Influence of Pseudomonas aeruginosa as PGPR on oxidative stress tolerance in wheat under Zn stress.
Plant Growth Promoting Rhizobacteria (PGPR), whose role is still underestimated, plays an important (or perhaps essential) role in improving plant growth. The comprehensive understanding of bacterial plant growth promoting mechanism helps to get sustainable agriculture production under biotic and abiotic stresses. In the present study, plant growth promoting (PGP) bacterial strain Pseudomonas aeruginosa having maximum inhibitory concentration of 1500mg kg(-1) against Zn was isolated from arable land, irrigated with industrial effluent and evaluated to determine it bioremediation potential. The study was mainly focused on plant biomass production, nutrient uptake and oxidative stress tolerance in relation to the activities of antioxidative enzymes and the content of non-enzymatic antioxidants. The oxidative stress tolerance was measured by estimating the MDA accumulation as well as H2O2 production in wheat plants under Zn (1000mg kg(-1)) stress and inoculation of soil with Zn resistant Pseudomonas aeruginosa. Zn in rooting medium reduced the plant growth, leaf photosynthetic pigments as well as uptake of N and P. However, content of MDA and H2O2 increased at higher concentration of Zn. Inoculation of P. aeruginosa improved the uptake of P and N in wheat plants with an increase in leaf chlorophyll, total soluble protein and plant biomass production. Analysis of plant root and shoot disclosed that Zn concentration was significantly lowered in P. aeruginosa inoculated zinc stressed plants as compare to the plants grown under Zn stress only. The amelioration of adverse effects of Zn stress on biomass production due to P. aeruginosa inoculation was related with enhanced antioxidative enzyme activities (SOD, POD and CAT), and the contents of non-enzymatic components such as ascorbic acid and total phenolics (TPC) as compare to Zn-treated plants. The up-gradation in antioxidative defense mechanism, resulted a reduction in H2O2 and MDA content due to the scavenging of ROS by antioxidants. It was concluded that P. aeruginosa is an ideal candidate for bioremediation and wheat growth promotion against Zn-induced oxidative stress by improving the availability of necessary nutrient, eliciting antioxidant defense system as well as by lowering the Zn metal uptake.


Prostaglandin E1 induces c-Fos and Myc proteins and protects rat hippocampal cells against hypoxic injury.
We investigated the effects of prostaglandin (PG) E1 on the hypoxic injury of fetal rat hippocampal cells. Primary hippocampal cell cultures (embryonic day 18) were established and maintained. After 72 h in culture, PGE1 was added to the serum-free medium at a final concentration of 10(-5)-10(-9) M. Cultures were divided into two groups: The normoxia group was in culture for another 48 h, and the hypoxia group was exposed to 24 h of hypoxia followed by continuation of culture for another 24 h. As a quantitative measure of cell death, lactate dehydrogenase (LDH) activity was estimated in the culture medium. The LDH activity, released by the hypoxic insult, was significantly smaller with PGE1 treatment at 10(-6), 10(-7), and 10(-8) M (p < 0.01) and 10(-9) M (p < 0.05) compared with the control. No differences in the LDH activities were observed in the normoxia group. Glial culture was not affected by the hypoxia. Western blot analysis showed an increased induction of 62-kDa c-Fos and 58, 60, and 66 kDa Myc proteins in rat hippocampal cells with 10(-7) M PGE1 treatment. We conclude that PGE1 at concentrations of 10(-6)-10(-9) M protects rat hippocampal neurons against hypoxic insult.


Respiratory effects of nitrous oxide during halothane or enflurane anaesthesia in children.
The respiratory effects of nitrous oxide (N2O) were studied during halothane and enflurane anaesthesia in 12 children (mean age 46.4 +/- 29.3 months, mean weight 15.3 +/- 4.2 kg) during surgery under continuous extradural anaesthesia. Four equipotent anaesthetic states were studied in random order: 1) halothane 1 MAC in oxygen, 2) halothane 0.5 MAC + 50% N2O, 3) enflurane 1 MAC in oxygen, 4) enflurane 0.5 MAC +50% N2O. End-tidal fractions of CO2 (PetCO2) and halothane and enflurane were measured using infrared analysers. The respiratory variables (tidal volume VT, minute ventilation VE, respiratory frequency F, inspiratory time Ti, mean inspiratory flow VI, effective inspiratory time Ti/Ttot) were measured using a pneumotachograph. Significant changes were observed between the four states for VE, VI, F and PetCO2, whereas the values of VT, Ti and Ti/Tot did not differ significantly. The respiratory depressant effect of 1 MAC of either halothane alone or of the mixture of halothane and N2O was very similar. During enflurane anaesthesia, PetCO2 was less increased when N2O was substituted for enflurane, owing to a significant increase in respiratory frequency. A marked decrease in VE together with an increase in PetCO2 was observed during enflurane anaesthesia (states 3 and 4) when compared to the corresponding states during halothane anaesthesia (states 1 and 2). The respiratory depressant effect of enflurane is greater than that of halothane in unpremedicated children, even when substituting N2O for an equal MAC fraction of enflurane.2+ The effect of N2O on respiratory patterns seems to depend on the inhalational agent used and/or on the vesting respiratory frequency.


Identifying trends in ultrafine particle infiltration and carbon dioxide ventilation in 92 vehicle models.
There has been ongoing research aimed at reducing pollution concentrations in vehicles due to the high exposure which occurs in this setting. These studies have found using recirculate (RC) settings substantially reduces in-cabin traffic-related pollution concentrations but possibly leads to an adverse accumulation of carbon dioxide (CO2) from driver respiration. The aim of this study was to highlight how vehicle models and ventilation settings affect in-cabin concentrations to ultrafine particles (UFP) and CO2 in real-world conditions. We assessed the ability of different vehicles to balance reductions in UFP against the build-up of in-cabin CO2 concentrations by measuring these pollutants concurrently both inside and outside the vehicle to derive an in/out ratio. When ventilation settings were set to RC, UFP concentrations inside the vehicles (median: 3205 pt./cm3) were 86% lower compared to outside air (OA) (23,496 pt./cm3) across a 30-min real-world driving route. However, CO2 concentrations demonstrated a rapid linear increase under RC settings, at times exceeding 2500 ppm. These concentrations have previously been associated with decreased cognitive performance. Our study did not find an effect of gasoline fuelled vehicles affecting in-cabin UFP levels compared to hybrid or electric vehicles, suggesting that self-pollution was not an issue. We also found that certain vehicle models were better at reducing both in-cabin UFP and CO2 concentrations. The results suggest that under RC settings in/out CO2 ratios are largely determined by the leakiness of the vehicle cabin, whereas in/out UFP ratios are primarily determined by the efficacy of the in-built air filter in the vehicles ventilation system.


Foundational Study on the Simple Detection of Impairment Resulting in Dangerous Driving in Patients with Higher Brain Dysfunction.
We performed a survey of medical records to reveal the cognitive deficits behind dangerous driving in patients with higher brain dysfunction. Thirty-four patients with higher brain dysfunction were included in this study. Patients' basic characteristics, neuropsychological test results, scores on two types of driving aptitude tests, and accident/near miss data from a driving simulator were extracted from medical records. We conducted χ2 tests for independence between comprehensive driving aptitude scores and "traffic accidents" / "being prohibited from driving as defined by the number of traffic accidents and near misses." Backward logistic regression analysis was carried out to assess correlations of "traffic accidents" and "being prohibited from driving as defined by the number of traffic accidents and near misses" with neuropsychological test scores. No significant correlation was observed between the comprehensive driving aptitude score and "traffic accidents" / "being prohibited from driving as defined by the number of traffic accidents and near misses." The score on the Raven's Colored Progressive Matrices test was the only factor identified as a significant predictor of "being prohibited from driving as defined by the number of traffic accidents and near misses." The results of this study suggest that it is important to focus on the decline in problem-solving ability as a predictor of "being prohibited from driving as defined by the number of traffic accidents and near misses."


Automated unwrapping of MR phase images applied to BOLD MR-venography at 3 Tesla.
To improve the diagnostic value of BOLD MR-Venography by removing artifacts related to phase wrapping, particularly in regions of large background susceptibilities at high magnetic field strengths. High resolution, T(2)(*)-weighted, single echo images were acquired on a 3 T system (Medspec 30/80 Avance, Bruker Medical, Ettlingen, Germany) with a three-dimensional, first order velocity compensated gradient echo sequence using a quadrature transmit/receive birdcage head coil. Data of nine healthy subjects and 19 patients were evaluated (age range: 27 to 76 years). To achieve improved MR-venograms, a fully automated region-growing phase unwrapping algorithm and subsequent high pass filtering were applied to phase images prior to the computation of minimum intensity projections. Considerably improved visualization of venous structures in regions of large background susceptibility-induced field inhomogeneities is demonstrated in healthy subjects and patients with brain tumors. BOLD MR venograms are improved compared to previous post-processing algorithms. It is now feasible to obtain high-resolution images also in inhomogeneous regions, which increases the clinical potential of BOLD MR-Venography.


Identification of two new HLA class II alleles: DRB1*01:50 and DQB1*05:18.
Two new human leukocyte antigen (HLA) class II alleles were identified during routine sequence-based typing.


Evidence from diverse clinical populations supported clinical validity of PROMIS pain interference and pain behavior.
To evaluate clinical validity, including responsiveness, of Patient-Reported Outcomes Measurement Information System (PROMIS) pain interference (PROMIS-PI) and pain behavior (PROMIS-PB) T-scores. Data were aggregated from longitudinal studies of cancer, chronic low back pain (cLBP), rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and major depressive disorder (MDD). Linear mixed-effects models were used to compare baseline score differences and score changes over time. We calculated standardized response means (SRMs) for subgroups defined by self-reported change in general health and pain. A total of 1,357 individuals participated at baseline and 1,225 at follow-up. Hypotheses of significant change in PROMIS-PI and PROMIS-PB scores were supported in the intervention groups (cLBP and MDD). Differences in baseline scores for COPD exacerbators compared to stable COPD patients were in the hypothesized direction but were not statistically significant. Subgroups reporting better health showed corresponding negative SRM values supporting responsiveness of T-scores to improvement. Responsiveness to decrements was supported in some but not all clinical groups and varied by anchor. More congruent values were obtained when using a pain-specific anchor. This study provides evidence that PROMIS-PI and PROMIS-PB scores are sensitive to changes in pain in studies of interventions expected to impact pain. The results inform estimation of meaningful change and support power analyses for comparative effectiveness research.


