Synthesis and antitumor evaluation of cis-(1,2-diaminoethane) dichloroplatinum (II) complexes linked to 5- and 6-methyleneuracil and -uridine analogues.
The search for platinum (II)-based compounds with improved therapeutic properties was prompted to design and synthesize a new family of water-soluble, third generation cis-diaminedichloroplatinum (II) complexes linked to uracil and uridine. Six heretofore unreported uracil and uridine-platinum (II) complexes are; [N-(uracil-5-yl-methyl)ethane-1,2-di-amine]dichloroplatinum (II) (3a), [N-(uracil-6-yl-methyl)ethane-1,2-diamine] dichloroplatinum (II) (3b), ¿[N-(2', 3',5'-tri-O-acetyl)uridine-5-yl-methyl] ethane-1,2-diamine¿dichloroplatinum (II) (6a), ¿[N-(2',3', 5'-tri-O-acetyl) uridine-6-yl-methyl)ethane-1,2-diamine¿dichloroplatinum (II) (6b), [N-(uridine-5-yl-methyl)ethane-1,2-diamine]dichloroplatinum (II) (7a), [N-(uridine-6-yl-methyl)ethane-1,2-diamine]dichloroplatinum (II) (7b). These analogues were prepared from the key starting materials, 5-chloromethyluracil (1a) and 6-chloromethyluracil (1b) which were reacted with ethylenediamine to afford the respective 5-[(2-aminoethyl)amino] methyluracil (2a) and 6-[(2-aminoethyl)amino]methyluracil (2b). The cis-platin complexes 3a and 3b were obtained through the reaction of the respective 2a and 2b with potassium tetrachloroplatinate (II). The heterocyclic nucleic acid bases 1a and 1b were efficiently introduced on the beta-D-ribose ring via a Vorbruggen-type nucleoside coupling procedure with hexamethyldisilazane, trimethylchlorosilane and stannic chloride under anhydrous acetonitrile to yield the stereospecific beta-anomeric 5-chloromethyl-2',3',5'-tri-O-acetyluridine (4a) and 6-chloromethyl-2',3',5'-tri-O-acetyluridine (4b), respectively. The nucleosides 4a and 4b were coupled with ethylenediamine to provide the respective 5-[(amino-ethyl)amino]methyl-2',3',5'-tri-O-acetyluridine (5a) and 6-[(aminoethyl)amino] methyl-2',3',5'-tri-O-acetyluridine (5b). The diamino-uridines 5a and 5b were reacted with potassium tetrachloroplatinate (II) to give the novel nucleoside complexes, 6a and 6b, respectively which were deacetylated into the free nucleosides, 7a and 7b by the treatment with CH3ONa. The cytotoxic activities were evaluated against three cell lines (FM-3A, P-388 and J-82) and none of the synthesized compounds showed any significant activity.


[Isolated dissection of the renal artery treated by conservative surgery in 3 patients].
We reported 3 cases of male patients with isolated dissecting aneurysm of the renal artery. The clinical presentation included lumbar pain followed by hypertension (malignant in 2 cases) in the next 3 months. These three patients have underwent surgical renal artery repair. At maximal follow-up (4, 5, 11 years after surgery), the blood pressure was normalized in these 3 patients (with one antihypertensive drug in 2) and the renal function remained stable.


Efferent Auditory Pathways Inhibition in Turner syndrome.
The goal of this study is to investigate the efferent auditory pathways inhibition in Turner's syndrome and to relate it to the cytogenetic profile. This is a cross-sectional study with a comparison group. A sample with 94 participants divided into two groups: The study group was a sample of 40 patients diagnosed with Turner's syndrome (17.6 years of age). The control group was composed of 54 volunteers (18.9 years of age), female, without syndrome. The selected individuals were submitted to efferent auditory pathways inhibition research. The mean of the inhibitory effect of the efferent auditory pathway in the study group in the right ear was 0.4 dB and in the comparison group it was 1.9 dB, however in the left ear the mean of the inhibitory effect of the efferent auditory pathway was 1.4 dB in the study group and 0.8 dB in the comparison group. The inhibitory effect of the efferent auditory pathway was present in 14 individuals with monosomy and in 15 with other cytogenetic alterations. In the study group, the efferent auditory pathways inhibition value was significantly higher in the left ear and significantly lower than the control group in the right ear. There was no significant difference in efferent auditory pathways inhibition of right ear and left ear between the karyotype types.


Gating the bacterial mechanosensitive channel MscL invivo.
YggB and MscL are the major mechanosensitive channels in Escherichia coli, and each can rescue the double knockout mutant from osmotic downshock. However, the role of MscL in wild-type bacteria is in question, not only because cells without MscL survive severe osmotic downshocks, but because 1.8 times more suction is required to gate MscL than YggB under patch clamp. Here, we extend previous evidence [Ajouz, B., Berrier, C., Garrigues, A., Besnard, M. & Ghazi, A. (1998) J. Biol. Chem. 273, 26670-26674] to show that downshock gates MscL in vivo even in the presence of YggB. We have made this determination by engineering a channel we can structurally modify in vivo (Leu-19-->Cys MscL). MscLs with charges in their constrictions are known to open easily and transiently to substates and stop cell growth. In this study, we use downshock to stretch this region open to allow attachment of a charged thiosulfonate reagent MTSET(+), thereby creating a toxic channel. Therefore, channel opening can be monitored by loss of colony forming units. By this measure, we find that an approximately 800 mmol/kg downshock from 1,200 mmol/kg medium opens Leu-19-->Cys MscL in the presence of YggB, but a downshock of only approximately 400 mmol/kg is required in the absence of YggB. In parallel, Leu-19-->Cys MscL, stretched open by large sustained suction in the presence of MTSET(+) in voltage-clamped patches, subsequently flickers open with little suction. These observations show that MscL opening is triggered by a specific downshock, even in the presence of YggB, that YggB buffers MscL gating in vivo, and that residue 19 becomes exposed upon channel opening.


Adaptive Fourier estimation of time-varying evoked potentials.
An estimation procedure for dealing with time-varying evoked potentials is presented here. The evoked response is modeled as a dynamic Fourier series and the Fourier coefficients are estimated adaptively by the least mean square algorithm. Approximate expressions have been developed for the estimation error and time constant of adaptation. A procedure for optimizing the estimator performance is also presented. The effectiveness of the estimator in dealing with simulated as well as actual evoked responses is demonstrated.


Growth-associated catabolic potential of Acetoanaerobium sticklandii DSM 519 on gelatin and amino acids.
Acetoanaerobium sticklandii DSM 519 is a hyperammonia-producing anaerobe that catabolizes proteins and amino acids into organic solvents and volatile acids via the Stickland reactions. However, the specific growth rate and metabolic capability of this organism on proteins and amino acids are not yet known. Therefore, the present study was intended to evaluate its specific growth rate and metabolic potential on gelatin and amino acids in the experimental media. We carried out metabolic assay experiments to calculate its ability to utilize pure gelatin, single amino acids, and amino acid pairs at different growth phases. The results of this study show that complete assimilation of gelatin was achieved by its log-phase culture. The subsequent fermentation of amino acids was much faster than gelatin hydrolysis. The rate of gelatin degradation was associated with the growth and catabolic rates of this organism. Many amino acids were not assimilated completely for its growth and energy conservation. A log-phase culture of this organism preferably utilized l-cysteine, l-arginine, and l-serine, and released more fraction of ammonia. As shown by our analysis, the catabolic rates of these amino acids were determined by the rates of respective enzymes involved in amino acid catabolic pathways and feedback repression of ammonia. The growth kinetic data indicated that at the initial growth stage, a metabolic shift in its solventogenesis and acidogenesis phases was associated with catabolism of certain amino acids. Thus, the results of this study provide a new insight to exploit its log-phase culture as a starter for the production of biofuel components from gelatin processing industries.


Patterns of relative magnitudes of soil energy channels and their relationships with environmental factors in different ecosystems in Romania.
The percentage compositions of soil herbivorous, bacterivorous and fungivorous nematodes in forests, grasslands and scrubs in Romania was analysed. Percentages of nematode abundance, biomass and metabolic footprint methods were used to evaluate the patterns and relative size of herbivory, bacterial- and fungal-mediated channels in organic and mineral soil horizons. Patterns and magnitudes of herbivore, bacterivore and fungivore energy pathways differed for a given ecosystem type and soil depth according to the method used. The relevance of herbivore energy channel increased with soil depth due to higher contribution of root-feeders. Ectoparasites, sedentary parasites and epidermal cell and root hair feeders were the most important contributors to the total biomass and metabolic footprints of herbivores. Metabolic footprint method revealed the general dominance of bacterial-based energy channel in all five types of ecosystems. The influence of altitude and climatic factors on percentages of abundance, biomass and metabolic footprints of herbivores, bacterivores and fungivores decreased with soil depth, whereas the influence of humus content, cation-exchange capacity and base saturation increased. Vegetation, altitude, climate and soil physico-chemical characteristics are important factors that influenced the abundance, biomass and metabolic footprints of herbivores, bacterivores and fungivores.


Combined medial gastrocnemius and hemisoleus flap: a reproducible alternative for open tibial fractures complicated with large or double soft tissue defects.
Utilization of combined local muscle flaps for Gustilo type IIIB open tibial fractures has not been clearly delineated. We describe a combination of medial gastrocnemius and hemisoleus flaps for managing open tibial fractures accompanying large or double soft tissue defects. Twelve patients with Gustilo IIIB open fractures of the tibial shaft with large (9) or double (3) defects were operated on by fracture stabilization and combined medial gastrocnemius and hemisoleus flap coverage. Data were collected on types of implants, types of flaps, union time, postoperative complications, and Puno functional scores. Regarding implants for fixation, an intramedullary nail was used in three patients, plate and screws in five, combined plate and intramedullary nail in one, and definitive external fixation was used in three. Regarding soft tissue coverage, combined medial gastrocnemius and hemisoleus flaps were used in ten patients, combined hemigastrocnemius and hemisoleus in one, and combined medial gastrocnemius and reversed hemisoleus in one. All flaps survived, and all fractures were united with a mean union time of 19.7 weeks (range 16-24). Tip necrosis of the hemisoleus flap occurred in two patients. Regarding Puno functional score, one was determined to be excellent, nine was good and two was fair. Combined medial gastrocnemius and hemisoleus flaps are reliable and effective for open tibial fractures complicated with large or double soft tissue defects.


