters of echocardiography and first-pass and gated radionuclide angiography, and baseline examination in 31 patients with bronchial asthma and 16 healthy controls. Patients with severe asthma had higher mean pulmonary artery pressure (MPAP) compared to the healthy controls. The subgroup analysis of patients who suffered from asthma in their childhood showed that individuals with severe asthma were characterized by significantly higher MPAP than those with the mild/moderate condition (19.16 ±7.51 mm Hg vs. 5.0 ±1.15 mm Hg, p = 0.025). Gated, but not first-pass, radionuclide angiography revealed that individuals with severe asthma were characterized by a lower right ventricular ejection fraction (RVEF). Further analysis of the subgroup of patients in whom the initial manifestation of dyspnoea occurred no earlier than 6 years prior to the study showed that the RVEF of individuals with severe asthma was significantly lower compared to those with mild/moderate asthma (39.8 ±4.79% vs. 51.4 ±8.65%, p = 0.019). The pulmonary artery pressure in patients with severe asthma is significantly higher than in healthy individuals; in contrast, these two groups did not differ significantly in terms of the right ventricular echocardiographic characteristics. Gated radionuclide angiography, but not the first-pass technique, allowed for the detection of subtle right ventricular ejection fraction changes in asthma patients.


Age-related changes in non-receptor dependent generation of reactive oxygen species from phagocytes of healthy adults.
Several authors have shown that neutrophil generation of reactive oxygen species (ROS) declines with advancing age. Similar changes have also been suggested in monocytes. In both cases alterations in second messenger activity have been implicated as the most likely explanation for these observations. The aim of this study was to investigate the effect of age on phagocyte ROS generation, stimulated by the direct activation of protein kinase C (PKC). Venous blood was drawn from normal healthy subjects, cells were separated on a double density gradient into mononuclear and polymorphonuclear (pmn) cells. Phorbol myristate acetate (PMA) was employed as a cell stimulus. Superoxide generation was measured by cytochrome c reduction and myeloperoxidase (MPO) products by measurement of peak luminol chemiluminescence (CL). Fifty-eight subjects, 25 males and 33 females, were studied, median age 49 years (range 26-88 years). Polymorphonuclear cell superoxide generation was significantly higher in males and there was a trend towards higher pmn MPO product generation in males. Using Spearman's ranked correlation coefficient, monocyte superoxide generation was negatively correlated with age (r = -0.473, P < 0.001). No changes in the generation of MPO products was found. There were also trends towards a negative correlation of pmn cytochrome c reduction and peak luminol CL with age in males but not females. Since PMA directly activates protein kinase C, reduced monocyte superoxide generation with increasing age appears to be related to alterations in the ROS generating system downstream of the cell receptor. Impaired monocyte superoxide generation may have implications for non-specific defence against certain infections and early tumour growth in the elderly. Factors underlying these changes in monocyte function therefore require further study.


Sulfation modulates the targeting properties of hyaluronic acid to P-selectin and CD44.
Many targeting strategies can be employed to direct nanoparticles to tumors for imaging and therapy. However, tumors display a dynamic, heterogeneous microenvironment that undergoes spatiotemporal changes, including the expression of targetable cell-surface biomarkers. Here, we develop a nanoparticle system to effectively target two receptors overexpressed in the microenvironment of aggressive tumors. Hyaluronic acid (HA) was regioselectivity modified using a multi-step synthetic approach to alter binding specificities for CD44 and P-selectin to tumor cell interaction. The dual-targeting strategy utilizes sulfate modifications on HA that targets P-selectin, in addition to native targeting of CD44, which exploits spatiotemporal alterations in the expression patterns of these two receptors in cancer sites. Using biophysical characterization and in vitro studies, we demonstrate that modified HA nanoparticles effectively targets both P-selectin+ and CD44+ cells, which lays the groundwork for future in vivo biomedical applications.


Effects of acupuncture on sensory perception: a systematic review and meta-analysis.
The effect of acupuncture on sensory perception has never been systematically reviewed; although, studies on acupuncture mechanisms are frequently based on the idea that changes in sensory thresholds reflect its effect on the nervous system. Pubmed, EMBASE and Scopus were screened for studies investigating the effect of acupuncture on thermal or mechanical detection or pain thresholds in humans published in English or German. A meta-analysis of high quality studies was performed. Out of 3007 identified articles 85 were included. Sixty five studies showed that acupuncture affects at least one sensory threshold. Most studies assessed the pressure pain threshold of which 80% reported an increase after acupuncture. Significant short- and long-term effects on the pressure pain threshold in pain patients were revealed by two meta-analyses including four and two high quality studies, respectively. In over 60% of studies, acupuncture reduced sensitivity to noxious thermal stimuli, but measuring methods might influence results. Few but consistent data indicate that acupuncture reduces pin-prick like pain but not mechanical detection. Results on thermal detection are heterogeneous. Sensory threshold changes were equally frequent reported after manual acupuncture as after electroacupuncture. Among 48 sham-controlled studies, 25 showed stronger effects on sensory thresholds through verum than through sham acupuncture, but in 9 studies significant threshold changes were also observed after sham acupuncture. Overall, there is a lack of high quality acupuncture studies applying comprehensive assessments of sensory perception. Our findings indicate that acupuncture affects sensory perception. Results are most compelling for the pressure pain threshold, especially in pain conditions associated with tenderness. Sham acupuncture can also cause such effects. Future studies should incorporate comprehensive, standardized assessments of sensory profiles in order to fully characterize its effect on sensory perception and to explore the predictive value of sensory profiles for the effectiveness of acupuncture.


