Endoscopic enucleation of upper-GI submucosal tumors by using an insulated-tip electrosurgical knife.
Submucosal tumors often are found incidentally at upper endoscopy. Although the majority of the ones less than 5 cm in size are benign, periodic monitoring for incremental changes in size, which can be stressful and bothersome to patients, is essential. If relatively easy and safe, an endoscopic method of removal would be optimal treatment. Conventional endoscopic enucleation technically is difficult and often leads to serious complications, such as bleeding and perforation. A novel method for endoscopic enucleation of submucosal tumors with an insulated-tip electrosurgical knife is reported. En bloc enucleation was attempted by using an insulated-tip electrosurgical knife in 15 patients (10 men, 5 women; median age 48 years) with submucosal tumors of the esophagus (5) or stomach (5 cardia/fundus, 4 body, one antrum). EUS was performed to determine the layer of origin and the exact size of the submucosal tumor. Tumors arose in the muscularis propria in 11 cases, submucosa in two, and muscularis mucosa in one. Enucleation was relatively easy and successful in 14 cases. In one case, however, piecemeal resection was unavoidable because of fibrotic adhesions with the surrounding tissue; this tumor later was confirmed to be a glomus tumor. Median procedure time was 35 minutes (8-180 minutes) and median size of the submucosal tumors was 2x1.7 cm. The largest lesion, located in the esophagus, measured 6x3 cm. Histopathologic diagnoses included leiomyoma (9), GI stromal tumor (4), stromal tumor of unknown malignant potential (1), and glomus tumor (1). A small perforation occurred in one patient with a 2.5-cm tumor in the anterior wall of proximal gastric body but was managed successfully by endoscopic clip application. Follow-up endoscopy at 2 months in this patient revealed no tumor recurrence and complete healing of the treatment-related ulcer. En bloc endoscopic enucleation of submucosal tumors by using an insulated-tip electrosurgical knife appears to be safer, easier, and less time consuming compared with previously described methods. However, further investigation and comparative studies are required to confirm the safety and efficacy of this method.


Simulation of oligopeptide dynamics and folding. The use of NMR chemical shifts to analyse the MD trajectories.
In this paper, a simulation of the folding process, based on a random perturbations of the phi, psi, chi1 dihedral angles, is proposed to approach the formation at the atom level of both principal elements of protein secondary structure, the alpha-helix and the beta-hairpin structures. Expecting to understand what may happen in solution during the formation of such structures, the behaviour of large sets of random conformations that are generated for small oligopeptides was analysed. Different factors that may influence the folding (as conformational propensity, hydrophobic interactions and side-chain mobility) were investigated. The difference between the corresponding theoretical folding and the real conformational diversity that is observed in solution is appraised by a comparison between the calculated and observed NMR secondary chemical shifts. From this study it appears that hydrophobic interactions and mobility represent the principal factors that initiate folding and determine the observed hydrogen-bond pattern, which subsequently allows packing between the peptide side chains.


Loss of resealing ability in erythrocyte membranes. Effect of divalent cations and spectrin release.
Washed human erythrocyte membranes can recover impermeability to macromolecules upon warming in solutions of sufficient ionic strength. This ability is rapidly lost from most ghost preparations in dilute salt solution at temperatures of 15 degrees C of higher. Divalent cations both reseal ghosts in the absence of high ionic strength and prevent loss of resealing ability. The effective concentrations are 40 micron for Ca2+ and 200 micron for Mg2+. The loss of resealing ability is associated with the release of spectrin polypeptides from the inner surface of the membrane. In ghost preparations that have not become irreversibly leaky, or in the presence of Ca2+, loss of spectrin does not occur. These results suggest that an intact spectrin netwoek is required for resealing to macromolecules, and divalent cations stabilize this network. In light of this information, the effect of temperature on resealing kinetics is described.


Determining specified intraocular lens powers when silicone oil is to be used in the vitreous chamber.
To apply a theoretical approach to determining how specified intraocular lens (IOL) powers should change when vitreous oil substitution is combined with IOL implantation. University laboratory, private Ophthalmological practice. Theoretical raytracing. Raytracing was done backwards from the retina with equi-convex 20 diopters (D) and 25 D IOLs, of refractive index 1.5332, to the object side of the anterior IOL surface. The 1.336 vitreous index was replaced with a high index 1.405 silicone oil. Raytracing was repeated with increase in specified power, that power as if 1.336 index was still surrounding the IOL, so that the object reduced vergence on the anterior side of the lens matched that of the original IOL power. This was done for a range of lens shapes from plano-convex (front surface flat), through equi-convex, to plano-convex (back surface flat), and for a range of axial lengths. The true power, the power with 1.336 index on the object side and silicone oil on the image side, was also determined. Replacing vitreous by silicone oil increases the necessary specified IOL power. This increase varies from approximately 14% for flat back surfaces, to 40% for equi-convex lenses, to 80% for flat front surface IOLs. True powers increase by about 15% across the range of IOL shapes. In terms of percentages, effects of changing the original IOL power and the axial length are small. When silicone oil is to remain in an eye after cataract surgery, biconvex IOLs require much higher specified powers than convex-plano IOLs.


Method of expired gas collection during cardiopulmonary exercise testing does not affect respiratory gas exchange measurements in patients with heart failure.
Cardiopulmonary exercise testing is commonly used to assess patients with heart failure. Analysis of expired gases during exercise requires the use of either a facemask or mouthpiece with nose clip. The authors sought to determine if the method of expired gas collection during exercise testing (facemask or mouthpiece) influences gas exchange measurements in patients with heart failure. Nine patients with heart failure performed two maximal treadmill tests. Expired gases were collected with a facemask in one exercise test and a mouthpiece in the other. There were no significant differences in exercise test duration, peak oxygen uptake, heart rate, respiratory exchange ratio, or perceived exertion during maximal exercise performed with the facemask when compared to the mouthpiece. Test subjects reported that the overall comfort of the facemask was significantly greater than that of the mouthpiece (P < .02). The method of expired gas collection during cardiopulmonary exercise testing does not significantly affect measures of gas exchange or exercise performance in patients with heart failure. Heart failure patients find the overall comfort of the facemask superior to that of the mouthpiece, but this comfort preference does not affect exercise performance.


[Sudden unexpected death of cardiac origin in the 6 to 18 years population. Pathologic data. Role of sports? How can we prevent it?].
There is only a few data on sudden unexpected death (SUD) in the pediatric population, as well as the role of sport. Between 1980 and 2003, 2220 autopsies were performed at the Lyon's forensic institute for SUD (all ages) as defined by world health organization. Fifty-seven cases of SUD of cardiac origin concerned 6 to 18-year-old children. Hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy remained the main causes of SUD. Mitral valve prolapse were frequently observed and for the most part of the cases associated with other diseases. Twenty-four were observed during physical activity. Our study confirms the low incidence of SUD and its male predominance in the pediatric population (47 males, 10 females). It seems that physical activity is not the decisive factor for SUD. The authors emphasized the necessity to get a rapid access to cardiac resuscitation devices, as well as the formation of collaborators. Some preventive measures could be done.


Sonography of tuberculous kidney.
Sonography of 8 patients with renal tuberculosis is reported and collated with 3 additional cases reported in the literature. The patterns of hydronephrosis versus granuloma formation are presented and the differential diagnoses at sonography reviewed.


Proprotein convertase subtilisin/kexin type 9 potentially influences cholesterol uptake in macrophages and reverse cholesterol transport.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of low-density lipoprotein receptor (LDLRs) molecules expressed on the cell surface. Gene inactivation of PCSK9 reduces the areas of atherosclerotic lesions in mice, and the effect is mainly dependent on LDLRs. Furthermore, a positive relationship between PCSK9 and cholesterol accumulation in the wall of the aorta has been established. However, the mechanism remains unknown. As PCSK9 is mainly expressed in atherosclerotic plaque and in the liver, we hypothesize that PCSK9 might increase oxidized LDL uptake and impair macrophage-mediated reverse cholesterol transport, contributing to the development of atherosclerosis.


Cogs in the endless machine: lakes, climate change and nutrient cycles: a review.
Lakes have, rather grandly, been described as sentinels, integrators and regulators of climate change (Williamson et al., Limnol. Oceanogr. 2009; 54: 2273-82). Lakes are also part of the continuum of the water cycle, cogs in a machine that processes water and elements dissolved and suspended in myriad forms. Assessing the changes in the functioning of the cogs and the machine with respect to these substances as climate changes is clearly important, but difficult. Many other human-induced influences, not least eutrophication, that impact on catchment areas and consequently on lakes, have generally complicated the recording of recent change in sediment records and modern sets of data. The least confounded evidence comes from remote lakes in mountain and polar regions and suggests effects of warming that include mobilisation of ions and increased amounts of phosphorus. A cottage industry has arisen in deduction and prediction of the future effects of climate change on lakes, but the results are very general and precision is marred not only by confounding influences but by the complexity of the lake system and the infinite variety of possible future scenarios. A common conclusion, however, is that warming will increase the intensity of symptoms of eutrophication. Direct experimentation, though expensive and still unusual and confined to shallow lake and wetland systems is perhaps the most reliable approach. Results suggest increased symptoms of eutrophication, and changes in ecosystem structure, but in some respects are different from those deduced from comparisons along latitudinal gradients or by inference from knowledge of lake behaviour. Experiments have shown marked increases in community respiration compared with gross photosynthesis in mesocosm systems and it may be that the most significant churnings of these cogs in the earth-air-water machine will be in their influence on the carbon cycle, with possibly large positive feedback effects on warming.


Magnetoresistance reversals and anomalous Hall effect in Mn3SnC and effects of carbon deficiency.
The transport behavior of Mn3SnC and Mn3SnC0.8compounds was investigated. Positive magnetoresistance (MR) and an anomalous Hall effect (AHE) are observed for each compound near respective Curie temperature,TC. The positive MR is reversed during cooling fromTCbut is reentrant at low temperature. A 20% carbon deficiency of Mn3SnC0.8enlarges the positive MR atTCand shifts the temperatures for MR reversals. Ferromagnetic (FM) resonance measurements reveal that the MR reversals are related to the competition between FM and antiferromagnetic components of Mn atoms in each compound. A sign change of the Hall resistivity is observed during cooling of Mn3SnC but not for Mn3SnC0.8. A scaling analysis suggests that the AHE in each compound is mostly due to an intrinsic contribution and that the intrinsic contribution is decreased by the carbon deficiency in Mn3SnC0.8.