Balloon-compression endoscopic injection sclerotherapy versus transjugular intrahepatic portosystemic shunt for esophageal variceal rebleeding.
In cirrhotic patients, recurrent bleeding after the first episode of esophageal variceal bleeding (EVB) is common and lethal. The present study was aimed to compare balloon-compression endoscopic injection sclerotherapy (bc-EIS) with transjugular intrahepatic portosystemic shunt (TIPS) for the prophylaxis of variceal rebleeding. Between June 2020 and September 2022, 81 cirrhotic patients with EVB (42 in the bc-EIS group and 39 in the TIPS group) were evaluated retrospectively. The occurrence of rebleeding, hepatic encephalopathy (HE) or other complications, as well as liver functions and survival rate were compared between two groups. During the 12 months of follow-up, variceal eradication was achieved in 40 (95.24%) patients of the bc-EIS group after a mean of 1.80 ± 0.94 sessions. TIPS was successfully performed in 39 (100%) patients. No significant difference in the variceal rebleeding rate was observed between bc-EIS and TIPS groups (16.67 vs. 17.95%; p = 0.111). While the bc-EIS group showed significantly decreased incidence of HE (2.38 vs. 17.95%; p < 0.001) and lower level of total bilirubin (p < 0.05) in comparison with the TIPS group. The difference in mortality between the two groups failed to reach statistical significance (0.00 vs. 7.69%; p = 0.107). Bc-EIS is not inferior to TIPS in the survival and control of variceal rebleeding, but associated with decreased risk of HE and liver dysfunction.


Design, synthesis, and pharmacological evaluation of novel 1,2,4-triazol-3-amine derivatives as potential agonists of GABAA subtype receptors with anticonvulsant and hypnotic effects.
In the current study, a series of novel 1,2,4-triazol-3-amine derivatives were designed, synthesized, and biologically evaluated in vivo for their anticonvulsant and hypnotic effects in the pentylenetetrazole (PTZ)-induced seizures, maximal electroshock (MES)-induced seizures, and pentobarbital-induced sleeping tests. Furthermore, the possible side effects of the most potent compounds on the memory, motor coordination, and muscle strength were evaluated in passive avoidance, rotarod, and grip strength tests, respectively. The designed compounds with the main benzodiazepine pharmacophores including aromatic ring and proton accepting group completely mimiced the structure of zolpidem as an α1-selective agonist of GABAA receptor. Compounds 5c (ED50 ≈ 52.5 mg/kg) and 5 g (ED50 ≈ 16.5 mg/kg) in the PTZ test were the most potent compounds among the designed compounds. In the MES test, the observed ED50s for compounds 5c and 5 g were reduced to around 11.8 mg/kg and 10.5 mg/kg, respectively. The considerable hypnotic effect in a dose-dependent manner was observed following the administration of newly synthesized compounds. In all experiments administration of flumazenil as an antagonist of benzodiazepines receptor fully antagonized observed effects which indicated the involvement of GABAA receptors. Since there was no negative effect on memory, motor coordination, and muscle strength following the administration of compounds 5c and 5g as the most potent compounds, it could be concluded that the novel compounds most likely act through α1-containing GABAA receptors and possess no affinity for α5-containing receptors. The newly designed compounds could be considered as leading compounds in synthesizing novel GABAA receptor agonists with minimum side effects.


Titers of ABO antibodies in group O blood donors.
Plasma components of group O blood donations are rarely submitted to ABO antibody titrations even though it is well known that passively acquired antibodies may destroy the recipient's own red cells and tissue grafts. Thus, group O donations stratified by gender and age were randomly titrated to identify the best source of products for apheresis and exsanguinous transfusion. Samples from 603 blood donors were tested by ABO antibody titration using the conventional tube technique at room temperature. ABO antibody levels higher than 64 were considered high. After correction for gender, statistical analyses were performed using the Fisher exact and Kruskal-Wallis tests. Most donors in the blood bank were male (65.7%). ABO antibody titers ranged from 1 to 2048. The estimations of prevalence for the titers were: anti-A,B < 128 = 86.9% and = 128 = 2.16%; Anti-A = 128 = 9.29% and anti-B = 128 = 4.81%. Low mean titers for both anti-A and anti-B antibodies were found in over 50-year-old men (p-value = 0.040). High anti-B antibody levels were found in young women (p-value = 0.002). This study confirms that over 50-year-old O group men should be selected as blood donors in non-identical ABO transfusion situations. Also, titration of ABO antibodies in blood banks will increase safety in non-identical ABO transfusions.


Structural characterization of exopolysaccharides from Weissella cibaria NC516.11 in distiller grains and its improvement in gluten-free dough.
In this study, an exopolysaccharide (EPS) was produced by Weissella cibaria NC516.11 isolated from distiller grains of Chinese Baijiu. The structural characterization of EPS determined using fourier transform infrared spectra and nuclear magnetic resonance spectra demonstrated that W. cibaria NC516.11 had α-(1 → 6) (93.46%) d-glucose linkages with a few α-(1 → 3) (6.54%) d-glucose linked branches. The monosaccharide composition of the EPS was glucose, and its molecular weight was 2.82 × 106 Da. Scanning electron microscopy showed that the microstructure of EPS had a three-dimensional structure at low magnification and a particle structure that protruded from the surface at high magnification. The addition of EPS into dough can promote the cross-linking of starch molecules and increase the water-holding capacity. Dynamic rheology indicated that the aqueous solution of EPS is a pseudoplastic fluid, and the higher the concentration of EPS, the greater the viscosity. The addition of EPS to the gluten-free dough showed G' > G″, which could increase the viscoelastic properties of the dough and enhance the gluten network.


Predicting postoperative haemodynamics in valve patients.
Patients with combined valve and myocardial disease often have poor haemodynamic status early postoperatively. This occurs in spite of normalization of the left ventricular work load by technically uncomplicated valve replacement. Therefore an algorithm was developed for predicting postoperative left ventricular performance, based on the Emax concept, (end-systolic wall stress/volume relationship as a load-independent ventricular function parameter). Load changes effected by valve normalization were included in the predictive methodology, with ventricular function assumed unchanged by surgery. The algorithm was tested in 12 valve patients who had less than 10% change in heart rate and left atrial pressure pre- vs postoperatively. Preoperative data were obtained during catheterization with quantitative ventriculography. The predicted data were compared to measured data on postoperative day I. There were non-significant differences between the means of predicted and of measured postoperative left ventricular stroke volume, end-systolic volume, end-systolic stress, stroke work, and aortic pressure. The postoperative myocardial function parameter fell by 3-20% below preoperative values in 8 patients not requiring high-dose catechol support and rose by 3-36% in those requiring support. This pilot study suggests the feasibility of a predictive haemodynamic algorithm in surgical valve disease.


Responses of differentiated MC3T3-E1 osteoblast-like cells to reactive oxygen species.
MC3T3-E1 osteoblast-like cells represent a suitable model for studying osteogenic development in vitro. The current investigation extends our previous work on the response of these cells to hydrogen peroxide by considering the effects of reactive oxygen species from other sources, and by determining whether differentiation alters sensitivity to oxidative damage. Aspects of hydrogen peroxide-mediated apoptotic and necrotic death were also examined. Cell viability was determined using the Alamar Blue assay; and accompanying morphological changes monitored by phase-contrast microscopy. Sensitivity to hydrogen peroxide increased significantly in cultures which had been induced to differentiate. Hydrogen peroxide and copper (II) ions, when combined, produced greater damage than hydrogen peroxide alone, whilst the hydroxyl radical scavengers mannitol or dimethylsulphoxide had no effect. Cyclosporin A and nicotinamide afforded partial protection. The tryptophan metabolite, 3-hydroxykynurenine significantly reduced viability, although 3-hydroxyanthranilic acid did not. The xanthine/xanthine oxidase system also reduced cell viability, an effect prevented by catalase but potentiated by superoxide dismutase. S-nitroso-N-acetylpenicillamine did not impair viability at the concentrations tested. Cultures were resistant to mitochondrial poisoning by potassium cyanide, but succumbed to 24-h exposures to 3-nitropropionic acid (1 mM). The results reveal a differential sensitivity of MC3T3-E1 cells to hydrogen peroxide-induced oxidative stress, an enhancement of sensitivity by cellular differentiation, and a potential preference for the glycolytic pathway by MC3T3-E1 cells. This study gives new insight into how bone cells may succumb to the toxic effects of oxidative stress generated by different stimuli and has relevance to conditions such as osteoporosis.


Cardiac involvement in juvenile rheumatoid arthritis. A follow-up study.
Cardiac involvement was diagnosed in 15 of 320 cases of JRA (4.7%) and was most frequent in children with active systemic disease. Ten children had pericarditis, 2 had myocarditis, 2 had peri-myocarditis and 1 had aortic valvulitis. The highest risk of heart involvement was found during the first three years but it could occur at any time. Recurrent episodes were seen in 60% of cases. The prognosis in pericarditis seems to be good since no patient developed cardiac tamponade or constrictive pericarditis and cardiac function evaluated by echocardiography was normal in all patients at follow-up. In patients with myocarditis and peri-myocarditis, a dilated left ventricle was found in 2 of 4 patients and 1 patient who died, had severe cardiac changes at autopsy. The prognosis in myocarditis thus seems to be worse. In valvulitis the prognosis depends on which valve is involved. The benefit of early treatment with corticosteroids is discussed.


Targeting Excessive EZH1 and EZH2 Activities for Abnormal Histone Methylation and Transcription Network in Malignant Lymphomas.
Although global H3K27me3 reprogramming is a hallmark of cancer, no effective therapeutic strategy for H3K27me3-high malignancies harboring EZH2WT/WT has yet been established. We explore epigenome and transcriptome in EZH2WT/WT and EZH2WT/Mu aggressive lymphomas and show that mutual interference and compensatory function of co-expressed EZH1 and EZH2 rearrange their own genome-wide distribution, thereby establishing restricted chromatin and gene expression signatures. Direct comparison of leading compounds introduces potency and a mechanism of action of the EZH1/2 dual inhibitor (valemetostat). The synthetic lethality is observed in all lymphoma models and primary adult T cell leukemia-lymphoma (ATL) cells. Opposing actions of EZH1/2-polycomb and SWI/SNF complexes are required for facultative heterochromatin formation. Inactivation of chromatin-associated genes (ARID1A, SMARCA4/BRG1, SMARCB1/SNF5, KDM6A/UTX, BAP1, KMT2D/MLL2) and oncovirus infection (HTLV-1, EBV) trigger EZH1/2 perturbation and H3K27me3 deposition. Our study provides the mechanism-based rationale for chemical dual targeting of EZH1/2 in cancer epigenome.


