Switching from risperidone to paliperidone palmitate in schizophrenia: Changes in social functioning and cognitive performance.
Previous studies suggest that paliperidone might show a better profile for social functioning and cognitive abilities than risperidone. We aimed to study whether switching from risperidone to paliperidone palmitate (PP) is associated with improved cognitive abilities at 3 or 6 months after the switch. Thirty-eight patients with a DSM-IV diagnosis of schizophrenia were studied. All patients were treated with oral risperidone or risperidone long-acting injection (RLAI) and had an indication to be switched to PP by their psychiatrists. Statistical analyses were conducted in a final sample of 27 patients who completed the follow-up visits. Three assessments were completed: 1) baseline (preswitch), 2) 3 months postswitch, and 3) 6 months postswitch. Social functioning at each visit was assessed with the Personal and Social Performance Scale. Cognitive assessment was conducted at each visit with the MATRICS Consensus Cognitive Battery. Statistical analyses were performed with R. Linear mixed models were used to explore longitudinal changes in social functioning and cognitive outcomes. PSP scores significantly improved over time after the switch from risperidone to PP. A sensitivity analysis found a significant negative interaction between time and PP maintenance doses (greater improvement in those patients receiving lower doses when compared to higher doses). Regarding longitudinal changes in cognitive functioning, patients improved in 6 out of 10 cognitive tasks involving processing speed, working memory, visual memory, reasoning and problem solving, and attention and vigilance. Our study suggests that switching from risperidone to PP in patients with schizophrenia is associated with an improvement in social functioning and cognitive performance.


Recombinant bovine lactoperoxidase as a tool to study the heme environment in mammalian peroxidases.
The cDNA encoding bovine lactoperoxidase (LPO) has been expressed in CHO cells. The recombinant LPO was secreted as an enzymatically active single chain molecule presenting two immunoreactive forms of 88 kDa and 82 kDa, differing by their glycosylation. rLPO exhibited the characteristic absorbance spectrum with a Soret peak at 413 nm. Engineering of rLPO into a myeloperoxidase (MPO)-like molecule was attempted by substituting Gln-376 by Met, a residue known to achieve covalent binding with the heme in MPO. However, the resulting bovine LPO mutant failed to acquire the peculiar absorbance spectrum and the chlorinating activity of MPO, underlining the complex nature of interactions in the heme vicinity.


"We are not completely Westernised": dual medical systems and pathways to health care among Chinese migrant women in England.
This examination of how Chinese migrant women resident in England engage with Western and Chinese healthcare systems when seeking treatment considers whether medical pluralism can enhance the cultural appropriateness of health care. The paper identifies the extent to which women's pathways to healthcare can be seen as 'Chinese' or as a reflection of the Western culture in which they live. It is based on an analysis of in-depth interviews with 42 women of Chinese origin living in the South East of England. Their use of Western and Chinese medicine is related to explanatory models underpinning health beliefs, treatment barriers encountered and resources drawn upon when seeking treatment. Variation is described, with some women using only Western medicine and others returning to their place of origin for indigenous Chinese medical treatment. Most, however, draw upon both medical systems. Women who are more connected with majority English culture are more successful in their consultations with Western health service practitioners but do not necessarily discontinue using Chinese medicine. We find that recourse to two different systems helps to overcome barriers when accessing health care. The health policy implications of the findings would suggest that a system that acknowledges and embraces medical pluralism would assist the development of culturally appropriate health care provision.


Characterizing Vocal Fold Injury Recovery in a Rabbit Model With Three-Dimensional Virtual Histology.
In animal studies of vocal fold scarring and treatment, imaging-based evaluation is most often conducted by tissue slicing and histological staining. Given variation in anatomy, injury type, severity, and sacrifice timepoints, planar histological sections provide limited spatiotemporal details of tissue repair. Three-dimensional (3D) virtual histology may provide additional contextual spatial information, enhancing objective interpretation. The study's aim was to evaluate the suitability of magnetic resonance imaging (MRI), microscale computed tomography (CT), and nonlinear laser-scanning microscopy (NM) as virtual histology approaches for rabbit studies of vocal fold scarring. A unilateral injury was created using microcup forceps in the left vocal fold of three New Zealand White rabbits. Animals were sacrificed at 3, 10, and 39 days postinjury. ex vivo imaging of excised larynges was performed with MRI, CT, and NM modalities. The MRI modality allowed visualization of injury location and morphological internal features with 100-μm spatial resolution. The CT modality provided a view of the injury defect surface with 12-μm spatial resolution. The NM modality with optical clearing resolved second-harmonic generation signal of collagen fibers and two-photon autofluorescence in vocal fold lamina propria, muscle, and surrounding cartilage structures at submicrometer spatial scales. Features of vocal fold injury and wound healing were observed with MRI, CT, and NM. The MRI and CT modalities provided contextual spatial information and dissection guidance, whereas NM resolved extracellular matrix structure. The results serve as a proof of concept to motivate incorporation of 3D virtual histology techniques in future vocal fold injury animal studies. NA Laryngoscope, 131:1578-1587, 2021.


[General anesthesia in pediatric radiotherapy].
The majority of children under 3 years require anesthesia for radiotherapy. This work reports the experience of Paul-Strauss Center over a 4-year period on 15 children and covering 386 general anesthesia. The rate of anesthesia-related complications was low (0.5%) subject to the experience of the anesthesiologists and follow-up recommendations.


