Development and validation of a prediction model for strokes after coronary artery bypass grafting.
A prospective study of patients undergoing coronary artery bypass graft surgery (CABG) was conducted to identify patient and disease factors related to the development of a perioperative stroke. A preoperative risk prediction model was developed and validated based on regionally collected data. We performed a regional observational study of 33,062 consecutive patients undergoing isolated CABG surgery in northern New England between 1992 and 2001. The regional stroke rate was 1.61% (532 strokes). We developed a preoperative stroke risk prediction model using logistic regression analysis, and validated the model using bootstrap resampling techniques. We assessed the model's fit, discrimination, and stability. The final regression model included the following variables: age, gender, presence of diabetes, presence of vascular disease, renal failure or creatinine greater than or equal to 2 mg/dL, ejection fraction less than 40%, and urgent or emergency. The model significantly predicted (chi(2) [14 d.f.] = 258.72, p < 0.0001) the occurrence of stroke. The correlation between the observed and expected strokes was 0.99. The risk prediction model discriminated well, with an area under the relative operating characteristic curve of 0.70 (95% CI, 0.67 to 0.72). In addition, the model had acceptable internal validity and stability as seen by bootstrap techniques. We developed a robust risk prediction model for stroke using seven readily obtainable preoperative variables. The risk prediction model performs well, and enables a clinician to estimate rapidly and accurately a CABG patient's preoperative risk of stroke.


Peripheral Artery Disease: Overview of Diagnosis and Medical Therapy.
Peripheral artery disease (PAD) affects approximately 230 million people worldwide and is associated with an increased risk of major adverse cardiovascular and limb events. Even though this condition is considered a cardiovascular equivalent, it remains an underrecognized and undertreated entity. Antiplatelet and statin therapy, along with smoking cessation, are the foundations of therapy to reduce adverse events but are challenging to fully implement in this patient population. Race and socioeconomic status also have profound impacts on PAD outcomes.


Fucosylated forms of alpha-1-antitrypsin that predict unresponsiveness to chemotherapy in ovarian cancer.
We have discovered modified fucosylation of alpha 1-antitrypsin (F-AT) in the sera of ovarian cancer patients. This was detected by SDS/electrophoresis and silver-staining after extracting the sera with the fucose-binding lectin, Lotus tetragonolobus, and was identified as alpha 1-antitrypsin by Western blotting. Initially, high F-AT levels appeared to be related to the recurrence of cancer, but later measurements showed that elevated levels were also present in patients who did not respond to therapy. Using an arbitrary grading system, the level of F-AT was assessed in pairs of sera from 29 ovarian cancer patients undergoing therapy; one specimen collected just after the start of therapy and the other on a later occasion. In 75% of the 15 non-responders, F-AT was higher when measured on a second occasion; whereas in 86% of the 14 responders the second measurement was either unchanged or lower, being frequently undetectable. F-AT levels were also low or undetectable in sera from healthy women. Eight responders were monitored for F-AT throughout cyclophosphamide chemotherapy. Despite a high tumour burden at the start of therapy, all patients had relatively low levels of F-AT and this was maintained throughout remission; the levels only becoming elevated with the recurrence of tumour growth. Increased F-AT expression did not appear to be particularly associated with the presence of liver metastases and frequently predated any clinical signs of a recurrence. The interesting characteristics of these molecules could make them useful in the management of ovarian cancer.


[Cervical and high vaginal aplasia with a functioning uterus. Surgical technic].
The authors describe the conservative surgical treatment of a cervical and high vaginal aplasia with functional uterus. They insist on complete resection of the aplasic area, key of the utero-vaginal continuity.


Evaluation of direct oral anticoagulant use on thromboelastography in an emergency department population.
Direct oral anticoagulant (DOAC) use presents a challenge to all providers involved in emergency care of patients since widely accepted laboratory tests to assess the level of anticoagulation for such medications are lacking. Viscoelastic tests such as thromboelastography (TEG) tests are increasingly used throughout major trauma centers to help guide resuscitation efforts in patients presenting with trauma and/or hemorrhagic shock. The primary outcome compared TEG parameters between emergency department trauma patients reporting DOAC therapy and known normal TEG parameter values. The secondary outcome evaluated patients who reported time of last known DOAC dose within a preferred time frame of <12 h for once daily dosing DOAC therapy or < 6 h for twice daily dosing DOAC therapy. This single-center, retrospective cohort study assessed TEG values in patients receiving DOAC therapy and compared these to institution TEG ranges considered normal. TEG values of reaction time (R time), kinetics (K), alpha angle (AA), maximum amplitude (MA), and percent lysis in 30 min (LY30) were collected for patients reporting DOAC therapy. 40 patients were included in this study. 19 patients reported apixaban therapy and 21 reported rivaroxaban therapy. 5 (12.5%) patients had an elevated R time and 1 (2.5%) patient had a reduced MA. All other TEG values did not suggest hypocoagulability. For the secondary outcome assessing patients reporting last known dose within the preferred time frame, only the R time was elevated in 2 (14.3%) patients. Lastly, in a subgroup analysis of patients with elevated low-molecular-weight heparin (LMWH) orAnti- Xa levels, the R time was the only parameter affected in 25% of patients. TEG values were typically not affected by rivaroxaban or apixaban use in an emergency department trauma population suggesting that TEG is not sensitive for Xa inhibitor detection and should not be relied upon for assessing anticoagulation in such settings.


[Status of the subretinal implant project. An overview].
The development of a subretinal prosthesis has come to a stage where human trials are forthcoming. Subretinal prostheses are designed to replace degenerated photoreceptors in diseases such as retinitis pigmentosa or age-related macular degeneration. Microphotodiode arrays are implanted between retinal pigment epithelium and retina. Our group has collected convincing evidence for the principle feasibility of a subretinal prosthesis. Animal experiments have shown that subretinal electrical stimulation can successfully elicit spatially ordered responses in the visual cortex; visual acuity is estimated to reach 0.25 degrees of visual angle. Histological long-term examinations have demonstrated that the retina tolerates a subretinal implant well and also that the implant itself sustains the ocular environments. Surgical procedures have been successfully developed to implant complex subretinal devices.


Theoretical Prediction on Properties of 3,4-Bisnitrofurazanfuroxan (DNTF) Crystal and its Polymer Bonded Explosives (PBXs) Through Molecular Dynamics (MD) Simulation.
3,4-Bisnitrofurazanfuroxan (DNTF) is a typical high energy density compound (HEDC), it has high crystal density and detonation parameters, but also high mechanical sensitivity. To decrease its mechanical sensitivity, the DNTF based polymer bonded explosives (PBXs) was designed. The pure DNTF crystal and PBXs models were established. The stability, sensitivity, detonation performance and mechanical properties of DNTF crystal and PBXs models were predicted. Results show that PBXs models containing fluorine rubber (F2311) and fluorine resin (F2314) have higher binding energy, meaning that DNTF/F2311 and DNTF/F2314 is relatively more stable. PBXs models have higher value of cohesive energy density (CED) than pure DNTF crystal, DNTF/F2311 and DNTF/F2314 have the highest value of CED, implying that the sensitivity of PBXs is effectively decreased, DNTF/F2311 and DNTF/F2314 is more insensitive. PBXs have lower crystal density and detonation parameters than DNTF, the energy density is declined, DNTF/F2314 has higher energetic performance than other PBXs. Compared with pure DNTF crystal, engineering moduli (tensile modulus, shear modulus, bulk modulus) of PBXs models are obviously decreased, but Cauchy pressure is increased, implying that the mechanical properties of PBXs is superior to pure DNTF component, the PBXs containing F2311 or F2314 have more preferable mechanical properties. Consequently, DNTF/F2311 and DNTF/F2314 have the best comprehensive properties and is more attractive among the designed PBXs, indicating that F2311 and F2314 are more advantageous and promising in ameliorating properties of DNTF. The properties of DNTF crystal and PBXs models were predicted through molecular dynamics (MD) method under Materials Studio 7.0 package. The MD simulation was performed with isothermal-constant volume (NVT) ensemble, and the force field was chosen as COMPASS force field. The temperature was set as 295 K, the time step was 1 fs and the total MD simulation time was 2 ns.


Correlation between nurses' attitude and practice toward communication with patients of decreased level of consciousness and its relationship with ethical care in ICU: A cross-sectional study.
Communication between intensive care unit (ICU) nurses and patients with decreased Level of Consciousness (DLOC) is now regarded as a difficult task. Proper communication is regarded as a crucial component of care and stems from the attitude and practice of nurses. Intensive care nurses are responsible for providing care to patients with DLOC in accordance with ethical principles because care and ethics cannot be separated. To better understand ICU nurses' attitudes and practice toward communicating with patients who have decreased levels of consciousness and how this affects the provision of ethical care, the current study was conducted. This is a cross-sectional study. Two hundred ICU nurses from southeast Iran took part in this study. Three questioners, including attitude and practice toward communicating with patients who decreased Levels of consciousness, and ethical Care were used as data collection tools. The mean score for ICU nurses' attitude, practice, and ethical care towards communicating with patients with DLOC were, respectively, 4.02 ± 0.45,2.91 ± 0.49. The findings demonstrated a very weak correlation between the ICU nurses' attitude score and communication practice for DLOC patients (p = 0.04; r = 0.14). Nurses who had a more positive attitude toward communicating with DLOC patients performed better in this area. It is suggested that nurses employed in ICUs should be monitored and judged based on how well they communicate with DLOC patients through workshops and conferences. By doing this, they would become more cognizant of the necessity for and effective methods of communication with these patients as well as the repercussions of their poor communication practice.


Circulating alanine production and disposal in healthy subjects.
Circulating-alanine production and disposal rates were estimated in eight healthy postabsorptive subjects by means of U-14C alanine and U-14C glucose infusions. The mean circulating-alanine production rate was 368 +/- S.E.M. 28 mumol/min. -1.8(2). Approximately 50 percent of circulating-alanine carbon exchanged rapidly with that of circulating lactate. Approximately 30 per cent of circulating alanine exchanged with protein stores. Other disposal was 29 +/- 2 per cent to circulating glucose and 40 +/- 4 per cent to oxidation. (1) The carbon moieties of circulating alanine and lactate are freely exchangeable. (2) Assessment of the contribution of alanine to gluconeogenesis will depend on establishing the extent to which the precursor pyruvate carbon is derived from glycolysis or from proteolysis. (3) If the principal pyruvate precursor is glycolysis, then the principal specific function of the glucose-alanine cycle appears to be ammonia transport.