Young human PRP promotes the rejuvenation of aged bone marrow mesenchymal stem cells and the therapeutic effect on ischemic heart disease.
Bone marrow mesenchymal stem cell (BMSC) transplantation is an effective treatment for ischemic heart disease, but its effectiveness is limited in aging populations due to decreased viability and injury resistance of autologous BMSCs. The purpose of this study was to compare the differences between platelet-rich plasma (PRP) derived from young and aged donors, and to investigate whether it is possible to enhance the viability of elderly human BMSCs (hBMSCs) using PRP, and to apply the rejuvenated hBMSCs for the treatment of ischemia. The key growth factors in PRP, including IGF-1, EGF, and PDGF-BB, were found to have significant differences between young and old individuals. Our results showed that PRP could enhance the proliferation, cloning, and rejuvenation of aged hBMSCs, with a superior effect observed when using PRP derived from younger donors. In the SD rat infarct model, the application of hBMSCs optimized with PRP resulted in a smaller infarct area compared to the control group (NC-Old). Specifically, the infarct area in the group treated with hBMSCs cultured with PRP from young donors (YPRP-Old) was smaller than that in the group treated with PRP from older donors (OPRP-Old). The survival rate of hBMSCs after transplantation, the number of neovascularization in the infarct area of SD rats and the recovery of cardiac function were all higher in the YPRP-Old group than the OPRP-Old group, and both groups were better than the group treated with aged hBMSCs alone. In conclusion, PRP may provide a new stem cell transplantation therapy option for ischemic diseases.


Neuronal MEK is important for normal fear conditioning in mice.
The extracellular signal-regulated kinase (ERK) cascade has received much attention for its possible role in neuronal synaptic plasticity. Although ERK activation has been linked to learning behaviors and activity-dependent neuronal function, much of the acquired data has relied upon pharmacological agents that suppress ERK function in both neurons and nonneuronal cells. To determine the function of neuronal ERK activity in learning, a new line of transgenic mice was generated wherein dominant-negative MEK1, the upstream obligate activator of ERK1/2, was expressed by using a neuronal-specific and pan-neuronal Talpha1 alpha-tubulin promoter element. Mice expressing this construct exhibited decreased ERK1/2 activity in the hippocampus and thus were tested for learning impairments. In a battery of control tests, including open field, rotarod, and shock threshold, the transgenic mice displayed no deficits and performed as well as their wild-type littermate counterparts. However, the mice displayed a significant impairment in contextual fear conditioning compared with the wild-type littermates. These findings indicate that the MEK1/ERK1/2 cascade within neurons plays an important role in the processes of learning and memory.


Qualitative and quantitative analysis of the unsaponifiable fraction of vegetable oils by using comprehensive 2D GC with dual MS/FID detection.
The present investigation is focused on the development of a comprehensive two-dimensional GC (GC × GC) method, with dual MS/FID detection, for the qualitative and quantitative analysis of the entire unsaponifiable fraction of vegetable oils. The unsaponifiable fraction forms a minor, highly specific part of a vegetable oil, and can be used as an indicator of genuineness. The column set used consisted of a low-polarity first dimension, and a medium-polarity secondary one, both characterized by a high thermal stability. The use of dual detection enabled the attainment of both mass spectral information and relative % FID data. The complexity of the fingerprint, generated by the unsaponifiable fraction, fully justified the employment of the two-dimensional GC technology. Furthermore, two other GC × GC benefits contributed greatly to the attainment of promising results, namely sensitivity enhancement and the formation of group-type patterns. The method herein proposed could potentially open a new opportunity for the more in-depth knowledge of the unsaponifiable fraction of vegetable oils.


Analysis of high-throughput sequencing for cecal microbiota diversity and function in hens under different rearing systems.
Rearing systems play an important role in animal welfare, health and the composition of the gut microbiome. Therefore, the purpose of this study was to investigate the effects of different rearing systems on the composition and function of cecal microbiota in chickens. The 120-day-old Lohmann hens of cage rearing systems (CRS) and free-range systems (FRS) were studied. The cecal bacterial populations of hens were surveyed by high-throughput sequencing (HTS) of the bacterial 16S rRNA hypervariable region V3-V4 combined with metagenomic sequencing analysis. The 16S rRNA sequencing analysis showed that the cecal microbiota differed between the FRS and CRS. The three most abundant bacteria phyla in the two systems were the Bacteroidetes (> 48%), Firmicutes (> 37%), and Proteobacteria (> 6%), the Deferribacteres (> 2.4%) were found in FRS and almost absent in CRS (< 0.01%). The three most abundant genera were the Bacteroides, Rikenellaceae_RC9, and Faecalibacterium, and we found relative abundance of the Parabacteroides (P < 0.05), Prevotellaceae_Ga6A1 (P < 0.01), unclassified Proteobacteria (P < 0.05), and unclassified Spirochaetaceae (P < 0.01) was greater in FRS, whereas abundance of Faecalibacterium, Ruminococcaceae, and Helicobacter was greater in CRS (P < 0.05). Functional gene classification of metagenomic sequencing suggested that energy production and conversion, carbohydrate transport and metabolism, as well as amino acid transport and metabolism were significantly more abundant in FRS, and we identified a range of antibiotic resistance categories in gut microbes of hens reared under both systems. We confirmed differences in microbe gut composition and function in hens reared using two contrasting systems, and ARGs were also identified in the microbiota of these hens. This work has produced new data for laying hens in different production systems and increased the understanding of intestinal microorganisms in laying hens.


New insights on labor progression: a systematic review.
The past 20 years witnessed an invigoration of research on labor progression and a change of thinking regarding normal labor. New evidence is emerging, and more advanced statistical methods are applied to labor progression analyses. Given the wide variations in the onset of active labor and the pattern of labor progression, there is an emerging consensus that the definition of abnormal labor may not be related to an idealized or average labor curve. Alternative approaches to guide labor management have been proposed; for example, using an upper limit of a distribution of labor duration to define abnormally slow labor. Nonetheless, the methods of labor assessment are still primitive and subject to error; more objective measures and more advanced instruments are needed to identify the onset of active labor, monitor labor progression, and define when labor duration is associated with maternal/child risk. Cervical dilation alone may be insufficient to define active labor, and incorporating more physical and biochemical measures may improve accuracy of diagnosing active labor onset and progression. Because the association between duration of labor and perinatal outcomes is rather complex and influenced by various underlying and iatrogenic conditions, future research must carefully explore how to integrate statistical cut-points with clinical outcomes to reach a practical definition of labor abnormalities. Finally, research regarding the complex labor process may benefit from new approaches, such as machine learning technologies and artificial intelligence to improve the predictability of successful vaginal delivery with normal perinatal outcomes.


Endoscopy management of sleeve gastrectomy stenosis: what we learned from 202 consecutive patients.
Gastric sleeve stenosis (GSS) is described in 1%-4% of patients. To evaluate the role of endoscopy in the management of stenosis after laparoscopic sleeve gastrectomy using a standardized approach according to the characteristic of stenosis. Retrospective, observational, single-center study on patients referred from several bariatric surgery departments to an endoscopic referral center. We enrolled 202 patients. All patients underwent endoscopy in a fluoroscopy setting, and a systematic classification of the type, site, and length of the GSS was performed. According to the characteristics of the stenosis, patients underwent pneumatic dilatation or placement of a self-expandable metal stent or a lumen-apposed metal stent. Failure of endoscopic treatment was considered an indication for redo surgery, whereas patients with partial or complete response were followed up for 2 years. In the event of a recurrence, a different endoscopic approach was used. We found inflammatory strictures in 4.5% of patients, pure narrowing in 11%, and functional stenosis in 84.5%. Stenosis was in the upper tract of the stomach in 53 patients, whereas medium and distal stenosis was detected in 138 and 11 patients, respectively, and short stenosis in 194 patients. A total of 126 patients underwent pneumatic dilatation, 8 self-expandable metal stent placement, 64 lumen-apposed metal stent positioning, and 36 combined therapy. The overall rate of endoscopy success was 69%. GSS should be considered to be a chronic disease, and the endoscopic approach seems to be the most successful treatment, with a prolonged positive outcome of 69%. Characteristics of the stenosis should guide the most suitable endoscopic approach.


Associations between Pittsburgh Sleep Quality Index factors and health outcomes in women with posttraumatic stress disorder.
The Pittsburgh Sleep Quality Index (PSQI) is a widely used measure of subjective sleep disturbance in clinical populations, including individuals with posttraumatic stress disorder (PTSD). Although the severity of sleep disturbance is generally represented by a global symptom score, recent factor analytic studies suggest that the PSQI is better characterized by a two- or three-factor model than a one-factor model. This study examined the replicability of two- and three-factor models of the PSQI, as well as the relationship between PSQI factors and health outcomes, in a female sample with PTSD. The PSQI was administered to 319 women with PTSD related to sexual or physical assault. Confirmatory factor analyses tested the relative fit of one-, two-, and three-factor solutions. Bivariate correlations were performed to examine the shared variance between PSQI sleep factors and measures of PTSD, depression, anger, and physical symptoms. Confirmatory factor analyses supported a three-factor model with Sleep Efficiency, Perceived Sleep Quality, and Daily Disturbances as separate indices of sleep quality. The severity of symptoms represented by the PSQI factors was positively associated with the severity of PTSD, depression, and physical symptoms. However, these health outcomes correlated as much or more with the global PSQI score as with PSQI factor scores. These results support the multidimensional structure of the PSQI. Despite this, the global PSQI score has as much or more explanatory power as individual PSQI factors in predicting health outcomes.


AKT1-targeted proapoptotic activity of compound K in human breast cancer cells.
Breast cancer is a severe disease and the second leading cause of cancer death in women worldwide. To surmount this, various diagnosis and treatment options for breast cancer have been developed. One of the most effective strategies for cancer treatment is to induce apoptosis using naturally occurring compounds. Compound K (CK) is a ginseng saponin metabolite generated by human intestinal bacteria. CK has been studied for its cardioprotective, antiinflammatory, and liver-protective effects; however, the role of CK in breast cancer is not fully understood. To investigate the anticancer effects of CK in SKBR3 and MDA-MB-231 cells, cell viability assays and flow cytometry analysis were used. In addition, the direct targets of CK anticancer activity were identified using immunoblotting analysis and overexpression experiments. Invasion, migration, and clonogenic assays were carried out to determine the effects of CK on cancer metastasis. CK-induced cell apoptosis in SKBR3 cells as determined through 3-(4-5-dimethylthiazol-2-yl)-2-5-diphenyltetrazolium bromide assays, propidium iodide (PI) and annexin V staining, and morphological changes. CK increased the cleaved forms of caspase-7, caspase-8, and caspase-9, whereas the expression of Bcl-2 was reduced by CK. In assays probing the cell survival pathway, CK activated only AKT1 and not AKT2. Moreover, CK inhibited breast cancer cell invasion, migration, and colony formation. Through regulation of AKT1 activity, CK exerts anticancer effects by inducing apoptosis. Our results suggest that CK could be used as a therapeutic compound for breast cancer.