Periodontal microsurgery.
The purpose of this article is to introduce the history of microsurgery in the surgical disciplines. It reviews the benefits and potential applications of magnification and microsurgery in the specialty of periodontics. Esthetic procedures encompassing periodontal plastic microsurgery are described with an emphasis on clinical cases to demonstrate their application. The use of magnification, in particular the use of surgical operating microscopes, has increased in many areas of dentistry. This article demonstrates the usefulness of microscope-enhanced periodontal surgery and addresses many issues involved in its application to the surgical discipline of periodontics.


Outcomes of Heart Transplantation in Cardiac Amyloidosis Patients: A Single Center Experience.
Indications for heart transplantation are expanding to include amyloid light chain (AL) and transthyretin-related (TTR) amyloidosis. Previously, AL amyloid had been a contraindication to heart transplantation given inferior outcomes. These patients typically have biventricular failure requiring mechanical circulatory support (MCS). We report the outcomes of patients with end-stage cardiac amyloidosis who underwent cardiac transplantation, including some who were bridged to transplantation with a durable biventricular MCS METHODS: The records for patients with cardiac amyloidosis who underwent cardiac transplant between 2010 and 2018 were reviewed. Primary endpoint was post-transplant 1-year survival. Secondary endpoints included 1-year freedom from cardiac allograft vasculopathy (as defined by stenosis ≥ 30% by angiography), nonfatal major adverse cardiac events (myocardial infarction, new congestive heart failure, percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, stroke), and any rejection. A total of 46 patients received heart transplantation with a diagnosis of either AL or TTR amyloidosis. Of these, 7 patients were bridged to transplantation with a durable biventricular MCS device (6 AL, 1 TTR) and 39 patients were transplanted without MCS bridging. The MCS group consisted of 5 total artificial hearts and 2 biventricular assist devices. The 1-year survival was 91% for the entire cohort, 83% for those with AL amyloidosis, 94% for those with TTR amyloidosis, and 86% for those who received MCS bridging. Cardiac transplantation can be safely performed in selected amyloidosis patients with reasonable short-term outcomes. Those bridged to transplantation with biventricular MCS appear to have short-term outcomes similar to those transplanted without MCS. Larger numbers and longer observation are required to confirm these findings.


Sturge-Weber syndrome: clinical and radiological correlates in 86 patients.
To correlate the extent of the leptomeningeal angiomatosis with clinical features in Sturge-Weber syndrome (SWS). The study group consisted of 86 consecutive patients aged two months to 56 (mean 7.9 +/- 10.3) years with SWS and epilepsy. Clinical and MRI data were analyzed. Based on the extent of leptomeningeal angiomatosis, patients were divided into two subgroups: 43 patients had hemispheric angiomatosis and atrophy, whereas, another 43 had focal involvement. Nine of the 43 hemispherial patients (10%) showed bilateral involvement: all of these bilateral cases demonstrated dominance in a single side with hemispheric leptomeningeal angiomatosis and contralateral focal extension. Hemispheric and focal subgroups were clinically different. Patients with hemispheric SWS were younger at the age of epilepsy onset (p < 0.001) and age at MRI examination (p < 0.05). Neither gender, lateralization, duration of epilepsy, appearance of secondarily generalized seizures, nor seizure frequency revealed a significant difference between subgroups. Bilateral involvement is frequent and occurs in cases with a hemisperic involvement on one side. The age of epilepsy onset is related to the extent of leptomeningeal angiomatosis. Patients with hemispheric form of SWS presented with earlier age of seizure onset. Focal pial angiomatoses do not tend to progress (a longer duration is not associated with more frequent hemispheric involvement). Other variables including seizure frequency and secondary generalized tonic-clonic seizures are not associated with the extent of angiomatosis.


Myocardial energetics and diastolic dimensions of the heart in experimental hypertension.
The present study examined changes in left ventricular design and function in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY), and in SHR exposed to voluntary physical exercise in running wheels (R-SHR) and their respective sedentary controls (C-SHR). End-diastolic volumes were obtained in vitro by determining the pressure-volume relationships of isolated hearts arrested in diastole. Cardiac function and myocardial oxygen consumption were also assessed in vitro by means of an antegrade working heart perfusion technique. Compared with WKY and C-SHR respectively, ordinary SHR and R-SHR had increased end-diastolic volumes, whereas the ratios between wall thickness and internal radius were relatively unchanged. Maximal cardiac performance was elevated in the structurally enlarged SHR heart compared with WKY, whereas it remained unchanged after chronic physical exercise. Long-term voluntary running in SHR caused an elevation of cardiac output due to an increased stroke volume, while arterial pressure was unaltered. The stimulus for the cardiac redesign to a structurally enlarged heart can probably best be explained by a chronic elevation in cardiac filling. Hence, enlarged left ventricles can then produce higher stroke volumes for given degrees of myocardial fibre shortenings. Thus, despite structurally enlarged left ventricles in SHR and in R-SHR and also increased arterial pressure in SHR compared with WKY (thereby elevating systolic wall stress), cardiac function was maintained and even augmented, which was not associated with an increase in total myocardial oxygen consumption.