Establishing sample-preparation protocols for X-ray phase-contrast CT of rodent spinal cords: Aldehyde fixations and osmium impregnation.
Dense and unbiased cellular-resolution representations of extended volumetric central nervous system soft-tissue anatomy are difficult to obtain, even in experimental post-mortem settings. Interestingly, X-ray phase-contrast computed tomography (X-PCI-CT), an emerging soft-tissue-sensitive volumetric imaging technique, can provide multiscale organ- to cellular-level morphological visualizations of neuroanatomical structure. Here, we tested different nervous-tissue fixation procedures, conventionally used for transmission electron microscopy, to better establish X-PCI-CT-specific sample-preparation protocols. Extracted rat spinal medullas were alternatively fixed with a standard paraformaldehyde-only aldehyde-based protocol, or in combination with glutaraldehyde. Some specimens were additionally post-fixed with osmium tetroxide. Multiscale X-PCI-CT datasets were collected at several synchrotron radiation facilities, using state-of-the-art setups with effective image voxel sizes of 3.03 to 0.33 μm3, and compared to high-field magnetic resonance imaging, histology and vascular fluorescence microscopy data. Multiscale X-PCI-CT of aldehyde-fixed spinal cord specimens resulted in dense histology-like volumetric representations and quantifications of extended deep spinal micro-vascular networks and of intra-medullary cell populations. Osmium post-fixation increased intra-medullary contrast between white and gray-matter tissues, and enhanced delineation of intra-medullary cellular structure, e.g. axon fibers and motor neuron perikarya. Volumetric X-PCI-CT provides complementary contrast and higher spatial resolution compared to 9.4 T MRI. X-PCI-CT's advantage over planar histology is the volumetric nature of the cellular-level data obtained, using samples much larger than those fit for volumetric vascular fluorescence microscopy. Deliberately choosing (post-)fixation protocols tailored for optimal nervous-tissue structural preservation is of paramount importance in achieving effective and targeted neuroimaging via the X-PCI-CT technique.


Vancomycin Taper and Risk of Failure of Fecal Microbiota Transplantation in Patients With Recurrent Clostridium difficile Infection.
We retrospectively analyzed a cohort of 109 subjects treated for recurrent Clostridium difficile infection with fecal microbiota transplantation (FMT) at a tertiary referral center between 2011 and 2014 to determine risk factors for FMT failure. In a multivariate analysis, failure to use an oral vancomycin taper preceding FMT was associated with a significant risk of FMT failure (odds ratio, 0.15; 95% confidence interval, .007-.40).


Parental Self-Efficacy for Reducing the Risk of Adolescent Depression and Anxiety: Scale Development and Validation.
Burgeoning research suggests that parents can reduce the risk of anxiety and depression in their adolescents and that parental self-efficacy (PSE) may be related to parental risk and protective factors for these disorders. As there are currently no measures available to assess PSE in relation to parenting behaviors that may reduce adolescent risk for depression and anxiety, we developed and validated a measure of PSE, the Parental Self-Efficacy Scale (PSES). Using a sample of 359 parents and 332 adolescents (aged 12-15), the PSES was found to have high reliability, confirmatory factor analysis supported its validity, and most of the hypothesized relationships between the PSES and other measures of parenting practices and adolescent depressive and anxiety symptoms were supported.


Reactivity of the 4,5-didehydroisoquinolinium cation.
The chemical properties of a 1,8-didehydronaphthalene derivative, the 4,5-didehydroisoquinolinium cation, were examined in the gas phase in a dual-cell Fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometer. This is an interesting biradical because it has two radical sites in close proximity, yet their coupling is very weak. In fact, the biradical is calculated to have approximately degenerate singlet and triplet states. This biradical was found to exclusively undergo radical reactions, as opposed to other related biradicals with nearby radical sites. The first bond formation occurs at the radical site in the 4-position, followed by that in the 5-position. The proximity of the radical sites leads to reactions that have not been observed for related mono- or biradicals. Interestingly, some ortho-benzynes have been found to yield similar products. Since ortho-benzynes do not react via radical mechanisms, these products must be especially favorable thermodynamically.