Three-dimensional architecture of common benign and precancerous prostate epithelial lesions.
Many glandular lesions can mimic prostate cancer microscopically, including atrophic glands, adenosis and prostatic intraepithelial neoplasia. While the characteristic histopathological and immunohistochemical features of these lesions have been well established, little is known about their three-dimensional architecture. Our objective was to evaluate the three-dimensional organisation of common prostate epithelial lesions. 500 μm-thick punches (n = 42) were taken from radical prostatectomy specimens, and stained with antibodies targeting keratin 8-18 and keratin 5 for identification of luminal and basal cells, respectively. Tissue samples were optically cleared in benzyl alcohol:benzyl benzoate and imaged using a confocal laser scanning microscope. The three-dimensional architecture of peripheral and transition zone glands was acinar, composed of interconnecting and blind-ending saccular tubules. In simple atrophy, partial atrophy and post-atrophic hyperplasia, the acinar structure was attenuated with branching blind-ending tubules from parental tubular structures. Three-dimensional imaging revealed a novel variant of prostate atrophy characterised by large Golgi-like atrophic spaces parallel to the prostate surface, which were represented by thin, elongated tubular structures on haematoxylin and eosin (H&E) slides. Conversely, adenosis lacked acinar organisation, so that it closely mimicked low-grade prostate cancer. High-grade prostatic intraepithelial neoplasia displayed prominent papillary intraluminal protrusions but retained an acinar organisation, whereas intraductal carcinoma predominantly consisted of cribriform proliferations with either spheroid, ellipsoid or complex interconnecting lumens. While various prostate epithelial lesions might mimic malignancy on H&E slides, their three-dimensional architecture is acinar and clearly different from the tubular structure of prostate cancer, with adenosis as an exception.


Incidence of uterine leiomyoma in relation to urinary concentrations of phthalate and phthalate alternative biomarkers: A prospective ultrasound study.
Numerous studies suggest that some phthalates have adverse reproductive effects. However, literature on the association between phthalates and incidence of uterine leiomyomata (UL) is limited and inconsistent, with no existing prospective studies. We examined the association of urinary concentrations of phthalate and phthalate alternative biomarkers with UL incidence. We conducted a case-cohort analysis within a subgroup of 754 participants in the Study of the Environment, Lifestyle, and Fibroids (SELF), a prospective cohort of premenopausal Black women aged 23-35 years who were recruited during 2010-2012. We quantified fourteen phthalates and two phthalate alternative [1,2-cyclohexane dicarboxylic acid, diisononyl ester (DINCH)] biomarkers in urine collected at baseline, 20 months, and 40 months. Transvaginal ultrasounds identified UL at baseline and every 20 months during 60 months of follow-up. We evaluated the individual biomarkers, molar sum of di(2-ethylhexyl) phthalate [ΣDEHP] and potency-weighted sum of anti-androgenic [WΣAA] biomarkers. We used Cox proportional hazards regression to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between biomarkers and UL incidence. We then used quantile g-computation to examine joint associations of multiple phthalate biomarkers with UL incidence. Most individual biomarkers showed weak-to-moderate inverse associations with UL incidence. HRs comparing highest vs. lowest quartiles of mono-isobutyl phthalate (MiBP) and mono-hydroxyisobutyl phthalate (MHiBP) concentrations were 0.63 (95% CI: 0.40, 1.01) and 0.61 (95% CI: 0.38, 0.96), respectively. Inverse associations for specific phthalates were stronger among women with BMI ≥ 30 kg/m2. HRs comparing detectable vs. nondetectable concentrations of DINCH biomarkers were 0.92 (95% CI: 0.62, 1.35) for cyclohexane-1,2-dicarboxylic acid mono hydroxyisononyl ester (MHNCH) and 0.68 (95% CI: 0.38, 1.18) for cyclohexane-1,2-dicarboxylic acid mono carboxyisoocytl ester (MCOCH). For the DEHP metabolite of mono(2-ethylhexyl) phthalate (MEHP), we observed weak-to-moderate positive associations. HRs comparing highest vs. lowest quartiles for MEHP and ΣDEHP were 1.29 (95% CI: 0.82, 2.06) and 0.96 (95% CI: 0.61, 1.50), respectively. In the mixtures analysis, the HR for a joint quartile increase in phthalate biomarker concentrations was 0.90 (95% CI: 0.73, 1.08). In this prospective ultrasound study of reproductive-aged Black women, urinary concentrations of phthalate and DINCH biomarkers were not appreciably associated with higher risk of UL, either individually or jointly.


A live attenuated Edwardsiella tarda vaccine induces immunological expression pattern in Japanese flounder (Paralichthys olivaceus) in the early phase of immunization.
A previous study showed that an attenuated Edwardsiella tarda strain, TXhfq, as a live vaccine could elicit protective immune effects in fish against E. tarda infection. In the current study, in order to clarify the molecular mechanism of fish immune response at the early stage after TXhfq vaccination, RNA-Seq technology was used to compare the transcriptomes of skin, intestine, and spleen between bath-vaccinated and unvaccinated Japanese flounder (Paralichthys olivaceus). An average of 46.6 million clean reads per library was obtained, ~88.04% of which were successfully mapped to the reference genome, and approximately 24,600 genes were detected in each sample. A total of 565, 878, and 1258 differential expression genes (DEGs) were found in skin, intestine, and spleen, respectively, including 1263 up-regulated genes and 1438 down-regulated genes. The DEGs exhibited different characteristics in each tissue. One hundred and sixteen DEGs belonging to six immune related categories were scrutinized, i.e., inflammatory factors, cytokines, complement and coagulation system, mucins, phagocytosis, and antigen processing and presentation. A protein-protein interaction network was constructed to get the interaction network between immune genes during the early stage of immunization. The top six hub genes highly regulated by TXhfq formed complicated interaction relationship with each other, which were involved in immune processes, notably inflammation and phagocytosis. Our results provide valuable information for the understanding of the immune mechanism underlying the protection of live attenuated vaccines in fish.


Simultaneous determination of acrylamide and 4-hydroxy-2,5-dimethyl-3(2H)-furanone in baby food by liquid chromatography-tandem mass spectrometry.
A liquid chromatography triple quadrupole mass spectrometry method was developed and validated for the simultaneous determination of acrylamide and 4-hydroxy-2,5-dimethyl-3(2H)-furanone (HDMF) in baby food. The sample preparation involves acetonitrile-based extraction combined with dispersive primary secondary amine (PSA) cleanup and cation-exchange solid-phase extraction (SPE), which promotes efficient removal of matrix interferences. Analytical selectivity and sensitivity were achieved for the quantification of acrylamide and HDMF in complex matrices such as fruit, cereal and milk-based baby foods; furthermore, adequate linearity (range 10-300μgkg-1) in solvent and matrix-matched calibration curves, and appropriate recoveries (94-110%) and precision (RSD≤10%), under repeatability and within-laboratory reproducibility conditions, were also obtained. Expanded measurement uncertainty was estimated at the 20μgkg-1 level (limit of quantification) on the basis of data obtained from in-house validation, with values of 25.5 and 16.5% for acrylamide and HDMF, respectively. The fitness for purpose of developed method was verified by analyzing 15 commercial baby foods available in the Brazilian market. Acrylamide was detected in one plum-based baby food (35μgkg-1) while HDMF in 67% of the samples analyzed (levels between 25 and 262μgkg-1).


scTEM-seq: Single-cell analysis of transposable element methylation to link global epigenetic heterogeneity with transcriptional programs.
Global changes in DNA methylation are observed in development and disease, and single-cell analyses are highlighting the heterogeneous regulation of these processes. However, technical challenges associated with single-cell analysis of DNA methylation limit these studies. We present single-cell transposable element methylation sequencing (scTEM-seq) for cost-effective estimation of average DNA methylation levels. By targeting high-copy SINE Alu elements, we achieve amplicon bisulphite sequencing with thousands of loci covered in each scTEM-seq library. Parallel transcriptome analysis is also performed to link global DNA methylation estimates with gene expression. We apply scTEM-seq to KG1a acute myeloid leukaemia (AML) cells, and primary AML cells. Our method reveals global DNA methylation heterogeneity induced by decitabine treatment of KG1a cells associated with altered expression of immune process genes. We also compare global DNA methylation estimates to expression of transposable elements and find a predominance of negative correlations. Finally, we observe co-ordinated upregulation of many transposable elements in a sub-set of decitabine treated cells. By linking global DNA methylation heterogeneity with transcription, scTEM-seq will refine our understanding of epigenetic regulation in cancer and beyond.


Spermatogenesis in the turkey (Meleagris gallopavo): quantitative approach in immature and adult males subjected to various photoperiods.
The objectives of this study were to identify and quantitate the germ cell populations of the testes in sexually mature male turkeys (Trial 1), determine the duration of meiosis based on BrdU labeling and stereological analyses (Trial 2), and examine the impact of various photoperiods on germinal and somatic cell populations in immature and adult males (Trial 3). In Trial 1, both testes within a male had similar stereological components (P>0.05) for all parameters analyzed. In Trial 2, the duration of Type-1 spermatocytes and round spermatids in turkeys lasted 4.5+/-0.5 and 2.0+/-0.5 days, respectively. In Trial 3, the short photoperiod (7L:17D) delayed testicular growth (in the stereological parameters analyzed). In contrast, the effect of a moderately short photoperiod (10.5L:13.5D) was comparable to the effect of a long (14L:10D) or increasing photoperiod (7L:17D to 14L:10D) on the stereological parameters examined. With the exception of the short photoperiod, all other photoperiods used in this study induced comparable early testicular maturation, with maximum testis weight at 29-35 weeks of age. As the males got older, there was a progressive, linear decline in testis weight through 60 weeks, at which time there were no significant differences among photoperiods. In conclusion, the duration of meiosis in the turkey was similar to that observed in the fowl and guinea-fowl. The existence of a threshold of photosensitivity to gonad stimulation in male turkeys is suggested to be between 7.0 and 10.5 h of light.


The topography of scalp potentials evoked by pattern pulse stimuli.
Pattern pulse stimuli evoke activity in two distinct regions of the human visual cortex in temporal sequence. The earlier responding region (implicit time 93 msec) is localized to a relatively small region near Oz. Its topography is very sensitive to the position of the evoking stimulus in the visual field; it is dominated by a representation of the visual field near the vertical meridian. The later responding cortical region (implicit time 131 msec) is larger than the earlier one. Its medial border touches the lateral border of the earlier responding cortical region and it extends several cm laterally. Its topography is much less sensitive to the position of the evoking stimulus in the visual field. Stimuli presented to the ipsilateral field evoke either weak or no measurable activity in the earlier responding cortical region but often evoke measurable activity near the lateral boundary of the later responding cortical region. These results suggest that the earlier responding cortical region is striate cortex and that the later responding cortical region is composed of visual areas V2, V3, V3A, and V4.