Identification and characterization of a negative regulatory element within the epidermal growth factor receptor gene first intron in hormone-dependent breast cancer cells.
The epidermal growth factor receptor (EGFR) exhibits an inverse correlation with estrogen receptor (ER) expression in the majority of breast cancers, predicting a poor response to endocrine therapy and poor survival rate. Inappropriate overexpression of EGFR in breast cancer is associated with a more aggressive phenotype. Transcriptional regulation is the major regulatory mechanism controlling EGFR overexpression in breast cancer cells. We have identified a region within the first intron of the EGFR gene that mediates transcriptional repression of EGFR gene expression in ER +/low EGFR expressing but not in ER-/high EGFR expressing breast cancer cells. Utilizing transient transfections of homologous and heterologous promoter-reporter constructs, we localized optimal repressive activity to a 96 bp intron domain. The 96 bp fragment displayed differential DNA-protein complex formation with nuclear extracts from ER + vs. ER- breast cancer cells. Moreover, factors interacting with this intron negative regulatory element appear to be estrogen-regulated. Consequently, our results suggest that we have identified a potential mechanism by which maintenance of low levels of EGFR expression and subsequent EGFR upregulation may be attributed to the loss of transcriptional repression of EGFR gene expression in hormone-dependent breast cancer cells.


[Application of the technique of analytical structure of project for the sub-project of websites catalog of the Virtual Health Library-Nursing].
This work intents, in a didactic form, to explain the benefits of use of a technique of project management, named Work Breakdown Structure: a graphical tool to identify the main results to be developed in a project. The real examples are applied to a sub-project of the Virtual Library in Health in Nursing (BVS-Enfermagem) to development of the Sites Catalogs. The benefits of graphical visualization for a major agreement between professionals of different expertise are presented.


Are visual processes causally involved in "perceptual simulation" effects in the sentence-picture verification task?
Many studies have shown that sentences implying an object to have a certain shape produce a robust reaction time advantage for shape-matching pictures in the sentence-picture verification task. Typically, this finding has been interpreted as evidence for perceptual simulation, i.e., that access to implicit shape information involves the activation of modality-specific visual processes. It follows from this proposal that disrupting visual processing during sentence comprehension should interfere with perceptual simulation and obliterate the match effect. Here we directly test this hypothesis. Participants listened to sentences while seeing either visual noise that was previously shown to strongly interfere with basic visual processing or a blank screen. Experiments 1 and 2 replicated the match effect but crucially visual noise did not modulate it. When an interference technique was used that targeted high-level semantic processing (Experiment 3) however the match effect vanished. Visual noise specifically targeting high-level visual processes (Experiment 4) only had a minimal effect on the match effect. We conclude that the shape match effect in the sentence-picture verification paradigm is unlikely to rely on perceptual simulation.


Emergency Department Visits, Care, and Outcome After Stroke and Myocardial Infarction During the COVID-19 Pandemic Phases.
It is not known if initial reductions in hospitalization for stroke and myocardial infarction early during the coronavirus disease-2019 pandemic were followed by subsequent increases. We describe the rates of emergency department visits for stroke and myocardial infarction through the pandemic phases. We used linked administrative data to compare the weekly age- and sex-standardized rates of visits for stroke and myocardial infarction in Ontario, Canada in the first 9 months of 2020 to the mean baseline rates (2015-2019) using rate ratios (RRs) and 95% confidence intervals (CIs). We compared care and outcomes by pandemic phases (pre-pandemic was January-March, lockdown was March-May, early reopening was May-July, and late reopening was July-September). We identified 15,682 visits in 2020 for ischemic stroke (59.2%; n = 9279), intracerebral hemorrhage (12.2%; n = 1912), or myocardial infarction (28.6%; n = 4491). The weekly rates for stroke visits in 2020 were lower during the lockdown and early reopening than at baseline (RR 0.76, 95% CI [0.66, 0.87] for the largest weekly decrease). The weekly rates for myocardial infarction visits were lower during the lockdown only (RR 0.61, 95% CI [0.46, 0.77] for the largest weekly decrease), and there was a compensatory increase in visits following reopening. Ischemic stroke 30-day mortality was increased during the lockdown phase (11.5% pre-coronavirus disease; 12.2% during lockdown; 9.2% during early reopening; and 10.6% during late reopening, P = 0.015). After an initial reduction in visits for stroke and myocardial infarction, there was a compensatory increase in visits for myocardial infarction. The death rate after ischemic stroke was higher during the lockdown than in other phases.


[Tracheomalacia inadvertently diagnosed by CT angiography originally performed to rule out pulmonary embolism].
Tracheomalacia is a frequent disease in the older population involving excessive airway collapse and it may present symptoms similar to pulmonary emboli. This is a case study depicting a patient's inadvertent breathing during a CT scan, performed to rule out pulmonary emboli. This examination revealed significant tracheomalacia, a condition usually diagnosed by bronchoscopy or specially tailored CT.


Clinical efficacy of ceramic versus resin-based composite endocrowns in Chinese adults: study protocol for a randomized controlled trial.
Endocrown restoration is widely used to restore endodontically treated teeth. However, the clinical effects of different computer-aided design/computer-aided manufacturing (CAD/CAM) materials for endocrown restoration are not clear. The primary objective of this trial is to compare the clinical efficacy of resin-based bloc and ceramic endocrowns for restoring endodontically treated teeth. The proposed resin-based bloc and ceramic endocrown assessment trial is a parallel group-designed randomized controlled trial. We will recruit 156 adults between 18 and 75 years old with a minimum of one such molar. The inclusion criteria were good oral hygiene habits, root apex of molar without evident damage, receipt of standard endodontic treatment, need for endocrown restoration, and only one endocrown restoration performed per patient. Patients participating in another study or those with systemic diseases, disabilities, or known allergies to used materials will be excluded. All patients will be randomized and restored with resin-based bloc and ceramic endocrown according to a random number table. Clinical evaluations will be performed at baseline and after treatment at 6, 12, and 24 months, in accordance with the modified Federation Dentaire Internationale (FDI) criteria, by two independent evaluators. The primary outcome is marginal adaptation; secondary outcomes include wear, tooth integrity, fracture of material and retention, marginal staining, and patient view. All data will be analyzed by an independent statistician. Signed rank-sum tests will be used for intragroup comparisons. Wilcoxon rank-sum tests will be used for intergroup comparisons. Hierarchical logistic regression will be used to adjust the baseline and other important indicators. This study will investigate endocrowns of two CAD/CAM materials for endodontically treated molars. The results may help clinicians choose the better CAD/CAM material option and explain to patients the advantages and disadvantages of these two materials with evidence-based support. For patients, the results may lead to improvement in long-term restoration. ClinicalTrials.gov NCT04033380. Registered on 24 July 2019.


CSNAP Is a Stoichiometric Subunit of the COP9 Signalosome.
The highly conserved COP9 signalosome (CSN) complex is a key regulator of all cullin-RING-ubiquitin ligases (CRLs), the largest family of E3 ubiquitin ligases. Until now, it was accepted that the CSN is composed of eight canonical components. Here, we report the discovery of an additional integral and stoichiometric subunit that had thus far evaded detection, and we named it CSNAP (CSN acidic protein). We show that CSNAP binds CSN3, CSN5, and CSN6, and its incorporation into the CSN complex is mediated through the C-terminal region involving conserved aromatic residues. Moreover, depletion of this small protein leads to reduced proliferation and a flattened and enlarged morphology. Finally, on the basis of sequence and structural properties shared by both CSNAP and DSS1, a component of the related 19S lid proteasome complex, we propose that CSNAP, the ninth CSN subunit, is the missing paralogous subunit of DSS1.


Addressing the paediatric HIV epidemic: a perspective from the Western Cape Region of South Africa.
In the Western Cape province of South Africa, a prevention of mother-to-child-transmission (PMTCT) intervention programme, based on short-course nevirapine, achieved universal coverage in 2003. Despite this programme, an estimated 1,400-1,650 HIV-infected children were born in the province in that year. These crude estimates suggest that there are many children in the province who need medical care. Several strategies could collectively reduce the size of the paediatric epidemic and improve the outcome of HIV-infected children in the region, including intensification of the existing PMTCT programme and provision of antiretroviral therapy (ART) for children with moderate or severe disease. Progress towards implementing these interventions is discussed. Future challenges include understanding the factors that favour long-term survival of children on highly active antiretroviral therapy in resource-limited settings, identifying appropriate treatment for the metabolic complications of ART, and the provision of adolescent services for long-term survivors. Developments over the next few years will determine whether these challenges can be met.


Exogenous fibrin matrix precursors stimulate the temporal progress of nerve regeneration within a silicone chamber.
The silicone chamber model permits the investigation of the cellular and molecular events underlying successful regeneration of the rat sciatic nerve across a 10 mm gap. When 25 microliter chambers are implanted prefilled with phosphate-buffered saline (PBS), it takes 5-7 days before sufficient fibrin matrix (derived from plasma precursors) accumulates naturally to form a complete bridge across the chamber gap; at 1 week postimplantation, cellular migration into the matrix from the nerve stumps is just beginning. The temporal progress of regeneration might be stimulated if a fibrin matrix, conducive to cell migration, was provided to the nerve stumps at or shortly after the time of chamber implantation. To test this hypothesis, chambers were prefilled, at the time of implantation, with different preparations of homologous plasma. A solution of 90% platelet-free plasma dialyzed against PBS (DP) formed a fibrin matrix by 24 hours postimplantation that, like the naturally formed matrix, had a predominantly longitudinal orientation. The temporal progress of regeneration was stimulated in the DP-prefilled chambers; at 17 days postimplantation, the extents of Schwann cell migration and axonal elongation were significantly greater than in the control system. In contrast, prefilling chambers with either non-citrated plasma or DP + calcium resulted in the generation of a matrix within 8 minutes that was composed of randomly oriented fibrin polymers. These matrices significantly retarded the progress of regeneration.


Leu-enkephalin content in rat brain during prolonged treatment with imipramine or amitriptyline.
The influence of imipramine (IMI) or amitriptyline (AMI) on the level of immunoreactive leu-enkephalin (ir-LENK) in the striatum and hypothalamus was studied in rats. Each drug was given by drinking water once or over periods of 1, 3, 4 and 6 months. The ir-LENK in brain perfusates was measured after 3 or 9 month treatment with IMI. The results obtained indicate that during prolonged administration of IMI the central enkephalinergic system is dynamically changed. We have observed that chronic (but not acute) administration of IMI induced different effects on LENK level in the examined structures than changes caused by treatment with AMI.