Ciprofloxacin-resistant Escherichia coli isolated from the intestinal microbiota of goats in Greece in the absence of selective pressure.
The presence of ciprofloxacin resistance commensal Escherichia coli (C-R-Ec) was determined for goats in the absence of selective pressure in Northern and Central Greece. The C-R-Ec was categorized in 3 groups with respect to their phenotypic resistance to other antibiotics as well as the carriage of antibiotic resistance genes. The first group consisted of 7 C-R-Ec that were found also resistant to tetracycline. Among them tet(B) (n = 7), qnr(S) (n = 7), and qnr(B) (n = 3) producers were identified by polymerase chain reaction. The second group consisted of 10 C-R-Ec that were found sensitive to all other antibiotics, and their phenotypic resistance to ciprofloxacin was not attributed to the presence of resistance genes. Finally, the third group consisted of 2 C-R-Ec also resistant to sulfamethoxazole. These strains were not carrying any transferable elements that contribute to resistance either to ciprofloxacin or to sulfamethoxazole. This is the first report of ciprofloxacin-resistant E. coli isolated from goats in Greece.


Novel Benzylated (Pyrrolidin-2-one)/(Imidazolidin-2-one) Derivatives as Potential Anti-Alzheimer's Agents: Synthesis and Pharmacological Investigations.
A series of N-benzylated (pyrrolidin-2-one)/(imidazolidin-2-one) derivatives were synthesized and evaluated for anti-Alzheimer's activity. The analogs were designed and synthesized on the basis of lead compound donepezil, which is currently prescribed as a major drug for the management of mild to severe Alzheimer's disease. Considering the structure activity relationship (SAR) of the lead compound, we first replaced the 5,6-dimethoxy-1-indanone moiety with N-benzylated (pyrrolidin-2-one)/(imidazolidin-2-one) (head) without depriving the key functionality interactions like carbonyl and dimethoxyphenyl and second substituted the spacer linkage (tail) in donepezil. The newly synthesized compounds were characterized by structural conformity and purity using various techniques. The compounds were then subjected to in vivo (behavioral studies) and in vitro (biochemical assays) evaluation using appropriate animal models against the standard drug. Compounds 3-(4-(4-fluorobenzoyl)-piperidin-1-yl)-1-(4-methoxybenzyl)-pyrrolidin-2-one (10b) and 1-(3,4-dimethoxybenzyl)-3-((1-(2-(trifluoromethyl)-benzyl)-piperidin-4-yl)-methyl)-imidazolidin-2-one (18c) displayed an excellent anti-Alzheimer's profile, while the rest of the compounds showed satisfactory results in comparison to donepezil.


Evidence of en bloc duplication in vertebrate genomes.
It has been 30 years since it was first proposed that the vertebrate genome evolved through several rounds of genome-wide duplications (polyploidizations). Despite rapid advances in genetics, including sequencing of the complete genomes of several divergent species, this hypothesis has not been tested rigorously and is still a matter of debate. If polyploidizations occurred during chordate evolution, there should be a network of paralogous regions in the present-day jawed vertebrate (Gnathostomata) genomes. Here we present an investigation of the major histocompatibility complex (MHC) paralogous regions, which we accomplished by characterizing the corresponding region in amphioxus by identifying nine anchor genes and sequencing both the anchor genes and the regions that flank them (a total of 400 kb). Phylogenetic analysis of 31 genes (including the anchor genes) in these regions shows that duplications occurred after the divergence of cephalochordates and vertebrates but before the Gnathostomata radiation. The distribution of human and amphioxus orthologs in their respective genomes and the relationship between these distributions support the en bloc duplication events. Our analysis represents the first step towards demonstrating that the human ancestral genome has undergone polyploidization. Moreover, reconstruction of the pre-duplicated region indicates that one of the duplicated regions retains the ancestral organization.


Anti-myelin antibodies in cerebrospinal fluid and serum of patients with meningopolyneuritis Garin-Bujadoux-Bannwarth and other neurological diseases.
Anti-myelin antibodies (AMA) of IgG, IgM, and IgA class were investigated by ELISA in CSF and serum from patients with meningopolyneuritis Garin-Bujadoux-Bannwarth (GBB), other inflammatory diseases of the nervous system (ID) comprising meningoencephalitis (ME), multiple sclerosis (MS), and Guillain-Barré syndrome (GBS), and various noninflammatory neurological diseases (NID). Anti-Borrelia antibodies (ABA) were determined by ELISA in GBB patients. In CSF, a high incidence of IgG-AMA, IgM-AMA, and IgA-AMA was found in GBB as compared with ID and NID. On average, positive AMA titers were higher in GBB than in ID and NID, IgM-AMA titers in GBB being most prominent. In serum, AMA were found in all but 2 patients investigated. On average, IgM-AMA titers were higher in GBB and MS than in other diseases; IgG-AMA titers in GBB and ME were relatively low. Antibody indices, calculated from titer values and Ig concentrations in CSF and serum, indicate intrathecal synthesis mainly of IgG- and IgA-AMA, and of IgG- and IgM-ABA. Participation of AMA in the pathogenesis of GBB may be envisaged, but needs further confirmation.