Discovery and synthesis of cyclohexenyl derivatives as modulators of CC chemokine receptor 2 activity.
A novel cyclohexenyl series of CCR2 antagonists has been discovered. This series of small, rigid compounds exhibits submicromolar binding affinity for CCR2. Modification of the substituents on the cyclohexene ring led to the identification of potent CCR2 antagonists. Progress from initial lead 5 (IC50=700nM) to (-)-38 (IC50=9.0nM) is discussed.


Streptokinase salvage of a free-tissue transfer: case report and review of the literature.
Postoperative thrombosis is a devastating complication after a microvascular free-tissue transfer. We are reporting the case of a clinical free osteomyocutaneous flap (fibula, peroneal, and soleus muscle, and skin) which suffered recalcitrant postoperative venous thrombosis and was salvaged only after isolated selective infusion of streptokinase. The use of a fibrinolytic agent or plasminogen activator for this purpose in humans has not previously been reported.


Increased risk of ischemic heart disease in patients with bipolar disorder: A population-based study.
This study investigated the national prevalence and incidence of ischemic heart disease and associated factors among Taiwanese patients with bipolar disorder. We used a random sample of 766,427 subjects who were ≥18 years old from the National Health Research Institute database in 2005. Subjects with at least one primary diagnosis of bipolar disorder or ischemic heart disease were identified. We compared the prevalence and incidence of ischemic heart disease in bipolar patients and the general population in 2005 and the same cohort from 2006 to 2010. These associated factors with respect to ischemic heart disease among patients with bipolar disorder were also analyzed. The prevalence of ischemic heart disease in patients with bipolar disorder was 1.69 times higher than in the general population (7.85% vs 4.67%; odds ratio 1.69; 95% confidence interval, 1.41-2.03) in 2005. The average annual incidence of ischemic heart disease in patients with bipolar disorder was also 1.60 times higher than in the general population (2.02% vs 1.24; risk ratio 1.60; 95% confidence interval, 1.36-1.90) from 2006 to 2010. The higher prevalence of ischemic heart disease among bipolar patients was associated with increased age, diabetes, hypertension, and antidepressant use. Patients with bipolar disorder had a significantly higher prevalence and incidence of ischemic heart disease than the general population in both sexes, especially at younger ages. Among patients with bipolar disorder, older age, and hyperlipidemia were risk factors of ischemic heart disease.


Renal failure in the recent 2011 Escherichia coli O104:H4 outbreak: a summary on up-to-date data.
The recent 2011 Escherichia coli outbreak in Europe is considered as one of the biggest E. coli outbreak in the modern medical history. Although the induction of renal impairment is well described in E. coli infection, the specific knowledge on E. coli O104:H4 is very limited. To add up to known knowledge, the author hereby summarizes up-to-date information on renal failure among patients in 2011 E. coli O104:H4 outbreak.


Dynamic localization and functional implications of C-peptide might for suppression of iNOS in high glucose-stimulated rat mesangial cells.
Although C-peptide has unique beneficial effects on diabetic nephropathy (DN), its functional localization and molecular mechanism have not been fully clarified. Whether C-peptide exhibits its protective role through the regulation of inducible nitric oxide synthase (iNOS), a key enzyme in oxidative stress, is not clear. In this study, it was revealed that C-peptide could enter the nucleus of high glucose-stimulated mesangial cells, especially in a time-dependent manner by high glucose pretreatment, while no C-peptide was detected in low glucose-cultured mesangial cells. The dynamic functional localization of C-peptide might be the intrinsic cause of its unique beneficial effects for DN, which may provide a foundation for further clarification of its underlying mechanism. Our preliminarily data also shown C-peptide suppressed the iNOS expression. Taking together, these results revealed the dynamic functional localization of C-peptide by high glucose stimulation in rat mesangial cells, which might suppress expression of iNOS to exhibit its protective effects.


Role of non-HLA gene polymorphisms in graft-versus-host disease.
A large number of reports have associated various non-HLA gene polymorphisms with the risk and severity of graft-versus-host disease (GVHD). To date, candidate gene studies and genome-wide association studies have been performed to investigate such non-HLA gene polymorphisms in relation to GVHD. Candidate gene studies are hypothesis-driven and cost-effective, whereas genome-wide association studies have the potential to discover new gene polymorphisms, including possible biomarkers and therapeutic targets. Some gene polymorphisms have the potential to affect protein function or gene expression, or to encode minor histocompatibility antigens. Non-HLA genotyping for genes influencing GVHD prior to transplantation should provide useful information that will facilitate choosing the donor, type of graft, conditioning treatment, and GVHD prophylaxis. However, attention should be paid to the need for validation studies and ethical issues.


Sleep disruption impairs haematopoietic stem cell transplantation in mice.
Many of the factors affecting the success of haematopoietic cell transplantation are still unknown. Here we show in mice that donor sleep deprivation reduces the ability of its haematopoietic stem cells (HSCs) to engraft and reconstitute the blood and bone marrow of an irradiated recipient by more than 50%. We demonstrate that sleep deprivation downregulates the expression of microRNA (miR)-19b, a negative regulator of the suppressor of cytokine signalling (SOCS) genes, which inhibit HSC migration and homing. Accordingly, HSCs from sleep-deprived mice have higher levels of SOCS genes expression, lower migration capacity in vitro and reduced homing to the bone marrow in vivo. Recovery of sleep after sleep deprivation restored the reconstitution potential of the HSCs. Taken together, this study provides insights into cellular and molecular mechanisms underlying the effects of sleep deprivation on HSCs, emphasizing the potentially critical role of donor sleep in the success of bone marrow transplantation.


[The preliminary study on transforming growth factor-beta 3, activin receptor-like kinase 5 expression in 2, 3, 7, 8-tetrachloro-p-dibenzodioxin and dexamethasone induced palatal cleft in mice].
To establish a good animal model of cleft palate and confirm whether 2, 3, 7, 8-tetrachloro-p-dibenzodioxin (TCDD) and Dexamethasone (DEX) induced palatal cleft in mice is related to the fold change of transforming growth factor-beta 3 (TGF-beta3) and activin receptor-like kinase 5 (Alk5). Pregnant mice were treated with oral medication of TCDD and intraperitoneal injection with DEX on GD10-12 in experimental group while the control group without any treatment. Then embryos were examined on GD17.5 under stereomicroscope for calculating the incidence of cleft palate and palatal shelves were dissected from the staged embryos respectively for RNA extraction on GD13.5, GD14.5 and GD15.5. At last the real-time PCR and SYBR Green I detection were used for RNA relative quantification. Cleft palate could be induced 100% in C57BL/6J fetal mice with TCDD and DEX, thus established a stable animal model for further molecular studies of cleft palate. There were no significant difference in expression level of TGF-beta3 and Alk5 on GD13.5 among the groups, but the differences were statistically significant on GD14.5 and GD15.5 (P < 0.05). On the contrary, the expression level of Alk5 were significantly higher in experimental group (P < 0.05). Combined effects of TCDD and DEX could induce a stable formation of cleft palate and down-regulated mRNA of TGF-beta3 and up-regulated Alk5 may contribute to the occurrence of cleft palate.


Dissection of the poly(glu60 ala30 tyr10) (GAT)-specific T-cell repertoire in H-2Ik mice. I. GAT plus self-I-Ak-reactive T-cell clones can recognize alloactivating and/or restriction determinants on nonself-Ia molecules.
We examined the antigen recognition of the class II major histocompatibility complex (MHC) of 45 poly(glu60 ala30 tyr10) (GAT)-reactive T-cell clones isolated by limiting dilution cloning of a pool of in vivo-primed and in vitro-restimulated A.TL lymph-node T cells. Each clone expressed the Thy-1.2+, Lyt-1+, Lyt-2-, LFA-1+, Ia-, and H-2Dd+ cell-surface phenotype and exhibited strict specificity for GAT on syngeneic antigen-presenting cells (APCs). The monitoring of the proliferative responses of these clones in the presence or absence of GAT, using APCs from strains with 11 independent H-2 haplotypes, revealed several distinct specificity patterns: (i) most (31 of 45, 73%) T-cell clones recognized GAT in a self-I-Ak-restricted manner; (ii) other alloreactive clones (5 of 45, 11%) were stimulated to proliferate, irrespective of the presence of GAT, in response to allodeterminants expressed on H-2s, H-2d, H-2f or H-2u spleen cells; (iii) a third T-cell clone subset (4 of 45, 9%) was activated by GAT in the context of not only self-I-Ak but also nonself restriction Ia determinants; and (iv) three clones (7%) exhibited a triple specificity, i.e., they recognized GAT in the context of self and nonself Ia determinants and were alloreactive. One of the latter clones responded to GAT in an apparently non-MHC-restricted manner and recognized an I-Ab allodeterminant. These data provide direct evidence that the antigen-specific and alloreactive T-cell repertoires overlap and that the self-MHC restriction of GAT-specific T-cell responses is not absolute in A.TL mice.


Intimal granulomatous angiitis in sarcoid pulmonary vasculitis: worth remembering.
Intimal granulomatous angiitis is a facet of pulmonary sarcoidosis vasculitis that has almost been forgotten. Its observation may offer new understanding of the various patterns of pulmonary hypertension associated with sarcoidosis. https://bit.ly/3g6Ms76.


Tracking Daily Concentrations of PM2.5 Chemical Composition in China since 2000.
PM2.5 chemical components play significant roles in the climate, air quality, and public health, and the roles vary due to their different physicochemical properties. Obtaining accurate and timely updated information on China's PM2.5 chemical composition is the basis for research and environmental management. Here, we developed a full-coverage near-real-time PM2.5 chemical composition data set at 10 km spatial resolution since 2000, combining the Weather Research and Forecasting-Community Multiscale Air Quality modeling system, ground observations, a machine learning algorithm, and multisource-fusion PM2.5 data. PM2.5 chemical components in our data set are in good agreement with the available observations (correlation coefficients range from 0.64 to 0.75 at a monthly scale from 2000 to 2020 and from 0.67 to 0.80 at a daily scale from 2013 to 2020; most normalized mean biases within ±20%). Our data set reveals the long-term trends in PM2.5 chemical composition in China, especially the rapid decreases after 2013 for sulfate, nitrate, ammonium, organic matter, and black carbon, at the rate of -9.0, -7.2, -8.1, -8.4, and -9.2% per year, respectively. The day-to-day variability is also well captured, including evolutions in spatial distribution and shares of PM2.5 components. As part of Tracking Air Pollution in China (http://tapdata.org.cn), this daily-updated data set provides large opportunities for health and climate research as well as policy-making in China.