Nitric oxide-mediated alleviation of arsenic stress involving metalloid detoxification and physiological responses in rice (Oryza sativa L.).
Rice is a staple crop, and food chain contamination of arsenic in rice grain possesses a serious health risk to billions of population. Arsenic stress negatively affects the rice growth, yield and quality of the grains. Nitric oxide (NO) is a major signaling molecule that may trigger various cellular responses in plants. The protective role of NO during arsenite (AsIII) stress and its relationship with plant physiological and metabolic responses is not explored in detail. Exogenous NO, supplemented through the roots in the form of sodium nitroprusside, has been shown to provide protection vis-à-vis AsIII toxicity. The NO-mediated variation in physiological traits such as stomatal density, size, chlorophyll content and photosynthetic rate maintained the growth of the rice plant during AsIII stress. Besides, NO exposure also enhanced the lignin content in the root, decreased total arsenic content and maintained the activities of antioxidant isoenzymes to reduce the ROS level essential for protecting from AsIII mediated oxidative damage in rice plants. Further, NO supplementation enhanced the GSH/GSSG ratio and PC/As molar ratio by modulating PC content to reduce arsenic toxicity. Further, NO-mediated modulation of the level of GA, IAA, SA, JA, amino acids and phenolic metabolites during AsIII stress appears to play a central role to cope up with AsIII toxicity. The study highlighted the role of NO in AsIII stress tolerance involving modulation of metalloid detoxification and physiological pathways in rice plants.


Risk of Late-Onset Depression and Cognitive Decline: Results From Inflammatory Proteome Analyses in a Prospective Population-Based Cohort Study.
Research suggests that inflammation is linked to both late-onset depression (LOD) and cognitive decline, and that LOD might have biological underpinnings differentiating it from recurrent depression. Evidence from inflammatory proteome analyses in large prospective cohorts is scarce. The aim of this study was to assess whether and which inflammation-related biomarkers are associated with LOD, recurrent depression, and cognitive decline due to vascular pathology (vascular dementia). Ongoing population-based cohort study of older adults followed for up to 17 years with regard to clinical diagnosis of various age-related diseases (ESTHER study, n = 9,940). Longitudinal cohort started in 2000-2002 in a community setting in Saarland, a southwestern German state. Subgroup of randomly selected participants of the ESTHER study (n = 1,665). Inflammatory biomarkers were measured with the Olink Target 96 in baseline samples. Out of 78 biomarkers interleukin 10 (IL-10) and C-C chemokine ligand 4 (CCL4) were associated with significantly increased risk of LOD after multiple testing correction. Hazard ratios (95-confidence interval) per 1 standard deviation increase were 1.37 (1.15-1.63) for IL-10 and 1.34 (1.13-1.59) for CCL4. None of the inflammatory markers was associated with recurrent depression. The dose-response analysis showed a similar monotonic risk increase for LOD and vascular dementia with increasing IL-10 levels. These results suggest that inflammatory markers are involved in the etiology of LOD, but not of recurrent depression and that LOD and vascular dementia might share common inflammatory etiology with respect to IL-10.


24-h Systolic blood pressure and heart rate recordings in lean and obese adolescents.
We assessed the hypothesis that differences in day and night-time systolic blood pressure (SBP) and heart rate (HR) recordings were smaller in obese versus lean children and adolescents, and whether measurements obtained during a school week or during weekends or holidays influenced these nocturnal falls. We also wanted to determine whether the results were influenced by gender. Ambulatory 24-h BP and HR measurements were performed in 80 subjects, 51 girls and 29 boys. Lean (n = 25) and obese (n = 55) subjects were classified according to body mass index (BMI)-standard deviation (SD) criteria. Forty-eight subjects had their 24-h recordings performed during a school week and 32 during leisure time. The SBP nocturnal dipping response was less pronounced in obese subjects (16.2 +/- 6.3 mmHg) compared with lean controls (21.1 +/- 5.7 mmHg) (P < 0.01) of which the girls constituted most of the difference. HR change between day and night was similar in both groups being approximately 15 b/min. A small but statistical negative correlation was observed between BMI-SD and nocturnal fall in SBP (r = -0.3, P = 0.0065). In all subjects, regardless of BMI-SD, daytime SBP was higher when readings were obtained during a school week (123 +/- 7 mmHg) than during weekends or holidays (119 +/- 7 mmHg) (P = 0.029). Obese children and adolescents showed smaller nocturnal falls in SBP compared with lean subjects. This pattern may cause increased cardiovascular loading; thus, it may reflect an early sign of high blood pressure development and adds to cardiovascular risk in young obese individuals.


Novel gait training alters functional brain connectivity during walking in chronic stroke patients: a randomized controlled pilot trial.
A recent study has demonstrated that a turning-based treadmill program yields greater improvements in gait speed and temporal symmetry than regular treadmill training in chronic stroke patients. However, it remains unknown how this novel and challenging gait training shapes the cortico-cortical network and cortico-spinal network during walking in chronic stroke patients. The purpose of this study was to examine how a novel type of gait training, which is an unfamiliar but effective task for people with chronic stroke, enhances brain reorganization. Subjects in the experimental and control groups received 30 min of turning-based treadmill training and regular treadmill training, respectively. Cortico-cortical connectivity and cortico-muscular connectivity during walking and gait performance were assessed before and after completing the 12-session training. Eighteen subjects (n = 9 per group) with a mean age of 52.5 ± 9.7 years and an overground walking speed of 0.61 ± 0.26 m/s consented and participated in this study. There were significant group by time interactions for gait speed, temporal gait symmetry, and cortico-cortical connectivity as well as cortico-muscular connectivity in walk-related frequency (24-40 Hz) over the frontal-central-parietal areas. Compared with the regular treadmill training, the turning-based treadmill training resulted in greater improvements in these measures. Moreover, the increases in cortico-cortical connectivity and cortico-muscular connectivity while walking were associated with improvements in temporal gait symmetry. Our findings suggest this novel turning-based treadmill training is effective for enhancing brain functional reorganization underlying cortico-cortical and corticomuscular mechanisms and thus may result in gait improvement in people with chronic stroke. ACTRN12617000190303 . Registered 3 February 2017, retrospectively registered.


Improved myocardial blood flow estimation with residual activity correction and motion correction in 18F-flurpiridaz PET myocardial perfusion imaging.
We sought to evaluate the diagnostic performance for coronary artery disease (CAD) of myocardial blood flow (MBF) quantification with 18F-flurpiridaz PET using motion correction (MC) and residual activity correction (RAC). In total, 231 patients undergoing same-day pharmacologic rest and stress 18F-flurpiridaz PET from Phase III Flurpiridaz trial (NCT01347710) were studied. Frame-by-frame MC was performed and RAC was accomplished by subtracting the rest residual counts from the dynamic stress polar maps. MBF and myocardial flow reserve (MFR) were derived with a two-compartment early kinetic model for the entire left ventricle (global), each coronary territory, and 17-segment. Global and minimal values of three territorial (minimal vessel) and segmental estimation (minimal segment) of stress MBF and MFR were evaluated in the prediction of CAD. MBF and MFR were evaluated with and without MC and RAC (1: no MC/no RAC, 2: no MC/RAC, 3: MC/RAC). The area-under the receiver operating characteristics curve (AUC [95% confidence interval]) of stress MBF with MC/RAC was higher for minimal segment (0.89 [0.85-0.94]) than for minimal vessel (0.86 [0.81-0.92], p = 0.03) or global estimation (0.81 [0.75-0.87], p < 0.0001). The AUC of MFR with MC/RAC was higher for minimal segment (0.87 [0.81-0.93]) than for minimal vessel (0.83 [0.76-0.90], p = 0.014) or global estimation (0.77 [0.69-0.84], p < 0.0001). The AUCs of minimal segment stress MBF and MFR with MC/RAC were higher compared to those with no MC/RAC (p < 0.001 for both) or no MC/no RAC (p < 0.0001 for both). Minimal segment MBF or MFR estimation with MC and RAC improves the diagnostic performance for obstructive CAD compared to global assessment.


Triamcinolone acetonide release modelling from novel bilayer mucoadhesive films: an in vitro study.
Recurrent aphthous stomatitis (RAS) is a painful disorder that commonly appears as ulcers on the oral mucosa, lasting ∼two weeks (minor) to months (major and herpetiform). Current treatment often necessitates the use of topical steroids in the form of pastes, mouthwashes, or gels, but these forms are often ineffective due to inadequate drug contact time with the ulcers. In this study, the performance of novel bilayer mucoadhesive buccal films loaded with triamcinolone acetonide (TA) has been evaluated for targeted drug delivery. Experimental mucoadhesive films of hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), and polyvinyl pyrrolidone (PVP) were prepared by the solvent casting method, and ethyl cellulose (EC) was applied as the backing layer. The films were characterized for their physical properties, including swelling index (SI), folding endurance, adhesion force with porcine buccal mucosa, residence time and in-vitro drug release. The data showed that the films were flexible with folding endurance> 300 times. With porcine buccal mucosa i) suitable adhesion forces were obtained (between 2.72 and 4.03 N), ii) residence times of> 24 h, and iii) surface pH between 6.8 and 7.1 indicating they would be non-irritant. All films released 100% TA over 6 h, but with varying profiles. The release of TA (over 6 h) from PVP-free films followed Fickian diffusion kinetics (diffusion-controlled release of drug), whereas the mechanism of release from PVP-containing films was found to be a superposition of diffusion-controlled and erosion-controlled release (anomalous). The developed films hold great promise for potentially treating RAS and other oral conditions.


Come and Knock on Our Door: Offenders' Perspectives on Home Visits Through Ecological Theory.
The use of home visits has a long and storied history in the United States from different disciplines, such as nursing, prenatal mothers, young families, health promotion, and community corrections. Ecological theory explains how formal actors play a role in the promotion in the health field through home visits, but does not address community corrections home visits. Through the use of 30 semi-structured interviews, this research seeks to expand the understanding of ecological theory by capturing the perceptions of offenders sentenced to home visits conducted by a sheriff's office. The findings suggest the participants supported the home visits by formal agents and, in general, the home visits created an atmosphere of respect between the participants and sheriff's office personnel. This study creates the context for future research to understand the role of formal agents in recidivism and evaluate the efficacy of home visits by community corrections agencies.