Fetal spinal cord homografts ameliorate the severity of lesion-induced hind limb behavioral deficits.
Fetal spinal cord grafts survive for long periods in host spinal cord. We explored the ability of such grafts into a lesion in C3 fasciculus gracilis to influence the expected deterioration of hind limb performance following this lesion. Ten adult Sprague-Dawley rats were placed on a schedule of 23 h off and 1 h on water. These subjects were then trained to traverse a narrow platform for a water reward. Criterion was established as 10 trials/day completed in 15 s a trial for 2 consecutive days. Animals were ranked for hind limb and forelimb performance utilizing slips, recovery, and manner of traversing the platform. In a triple-blind experimental design, the animals' identification was coded and laminectomy performed at C3. The fasciculus gracilis was bilaterally transected at the rostral and caudal borders of the segment and aspirated. Five subjects were chosen at random immediately after the lesion was made for the implantation of two 1-mm segments of E14 spinal cord from fetuses of timed pregnant Sprague-Dawley dams at the time of the lesion. Coded lesion and lesion-transplant animals were then tested after 21, 30, 45, 60, and 90 days until criterion or for 4 days. Hind limb performance of the lesion-only (ANOVA chi 2 = 13.04, df 5; P less than 0.05) and lesion-transplant groups (ANOVA chi 2 = 11.82, df 5; P less than 0.05) showed that the C3 fetal transplants significantly decreased (P less than 0.05) the severity of hind limb deficit at 21 days postlesion and significantly (P less than 0.05) decreased the expected foot slips and limb recovery to the platform that was expected and did develop in lesion-only animals at 90 days. There were no significant differences in forelimb performance (ANOVAs P greater than 0.05). There were few small-caliber nerve fibers in the fasciculus gracilis at the level of C1 indicating that reinnervation was not a major factor in the reduction of the deficit.


TNF-induced Lupus. A Case-Based Review.
Nowadays, tumor necrosis factor-alpha (TNFα) inhibitors have revolutionised the treatment of inflammatory arthritides by demonstrating efficacy with an acceptable toxicity profile. However, autoimmune phenomena and clinical entities have been reported ranging from an isolated presence of autoantibodies to full-blown autoimmune diseases, including drug-induced lupus (DIL). Case Presentation: A 62-year-old woman with rheumatoid arthritis (RA) refractory to methotrexate and prednisone was treated with adalimumab (ADA). 4 months later, she presented acute cutaneous eruptions after sun exposure, positive ANA (1/640 fine speckled pattern), Ro (SSA) and anti- Smith (Sm) antibodies with no other clinical or laboratory abnormalities. The diagnosis of DIL was made, ADA was discontinued, and she was treated successfully with prednisone plus local calcineurin inhibitors. Conclusion: Thus, we review the literature for cases of DIL development in patients treated with TNFα inhibitors. Rheumatologists should be aware of the possible adverse events and the requirement of careful clinical evaluation and monitoring.


A novel dRYBP-SCF complex functions to inhibit apoptosis in Drosophila.
A balanced response to intrinsic and extrinsic apoptotic signals is crucial to support homeostatic development and animal survival. Regulation of activation and inhibition of apoptotic pathways involves diverse mechanisms including protein ubiquitylation to control expression levels of apoptotic factors. Here we report that drosophila Ring and YY1 Binding Protein (dRYBP) protein interacts both genetically and biochemically with the E3 ubiquitin ligase SKPA, dCULLIN, F-box (SCF) complex to synergistically inhibit apoptosis in Drosophila. Further, we show that the loss of skpA function activates the intrinsic pathway of apoptosis and down-regulates the levels of expression of the anti-apoptotic DIAP1 protein. Accordingly, the apoptosis induced by inactivation of skpA and dRYBP is rescued by loss of function of the pro-apoptotic gene reaper and overexpression of DIAP1. Of interest, we also find that high levels of SKPA protein rescue the wing phenotype induced by overexpression of Reaper protein. Finally, we demonstrate that overexpression of SKPA inhibits both developmental and radiation-induced apoptosis. We propose that the function of the dRYBP-SCF complex in the inhibition of apoptosis might possibly be to control the levels of the pro-apoptotic and anti-apoptotic proteins most likely by promoting their ubiquitylation and consequently, proteasomal degradation. Given the evolutionary conservation of the dRYBP and the SCF proteins, our results suggest that their mammalian homologs may function in balancing cell survival versus cell death during normal and pathological development.


Stepwise extraction of high-value chemicals from Arthrospira (Spirulina) and an economic feasibility study.
Arthrospira (Spirulina) consists of diverse high-value chemicals, such as phycocyanin, lipids/total fatty acids (TFA), and polysaccharides, which have been used for food, cosmetic and pharmacological applications. This study compared various stepwise extraction processes for these high-value chemicals. Considering the yield and properties of extracts, the most suitable extraction order was phycocyanin, lipid/TFA and polysaccharides. The yield of the main product (food-grade phycocyanin) was 8.66% of the biomass dry weight, whereas the yields of the subsequent lipid/TFA and polysaccharide coproducts were 3.55% and 0.72%, respectively. The economic analysis showed that producing phycocyanin alone was economically feasible, but producing coproducts (lipid/TFA and polysaccharides) was not. The production cost of phycocyanin was US$ 249.70 kg-1, which is an encouraging figure for large-scale production. Moreover, the phycocyanin content of Arthrospira materials utilized for extraction should not be lower than 15% of dry weight to ensure positive the net present value (NPV) of investment.