Minimizing perinatal neurologic injury at term: is cesarean section the answer?
Despite advances in obstetric and neonatal care, the last several decades have not witnessed an improvement in the prediction or prevention of term cerebral palsy. Obstetric interventions such as electronic fetal heart rate monitoring and cesarean delivery, although biologically plausible as intervention strategies, do not improve perinatal outcomes in clinical practice. In reaction to mounting medicolegal pressure, obstetricians continue to increase the number of cesarean deliveries they perform as a form of defensive medicine, despite evidence that this practice is not associated with improved perinatal outcomes. The current standard for expeditious delivery in a case of potential fetal compromise is described by the "30-minute rule." However, obstetricians' determinations of the need for expedited delivery may be a preferable guide for appropriate delivery timing.


Core-shell nanocarriers with high paclitaxel loading for passive and active targeting.
Rapid blood clearance and premature burst release are inherent drawbacks of conventional nanoparticles, resulting in poor tumor selectivity. iRGD peptide is widely recognized as an efficient cell membrane penetration peptide homing to αVβ3 integrins. Herein, core-shell nanocapsules (NCs) and iRGD-modified NCs (iRGD-NCs) with high drug payload for paclitaxel (PTX) were prepared to enhance the antitumor activities of chemotherapy agents with poor water solubility. Improved in vitro and in vivo tumor targeting and penetration were observed with NCs and iRGD-NCs; the latter exhibited better antitumor activity because iRGD enhanced the accumulation and penetration of NCs in tumors. The NCs were cytocompatible, histocompatible, and non-toxic to other healthy tissues. The endocytosis of NCs was mediated by lipid rafts in an energy-dependent manner, leading to better cytotoxicity of PTX against cancer cells. In contrast with commercial product, PTX-loaded NCs (PTX-NCs) increased area under concentration-time curve (AUC) by about 4-fold, prolonged mean resident time (MRT) by more than 8-fold and reduced the elimination rate constant by greater than 68-fold. In conclusion, the present nanocarriers with high drug-loading capacity represent an efficient tumor-targeting drug delivery system with promising potential for cancer therapy.


[From molecular biology to new treatment approaches to colorectal cancer: basic research, experimental trials and surgical implications].
The Authors review the natural history of colorectal cancer from the point of view of molecular biology and genetics from aberrant crypts foci and familiar adenomatous polyposis to hereditary non polyposis colon cancer and sporadic colorectal cancer. They carry out international literature about basis knowledges, experimental trials and personal studies. Up to day traditional colorectal cancer surgical treatments and adjuvant or neoadjuvant pharmacological therapy cannot be modified, nevertheless "new drugs generation" known as signal transduction inhibitor could, in the future, prove to be an effective cancer treatment. The Authors highlight recent experimental clinical trials probably able to prevent sporadic colorectal cancer spreading and precursor evolution.


Characterization of three pheromone-binding proteins (PBPs) of Helicoverpa armigera (Hübner) and their binding properties.
Three pheromone-binding proteins of Helicoverpa armigera were cloned and expressed in Escherichia coli. In order to characterize their physiological properties, ligand-binding experiments were performed using five biologically relevant substances including sex pheromones and interspecific signals. The results showed that one of the pheromone-binding proteins, HarmPBP1, binds strongly to each of the two principal pheromone components of H. armigera, (Z)-11-tetradecenal and (Z)-9-hexadecenal, but not to the interspecific signal (Z)-9-tetracecenal. The two remaining pheromone-binding proteins, HarmPBP2 and HarmPBP3, showed only weak affinities with the ligands tested. The 3-D structure of HarmPBP1 was predicted and the docking experiments indicate that the key binding site of (Z)-9-hexadecenal to HarmPBP1 includes Thr112, Lys111, and Phe119 whereas that of (Z)-11-tetradecenal includes Ser9, Trp37, Phe36, and Phe119.


Liquid Biopsy in Gastrointestinal Cancers: How Close Are We to Reaching the Clinic?
Gastrointestinal (GI) cancers are malignancies that develop within the digestive system and account for one in four cancer cases according to WHO data [...].


The value of intraoperative angiography for surgical treatment of cerebral arteriovenous malformations in eloquent brain areas.
Intraoperative digital subtraction angiography (DSA) allows intraoperative assessment of outcome of cerebral arteriovenous malformations (AVM). This study reports on 21 patients with AVMs in eloquent areas of the brain extirpated between July 1995 to March 1998. Extirpation was always followed by intraoperative DSA. Intraoperative angiography disclosed an occult residual nidus in 4 cases (19%). Complete extirpation of the AVM was achieved in all cases. Following surgery the neurological condition improved in 15 cases (71%), remained unchanged in 5 (24%), and worsened in 1. There were no secondary postoperative haemorrhages, nor complications related to the angiography. These results indicate that intraoperative DSA should be considered in the course of surgical treatment of cerebral AVMs in eloquent areas of the brain.


Plasma epinephrine concentration in healthy men: correlation with systolic pressure and rate-pressure product.
Relations among plasma epinephrine, norepinephrine and renin activity and systolic pressure, diastolic pressure, heart rate and the product of heart rate and systolic pressure (rate-pressure product) were evaluated in 31 healthy men whose arterial pressure spanned the range from normal to mildly elevated. Measurements were made during 60 minutes with the patient in the supine position and during 10 minutes of quiet standing. In the supine position, highly significant regressions were found between systolic pressure or rate-pressure product and plasma epinephrine, but not between these variables and norepinephrine or renin activity. A weakly significant correlation was also found between heart rate and norepinephrine. On standing, norepinephrine and epinephrine increased significantly. In this position, rate-pressure product was significantly related by regression analysis only with plasma epinephrine. Weakly significant correlations between systolic pressure and epinephrine and between heart rate and norepinephrine and epinephrine were also found. Plasma renin activity was not significantly correlated with arterial pressure, heart rate or rate-pressure product in either position. These results suggest that plasma epinephrine is a determinant of systolic pressure when postural reflexes are minimized and that epinephrine may participate in control of cardiac work load, as reflected by rate-pressure product in the absence of exercise or definable stress.


Long-term efficacy, safety and neurotolerability of MATRix regimen followed by autologous transplant in primary CNS lymphoma: 7-year results of the IELSG32 randomized trial.
219 HIV-negative adults ≤70 years with primary CNS lymphoma (PCNSL) were enrolled in the randomized IELSG32 trial. Enrolled patients were randomly assigned to receive methotrexate-cytarabine (arm A), or methotrexate-cytarabine-rituximab (B), or methotrexate-cytarabine-thiotepa-rituximab (MATRix; arm C). A second randomization allocated patients with responsive/stable disease to whole-brain irradiation (WBRT) or carmustine-thiotepa-conditioned autologous transplantation (ASCT). First results, after a median follow-up of 30 months, showed that MATRix significantly improves outcome, with both WBRT and ASCT being similarly effective. However, sound assessment of overall survival (OS), efficacy of salvage therapy, late complications, secondary tumors, and cognitive impairment requires longer follow-up. Herein, we report the results of this trial at a median follow-up of 88 months. As main findings, MATRix was associated with excellent long-lasting outcome, with a 7-year OS of 21%, 37%, and 56% respectively for arms A, B, and C. Notably, patients treated with MATRix and consolidation had a 7-year OS of 70%. The superiority of arm B on arm A suggests a benefit from the addition of rituximab. Comparable efficacy of WBRT and ASCT was confirmed. Salvage therapy was ineffective; benefit was recorded only in patients with late relapse re-treated with methotrexate. Eight (4%) patients developed a second cancer. Importantly, MATRix and ASCT did not result in higher non-relapse mortality or second tumors incidence. Patients who received WBRT experienced impairment in attentiveness and executive functions, whereas patients undergoing ASCT experienced improvement in these functions as well as in memory and quality of life.


Transcriptome profiling reveals the developmental regulation of NaCl-treated Forcipomyia taiwana eggs.
The biting midge, Forcipomyia taiwana, is one of the most annoying blood-sucking pests in Taiwan. Current chemical control methods only target the adult, not the immature stages (egg to pupa), of F. taiwana. Discovering new or alternative tactics to enhance or replace existing methods are urgently needed to improve the effectiveness of F. taiwana control. The egg is the least understood life stage in this pest species but may offer a novel point of control as addition of NaCl to the egg environment inhibits development. Thus, the objective of this study was to use RNA profiling to better understand the developmental differences between wild-type melanized (black) and NaCl-induced un-melanized (pink), infertile F. taiwana eggs. After de novo assembly with Trinity, 87,415 non-redundant transcripts (Ft-nr) with an N50 of 1099 were obtained. Of these, 26,247 (30%) transcripts were predicted to have long open reading frames (ORFs, defined here as ≥300 nt) and 15,270 (17.5%) transcripts have at least one predicted functional domain. A comparison between two biological replicates each of black and pink egg samples, although limited in sample size, revealed 5898 differentially expressed genes (DEGs; 40.9% of the transcripts with long ORFs) with ≥2-fold difference. Of these, 2030 were annotated to a Gene Ontology biological process and along with gene expression patterns can be separated into 5 clusters. KEGG pathway analysis revealed that 1589 transcripts could be assigned to 18 significantly enriched pathways in 2 main categories (metabolism and environmental information processing). As expected, most (88.32%) of these DEGs were down-regulated in the pink eggs. Surprisingly, the majority of genes associated with the pigmentation GO term were up-regulated in the pink egg samples. However, the two key terminal genes of the melanin synthesis pathway, laccase2 and DCE/yellow, were significantly down-regulated, and further verified by qRT-PCR. We have assembled and annotated the first egg transcriptome for F. taiwana, a biting midge. Our results suggest that down-regulation of the laccase2 and DCE/yellow genes might be the mechanism responsible for the NaCl-induced inhibition of melanization of F. taiwana eggs.


High fetal hemoglobin level is associated with increased risk of cerebral vasculopathy in children with sickle cell disease in Mayotte.
Understanding the genetics underlying the heritable subphenotypes of sickle cell anemia, specific to each population, would be prognostically useful and could inform personalized therapeutics.The objective of this study was to describe the genetic modulators of sickle cell disease in a cohort of pediatric patients followed up in Mayotte. This retrospective cohort study analyzed clinical and biological data, collected between January1st2007 and December 31st2017, in children younger than 18 years. We included 185 children with 72% SS, 16% Sβ0-thalassemia and 12% Sβ + thalassemia. The average age was 9.5 years; 10% of patients were lost to follow up. The Bantu haplotype was associated with an increase in hospitalizations and transfusions. The alpha-thalassemic mutation was associated with a decrease of hemolysis biological parameters (anemia, reticulocytes), and a decrease of cerebral vasculopathy. The Single Nucleotide Polymorphisms BCL11A rs4671393, BCL11A rs11886868, BCL11A rs1427407 and HMIP rs9399137 were associated with the group of children with HbF > 10%. Patients with HbF > 10% presented a significant risk of early onset of cerebral vasculopathy. The most remarkable result of our study was the association of SNPs with clinically relevant phenotypic groups. BCL11A rs4671393, BCL11A rs11886868, BCL11A rs1427407 and HMIP rs9399137 were correlated with HbF > 10%, a group that has a higher risk of cerebral vasculopathy and should be oriented towards the hemolytic sub-phenotype.