The first salamander defensin antimicrobial peptide.
Antimicrobial peptides have been widely identified from amphibian skins except salamanders. A novel antimicrobial peptide (CFBD) was isolated and characterized from skin secretions of the salamander, Cynops fudingensis. The cDNA encoding CFBD precursor was cloned from the skin cDNA library of C. fudingensis. The precursor was composed of three domains: signal peptide of 17 residues, mature peptide of 41 residues and intervening propeptide of 3 residues. There are six cysteines in the sequence of mature CFBD peptide, which possibly form three disulfide-bridges. CFBD showed antimicrobial activities against Staphylococcus aureus, Bacillus subtilis, Candida albicans and Escherichia coli. This peptide could be classified into family of β-defensin based on its sequence similarity with β-defensins from other vertebrates. Evolution analysis indicated that CFBD was close to fish β-defensin. As far as we know, CFBD is the first β-defensin antimicrobial peptide from salamanders.


Antipsychotic drug effects on dopamine and serotonin receptors: in vitro binding and in vivo turnover studies.
The stereospecific binding sites of [3H]spiroperidol in frontal cortical regions of the rat brain have a higher affinity for serotonin than they do for dopamine, although the reverse relative affinity is observed in the caudate nucleus and in mesolimbic regions. The antipsychotic butyrophenones haloperidol and butaclamol compete with comparably high affinities for [3H]spiroperidol binding sites in all of the above brain regions. Both butyrophenones accelerated dopamine turnover in these three brain regions without altering serotonin turnover. A chronic treatment regimen with fluphenazine which induced tolerance to the metabolic effects of haloperidol in all three brain regions also induced tolerance to its behavioral effects. The number of binding sites of [3H]spiroperidol were increased in the caudate nucleus and mesolimbic regions but not in the frontal cortex of tolerant animals. These results are consistent with the hypothesis that [3H]spiroperidol interacts with a serotonergic site in the frontal cortex. However, the in vitro interaction of antipsychotic drugs with this receptor does not seem to be related to their acute or chronic effects on neurotransmitter function in the frontal cortex in vivo.


The IMPROVE_A temperature protocol for thermal/optical carbon analysis: maintaining consistency with a long-term database.
Thermally derived carbon fractions including organic carbon (OC) and elemental carbon (EC) have been reported for the U.S. Interagency Monitoring of PROtected Visual Environments (IMPROVE) network since 1987 and have been found useful in source apportionment studies and to evaluate quartz-fiber filter adsorption of organic vapors. The IMPROVE_A temperature protocol defines temperature plateaus for thermally derived carbon fractions of 140 degrees C for OC1, 280 degrees C for OC2, 480 degrees C for OC3, and 580 degrees C for OC4 in a helium (He) carrier gas and 580 degrees C for EC1, 740 degrees C for EC2, and 840 degrees C for EC3 in a 98% He/2% oxygen (O2) carrier gas. These temperatures differ from those used previously because new hardware used for the IMPROVE thermal/optical reflectance (IMPROVE_TOR) protocol better represents the sample temperature than did the old hardware. A newly developed temperature calibration method demonstrates that these temperatures better represent sample temperatures in the older units used to quantify IMPROVE carbon fractions from 1987 through 2004. Only the thermal fractions are affected by changes in temperature. The OC and EC by TOR are insensitive to the change in temperature protocol, and therefore the long-term consistency of the IMPROVE database is conserved. A method to detect small quantities of O2 in the pure He carrier gas shows that O2 levels above 100 ppmv also affect the comparability of thermal carbon fractions but have little effect on the IMPROVE_TOR split between OC and EC.


Lack of regulatory changes of µ-opioid receptors by 14-methoxymetopon treatment in rat brain. Further evidence for functional selectivity.
Here we have studied regulatory changes of µ-opioid receptors accompanying in vivo 14-methoxymetopon treatments of rats. Previously, this ligand has been shown to be an extremely potent, centrally acting µ-opioid specific analgesic with low physical dependence, tolerance, respiratory depression, constipation and other side effects. Our work shows that it is a highly potent full agonist of µ-opioid receptor coupled G-protein signaling in vitro, alike the well-known opioid agonist, etorphine. However, unlike etorphine, which desensitized and down-regulated the endogenous µ-opioid receptors, 14-methoxymetopon, given to rats intraperitoneally (i.p.) either acutely or chronically, did not change the binding or G-protein signaling of µ-opioid receptors in rat brain subcellular membranes. Thereby, these data provide further evidence that there is no direct relationship between the efficacy of the ligand in signaling and its ability to internalize or desensitize the receptor. Viewed collectively with published work, it is discussed that µ-opioid receptors display functional selectivity, also called 'biased agonism'. This concept implies that each ligand may induce unique, ligand-specific receptor conformation that can result in distinct agonist- directed trafficking and/or signal transduction pathways associated with the receptor. Ligand-specific signaling may open up new directions for designing potent analgesics that do not interact with unwanted signaling pathways, which mediate undesired side-effects, such as tolerance and dependence.


Presidential perspectives: SOHN 1976-2001.
Each issue of ORL-Head and Neck Nursing includes "Presidential Perspectives", a feature that enables the current President of SOHN to share her point of view on a topic related to organizational activities or current issues in nursing practice. In celebration of SOHN's 25th anniversary, we asked each former president to recall and summarize major accomplishments during her term of office and to share her perspectives on the climate of nursing during that period of time. In addition to this feature, symbolic presidential quotes appear throughout this issue. Enjoy this walk through SOHN's history.