Management and outcome of pregnancy in diabetes mellitus, classes B to R.
During the period 1971 to 1975, 260 women with diabetes mellitus, Classes B through R, were delivered of their infants at Los Angeles County Women's Hospital. The plan of patient management included frequent clinic visits and hospitalization to assure good control. A program of intensive antepartum fetal surveillance was begun at 34 weeks' gestation, with the use of daily 24 hour urinary estriol determinations and a weekly contraction stress test (CST). A lecithin/sphingomyelin ratio was evaluated for all patients before elective delivery. The perinatal mortality rate in these diabetic pregnant women was 46 per 1,000 as compared to 24 per 1,000 in the general population. Only three stillbirths occurred in the diabetic group, none within one week of a negative CST. Congenital malformations were responsible for almost half of the neonatal deaths. There were no deaths due to iatrogenic prematurity or trauma. Mean gestational age at delivery was 37.9 weeks and vaginal delivery was the mode for approximately half of the women. Two thirds of the infants did experience some morbidity.


Multicenter evaluation of a lateral-flow device test for diagnosing invasive pulmonary aspergillosis in ICU patients.
The incidence of invasive pulmonary aspergillosis (IPA) in intensive care unit (ICU) patients is increasing, and early diagnosis of the disease and treatment with antifungal drugs is critical for patient survival. Serum biomarker tests for IPA typically give false-negative results in non-neutropenic patients, and galactomannan (GM) detection, the preferred diagnostic test for IPA using bronchoalveolar lavage (BAL), is often not readily available. Novel approaches to IPA detection in ICU patients are needed. In this multicenter study, we evaluated the performance of an Aspergillus lateral-flow device (LFD) test for BAL IPA detection in critically ill patients. A total of 149 BAL samples from 133 ICU patients were included in this semiprospective study. Participating centers were the medical university hospitals of Graz, Vienna and Innsbruck in Austria and the University Hospital of Mannheim, Germany. Fungal infections were classified according to modified European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. Two patients (four BALs) had proven IPA, fourteen patients (sixteen BALs) had probable IPA, twenty patients (twenty-one BALs) had possible IPA and ninety-seven patients (one hundred eight BALs) did not fulfill IPA criteria. Sensitivity, specificity, negative predictive value, positive predictive value and diagnostic odds ratios for diagnosing proven and probable IPA using LFD tests of BAL were 80%, 81%, 96%, 44% and 17.6, respectively. Fungal BAL culture exhibited a sensitivity of 50% and a specificity of 85%. LFD tests of BAL showed promising results for IPA diagnosis in ICU patients. Furthermore, the LFD test can be performed easily and provides rapid results. Therefore, it may be a reliable alternative for IPA diagnosis in ICU patients if GM results are not rapidly available. ClinicalTrials.gov NCT02058316. Registered 20 January 2014.


Transport of leucine-enkephalin across the blood-brain barrier in the perfused guinea pig brain.
Transport of [tyrosyl-3,5-3H]enkephalin-(5-L-leucine) [( 3H]Leu-enkephalin) across the blood-brain barrier was studied in the adult guinea pig, by means of vascular perfusion of the head in vivo. The unidirectional transfer constant (Kin) estimated from the multiple-time uptake data for [3H]Leu-enkephalin ranged from 3.62 X 10(-3) to 3.63 X 10(-3) ml min-1 g-1 in the parietal cortex, caudate nucleus, and hippocampus. Transport of [3H]Leu-enkephalin was not inhibited by unlabelled L-tyrosine (the N-terminal amino acid) at a concentration as high as 5 mM, or by the inhibitor of aminopeptidase activity bacitracin (2 mM), suggesting that there was no enzymatic degradation of peptide at the blood-brain barrier. By contrast, 2 mM unlabelled Leu-enkephalin strongly inhibited the unidirectional blood-to-brain transport of [3H]Leu-enkephalin by 74-78% in the parietal cortex, caudate nucleus, and hippocampus. The tetrapeptide tyrosyl-glycyl-glycyl-phenylalanine (without the C-terminal leucine of Leu-enkephalin), at a concentration of 5 mM, caused a moderate inhibition ranging from 15 to 29% in the brain regions studied, whereas the tetrapeptide glycyl-glycyl-phenylalanyl-leucine (without the N-terminal tyrosine) at 5 mM was without effect on Leu-enkephalin transport. Unidirectional brain uptake of Leu-enkephalin was not altered in the presence of naloxone at a concentration as high as 3 mM (1 mg/ml), suggesting that there is no binding of Leu-enkephalin to opioid receptors at the blood-brain barrier. It is concluded that there is a specific transport mechanism for Leu-enkephalin at the blood-brain barrier in the guinea pig.(ABSTRACT TRUNCATED AT 250 WORDS)


The phenomenology of spatial integration: data and models.
A briefly presented visual stimulus followed by darkness seems to persist beyond its physical offset. We are concerned here with the relation between two characteristics of this visible persistence: first, its phenomenological resemblance to the stimulus that spawned it and second, its usefulness as a basis for integrating visual stimuli that are separated in time. We describe two experiments using a task in which two halves of a visual stimulus were presented successively and observers reported how complete the stimulus appeared to be. Stimuli appeared less complete with increases in both the duration of the interval intervening between presentation of the two halves and the duration of the initially presented stimulus half. This data pattern is similar to that obtained in tasks in which spatial integration of two temporally disparate stimuli is necessary for correct responding. On the basis of this similarity, we argue that phenomenological appearance and ability to integrate stimuli over time are two facets of the same perceptual events. We describe a formal model to account for these and other data.