GPU-Accelerated Adjoint Algorithmic Differentiation.
Many scientific problems such as classifier training or medical image reconstruction can be expressed as minimization of differentiable real-valued cost functions and solved with iterative gradient-based methods. Adjoint algorithmic differentiation (AAD) enables automated computation of gradients of such cost functions implemented as computer programs. To backpropagate adjoint derivatives, excessive memory is potentially required to store the intermediate partial derivatives on a dedicated data structure, referred to as the "tape". Parallelization is difficult because threads need to synchronize their accesses during taping and backpropagation. This situation is aggravated for many-core architectures, such as Graphics Processing Units (GPUs), because of the large number of light-weight threads and the limited memory size in general as well as per thread. We show how these limitations can be mediated if the cost function is expressed using GPU-accelerated vector and matrix operations which are recognized as intrinsic functions by our AAD software. We compare this approach with naive and vectorized implementations for CPUs. We use four increasingly complex cost functions to evaluate the performance with respect to memory consumption and gradient computation times. Using vectorization, CPU and GPU memory consumption could be substantially reduced compared to the naive reference implementation, in some cases even by an order of complexity. The vectorization allowed usage of optimized parallel libraries during forward and reverse passes which resulted in high speedups for the vectorized CPU version compared to the naive reference implementation. The GPU version achieved an additional speedup of 7.5 ± 4.4, showing that the processing power of GPUs can be utilized for AAD using this concept. Furthermore, we show how this software can be systematically extended for more complex problems such as nonlinear absorption reconstruction for fluorescence-mediated tomography.


A galactose-specific lectin from the hemolymph of the pearl oyster, Pinctada fucata martensii.
1. A lectin in the serum of Pinctada fucata martensii was purified by a combination of affinity chromatography on Sepharose 4B coupled with bovine submaxillary gland mucine, anion exchange chromatography on Mono Q and gel filtration on Superose 6. 2. The purified lectin was indicated to be homogeneous by polyacrylamide electrophoresis and rechromatography on Mono Q. 3. The purified lectin was approximately 440,000 in molecular weight and was composed of identical subunits with a molecular weight of approximately 20,000. 4. D-galactose and N-acetylgalactosamine gave a 50% inhibition of agglutination of horse erythrocytes by the lectin at 0.3 and 1.2 mM, respectively. 5. The antibody obtained from rabbit immunized with the purified lectin was monospecific to the lectin judged from the hemagglutination blocking test, immunoelectrophoresis and immunoblotting.


[PACS: from project to reality. Report of experiences on full digitalisation of the radiology department of a major hospital].
To assess the time needed and the resulting effects of a complete digitalisation of a radiological department of a major hospital (856 beds, 28,000 in-patients, 35,000 out-patients/year) a pilot study was performed. This had to be done without interrupting routine services. After intensive preparations were performed and the hospital-network was completed, within a two year period all radiological functions (mammography excluded), reporting stations and archives were changed to a complete digital workflow. All modalities (provided by 3 different companies) are now connected by DICOM-work lists. The picture-files (4 GB/day) are automatically routed to the work-stations (n = 10), where the reporting and file shows are performed, to the digital archive and to the peripheral viewing-stations (n = 44). The distribution of the digital pictures takes place all over the hospital including the ORs and special units. We accomplished, to connect electronically the report and the image data. The clinical file shows are also performed completely digitally. The access to the data of the deep archive is possible by the dept. of radiology without any manual interaction. The film consumption was reduced to an amount of less than 10%, as compared to the prior PACS situation. Since PACS has been introduced the radiological productivity increased by more than 15% and throughput-time was clearly reduced. The complete digitalisation increases productivity and attractiveness of a hospital-radiology and helps to shorten diagnostic and therapeutic decision-making. The transfer from a conventional to a digital workflow is possible without interrupting the clinical services. Extensive preparations and ongoing assistance of such projects though are clearly needed.


Steroid-refractory chronic idiopathic thrombocytopenic purpura associated with hepatitis C virus infection.
Hepatitis C virus infection has often been suggested as a possible cause of various kinds of autoimmune diseases. The aim of this study was to determine the relationship between chronic idiopathic thrombocytopenic purpura (ITP) and hepatitis C virus infection and to characterize the clinical features of anti-HCV antibody (HCVab) positive chronic ITP patients. We studied HCVab in 79 patients with chronic ITP (25 males, 54 females, mean age 42.3 yr, range 11-86 yr) using the third-generation ELISA method. HCVab was detected in 11 of the 79 patients (13.9%). Quantitative HCV-RNA studies showed a high serum concentration of HCV-RNA in these patients. The platelet counts in these 11 HCVab-positive patients (Group 1) were lower than in the 68 HCVab-negative patients (Group 2) [(2.6 +/- 0.9) versus (4.9 +/- 3.0) x 10(10)/L, respectively; p<0.02]. Significantly more patients in Group 1 required prednisolone therapy (10/11, 90.9%) than in Group 2 (31/68, 45.6%) (P < 0.005). The response rate to prednisolone treatment was significantly higher in Group 2 (19/31, 61.3%) than in Group 1(0/10, 0%) (P < 0.001). There was no difference in the response to splenectomy between Groups 1 (4/7, 57.1%) and 2 (3/5, 60%). Given these findings, we recommend that HCVab is measured upon diagnosis of chronic ITP, and that splenectomy is planned in patients with HCVab in the event that prednisolone treatment is ineffective.


Proteolytic cleavage of membrane proteins by membrane type-1 MMP regulates cancer malignant progression.
Strategies to develop cancer therapies using inhibitors that target matrix metalloproteinases (MMPs), particularly membrane type-1 MMP (MT1-MMP), have failed. This is predominantly attributed to the specificity of MMP inhibitors and numerous functions of MMPs; therefore, targeting substrates with such broad specificity can lead to off-target effects. Thus, new drug development for cancer therapeutics should focus on the ability of MT1-MMP to break down substrates, such as functional cell membrane proteins, to regulate the functions of these proteins that promote tumor malignancy. In this review, we discuss the mechanism by which proteolysis of cell surface proteins by MT1-MMP promotes progression of malignant tumor cells. In addition, we discuss the two protein fragments generated by limited cleavage of erythropoietin-producing hepatoma receptor tyrosine kinase A2 (EphA2-NF, -CF), which represent a promising basis for developing new cancer therapies and diagnostic techniques.


Insights into the effect of cations on cathodic behavior and microstructure in cadmium electrochemical recovery process.
Secondary resources provide an essential source for cadmium recovery, but also bring severe environmental problems. Due to the short process and high product purity, electrodeposition is suitable for realizing the reduction, reuse, and recycling of cadmium, while the complex composition of the resources contributes to a complicated electrochemical system. In this work, the effect of common cations (Cu2+, Ni2+, Fe2+, and Zn2+) on cadmium electrochemical recovery was investigated from the perspective of electrochemical behavior and microstructure. The results indicated that Cu affected the electrochemical process most prominently, which was deposited on the cathode and formed microcell with Cd, not only impeding the recovery of Cd, but also influencing the purity severely. Comparatively, Ni showed a relatively minor effect, which made the formal potential more negative and alleviated cathodic polarization to some degree. Besides, Fe2+ was oxidized by the oxygen released from the anode, and followed by the reaction with Cd, resulting in the redissolution of Cd. With respect to Zn, a low concentration of Zn (≤1 g L-1) had little influence on electrochemical behavior of Cd, while it was deposited simultaneously with Cd on the cathode at a high concentration (5 g L-1). Based on the microstructural characterization, the lithops-like cathode cadmium grew up in the presence of Cu, while dendritic Cd was formed affected by Zn, Fe2+, and Ni, especially Fe2+.


Uterine development in Turner syndrome.
To evaluate uterine development of women with Turner syndrome (TS) receiving conventional medical care. In a cross-sectional study we used ultrasonography for uterine evaluation in 86 women with TS 18 to 45 years of age participating in an intramural NIH study, and who had abnormal karyotypes in >70% of white blood cells. Outcomes were uterine dimensions and shape. Information on hormone treatment was obtained by personal interview. Twenty-five percent had a mature in size and shape uterus, and 31% had an immature uterus, with the remainder in a transitional category. Twenty percent of all participants were not taking hormone replacement therapy (HRT) in the preceding year. The majority on treatment were taking conjugated estrogens (CE) or oral contraceptives (OC). Factors associated with uterine maturity were history of spontaneous puberty and duration and type of HRT, with estradiol-based treatment being the most effective. The age at starting HRT was not a critical factor. Women with TS may develop a normal uterus even at a late start of HRT given adequate duration of treatment and regardless of karyotype.


Isolation and characterization of native human renin derived from Chinese hamster ovary cells.
Transfection of Chinese hamster ovary (CHO) cells with a plasmid containing the cDNA for human preprorenin has provided cell lines that secrete 15 mg of native prorenin per liter of culture medium. Tryptic activation of the prorenin occurs by selective cleavage of the Arg66-Leu67 bond (numbering as in preprorenin). The renin product, purified in a single step and in high yield by affinity chromatography, is fully stable for as long as 8 months when stored in solution at 4 degrees C and pH 6.5. Purity of the renin was judged to be greater than 95% by gel electrophoresis, compositional and N-terminal sequence analyses, and specific enzyme activity. An important aspect of the present work is the development of a direct assay for renin which permits accurate and reproducible evaluation of enzyme units and kinetic parameters. Application of methods described herein, combined with appropriate scale-up fermentation capabilities, provides the means for generating gram quantities of human renin and its zymogen.


Infertility, chemical exposure, and farming in Iowa: absence of an association.
An increased incidence of infertility and abnormal semen analysis has been described in men and experimental animals exposed to agricultural chemicals. These reports led us to review the records of 382 consecutive new male patients who had semen analyses performed at the University of Iowa Hospitals and Clinics. No significant differences in the incidence of abnormalities in either the physical examination or the semen analysis were discovered with respect to occupation or possible exposure to chemical agents.