MicroRNA miR124 is required for the expression of homeostatic synaptic plasticity.
Homeostatic synaptic plasticity is a compensatory response to alterations in neuronal activity. Chronic deprivation of neuronal activity results in an increase in synaptic AMPA receptors (AMPARs) and postsynaptic currents. The biogenesis of GluA2-lacking, calcium-permeable AMPARs (CP-AMPARs) plays a crucial role in the homeostatic response; however, the mechanisms leading to CP-AMPAR formation remain unclear. Here we show that the microRNA, miR124, is required for the generation of CP-AMPARs and homeostatic plasticity. miR124 suppresses GluA2 expression via targeting its 3'-UTR, leading to the formation of CP-AMPARs. Blockade of miR124 function abolishes the homeostatic response, whereas miR124 overexpression leads to earlier induction of homeostatic plasticity. miR124 transcription is controlled by an inhibitory transcription factor EVI1, acting by association with the deacetylase HDAC1. Our data support a cellular cascade in which inactivity relieves EVI1/HDAC-mediated inhibition of miR124 gene transcription, resulting in enhanced miR124 expression, formation of CP-AMPARs and subsequent induction of homeostatic synaptic plasticity.


The Role of Implicit Bias in Surgical Resident Evaluations.
Implicit bias is a key factor preventing the advancement and retention of women and underrepresented minorities in academic surgery. We examined the role of implicit bias in the technical component of the residency performance evaluation. The Fundamentals of Laparoscopic Surgery (FLS) score, an objective measure of technical performance, was compared to the subjective technical skills (TS) score given by attending surgeons. FLS scores and the average TS scores from chief resident evaluations at a university program were analyzed from 2015 to 2019 (n = 29 residents; female 22%, underrepresented minorities 27%). The average TS score for each resident was calculated, scores dichotomized above and below the mean for the program and analyzed across gender and racial identity. There were no significant differences in FLS or TS scores between male and female trainees or racial identity. The Kappa correlation coefficient between the 2 dichotomized scores was significantly lower for female (-0.50) versus male (0.23) trainees (p < 0.01); it was not significantly different between racial groups (p = 0.34). There was statistically significant difference in agreement between the FLS and TS scores of individual female and male trainees, suggesting the presence of implicit bias in our pilot study. Further research with a larger sample size is warranted. To investigate the presence of implicit bias against women and underrepresented minorities in the technical component of the residency performance evaluation. We hypothesized that women and underrepresented racial minorities would have lower subjective technical skills (TS) scores as compared to their objective FLS scores, relative to the mean for the training program. FLS scores and the average TS scores from chief resident performance evaluations were analyzed from 2015-2019. Both FLS and the average TS scores were dichotomized above and below the mean for the program and analyzed across gender and racial identity. Research was approved by institutional IRB. This study was conducted at the University of Arizona General Surgery Residency Program at Banner University Medical Center in Tucson, Arizona. This is a tertiary care university training program. Educational records of graduated general surgery chief residents from 2015 to 2019 were accessed for the study. We analyzed 37 TS scores from attending performance evaluations and 29 FLS scores reported to the program during the study period (22% female, 27% underrepresented racial minorities). There were no significant differences in FLS or TS scores between male and female trainees or racial identity. The Kappa correlation coefficient between the 2 dichotomized scores was significantly lower for female (-0.50) versus male (0.23) trainees (p < 0.01); it was not significantly different between racial groups (p = 0.34). There was a statistically significant difference in agreement between the FLS and TS score of individual female and male trainees, suggesting the presence of implicit bias in this pilot study. Further research with a larger sample size is warranted.


The effects of generation on auditory implicit memory.
The generation manipulation produces the classic functional dissociation between explicit and implicit memory. This dissociation has been explained by the transfer-appropriate processing (TAP) framework, which emphasizes the overlap in cognitive processes operative at encoding and at retrieval. However, the vast majority of implicit memory studies have been conducted in the visual modality; in the auditory modality, the effects of generation have never been investigated. In four experiments, we examined the effects of generating from semantic and nonsemantic cues on auditory implicit tests. Generating from antonyms produced a reversed generation effect on priming in auditory perceptual identification and word stem completion, while producing the traditional positive effect on explicit recognition. Generating from definitions, as well as from rhymes, also produced a reversed generation effect on auditory priming. These results are critical for more fully characterizing auditory priming and are consistent with an extended TAP analysis.


Methylprednisolone therapy in multiple sclerosis: a profile of adverse effects.
A retrospective analysis of 350 treatment courses using high dose pulsed intravenous methylprednisolone for relapses of multiple sclerosis revealed a low number of adverse effects. This study confirms that high dose methylprednisolone is a safe therapeutic option in multiple sclerosis.


Magnetic resonance imaging/transrectal ultrasonography fusion targeted prostate biopsy finds more significant prostate cancer in biopsy-naïve Japanese men compared with the standard biopsy.
To assess the clinical benefits of magnetic resonance imaging/transrectal ultrasound fusion-targeted biopsy for biopsy-naïve Japanese men. Between February 2017 and August 2018, 131 biopsy-naïve men who underwent targeted biopsy together with 10-core systematic biopsy at Hiroshima University Hospital were retrospectively investigated. Multiparametric magnetic resonance imaging findings were reported based on Prostate Imaging Reporting and Data System version 2. The overall cancer detection rates per patient were 69.5% in systematic biopsy + targeted biopsy cores, 61.1% in systematic biopsy cores and 61.1% in targeted biopsy cores. The detection rates for clinically significant prostate cancer were 43.5% in targeted biopsy cores and 35.9% in systematic biopsy cores (P = 0.04), whereas the detection rates for clinically insignificant prostate cancer were 17.6% and 25.2% respectively (P = 0.04). Lesions in the peripheral zone were diagnosed more with clinically significant prostate cancer (54.8% vs 20.7%, P < 0.001) and International Society of Urological Pathology grade (3.2 vs 2.7, P = 0.02) than that in the inner gland. Just 4.2% (3/71) of Prostate Imaging Reporting and Data System category 2 and 3 lesions in the middle or base of the inner gland were found to have clinically significant prostate cancer. The cancer detection rate per core was 42.3% in targeted biopsy cores, whereas it was 17.9% in systematic biopsy cores (P < 0.001). Targeted biopsy is able to improve the diagnostic accuracy of biopsy in detection of clinically significant prostate cancer by reducing the number of clinically insignificant prostate cancer detections compared with 10-core systematic biopsy in biopsy-naïve Japanese men. In addition, the present findings suggest that patients with Prostate Imaging Reporting and Data System category 2 or 3 lesions at the middle or base of the inner gland might avoid biopsies.


Management of combined oral antithrombotic therapy by an antithrombotic stewardship program: A prospective study.
Antithrombotic management initiatives could prevent inappropriate prescribing and improve patient outcomes especially in patients on combined antithrombotic therapy. To investigate this, a multidisciplinary antithrombotic stewardship program (ASP) was implemented in our hospital. The primary aim of this study was to determine the efficacy of this ASP by assessing the number of patients on combined antithrombotic therapy for whom one or more interventions were needed. A prospective cohort study in a large teaching hospital was conducted. Hospitalized patients were included who received combined antithrombotic therapy in which an oral anticoagulant was combined with one (double therapy) or two (triple therapy) platelet aggregation inhibitors. The ASP proactively evaluated the appropriateness of this combined antithrombotic therapy. If needed, ASP improved the concerned therapy. Each improvement measurement recommended by the ASP was counted as one intervention. A total of 460 patients were included over a period of 12 months. Of these, 251 (54.6%) patients required at least one intervention from the ASP. The most common interventions were: (1) to define and document the maximum duration of the combined antithrombotic therapy needed instead of lifetime use of the combination (65.5%), (2) to discontinue antithrombotic therapy as the proper indication was lacking (19.4%), and (3) to adjust the dosage (8.1%). An intervention was needed in more than half of the patients on combined antithrombotic therapy. Implementation of a dedicated ASP evaluating combined antithrombotic therapy improves the use and safety of antithrombotic medication.


Fatigue during an episode of benign paroxysmal positional vertigo.
Fatigue is characterized by weariness unrelated to exertion levels. It has been reported in chronic neurological diseases such as multiple sclerosis, Parkinson disease and stroke. Patients with benign paroxysmal positional vertigo (BPPV) often complain about fatigue during a vertigo attack. No attention has been paid to this symptom in the literature so far. We were interested to evaluate the frequency and factors influencing fatigue in BPPV. Patients treated for idiopathic BPPV during the years 2011-2012 were prospectively evaluated for the presence of fatigue. During the first visit, patients were asked to complete two questionnaires based on their experience during the last week: the Fatigue severity scale and the Hospital anxiety and depression scale. Patients' demographic data and BPPV characteristics were registered. Among 172 patients treated for BPPV, 40 (23.2 %) reported fatigue. The mean fatigue score was 4.73 ± 1.98 indicating moderate fatigue. No correlation was found between fatigue and anxiety or fatigue and depression. Fatigue scores were inversely related to age (r = -0.36, p = 0.020) and were not dependent on the type of BPPV, its recurrence, background diseases, gender, duration of vertigo or the presence of autonomic symptoms. Moderate fatigue is quite common during an attack of BPPV. It seems to be a genuine symptom of the entity that might worsen patients' distress. For severe or persistent fatigue treatment with fatigue relieving drugs such as amantadine, methylphenidate or modafinil could be tried in the future.


Microarray analysis of early adipogenesis in C3H10T1/2 cells: cooperative inhibitory effects of growth factors and 2,3,7,8-tetrachlorodibenzo-p-dioxin.
C3H10T1/2 mouse embryo fibroblasts differentiate into adipocytes when stimulated by a standard hormonal mixture (IDMB). 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), via the aryl hydrocarbon receptor (AhR), inhibits induction of the key adipogenic gene peroxisome proliferator-activated receptor gamma (PPARgamma) and subsequent adipogenesis. This TCDD-mediated inhibition requires activation of the extracellular signal-regulated kinase (ERK) pathway, which can be accomplished by serum, epidermal growth factor (EGF), or fibroblast growth factor (FGF). In the absence of serum or growth factors, IDMB induced adipogenesis without mitosis. Microarray analysis identified 200 genes that exhibited expression changes of at least twofold after 24 h of IDMB treatment. This time precedes most PPARgamma stimulation but follows the period of TCDD/ERK cooperation and periods of increased cell contraction and DNA synthesis. Functionally related gene clusters include genes associated with cell structure, triglyceride and cholesterol metabolism, oxidative regulation, and secreted proteins. In the absence of growth factors TCDD inhibited 30% of these IDMB responses without inhibiting the process of differentiation. A combination of EGF and TCDD that blocks differentiation cooperatively blocked a further 44 IDMB-responsive genes, most of which have functional links to differentiation, including PPARgamma. Cell cycle regulators that are stimulated by EGF were substantially inhibited by IDMB but these responses were unaffected by TCDD. By contrast, TCDD and EGF cooperatively reversed IDMB-induced changes in cell adhesion complexes immediately prior to increases in PPARgamma1 expression. Changes in adhesion-linked signaling may play a key role in TCDD affects on differentiation.