Metabolic Acidosis and Adverse Outcomes and Costs in CKD: An Observational Cohort Study.
Metabolic acidosis is a risk factor for progression of chronic kidney disease (CKD), but little is known about its effect on health care costs and resource utilization. We describe the associations between metabolic acidosis, adverse kidney outcomes, and health care costs in patients with CKD stages G3-G5 and not receiving dialysis. Retrospective cohort study. An integrated claims-clinical data set of US patients with CKD stages G3-G5, with serum bicarbonate values of 12 to <22 mEq/L (metabolic acidosis group) or 22 to 29 mEq/L (normal serum bicarbonate level group). The primary exposure variable was the baseline serum bicarbonate level. The primary clinical outcome was the composite of all-cause mortality, maintenance dialysis, kidney transplant, or a decline in the estimated glomerular filtration rate of ≥40% (DD40). The primary cost outcome was all-cause predicted per-patient per-year cost, assessed over a 2-year outcome period. Logistic and generalized linear regression models, adjusted for key covariates such as age, sex, race, kidney function, comorbidities, and pharmacy insurance coverage, were used to assess serum bicarbonate levels as a predictor of DD40 and health care costs, respectively. 51,558 patients qualified. The metabolic acidosis group experienced higher rates of DD40 (48.3% vs. 16.7%, P < 0.001) and higher all-cause yearly costs ($65,172 vs. $24,681, P < 0.001). Two-year adjusted odds ratio of DD40 per 1-mEq/L increase in serum bicarbonate levels was 0.873 (95% CI, 0.866-0.879); the parameter estimate (±SE) for costs was -0.070 ± 0.0075 (P < 0.001). Possible residual confounding. Patients with CKD and metabolic acidosis had higher costs and rates of adverse kidney outcomes compared with patients with normal serum bicarbonate levels. Each 1-mEq/L increase in serum bicarbonate levels was associated with a 13% decrease in 2-year DD40 events and a 7% decrease in per-patient per-year cost.


Lower and extended dosage of misoprostol for cervical ripening in 1st trimester miscarriage (MISO200): A randomized clinical trial.
To compare the efficacy of priming the uterine cervix before Manual Vaccum Aspiration (MVA) using 200 µg or 400 µg of vaginal misoprostol, inserted a mean time of 6 h before MVA in first trimester miscarriage. Randomized, triple-blind, non-inferiority clinical trial. Patients between 18 and 50 years old, with a diagnosis of miscarriage, were eligible for the study. Patients were allocated to receive either 200 μg or 400 µg of misoprostol before the MVA. The primary outcome was the need to dilate the uterine cervix with mechanical dilators (Hegar dilators). As a secondary outcome, cervical dilatation ≥8 mm before the procedure was considered successful. A difference of <25% was considered as non-inferior. Between December 21, 2016 and October 6, 2019, 269 women were screened. After screening, 105 and 106 women received 200 µg and 400 µg of misoprostol, respectively. Mechanical cervical dilatation was not necessary in 84.8% (95%CI 77% to 90%) and 96.2% (95%CI 91% to 99%), in the 200 µg and 400 µg groups, respectively [difference = 11.5% (95%CI 3.7% to 19.2%). Cervical dilatation of ≥8 mm was 52.4% (95%CI 42.9% to 61.7%) in the 200 µg misoprostol group, while in the 400 µg group was 71.7% (95%CI 62.5% to 79.4%) [difference = 19.3% (95%CI 6.5 to 32.2). After a mean time of 6 h, 200 µg of vaginal misoprostol is not inferior to 400 µg of misoprostol for cervical priming before MVA, in first trimester miscarriage. This non-inferiority was not observed when the ≥8 mm criterion was considered.


Two types of K+ channels in excised patches of somatic membrane of the leech AP neuron.
The patch-clamp technique has been applied to the somatic membrane of the leech AP neurons. Ionic currents from single potassium channels were recorded in inside-out configuration. Two types of channels, sharing close values of conductance in symmetrical K+, were identified as distinct, according to their properties of rectification, Ca2+ sensitivity and voltage dependence. The channels designated as VCI exhibited an outward rectification and their gating was quite independent on changes of patch potential and of [Ca2+]i. The channels designated as VCD showed a linear I-V relationship and their activity was dependent on both the membrane potential and the intracellular [Ca2+].


Artesunate Protects Against Sepsis-Induced Lung Injury Via Heme Oxygenase-1 Modulation.
Artesunate, a derivative of artemisinin, has anti-inflammatory properties and exerts protective roles in sepsis. Heme oxygense-1 (HO-1) inhibits the inflammatory response through reduction of proinflammatory cytokines and leukocyte influx into tissues. The present study investigated the effects of artesunate on HO-1 and septic lung injury. Cecal ligation and puncture (CLP) was employed to induce septic lung injury. Mice pretreated with artesunate (AS) (15 mg/kg) exhibited decreased sepsis-induced mortality and lung injury and alleviated lung pathological changes and neutrophil infiltration. In addition, AS lowered the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the serum and bronchoalveolar lavage fluid (BALF) and inhibited cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase isoform (iNOS) expression and NF-κB activation in lung tissue. In addition, AS enhanced NF-E2-related factor-2 (Nrf2) activation and HO-1 expression and enzymatic activity in lung tissue. However, the protective effects of AS on sepsis-induced lung injury were eliminated by ZnPP IX, an HO-1 competitive inhibitor. Therefore, AS plays protective roles in septic lung injury related to the upregulation of HO-1. These findings suggest an effective and applicable treatment to sepsis-induced lung injury and provide new insights into the molecular mechanisms and actions of AS.