The specificity of H-2-restricted cytotoxic T lymphocytes directed to AKR/Gross leukemia virus-induced tumors. II. Altered gp70 display and production of noninfectious virus particles by an insusceptible variant tumor.
Derived from the susceptible AKR.H-2bSL1 tumor cell line, a variant tumor subclone, cl.18-5, was selectively insusceptible to H-2-restricted anti-AKR/Gross virus cytotoxic T lymphocytes (CTL) due to its failure to be recognized. In this study, the expression of virus-related products by variant cl.18-5 cells was compared to that of AKR.H-2bSL1 cells and a susceptible clone, as an approach towards defining the virus-associated antigens recognized by anti-AKR/Gross virus CTL. Despite the type specificity of the CTL, cl.18-5 displayed normal levels of the group-specific antigen (gag) encoded proteins p30, p15, p12 and p10, and the gag-associated Gross cell surface antigen. These results were confirmed by fluorescence-activated cell sorter analysis employing monoclonal antibodies specific for either AKR p12 or the cell surface glycosylated form of AKR ecotropic gag product. In contrast, cl.18-5 was variably less sensitive than AKR.H-2bSL1 to the action of complement and xenogeneic antisera directed against the envelope (env) product gp70. In addition, a panel of five monoclonal antibodies to gp70, which detect distinct endogenous ecotropic viral determinants, lysed AKR.H-2bSL1, but not cl.18-5 cells. However, absorption experiments indicated that cl.18-5 did express near normal levels of these specificities, suggesting an alteration in the orientation or topographical distribution of these determinants. Consistent with an inappropriate display of env products, cl.18-5 was found to be deficient in the production of infectious ecotropic leukemia virus. The particulate fraction of the cell-free supernatant of cl.18-5 contained normal levels of reverse transcriptase activity, indicating that noninfectious viral particles were being produced. Collectively, these results point to an association between recognition by anti-AKR/Gross virus CTL and the expression of ecotropic gp70 required for infectivity of virus.


Attention and time estimation in 5- and 8-year-old children: a dual-task procedure.
This experiment tested the effect of a dual-task on time reproduction in 5- and 8-year-olds. Children had to reproduce a stimulus duration lasting for 6 or 12 s, during which they either did or did not perform a concurrent non-temporal task (i.e. picture naming) both in low (LA) and high (HA) attentional demand conditions. The results showed that children reproduced shorter durations in the dual-task than in the single-task condition, whatever the duration value used. However, this shortening effect was greater in the 5-year-olds than in the 8-year-olds. Furthermore, in the 5-year-olds, temporal reproductions were significantly shorter in both dual-tasks (LA or HA) than in the single-task, whereas, in the 8-year-olds, differences reached significance only between the HA dual-task and the single-task. In the non-temporal task, the proportion of naming errors was also greater in the dual-task than in the single-task, especially under high attentional demand, but it did not significantly differ between the two age groups tested.


Level of serum IL-33 and emphysema paraseptal in clove cigarette smoker with spontaneous pneumothorax: A case report.
A young male clove cigarette smoker experienced spontaneous pneumothorax and later paraseptal emphysema was detected on high-resolution computed tomography (HRCT) scan without respiratory symptoms. Smoking is a known risk factor for emphysema. Paraseptal emphysema is a type of emphysema that rarely causes respiratory symptoms, nevertheless, usually accompanied by spontaneous pneumothorax. Interleukin 33 (IL-33) is an alarmin cytokine that belongs to the IL-1 family. The effects of IL-33 depend on its structure. In its mature form, it is a cytokine alarmin that binds to ST2 (suppression of tumorigenicity) receptors on the surface of macrophages and innate immune cells to drive Th1/Th2 immune responses, causing oxidative stress, and increased IL-33 production causes polarization of alveolar macrophages to an M2 phenotype. In this study, long-term exposure to clove cigarette smoke caused an increased serum level of IL-33 (43.72 pg/mL) and paucigranulocytic airway inflammation. In paucigranulocytic inflammation, IL-33 is involved in lung parenchymal damage presumably through oxidative stress, activation of alveolar macrophage and increased MMP12 secretion, resulting in alveolar destruction and airspace enlargement.


[Complexes of apo-B-containing lipoproteins and glycosaminoglycans with a density greater than 1.063 gML in the human aorta].
Interaction of lipoproteins of very low and low density with glycosaminoglycans was studied in vitro. Using analytical and preparative ultracentrifugation the complexes formed were shown to possess a density above 1.063 g/ml. Similar complexes were identified in extracts of human aorta. The formation of the complexes was stimulated in atherosclerotic impairments of aorta.


Outcomes of bladder neck closure for intractable urinary incontinence in patients with neurogenic bladders.
Recent reports of outcomes of bladder neck closure for neurogenic urinary incontinence reveal poor initial continence and high vesicourethral fistula rates. We evaluated a large series of patients who underwent complete transection and closure of the bladder neck with modified abdominal stoma creation. The medical records of 52 consecutive patients (23 males and 29 females) undergoing bladder neck closure by a single surgeon between July 1996 and January 2003 were reviewed. Mean follow up was 20 months (range 2-68 months) and mean age was 13.9 years (range 1.5-58 years). Forty-two patients (81%) underwent concomitant bladder augmentation. Catheterizable stomas included 46 appendicovesicostomies (88%) and six Monti tubes (12%). Of the 52 patients, 22 were confined to wheelchairs (42%), and the majority of patients had spinal cord pathology (40/52, 77%). Mean preoperative vesical leak point pressure was 25 cm/H(2)O (range 4-69 cm/H(2)O). Complete postoperative urinary continence was achieved in 44 patients (88%) after one procedure. Of the six patients who were incontinent (12%), one had a vesicourethral fistula (2%) and five had incontinence at the urinary diversion stoma (10%). Twelve of 50 patients had urinary stomal stenosis (24%), with six requiring urgent evaluation (12%) and six requiring surgical revision (12%). Postoperative urinary continence was unknown in two patients due to inadequate follow-up data. Our findings suggest that bladder neck closure is a safe and effective method of achieving urinary continence in children with neurogenic voiding dysfunction. While there are risks of stomal stenosis and fistula formation, modifications in surgical technique may reduce them to acceptable levels.


Mortality in schizophrenia and bipolar disorder: Clinical and serological predictors.
Persons with schizophrenia and with bipolar disorder have a reduced life expectancy due largely to death from natural causes. The reasons for this increased mortality have not been completely defined. We prospectively assessed a cohort of persons with schizophrenia and one with bipolar disorder with a clinical evaluation and a blood sample from which immune and infectious disease markers were measured. Mortality was determined with data from the National Death Index following a period of up to 14years. We examined the role of demographic, clinical, and serological factors on mortality in bivariate and multivariate models. A total of 43/710 (6.1%) persons with schizophrenia and 12/406 (3.0%) with bipolar disorder died of natural causes. In the schizophrenia group, mortality was predicted by the following variables in a multivariate model: cigarette smoking (RR=6.93, 95% CI 1.59, 30.1, p=0.0099); autoimmune disorder (RR=8.08, 95% CI 2.50, 26.1, p=0.00047); gastrointestinal disorder (GI) (RR=3.53, 95% CI 1.43, 8.69 p=0.0061); and reduced maternal education (RR=0.84, 95% CI 0.72, 0.97), p=0.018. The combination of smoking and an autoimmune disorder yielded an unadjusted relative risk of 18.1 for mortality, and the combination of smoking and a GI disorder an unadjusted relative risk of 9.45, compared with individuals with neither risk factor. In the bipolar disorder group, significant bivariate predictors of mortality included lower cognitive score (RR=0.95, p=.0085) and the presence of type 1 or 2 diabetes (RR=3.90, p=.026). Given the extraordinary high risk of death due to smoking in schizophrenia, smoking cessation remains an urgent priority.


Lack of evidence for the association of tumor necrosis factor-alpha gene promoter polymorphism with calcium oxalate stone and bladder cancer patients.
Urinary stone disease and bladder cancer are two of the most commonly seen urologic diseases in Taiwan. Tumor necrosis factor-alpha (TNF-alpha) is one of the cytokines secreted by macrophages and is related to a sequence of events in response to inflammation and cancer formation. We investigated the polymorphism of the TNF-alpha gene promoter -308 as a genetic marker in searching for the association between these two commonly seen urologic diseases. One hundred and fourteen patients with transitional cell carcinoma of the urinary bladder and 103 patients with calcium oxalate stone were compared with 150 healthy controls. The polymorphism was detected by polymerase chain reaction-based restriction analysis (Nco I endonuclease). The results revealed no significant differences between normal individuals and the patients with the two commonly seen urologic diseases (P > 0.05). We concluded that the polymorphism of the TNF-alpha promoter -308 is not a valid genetic marker for these two urologic diseases.


UV/ozone induced physicochemical transformations of polystyrene nanoparticles and their aggregation tendency and kinetics with natural organic matter in aqueous systems.
Once discharged into the environment, plastics debris are unavoidably subjected to natural weathering processes. Unfortunately, the impact of weathering on the aggregation tendency and kinetics of nanoplastics in complex environmental matrices is poorly understood. Here, we investigated the influence of weathering as induced by UV and O3 treatments, on the aggregation of polystyrene nanoparticles (PSNPs) in simulated waters containing representative organic molecules (humic acid, lysozyme, and alginate) and in natural waters. Results showed that UV/O3 weathering-induced physicochemical transformations of PSNPs, particularly the formation of oxygen-containing functional groups and the increase in hydrophilicity, altered the aggregation state of PSNPs to different extents. The presence of organic molecules destabilized the UV-aged PSNPs with strength of lysozyme > alginate > humic acid, owing to the decrease of sorption of macromolecules on their surface. Differently, the O3-aged PSNPs displayed strong stability in the absence or presence of organic molecules (except for lysozyme), probably due to steric repulsion arising from the leakage of endogenous organic matters. This work demonstrates that the aggregation behavior of PSNPs is determined by the complex interplays among weathering, natural organic matter, and solution chemistry, and provides significant insights into the fate and transport of PSNPs in realistic scenarios.


Innovative ways of integrating public health into the medical school curriculum.
This is one of six short papers that describe additional innovations to help integrate public health into medical education; these were featured in the "Patients and Populations: Public Health in Medical Education" conference. They represent relatively new endeavors or curricular components that had not been explored in prior publications. Although evaluation data are lacking, it was felt that sharing a description of the methods use by Morehouse School of Medicine to integrate public health in the curriculum would be of value to medical educators.


Characterization of the absorption phase of marijuana smoking.
Rapid blood collection, a paced smoking protocol and timely collection of physiologic and behavioral measures were used to characterize the absorption phase of marijuana smoking. Six healthy males smoked a single marijuana cigarette (placebo, 1.75%, or 3.55% delta-9-tetrahydrocannabinol) in a double-blind, randomized, Latin square study design. Rapid blood sampling with a continuous withdrawal pump allowed simultaneous collection with concurrent physiologic and behavioral measures. Mean plasma levels of 7.0 and 18.1 ng/ml delta-9-tetrahydrocannabinol were observed after the first inhalation of a 1.75% and 3.55% delta-9-tetrahydrocannabinol cigarette, respectively. Blood levels increased rapidly and peaked at 9 minutes, before initiation of the last puff sequence at 9.8 minutes. Three of six subjects reported increases in drug "liking" scores after the first puff, and all subjects responded by the second puff of a high dose cigarette. Significant increases in heart rate and diastolic blood pressure occurred shortly after peak blood levels. Previous studies have indicated that there is a substantial time delay between peak plasma levels of delta-9-tetrahydrocannabinol and drug-induced effects. This study showed that behavioral and physiologic effects appear concurrently or within minutes after the rapid appearance of delta-9-tetrahydrocannabinol in blood during marijuana smoking.