A sequence-based map of the nine genes of the human interleukin-1 cluster.
Six novel genes encoding proteins with the interleukin (IL)-1 fold have been identified recently. The classical family members are involved in inflammatory signaling. Previous work has placed the novel genes close to or within the same cluster as IL1A, IL1B, and IL1RN, which occupy an approximately 400-kb interval on chromosome 2. We have combined the incomplete public database sequence with our own sequence to generate a reference sequence and map that encompass all of the novel genes, allowing determination of the gene structures, precise localization of exons, and determination of distances between conventional SNP and microsatellite markers. Gene order from centromere to telomere is IL1A-IL1B-IL1F7-IL1F9-IL1F6-IL1F8-IL1F5-IL1F10-IL1RN, of which only IL1A, IL1B, and IL1F8 are transcribed towards the centromere. The gene order relates to the evolutionary relationship between the genes. Key features of exon boundaries are conserved. There is no evidence for other IL-1 family members within the cluster.


[Health care access of Sub-Saharan African migrants living with chronic hepatitis B].
Objective: The objective of this study was to analyse health care access of Sub-Saharan African migrants living with chronic hepatitis B (CHB) in France. Methods: The ANRS-Parcours survey was a life-event survey conducted in 2012-2013 among Sub-Saharan African migrants recruited by health care facilities managing CHB in the Paris region. Data were collected by face-to-face interview using a biographical grid and a standardized questionnaire. Results: 96.4% of the 619 participants basic health insurance coverage with CMU universal health insurance coverage in 18.6% of cases and AME state medical assistance in 23.4% of cases. One-third of basic health insurance beneficiaries did not have any complementary health insurance and 75.7% had long-term disease status. The median time to acquisition of health insurance cover after arrival in France was one year. 22.0% of participants reported delaying health care for financial reasons since their arrival in France and 9.7% reported being refused health care usually due to refusal of CMU or AME. Health care access was effective within one year of the diagnosis. Delayed health care access was more common among people without health insurance coverage in the year of diagnosis. Patients lost to follow-up for more than 12 months were rare. Conclusion: Sub-Saharan African migrants living with chronic hepatitis B rapidly access health insurance coverage and health care. However, barriers to health care access persist for some people, essentially due to absent or incomplete health insurance cover and refusal of care for AME or CMU beneficiaries.


[Childhood periodic syndromes and their long-term development].
The long term development of periodic syndromes among children is little known. Our research has revealed that about one third of periodic headaches, two thirds of cyclic vomiting and half the cases of recurring abdominal pain disappear either before puberty or during adolescence. Other Authors have shown that this also happens in most cases of early-onset vertigo. The remaining headache cases develop into migraines in adults. When there is persistent cyclic vomiting, the collateral neurologic phenomena (headaches, vertigo, pallor, hypotonia, drowsiness) become more intense. This also happens in some cases of abdominal pain and paroxysmal vertigo which start in late childhood. Other sufferers from acute abdominal pain develop ulcers, gastroduodenitis and colitis as adults. Altogether, some infantile periodic syndromes (in particular the multi-symptomatic ones) have a common outcome, i.e. develop into more or less typical migraine syndromes. In these cases one can presume a common pathogenetic mechanism. In those cases where the outcome is favorable the pathogenesis may be different. These cases may often be spotted in early childhood on account of the monosymptomatic nature of the complaint or the absence of collateral neurologic symptoms as well as of the infrequency of critical episodes.


Expression stability of candidate RT-qPCR housekeeping genes in Spodoptera frugiperda (Lepidoptera: Noctuidae).
Reverse-transcription quantitative polymerase chain reaction (RT-qPCR) is commonly used to quantify gene expression. For normalization, the expression of each gene is compared with a reference "housekeeping" gene that is stably expressed under relevant stress. Unfortunately, there have been no reports on the stability of such reference genes under various treatments of the Spodoptera frugiperda. In this study, we used five tools (RefFinder, GeNorm, NormFinder, BestKeeper, and ΔCt methods) to evaluate the stability of 12 candidate reference genes (RPS18, β-tubulin, GAPDH, RPS7, RPS15, RPL7, RPL32, Actin-5C, EF1-α, EF1-γ, RPL27, and ACE) in different instars, tissues, and treatments (high and low temperature, UV-A, and emamectin benzoate). Several ribosomal proteins (RPS7, RPS15, RPL32, RPS18, and RPL7), GAPDH, Actin-5C, and β-tubulin, were relatively stable, suggesting that they are ideal housekeeping genes for various treatments. ACE was extremely unstable under various experimental treatments, rendering it unsuitable as an internal reference. This study identified the reference housekeeping genes stably expressed by S. frugiperda under different treatments, thus setting a foundation for further exploration of the physiological and biochemical mechanisms.