Synthesis and in vitro antimycobacterial activity of novel 3-(1H-pyrrol-1-yl)-2-oxazolidinone analogues of PNU-100480.
Pursuing our search program for new antitubercular drugs we decided to explore the potentiality of oxazolidinone moiety by synthesizing novel 3-(1H-pyrrol-1-yl)-2-oxazolidinone analogues of PNU-100480. The new derivatives were tested against atypical mycobacteria as well as against drug resistant Mycobacterium tuberculosis and some of them exhibited a fairly good activity against Mycobacterium avium complex (MAC).


Fusarium proliferatum, an endophytic fungus from Dysoxylum binectariferum Hook.f, produces rohitukine, a chromane alkaloid possessing anti-cancer activity.
Rohitukine is a chromane alkaloid possessing anti-inflammatory, anti-cancer and immuno-modulatory properties. The compound was first reported from Amoora rohituka (Meliaceae) and later from Dysoxylum binectariferum (Meliaceae) and Schumanniophyton problematicum (Rubiaceae). Flavopiridol, a semi-synthetic derivative of rohitukine is a potent CDK inhibitor and is currently in Phase III clinical trials. In this study, the isolation of an endophytic fungus, Fusarium proliferatum (MTCC 9690) from the inner bark tissue of Dysoxylum binectariferum Hook.f (Meliaceae) is reported. The endophytic fungus produces rohitukine when cultured in shake flasks containing potato dextrose broth. The yield of rohitukine was 186 μg/100 g dry mycelial weight, substantially lower than that produced by the host tissue. The compound from the fungus was authenticated by comparing the LC-HRMS and LC-HRMS/MS spectra with those of the reference standard and that produced by the host plant. Methanolic extract of the fungus was cytotoxic against HCT-116 and MCF-7 human cancer cell lines (IC(50) = 10 μg/ml for both cancer cell lines).


The underappreciated role of monocarbonyl-dicarbonyl interconversion in secondary organic aerosol formation during photochemical oxidation of m-xylene.
Photochemical oxidation (including photolysis and OH-initiated reactions) of aromatic hydrocarbon produces carbonyls, which are involved in the formation of secondary organic aerosols (SOA). However, the mechanism of this process remains incompletely understood. Herein, the monocarbonyl-dicarbonyl interconversion and its role in SOA production were investigated via a series of photochemical oxidation experiments for m-xylene and representative carbonyls. The results showed that SOA mass concentration peaked at 113.5 ± 3.5 μg m-3 after m-xylene oxidation for 60 min and then decreased. Change in the main oxidation products from dicarbonyl (e.g., glyoxal, methylglyoxal) to monocarbonyl (e.g., formaldehyde) was responsible for this decrease. The photolysis of methylglyoxal or glyoxal produced formaldehyde, favoring SOA formation, while photopolymerization of formaldehyde to glyoxal decreased SOA production. The presence of ·OH altered the balance of photolysis interconversion, resulting in greater production of formaldehyde and SOA from glyoxal than methylglyoxal. Both photolysis and OH-initiated transformations of glyoxal to formaldehyde were suppressed by methylglyoxal, while glyoxal accelerated the reaction of ·OH with methylglyoxal to generate products which reversibly converted to glyoxal and methylglyoxal. These interconversion reactions reduced SOA production. The present study provides a new research perspective for the contribution mechanism of carbonyls in SOA formation and the findings are also helpful to efficiently evaluate the atmospheric fate of aromatic hydrocarbons.


Implementation of artificial intelligence and machine learning-based methods in brain-computer interaction.
Brain-computer interfaces are used for direct two-way communication between the human brain and the computer. Brain signals contain valuable information about the mental state and brain activity of the examined subject. However, due to their non-stationarity and susceptibility to various types of interference, their processing, analysis and interpretation are challenging. For these reasons, the research in the field of brain-computer interfaces is focused on the implementation of artificial intelligence, especially in five main areas: calibration, noise suppression, communication, mental condition estimation, and motor imagery. The use of algorithms based on artificial intelligence and machine learning has proven to be very promising in these application domains, especially due to their ability to predict and learn from previous experience. Therefore, their implementation within medical technologies can contribute to more accurate information about the mental state of subjects, alleviate the consequences of serious diseases or improve the quality of life of disabled patients.


[Unmasking effect of trypsin on Sendai virions obtained in KB cell cultures (author's transl)].
The infectivity of virus grown in KB cell cultures can be directly activated by trypsin. Thus the fit conditions for seeding are effected from subculture to subculture if the cell inoculum is pretreated by trypsin.


Antimicrobial activity of plant extract Ankaferd Blood Stopper.
The in vitro antimicrobial activity of Ankaferd Blood Stopper (ABS) was assessed on 102 clinical isolates from both Gram negative and Gram positive bacteria and four standard strains, including MRSA ATCC 43300, MSSA ATCC 25923, P. aeruginosa ATCC 27853 and E. coli ATCC 35218. ABS was significantly active against all bacteria investigated.