Suppression of axonal attractant netrin-1 injured dopaminergic neuronal and motor function of mice during manganese overexposure.
Manganese (Mn) can accumulate in the striatum through the blood-brain barrier and cause neurotoxicity. It is mainly due to the decrease of dopamine (DA) levels in the striatum, which leads to extrapyramidal dysfunction. Netrin-1, as an axon guidance factor, can regulate the normal transmission of DA. However, few people have explored the role of netrin-1 in Mn-induced neurotoxicity. The purpose of the present study is to verify whether overexposure of Mn inhibits the axon attractant netrin-1, thereby damaging dopaminergic neuronal and motor function of mice. Here, we found that excessive Mn exposure reduces the expression of striatum netrin-1, tyrosine hydroxylase, DA receptor D3, and dopamine transporter 1, and the levels of serum netrin-1, and promotes dopaminergic neuronal and striatum injury, leading to DA transmission and motor dysfunction. Notably, recombinant mouse netrin-1 protein significantly antagonized Mn-induced neurotoxicity. These findings suggest that netrin-1 participates in Mn-induced motor dysfunction. Our findings may provide an experimental basis for fully elucidating the effects of Mn-induced neurotoxicity.


Factors Associated with Prolonged Recipient Hepatectomy Time During Liver Transplantation: A Single-Centre Experience.
Recipient hepatectomy during liver transplantation can be a challenging operation and can increase cold ischaemic time. The aim of this study is to assess factors associated with prolonged recipient hepatectomy. From 2005 to 2015, 930 patients were submitted to liver transplantation in our hospital. Prolonged hepatectomy time was defined as operative time >180 min (from knife on skin to total hepatectomy). Patients undergoing early liver retransplantation and living donation were excluded. A total of 715 patients were included in our study. Median age at transplantation was 53 (18-70) years, and median BMI was 26.2 (16-40). Median hepatectomy time was 131 min. Prolonged hepatectomy time occurred in 89 (12.4%) patients. At univariate analysis, previous decompensated cirrhosis with variceal bleeding and/or ascites, higher BMI and previous abdominal surgery were associated with prolonged operating time. Higher surgeon experience and acute liver failure were associated with shorter hepatectomy time. At multivariate analysis, previous episodes of variceal bleeding (p = 0.027, OR 1.78), BMI > 27 (p = 0.01, OR 1.75), previous abdominal surgery (p = 0.04, OR 1.68) and surgeon experience (p = 0.007, OR 2.04) were independently associated with operating time. Prolonged hepatectomy time was significantly associated with cold and total ischaemic time and intraoperative bleeding (p < 0.001, p = 0.002 and p = 0.002, respectively). Recipient BMI, previous episodes of variceal bleeding, previous abdominal surgery and surgeon experience are independently associated with hepatectomy duration. These factors can be helpful to identify those patients with potentially prolonged hepatectomy time, and therefore, strategies can be put in place to optimize outcomes in this group of patients.


Predicting the efficacy of opioid sequestration by intravenous lipid emulsion using biologically relevant in vitro models of drug distribution.
Intravenous lipid emulsions (ILE), among other uses, are utilized in the treatment of poisonings caused by lipophilic substances. The body of evidence regarding the benefits of this treatment is growing but information about opioids-ILE interaction is still very scarce. In this work, the impact of ILE on the distribution of buprenorphine, fentanyl and butorphanol used in various concentrations (100-500 ng/ml) was investigated. Two different in vitro models were used: disposition of the drugs in plasma after ultracentrifugation and distribution into the simulated biophase (cell monolayer of 3T3 fibroblasts or J774.E macrophages). We confirmed the ability of ILE to sequester the three drugs of interest which results in their decrease in the aqueous part of the plasma by 34.2-38.2%, 11.7-28.5% and 6.0-15.5% for buprenorphine, fentanyl and butorphanol, respectively. Moreover, ILE affected the drug distribution to the biophase in vitro, however, in this case the drug concentration in cells decreased by 97.3 ± 3.1%, 28.6 ± 5.4% and 13.0 ± 7.5% for buprenorphine, fentanyl and butorphanol, respectively. The two models revealed notable differences in ILE's potential for drug sequestration, especially for buprenorphine. Similar, but not as pronounced tendencies were observed for the two other drugs. These discrepancies may result from the difference in protein abundance and resulting drug-protein binding in both systems. Nevertheless, the results obtained with both in vitro models correlated well with the partition coefficient (logP) values for these drugs.


A technique for replacement of long term venous access catheters.
A technique for tunneled, right atrial catheter replacement using a guide wire is described. It is simple, safe and allows for the conservation of veins in patients who may need multiple venous access routes throughout the therapeutic period.


Back Table Preparation of the Right Lobe Live Donor Liver Allograft: A Crucial Part of the Adult Live Donor Liver Transplant Procedure.
We aimed to describe our procedure for vascular reconstruction and back table bench preparation for the right lobe live donor allograft. Live donor liver transplantation (LDLT) remains an important option for the expansion of the donor pool. The procedure has been widely used, and its success is dependent on a technically perfect operation with appropriate inflow and outflow of the allograft. Adequate preparation of the right lobe (RL) allograft prior to implantation remains a vital part of the procedure. Our technique of back table vascular reconstruction of the RL allograft has been performed using a hepatic vein patch venoplasty, inferior hepatic vein inclusion, portal vein reconstruction, and segment V and VIII reconstruction for all of our LDLTs. Between March 2009 and January 2020, 321 consecutive adult LDLTs were performed and underwent back table reconstruction with the techniques described. During that time period, no patients had hepatic insufficiency. There was a single thrombosis of a superior mesenteric vein (SMV) to PV jump conduit. Our technique of back table reconstruction of the LDLT right lobe graft remains a crucial part of the operative procedure. Our experience with RL grafts without middle hepatic vein (MHV) and our systematic approach for inflow and outflow reconstruction has yielded excellent results with no technical outflow issues and minimal inflow complications.


3-Nitropropionic acid-induced depression of spinal reflexes involves mechanisms different from ischemia-induced depression.
Effect of 3-nitropropionic acid (3-NPA) and ischemia (glucose- and O(2)-free solution) on synaptic transmission in hemisected spinal cord from 4 to 8 day old rats was examined in vitro. Stimulation of a dorsal root (L3-5 segments) evoked monosynaptic (MSR) and polysynaptic reflex (PSR) potentials in the segmental ventral root. Superfusion of 3-NPA (0.17-3.4 mM) depressed the reflexes in a concentration- and time-dependent manner. At 3.4 mM of 3-NPA, the reflexes were abolished by 35 min. Time required to produce 50% depression (T-50) was around 170, 80, 40 and 17 min for MSR and 110, 70, 25 and 16 min for PSR at 0.17, 0.51, 1.7 and 3.4mM of 3-NPA, respectively. Ischemia also produced a time-dependent depression of reflexes and abolished them by 35 min and the T-50 values were around 18 min. Presence of creatine phosphate (10mM) in the superfusing medium did not alter the time course of 3-NPA-induced depression of reflexes but prolonged the ischemia-induced depression. dl-2-amino-5-phosphonovaleric acid (NMDA receptor antagonist; 10 microM) failed to block the 3-NPA (3.4 mM)-induced depression of reflexes, but blocked the ischemia-induced depression. The results indicate that 3-NPA-induced depression of spinal reflexes does not involve NMDA receptors and is different from ischemia-induced depression.


Sarcopenia prevalence and associations with mortality and hospitalisation by various sarcopenia definitions in 85-89 year old community-dwelling men: a report from the ULSAM study.
Operational definitions of sarcopenia, i.e. loss of muscle function and mass, have been proposed by the European Working Group on Sarcopenia in Older People (EWGSOP) and the Foundation for the National Institutes of Health Sarcopenia Project (FNIH). The aim of this study was to analyse the prevalence and outcome, i.e. all-cause mortality and hospitalisation, of sarcopenia and its diagnostic components in octogenarian community-dwelling men. In total 287 men, aged 85-89 y, participating in the Uppsala Longitudinal Study of Adult Men (ULSAM) underwent Dual X-ray Absorptiometry (DXA), measurement of hand grip strength (HGS), gait speed (GS), and a five-times chair stand test (CS). Sarcopenia and probable sarcopenia were defined according to EWGSOP (2010), EWGSOP2 (2018), and FNIH (2014). All-cause mortality and hospitalisations over 3 years were registered. Sarcopenia according to EWGSOP, EWGSOP2 and FNIH was observed in 21%, 20%, and 8% of the men, respectively, while probable sarcopenia (EWGSOP2; eq. reduced muscle strength only) was seen in 73%. "Sarcopenia (EWGSOP)" and "probable sarcopenia (EWGSOP2)" were associated with increased mortality (HR 1.95, 95% CI 1.12-3.40 and HR 3.26, 95% CI 1.38-7.70, respectively). "Probable sarcopenia (EWGSOP2)" was associated with days of hospitalisation (RR 2.12, 95% CI 1.36-3.30), whereas sarcopenia according to FNIH showed an association with the number of hospitalisations (RR 1.75, 95% CI 1.10-2.81). In very old men, reduced muscle strength, i.e. probable sarcopenia, was common and associated with mortality and length of stay during hospitalisation. When combined with low muscle mass (according to DXA), i.e. sarcopenia, the various definitions were associated more weakly with the adverse outcomes. The findings support the emphasis on reduced muscle strength as the major determinant of sarcopenia.


Antitumor alkylating agents: in vitro cross-resistance and collateral sensitivity studies.
Cell lines resistant to five antitumor alkylating agents (CDDP, PAM, 4-HC, HN2, and BCNU) were developed from five parental human tumor lines representative of solid tumors with a range of sensitivities to antitumor alkylating agents. The parental cell lines were SCC-25 squamous carcinoma of the head and neck, MCF-7 breast carcinoma, SW2 small-cell lung cancer, SL6 non-small-cell lung carcinoma, and G3361 melanoma. Survival curves using colony formation as the endpoint were generated for each of the 25 cell lines to each of the five alkylating agents. Comparison of the drug concentrations that reduced the survival of the alkylating agent-resistant cell lines by 90% (IC90 values) with the IC90 values obtained for the corresponding parental cell lines was used as a measure of the resistance/sensitivity of the alkylating agent-resistant lines to each drug tested. Although cross-resistance among the alkylating agents was generally uncommon, several patterns of response emerged. Cross-resistance occurred in 27 of the 105 determinations and occurred most frequently in the cell lines in which resistance was developed to PAM (57%) or BCNU (38%). Cross-resistance to HN2 occurred most frequently. Collateral sensitivity was equally as common, occurring in 25 of the 105 determinations. Collateral sensitivity occurred most frequently in the cell lines made resistant to 4-HC. The 4-HC-resistant cell lines were most frequently collaterally sensitive to PAM and to BCNU. Cross-resistance developed most frequently in the MCF-7 breast carcinoma and SCC-25 squamous-cell carcinoma cell lines, whereas collateral sensitivity developed most frequently in the SW2 small-cell lung cancer line and the G3361 melanoma cell line and least frequently in the MCF-7 breast carcinoma cell line and the SL6 non-small-cell lung cancer cell line. The implication of these findings for the development of strategies for clinical treatment are discussed.