Non-Poissonian photon statistics from macroscopic photon cutting materials.
In optical materials energy is usually extracted only from the lowest excited state, resulting in fundamental energy-efficiency limits such as the Shockley-Queisser limit for single-junction solar cells. Photon-cutting materials provide a way around such limits by absorbing high-energy photons and 'cutting' them into multiple low-energy excitations that can subsequently be extracted. The occurrence of photon cutting or quantum cutting has been demonstrated in a variety of materials, including semiconductor quantum dots, lanthanides and organic dyes. Here we show that photon cutting results in bunched photon emission on the timescale of the excited-state lifetime, even when observing a macroscopic number of optical centres. Our theoretical derivation matches well with experimental data on NaLaF4:Pr3+, a material that can cut deep-ultraviolet photons into two visible photons. This signature of photon cutting can be used to identify and characterize new photon-cutting materials unambiguously.


Combination chemotherapy in disseminated melanoma and other solid tumors in adults.
Eighty-eight patients with disseminated melanoma and 22 patients with various other solid tumors were treated with combination chemotherapy consisting of DTIC, at a fixed dose, with either adriamycin, CCNU, or hydroxyurea, at several dosages. An objective response rate of 20% was observed in 84 evaluable melanoma patients. The addition of the other agents to DTIC did not provide enhanced antitumor activity. Combination chemotherapy increased toxicity. Encouraging objective responses were observed in patients with synovial sarcoma (4/7) and teratocarcinoma of the testis (1/1) treated with the combination of adriamycin and DTIC.


Infective endocarditis due to Streptococci and Enterococci: A 3-year retrospective study.
Infective endocarditis (IE) is an infection of the heart valves with an aggregation of bacteria in a fibrin plaque called vegetation. This is a retrospective study of all infective endocarditis cases due to alpha haemolytic streptococci and enterococci. All cases of infective endocarditis cases due to alpha haemolytic streptococci and enterococci in a period of three years from 1st January 2010 to 31st December 2012 were included. Isolation of the same organism from more than one set of blood cultures was taken as a confirmed case of infective endocarditis. Clinical and serological parameters were recorded using a proforma. Native valve endocarditis was more common with only five prosthetic valves being involved. Out of 89 clinically suspected cases of IE in the three years from Jan 2010 to Dec 2012, for which blood was sent for culture, 63(70.78%) samples were positive by culture. Of these, 42/63(66.66%) were due to alpha-lytic Streptococci, enterococci and rare gram positive cocci. The rare ones included Enterococcus gallinarum, abiotropha defective, Vagococcus fluvialis and Nutritionally Variant Streptococci(NVS). High level Aminoglycoside resistance(HLAR) was also encountered. The varied and important features of these isolates are discussed. Complications and treatment are described. From a clinical microbiology point of view, the major challenge faced by the microbiologist in diagnosis of IE is proper aseptic collection of sample before starting antibiotics with a need for multiple samples to detect and also to prove the causative organism. Sensitivity reporting can be a difficult task in the context of NVS, HLAR and gram positives that are slow growing. Congestive failure and embolisation occurs even when the antibiotic treatment is successful.When patients go in for complications, it is very rarely due to wrong antibiotics.


[Occurrence of swimmer's itch in Tyrol].
Cercariae from trematodes of birds are capable of penetrating human skin causing a dermatitis, called swimmer's itch. In 1992, after a hot dry summer there was a marked increase in the incidence of cercarial dermatitis in Austria. Although the increased incidence of this complaint can be quite worrisome for the population, the occurrence of swimmer's itch can, in fact, generally be seen as harmless. Cercarial dermatitis responds well to treatment with topical antihistamines or cortisone; even without medication the skin rash heals within 2-3 weeks. The effectiveness of various preventive measures (such as protective sun cream or patting the skin dry) is controversial. The use of molluscicides is definitely contraindicated due to the inoffensive nature of this dermatitis. While it is usually easy to recognize swimmer's itch when there is an increased incidence, the diagnosis is often missed when it occurs sporadically, due to its unspecific characteristics.


15-year history of spontaneous appendico-vesical fistula (case report).
Appendicovesical (AVF) fistula is rare complication in the modern era. Only a few cases of AVF were described in the literature of the last decade. AVF is meanly associated with a history of appendicitis. The guiding symptoms are coprosuria and pneumaturia, with recurrent infection of the urinary tract. The accurate pre-operative diagnosis is difficult to make. It usually took at least one year from the onset of symptom to confirm diagnosis. It has been reported a few cases of 15 year history of undiagnosed AVF. We represent a case of EVF, spontaneously developed after treated acute appendicular colic presenting an unusual long - 15 years undiagnosed history, without presenting of typical symptoms. The analyses of disease history after cystoscopy lead to correct pre-operative diagnosis. AVF can develop as a complication not only after untreated appendicitis, but also after "successfully" treated with antibiotics appendicular colic may indicate the presence of an AVF and needs to assessing patient's history and applying cystoscopy and modern examination methods in complex diagnosis issues.