Relationship between previous training and experience and results of the certification examination in cardiovascular computed tomography.
Examinees of the first Certifying Examination in Cardiovascular Computed Tomography were surveyed regarding their training and experience in cardiac computed tomography. The results support the current training pathways within the American College of Cardiology/American Heart Association competency criteria that include either experience-based or formal training program in cardiovascular computed tomography. Increased duration in clinical practice, the number of scans clinically interpreted in practice, and level 3 competency were associated with higher passing rates.


Bioleaching of cadmium and nickel from synthetic sediments by Acidithiobacillus ferrooxidans.
The microbial leaching process was evaluated for the treatment of synthetic sediments contaminated with cadmium and nickel sulfides. A series of batch leaching experiments was conducted to compare metal solubilization in sediment inoculated with Acidithiobacillus ferrooxidans -inoculated sediments to that in sterile control sediment. The rate and extent of metal solubilization were significantly higher in A. ferrooxidans -inoculated reactors than in acidified sterile reactors. The efficiency of cadmium (Cd) solubilization (80) in the bioleaching process was higher than that of nickel (Ni) solubilization (60). The performance of leaching reactors containing only culture supernatants was comparable to that of A. ferrooxidans -inoculated reactors, indicating that indirect non-contact leaching by the products of microbial metabolism is the predominant mechanism for metal solubilization rather than direct microbial sulfide oxidation. Moreover, the similar (60-75%) extents of Cd(2+) leaching with A. ferrooxidans , cell-free filtrate, and Fe(3+) suggest that abiotic oxidation of CdS by Fe(3+) controls the overall leaching rate, and the role of A. ferrooxidans is most likely not to oxidize CdS mineral directly but to regenerate Fe(3+) as an oxidant.


Immunolocalization of transforming growth factor-beta s and type I and type II receptors in rat articular cartilage.
The activities of TGF-beta s and their receptors (T beta R) in the articular cartilage have not been fully elucidated as yet. Temporal and spatial expression of TGF-beta s and their receptors were examined immunohistochemically in the articular cartilage of growing rats to clarify their role in chondrogenesis. TGF-beta 1, -beta 2 and -beta 3 were strongly expressed from 6 to 50 weeks in the superficial, transitional, and least mature zones. The expression of TGF-beta s in hypertrophic chondrocyte was weak except TGF-beta 1. T beta R-I and T beta R-II were co-expressed with the ligand in the superficial, transitional, and least mature zones throughout the growth phase. This study revealed that TGF-beta s in the articular cartilage plays a major role in the modulation of endochondral ossification ensuring the growth and maintenance of the chondrocyte lineage in articular cartilage.


LCL161 enhances expansion and survival of engineered anti-tumor T cells but is restricted by death signaling.
The genesis of SMAC mimetic drugs is founded on the observation that many cancers amplify IAP proteins to facilitate their survival, and therefore removal of these pathways would re-sensitize the cells towards apoptosis. It has become increasingly clear that SMAC mimetics also interface with the immune system in a modulatory manner. Suppression of IAP function by SMAC mimetics activates the non-canonical NF-κB pathway which can augment T cell function, opening the possibility of using SMAC mimetics to enhance immunotherapeutics. We have investigated the SMAC mimetic LCL161, which promotes degradation of cIAP-1 and cIAP-2, as an agent for delivering transient costimulation to engineered BMCA-specific human TAC T cells. In doing so we also sought to understand the cellular and molecular effects of LCL161 on T cell biology. LCL161 activated the non-canonical NF-κB pathway and enhanced antigen-driven TAC T cell proliferation and survival. Transcriptional profiling from TAC T cells treated with LCL161 revealed differential expression of costimulatory and apoptosis-related proteins, namely CD30 and FAIM3. We hypothesized that regulation of these genes by LCL161 may influence the drug's effects on T cells. We reversed the differential expression through genetic engineering and observed impaired costimulation by LCL161, particularly when CD30 was deleted. While LCL161 can provide a costimulatory signal to TAC T cells following exposure to isolated antigen, we did not observe a similar pattern when TAC T cells were stimulated with myeloma cells expressing the target antigen. We questioned whether FasL expression by myeloma cells may antagonize the costimulatory effects of LCL161. Fas-KO TAC T cells displayed superior expansion following antigen stimulation in the presence of LCL161, suggesting a role for Fas-related T cell death in limiting the magnitude of the T cell response to antigen in the presence of LCL161. Our results demonstrate that LCL161 provides costimulation to TAC T cells exposed to antigen alone, however LCL161 did not enhance TAC T cell anti-tumor function when challenged with myeloma cells and may be limited due to sensitization of T cells towards Fas-mediated apoptosis.


COVID-19 impacts on mobility and travel demand.
Since the beginning of the COVID-19 pandemic, many travel restriction policies were implemented to reduce further spread of the virus. These measures significantly affected travel demand to levels which could not have been anticipated by most planners in transportation agencies. As the pandemic has proven to have significant short-term impacts, it is anticipated that some of these impacts may translate to longer-term impacts on overall travel behavior and the movement of people and goods. Beyond the pandemic, the observed travel patterns during this period also provides a great opportunity for planners to assess policies such as work from home and remote learning as strategies to manage travel demand. This study provides a scenario analysis framework to re-evaluate travel demand forecasts under uncertain future conditions using the Maryland Statewide Transportation Model (MSTM). Model parameters associated with working from home, household income, changes in discretionary travel, distance learning, increased e-commerce, vehicle occupancy and mode choice were identified. Parameter values were assigned under the various scenarios using employer surveys on workforce teleworking and observed data on e-commerce growth and shopping behavior. The main findings of this study capture the sensitivities of systemwide vehicle miles travel, and vehicle hours travel under different scenarios and implications on future investment decisions. The study found that future investments under the scenarios remain beneficial to systemwide performance and therefore justified. Although this study focuses on the state of Maryland, the scenario framework and parameter definitions can be used in other states or agencies within a travel demand model environment.


Pulmonary Artery Pressure-Guided Management of Patients With Heart Failure and Reduced Ejection Fraction.
Despite increased use of guideline-directed medical therapy (GDMT), some patients with heart failure and reduced ejection fraction (HFrEF) remain at high risk for hospitalization and mortality. Remote monitoring of pulmonary artery (PA) pressures provides clinicians with actionable information to help further optimize medications and improve outcomes. CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients trial) analyzed PA pressure-guided heart failure (HF) management in patients with HFrEF based on their ability to tolerate GDMT. CHAMPION enrolled 550 patients with chronic HF regardless of left ventricular ejection fraction. A pre-specified sub-group analysis compared HF hospitalization and mortality rates between treatment and control groups in HFrEF patients (left ventricular ejection fraction ≤40%). Post hoc analyses in patients who tolerated GDMT were also performed. Hospitalizations and mortality were assessed using Andersen-Gill and Cox proportional hazards models. In 456 patients with HFrEF, HF hospitalization rates were 28% lower in the treatment group than in the control group (hazard ratio [HR]: 0.72; 95% confidence interval [CI]: 0.59 to 0.88; p = 0.0013), with a strong trend for 32% lower mortality (HR: 0.68; 95% CI: 0.45 to 1.02; p = 0.06). A 445-patient subset received at least 1 GDMT (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, or beta-blocker) at baseline; these patients had 33% lower HF hospitalization rates (HR: 0.67; 95% CI: 0.54 to 0.82; p = 0.0002) and 47% lower mortality (HR: 0.63; 95% CI: 0.41 to 0.96, p = 0.0293) than controls. Compared with controls, patients receiving both components of optimal GDMT (n = 337) had 43% lower HF hospitalizations (HR: 0.57; 95% CI: 0.45 to 0.74; p < 0.0001) and 57% lower mortality (HR: 0.43; 95% CI: 0.24 to 0.76; p = 0.0026). PA pressure-guided HF management reduces morbidity and mortality in patients with HFrEF on GDMT, underscoring the important synergy of addressing hemodynamic and neurohormonal targets of HF therapy. (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients [CHAMPION]; NCT00531661).


Effects of the neuronal phosphoprotein synapsin I on actin polymerization. I. Evidence for a phosphorylation-dependent nucleating effect.
Synapsin I is a synaptic vesicle-specific phosphoprotein which is able to bind and bundle actin filaments in a phosphorylation-dependent fashion. In the present paper we have analyzed the effects of synapsin I on the kinetics of actin polymerization and their modulation by site-specific phosphorylation of synapsin I. We found that dephosphorylated synapsin I accelerates the initial rate of actin polymerization and decreases the rate of filament elongation. The effect was observed at both low and high ionic strength, was specific for synapsin I, and was still present when polymerization was triggered by F-actin seeds. Dephosphorylated synapsin I was also able to induce actin polymerization and bundle formation in the absence of KCl and MgCl2. The effects of synapsin I were strongly decreased after its phosphorylation by Ca2+/calmodulin-dependent protein kinase II. These observations suggest that synapsin I has a phosphorylation-dependent nucleating effect on actin polymerization. The data are compatible with the view that changes in the phosphorylation state of synapsin I play a functional role in regulating the interactions between the nerve terminal cytoskeleton and synaptic vesicles in various stages of the exoendocytotic cycle.


Is pain sensitivity altered in people with Alzheimer's disease? A systematic review and meta-analysis of experimental pain research.
Clinical studies suggest people with Alzheimer's disease (AD) have altered pain sensitivity. Experimental pain research is equivocal. Conduct a meta-analysis to investigate if people with AD have altered pain sensitivity compared to healthy controls (HCs). Three authors searched electronic databases from inception till November 2015 for experimental pain studies in AD vs. HCs. Outcome measures were pain threshold, tolerance, pain ratings, heart rate response to noxious stimuli and the Facial Action Coding System (FACS). Random effect meta-analysis calculating Hedges' g±95% confidence intervals (CI) was conducted. Thirteen studies were identified, including 256 people with AD (74.6 (±5.6) years, 59% females with a mean mini mental state examination (MMSE) score of 19.2) and 260 HCs. Meta-analysis demonstrated no significant difference in pain threshold (g=0.025, 95% CI -0.315-0.363, p=0.88, n AD=135, n HCs=157), pain tolerance (g=-0.363, 95% CI -2.035-1.309, p=0.67, n AD=41, n HCs=53) or pain intensity ratings (g=0.03, p=0.89, n AD=138, n HCs=135). Heart rate response to pain was less pronounced in AD but not significant (g=-0.746, p=0.11). People with AD (n=90) had significantly higher FACS scores versus HCs (n=109) (g=0.442, p=0.03) indicating increased pain. Meta-regression demonstrated that an increasing percentage of AD female participants moderated pain threshold (p=0.02) whilst MMSE scores did not (p=0.19). People with AD have a greater sensitivity to pain when validated observer ratings of facial expressions are used. Verbal response to painful stimuli, even under experimental conditions, may mean pain is not identified in people with AD. Clinically useful observer rated pain tools may be the most appropriate way to assess pain in AD.