Primary structure of chicken erythrocyte histone H2A.
The complete amino acid sequence (128 residues) of the chicken erythrocyte histone H2A was deduced from the data provided by structural studies on the tryptic peptides from the maleylated histone and of the peptides obtained by thermolysin digestion of the native protein. The sequence of chicken histone H2A differs from the calf homologous histone by the deletion of one residue of histidine at position 123 or 124 and three conservative substitutions: a residue of serine replaces a residue of threonine at position 16, a residue of aspartic acid replaces a residue of glutamic acid at position 121 and a residue of alanine replaces a residue of glycine at position 128.


A spin-label study of sciatic nerves from quaking, jimpy and trembler mice.
The spin labels, 5-nitroxide stearic acid and 16-nitroxide stearic acid were incorporated into whole sciatic nerves dissected from normal, quaking, jimpy and trembler mice. With 5-nitroxide stearic acid, we have studied the thermal variation of the maximal apparent coupling constant (T) between 0 degrees C and 50 degrees C. Within this range of temperatures, we obtained identical values of 2 T for nerves from normal and jimpy mice, whereas 2 T was smaller for nerves from quaking and trembler mice. With 16-nitroxide stearic acid, composite spectra were recorded, particularly in the high-field range. A line characteristic of myelin was clearly observed in the spectra of nerves from normal and jimpy mice; its intensity was somewhat less in nerves from quaking mice and much less in spectra from trembler mice. A shoulder in the principal highfield line of the spectrum is modified only with nerves from jimpy mice. The results agree well with those obtained by electron microscopy, which reveal normal myelination in nerves from jimpy mice, a slight modification of the myelin from those of quaking mice and a practically complete demyelination in peripheral nerves from trembler mice. However, the structure of the nerves of jimpy mice also seems to be modified at an, as yet, undetermined level.


Antioxidative system response of pedunculate oak (Quercus robur L.) seedlings to Cd exposure.
The use of pedunculate oak (Quercus robur L.), along with other tree species, for the afforestation of heavy metal contaminated lands is an attractive prospect. Little, however, is known of Q. robur tolerance and its antioxidative system response to heavy metal exposure. The main objective of the study was to determine the cadmium-induced changes in antioxidative system of pedunculate oak in an attempt to identify molecular mechanisms underlying Cd tolerance. This may be of great importance in respect of using Q. robur for phytoremediation purposes. As the response of the antioxidative system to heavy metal contamination can vary within species, the research was conducted on oak seedlings from two different regions of origin. Differences in antioxidative system response of seedlings derived from tested regions of origin were noticed both at the transcript and enzyme activity levels. The obtained results indicate that ascorbate peroxidase (APX; EC 126.96.36.199) and superoxide dismutase (SOD; EC 18.104.22.168) play a first barrier role in oak seedlings response to the oxidative stress caused by Cd exposure. Catalase (CAT; EC 220.127.116.11) is involved in reducing the negative effects of prolonged Cd treatment.


Quantitative, three-dimensional diagnostics of multiphase drop fragmentation via digital in-line holography.
Quantitative application of digital in-line holography (DIH) to characterize multiphase fragmentation is demonstrated. DIH is applied to record sequential holograms of the breakup of an ethanol droplet in an aerodynamic flow field. Various stages of the breakup process are recorded, including deformation, bag growth, bag breakup, and rim breakup. A recently proposed hybrid method is applied to extract the three-dimensional (3D) location and size of secondary droplets as well as the 3D morphology of the rim. Particle matching between sequential frames is used to determine the velocity. Coincidence with the results obtained from phase Doppler anemometry measurement demonstrates the accuracy of measurement by DIH and the hybrid method.


[Vaccinations for the immunologic memory-Repeatedly or once only?]
Due to the effectiveness of vaccines some particularly threatening infectious diseases have become rare; however, vaccines are meanwhile the victims of their own success. Due to insufficient compliance and inadequate vaccination rates, there is a danger that the effectiveness of vaccination as a preventive measure will continuously disappear. In 2019 the World Health Organization classified doubts on the effectiveness of vaccines as 1 of the 10 greatest dangers to health worldwide. This article discusses important questions on vaccinations and vaccines as well as their effects in the interplay with the immune system. The following topics are covered: comparison of naturally acquired immunity and that acquired by vaccination, factors that necessitate a refresher vaccination, the role of herd immunity, prerequisites for successful eradication of a disease, influence of various T cells on the effect of vaccination, the role of immunologic memory, factors that influence protection by vaccination, vaccinations in cases of immunodeficiency, the potential and areas of implementation of passive immunization. In view of the corona pandemic and the running vaccination campaign, it must be hoped that this triggers a general renaissance of vaccinations against infectious diseases.


Vascular surgery patients: perioperative and long-term risk according to the ACC/AHA guidelines, the additive role of post-operative troponin elevation.
The objectives of this study are to evaluate the prognostic role of pre-operative stratification in patients undergoing elective major vascular surgery, the timing of adverse outcomes, and the predictive role of troponin (cTn). Consecutive vascular surgery candidates (n=391) were prospectively stratified and treated according to the ACC/AHA guidelines. The patients were categorized into three groups: (1) with coronary revascularization in the past 5 years, (2) with intermediate clinical risk predictors, and (3) with minor or no clinical risk predictors. cTnI was measured post-operatively. By 18 months, 18.7% of subjects had experienced death or acute myocardial infarction (MI) (by the ACC/ESC criteria). The hazard ratio (HR) was 5.21 (95% CI=2.60-10.43; P<0.0001) in group 1 and 2.58 (95% CI=1.27-4.38; P=0.004) in group 2 when compared with group 3. Most events occurred within 30 days. Elevations of cTnI were associated with adverse outcomes even after multivariable adjustment at long-term (adjusted overall HR=4.73, 95% CI=2.92-7.65; P<0.0001) and at 30 days (adjusted HR=5.52, 95% CI=3.23-9.42; P<0.0001). After pre-operative stratification, patients undergoing elective major vascular surgery remain at high risk of MI and death. Events occur mainly early after surgery. cTnI elevations are frequent and independently associated with increased risk. These findings suggest the need for a major re-evaluation of our approach to these patients.


Single-chemical and mixture effects of multiple volatile organic compounds exposure on liver injury and risk of non-alcoholic fatty liver disease in a representative general adult population.
Evidence on liver injury and non-alcoholic fatty liver disease (NAFLD) from volatile organic compounds (VOCs) exposure is insufficient. A cross-sectional study including 3011 US adults from the National Health and Nutrition Examination Survey was conducted to explore the associations of urinary exposure biomarkers (EBs) for 13 VOCs (toluene, xylene, ethylbenzene, styrene, acrylamide, N,N-dimethylformamide, acrolein, crotonaldehyde, 1,3-butadiene, acrylonitrile, cyanide, propylene oxide, and 1-bromopropane) with liver injury biomarkers and the risk of NAFLD by performing single-chemical (survey weight regression) and mixture (Bayesian kernel machine regression [BKMR] and weighted quantile sum [WQS]) analyses. We found significant positive associations of EBs for toluene and 1-bromopropane with alanine aminotransferase (ALT), EBs for toluene, crotonaldehyde, and 1,3-butadiene with asparate aminotransferase (AST), EBs for 1,3-butadiene and cyanide with alkaline phosphatase (ALP), EBs for xylene and cyanide with hepamet fibrosis score (HFS), EBs for the total 13 VOCs (except propylene oxide) with United States fatty liver index (USFLI), and EBs for xylene, N,N-dimethylformamide, acrolein, crotonaldehyde, and acrylonitrile with NALFD; and significant inverse associations of EBs for ethylbenzene, styrene, acrylamide, acrolein, crotonaldehyde, 1,3-butadiene, acrylonitrile, cyanide, and propylene oxide with total bilirubin, EBs for ethylbenzene, styrene, acrylamide, acrolein, 1,3-butadiene, acrylonitrile, and cyanide with albumin (ALB), EBs for ethylbenzene, styrene, acrylamide, N,N-dimethylformamide, acrolein, crotonaldehyde, 1,3-butadiene, acrylonitrile, cyanide, and propylene oxide with total protein (TP), and EB for 1-bromopropane with AST/ALT (all P-FDR<0.05). In BKMR and WQS, the mixture of VOC-EBs was significantly positively associated with ALT, AST, ALP, HFS, USFLI, and the risk of NAFLD, while significantly inversely associated with TBIL, ALB, TP, and AST/ALT. VOCs exposure was associated with liver injury and increased risk of NAFLD in US adults. These findings highlight that great attention should be paid to the potential risk of liver health damage from VOCs exposure.