Protein kinase A coordinately regulates both basal expression and cyclic AMP-mediated induction of three catecholamine-synthesizing enzyme genes.
Studies have shown that the cyclic AMP-regulated pathway is involved in the activation of tyrosine hydroxylase (TH) and in the induction of gene expression of the three catecholamine-synthesizing enzymes, TH, dopamine beta-hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT). In the present study we investigated further the role of protein kinase A (PKA) in the regulation of both basal and cyclic AMP-inducible transcription of the three catecholamine-synthesizing enzymes in primary cultured bovine chromaffin cells by using the PKA-specific inhibitor N-[2-(p-bromocinnamylamine)ethyl]-5-isoquinolinesulfonamide (H-89). In the presence of 40 microM H-89, mRNA levels of TH, DBH, and PNMT were reduced to 17 +/- 8, 19 +/- 8, and 14 +/- 2% of the untreated control, respectively, in 24 h, and intracellular norepinephrine and epinephrine levels were decreased to 20 and 34%, respectively, in 72 h. At 20 microM, although the basal enzyme gene expression levels were little affected, their induction by forskolin was abolished and norepinephrine and epinephrine levels fell to 55 and 74%. This reduction in catecholamines at 20 microM was probably due to changes in the phosphorylation state of TH, as its enzymatic activity was found to be decreased to 66 and 69% in 48 and 72 h, respectively. Thus, PKA activity in bovine adrenal medullary cells coordinately regulates both basal and cyclic AMP-inducible gene expression of specific catecholamine-synthesizing enzymes, resulting in changes in intracellular catecholamine levels available for consequent neurohormonal activities.


The Motherhood Penalty in Context: Assessing Discrimination in a Polarized Labor Market.
Prior research provides important insights into employer discrimination against mothers but has focused exclusively on college-educated mothers in professional and managerial occupations. As a result, we lack evidence about whether less-educated mothers navigating the low-wage labor market experience similar disadvantages and whether the mechanisms underlying discrimination vary across contexts. These gaps are important because more- and less-educated mothers increasingly possess distinct resources and face unique demands both at home and at work, which may impact employer perceptions of conflicts between motherhood and job performance. This study reports results from an original field experiment in which 2,210 fictitious applications were submitted to low-wage service and professional/managerial job openings across six U.S. cities, experimentally manipulating signals of motherhood status. Findings provide causal evidence that employers in both contexts discriminate against mothers relative to equally qualified childless women. However, within labor market segments, distinct job demands listed in job advertisements are associated with stronger discrimination: time pressure, collaboration, and travel in professional/managerial jobs and schedule instability in low-wage service jobs. These findings have important implications for our understanding of the mechanisms underlying mothers' disadvantages in an increasingly polarized labor market.


Primary Aortoenteric Fistula in a Patient With Prior Abdominopelvic Surgery and Opioid-Induced Constipation.
Aortoenteric fistulas (AEF) represent a rare, life-threatening cause of gastrointestinal bleeding with an incidence of 0.007 per million. Iliac artery-enteric fistulas represent an even more uncommon variant of AEFs. Prompt diagnosis and intervention are required to prevent associated morbidity and mortality. Herein, we report a rare case of iliac-enteric fistula in a patient with hematochezia.


Development and Optimization of an UPLC-QTOF-MS/MS Method Based on an In-Source Collision Induced Dissociation Approach for Comprehensive Discrimination of Chlorogenic Acids Isomers from Momordica Plant Species.
Chlorogenic acids (CGA) have been profiled in the leaves of Momordica balsamina, Momordica charantia, and Momordica foetida. All three species were found to contain the trans and cis isomers of 4-acyl para-coumaroylquinic acid (pCoQA), caffeoylquinic acid (CQA), and feruloylquinic acid (FQA). To the best of our knowledge, this is the first report of pCoQA and FQA and their cis isomers in these Momordica species. These profiles were obtained by a newly developed UPLC-qTOF-MS method based on the in-source collision induced dissociation (ISCID) method optimized to mimic the MS(2) and MS(3) fragmentation of an ion trap-based MS. The presence of the cis isomers is believed to be due to high UV exposure of these plants. Furthermore, the absence of the 3-acyl and 5-acyl CGA molecules points to a metabolic mark that is unusual and represents a very interesting biochemical phenotype of these species. Our optimized ISCID method was also shown to be able to distinguish between the geometrical isomers of all three forms of CGA, a phenomenon previously deemed impossible with other common mass spectrometry systems used for CGA analyses.


Threshold dynamics of an HIV-1 model with both viral and cellular infections, cell-mediated and humoral immune responses.
Human specific immunity consists of two branches: humoral immunity and cellular immunity. To protect us from pathogens, cell-mediated and humoral immune responses work together to provide the strongest degree of efficacy. In this paper, we propose an HIV-1model with cell-mediated and humoral immune responses, in which both virus-to-cell infection and cell-to-cell transmission are considered. Five reproduction ratios, namely, immunity-inactivated reproduction ratio, cell-mediated immunity-activated reproduction ratio, humoral immunity-activated reproduction ratio, cell-mediated immunity-competed reproduction ratio and humoral immunity-competed reproduction ratio, are calculated and verified to be sharp thresholds determining the local and global properties of the virus model. Numerical simulations are carried out to illustrate the corresponding theoretical results and reveal the effects of some key parameters on viral dynamics.