Structural studies of the manganese stabilizing subunit in photosystem II.
Photosystem II (PSII) is the plant photosynthetic reaction center that carries out the light driven oxidation of water. The water splitting reactions are catalyzed at a tetranuclear manganese cluster. The manganese stabilizing protein (MSP) of PSII stabilizes the manganese cluster and accelerates the rate of oxygen evolution. MSP can be removed from PSII, with an accompanying decrease in activity. Either an Escherichia coli expressed version of MSP or native, plant MSP can be rebound to the PSII reaction center; MSP reconstitution reverses the deleterious effects associated with MSP removal. We have employed Fourier transform infrared (FTIR) spectroscopy and solution small angle x-ray scattering (SAXS) techniques to investigate the structure of MSP in solution and to define the structural changes that occur before and after reconstitution to PSII. FTIR and SAXS are complementary, because FTIR spectroscopy detects changes in MSP secondary structure and SAXS detects changes in MSP size/shape. From the SAXS data, we conclude that the size/shape and domain structure of MSP do not change when MSP binds to PSII. From FTIR data acquired before and after reconstitution, we conclude that the reconstitution-induced increase in beta-sheet content, which was previously reported, persists after MSP is removed from the PSII reaction center. However, the secondary structural change in MSP is metastable after removal from PSII, which indicates that this form of MSP is not the lowest energy conformation in solution.


High calcium concentration and calcium oxalate crystals cause significant inaccuracies in the measurement of urinary osteopontin by enzyme linked immunosorbent assay.
Strong evidence that osteopontin (OPN) is a determinant of urolithiasis has prompted studies comparing the protein's urinary excretion in healthy subjects and stone formers. However, reported mean urinary values have varied widely, from <1 microg/mL to more than 20 times that value. Since OPN binds to CaOx crystals, the presence of crystals in urine may cause underestimation of its urinary levels. Using a commercial ELISA, we measured urinary OPN levels in the presence of endogenous or exogenous CaOx monohydrate (COM) and dihydrate (COD) crystals. OPN concentrations decreased in the presence of endogenous and exogenous CaOx crystals, but never below 2 microg/mL. Increasing the urinary calcium concentration decreased detectable OPN levels, possibly as a result of changes in the three-dimensional conformation of the protein. Because calcium concentration and the formation of CaOx crystals cannot be controlled in urine, the use of urinary OPN levels as a biomarker for any human pathology must be seriously questioned, but particularly for the investigation of stone formers in whom hypercalciuria and crystalluria are more common than in healthy subjects.


Analysis of the genotypes for aldehyde dehydrogenase 2 in Japanese patients with primary gout.
Alcoholic ingestion is one of the major factors for increasing serum uric acid levels. Genotypes of aldehyde dehydrogenase 2 (ALDH2, E.C.184.108.40.206), which regulates the sensitivity of an individual to ethanol, were determined in Japanese patients with gout and control subjects by allele specific oligonucleotide hybridization using PCR amplified gene. The most common allele ALDH2*1 codes for normal ALDH2 activity, while the less common allele ALDH2*2 codes for a lower enzyme activity. The frequency of homozygotes of ALDH2*2 was significantly lower in patients with gout than those with rheumatoid arthritis or a normal population. Plasma and urinary hypoxanthine levels were strikingly increased after ethanol drinking in homozygotes for ALDH2*1 but not in heterozygotes for ALDH2*1/ALDH2*2, indicated extensive purine nucleotide degradation in homozygote for ALDH2*1. These data indicated that alcohol ingestion may not be the requisite factor but is deeply involved in the pathogenesis of gout and hyperuricemia.


Ablative Approaches for Pulmonary Metastases.
Pulmonary metastases are common in patients with cancer for which surgery is considered a standard approach in appropriately selected patients. A number of patients are not candidates for surgery due to a medical comorbidities or the extent of surgery required. For these patients, noninvasive or minimally invasive approaches to ablate pulmonary metastases are potential treatment strategies. This article summarizes the rationale and outcomes for non-surgical treatment approaches, including radiotherapy, radiofrequency and microwave ablation, for pulmonary metastases.


In Vivo Generation of Organs by Blastocyst Complementation: Advances and Challenges.
The ultimate goal of regenerative medicine is to replace damaged cells, tissues or whole organs, in order to restore their proper function. Stem cell related technologies promise to generate transplants from the patients' own cells. Novel approaches such as blastocyst complementation combined with genome editing techniques open up new perspectives for organ replacement therapies. This review summarizes recent advances in the field and highlights the challenges that still remain to be addressed.


Pelvic fibrous mesothelioma with obstructive symptoms.
A case report of a fifty-eight-year-old man with complaints of urinary obstructive symptoms and constipation is presented. At laparotomy the patient was found to have a large pelvic mass elevating the bladder and prostate which proved to be a fibrous mesothelioma. A review of peritoneal mesotheliomas is presented.


Anatomic evaluation of postural bronchial drainage of the lung with special reference to patients with tracheal intubation: which combination of postures provides the best simplification?
Although several sequences of specific postures, each corresponding to a particular lung segment, have been recommended for therapeutic bronchial drainage, these are based on little or no anatomic evidence. Moreover, because these sequences are too complex, especially for intubated patients, they require simplification. The courses of the segmental bronchi B(1), B(2), B(1 + 2), B(3), and B(6) and their subsegmental bronchi are extremely variable. This can result in a small branching angle at the subsegmental bronchial origin. Using 106 lungs, we measured the branching angles of the subsegmental bronchi and examined their running directions in each posture of the sequences recommended for bronchial drainage. A small branching angle (< 120 degrees ) at the subsegmental bronchial origin was sometimes evident, and this made postural drainage difficult. Drainage of B(3) and B(6) was often difficult because they formed angles of < 45 degrees from the horizontal in certain postures (supine for B(3) and prone for B(6)). Further, we found a 45 degrees rotative prone position effective for draining B(1)a and B(6). Our anatomic findings predicted increased effectiveness in a sequence of postures: supine, 45 degrees rotative prone with left side up, 45 degrees rotative prone with right side up, and return to supine for simple, safe, and effective bronchial drainage, especially for patients with tracheal intubation. The 10 degrees right-side-up supine and 45 degrees rotative prone with head raised 45 degrees positions seemed helpful if added to the basic sequence.


Prostatectomy : its safety in an Australian teaching hospital.
A comparison of the results of prostatectomy in the same hospital after a 15-year interval has shown that there has been a significant reduction in the mortality (2-3 per cent versus 6-7 per cent). However, on reviewing the results of prostatectomy over the past 30 years it is evident that in spite of improved pre- and postoperative care the mortality and morbidity for high risk patients have remained constant. If the safety for this operation is to improve, it would seem that more care in patient selection is necessary and that other means of achieving urinary drainage will need consideration and evaluation in elderly men with significant cardiovascular and respiratory disease.


Thrombotic thrombocytopenic purpura precipitated by acute pancreatitis.
A 20 year old woman, admitted with acute pancreatitis, subsequently developed microangiopathic haemolytic anaemia, thrombocytopenia and mild neurological compromise. A diagnosis of thrombotic thrombocytopenic purpura (TTP) was made, and she was treated with plasma exchange leading to complete resolution of this condition. TTP is a rare multisystem disorder which may be life threatening if not treated promptly. The increasing recognition of acute pancreatitis as a potential aetiological factor offers new insights into the pathogenesis, diagnosis and treatment of TTP.


Trace elements in the livers of cod (Gadus morhua L.) from the Baltic Sea: levels and temporal trends.
This paper presents and discusses the levels and temporal trends of concentrations of Cd, Pb, Hg, Cu, Zn, and As in livers and Hg in the muscle tissues of cod (Gadus morhua L) from the Baltic Sea during the period 1994-2010. Concentrations of Pb, Hg, and Cd exhibited significant downward trends. Cu and Zn concentrations exhibited upward trends in the period 1994 to 2010. No trends were detected for concentrations of As. The temporal trends identified in heavy metal concentrations in cod livers corresponded to the directions of changes in concentrations of these elements introduced into the Baltic Sea via river runoff and atmospheric emission, and those in surface and deep waters of the Baltic. Downward trends in the concentrations of toxic metals in cod livers suggest that advantageous changes are occurring in concentrations of heavy metals in the environment of the southern Baltic Sea.


Patient-specific instrument guidance of glenoid component implantation reduces inclination variability in total and reverse shoulder arthroplasty.
The aim of this study was to assess the influence of 3-dimensional (3D) preoperative planning and patient-specific instrument (PSI) guidance of glenoid component positioning on its inclination in total shoulder arthroplasty (TSA) and reverse shoulder arthroplasty (RSA). Thirty-six shoulder arthroplasties (12 TSAs, 24 RSAs) were analyzed, of which 18 procedures (6 TSAs, 12 RSAs) were executed using preoperative 3D planning and patient-specific guides to position the central guide pin for glenoid component implantation. In 9 cases, the glenoid anatomy was severely distorted through wear or previous surgery. The inclination of the glenoid component was measured by 2 observers, using the angle between the glenoid baseplate and the floor of the supraspinatus fossa (angle β) on postoperative radiographs. For TSA, the average angle β was 74 ± 9 in the PSI group and 86 ± 12 in the non-PSI group; for RSA, the average angle β was 83 ± 7 in the PSI group and 90 ± 17 in the non-PSI group. Extreme angles β, which represent extreme values of glenoid component inclination, are more likely to occur in the non-PSI group than in the PSI group (P < .001 for TSA; P = .02 for RSA). The3D preoperative surgical planning and PSI guidance reduce variability in glenoid component inclination and avoid extreme inclination errors for TSA and RSA.