Epithelial Lacrimal Gland Tumours in Nigeria: Clinicopathological Features and Treatment.
Epithelial lacrimal gland tumours are uncommon orbital tumours and are not widely reported among African populations. This study aimed to describe the clinicopathological features, treatment, and outcomes of epithelial lacrimal gland tumours in Nigeria. Retrospective case series. Ocular Oncology Unit, Ophthalmology Department and Pathology Department of University College Hospital, Ibadan, Nigeria. A review of the medical records of all patients with histopathological diagnoses of epithelial lacrimal gland tumours managed at a tertiary health facility, southwestern Nigeria over 11.5 years was carried out. Eighteen patients with equal numbers of men and women, and mean age at presentation of 42.2 ± 15.7 years (median 42 years, range 17-70 years) were managed. All patients presented with orbital swelling and had nonaxial proptosis with palpable firm to hard mass in the superotemporal quadrant of the orbit. The mean duration of symptoms was 42.2 ± 38.6 months (median 24 months, range 3-120 months). Visual acuity was <3/60 at presentation in eight (44.4%) of the affected eyes. Thirteen (72.2%) patients underwent orbitotomy and tumour excision, while five (27.8%) patients had orbital exenteration, and two of whom (11.1%) had combined orbital exenteration and craniotomy. Histopathological examination of the specimens revealed pleomorphic adenoma in nine (50.0%) patients, low-grade mucoepidermoid carcinoma in three (16.7%) patients, high-grade mucoepidermoid carcinoma in two (11.1%) patients, adenoid cystic carcinoma in three (16.7%) patients, and adenocarcinoma "not otherwise specified" in one (5.6%) patient. Mortality was reported in four (44.4%) of nine patients with malignant tumours, while no mortality was noted in the patients with benign pleomorphic adenoma. The mean follow-up period for the patients was 28.9 months (median, 4.5 months; range, 2-140 months). The main presenting symptom of epithelial lacrimal gland tumours in our patients was an orbital mass and the most common clinical finding, in addition to the orbital mass, was nonaxial proptosis. The tumours were equally divided into benign and malignant lesions in our studied population. Pleomorphic adenoma was the only benign tumour while mucoepidermoid carcinoma was the commonest malignant lesion. Orbital exenteration was performed in a high proportion of our patients and high mortality was noted among patients with malignant tumours.


Preparing students to deal with the consequences of the workforce shortage among health professionals: a qualitative approach.
Healthcare is facing a shortage of qualified healthcare professionals. The pandemic has brought to light the fragile balance that affects all healthcare systems. Governments have realized that these systems and the professionals working in them need support at different levels to strengthen the retention of the workforce. Health professionals' education can play an important role in ensuring that new generations of workers have sound personal and professional competencies to successfully face the challenges of professional practice. These challenges are described in the literature, but the extent to which they are considered in health professionals' education is less clear. This qualitative study compares the professional challenges and educational needs described in the literature with the current curricula for health professionals offered in Switzerland. Data were collected nationally through focus group interviews with 65% of Switzerland's directors of bachelor's and master's programs of health professions (nursing, physiotherapy, occupational therapy, midwifery, nutrition and dietetics, osteopathy, radiologic medical imaging technology, health promotion and prevention, and health sciences). The data attained were analyzed using knowledge mapping. The results reveal a gap among education programs with regard to occupational health promotion and cultural diversity. Both topics are taught with a sole focus on patients, and students are expected to adopt similar strategies for their health promotion and stress management. Physicians are insufficiently involved in interprofessional education. The programs fail to enhance health professionals' political, economic and digital competencies. The results of this study offer clear guidance about what topics need to be integrated into curricula to improve health professionals' well-being at work and their preparedness to face daily professional challenges.


A history of the cancer registration system in Japan.
In Japan, the first actual survey of morbidity from cancer was conducted by Dr. Mitsuo Segi in Miyagi Prefecture from 1951 to 1953. Population-based cancer registries were started in 1957 in Hiroshima and 1958 in Nagasaki for the follow-up of survivors of the atomic bombings. Public population-based cancer registries, under the cancer control programs of the prefectural governments, were started in Aichi and Osaka prefectures in 1962. After the Law on Health and Medical Services for the Aged was enacted in 1983, population-based cancer registries were initiated promptly in many prefectures. As of 2007, there were population-based cancer registries in 35 of Japan's 47 prefectures and in one city. The Research Group for Population-Based Cancer Registration in Japan was organized by Dr. Isaburo Fujimoto, the chairperson in 1975, with a grant-in-aid from the National Cancer Research Promotion Program. This research group has continued until now and has been making continuous efforts. To promote standardization of the registry process and to improve the quality of registry data, the Japanese Association of Cancer Registries (JACR) was organized in 1992. The Japanese government Third-Term 10-Year Comprehensive Strategy for Cancer Control was launched in 2004, with the slogan "Targeting a drastic reduction in cancer morbidity and mortality." This strategy includes not only promoting cancer research but also promoting cancer prevention, improving the quality of cancer care, promoting social support systems, and promoting effective systems for monitoring cancer incidence and survival.


Tuberculosis detection by giant african pouched rats.
In recent years, operant discrimination training procedures have been used to teach giant African pouched rats to detect tuberculosis (TB) in human sputum samples. This article summarizes how the rats are trained and used operationally, as well as their performance in studies published to date. Available data suggest that pouched rats, which can evaluate many samples quickly, are sufficiently accurate in detecting TB to merit further investigation as a diagnostic tool.


[Specialized pain care in Germany].
In order to characterize the pain care situation in Germany, a health technology assessment (HTA) was carried out on behalf of the German Institute for Medical Documentation and Information (DIMDI). An up to date literature search was conducted using the database Pubmed. Reviews and studies which describe the pain care in Germany were included. The Physicians' Health Insurance Associations conducted an additional database survey. Overall 12 studies were included and the results of the analysis showed that there is a lack of some 2,500 curative pain care institutions in Germany. There is also clear under use of inpatient and outpatient institutions in palliative care. The results prove the benefits of the interdisciplinary approach in pain care. Further development should strive to increase the provision of pain and palliative care. There is a great need for pain care research in order to concrete the needs.


Traumatic injuries: imaging and intervention in post-traumatic complications (delayed intervention).
The nonoperative management (NOM) of abdominal trauma has gained increasing acceptance over the past decade. This approach has been extended to severe trauma patients previously considered as candidates for surgery. Consequently, the incidence of delayed and uncommonly encountered complications has increased. Causes of delayed complications are multiple and include: (a) abnormal or insufficient injury healing process; (b) retention of necrotic tissue; (c) secondary infection of initially sterile collections; and (d) underestimation of injury severity. The purpose of this review article is to explain the role of various imaging modalities in detecting post-traumatic delayed complications and to highlight the usefulness of minimally invasive techniques, including laparoscopy, biliary endoscopy, therapeutic angiography and image-guided drainage. Subsequent complications, which do not necessarily negatively influence the final outcome, are often predictable, virtually obligatory consequences of the successful NOM of high-grade or complex abdominal injuries. Between 50 and 60% of those patients with grade-IV or grade-V liver or splenic lacerations require some type of interventional treatment; therefore, indiscriminate discharge of patients with solid organ injury managed conservatively may be potentially harmful. As the incidence of complications is higher for more severe grade-IV or grade-V liver, spleen, or kidney injuries, scheduled follow-up CT scans may be rational in this subset of patients to identify potential complications amenable to early application of interventional techniques. Follow-up CT scans are unnecessary in stable adults or children with low-grade injury. Delayed splenic or hepatic rupture is one of the major concerns because this type of complication remains difficult to predict and historically often requires emergent surgery. These ruptures may benefit from NOM, should the same criteria as for primary rupture be respected. Conversely, parenchymatous focal pooling of contrast on initial CT is a good predictor for the development of delayed vascular malformation. In children, as a large part of splenic and hepatic vascular malformations resolve spontaneously, expectant observation may be indicated provided that a strict imaging follow-up is performed until complete disappearance of these lesions. If needed, embolization of parenchymal vascular lesions should be performed as selectively as possible in order to avoid functional parenchyma loss and to reduce the risk of secondary infection of hematoma or ischemic tissue. Technical improvements, such as microcatheter systems and direct percutaneous approach to targeted lesions, have widened the potential for safe endovascular management of acquired vascular malformations. Advantages and disadvantages relative to the different embolic agents are explained. Endoscopic retrograde pancreatography is the chief investigational tool for detecting biliary and pancreatic ducts injuries. The respective roles of endoscopic, percutaneous and surgical approaches in the management of these complications are discussed. The CT scan and ultrasound-guided drainage provide effective nonoperative options in the management of post-traumatic parenchymatous and (retro)-peritoneal collections. Treatment modalities of less common complications, such as bowel stricture or perforation, mesenteric vascular injuries and renal trauma-induced hypertension, are reviewed.


Proteomic Analysis of Murine Bone Marrow Very Small Embryonic-like Stem Cells at Steady-State Conditions and after In Vivo Stimulation by Nicotinamide and Follicle-Stimulating Factor Reflects their Germ-Lineage Origin and Multi Germ Layer Differentiation Potential.
Very small embryonic-like stem cells (VSELs) are a dormant population of development early stem cells deposited in adult tissues that as demonstrated contribute to tissue/organ repair and regeneration. We postulated developmental relationship of these cells to migrating primordial germ cells (PGCs) and explained the quiescent state of these cells by the erasure of differently methylated regions (DMRs) at some of the paternally imprinted genes involved in embryogenesis. Recently, we reported that VSELs began to proliferate and expand in vivo in murine bone marrow (BM) after exposure to nicotinamide (NAM) and selected pituitary and gonadal sex hormones. In the current report, we performed proteomic analysis of VSELs purified from murine bone marrow (BM) after repeated injections of NAM + Follicle-Stimulating Hormone (FSH) that in our previous studies turned out to be an effective combination to expand these cells. By employing the Gene Ontology (GO) resources, we have performed a combination of standard GO annotations (GO-CAM) to produce a network between BM steady-state conditions VSELs (SSC-VSELS) and FSH + NAM expanded VSELs (FSH + NAM VSELs). We have identified several GO biological processes regulating development, organogenesis, gene expression, signal transduction, Wnt signaling, insulin signaling, cytoskeleton organization, cell adhesion, inhibiting apoptosis, responses to extra- and intracellular stimuli, protein transport and stabilization, protein phosphorylation and ubiquitination, DNA repair, immune response, and regulation of circadian rhythm. We report that VSELs express a unique panel of proteins that only partially overlapped with the proteome of BM - derived hematopoietic stem cells (HSCs) and hematopoietic mononuclear cells (MNCs) and respond to FSH + NAM stimulation by expressing proteins involved in the development of all three germ layers. Thus, our current data supports further germ-lineage origin and multi germ layer differentiation potential of these cells.


The endoscopic intraventricular management of pineal cysts: a minimally invasive modus operandi.
The management of pineal cysts is still debatable, especially for asymptomatic incidental ones. For symptomatic cysts associated with hydrocephalus, the surgical management is mandatory and may include either classical microsurgical approaches to the pineal region or endoscopic trans-ventricular approaches in a minimally invasive philosophy. The authors expose a stepwise technique to treat a pineal cyst associated with an obstructive hydrocephalus in one procedure gathering a third ventriculostomy followed by an intraventricular marsupialisation of the pineal cyst. This endoscopic approach allows the treatment of the hydrocephalus and the pineal cyst in one short minimally invasive procedure.