Reproductive features of the Russian vole in laboratory breeding.
Reproductive features of newly bred Russian voles (Microtus rossiaemeridionalis) as a laboratory animal were studied. This species is a copulatory ovulator, and most couples copulated 6 to 16 h after pairing. The gestation period varied from 18 to 22 days (mean +/- SD: 20.6 +/- 0.9, n = 72), and the average litter size was 4.6 +/- 1.9 (n = 125). Compared with the litter size at the first parturition (3.6 +/- 1.6, n = 72), the litter size in the subsequent parturitions increased to 5.9 +/- 1.4 (n = 53). The animals exhibited postpartum estrus, and repeated pregnancy accompanied with suckling pups and parturition continuously in the laboratory condition unlike other vole species. In view of their complex stomach and good proliferation, the Russian voles were evaluated as a good laboratory animal, especially as a model animal for ruminant studies.


Changes in alcohol use among first year university students in Mexico.
Alcohol use and misuse is widespread among university students in many countries. Specific cultural factors may impact alcohol use after entering university. This paper considers changes in alcohol use among first year university students in Mexico. A qualitative study using ethnographic interviews with 57 female and 60 male student drinkers in Mexico City from March to June 2011. Each interview was evaluated by a set of thematic codes developed inductively from the interviews. Findings from excessive, heavy, regular, occasional drinkers, abstainers, and non-drinkers were analyzed to explore whether or not linkages existed between and/or among particular themes. Students reported factors associated with changes in role and status, friendships, and increased autonomy as reasons for increasing or decreasing their alcohol use after entering university. CONCLUSIONS/IMPORTANCE: Understanding the influence of Mexican cultural norms on alcohol use among Mexican and Mexican Americans can be helpful in informing studies and preventive efforts among both Mexican and Mexican American young people.


Effect of emersion/immersion cycles on the elemental and isotopic compositions of the organic matter from surface sediments of an intertidal mud bank (French Guiana): a preliminary study.
In various marine environments, the combination of elemental ratios and stable isotopic compositions is usually used to trace the sources of organic matter (OM) in sediments. However, in intertidal areas, the sediments might be temporarily exposed to air during a more or less prolonged duration and the impact of this exposure on the latter parameter is unknown. The spatial variations of atomic Total Organic Carbon (TOC) and Total Nitrogen (TN) ratios, and δ(13)C and δ(15)N values, were measured on surface sediments of French Guiana, at the beginning and the end of five consecutive days of emersion during equinoctial tides, as well as at the beginning of a new emersion phase after returning to a normal tidal cycle. The concentrations of chlorophyll a and phaeopigments in sediments were also measured, in order to estimate the influence of microphytobenthos (MPB), growing at surface sediments, on these geochemical parameters. The results showed that the emersion/immersion cycles influenced the development of MPB at the surface sediments, which, in turn, significantly controlled the spatio-temporal changes in the atomic elemental ratios and the δ(13)C values. This variability seemed not to be significantly altered by OM degradation. On the contrary, sediments were always (15) N-enriched compared with OM sources, indicating that OM diagenetic processes mainly controlled their spatio-temporal fluctuations. The [TOC/TN]atomic ratios and the δ(13)C values, indicating the primary signal of OM sources, represented the most reliable geochemical proxies for calculating the relative contribution of OM sources to sediments in environments characterized by variable air exposure duration. The use of δ(15)N values in such environments is limited by OM degradation processes but their variation might enable the nature and the degree of these processes to be identified.


The effect of retinoic acid on growth and proto-oncogene expression in hamster tracheal epithelial cells.
Retinoic acid (RA) has been shown to be required for the maintenance of epithelial differentiation. Vitamin A deficiency in hamsters induces the tracheal epithelial cells to undergo squamous metaplasia. Reversing the vitamin deficiency restores the tracheal epithelial cells to their normal morphology and function. Using a hamster tracheal epithelial (HTE) cell culture system which undergoes differentiation to predominantly secretory cells in vitro, we found that RA can convert flat, squamous-like cells to compact, cuboidal-like cells, and that it stimulated cell proliferation. The mitogenic response to RA was maximal at 10(-7) M and required at least 48 h of treatment to observe the effect. RNA levels of growth-related genes during the growth and differentiation phases of primary HTE cultures were examined by Northern analysis. RA maintained a high level of c-myc RNA expression in preconfluent cultures, whereas untreated cells had low amounts of c-myc RNA. Expression of RNA for the replication-dependent histone 3.2 followed a similar pattern, i.e., its level was high in retinoid-treated versus control preconfluent cultures. In confluent (fully differentiated) HTE cell cultures, both retinoid-treated and control cells had low RNA levels of c-myc and histone 3.2. c-fos RNA levels were undetectable in either control or treated cells at any stage during primary culture. The RNA level of c-Ha-ras was very low in both control and treated cultures and did not vary with the state of growth or differentiation, except that when RA-treated cultures reached confluence, no c-Ha-ras RNA was detected.(ABSTRACT TRUNCATED AT 250 WORDS)