Circulating magnesium as a potential risk stratification tool for sudden cardiac death: a systematic review.
Sudden cardiac death (SCD) is one of the main causes of cardiovascular mortality and accounts for 15-20% of deaths worldwide. The current stratification strategy using depressed left ventricular ejection fraction is insufficient to stratify the risk of SCD, especially in the general population. In recent years, there has been increasing evidence showing the antiarrhythmic properties of magnesium. In this systematic review, the authors aim to determine circulating magnesium as a potential risk stratification tool for SCD. This systematic review was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and was conducted in July 2021 with sources from Google Scholar, PubMed, Science Direct, EBSCO Medline, and ProQuest. A total of six studies were included in this review. Three studies conducted in the general population consistently showed lower risk of SCD in populations with high circulating magnesium. There was no association between circulating magnesium level and risk of SCD in intensive cardiac care unit (ICCU) patients, whilst the results were conflicting in congestive heart failure (CHF) patients. High circulating magnesium might have the potential to be utilized as a risk stratification tool for SCD, especially in the general population. However, further study is needed to support this evidence.


Sucrose octaacetate-taster mice have more vallate taste buds than non-tasters.
Taste buds were counted in two strains of mice which have been characterized in terms of their taste avoidance of the bitter-tasting substance, sucrose octaacetate (SOA). One strain (SWR/J) avoids SOA and is referred to as "taster' while the other strain (C57BL/6J) does not avoid SOA at the same concentration and is termed "non-taster'. The taster-strain contains a significantly greater number of taste buds in its vallate papillae than the non-tasters do. The relative number of taste buds which individual mice and humans possess probably contributes to the relative differences in their sensitivity and preference behaviors.


Chlamydial serology in genital infections: ImmunoComb versus Ipazyme.
The ImmunoComb Chlamydia trachomatis IgG/IgA (Orgenics, Israel) is a new serologic test using C. trachomatis L2 elementary bodies (Washington Research Foundation, Seattle) as antigen. The Ipazyme IgG/IgA test (Savyon, Israel) employs whole cells with C. trachomatis L2 inclusions, i.e. elementary and reticulate bodies. Theoretically, the ImmunoComb is expected to be less cross-reactive (LPS) with Chlamydia pneumoniae than the Ipazyme (LPS and reticulate body group specific antigens). Compared with the Ipazyme, the ImmunoComb IgA showed both a higher positive predictive value (36% versus 25%) and sensitivity (67% versus 33%) for antigen detection in a control group of 100 post partum women with a 6% prevalence of C. trachomatis positive cervical smears. In sterility patients (45 cases with occluded and 53 with open fallopian tubes) the tube status was predicted by the ImmunoComb (Ipazyme) with 74% (72%) positive predictive value, 87% (80%) sensitivity, and 87% (81%) negative predictive value. IgG/IgA prevalence in 118 patients with C. trachomatis positive cervical smears was 85%/55% for the ImmunoComb and 84%/49% for the Ipazyme. The ImmunoComb is considerably faster and easier in handling and less subjective in reading than the Ipazyme.


Large-scale analysis of Drosophila core promoter function using synthetic promoters.
The core promoter plays a central role in setting metazoan gene expression levels, but how exactly it "computes" expression remains poorly understood. To dissect its function, we carried out a comprehensive structure-function analysis in Drosophila. First, we performed a genome-wide bioinformatic analysis, providing an improved picture of the sequence motifs architecture. We then measured synthetic promoters' activities of ~3,000 mutational variants with and without an external stimulus (hormonal activation), at large scale and with high accuracy using robotics and a dual luciferase reporter assay. We observed a strong impact on activity of the different types of mutations, including knockout of individual sequence motifs and motif combinations, variations of motif strength, nucleosome positioning, and flanking sequences. A linear combination of the individual motif features largely accounts for the combinatorial effects on core promoter activity. These findings shed new light on the quantitative assessment of gene expression in metazoans.


De novo 9-break-event in one chromosome 21 combined with a microdeletion in 21q22.11 in a mentally retarded boy with short stature.
We report on a moderately mentally retarded 12-year-old boy of short stature showing the most complex chromosomal rearrangement (CCR) within a single chromosome ever described. A de novo derivative chromosome 21 was recognized in GTG-banding shortly after birth. However, the nature of the rearrangement remained obscure up to the application of the chromosome 21-specific centromere-near multicolor-FISH (subcenM-FISH) probe set and of six selected locus-specific probes along chromosome 21. An unbalanced 9-break-event was uncovered with breakpoints in 21p13, 21p13-->12, 21q11.2, 21q21.1, 21q22.11, 21q22.11, 21q22.12, 21q22.22 and 21q22.3. A deletion of 21q22.11 was detected by application of the BAC probe bk249H10. The karyotype can be described as 46,XY,der(21)(:p13-->p1213::q22.3-->q22.22:: q11.2-->p1213::q11.2-->q21.1::q22.11-->q21.1::q22.12--> q22.22::p13-->p13). The clinical signs can either be due to gene inactivation in connection with structural changes at the break and fusion regions, to the building of new fusion genes within the CCR and/or to the deletion of genes in 21q22.11.


Extreme nearly neutral evolution in mitochondrial genomes of laboratory mouse strains.
Relaxation of the selective constraint during the domestication process is known. In this study, we report unexpected closeness to neutral evolution of mitochondrial genomes of laboratory mouse strains: estimated non-synonymous/synonymous rate ratio being very close to 1 (ω^=1.32). Probably it is due to the extreme inbreeding extending over 100 years as well as to their recent origin (middle of the last millennium). There is no rate difference observed among three codon positions as well as ribosomal RNA and control regions. However, the amino acid substitutions occurred not randomly, and substitutions were more frequent between physico-chemically similar amino acids than between dissimilar ones. Probably this is inevitable consequence caused by the codon table itself, but not by selections. This implies that a large portion of the new mutations are conservative, and most of them are slightly deleterious and not lethal. It seems that, even though the selection pressures do not hold normally, the function of genes may not be impaired in most cases.


Testosterone Therapy in a Man with Intermediate-risk Prostate Cancer: Pro.
The original prohibition of testosterone therapy for men with prostate cancer was based on outdated concepts developed more than 70 yr ago. Current evidence, although limited, provides consistently reassuring results that testosterone therapy may be reasonably offered to many men with prostate cancer. These men may experience valuable benefits in quality of life if they suffer from symptoms of testosterone deficiency (hypogonadism).


Cell suspension cultures of allogenic keratinocytes are efficient carriers for ex vivo gene transfer and accelerate the healing of full-thickness skin wounds by overexpression of human epidermal growth factor.
The concept of using growth factor therapy to induce wound repair has been endorsed in studies that show reduced growth factors in wound fluid from chronic and aged wounds. In this study, we used cell suspensions of allogenic keratinocytes as gene-delivery vehicles for human epidermal growth factor (hEGF) and analyzed their impact on wound repair in a porcine wound-healing model. Full-thickness wounds were created on the backs of six Yorkshire pigs and covered with a wound chamber to create a wet wound-healing environment. First, 5 x 10(5) allogenic, autogenic, or mixed keratinocytes were transplanted into wounds and healing parameters were analyzed. Second, we measured long-term reepithelialization and contraction rates from day 8 until day 35. In the third experiment, allogenic keratinocytes were transfected with an hEGF-expressing plasmid pCEP-hEGF and transplanted in full-thickness wounds to improve repair. Wounds treated with autogenic, allogenic, or mixed keratinocytes showed a significantly higher rate of reepithelialization relative to saline-treated control wounds. Repetitive biopsies indicated that the use of allogenic keratinocytes did not lead to long-term wound breakdown. Wounds treated with hEGF-expressing allogenic keratinocytes reepithelialized faster than wounds treated with allogenic keratinocytes or control wounds. With a peak hEGF expression of 920.8 pg/mL, hEGF was detectable until day 5 after transplantation compared with minimal hEGF expression in control wounds. This study shows that allogenic keratinocytes can serve as efficient gene transfer vehicles for ex vivo growth factor delivery to full-thickness wounds and overexpression of hEGF further improves reepithelialization rates.


[Residual variation of morphochronometric traits in hybrid tomatoes: analysis and possible mechanism of emergence].
Different expressivity of several morphometric and chronometric traits in tomato plants having similar genetic composition in the identical environmental conditions manifested as genotypic residual variation. Using correlation and artificial neural network analyses, we determined the relationship between productivity and other morphochronometric parameters. It was shown that chronology of the development may be important for the determination of productivity. Random epigenetic modifications independent of environmental factors are considered to underlie the residual variation. The different trait expression in different plants may lead to higher phenotypic diversity of a population characterized by low gene polymorphism.


A machine learning approach to estimating preterm infants survival: development of the Preterm Infants Survival Assessment (PISA) predictor.
Estimation of mortality risk of very preterm neonates is carried out in clinical and research settings. We aimed at elaborating a prediction tool using machine learning methods. We developed models on a cohort of 23747 neonates <30 weeks gestational age, or <1501 g birth weight, enrolled in the Italian Neonatal Network in 2008-2014 (development set), using 12 easily collected perinatal variables. We used a cohort from 2015-2016 (N = 5810) as a test set. Among several machine learning methods we chose artificial Neural Networks (NN). The resulting predictor was compared with logistic regression models. In the test cohort, NN had a slightly better discrimination than logistic regression (P < 0.002). The differences were greater in subgroups of neonates (at various gestational age or birth weight intervals, singletons). Using a cutoff of death probability of 0.5, logistic regression misclassified 67/5810 neonates (1.2 percent) more than NN. In conclusion our study - the largest published so far - shows that even in this very simplified scenario, using only limited information available up to 5 minutes after birth, a NN approach had a small but significant advantage over current approaches. The software implementing the predictor is made freely available to the community.


Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer's disease.
δ-secretase, also known as asparagine endopeptidase (AEP) or legumain, is a lysosomal cysteine protease that cleaves both amyloid precursor protein (APP) and tau, mediating the amyloid-β and tau pathology in Alzheimer's disease (AD). Here we report the therapeutic effect of an orally bioactive and brain permeable δ-secretase inhibitor in mouse models of AD. We performed a high-throughput screen and identified a non-toxic and selective δ-secretase inhibitor, termed compound 11, that specifically blocks δ-secretase but not other related cysteine proteases. Co-crystal structure analysis revealed a dual active site-directed and allosteric inhibition mode of this compound class. Chronic treatment of tau P301S and 5XFAD transgenic mice with this inhibitor reduces tau and APP cleavage, ameliorates synapse loss and augments long-term potentiation, resulting in protection of memory. Therefore, these findings demonstrate that this δ-secretase inhibitor may be an effective clinical therapeutic agent towards AD.