Weekly paclitaxel as first-line chemotherapy and trastuzumab in patients with advanced breast cancer. A Hellenic Cooperative Oncology Group phase II study.
To evaluate the activity and acute toxicity of the combination of weekly paclitaxel as first-line chemotherapy and trastuzumab, in patients with HER-2/neu overexpressing advanced breast cancer (ABC). Weekly paclitaxel has been shown to be a well tolerated treatment with considerable activity in patients with ABC. Clinical trials with transtuzumab, a humanized anti-p185 HER-2/neu monoclonal antibody have demonstrated that this agent produces objective responses in patients with ABC. From December 1998 to April 2000, 34 patients with HER-2/neu overexpressing ABC were treated with weekly paclitaxel; given by one-hour infusion at a dose of 90 mg/m2 immediately followed by trastuzumab, 4 mg/kg as a loading dose and 2 mg/kg i.v. given over 30 min, thereafter weekly for at least 12 weeks. Expression of HER-2/neu was determined by immunohistochemical analysis on fixed, paraffin-embedded tissues. Eligible patients were required to have > or = 25% stained tumor cells. Thirty-three patients completed at least 12 weeks of combined treatment. After completion of the 12th week of treatment, four patients (12%) achieved complete and 17 (50%) partial response. Median duration of response was 11.6 months. More frequent side effects included anemia (56%). neutropenia (27%), peripheral neuropathy (78%), diarrhea (30%), alopecia (70%), arthralgias/myalgias (62%), fatigue (59%) and hypersensitivity reactions (62%). Median time to progression was nine months while median survival had not been reached The combination of weekly paclitaxel and trastuzumab is a safe and active regimen for patients with HER-2/neu overexpressing ABC. Randomized phase III studies with this combination are warranted.


[Treatment results and the prognosis in patients with localization of non-Hodgkins-lymphoma in the central nervous system].
A description of clinical features and treatment results in patients with a central nervous system (CNS) localization of systemic non-Hodgkin's lymphoma (NHL). Retrospective. Department of Neuro-oncology and Haematology, Daniel den Hoed Cancer Centre, Rotterdam, the Netherlands. All patients with NHL (but not primary CNS lymphoma) treated in the period January 1st, 1990-December 31st, 1996 at the department of neuro-oncology were reviewed for presence of CNS localizations. Clinical characteristics like malignancy grade, disease stage, presence of extranodal localizations, B-symptoms, serum LDH, neurological signs and symptoms, results of ancillary investigations, treatment and response were recorded. In this period 25 patients were diagnosed with leptomeningeal lymphoma, 2 with an intracerebral lymphoma, and 7 with both. In almost all patients the CNS localization developed during systemic progression of the NHL. Most patients presented with a radicular syndrome, cranial nerve deficits, headache or encephalopathy. More than 80% of the patients showed clinical improvement after treatment with intrathecal chemotherapy, radiation therapy or a combination of both. The median survival was three and a half months, six month survival was 32%. Progression of systemic disease was the most frequent cause of death. In most patients good palliation of neurological signs and symptoms could be obtained with intrathecal chemotherapy and radiation therapy. Survival in these patients was limited, however, in part because of the frequent concurrent progression of systemic disease. Patients with CNS localizations with chemotherapeutic treatment possibilities with a realistic chance of cure or longterm survival should be treated accordingly. Otherwise, treatment should consist of intrathecal chemotherapy or radiation therapy of involved areas only.


Proinflammatory cytokines levels in patients with temporomandibular joint disorder undergoing arthroscopy.
Biomarkers represent objective indicators of normal processes, pathology, or responses to therapeutic intervention. The purpose of this study is to evaluate the levels of proinflammatory cytokines in synovial fluid of the temporomandibular joint (TMJ) and to investigate whether there is a correlation between elevated levels and disease progression. This is a prospective study that included patients who were diagnosed with internal derangement according to magnetic resonance imaging and were classified according to Wilkes's classifications. After failing to improve with conservative treatment, they were referred for TMJ arthroscopy. During arthroscopy, synovial fluid was collected for biomarker analyses that included the investigation of levels of proinflammatory cytokines: tumor necrosis factor (TNF-α), interleukin 6 (IL-6), and vascular endothelial growth factor (VEGF). The Mann-Whitney U test was used for differences between subgroups for TNF-α, IL-6, and VEGF. During the study period, 22 patients presented with a TMJ disorder and met the criteria of the study. There was a statistically significant correlation between the levels of VEGF, TNF-a, and osteoarthritis (P < 0.05). There was also a statistically significant correlation between TNF-a levels and a higher degree of chondromalacia (P = 0.019). An increase in inflammatory cytokines coupled with chondromalacia propose a more aggressive degenerative disease.


Racial disparities in the content of primary care office visits.
Little is known about racial disparities in primary care at the level of the office visit. To assess racial disparities in the receipt of commonly performed/recommended procedures during routine primary care office visits and examine trends in disparities over time. The sample included 88,303 visits by adults to 3,260 primary care physicians in office-based practices in the National Ambulatory Medical Care Surveys, 1985, 1989, 1990, 1991, 1992, and 1995 to 2001. Adjusted odds for receipt or recommendation of commonly performed office procedures. During the years 1985 to 2001, African Americans, compared with whites, had lower odds of receiving a Pap test (odds ratio (OR) 0.81; 95% confidence interval (CI) 0.70 to 0.93), rectal exam (OR 0.67; 95% CI 0.56 to 0.80), smoking cessation counseling (OR 0.80; 95% CI 0.66 to 0.96), and mental health advice (OR 0.51; 95% CI 0.38 to 0.69), but had higher odds for visual screening (OR 1.38; 95% CI 1.08 to 1.77), weight advice counseling (OR 1.27; 95% CI 1.13 to 1.44) and receiving a follow-up appointment (OR 1.45; 95% CI 1.29 to 1.64). These findings were not appreciably altered by adjustment for physician practice characteristics including percent African American or Medicaid patients. Disparities disfavoring African Americans in cholesterol testing and smoking cessation observed during 1985 to 1992 were not observed in 1995 to 2001. The findings suggest that race is associated with the type of primary care received by patients, at least for selected procedures, with evidence that some disparities have diminished over time.


Cytotoxicity of pyrrolizidine alkaloid in human hepatic parenchymal and sinusoidal endothelial cells: Firm evidence for the reactive metabolites mediated pyrrolizidine alkaloid-induced hepatotoxicity.
Pyrrolizidine alkaloids (PAs) widely distribute in plants and can cause hepatic sinusoidal obstruction syndrome (HSOS), which typically presents as a primary sinusoidal endothelial cell damage. It is well-recognized that after ingestion, PAs undergo hepatic cytochromes P450 (CYPs)-mediated metabolic activation to generate dehydropyrrolizidine alkaloids (DHPAs), which are hydrolyzed to dehydroretronecine (DHR). DHPAs and DHR are reactive metabolites having same core pyrrole moiety, and can bind proteins to form pyrrole-protein adducts, which are believed as the primary cause for PA-induced HSOS. However, to date, the direct evidences supporting the toxicity of DHPAs and DHR in the liver, in particular in the sinusoidal endothelial cells, are lacking. Using human hepatic sinusoidal endothelial cells (HSEC) and HepG2 (representing hepatic parenchymal cells), cells that lack CYPs activity, this study determined the direct cytotoxicity of dehydromonocrotaline, a representative DHPA, and DHR, but no cytotoxicity of the intact PA (monocrotaline) in both cell lines, confirming that reactive metabolites mediate PA intoxication. Comparing with HepG2, HSEC had significantly lower basal glutathione (GSH) level, and was significantly more susceptible to the reactive metabolites with severer GSH depletion and pyrrole-protein adducts formation. The toxic potency of two reactive metabolites was also compared. DHPA was more reactive than DHR, leading to severer toxicity. In conclusion, our results unambiguously provided the first direct evidence for the critical role of DHPA and DHR in the reactive metabolites-mediated PA-induced hepatotoxicity, which occurs predominantly in HSEC due to severe GSH depletion and the significant formation of pyrrole-protein adducts in HSEC.


Environmental bioavailability of arsenic, nickel and chromium in soils impacted by high geogenic and anthropogenic background contents.
High arsenic, chromium and nickel in soils can pose a hazard to the ecosystem and/or human health. Large areas can be affected by elevated potentially toxic elements (PTE) background contents, entailing a significant effort for managing the potential risk. Assessing the environmental hazard associated to PTE-contaminated soils requires the determination of soil PTE environmental bioavailability, which reflects the capacity of these elements to be transferred to living organisms. Here we assess the environmental bioavailability of As, Cr and Ni in topsoils from the Liège basin and Belgian Lorraine, two areas in Wallonia, Belgium, affected by elevated As, Cr and Ni background contents. The source of soil As, Cr and Ni differs in Liège and Lorraine: anthropogenic in the former location and geogenic in the latter. The environmental bioavailability of PTE was determined using two complementary approaches: (1) by chemical fractionation with the Community Bureau of Reference (BCR) three-step sequential extraction protocol and (2) by estimating the phytoavailability using a plant-based biotest (Lolium multiflorum as plant model). The results show that total As (6-130 mg·kg-1), Cr (15-268 mg·kg-1), and Ni (8-140 mg·kg-1) contents in the Liège and Lorraine soils frequently exceed the soil clean-up standards. However, no positive correlation was found between the total contents and BCR extraction results or rye-grass contents, except for As in Liège soils. Total As, Cr or Ni contents surpassing soil standards do not necessarily result in elevated mobile, potentially mobilizable and phytoavailable contents. In general, environmental bioavailability of As, Cr and Ni is higher in soils from Liège basin compared to those sampled in Belgian Lorraine. The mobile and potentially mobilizable fractions of As, Cr and Ni account for <30 % of their total contents following the BCR extractions. Our study provides valuable information for sustainable management at the regional scale of soils containing high PTE contents.


Lytic infection of pseudorabies virus in the presence of spermine, spermidine, or DFMO.
The effects of polyamines (spermine or spermidine) and DFMO (an ornithine decarboxylase inhibitor) on the infection of LM (tk-) cells by pseudorabies virus (PRV) were investigated. Results from radioactive methionine labeling showed that the synthesis of viral proteins was not affected; however, the expression of a distinctive cellular protein ( approximately 27 kDa) was induced after the treatment of spermine or spermidine. Using plaque assay, we found that the plaque formation of PRV was not affected by these three reagents either. Furthermore, the effects of these drugs on the transcription of PRV immediate-early gene (IE) promoter were examined by CAT assay, and results showed weak stimulation of transcription by these drugs. Taken together, our results demonstrated that lytic infection of PRV was not influenced by addition of exogenous polyamines or depletion of endogenous polyamines; this conclusion was similar to earlier studies by using herpes simplex virus.