Pitfalls of EEG interpretation in epilepsy.
Electroencephalogram remains the single most valuable investigation in patients with known or suspected seizure disorders. Errors made in the interpretation of electroencephalogram studies are common and have significant consequences for the patient. This article presents a logical approach to the analysis of electroencephalograms, illustrating the principle pitfalls in each step of this analysis.


Improving Communication in ADHD Care: Results from In-office Linguistic Research.
IntroductionAn in-office linguistic study was conducted to help improve understanding of how to better evaluate and treat attention-deficit/hyperactivity disorder (ADHD). Naturally occurring interactions were recorded among 7 psychiatrists and 23 patients and 8 pediatricians along with 22 patients and their parents. Participants were interviewed separately post-visit. Transcripts of interactions and interviews were analyzed using sociolinguistic techniques. Visits were variable in length and lacked concrete treatment plans. In the pediatric setting, children were typically excluded from dialogues, accounting for only 8% of words spoken. School was the primary metric used to evaluate symptoms. Pediatricians allayed parents' concerns about stimulant therapy by promising to prescribe the lowest possible dose, rather than discussing titrating to an optimal dose. Adults were evaluated idiosyncratically without the use of scales or tools. Stimulants were positioned as short-term "trials" without strong physician recommendations.DiscussionConversations about stimulant therapy lacked goal- and expectation-setting. Also missing from conversations was a definitive treatment plan based on the core symptoms of ADHD. Incorporating open-ended questions and tools or rating scales may result in a more effective and efficient in-office dialogue. Further research is warranted to assess the efficacy of communication strategies to enhance in-office discussions of ADHD and stimulant therapy.


Dining in: intracellular bacterial pathogen interplay with autophagy.
Intracellular bacterial pathogens have evolved many ways to manipulate host cells for successful infection. Many of these pathogens use specialized secretion systems to inject bacterial proteins into the host cytosol that manipulate cellular processes to favor infection. Autophagy is a eukaryotic cellular remodeling process with a critical role in many diseases, including bacterial clearance. A growing field of research highlights mechanisms used by intracellular bacteria to manipulate autophagy as a pro-survival strategy. This review focuses on a select group of bacterial pathogens with diverse intracellular lifestyles that exploit autophagy-derived nutrients and membrane for survival. This group of pathogens uses secretion systems and specific effectors to subvert distinct components of autophagy. By understanding how intracellular pathogens manipulate autophagy, we gain insight not only into bacterial pathogenesis but also host cell signaling and autophagolysosome maturation.


Interleukin-1A -889C/T polymorphism and risk of Alzheimer's disease: a meta-analysis based on 32 case-control studies.
The Interleukin-1A (IL-1A) -889C/T polymorphism has been reported to be associated with Alzheimer's disease (AD) susceptibility, but the results of these previous studies have been inconsistent. The aim of this study was to explore whether the IL-1A -889C/T polymorphism confers susceptibility to AD. All studies published up to July 2011 on the association between the IL-1A -889C/T polymorphism and AD risk were identified by searching electronic databases PubMed, Embase and Alzgene. The association between the IL-1A -889C/T polymorphism and AD risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs). A total of 32 case-control studies including 7,046 AD cases and 7,534 controls were eventually identified. Overall, positive associations of the IL-1A -889C/T polymorphism with AD risk were found in allele comparison T versus C (OR = 1.019, 95% CI= 1.027-1.198), recessive model TT versus CT + CC (OR = 1.278, 95% CI = 1.073-1.522) and dominant model TT + CT versus CC (OR = 1.102, 95% CI = 1.013-1.200). In subgroup analysis stratified by ethnicity, significant associations were demonstrated in Caucasians but not in Asians. In subgroup analysis according to the age of onset, no significant association was detected. The present meta-analysis suggests that the IL-1A is a candidate gene for AD susceptibility. The IL-1A -889C/T889C/T polymorphism may be a risk factor for AD in Caucasians. Further investigations taking the APOE ε4 status and other confirmed genetic factors and potential gene-gene and gene-environmental interactions into consideration for this polymorphism should be conducted.


A gold(I)-catalyzed intramolecular oxidation-cyclopropanation sequence of 1,6-enynes: a convenient access to [n.1.0]bicycloalkanes.
A gold(I)-catalyzed tandem oxidation/cyclopropanation reaction of 1,6-enynes with an external oxidant has been developed. This quite simple and rapid strategy will provide a safe, mild and versatile avenue to numerous carbo- and hetero [n.1.0]bicyclic frameworks.


The neuropathology of hereditary spastic paraparesis.
Hereditary spastic paraparesis or Strümpell's disease is a genetically determined neurodegenerative disorder in which the signs and symptoms are predominant in the legs. Inheritance is usually autosomal dominant and in a minority recessive. Neuropathological study reveals a degeneration of the corticospinal tract decreasing from lower lumbar to cervical level and of posterior columns increasing from lumbar to upper cervical level as well as degeneration of the spinocerebellar tracts in approximately 50%. The nature of this nucleo-distal central axonopathy and clinicopathological discrepancy for posterior columns, as well as the limits of the pathological process are poorly understood.


Computational insight into the contribution of para-substituents on the reduction potential, proton affinity, and electronic properties of nitrobenzene compounds.
New insight is provided into the chemistry of 12 para-substituted nitrobenzene compounds, using the high-level computational method G3(MP2) and DFT methods. The results show that the chemical properties of the nitrobenzene molecules, such as reduction potential, ionization energy, proton affinity, pKa, interaction energy of the fragments, hyperpolarizability, exaltation index, band gap, UV electron excitation, and QTAIM properties, are controlled by the strong coupling between the nitro group (NO2) and the nature of the various para-substituents via the benzene ring as their conducting link. As the electron donating tendency of the para-substituent increases in the molecules, the electron cloud around the nitro group also increases, resulting in contraction of the N-C bonds and elongation of the N=O bonds, consequently leading to gradually increasing electron conductivity, polarizability, and ionization energy but lower proton affinity, thereby progressively impeding the reduction potential of the molecules. The experimental reduction potential was reproduced to a high degree of accuracy, with a mean absolute deviation (MAD) of 0.048 V, depending on the computational method used and the choice of the free energy circle. Additionally, the experimental electron affinity and proton affinity of the 12 molecules were reproduced to a high degree of accuracy. Graphical abstract The correlation of experimental and computational reduction potential of twelve nitrobenzen compounds.


Adaptive upregulation of gastric and hypothalamic ghrelin receptors and increased plasma ghrelin in a model of cancer chemotherapy-induced dyspepsia.
Chemotherapy treatment can lead to delayed gastric emptying, early satiety, anorexia, nausea and vomiting, described collectively as the cancer-associated dyspepsia syndrome (CADS). Administration of ghrelin (GHRL), an endogenous orexigenic peptide known to stimulate gastric motility, has been shown to reduce the symptoms of CADS induced in relevant animal models with the potent chemotherapeutic agent, cisplatin. We examined the effects in the rat of cisplatin (6 mg/kg i.p.) treatment on the expression of GHRL and ghrelin receptor (GHSR) mRNAs in the hypothalamus and the stomach at a time-point (2 days) when the effects of cisplatin are pronounced. In addition, plasma levels of GHRL (acylated and total including des-acyl GHRL) were measured and the effect on these levels of treatment with the synthetic glucocorticoid dexamethasone (2 mg/kg s.c. bd.) was investigated. Cisplatin increased GHSR mRNA expression in the stomach (67%) and hypothalamus (52%) but not GHRL mRNA expression and increased the percentage of acylated GHRL (7.03+/-1.35% vs. 11.38+/-2.40%) in the plasma. Dexamethasone reduced the plasma level of acylated GHRL and the percentage of acylated GHRL to values below those in animals treated with saline alone (7.03+/-1.35% vs. 2.60+/-0.49%). Our findings support the hypothesis that an adaptive upregulation of the ghrelin receptor may occur during cancer chemotherapy-associated dyspepsia. This may have a role in defensive responses to toxic challenges to the gut. In addition, our results provide preliminary evidence for glucocorticoid modulation of plasma ghrelin levels.


Cost-effectiveness of rivaroxaban and aspirin compared to aspirin alone in patients with stable cardiovascular disease: An Australian perspective.
In light of the Cardiovascular Outcomes for People using Anticoagulation Strategies (COMPASS) trial, our objective was to assess the cost-effectiveness, from the Australian healthcare perspective, of rivaroxaban in combination with aspirin versus aspirin alone for the prevention of recurrent cardiovascular disease among patients with stable atherosclerotic vascular disease. A Markov model was developed using input data from the COMPASS trial to predict the clinical course and costs of patients over a 20-year time-horizon. The model comprised of three health states: 'Alive without recurrent CVD', 'Alive after recurrent CVD' and 'Dead'. Costs were from the Australian public healthcare system perspective, and estimated from published sources, as were utility data. The costs of rivaroxaban were based on current acquisition prices on the Australian Pharmaceutical Benefits Schedule (PBS) and assumed as AUD$3.09/day. The main outcome of interest was the incremental cost-effectiveness ratio (ICER) in terms of cost per quality adjusted life year (QALY) gained, and cost per year of life saved (YoLS). Costs and benefits were discounted by 5.0% per year. Compared to aspirin alone, rivaroxaban plus aspirin was estimated to cost an additional AUD$12,156 (discounted) per person, but lead to 0.516 YoLS (discounted) and 0.386 QALYs gained (discounted), over 20 years. These equated to ICERs of AUD$23,560/YoLS and AUD$31,436/QALY gained. We have assumed a threshold of AUD$50,000/QALY gained to signify cost-effectiveness. Compared to aspirin, rivaroxaban in combination with aspirin is likely to be cost-effective in preventing recurrent cardiovascular events in patients with stable atherosclerotic vascular disease.


The impact of hospital volume on racial disparities in resected rectal cancer.
Although high volume centers (HVC) equate to improved outcomes in rectal cancer, the impact of surgical volume related to race is less defined. Patients who underwent surgical resection for stage I-III rectal adenocarcinoma were divided into cohorts based on race and hospital surgical volume. Outcomes were analyzed following 1:1 propensity-score matching using logistic, Poisson, and Cox regression analyses with marginal effects. Fifty-four thousand one hundred and eighty-four (91.5%) non-Black and 5043 (8.5%) Black patients underwent resection of rectal cancer. Following 1:1 matching of non-Black (N = 5026) and Black patients, 5-year overall survival (OS) of Black patients was worse (72% vs. 74.4%, average marginal effects [AME] 0.66, p = 0.04) than non-Black patients. When compared to non-Black patients managed at HVCs, Black patients had worse OS (70.1% vs. 74.7%, AME 1.55, p = 0.03), but this difference was not significant when comparing OS between non-Black and Black patients managed at HVCs (72.3% vs. 74.7%, AME 0.62, p = 0.06). Length of stay was longer among Black and HVC patients across all cohorts. There was no difference across cohorts in 90-day mortality. Although racial disparities exist in rectal cancer, this disparity appears to be ameliorated when patients are managed at HVCs.