Low dose compared to variable dose Warfarin and to Fondaparinux as prophylaxis for thromboembolism after elective hip or knee replacement surgery; a randomized, prospective study.
Deep vein thrombosis (DVT) and pulmonary emboli (PE), known together as venous thromboembolic (VTE) disease remain major complications following elective hip and knee surgery. This study compares three chemoprophylactic regimens for VTE following elective primary unilateral hip or knee replacement, one of which was designed to minimize risk of post-operative bleeding. Patients were randomized and stratified for hip vs. knee to receive A: variable dose warfarin (first dose on the night preceding surgery with subsequent target INR 2.0-2.5), B: 2.5 mg fondaparinux daily starting 6-18 h postoperatively, or C: fixed 1.0 mg dose warfarin daily starting 7 days preoperatively. All treatments continued until bilateral leg venous ultrasound day 28 ± 2 or earlier upon a VTE event. The study examined primary endpoints including leg DVT, PE or death due to VTE and secondary endpoints including effects on D-dimer, estimated blood loss (EBL) at surgery and hemorrhagic complications. Three hundred fifty-five patients were randomized. None was lost to follow-up. Taking 1.0 mg warfarin for seven days preoperatively did not prolong the prothrombin time (PT). Two patients in Arm C had asymptomatic distal DVT. One major bleed occurred in Arm B and one in Arm C (ischemic colitis). Elevated d-dimer did not predict delayed VTE for one year. Fixed low dose warfarin started preoperatively is equivalent to two other standards of care under study (95 % CI: -0.0428, 0.0067 for both) as VTE prophylaxis for the patients having elective major joint replacement surgery. ClinicalTrials.gov identifier # NCT00767559 FDA IND: 103,716.


The centriolar antigen expression in TC7 cells is dependent on growth conditions and occurs at a particular time point in G1.
The correlation between growth conditions and centriolar antigen (Cag) expression in TC7 cells, a subline of African green monkey kidney cells, was studied. TC7 cells became quiescent when their number reached a high cell density, or when serum factors were depleted from media containing a low concentration of fetal bovine serum (FBS). There was a stoichiometric relationship between the concentration of serum present and the number of new cells produced. During proliferation, the projected cell area decreased as a function of cell density with two abrupt transitions. The first transition appeared to be independent of cell-cell contact. However, the second transition seemed to occur mainly as a result of the limitation of the available substratum surface on which the cells could grow. The appearance of Cag in TC7 cells was found to be associated with the cells' growth conditions as well as with the particular phase in cell cycle. In an exponentially growing culture of cells with 10% FBS and in cells that were growth restricted due to a high density (above 2-3 X 10(5) cells/cm2), the incidence of cells with Cag-positive staining was about 10-20%. It increased, however, to about 40-60% at cell densities between 2 X 10(4) cells/cm2 and 1 X 10(5) cells/cm2. The frequency of cells with positive Cag staining was as high as 80% in TC7 cells that were growth restricted by depletion of serum factor(s). Thus, the quiescent states attained by the two different growth restrictions seem to be different in their ability to express Cag. The frequency of Cag could be further increased by stimulating the quiescent cell population by FBS. In mitotically selected TC7 cells, Cag staining appeared about 4 hr after mitosis and about 2-4 hr before the onset of DNA synthesis. Thus, expression of Cag in TC7 cells is related to their growth conditions, and is characteristic of a part of the G1 phase of the cell cycle.


Coping with multiple sclerosis as a couple: 'peaks and troughs' - an interpretative phenomenological exploration.
Multiple Sclerosis (MS) is a chronic degenerative condition where illness uncertainty is a key difficulty that people with MS and their significant others have to cope with. Clinicians acknowledge that people with MS need to be seen in the context of their families, however there is little knowledge on what to expect about how people cope as a couple, which this study set out to explore. Interpretative Phenomenological Analysis (IPA) exploring, through semi-structured interviews, how seven couples, where one had MS, experienced coping with their situation. Two overarching themes pertaining to coping as a couple emerged from the data: Coping Together: "Peaks and Troughs" and Coping Over the Long Haul, with each overarching theme relating to sub-themes. Two integrative themes emerged also, which were called Faith in Self and Faith in Each Other. These results will assist clinicians better comprehend how those with MS and their spouses cope in an interconnected way and this in turn affects their experience of rehabilitation. Results from this research indicated that clinicians need to be sensitive to the individual coping strategies of both members of a couple where one has MS, and address the changing needs of their relationship.


Haemonchus contortus: development of a two-step, differential-display PCR to detect differential gene expression in nematodes from immune and naïve sheep.
Haemonchus contortus is a blood-feeding nematode which parasitizes the abomasum of sheep and represents a serious constraint to sheep production. Anthelmintics are currently the most common method of worm control but the worldwide development of multiple-drug resistance and issues of residues in the food chain make alternatives to anthelmintics a priority. Biotechnology-driven solutions to parasitism include vaccines and silencing of genes regulating nematode development. To pursue gene targets that may be suitable for parasite control, a two stage differential-display PCR (dd-PCR) approach was developed to observe differential gene expression between Haemonchus from immune and control sheep. Twenty-four reproducible differentially-expressed bands were identified in 60 pairs of dd-PCR comparisons. The first of these cloned and sequenced corresponded to the H. contortus 60S ribosomal protein L35A. The remaining bands are being cloned and validated and may provide new targets for parasite control.


Haemodynamic effects of methoxyflurane versus fentanyl and placebo in hypovolaemia: a randomised, double-blind crossover study in healthy volunteers.
Methoxyflurane is approved for relief of moderate to severe pain in conscious adult trauma patients: it may be self-administrated and is well suited for use in austere environments. Trauma patients may sustain injuries causing occult haemorrhage compromising haemodynamic stability, and it is therefore important to elucidate whether methoxyflurane may adversely affect the haemodynamic response to hypovolaemia. In this randomised, double-blinded, placebo-controlled, three-period crossover study, inhaled methoxyflurane 3 ml, i.v. fentanyl 25 μg, and placebo were administered to 15 healthy volunteers exposed to experimental hypovolaemia in the lower body negative pressure model. The primary endpoint was the effect of treatment on changes in cardiac output, while secondary endpoints were changes in stroke volume and mean arterial pressure and time to haemodynamic decompensation during lower body negative pressure. There were no statistically significant effects of treatment on the changes in cardiac output, stroke volume, or mean arterial pressure during lower body negative pressure. The time to decompensation was longer for methoxyflurane compared with fentanyl (hazard ratio 1.9; 95% confidence interval 0.4-3.4; P=0.010), whereas there was no significant difference to placebo (hazard ratio -1.3; 95% confidence interval -2.8 to 0.23; P=0.117). The present study does not indicate that methoxyflurane has significant adverse haemodynamic effects in conscious adults experiencing hypovolaemia. ClinicalTrials.gov (NCT04641949) and EudraCT (2019-004144-29) https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004144-29/NO.


Triglyceride to high-density lipoprotein cholesterol ratio and risk of atherosclerotic cardiovascular disease in a Chinese population.
Triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C) ratio may play a role in predicting cardiovascular events. We aimed to prospectively explore the association between the TG/HDL-C ratio and atherosclerotic cardiovascular disease (ASCVD), ischemic stroke, as well as coronary heart disease (CHD) in a Chinese population. This prospective cohort study included 9368 participants from four Chinese populations in the People's Republic of China-United States of America (PRC-USA) Collaborative Study of Cardiovascular and Cardiopulmonary Epidemiology. Over a follow-up period of 20 years, 624 cases of ASCVD events including 458 ischemic stroke events and 166 CHD events were recorded. The relationship between the TG/HDL-C ratio and the endpoints was evaluated through multivariate Cox proportional hazard models adjusted for potential confounding variables, including age, sex, urban or rural residence, northern or southern China, occupational type, education, physical exercise, smoking status, drinking status, body mass index, hypertension, high low-density lipoprotein cholesterol, diabetes, and antihypertensive medication use at baseline. With the lowest TG/HDL-C tertile as the reference, the middle and highest tertiles had the hazard ratios (HRs) and 95% confidence intervals (CIs) of 1.13 (0.91, 1.40), 1.36 (1.10, 1.67) respectively for ASCVD (p for trend = 0.0028), and 1.19 (0.93, 1.54),1.47 (1.15, 1.87) respectively for ischemic stroke (p for trend = 0.0016). However, no significant association was found for CHD events. TG/HDL-C ratio was positively associated with the risk of ASCVD and ischemic stroke events in the Chinese population.


Immune scoring model based on immune cell infiltration to predict prognosis in diffuse large B-cell lymphoma.
Diffuse large B-cell lymphoma (DLBCL) is genetically heterogeneous in both pathogenesis and clinical symptoms. Most studies on tumor prognosis have not fully considered the role of tumor-infiltrating immune cells. This study focused on the role of tumor-infiltrating immune cells in the prognosis of DLBCL. The GSE10846 data set from the National Center for Biotechnology Information's Gene Expression Omnibus was used as the training set, and the GSE53786 data set was used as the validation set. The proportion of immune cells in each sample was calculated with the CIBERSORT algorithm using R software. After 10 immune cells were screened out (activated memory CD4 positive T cells, follicular helper T cells, regulatory T cells, gamma-delta T cells, activated natural killer cells, M0 macrophages, M2 macrophages, resting dendritic cells, and eosinophils) by univariate Cox analysis, Lasso regression and random forest sampling analyses were performed, the intersecting immune cells were selected for multifactor Cox analysis, and a predictive model was constructed combined with clinical information. Predictive performance was assessed using survival analysis and time-dependent receiver operating characteristic curve analysis. In total, 539 samples were included in this study, and samples with p < .05 were retained using CIBERSORT. Univariate Cox analysis yielded 10 cell types that were associated with overall survival. Two kinds of immune cells were obtained by Lasso regression combined with the random forest method and were used to construct a prognostic model combined with clinical information. The reliability of the model was validated in two data sets. The immune cell-based prediction model constructed by the authors can effectively predict the prognostic outcome of patients with DLBCL, whereas nomogram plots can help clinicians assess the probability of long-term survival.