The misconception of plastic surgery scope amongst general practitioners in East Nusa Tenggara, Indonesia.
The scope of plastic reconstructive and aesthetic surgery is often misunderstood amongst both public and professionals, including the general practitioners (GP) who play vital roles in referring patients. Unlike other subspecialties, which are circumscribed by subgroup patients, specific organs, or diseases, the versatility of plastic surgery is driven by the principle of the surgical technique being malleable to each clinical case. This study aimed to demonstrate how well general practitioners in Kupang City acknowledge the scope of plastic surgery. The 30-Question electronic survey was filled out by GPs in several hospitals, PHCs, and clinics whose certificate of registration is based in Kupang City. Respondents should match the given cases to one subspecialist surgeon that the GPs think fits best. In total, 83 GPs participated; 63.9% (n = 53) were female, aged 27.95 (±3.53 years), 77.1% (n = 64) practised in a hospital, and 67.5% (n = 56) graduated from medical school in Java. Only 2.4% (n = 2) chose a plastic surgeon whom they will refer to among three hand cases, 6% (n = 5) in four craniomaxillofacial cases, and 10.8% (n = 9) in five reconstructive cases. The GPs tend to associate cosmetic procedures with plastic surgeons, while reconstructive surgery cases like hand or craniomaxillofacial cases were correlated with non-plastic surgeons. The scope of plastic surgery needs to be further introduced in the medical student curriculum; thus, GP can be more exposed to the field and refer patients accurately.


Cryogenic Ion Spectroscopy of the Green Fluorescent Protein Chromophore in Vacuo.
We present the spectrum of the S1 ← S0 transition of an anionic model for the chromophore of the green fluorescent protein in vacuo at cryogenic temperatures, showing previously unresolved vibrational features, and resolving the band origin at 20 930 cm-1 (477.8 nm) with unprecedented accuracy. The vibrational spectrum establishes that the molecule is in the Z isomer at low temperature. At increased temperature, the S1 ← S0 band shifts to the red, which we tentatively attribute to emergent population of the E isomer.


Cytogenetics of childhood acute nonlymphocytic leukemia.
Interest in more precise subclassification of the acute leukemias by cytogenetic criteria led us to identify and characterize the full range of chromosomal abnormalities in 121 children with de novo acute nonlymphocytic leukemia (ANLL). Only 21% of the cases had normal karyotypes; 62% had consistent or recurrent alterations, most commonly inv(16) or del(16), t(8;21), t(15;17), t(9;11), t(11;V) or del(11), and -7 or 7q-; and 17% had miscellaneous, apparently random, clonal abnormalities. Statistically significant associations between chromosomal abnormalities and the morphologic/cytochemical subtypes of ANLL, defined by criteria of the French-American-British (FAB) cooperative group were demonstrated for the t(8;21) in M1 and M2 leukemia, t(15;17) in M3, t(9;11) in M5, and translocations involving 11q23 other than t(9;11) [t(11;V)] or del(11q) in M4 and M5. The chromosome 16 inversion was not restricted to the M4 subtype, as is generally reported, and was not uniformly associated with increased and/or abnormal marrow eosinophils. None of these 121 cases were characterized by the Philadelphia chromosome, nor did any have the t(6;9), t(16;16), or inv(3), which have been noted previously in this disease. In addition to confirming several recognized correlations between recurrent structural chromosome abnormalities and FAB subtypes, this study identified novel abnormalities that have not been reported by others. It also disclosed an unusual heterogeneity of chromosome 16 abnormalities with respect to their distribution among FAB subtypes, their association with marrow eosinophilia, and their participation with other chromosomes in translocations.


Effects of acupuncture and computer-assisted cognitive training for post-stroke attention deficits: study protocol for a randomized controlled trial.
A majority of stroke survivors present with cognitive impairments. Attention disturbance, which leads to impaired concentration and overall reduced cognitive functions, is strongly associated with stroke. The clinical efficacy of acupuncture with Baihui (GV20) and Shenting (GV24) as well as computer-assisted cognitive training in stroke and post-stroke cognitive impairment have both been demonstrated in previous studies. To date, no systematic comparison of these exists and the potential beneficial effects of a combined application are yet to be examined. The main objective of this pilot study is to evaluate the effects of computer-assisted cognitive training compared to acupuncture on the outcomes of attention assessments. The second objective is to test the effects of a combined cognitive intervention that incorporates computer-assisted cognitive training and acupuncture (ACoTrain). An international multicentre, single-blinded, randomised controlled pilot trial will be conducted. In a 1:1:1 ratio, 60 inpatients with post-stroke cognitive dysfunction will be randomly allocated into either the acupuncture group, the computer-assisted cognitive training group, or the ACoTrain group in addition to their individual rehabilitation programme. The intervention period of this pilot trial will last 4 weeks (30 minutes per day, 5 days per week, Monday to Friday). The primary outcome is the test battery for attentional performance. The secondary outcomes include the Trail Making Test, Test des Deux Barrages, National Institute of Health Stroke Scale, and Modified Barthel Index for assessment of daily life competence, and the EuroQol Questionnaire for health-related quality of life. This trial mainly focuses on evaluating the effects of computer-assisted cognitive training compared to acupuncture on the outcomes of attention assessments. The results of this pilot trial are expected to provide new insights on how Eastern and Western medicine can complement one another and improve the treatment of cognitive impairments in early stroke rehabilitation. Including patients with different cultural backgrounds allows a more generalisable interpretation of the results but also poses risks of performance bias. Using standardised and well-described assessments, validated for each region, is pivotal to allow pooling of the data. Clinical Trails.gov ID: NCT02324959 (8 December 2014).


Routine sonographic measurement of the near-field lateral ventricle during second-trimester morphologic scans.
The purpose of this study was to determine whether measurement of the near-field lateral ventricular diameter can be reliably obtained within a practical time frame during second-trimester obstetric scans by angling the fetal head approximately 30° away from the horizontal image axis such that the posterior aspect of the fetal head lies closer to the transducer. Fifty consecutive singleton pregnancies presenting for a routine-second trimester scan were recruited for this study. The far-field lateral ventricular diameter was measured, followed by the near-field lateral ventricular diameter using the proposed technique. The measurements were repeated by a second operator who was blinded to the first measurement. Both operators recorded the measurements taken and scored the level of visibility of the near-field lateral ventricle. The difference between the two operators' measurements was compared by a κ analysis. The near-field lateral ventricle was visualized in 49 of 50 cases (98%). There was no statistically significant difference in the measurement of the near-field lateral ventricular diameter by the two operators (P = .34). There was, however, a statistically significant difference in the time it took each operator to obtain the near-field measurement after the far-field measurement (P = .01). Manipulating the transducer to position the falx of the fetal head approximately 30° away from the horizontal image axis allows the near-field lateral ventricle to be routinely visualized and measured with a high degree of interoperator agreement and within a practical time frame once the operator is experienced in performing the technique.


Varied presentations of unilateral lung hypoplasia and agenesis: a report of four cases.
Unilateral lung hypoplasia or agenesis can be asymptomatic or present with recurrent respiratory symptoms. The latter may be amenable to surgical treatment in selected cases. Of four children in this report, two are being managed without surgery. A third was relieved of his symptoms by pneumonectomy. The fourth presented with acute foreign-body inhalation into the healthy right main bronchus, and coexistent left pulmonary agenesis was discovered at bronchoscopy. Bronchoscopy and computed tomography were found to be the most useful investigations in management.


Catabolic enzyme activities in the pectoralis muscle of premigratory and migratory juvenile Reed Warblers Acrocephalus scirpaceus (Herm.).
Differences in catabolic capacity in the pectoralis major muscle of premigratory and migratory Reed Warblers were examined. The oxidative capacity was greater in the migratory birds, probably reflecting a "training effect" caused by the increased locomotion activity just prior to migration.Fatty acid oxidation was already high in the premigratory birds, possibly reflecting a saving of carbohydrate for anabolic purposes (feather growth) during the moult. Glycolytic capacity was slightly increased in the migratory birds, suggesting an increased carbohydrate oxidation during migration in spite of the great contribution of fatty acid oxidation.


Association measures for estimating semantic similarity and relatedness between biomedical concepts.
Association measures quantify the observed likelihood a term pair co-occurs versus their predicted co-occurrence together if by chance. This is based both on the terms' individual occurrence frequencies, and their mutual co-occurrence frequencies. One application of association scores is estimating semantic relatedness, which is critical for many natural language processing applications, such as clustering of biomedical and clinical documents and the development of biomedical terminologies and ontololgies. In this paper we propose a method of generating association scores between biomedical concepts to estimate semantic relatedness. We use co-occurrence statistics between Unified Medical Language System (UMLS) concepts to account for lexical variation at the synonymous level, and introduce a process of concept expansion that exploits hierarchical information from the UMLS to account for lexical variation at the hyponymous level. State of the art results are achieved on several standard evaluation datasets, and an in depth analysis of hyper-parameters is presented.


Preparation and characterization of 4-dedimethylamino sancycline (CMT-3) loaded nanostructured lipid carrier (CMT-3/NLC) formulations.
Chemically modified tetracyclines (CMTs) have been reported to strongly inhibit proliferation and metastasis of various cancers, but their efficacy is restricted by poor water solubility. In the present study, a hydrophilic 4-dedimethylamino sancycline (CMT-3) loaded nanostructured lipid carrier (CMT-3/NLC) was produced by high pressure homogenization (HPH). The physical properties of CMT-3/NLC formulations were characterized by dynamic light scattering (DLS), high efficiency liquid chromatography (HPLC), atomic force microscopy (AFM), scanning electron microscopy (SEM), small-angle neutron scattering (SANS), small-angle X-ray scattering (SAXS) and wide-angle X-ray powder diffraction (XRD). The lipid and surfactant ingredients, as well as drug/lipid concentrations (m/m) were optimized to produce stable and sustained NLC formulations. In vitro cytotoxicity of CMT-3/NLC against HeLa cells was evaluated by MTT assay. The diameter of CMT-3/NLC was found to increase from 153.1±3.0 nm to a maximum of 168.5±2.0 nm after 30 days of storage, while the entrapment efficiency remained constant at >90%. CMT-3/NLC demonstrated a burst-sustained release profile in release media with different pH, a property attributed to the 3-dimensional structure of CMT-3/NLC. Cell uptake and localization studies indicated that NLC reached the cytoplasm and could thereby facilitate CMT-3 entry into HeLa cells.