Adipocytokine dysregulation, abnormal glucose metabolism, and lipodystrophy in HIV-infected adolescents receiving protease inhibitors.
Lipodystrophy is common in HIV-infected patients receiving protease inhibitors (PIs), stavudine, and zidovudine. Adipocytokines may be altered in lipodystrophy. We evaluated risk factors, adipocytokine levels, insulin resistance, and lipid profiles in HIV-infected adolescents with different lipodystrophy types. A cross-sectional study was conducted in 80 perinatally HIV-infected adolescents receiving PI-based highly active antiretroviral therapy for ≥ 6 months. Patients underwent oral glucose tolerance tests and measurements of high-molecular-weight (HMW) adiponectin, leptin, resistin, insulin, and lipids. They were classified into 3 groups based on the clinical findings: no lipodystrophy, isolated lipoatrophy, and any lipohypertrophy (isolated lipohypertrophy or combined type). Of the 80 patients (median age, 16.7 years), 18 (22.5%) had isolated lipoatrophy, while 8 (10%) had any lipohypertrophy (four with isolated lipohypertrophy, and four with the combined type). In a multivariate analysis, longer exposure to stavudine (OR: 1.03; 95% CI, 1.01-1.06; p = 0.005) and indinavir (OR: 1.03; 95% CI, 1.01-1.06; p = 0.012) were associated with lipoatrophy, while longer exposure to didanosine (OR: 1.04; 95% CI, 1.01-1.08; p = 0.017) and indinavir (OR: 1.10; 95% CI, 1.00-1.21; p = 0.045) were associated with any lipohypertrophy. Leptin levels were highest in the any-lipohypertrophy group and lowest in the isolated-lipoatrophy group (p = 0.013). HMW adiponectin levels were significantly lowest in the any-lipohypertrophy group and highest in the no-lipodystrophy group (p = 0.001). There were no significant differences in the levels of resistin among the three groups (p = 0.234). The prevalence of insulin resistance (p = 0.002) and prediabetes/diabetes (p < 0.001) were significantly highest in the any-lipohypertrophy group. Patients with lipoatrophy and those without lipodystrophy had comparable degrees of insulin resistance (p = 0.292). In multiple linear regression analysis, adjusted for age, sex, and waist-height ratio, HMW adiponectin levels were associated with Matsuda index (β = 0.5; p = 0.003) and quantitative insulin sensitivity check index (QUICKI) (β = 40.1; p = 0.010) and almost significantly associated with homeostatic model assessment of insulin resistance (HOMA-IR) (p = 0.054). Leptin and resistin levels were not associated with HOMA-IR, Matsuda index, or QUICKI (all p > 0.05). Abnormal glucose metabolism and dysregulation of adipocytokines were common in the HIV-infected adolescents with lipohypertrophy and the combined type. Preventive screening for cardiovascular diseases caused by metabolic alterations should be routinely performed.


The influence of gonadal steroids and the pituitary on the levels and composition of plasma phospholipids in the rat.
Gonadal steroids have been shown to influence plasma phospholipids. In the present study, the possible interaction between gonadal steroids and the pituitary in the regulation of plasma phospholipids was studied in rats. The total phospholipid concentration (higher in females) and the fatty acid composition of plasma lecithin was different in male compared to female rats. Gonadectomy resulted in a "feminization" of plasma phospholipids (total concentration and fatty acids in lecithin) in male rats but had no effect in females. Testosterone treatment of gonadectomized males or intact females resulted in a "masculinization" of plasma phospholipids, whereas estrogen treatment of intact males resulted in a "feminization." Hypophysectomy resulted in a marked decrease in plasma phospholipid concentration and the fatty acid composition of lecithin showed a "masculine" pattern in both males and females. Neither testosterone nor estrogen treatment had any effects on plasma phospholipids in hypophysectomized male and female rats, respectively. It is concluded that gonadal steroids and the hypothalamic-pituitary axis interact in the regulation of the synthetic and perhaps also degradative pathways controlling plasma phospholipids.


Screening for people with abnormal glucose metabolism in the European DE-PLAN project.
The aim of this report is to describe the application of the FINDRISC in clinical practice within the DE-PLAN project as a step to screen for Type 2 diabetes. Nine out of 24 possible centers were included. Six centers used opportunistic screening methods for participant recruitment whereas three centers provided study participants of a random population sample. Men (n=1621) and women (n=2483) were evaluated separately. In order to assess the prevalence of abnormal glucose tolerance (AGT) disorders across different risk categories, the FINDRISC was used. Anthropometric measurements included blood pressure, height, weight, and waist circumference. Blood lipids and an oral glucose tolerance test were performed in all participants. The primary outcome was identified risk of AGT and type 2 diabetes. There was no difference in the prevalence of smoking between the FINDRISC categories, people with a FINDRISC below 15 points tend to be more physically active and to eat more frequently fruits and vegetables. Men with a FINDRISC from 15 to 19 points had a prevalence of abnormal glucose tolerance of approximately 60% and women 50%. The prevalence for men and women with a FINDRISC >20 points was 80%. 30% of men and 20% of women with a FINDRISC between 15 and 19 points had Type 2 diabetes. Among people with a FINDRISC more than 20 points, 50% had previously undiagnosed Type 2 diabetes. The FINDRISC may be a practical tool to be used in primary health-care systems throughout the European population.


The hairless gene in androgenetic alopecia: results of a systematic mutation screening and a family-based association approach.
Genetic disposition and androgen dependence are important characteristics of the common patterned loss of scalp hair known as androgenetic alopecia (AGA). The genetic factors contributing to AGA are currently unknown. The human hairless gene (HR) has recently been cloned and mutations have been reported in families with autosomal recessive universal congenital alopecia and papular atrichia. The main feature of these disorders is persistent complete absence of hair at or shortly after birth. This suggests that HR is essential and specific for the development of hair. To test the hypothesis that HR may be involved in AGA. We systematically screened HR for genetic variability by means of single-strand conformation analysis (SSCA) in 46 unrelated men with AGA. To test for an involvement of HR in the development of AGA, seven common variants were genotyped in 61 families with 93 affected offspring. The results were analysed with the transmission/disequilibrium test (TDT). SSCA showed 15 single nucleotide substitutions: eight missense mutations, four silent mutations and three mutations in exon-flanking intronic sequences. TDT results showed a marginally significant association between AGA and variants 3379-29G/T (P = 0.024) and 2611-68C/T (P = 0.047). These results, however, did not remain significant after applying the conservative Bonferroni correction for multiple testing. Our results do not provide evidence for a strong involvement of HR in the development of AGA, although a minor role cannot be fully excluded.


Validation of the supinator fat pad sign in radial head and neck fractures.
To assess the displacement of the supinator fat pad in radial head and neck fractures and to validate its significance. One hundred two adult patients from the Royal Orthopaedic Hospital, Birmingham, United Kingdom and Sultan Qaboos University Hospital, Muscat, Oman with confirmed radial head and/or neck fractures were included. Fractures were classified using the Mason-Johnston classification. The displacement of the supinator fat pad from the radius was measured on anterior-posterior (AP) and lateral radiographs and correlated to fracture classification. The supinator fat pad was on average displaced by 10.6 mm and 13.8 mm from the radius on AP and lateral radiographs, respectively. The displacement of the fat pad progressively increased between non-displaced (Mason I) and severely comminuted (Mason III) fractures on both the AP (10.25 to 14.25 mm) and lateral (12.70 to 16.00 mm) projections. The progression of displacement on AP (p = 0.016) and on lateral (p = 0.007) projections was statistically significant. Fracture dislocation was not associated with increased fat pad displacement. The supinator fat pad sign is a useful adjunct in the assessment of radial head and neck fractures.


Social exclusion affects working memory performance in young adolescent girls.
Adolescence has been proposed to be a sensitive period of social development, during which the social environment has a heightened effect on brain and behaviour. As such, negative social experiences, such as social exclusion, may have particularly detrimental effects on psychological well-being. However, little is known about how social exclusion affects cognitive performance during this time of life. Here, we compared the effects of exclusion between adolescence and adulthood. We recruited 98 females in three age groups: young adolescents (N = 36, aged 10.1-14.0), mid-adolescents (N = 35, aged 14.3-17.9) and adults (N = 27, aged 18.3-38.1). All age groups showed reductions in mood after exclusion, compared to inclusion, in a virtual ball-tossing game. Young adolescents also showed reduced verbal working memory accuracy following exclusion. There was no effect of exclusion on visuo-spatial working memory in any age group. These results suggest young adolescent girls' verbal working memory accuracy was affected by a short, virtual social exclusion experience. This highlights the importance of the social environment in adolescence and underlines the need to consider age differences in response to exclusion in the design and timing of social exclusion interventions in schools.


Glioblastoma extracellular vesicles influence glial cell hyaluronic acid deposition to promote invasiveness.
Infiltration of glioblastoma (GBM) throughout the brain leads to its inevitable recurrence following standard-of-care treatments, such as surgical resection, chemo-, and radiotherapy. A deeper understanding of the mechanisms invoked by GBM to infiltrate the brain is needed to develop approaches to contain the disease and reduce recurrence. The aim of this study was to discover mechanisms through which extracellular vesicles (EVs) released by GBM influence the brain microenvironment to facilitate infiltration, and to determine how altered extracellular matrix (ECM) deposition by glial cells might contribute to this. CRISPR was used to delete genes, previously established to drive carcinoma invasiveness and EV production, from patient-derived primary and GBM cell lines. We purified and characterized EVs released by these cells, assessed their capacity to foster pro-migratory microenvironments in mouse brain slices, and evaluated the contribution made by astrocyte-derived ECM to this. Finally, we determined how CRISPR-mediated deletion of genes, which we had found to control EV-mediated communication between GBM cells and astrocytes, influenced GBM infiltration when orthotopically injected into CD1-nude mice. GBM cells expressing a p53 mutant (p53R273H) with established pro-invasive gain-of-function release EVs containing a sialomucin, podocalyxin (PODXL), which encourages astrocytes to deposit ECM with increased levels of hyaluronic acid (HA). This HA-rich ECM, in turn, promotes migration of GBM cells. Consistently, CRISPR-mediated deletion of PODXL opposes infiltration of GBM in vivo. This work describes several key components of an EV-mediated mechanism though which GBM cells educate astrocytes to support infiltration of the surrounding healthy brain tissue.