Demographic and clinical features of schizoaffective (schizobipolar) disorder--a 5-year retrospective study. Support for a bipolar spectrum disorder.
Schizobipolar disorder is considered related to both schizophrenia and bipolar disorder. We aimed to describe with retrospective methodology the demographic, clinical, and treatment features in a group of schizobipolar disorder patients who have been treated for at least a 5-year period and compare them with bipolar I and schizophrenic patients who were treated during the same period. We compared the demographic and clinical data of 61 schizobipolar, 57 bipolar I, and 55 schizophrenic outpatients who were diagnosed and treated for at least 5 years in the outpatient clinic in the Federal University of Rio de Janeiro. The schizobipolar disorder patients had a profile similar to the bipolar I patients but are significantly different from schizophrenic patients in educational level, marital status, occupation, drug and alcohol abuse episodes, presence of depressive, mixed and maniac episodes, family history of bipolar I and mood disorders, and use of medications. Only the age of onset, suicide attempts, and family history of suicide are not significantly different among the groups. The schizophrenic patients used antipsychotics for more days and the schizobipolar and bipolar I used more antidepressants and mood stabilizers. 37 (60.6%) schizobipolar patients had their diagnosis changed to bipolar disorder by their physician in different periods during the period studied. It is a retrospective data description based on a naturalistic treatment. The family history was collected from the patient and whenever possible from one first-degree relative. Schizobipolar disorder patients have demographic, clinical and therapeutic features similar to bipolar I patients and data support its definite inclusion in the bipolar spectrum group.


The dermatopathology of Cowden's syndrome.
During the past 2 years we have studied eighty-nine biopsy specimens from nineteen patients with Cowden's syndrome. Among fifty-three facial lesions, twenty-nine were trichilemmomas. Twenty-three of the others were consistent with trichilemmoma, showed a non-specific benign verrucous acanthoma, or were not diagnostic; one was a blue naevus. All fourteen oral mucosal biopsy specimens were benign fibromas. Nineteen of twenty-two biopsy specimens from the hands and feet showed the pattern of benign keratosis. Multiple trichilemmomas were found in all patients with Cowden's syndrome, but at times several biopsy specimens were required before a diagnostic picture was uncovered. All patients with multiple facial trichilemmomas were found to have Cowden's syndrome. The combination of multiple facial trichilemmomas, oral fibromas, and benign acral keratoses enables one to diagnose Cowden's syndrome at a stage before serious internal complications develop.


The role of methylenetetrahydrofolate reductase in acute lymphoblastic leukemia in a Brazilian mixed population.
The polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene are associated with leukemogenesis. In order to investigate the influence of two polymorphisms in the MTHFR gene, 677C>T and 1298A>C, on the risk of acute lymphoblastic leukemia (ALL) we performed a case-control study in children from different Brazilians' regions. Genotyping of 176 ALL and 199 unselected healthy subjects was performed using PCR-RFLP assay. There was no association between the 677C>T or 1298A>C and risk of ALL in total case-control sample. However, 677T allele was linked to a decrease risk of ALL [odds ratio (OR), 0.43; 95% confidence interval (CI), 0.22-0.86], whereas the 1298A>C polymorphism presents an elevated risk factor [OR, 2.01; 95% CI, 1.01-3.99] in non-White children. Our investigation provides interesting data concerning the opposite effect of A1298C polymorphisms, particularly in the light of relatively scarce data regarding the MTHFR role in leukemia susceptibility in different populations.


Effect of water and fat on gastric emptying of solid meals.
Gastric emptying of solid egg meals tagged with 99mtechnetium sulfur colloid was studied in 10 normal subjects and in 6 patients after truncal vagotomy, antrectomy, and gastrojejunostomy (Billroth II) for peptic ulcer disease. Technetium sulfur colloid was found to bind more firmly to cooked egg whites than did the water soluble marker DTPA. Water accelerated gastric emptying in Billroth II patients to a greater degree than in normal subjects, in whom the effect of water was minimal and transient. Fat inhibited solid emptying both in normals and in Billroth II patients. These findings suggest that in humans there are jejunal receptors for fat that may inhibit gastric emptying even following truncal vagotomy.


The retrograde approach to the reverse dorsal metacarpal artery flap.
We present a short communication on the use of a retrograde approach in the DMCA Perforator flap in cases of reconstruction post SCC excision of the hand. We illustrate the anatomy, and present intra- and post-operative findings.


Inhibitory effect of adrenomedullin on basal and tumour necrosis factor alpha-stimulated endothelin-1 synthesis in bovine aortic endothelial cells is independent of cyclic AMP.
Adrenomedullin (ADM) is a potent vasodilator and reverses the vasoconstrictor action of endothelin-1 (ET-1). These studies aimed to determine the effect of ADM on ET-1 synthesis in bovine aortic endothelial cells (BAEC) and to identify the possible mechanisms involved. In this cell model, ADM increased cyclic AMP production by BAEC with threshold concentrations of 100 pM and an EC(50) of 1 nM. This effect was not blocked by co-treatment with the CGRP type 1 receptor antagonist CGRP(8--37). ADM caused a potent concentration-dependent inhibition of ET-1 release that was correlated with reduced preproET-1 mRNA levels. This reached a maximal reduction of 70% compared to basal levels after 2 and 6 hr exposure of BAEC to 1 nM ADM, with significant decreases at concentrations as low as 10 pM. However, a 100-fold discrepancy between the threshold ADM concentration for cyclic AMP production and inhibition of ET-1 release was observed. Treatment of BAEC with tumour necrosis factor alpha (TNFalpha; 10 ng/mL) caused a 2-fold increase over basal ET-1 release. ADM caused a more marked reduction in stimulated ET-1 synthesis with a threshold of 1 pM, and suppression of ET-1 release to basal levels at 100 nM. 8-Bromo cyclic AMP, showed no concentration-dependent inhibition of ET-1 release, yet caused a 50% reduction in TNFalpha-stimulated intercellular adhesion molecule-1 (ICAM-1) mRNA levels. Thus, physiological ADM concentrations inhibit ET-1 synthesis independently of cyclic AMP in BAEC at the level of preproET-1 mRNA expression. The high sensitivity of this inhibition implicates ADM as an important physiological regulator of endothelial ET-1 production.


Implications for assessing sludge hygienization: Differential responses of the bacterial community, human pathogenic bacteria, and fecal indicator bacteria to sludge pretreatment-anaerobic digestion.
Sewage sludge is the byproduct of wastewater treatment plants, which host enormous diversity of microbes including potential pathogens. However, there are still challenges in assessing hygienization during sludge stabilization due to the complex relationships between dominant microbes and human pathogenic bacteria (HPB), and the accuracy of fecal indicator bacteria (FIB) is also disputed. Here, the responses of the bacterial community, HPB, and FIB to sludge pretreatment-anaerobic digestion (AD) were comprehensively compared using culture-based and 16S rRNA gene molecular analysis methodologies. Bacterial and HPB communities differed in response to sludge pretreatment-AD. AD drove the variation of bacterial community, but led to the convergence of HPB communities in pretreated sludge, indicating the existence of ecological niches that favors HPB dissemination in digesters. The correlation analysis indicated that FIB was suitable for characterizing general pathogen removal instead of showing the real pattern of HPB (i.e., each HPB), implying the need for comprehensive assessment approaches. Moreover, AD-related parameters including pH, total solids destruction, and methane yield were found to play important role in assessing pathogen inactivation given their correlation. This work provides theoretical basis for the selection of appropriate sludge stabilization approaches and future supervision of biosolids biosafety, which finally benefits human health.


Hyperthermia thermometry evaluation: criteria and guidelines.
Results of the evaluation of thermometry devices used during hyperthermia treatments at 14 different clinics in the USA are presented. Measurements were made by the Hyperthermia Physics Center (HPC, a national hyperthermia quality assurance program under NCI contract No. N01-CM-37512) according to a protocol. Our sample included thermocouples, fiberoptic thermometers, and high lead resistance thermistors. We found that only some but not all of the thermometers of each kind performed within the +/- 0.2 degrees C acceptability criteria of accuracy. The precision, stability, and response times achieved with each type of thermometer are presented. A summary of perturbations and artifacts typical for each system is presented together with suggested precautions to avoid them during clinical usage. We conclude that although the technology used with each thermometer system is capable of producing a temperature accuracy of 0.2 degrees C, this accuracy is clinically achievable only with a concerted effort and a constant alertness on the part of the investigator. Based on the combined experience of this survey, the clinical investigators we visited, and published reports, we present certain guidelines and procedures that can help to reduce the inaccuracies and improve the reliability of temperature data obtained in clinical hyperthermia trials.


Brief communication: Locomotor limb preferences in captive chimpanzees (Pan troglodytes): implications for morphological asymmetries in limb bones.
Understanding the evolutionary origins of hemispheric specialization remains a topic of considerable interest in a variety of scientific disciplines. Whether nonhuman primates exhibit population-level limb preferences continues to be a controversial topic. In this study, limb preferences for ascending and descending locomotion were assessed as a means of examining the hypothesis that asymmetries in forelimb bones might be attributed to asymmetries in posture. The results indicated that captive chimpanzees showed a population-level leftward asymmetry in descending locomotion but no group bias for ascending locomotion. The results are consistent with previous behavioral studies in captive chimpanzees as well as studies on skeletal asymmetries of the forelimbs of chimpanzees.


Doxycycline decreases proteinuria in glomerulonephritis.
Treatment options for crescentic glomerulonephritis include the use of steroids, cytotoxic therapy, and, in severe cases, intravenous immunoglobulins and plasmapheresis. Injury and lysis of capillary glomerular basement membrane, which is made up of type IV collagen, laminin, fibronectin, and proteoglycans, by serine proteinases and matrix metalloproteinases (MMPs) likely is an important participant in the pathogenesis of crescentic glomerulonephritis. Tetracycline derivatives inhibit not only the activity of MMPs, but also their production, and have been investigated for the treatment of disorders in which the MMP system becomes amplified, such as degenerative osteoarthritis, periodontitis, cancer, and abdominal aortic aneurysm. We report an interesting case of crescentic glomerulonephritis in a young man who was treated with cyclophosphamide and prednisone. The patient developed steroid-induced acne that was treated with long-term oral doxycycline therapy. During the period the patient was administered doxycycline, proteinuria decreased by 70% and recurred when doxycycline was stopped. To our knowledge, this is the first report of possible benefits of a metalloproteinase inhibitor (doxycycline) in glomerulonephritis in humans. Future studies are urgently required to explore the option of metalloproteinase inhibitors in the treatment of proliferative glomerulonephritis.