Clinical outcomes and progression rate of tricuspid regurgitation in patients with rheumatic mitral valve disease.
A substantial proportion of patients with rheumatic heart disease (RHD) have tricuspid regurgitation (TR). This study aimed to identify the impact of functional TR on clinical outcomes and predictors of progression in a large population of patients with RHD. A total of 645 patients with RHD were enrolled, mean age of 47±12 years, 85% female. Functional TR was graded as absent, mild, moderate or severe. TR progression was defined either as worsening of TR degree from baseline to the last follow-up echocardiogram or severe TR at baseline that required surgery or died. Incidence of TR progression was estimated accounting for competing risks. Functional TR was absent in 3.4%, mild in 83.7%, moderate in 8.5% and severe in 4.3%. Moderate and severe functional TR was associated with adverse outcome (HR 1.91 (95% CI 1.15 to 3.2) for moderate, and 2.30 (95% CI 1.28 to 4.13) for severe TR, after adjustment for other prognostic variables. Event-free survival rate at 3-year follow-up was 91%, 72% and 62% in patients with no or mild, moderate and severe TR, respectively. During mean follow-up of 4.1 years, TR progression occurred in 83 patients (13%) with an overall incidence of 3.7 events (95% CI 2.9 to 4.5) per 100 patient-years. In the Cox model, age (HR 1.71, 95% CI 1.34 to 2.17), New York Heart Association functional class III/IV (HR 2.57, 95% CI 1.54 to 4.30), right atrial area (HR 1.52, 95% CI 1.10 to 2.10) and right ventricular (RV) dysfunction (HR 2.02, 95% CI 1.07 to 3.84) were predictors of TR progression. By considering competing risk, the effect of RV dysfunction on TR progression risk was attenuated. In patients with RHD, functional TR was frequent and associated with adverse outcomes. TR may progress over time, mainly related to right-sided cardiac chambers remodelling.


Implementation and Operational Analysis of an Interactive Intensive Care Unit within a Smart Health Context.
In the context of hospital management and operation, Intensive Care Units (ICU) are one of the most challenging in terms of time responsiveness and criticality, in which adequate resource management and signal processing play a key role in overall system performance. In this work, a context aware Intensive Care Unit is implemented and analyzed to provide scalable signal acquisition capabilities, as well as to provide tracking and access control. Wireless channel analysis is performed by means of hybrid optimized 3D Ray Launching deterministic simulation to assess potential interference impact as well as to provide required coverage/capacity thresholds for employed transceivers. Wireless system operation within the ICU scenario, considering conventional transceiver operation, is feasible in terms of quality of service for the complete scenario. Extensive measurements of overall interference levels have also been carried out, enabling subsequent adequate coverage/capacity estimations, for a set of Zigbee based nodes. Real system operation has been tested, with ad-hoc designed Zigbee wireless motes, employing lightweight communication protocols to minimize energy and bandwidth usage. An ICU information gathering application and software architecture for Visitor Access Control has been implemented, providing monitoring of the Boxes external doors and the identification of visitors via a RFID system. The results enable a solution to provide ICU access control and tracking capabilities previously not exploited, providing a step forward in the implementation of a Smart Health framework.


Pulmonary, pleural and thoracic changes complicating chemotherapy.
Chronic respiratory failure slowly developed in two pediatric patients following long-term cyclophosphamide therapy for lymphocytic malignancy. One patient survived 12 years after acute lymphocytic leukemia was diagnosed but died of respiratory failure at age 16 still in initial remission; the other, a 12-year survivor of Hodgkin disease, has progressive deterioration of pulmonary function. Each patient received cyclophosphamide (less than 70 g) during the initial years of the disease. Autopsy of the first patient and lung biopsy in the second revealed severe pulmonary fibrosis. There was loss of compliance and a dramatic change in the shape of the thorax which produced a markedly reduced anteroposterior diameter in both patients, and recurrent pneumothoraces in one.


Molecular imprinting of enzymes with water-insoluble ligands for nonaqueous biocatalysis.
Attaining higher levels of catalytic activity of enzymes in organic solvents is one of the major challenges in nonaqueous enzymology. One of the most successful strategies for enhancing enzyme activity in organic solvents involves tuning the enzyme active site by molecular imprinting with substrates or their analogues. Unfortunately, numerous imprinters of potential importance are poorly soluble in water, which significantly limits the utility of this method. In the present study, we have developed strategies that overcome this limitation of the molecular-imprinting technique and that thus expand its applicability beyond water-soluble ligands. The solubility problem can be addressed either by converting the ligands into a water-soluble form or by adding relatively high concentrations of organic cosolvents, such as tert-butyl alcohol and 1,4-dioxane, to increase their solubility in the lyophilization medium. We have succeeded in applying both of these strategies to produce imprinted thermolysin, subtilisin, and lipase TL possessing up to 26-fold higher catalytic activity in the acylation of paclitaxel and 17beta-estradiol compared to nonimprinted enzymes. Furthermore, we have demonstrated for the first time that molecular imprinting and salt activation, applied in combination, produce a strong additive activation effect (up to 110-fold), suggesting different mechanisms of action involved in these enzyme activation techniques.