Genetic diversity among and within cultured cyanobionts of diverse species of Azolla.
The cyanobionts isolated from 10 Azolla accessions belonging to 6 species (Azolla mexicana, A. microphylla, A. rubra, A. caroliniana, A. filiculoides, A. pinnata) were cultured under laboratory conditions and analyzed on the basis of whole cell protein profiles and molecular marker dataset generated using repeat sequence primers (STRR(mod) and HipTG). The biochemical and molecular marker profiles of the cyanobionts were compared with those of the free-living cyanobacteria and symbiotic Nostoc strains from Anthoceros sp., Cycas sp. and Gunnera monoika. Cluster analysis revealed the genetic diversity among the selected strains, and identified 3 distinct clusters. Group 1 included cyanobionts from all the 10 accessions of Azolla, group 2 comprised all the symbiotic Nostoc strains, while group 3 included the free-living cyanobacteria belonging to the genera Nostoc and Anabaena. The interrelationships among the Azolla cyanobionts were further revealed by principal component analysis. Cyanobionts from A. caroliniana-A. microphylla grouped together while cyanobionts associated with A. mexicana-A. filiculoides along with A. pinnata formed another group. A. rubra cyanobionts had intermediate relationship with both the subgroups. This is the first study analyzing the diversity existing among the cultured cyanobionts of diverse Azolla species through the use of biochemical and molecular profiles and also the genetic distinctness of these free-living cyanobionts as compared to cyanobacterial strains of the genera Anabaena and Nostoc.


When still waters become a soul tsunami: using the Tidal Model to recover from shipwreck.
The Tidal model, created by Phil Barker and Poppy Buchanan-Barker, metaphorically employs the natural resource of water to describe the person in crisis and offer a model toward recovery. The model, a midrange nursing theory used primarily in mental health settings, is applied to a women in crisis related to failed infertility treatment who attempts suicide.


Investigation into the use of cement kiln dust in high density sludge (HDS) treatment of acid mine water.
The purpose of this study was to investigate the potential to replace lime with cement kiln dust (CKD) in high density sludge (HDS) treatment of acid mine drainage (AMD). The bench-scale study used two water samples: AMD sampled from a lead-zinc mine with high concentrations of iron (Fe), zinc (Zn), and arsenic (As) (Fe/Zn-AMD) and a synthetic AMD solution (Syn-AMD) spiked with ferric sulfate (Fe2(SO4)3). Arsenic was found to be significantly reduced with CKD-HDS treatment of Fe/Zn-AMD compared to lime-HDS treatment, to concentrations below the stringent mine effluent discharge regulation of 0.10 mg As/L (i.e., 0.04 ± 0.02 mg/L). Both CKD- and lime-HDS treatment of the two AMD samples resulted in settled water Fe concentrations above the stringent discharge guideline of 0.3 mg Fe/L. CKD addition in the HDS process also resulted in high settled water turbidity, above typical discharge guidelines of 15 mg TSS/L. CKD-HDS treatment was found to result in significantly improved settled solids (i.e., sludge) quality compared to that generated in the lime-HDS process. HDS treatment with CKD resulted in 25-88% lower sludge volume indices, 2 to 9 times higher % wet solids, and 10 to 20 times higher % dry solids compared to lime addition. XRD and XPS testing indicated that CKD-HDS sludge consisted of mainly CaCO3 and SiO2 with Fe(3+) precipitates attached at particle surfaces. XRD and XPS testing of the lime-HDS generated sludge showed that it consisted of non-crystalline Fe oxides typical of sludge formed from precipitates with a high water concentration. Increased sedimentation rates were also found for CKD (1.3 cm/s) compared to lime (0.3 cm/s). The increased solids loading with CKD addition compared to lime addition in the HDS process was suggested to both promote surface complexation of metal precipitates with insoluble CKD particles and increase compression effects during Type IV sedimentation. These mechanisms collectively contributed to the reduced water content of CKD-HDS sludge. The results of this study suggest that solids loading is a significant factor in increased sludge density found with the HDS process compared to conventional lime precipitation-sedimentation.


Factor interaction influencing the distribution of the freshwater "shrimp" Gammarus.
The enormous variation in the environmental factors of south-eastern Norway makes this area particularly suitable for field studies on the relationship between environmental factors and fauna. Lakes are abundant, from 1 to 1,837 m a.s.l., and the geology of the surroundings as well as acid precipitation influence their chemical characteristics. In lowland areas the distribution of Gammarus lacustris is related to how rich in lime the lakes are. Populations found in mountain lakes tolerate much lower levels of calcium and higher H+ concentrations than populations inhabiting lowland lakes. The lowland populations probably have a higher calcium demand when stressed by high temperature. We predict that factor interaction may be used to explain the distribution patterns of the species also in other parts of Europe.


Lattice-dislocated Bi nanosheets for electrocatalytic reduction of carbon dioxide to formate over a wide potential window.
Electrochemical reduction of CO2 to HCOOH (ERC-HCOOH) is one of the most feasible and economically valuable ways to achieve carbon neutrality. Unfortunately, achieving optimal activity and selectivity for ERC-HCOOH remains a challenge. Herein, ultrathin Bi nanosheets (NS) with lattice dislocations (LD-Bi) were prepared by the topological transformation of Bi2O2CO3 NS under high current conditions. LD-Bi exhibited excellent activity and selectivity as well as stability in ERC-HCOOH. Electrochemical tests and DFT calculations revealed that the excellent performance of LD-Bi was attributed to lattice dislocations, which can induce the production of more active sites on the catalyst surface and improve the electronic transfer ability. In addition, LD-Bi was beneficial to enhance the adsorption of CO2 and key reaction intermediates (OCHO*), thus improving the reaction kinetics. The result provides a unique perspective on the crucial role of lattice dislocations, which may have a significant impact on highly selective electrochemical conversion of CO2.


Isolation, characterisation and quantification of the main oligomeric macrocyclic ellagitannins in Epilobium angustifolium by ultra-high performance chromatography with diode array detection and electrospray tandem mass spectrometry.
Tannins have beneficial effects in animal nutrition as they are able to decrease methane emission in ruminants and exert anthelminthic activity against intestinal nematodes. However, tannins can have very diverse structures and therefore, different activities. In order to enhance the research in tannin-rich forages we need tools which are able to quantify tannins individually. In this study we isolated and characterised the main tellimagrandin I (TI)-based oligomeric ellagitannins (ETs) from Epilobium angustifolium (willowherb) and developed a UHPLC-DAD-ESI-MS/MS method to quantify them in plant extracts. The mass spectrometer was operated in Multiple Reaction Monitoring mode to enable the selective detection of dimeric to heptameric ETs from the plant extract. The method proved to be sensitive, with limits of detection ranging from 0.1 to 1.3μgmL(-1). The stability test showed a good repeatability with an inter-run deviation of the results from 0.1 to 5%, except for the pentamer and hexamer where it reached 8%. The method was then successfully applied to evaluate the distribution of those ETs in the plant. This work also provides the first time evidence of the presence of tetrameric to heptameric TI in willowherb.


First molecular evidence of the simultaneous human infection with two species of Echinococcus granulosus sensu lato: Echinococcus granulosus sensu stricto and Echinococcus canadensis.
Cystic echinococcosis is a widespread zoonotic parasitic disease especially in Tunisia which is one of the most endemic countries in the Mediterranean area. The etiological agent, Echinococcus granulosus sensu lato, implies dogs and other canids as definitive hosts and different herbivore species as intermediate hosts. Human contamination occurs during the consumption of parasite eggs passed in the environment through canid feces. Hydatid cysts coming from a child operated for multiple echinococcosis were collected and analyzed in order to genotype and to obtain some epidemiological molecular information. Three targets, ribosomal DNA ITS1 fragment, NADH dehydrogenase subunit 1 (nad1), and mitochondrial cytochrome c oxydase subunit 1 (CO1) genes, were amplified and analyzed by RFLP and sequencing approach. This study presents the first worldwide report in human of a simultaneous infection with Echinococcus granulosus sensu stricto (genotype G1) and Echinococcus canadensis (genotype G6) species. This is also the first report of the presence of E. canadensis in the Tunisian population which argues in favor of a greater importance of this species in human infestation in Tunisia than previously believed.


Antibody Delivery into the Brain by Radiosensitizer Nanoparticles for Targeted Glioblastoma Therapy.
Glioblastoma is the most lethal primary brain malignancy in adults. Standard of care treatment, consisting of temozolomide (TMZ) and adjuvant radiotherapy (RT), mostly does not prevent local recurrence. The inability of drugs to enter the brain, in particular antibody-based drugs and radiosensitizers, is a crucial limitation to effective glioblastoma therapy. Here, we developed a combined strategy using radiosensitizer gold nanoparticles coated with insulin to cross the blood-brain barrier and shuttle tumor-targeting antibodies (cetuximab) into the brain. Following intravenous injection to an orthotopic glioblastoma mouse model, the nanoparticles specifically accumulated within the tumor. Combining targeted nanoparticle injection with TMZ and RT standard of care significantly inhibited tumor growth and extended survival, as compared to standard of care alone. Histological analysis of tumors showed that the combined treatment eradicated tumor cells, and decreased tumor vascularization, proliferation, and repair. Our findings demonstrate radiosensitizer nanoparticles that effectively deliver antibodies into the brain, target the tumor, and effectively improve standard of care treatment outcome in glioblastoma.


Identification of a Calcium Signalling Pathway of S-[6]-Gingerol in HuH-7 Cells.
Calcium signals in hepatocytes control cell growth, proliferation, and death. Members of the transient receptor potential (TRP) cation channel superfamily are candidate calcium influx channels. NF κ B activation strictly depends on calcium influx and often induces antiapoptotic genes favouring cell survival. Previously, we reported that S-[6]-gingerol is an efficacious agonist of the transient receptor potential cation channel subfamily V member 1 (TRPV1) in neurones. In this study, we tested the effect of S-[6]-gingerol on HuH-7 cells using the Fluo-4 calcium assay, RT-qPCR, transient cell transfection, and luciferase measurements. We found that S-[6]-gingerol induced a transient rise in [Ca(2+)] i in HuH-7 cells. The increase in [Ca(2+)] i induced by S-[6]-gingerol was abolished by preincubation with EGTA and was also inhibited by the TRPV1 channel antagonist capsazepine. Expression of TRPV1 in HuH-7 cells was confirmed by mRNA analysis as well as a test for increase of [Ca(2+)] i by TRPV1 agonist capsaicin and its inhibition by capsazepine. We found that S-[6]-gingerol induced rapid NF κ B activation through TRPV1 in HuH-7 cells. Furthermore, S-[6]-gingerol-induced NF κ B activation was dependent on the calcium gradient and TRPV1. The rapid NF κ B activation by S-[6]-gingerol was associated with an increase in mRNA levels of NF κ B-target genes: cIAP-2, XIAP, and Bcl-2 that encode antiapoptotic proteins.