The effect of non-isotonic solutions on human isolated airway smooth muscle.
In patients with asthma, bronchoconstriction can be provoked by the inhalation of aerosols of non-isotonic solutions. In order to determine if this bronchoconstriction results from a direct effect on airway smooth muscle we decided to examine the effects of non-isotonic solutions on the resting tone of human isolated bronchi and on responses to carbachol, histamine and field stimulation. Human bronchi were obtained from thoracotomy and dose-response relationships for each agonist were obtained for bronchial rings suspended in isotonic Krebs-Henseleit solution (290 mOsm). A second curve was then obtained with half the rings immersed in a solution made hypotonic (145 mOsm) or hypertonic (440 mOsm) by the addition of NaCl or salts and glucose. The other half remained in isotonic solutions as controls. In a separate series of experiments, field stimulation responses to a submaximal frequency (15 Hz) were measured before and after a change from isotonic to non-isotonic bathing solution. The resting tone of the preparations was transiently reduced by hypertonic solutions and increased by hypotonic solutions. Contractile responses to agonists were significantly diminished by non-isotonic solutions. Agonist potency was unaffected by hypertonic solutions but the potency of carbachol was reduced by hypotonic solutions. Responses to field stimulation were unaffected by the hypertonic solution but reduced by the hypotonic solution. We conclude that the bronchoconstrictor actions of non-isotonic solutions and their effects on airway reactivity are unlikely to be due to direct effects on airway smooth muscle.


Non-standard viral genome-derived RNA activates TLR3 and type I IFN signaling to induce cDC1-dependent CD8+ T-cell responses during vaccination in mice.
There is a critical need to develop vaccine adjuvants that induce robust immune responses able to protect against intracellular pathogens, including viruses. Previously, we described defective viral genome-derived oligonucleotides (DDOs) as novel adjuvants that strongly induce type 1 immune responses, including protective Th1 CD4+ T-cells and effector CD8+ T-cells in mice. Here, we unravel the early innate response required for this type 1 immunity induction. Upon DDO subcutaneous injection, type 1 conventional dendritic cells (cDC1s) accumulate rapidly in the draining lymph node in a Toll-like receptor 3 (TLR3)- and type I interferon (IFN)-dependent manner. cDC1 accumulation in the lymph node is required for antigen-specific CD8+ T-cell responses. Notably, in contrast to poly I:C, DDO administration resulted in type I IFN expression at the injection site, but not in the draining lymph node. Additionally, DDOs induced an inflammatory cytokine profile distinct from that induced by poly I:C. Therefore, DDOs represent a powerful new adjuvant to be used during vaccination against intracellular pathogens.


TTK promotes mesenchymal signaling via multiple mechanisms in triple negative breast cancer.
Abnormal expression of TTK kinase has been associated with the initiation, progression, and therapeutic resistance of breast and other cancers, but its roles remain to be clarified. In this study, we examined the role of TTK in triple negative breast cancer (TNBC), and found that higher TTK expression correlated with mesenchymal and proliferative phenotypes in TNBC cells. Pharmacologic inhibition and genomic silencing of TTK not only reversed the epithelial-to-mesenchymal transition (EMT) in TNBC cells, but also increased the expression of KLF5, an effector of TGF-β signaling and inhibitor of EMT. In addition, TTK inhibition decreased the expression of EMT-associated micro-RNA miR-21 but increased the expression of miR-200 family members and suppressed TGF-β signaling. To test if upregulation of KLF5 plays a role in TTK-induced EMT, TTK and KLF5 were silenced simultaneously, which reversed the decreased EMT caused by loss of TTK. Consistently, the decrease in miR-21 expression and increase in miR-200 expression caused by TTK silencing were rescued by loss of KLF5. Altogether, this study highlights a novel role and signaling pathway for TTK in regulating EMT of TN breast cancer cells through TGF-β and KLF5 signaling, highlighting targetable signaling pathways for TTK inhibitors in aggressive breast cancer.


Toxicity of copper nanoparticles and CuCl2 salt to Enchytraeus albidus worms: survival, reproduction and avoidance responses.
Environmental effects of copper nanoparticles are little studied in terrestrial ecosystems. In the present article, the toxicity of copper nanoparticles (Cu-NP) on the enchytraeid Enchytraeus albidus is compared to the toxicity of a copper-salt (CuCl(2)). The effect parameters studied were survival, reproductive output and avoidance behaviour. The results show that Cu-NP were more toxic to E. albidus than the same concentrations of the CuCl(2)-salt. The physic-chemical analysis of the particles indicated that only a small fraction was released as ions. Hence, the results indicated a nanoparticle-specific effect - lower reproductive output and higher avoidance. This was observed as 2-8 fold (significant) lower ECx values for Cu-NP (EC(50-reprod) = 95 mg Cu/kg; EC(50-avoid) = 241 mg Cu/kg) exposed organisms compared to CuCl(2) (EC(50)(-)(reprod) = 251 mg Cu/kg; EC(50-avoid) = 475 mg Cu/kg) exposed organisms. These results corroborate with a nanoparticle-specific effect.


Pushing the limits of the hydrogen bond enhanced halogen bond-the case of the C-H hydrogen bond.
C-H hydrogen bonds have remarkable impacts on various chemical systems. Here we consider the influence of C-H hydrogen bonds to iodine atoms. Positioning a methyl group between two iodine halogen bond donors of the receptor engendered intramolecular C-H hydrogen bonding (HBing) to the electron-rich belt of both halogen bond donors. When coupled with control molecules, the role of the C-H hydrogen bond was evaluated. Gas-phase density functional theory studies indicated that methyl C-H hydrogen bonds help bias a bidentate binding conformation. Interaction energy analysis suggested that the charged C-H donors augment the halogen bond interaction-producing a >10 kcal mol-1 enhancement over a control lacking the C-H⋯I-C interaction. X-ray crystallographic analysis demonstrated C-H hydrogen bonds and bidentate conformations with triflate and iodide anions, yet the steric bulk of the central functional group seems to impact the expected trends in halogen bond distance. In solution, anion titration data indicated elevated performance from the receptors that utilize C-H Hydrogen Bond enhanced Halogen Bonds (HBeXBs). Collectively, the results suggest that even modest hydrogen bonds between C-H donors and iodine acceptors can influence molecular structure and improve receptor performance.


A method of calculating spinal cord transit time from potentials evoked by tibial nerve stimulation in normal subjects and in patients with spinal cord disease.
Somatosensory potentials were evoked by stimulation of the tibial nerve at the ankle and recorded over the spine and scalp in 16 normal subjects and 26 patients with known or suspected spinal cord disease, with the aim of developing a method of measuring spinal sensory conduction velocity using a tolerable number of stimuli, applied unilaterally to alert subjects. In normal subjects N21 was consistently recorded over L1 vertebra and in most subjects a complex, N27/N29/P33, was recorded over the cervical spine referred to the vertex. Constant latencies at different spinal levels and, in one subject, comparison with the latency of the ascending volley indicate that the complex was not derived from the spinal cord but from more rostral structures, and therefore only transit time, rather than velocity, could be measured. In patients with clinically definite multiple sclerosis, even with minimal clinical signs, the N27/N29/P33 complex was always abnormal. Abnormalities in this and other forms of spinal cord disease were commonly absence or distortion of the complex, prolonged transit time being rare. The clinical value of the method is limited by the very low amplitude of the responses.


Validation of a cell-based assay to differentiate between the cytotoxic effects of elapid snake venoms.
Acanthophis genus (i.e. death adders) and the Naja genus (i.e. cobras) belong to the family elapidae. The current study compared the in vitro cytotoxicity of venoms from four Acanthophis spp. and three Naja spp. on rat aortic smooth muscle cells, A7r5, and rat skeletal muscle cells, L6. The ability of CSL death adder antivenom and SAIMR antivenom, for Acanthophis spp. and Naja spp. venom respectively, to negate the cytotoxicity was also examined. A cell proliferation assay was used to determine cell viability following treatment with venom in the presence or absence of antivenom. Sigmoidal growth curves were obtained, and IC(50) values were determined. Acanthophis spp. and Naja spp. venoms produced concentration-dependent inhibition of cell proliferation in both cell lines. Naja spp. venoms were significantly more cytotoxic than the most potent Acanthophis venom (i.e. A. antarcticus) in both cell lines. Naja spp. venoms also displayed higher sensitivity in L6 cells. SAIMR antivenom significantly inhibited the cytotoxic actions of all Naja spp. venoms in both A7r5 and L6 cells. However, death adder antivenom (CSL Ltd) was unable to negate the cytotoxic effects of Acanthophis spp. venoms. Concentrations of the predominantly cytotoxic Naja spp. venoms used were approximately three times less than the predominantly neurotoxic Acanthophis spp. venoms. SAIMR antivenom was partially effective in neutralising the effects of Naja spp. venoms. Death adder antivenom (CSL Ltd) was not effective in negating the cytotoxic effects of venom from Acanthophis spp. These results indicate that the cell-based assay is suited to the examination of cytotoxic snake venoms and may be used in conjunction with organ bath experiments to pharmacologically characterise snake venoms. Furthermore, the results suggest that the use of a skeletal muscle cell line is likely to be more clinically relevant for the examination of cytotoxic snake venoms.


Motor axonal polyneuropathy in the course of ulcerative colitis: a case report.
We describe an axonal motor polyneuropathy in a patient with ulcerative colitis. Symptoms of neuropathy occurred during active colitis. Electrophysiological study showed motor axonal degeneration. After treatment with steroid added to mesalazine, the patient had a gastrointestinal recovery and neurological symptoms were improved. Axonal motor polyneuropathy is an unusual extraintestinal manifestation of ulcerative colitis, and is probably associated with an autoimmune process.


Controllability analysis as a pre-selection method for sensor placement in water distribution systems.
Detection of contamination events in water distribution systems is a crucial task for maintaining water security. Online monitoring is considered as the most cost-effective technology to protect against the impacts of contaminant intrusions. Optimization methods for sensor placement enable automated sensor layout design based on hydraulic and water quality simulation. However, this approach results in an excessive computational burden. In this paper we outline the application of controllability analysis as preprocessing method for sensor placement. Based on case studies we demonstrate that the method decreases the number of decision variables for subsequent optimization dramatically to app. 30 to 40 percent.


In vitro influence of enkephalins on the proliferative response of mouse and rat splenic lymphocytes to phytohemagglutinin.
The opioid peptides leucine enkephalin (LENK) and methionine enkephalin (MENK) were investigated for their effect on the proliferative response of activated BALB/C mouse and Sprague-Dawley rat splenic lymphocytes in vitro. The results showed that LENK and MENK (1 x 10(-3) mg/ml to 1 x 10(-13) mg/ml) significantly suppressed the proliferative response of mouse lymphocytes to phytohemagglutinin (PHA) and enhanced the proliferation of rat lymphocytes at peptide concentrations similar to those effective in mice. It is proposed that endogenous ENKs play a neuroendocrine role between the central nervous system and the immune system.