Urine volume as an estimator of residual renal clearance and urinary removal of solutes in patients undergoing peritoneal dialysis.
In non-anuric patients undergoing peritoneal dialysis (PD), residual kidney function (RKF) is a main contributor to fluid and solute removal and an independent predictor of survival. We investigated if urine volume could be used to estimate renal clearances and removal of urea, creatinine, and phosphorus in PD patients. The observational, cross-sectional study included 93 non-anuric prevalent PD patients undergoing continuous ambulatory PD (CAPD; n = 34) or automated PD (APD; n = 59). Concentrations of urea, creatinine and phosphorus in serum and in 24-h collections of urine volume were measured to calculate weekly residual renal clearance (L/week) and removed solute mass (g/week). Median [interquartile range], 24-h urine output was 560 [330-950] mL and measured GFR (the mean of creatinine and urea clearances) was 3.24 [1.47-5.67] mL/min. For urea, creatinine and phosphorus, residual renal clearance was 20.60 [11.49-35.79], 43.02 [19.13-75.48] and 17.50 [8.34-33.58] L/week, respectively, with no significant differences between CAPD and APD. Urine volume correlated positively with removed solute masses (rho = 0.82, 0.67 and 0.74) and with weekly residual renal clearances (rho = 0.77, 0.62 and 0.72 for urea, creatinine, and phosphorus, respectively, all p < 0.001). Residual renal clearances and urinary mass removal rates for urea, creatinine, and phosphorus correlate strongly with 24-h urine volume suggesting that urine volume could serve as an estimator of typical values of residual solute removal indices in PD patients.


Immune surveillance for six vaccinable pathogens using paired plasma and dried blood spots in HIV infected and uninfected children in Kinshasa.
Child vaccination reduces infant mortality rates. HIV-infected children present higher risk of diseases than non-infected. We report the protection coverage rates for 6 vaccine-preventable diseases in a paediatric population from the Democratic Republic of the Congo (DRC) and the impact of HIV infection, providing the first data on the validity of dried blood samples (DBS) to monitor the immune protection. During 2016-2018 DBS from 143 children/adolescents were collected in Kinshasa (DRC), being 52 HIV-infected. Forty-two had a paired plasma sample. Protective IgG was quantified (VirClia-IgG,VIRCELL) to obtain the optimal cut-off in IgG detection in DBS. ROC curves were generated with R software and statistical analyses with Stata. Protective IgG levels varied across pathogens, not reaching herd immunity. HIV-infected presented lower vaccine protection than uninfected for all analyzed pathogens, except rubella, with statistically significant differences for measles (30.8% vs. 53.8%; p = 0.008) and tetanus (3.8% vs. 22%; p = 0.0034). New cut-offs were calculated when using DBS to improve test performance. We reinforce the necessity to increase pediatric vaccination coverage in Kinshasa, especially in HIV seropositive, with less capacity to maintain adequate antibody levels. DBS were useful to monitor vaccination coverage in seroprevalence studies in resource-limited settings, after optimizing the cut-off value for each pathogen.


Involvement of 15-lipoxygenase and prostaglandin EP receptors in aspirin-triggered 15-hydroxyeicosatetraenoic acid generation in aspirin-sensitive asthmatics.
The mechanism of aspirin (acetylsalicylic acid: ASA) hypersensitivity in asthmatic patients is related to arachidonic acid metabolism abnormalities, and specific triggering by ASA of 15-hydroxyeicosatetraenoic acid (15-HETE) generation was observed in leucocytes from aspirin-sensitive (AS) but not from aspirin-tolerant (AT) asthmatics. The aim of this study was to identify the enzymatic pathway involved in ASA-induced 15-HETE generation in AS asthmatics and to assess the regulatory role of prostaglandin EP receptors. Peripheral blood leucocytes (PBLs) were isolated from AS (n=18) and AT (n=20) asthmatics and challenged with ASA, with and without pre-incubation with caffeic acid (CA) [15-lipoxygenase (15-LO) inhibitor] or prostaglandin receptor non-specific (misoprostol, sulprostone) and specific EP1-4 receptors agonists. Eicosanoids were measured in supernatants using specific immunoassays. Aspirin triggered 15-HETE generation in PBLs of AS asthmatics (mean increase 292%) but not in AT asthmatics and inhibited prostaglandin(2) (PGE(2)) generation in both groups of patients to the same degree. Leucocytes from AS patients produced less PGE(2), both before and after ASA incubation. Pre-incubation of PBLs with CA decreased basal 15-HETE production in all patients and completely inhibited ASA-induced 15-HETE generation in AS asthmatics. CA did not change basal PGE(2) production but enhanced induced by ASA inhibition of PGE(2). Non-specific agonists of EP receptors (misoprostol and sulprostone) did not affect basal 15-HETE production but inhibited in a dose-dependent manner the ASA-induced increase of 15-HETE generation in AS asthmatics. On the contrary, in AT asthmatics, pre-incubation of PBLs with misoprostol or sulprostone resulted in a significant increase in 15-HETE generation after addition of ASA (200 microm). EP1-3 receptor agonists inhibited (range 72-94%) the ASA-induced 15-HETE production significantly. Our study demonstrated that ASA-triggered 15-HETE generation involves the activation of 15-LO and is modulated by prostaglandin EP1-3 receptors. The relevance of these observations to the mechanism of in vivo ASA-induced asthmatic attack remains to be established.


Contrast sensitivity function in children: normalized notation for the assessment and diagnosis of diseases.
The purpose of this article is to describe a normalized notation for the assessment of the contrast sensitivity in children. This notation is obtained dividing the log contrast sensitivity value found in a patient by the corresponding normative contrast sensitivity data. The ratio obtained describes the contrast sensitivity of a patient facilitating its understanding, assessment and consequently effective communications. This article shows the normalized notation developed for children aged from 3 to 7 years old. An evaluation of the contrast sensitivity in healthy and amblyopic patients has been shown in order to explain the procedure to follow. The use of normalized notation in clinical procedures will provide to the clinician a better understanding of the results and the changes over time as well by comparison in the assessment of an ocular disease.


Pathway-specific modulatory effects of neuromuscular electrical stimulation during pedaling in chronic stroke survivors.
Neuromuscular electrical stimulation (NMES) is extensively used in stroke motor rehabilitation. How it promotes motor recovery remains only partially understood. NMES could change muscular properties, produce altered sensory inputs, and modulate fluctuations of cortical activities; but the potential contribution from cortico-muscular couplings during NMES synchronized with dynamic movement has rarely been discussed. We investigated cortico-muscular interactions during passive, active, and NMES rhythmic pedaling in healthy subjects and chronic stroke survivors. EEG (128 channels), EMG (4 unilateral lower limb muscles) and movement parameters were measured during 3 sessions of constant-speed pedaling. Sensory-level NMES (20 mA) was applied to the muscles, and cyclic stimulation patterns were synchronized with the EMG during pedaling cycles. Adaptive mixture independent component analysis was utilized to determine the movement-related electro-cortical sources and the source dipole clusters. A directed cortico-muscular coupling analysis was conducted between representative source clusters and the EMGs using generalized partial directed coherence (GPDC). The bidirectional GPDC was compared across muscles and pedaling sessions for post-stroke and healthy subjects. Directed cortico-muscular coupling of NMES cycling was more similar to that of active pedaling than to that of passive pedaling for the tested muscles. For healthy subjects, sensory-level NMES could modulate GPDC of both ascending and descending pathways. Whereas for stroke survivors, NMES could modulate GPDC of only the ascending pathways. By clarifying how NMES influences neuromuscular control during pedaling in healthy and post-stroke subjects, our results indicate the potential limitation of sensory-level NMES in promoting sensorimotor recovery in chronic stroke survivors.


Two adjacent protein binding motifs in the cbh2 (cellobiohydrolase II-encoding) promoter of the fungus Hypocrea jecorina (Trichoderma reesei) cooperate in the induction by cellulose.
The cellulase system of the filamentous fungus Hypocrea jecorina (Trichoderma reesei) consists of several cellobiohydrolases, endoglucanases, and beta-glucosidases, encoded by separate genes, which are coordinately expressed in the presence of cellulose or the disaccharide sophorose. Using cell-free extracts from sophorose-induced and noninduced mycelia and various fragments of the cbh2 promoter of H. jecorina in electrophoretic mobility shift assay (EMSA) analysis and performing in vitro and in vivo footprinting analysis, we detected the nucleotide sequence 5'-ATTGGGTAATA-3' (consequently named cbh2-activating element (CAE)) to bind a protein complex with different migration in EMSA of induced and noninduced cell-free extracts. EMSA analysis, employing oligonucleotide fragments containing specifically mutated versions of CAE, revealed that protein binding requires the presence of an intact copy of either one of two adjacent motifs: a CCAAT (=ATTGG) box on the template strand and a GTAATA box on the coding strand, whereas a simultaneous mutation in both completely abolished binding. H. jecorina transformants, containing correspondingly mutated versions of the cbh2 promoter fused to the Escherichia coli hph gene as a reporter, expressed hph in a manner paralleling the efficacy of CAE-protein complex formation in EMSA, suggesting that the presence of either of both motifs is required for induction of cbh2 gene transcription. Antibody supershift experiments with anti-HapC antiserum as well as EMSA competition experiments with CCAAT binding promoter fragments of the Aspergillus nidulans amdS promoter suggest that the H. jecorina CCAAT box binding complex contains a homologue of HapC. The nature of the adjacent, GTAATA-binding protein(s) and its cooperation with the HapC homologue in cbh2 gene induction is discussed.


Correction: Immunological detection of pyrazine-2-carboxylic acid for the detection of pyrazinamide resistance in Mycobacterium tuberculosis.
[This corrects the article DOI: 10.1371/journal.pone.0241600.].


Dihydroxybergamottin caproate as a potent and stable CYP3A4 inhibitor.
We investigated the inhibitory activity of the furanocoumarin derivatives from grapefruit juice to the drug metabolizing enzyme, cytochrome P450 (CYP) 3A4. Although two known furanocoumarin dimers GF-I-1 (1) and GF-I-4 (2) showed potent CYP3A4 inhibition with IC50 value of 0.07 microM, a semi-synthetic dihydroxybergamottin caproate (11), which was more stable and more simple than the dimers, exhibited comparable activity against CYP3A4.