Effects of dissolved organic matter on the co-transport of mineral colloids and sorptive contaminants.
Colloid-facilitated transport of contaminants in the vadose zone has important implications to groundwater quality, and has received considerable attention. Natural organic matter (NOM) is ubiquitous in subsurface environments, and its influence on mineral colloids and solute transport has been well documented. However, research on the influence of NOM on colloid-facilitated transport is limited. The objective of this paper is to elucidate the effects of NOM on colloid-facilitated transport of a radioactive contaminant (Cs-137) within partially-saturated sediments. Measurements made with re-packed columns reveal that Cs-137 mobility was low when mineral colloids were absent and was unaffected by the presence of NOM. The addition of mineral colloids to influent increased Cs-137 mobility, and effluent Cs-137 was dominated by the colloid-associated form. When NOM was added to systems that contained mineral colloids and Cs-137, the mobility of Cs-137 further increased. A mathematical model simulating colloid-facilitated transport showed that NOM increases Cs-137 transport by increasing colloid mobility and reducing the rate of Cs-137 adsorption to the porous medium.


Inter- and Intra-Species Communication of Emotion: Chemosignals as the Neglected Medium.
Human body odors contain chemosignals that make species-specific communication possible. Such communication is without communicative intent and is generally below the threshold of consciousness. Human recipients of these chemosignals produced during emotional conditions display a simulacrum of the emotional state under which the chemosignal was produced. The investigation of an inter-species transfer of emotions via chemosignals was initiated by considerations of the historically anchored interdependence between humans and domesticated species, such as dogs and horses. Indeed, experiments with dogs have demonstrated that human body odors produced under emotional conditions of happiness and fear led dogs to manifest corresponding emotions to those experienced by humans. Preliminary data from horses also show that human body odors collected under fear and happiness conditions activate the autonomic nervous system of horses differentially. These studies indicate the possibility of a road to open our understanding of inter-species emotional communication via chemosignals.


The SERCA residue Glu340 mediates interdomain communication that guides Ca2+ transport.
The sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) is a P-type ATPase that transports Ca2+ from the cytosol into the sarco(endo)plasmic reticulum (SR/ER) lumen, driven by ATP. This primary transport activity depends on tight coupling between movements of the transmembrane helices forming the two Ca2+-binding sites and the cytosolic headpiece mediating ATP hydrolysis. We have addressed the molecular basis for this intramolecular communication by analyzing the structure and functional properties of the SERCA mutant E340A. The mutated Glu340 residue is strictly conserved among the P-type ATPase family of membrane transporters and is located at a seemingly strategic position at the interface between the phosphorylation domain and the cytosolic ends of 5 of SERCA's 10 transmembrane helices. The mutant displays a marked slowing of the Ca2+-binding kinetics, and its crystal structure in the presence of Ca2+ and ATP analog reveals a rotated headpiece, altered connectivity between the cytosolic domains, and an altered hydrogen bonding pattern around residue 340. Supported by molecular dynamics simulations, we conclude that the E340A mutation causes a stabilization of the Ca2+ sites in a more occluded state, hence displaying slowed dynamics. This finding underpins a crucial role of Glu340 in interdomain communication between the headpiece and the Ca2+-binding transmembrane region.


Comparison of Cold Atmospheric Plasma Devices' Efficacy on Osteosarcoma and Fibroblastic In Vitro Cell Models.
Cold atmospheric plasma (CAP) attenuates tumor cell proliferation and induces apoptosis in various cell lines. While exerting marginal effects on non-neoplastic cells this unfolds promising applications in cancer therapy. The aim of the study was to analyse the effects of different CAP sources and application times on osteosarcoma (OS) cells and non-malignant fibroblast cell proliferation. U2-OS and 3-T-3 fibroblasts were treated with three different approved medical devices. Carrier gas-treated cells served as controls. Cell proliferation was determined by viable cell count at different time points after treatment. Control exposed U2-OS and 3-T-3 cells exhibited characteristic cell growth. CAP application of U2-OS and 3-T-3 cells attenuated proliferation rates up to 98%. Attenuation rates varied between cell lines, plasma sources and application times. CAP treatment attenuates cell proliferation of OS cancer cells and fibroblasts in a treatment time-dependent manner, whereby U2-OS cells appeared more sensitive to CAP treatment as 3T3 fibroblasts after 10 sec of treatment.


The relationship between social roles and psychosocial adjustment in women with HIV: A structural equation model.
The human immunodeficiency virus is a unique social phenomenon that affects almost all the aspects of the social and economic life of individuals. The present study was conducted for the path analysis of the relationship between social roles and psychosocial adjustment in women with AIDS. This cross-sectional study was conducted in 2019 on 240 women with HIV who referred to the Counseling Center for Behavioral Diseases of Imam Khomeini Hospital in Tehran. The eligible individuals entered the study through convenience sampling, and data were collected using five questionnaires, including the Psychosocial Adjustment to Illness Scale, the Perceived Social Support Scale, the Multidimensional Health Locus of Control Scales, the Illness Perception Questionnaire, the Experiences in Close Relationship Scale, and a socio-demographic checklist. Data were analyzed using SPSS 16 and Lisrel 8.8 software. According to the results of the path analysis, internal health locus of control and patient's age have a significant positive relationship with psychosocial adjustment only through the direct path, and among them, patient's age has the greatest positive and direct relationship (B = 0.139). In the indirect path, education, external health locus of control, anxiety in experiences of close relationships, and perceived support have the greatest relationship with psychosocial adjustment, and among these variables, education has the highest positive relationship (B = 0.06). Illness perception, avoidance in experiences of close relationships, and chance locus of health control are associated with psychosocial adjustment through both direct and indirect paths, and among these variables, chance locus of health control has the greatest overall relationship with psychosocial adjustment (B = 0.238). Based on the results, social roles and physical health are directly/indirectly associated with psychosocial adjustment, which emphasizes the need to pay more attention to all three aspects of psychosocial health, especially in this vulnerable group of the society.


Xenogeneic rejection mechanisms shown by intravital microscopy.
The importance of this model is that it showed exactly where in the organ the xenogeneic damage occurred. The liver received the blood mainly via portal veins, which merge with the pulsatile arterioles in the Disse spaces. This periportal area is followed by the sinusoids and ends in the central or postsinusoidal vein. IVM enables us to differentiate between perfused and unperfused sinusoids and to calculate the ratio. Not all sinusoids are perfused at any time. It appears that 5% to 10% are unperfused. During xenoperfusion, only 65% of sinusoids show blood flow after a perfusion of 12 minutes. This is less than in hemorrhagic shock. Only the combined platelet inhibitors and apheresis resulted in remarkable improvement. The calculation of an index indicates the improvement of acinar perfusion. Thrombocytes and leukocytes remain, however, in the liver. In conclusion, the model used to analyze the dynamics of microvascular liver perfusion and sinusoidal perfusion is suitable for such investigations in a xenogeneic model. It has no major side effects, either on the perfusing blood or on the liver, as proved in the isogeneic control group. The important finding in our eyes is that the perfusion failure begins in the periportal fields, where the blood enters the foreign microvasculature and where the leukocytes first come in contact with the foreign endothelium. All previous manipulations had only a minor impact on this contact of cells with the foreign endothelium. The study indicates that the early events of xenogeneic hyperacute rejection are of unspecific character and involve leukocytes and thrombocytes to a major degree, thus being responsible for the dramatic decrease in the microcirculation in xenogeneic livers.


Overexpressed N-fucosylation on the cell surface driven by FUT3, 5, and 6 promotes cell motilities in metastatic pancreatic cancer cell lines.
Pancreatic cancer is a highly malignant tumor of the digestive system. Previous studies have shown that abnormal cell surface glycosylation is associated with cancer metastasis, which suggests that glycosylation changes may open a new window for discovering metastasis-related pathways. In this study, we used a microarray with 55 lectins to screen for altered glycosylation between two metastatic pancreatic cancer lines (Capan-1 and Su.86.86) and two nonmetastatic pancreatic cancer lines (Panc-1 and MIA PaCa-2), and we further analyzed three lectins with high-binding activities (AAL, UEA-I, and PHA-E) in cell motility assays using these pancreatic cancer cells to detect whether blocking certain forms of cell surface glycosylation affects any processes associated with metastasis. As a result, we found that AAL, a fucose-specific lectin, has different binding patterns between metastatic pancreatic cancer and nonmetastatic pancreatic cancer lines and inhibits cell motility in metastatic pancreatic cancer cells. Furthermore, the N-fucosylation-related genes FUT3, 5, and 6 were found to be responsible for the elevated fucosylation in metastatic pancreatic cells through real-time PCR screening. In summary, our findings that the specific bindings of AAL on cell surfaces and highly expressed FUT3, 5, and 6 in metastatic pancreatic cancer cells, although preliminary, are encouraging, and our established combined method is also suitable for discovering metastasis-related mechanisms in other cancers.


Ontogenetic changes in porcine adrenocortical adrenocorticotropic hormone receptors.
1. Binding of [125I]ACTH(1-38) analog to adrenal receptors was measured in fetal pigs (Sus domesticus) at 15-day intervals from midpregnancy (60 days) to near term (105 days; pregnancy length 114 days). 2. Binding was greatest at day 60 (0.42 +/- 0.03 fmol/200 micrograms protein or 0.50 +/- 0.08 fmol/50 micrograms DNA), and least at day 105 (0.13 +/- 0.03 fmol/200 micrograms protein or 0.16 +/- 0.04 fmol/50 micrograms DNA). Total adrenal binding was constant (0.61 +/- 0.02 fmol/paired adrenals). 3. Scatchard analyses at day 60 and day 105 showed comparable apparent affinities of ACTH receptors (Ka day 60 = 1.51 +/- 0.72 x 10(9) M-1 vs Ka day 105 = 1.94 +/- 0.78 x 10(9) M-1). 4. DNA per paired adrenals and membrane-associated protein increased 1.6-fold, providing a constant protein: DNA ratio. Concentrations of adrenal cortisol were constant from 60 to 90 days of gestation age but increased dramatically by day 105. 5. These data suggest that during 60-105 days of gestation age the number of ACTH receptors per cell is reduced.


Inhibition of ecdysone receptor (DcEcR) and ultraspiracle (DcUSP) expression in Diaphorina citri increased susceptibility to pesticides.
Diaphorina citri Kuwayama is of great concern because of its ability to transmit devastating citrus greening illness (Huanglongbing). One strategy for controlling HLB may involve limiting the spread of D. citri. Insecticides using dsRNA target genes may be a useful option to control D. citri. The ecdysone receptor (EcR) and ultraspiracle (USP) are crucial for the growth and reproduction of insects. This study identified the genes for D. citri ecdysone receptor (DcEcR) and ultraspiracle (DcUSP). According to the qPCR data, DcUSP peaked at the 5th-instar nymph stage, while DcEcR peaked at the adult stage. Females expressed DcEcR and DcUSP at much higher levels than males. RNAi was used to examine DcEcR and DcUSP function. The findings demonstrated that inhibition of DcEcR and DcUSP delayed nymph development and decreased survival and eclosion rates. dsEcR caused adults to develop deformed wings, and dsUSP caused nymphs to wither and die. Female adult ovaries developed slowly, and the females laid fewer eggs. Additionally, DcEcR and DcUSP were inhibited, increasing D. citri susceptibility to pesticides. These findings suggest that DcEcR and DcUSP are critical for D. citri development, growth, and reproduction and may serve as potential targets for D. citri management.