Baseline hypoxemia as a prognostic marker for pulmonary complications and outcome in patients with acute pancreatitis.
The purpose of the present study was to investigate the prognostic role of severe hypoxemia on admission as an independent risk factor of pulmonary complications and mortality in patients with acute pancreatitis. Pulmonary complications were studied in 166 previously healthy patients with acute pancreatitis. Forty-eight patients (28.9%) developed one or more pulmonary complications, including pleural effusion, atelectasis, pulmonary consolidations, and acute respiratory distress syndrome (ARDS). Pulmonary consolidations (odds ratio = 7.25) and, especially, ARDS (odds ratio = 22.9) were significantly associated with severe baseline hypoxemia (PaO2, <60 mm Hg). Mortality was mainly related to severity of disease (odds ratio = 46.45), while hypoxemia was also found to be an independent risk factor of poor outcome (odds ratio = 9.56). It seems that, in patients with acute pancreatitis, severe hypoxemia on admission may be an early predictive marker of pulmonary complications, especially ARDS, and, independently of severity score, it may also be a marker of poor outcome.


Investigations on latent erythropoietin (ESF) deficiency in non anemic patients with chronic renal disease using hypoxic stimulation methods.
So far the question has not been elucidated whether latent ESF-deficiency exists in patients with chronic renal disease during initial development of renal anemia. Therefore, ESF was determined in urine and serum of non anemic patients being exposed to acute hypoxia: 8 healthy volunteers and 8 patients who had a Ccreat below 48 ml/min were studied while in a hypobaric chamber for 4 subsequent periods of 10 h each (simulated maximal altitude 4000 m INA = 462 mm Hg). We also determined plasma iron turnover and reticulocyte counts. 10 h after the study began, the patients showed a significantly higher ESF-level than the normal volunteers. In the course of 48 h collection periods of urine under hypoxic conditions the mean ESF excretion in patients corresponded to 9.9 and in healthy persons to 7.3 Units. With regard to plasma iron turnover and reticulocyte count an increase was shown, but no significant differences existed between the two groups. A latent ESF-deficiency as the initial cause of renal anemia does not exist.


Tumor location on electroporation therapies by means of multi-electrode structures and machine learning.
Electroporation is a phenomenon produced in the cell membrane when it is exposed to high pulsed electric fields that increases its permeability. Among other application fields, this phenomenon can be exploited in a clinical environment for tumor ablation therapies. In this context to achieve optimum results, it is convenient to focus the treatment on the tumor tissue to minimize side effects. In this work, a pre-treatment tumor location method is developed, with the purpose of being able to precisely target the therapy. This is done by taking different impedance measurements with a multi-output electroporation generator in conjunction with a multi-electrode structure. Data are processed by means of a vector of independent artificial neural networks, trained and tested with simulation data, and validated with phantom gels. This algorithm proved to provide suitable accuracy in spite of the low electrode count compared to the number of electrodes of a standard electrical impedance tomography device.


Oxidation of caspase-8 by hypothiocyanous acid enables TNF-mediated necroptosis.
Necroptosis is a form of regulated cell death triggered by various host and pathogen-derived molecules during infection and inflammation. The essential step leading to necroptosis is phosphorylation of the mixed lineage kinase domain-like protein by receptor-interacting protein kinase 3. Caspase-8 cleaves receptor-interacting protein kinases to block necroptosis, so synthetic caspase inhibitors are required to study this process in experimental models. However, it is unclear how caspase-8 activity is regulated in a physiological setting. The active site cysteine of caspases is sensitive to oxidative inactivation, so we hypothesized that oxidants generated at sites of inflammation can inhibit caspase-8 and promote necroptosis. Here, we discovered that hypothiocyanous acid (HOSCN), an oxidant generated in vivo by heme peroxidases including myeloperoxidase and lactoperoxidase, is a potent caspase-8 inhibitor. We found HOSCN was able to promote necroptosis in mouse fibroblasts treated with tumor necrosis factor. We also demonstrate purified caspase-8 was inactivated by low concentrations of HOSCN, with the predominant product being a disulfide-linked dimer between Cys360 and Cys409 of the large and small catalytic subunits. We show oxidation still occurred in the presence of reducing agents, and reduction of the dimer was slow, consistent with HOSCN being a powerful physiological caspase inhibitor. While the initial oxidation product is a dimer, further modification also occurred in cells treated with HOSCN, leading to higher molecular weight caspase-8 species. Taken together, these findings indicate major disruption of caspase-8 function and suggest a novel mechanism for the promotion of necroptosis at sites of inflammation.


Defective CD8 Signaling Pathways Delay Rejection in Older Recipients.
CD8+ T cells play a cardinal feature in response to alloantigens and are able to generate effector/memory T cells independently from CD4+ T cells. To investigate the impact of aging on CD8 T cells, we used a fully mismatched mouse skin transplant model. Our findings showed a prolonged allograft survival in older recipients associated with a significant increase of CD4+ and CD8+ CD44high CD62Llow effector/memory T cells and a reduced systemic IFNγ production. When reconstituting young CBA Rag-1 mice that lack mature T and B cells with old CD8+ T cells expressing clonal anti-H2K T cell receptor (TCR) alloreactive for MHC I, graft survival was significantly prolonged and comparable to those receiving young CD8+ T cells. Moreover, our data showed that reduced systemic IFNγ levels observed in old recipients had been linked to a compromised expression of the IL-2R β subunit (CD122) by old CD8+ T cells. In addition, we observed an impaired IFNγ production on IL-2 receptor activation. At the same time, gene profiling analysis of old CD8 T cells demonstrated reduced chemokine ligand-3 and CD40L expression that resulted in compromised CD8+ T cell/dendritic cell communication, leading to impaired migratory and phagocytic activity of CD11c cells.Collectively, our study demonstrated that aging delays allograft rejection. CD8 T cells play a critical role in this process linked to a compromised production of IFNγ, in addition to a defective IL-2 receptor signaling machinery and a defective communication between CD8 T cells and dendritic cells.


Fisheries productivity in the northeastern Pacific Ocean over the past 2,200 years.
Historical catch records suggest that climatic variability has had basin-wide effects on the northern Pacific and its fish populations, such as salmon, sardines and anchovies. However, these records are too short to define the nature and frequency of patterns. We reconstructed approximately 2,200-year records of sockeye salmon abundance from sediment cores obtained from salmon nursery lakes on Kodiak island, Alaska. Large shifts in abundance, which far exceed the decadal-scale variability recorded during the past 300 years, occurred over the past two millennia. A marked, multi-centennial decline in Alaskan sockeye salmon was apparent from approximately 100 BC to AD 800, but salmon were consistently more abundant from AD 1200 to 1900. Over the past two millennia, the abundances of Pacific sardine and Northern anchovy off the California coast, and of Alaskan salmon, show several synchronous patterns of variability. But sardines and anchovies vary out of phase with Alaskan salmon over low frequency, which differs from the pattern detected in historical records. The coherent patterns observed across large regions demonstrate the strong role of climatic forcing in regulating northeastern Pacific fish stocks.


The effect of total peripheral resistance on indicator-dilution curves from the central circulation of the dog.
The influence of total peripheral resistance on the dispersion of indicator particles passing through the central circulation was studied in five dogs. The standard deviation of indocyanine green indicator-dilution curves provided a measure of dispersion. The peripheral vascular resistance of the dog was altered during the experiment by the intravenous administration of sodium nitroprusside and methoxamine. We calculated the area of each curve by fitting the first portion of the curve to a random walk function and the cardiac output and the total peripheral resistance were calculated in the usual manner. The mean, standard deviation and area of each of the curves were calculated from the least squares estimate of the random walk function. The relationship of the cardiac output, mean arterial pressure, and total peripheral resistance to the mean and the standard deviation were compared in a multiple stepwise linear regression. For each dog there was a definite linear relationship between total peripheral resistance and standard deviation (p less than 0.01). These results indicate that the dispersion of particles passing through the central circulation is directly related to the total peripheral resistance.


Three-week loading of the 4.5mm wide titanium implant in bone anchored hearing systems.
The purpose of this study is to assess implant stability, implant loss, adverse skin reactions and quality of life benefit following surgical implantation and early processor loading (3-weeks post-implantation) of the Oticon Ponto 4.5 mm osseointegrated auditory implant. This study also investigates the relationship between the type of post-operative skin reactions and the gender, BMI and medical co-morbidities of participants. Using a prospective, multicenter design, thirty adult patients 18 years or older who met medical and audiological candidacy for an osseointegrated auditory bone-anchored hearing device were evaluated. They underwent simultaneous implantation of the Oticon 4.5mm wide implant and a 3.75 mm sleeper implant. Sound processor loading occurred at three weeks post-implantation. Implant stability was measured using Radio Frequency Analysis (RFA) at surgery, 1, 3, 6, 12, 26 and 52 weeks. The Glasgow Benefit Inventory was used to assess quality of life benefit at 12 and 52 weeks following implantation. The results show a positive linear trend in implant stability measures in all subjects over time. There have been no implant losses with early 3-week loading. Skin reactions were limited to grade 0 and 1 of the modified Holger's grading scale. Due to the limited incidence of complications, no conclusion can be made regarding the relationship between patient demographic data and soft tissue reaction. Our findings confirm the safety and efficacy of early loading of the Oticon 4.5 mm wide implant. Participants showed satisfaction with the earlier use of their processor with no added complications after one year post-implantation.


Evaluation of real-time RigiScan monitoring in pharmacological erection.
The clinical assessment of pharmacologically induced erectile response was compared to the real-time RigiScan* monitoring response. Erection was induced by 521 intracavernous injections of a new alprostadil formulation. The clinical end point was "full rigidity" and the RigiScan criterion was radial rigidity of 70% or more for 10 consecutive minutes or longer. For 752 prostaglandin E1 injections the sensitivity and specificity of the RigiScan device compared to clinical evaluation were 53.8% (133 of 247 cases) and 92.9% (469 of 505), respectively. For rigidity of 60% or greater the sensitivity increased to 70.8% (175 of 247 cases) and specificity decreased to 85.0% (429 of 505). The RigiScan device is useful to document objectively a pharmacologically induced erection yet it appears to be more conservative than clinical evaluation.