Contingency proportion systematically influences contingency learning.
In the color-word contingency learning paradigm, each word appears more often in one color (high contingency) than in the other colors (low contingency). Shortly after beginning the task, color identification responses become faster on the high-contingency trials than on the low-contingency trials-the contingency learning effect. Across five groups, we varied the high-contingency proportion in 10% steps, from 80% to 40%. The size of the contingency learning effect was positively related to high-contingency proportion, with the effect disappearing when high contingency was reduced to 40%. At the two highest contingency proportions, the magnitude of the effect increased over trials, the pattern suggesting that there was an increasing cost for the low-contingency trials rather than an increasing benefit for the high-contingency trials. Overall, the results fit a modified version of Schmidt's (2013, Acta Psychologica, 142, 119-126) parallel episodic processing account in which prior trial instances are routinely retrieved from memory and influence current trial performance.


Safety and performance of the drug-eluting absorbable metal scaffold (DREAMS) in patients with de-novo coronary lesions: 12 month results of the prospective, multicentre, first-in-man BIOSOLVE-I trial.
Bioabsorbable vascular scaffolds were developed to overcome limitations of permanent bare-metal or drug-eluting coronary stents—ie, stent thrombosis (despite prolonged dual antiplatelet therapy), the life-long presence of a caged vessel segment that does not allow vasomotion or remodelling, and chronic vessel wall inflammation. We assessed the safety and performance of a new magnesium-based paclitaxel-eluting absorbable metal scaffold in symptomatic patients with de-novo coronary lesions. We did a prospective, multicentre, first-in-man trial (BIOSOLVE-1) of the drug-eluting absorbable metal scaffold (DREAMS). 46 patients with 47 lesions were enrolled at five European centres. The primary endpoint was target lesion failure, a composite of cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularisation, at 6 and 12 months. Clinical follow-up was scheduled at 1, 6, 12, 24, and 36 months. Patients were consecutively assigned to angiographic and intravascular ultrasonographic follow-up at 6 months or 12 months. Optical coherence tomography was done in some patients. All patients were recommended to take dual antiplatelet therapy for at least 12 months. This trial is registered with ClinicalTrials.gov, number NCT01168830. Overall device and procedural success was 100%. Two of 46 (4%) patients had target lesion failure at 6 months (both clinically driven target lesion revascularisations), which rose to three of 43 (7%) at 12 months (one periprocedural target vessel myocardial infarction occurred during angiography at the 12 month follow-up visit). We noted no cardiac death or scaffold thrombosis. Our results show feasibility, a good safety profile, and promising clinical and angiographic performance results up to 12 months for DREAMS. Our promising clinical results show that absorbable metal scaffolds might be an alternative to polymeric absorbable scaffolds. Biotronik.


Propofol context-sensitive decrement times in children.
Plasma drug concentration is the variable linking dose to effect. The decrement time required for plasma concentration of anesthetic agents to decrease by 50% (context-sensitive half-time) correlates with the time taken to regain consciousness. However, the decrement time to consciousness may not be 50%. An effect compartment concentration is associated more closely with return of consciousness than plasma concentration. An alternative decrement time, the time required for propofol to decrease to a predetermined effect compartment concentration associated with movement (eg, 2 µg.ml-1 ), was used to simulate time for the concentration to decrease from steady state at a typical targeted effect compartment concentration 3.5 µg.ml-1 in children. These times were short and reflected a decrement time to consciousness (CSTAWAKE ) increase that was small with longer infusion time. CSTAWAKE ranged from 7.5 min in 1-year-old infant given propofol for 15 min to 13.5 min in a 15-year-old adolescent given a 2-hour infusion. Changes in decrement time with age reflect maturation of drug clearance. Neonates had prolonged increment times, 10 min after 15 min infusion and 18 min after 120 min infusion using a target concentration of 3.5 µg.ml-1 . Decrement times to a targeted arousal concentration are context-sensitive. Use of a higher target concentration of 6 µg.ml-1 doubled decrement times. Decrement times are associated with variability: delayed recovery beyond these simulated times is likely more attributable to the use of adjuvant drugs or the child's clinical status. An understanding of propofol decrement times can be used to guide recovery after anesthesia.


Effect of rilmenidine on the cadiovascular responses to stress in the conscious rabbit.
Environmental stress can cause an increase in sympathetic nerve activity both in humans and animals. While centrally acting antihypertensive drugs such as rilmenidine are known to reduce sympathetic tone, it is not clear whether they also influence the cardiovascular responses to acute stress. In the present study we examined the effects of systemic treatment with rilmenidine on the sympathetic and haemodynamic responses to air jet or noise stress. Twelve conscious rabbits previously implanted with a renal nerve recording electrode were subjected to an 8 l/min stream of air directed at their face for 10 min or exposure to 10 min of white noise (approximately 85 dB). Both air jet and noise stress elicited increases in renal sympathetic nerve activity (RSNA) which were greatest in the first minute (+55+/-9% and +40+/-6%, respectively), but which quickly reached a stable level over the subsequent 9 min (+24+/-6% and +9+/-5%, respectively). This was accompanied by a small increase in heart rate (HR) and mean arterial pressure (MAP). Intravenous rilmenidine (273 microg/kg) reduced MAP from 85+/-3 mm Hg to 68+/-2 mm Hg and HR from 203+/-10 b/min to 188+/-10 b/min and lowered basal RSNA by 54%. Rilmenidine reduced the increase in RSNA seen during the first minute of air jet stress by 35% and reduced the average increase over the next 9 min by 68%. However, rilmenidine had little effect on either the initial or stable RSNA responses to noise stress. Saline treatment did not alter the RSNA responses to either air jet or noise stress. The results show that centrally-acting antihypertensive agents not only lower basal RSNA, but can differentially influence environmentally induced sympathetic responses. In addition, the differential effect of rilmenidine on noise and air jet stress suggests that they may involve quite different central processing.


A convenient enzyme-linked immunosorbent assay for testing whether monoclonal antibodies recognize the same antigenic site. Application to hybridomas specific for the beta 2-subunit of Escherichia coli tryptophan synthase.
Seven hybridoma clones, producing antibodies directed against the beta 2-subunit of Escherichia coli tryptophan synthase, have been obtained from mouse cells. To test whether the corresponding monoclonal antibodies recognize different epitopes on beta 2, an ELISA double antibody binding system has been developed and is reported here. The antigen is first coated onto a microtitration plate. Two monoclonal antibodies are then added either separately or simultaneously, and the amount of bound antibody is quantitatively measured by use of immunoglobulin (rabbit anti-mouse IgG) linked to beta-galactosidase. Additivity of the bound enzymatic activity is observed when the monoclonal antibodies bind to distinct epitopes. Using this test, it is shown that, of the 7 anti-beta 2 monoclonal antibodies obtained, 5 recognize the same antigenic site and the 2 others recognize a second site.


Mutagenicity, cytotoxicity and DNA crosslinking in V79 Chinese hamster cells treated with cis- and trans-Pt(II) diamminedichloride.
The mutagenicity and cytotoxicity of cis- and trans-Pt(II) diamminedichloride (PDD) were examined in V79 Chinese hamster lung cells and compared with effects on DNA measured by alkaline elution. DNA--protein crosslinks and DNA interstrand crosslinks were detected following doses of cis-PDD which reduced cell survival 80--90% and which produced a mutant frequency of 3 X 10(-4) at the HGPRT locus. Equitoxic doses of trans-PDD were much less mutagenic than cis-PDD. At equitoxic doses, trans-PDD produced more DNA-protein crosslinking than did cis-PDD, but interstrand crosslinking for the two isomers was comparable. Hence, the interstrand crosslink could be the cytotoxic lesion produced by these Pt compounds whereas neither of these DNA lesions are necessarily mutagenic. The mutagenesis produced by cis-PDD could be due to crosslinks of a different type than those produced by trans-PDD or it may be due to monofunctional damage.


Water permeability of human hematopoietic stem cells.
It is currently impossible to isolate or identify human hematopoietic progenitor cells from the bone marrow, yet the biophysical properties of these cells are important for the development of techniques to isolate and preserve stem cells for transplantation. Osmotic permeability properties of human bone marrow stem cells were estimated from the kinetics of cell damage in a hypotonic solution measured using in vitro colony assays for multipotential (CFU-GEMM) and committed (BFU-E, CFU-GM) progenitor cells. Cells exposed to a hypotonic solution swell as a result of water influx, and the rate of change of volume is proportional to the hydraulic conductivity of the plasma membrane. Cell damage occurs when the cell volume exceeds the maximum tolerable volume, so the hydraulic conductivity can be estimated from the kinetics of cell damage. For all the progenitor cells studied, the mean value of the hydraulic conductivity was 0.283 micron3/micron2/min/atm at 20 degrees C, with an Arrhenius activation energy of 6.41 kcal/mole. No significant differences were observed in the osmotic properties of the various progenitor cells. These data were used to predict the osmotic responses of human bone marrow stem cells at subzero temperatures during freezing.


The role of the sympathetic nervous system in controlling bone metabolism.
Experimental studies have generally shown that increased sympathetic nervous activity causes bone loss via an increase in bone resorption and a decrease in bone formation. Increased bone resorption is based on the stimulation of both osteoclast formation and osteoclast activity. These effects are associated with beta2-adrenergic activity towards both osteoblastic and osteoclastic cells. Decreased bone formation is based on the inhibition of osteoblastic activity through beta2-adrenergic receptors on osteoblasts. Such findings indicate that beta-blockers may be effective against osteoporosis, in which case there is increased sympathetic activity. In fact, in a population-based, case-control study, the current use of beta-blockers has been demonstrated to be associated with a reduced risk of fractures. These clinical studies suggest that pharmacological blockade of the beta-adrenergic system is beneficial to the human skeleton. In another prospective study, however, no association between beta-blocker use and fracture risk was shown in perimenopausal and older women. To confirm this important new therapeutic avenue to prevent bone loss, the relationship between the pharmacological effectiveness of beta-blockers and the pathogenesis of osteoporosis must be explored in detail.