Single and dual target inhibitors based on Bcl-2: Promising anti-tumor agents for cancer therapy.
B-cell lymphoma-2 (Bcl-2) proteins family is an essential checkpoint in apoptosis. Extensive evidences suggested that overexpression of anti-apoptotic Bcl-2 proteins can be observed in multiple cancer cell lines and primary tumor biopsy samples, which is an important reason for tumor cells to evade apoptosis and further acquire drug resistance for chemotherapy. Hence, down-regulation of anti-apoptotic Bcl-2 proteins is effective for the treatment of cancers. In view that Bcl-2 inhibitors and some other anti-tumor agents, such as HDAC inhibitors and Mdm2 inhibitors, exert synergy effects in tumor cells, it is pointed out that dual-targeting therapies based on these targets are regarded as rational strategies to enhance the effectiveness of single target agents for cancer treatment. This review briefly introduces the apoptosis, the structure of Bcl-2 family proteins, and focuses on the current status and recent advances of Bcl-2 inhibitors and the corresponding SARs of them. Moreover, we discuss the synergisms between Bcl-2 and other anti-tumor targets, and summarize the current dual-target agents.


From action to abstraction: The sensorimotor grounding of metaphor in Parkinson's disease.
Embodied cognition theories propose that the semantic representations engaged in during language comprehension are partly supported by perceptual and motor systems, via simulation. Activation in modality-specific regions of cortex is associated with the comprehension of literal language that describes the analogous modalities, but studies addressing the grounding of non-literal or figurative language, such as metaphors, have yielded mixed results. Differences in the psycholinguistic characteristics of sentence stimuli across studies have likely contributed to this lack of consensus. Furthermore, previous studies have been largely correlational, whilst patient studies are a critical way of determining if intact sensorimotor function is necessary to understand language drawing on sensorimotor information. We designed a battery of metaphorical and literal sentence stimuli using action and sound words, with an unprecedented level of control over critical psycholinguistic variables, to test hypotheses about the grounding of metaphorical language. In this Registered Report, we assessed the comprehension of these sentences in 41 patients with Parkinson's disease, who were predicted to be disproportionately affected by the action sentences relative to the sound sentences, and compared their performance to that of 39 healthy age-matched controls who were predicted to show no difference in performance due to sensory modality. Using preregistered Bayesian model comparison methods, we found that PD patients' comprehension of literal action sentences was not impaired, while there was some evidence for a slowing of responses to action metaphors. Follow up exploratory analyses suggest that this response time modality effect was driven by one type of metaphor (predicate) and was absent in another (nominal), despite the fact that the action semantics were similar in both syntactic forms. These results suggest that the conditions under which PD patients demonstrate hypothesized embodiment effects are limited. We offer a critical assessment of the PD action language literature and discuss implications for the embodiment debate. In addition, we suggest how future studies could leverage Bayesian statistical methods to provide more convincing evidence for or against embodied cognition effects.


Deletion mutants of protective antigen that inhibit anthrax toxin both in vitro and in vivo.
The anthrax toxin complex is primarily responsible for most of the symptoms of anthrax. This complex is composed of three proteins, anthrax protective antigen, anthrax edema factor, and anthrax lethal factor. The three proteins act in binary combination of protective antigen plus edema factor (edema toxin) and protective antigen plus lethal factor (lethal toxin) that paralyze the host defenses and eventually kill the host. Both edema factor and lethal factor are intracellularly acting proteins that require protective antigen for their delivery into the host cell. In this study, we show that deletion of certain residues of protective antigen results in variants of protective antigen that inhibit the action of anthrax toxin both in vitro and in vivo. These mutants protected mice against both lethal toxin and edema toxin challenge, even when injected at a 1:8 ratio relative to the wild-type protein. Thus, these mutant proteins are promising candidates that may be used to neutralize the action of anthrax toxin.


Perceived Health in Patients with Primary Immune Deficiency.
Perceived health (PH) is a subjective measure of global health of individuals. While many studies have evaluated outcomes in patients with primary immune deficiency (PID), published literature evaluating PH among patients with PID is sparse. We evaluated the results of the largest self-reported survey of patients with PID to determine the factors that may contribute to differences in PH. Data from a National Survey of Patients with Primary Immune Deficiency Diseases conducted by the Immune Deficiency Foundation was studied. Multivariate logistic regression was employed for data analysis. Thirty percent of the patients perceived their health status as excellent or very good (EVG), 31 % as good (G), and 39 % as fair, poor or very poor (P). Older patients were less likely to have EVG-PH compared to G-PH. Ones with college degrees were more likely to have P-PH compared to G-PH, and less likely to have EVG-PH. Patients who were acutely ill and hospitalized in the past 12 months, ones with limited activity, and chronic diseases, were more likely to have P-PH compared to G-PH. Patients with "on demand" access to specialty care and ones on regular IVIG had higher OR of having EVG-PH as opposed to G-PH. Patients cared for mostly by an immunologist were less likely to have P-PH compared to G-PH. Our results emphasize the importance of PH in clinical practice. We suggest that recognizing the factors that drive PH in patients with PID is important for the development of disease prevention and health promotion programs, and delivery of appropriate health and social services to individuals with PID.


N-linked glycosylation of thermostable lipase from Bacillus thermocatenulatus to improve organic solvent stability.
A thermostable lipase from Bacillus thermocatenulatus was glycosylated by forming the consensus sequence (-NXS/T-) for N-linked glycosylation by site-directed mutagenesis. Among the eight BTL2 mutants including the consensus sequence, six BTL2 mutants, A277 N, A290 N, Y200 N, T236 N, T238 N, and P261 N, were glycosylated. Among the six mutants, glycosylated A277 N and T236 N showed higher stability in the presence of 25% (v/v) DMSO (74.3 and 72.8% of initial activity was remained after incubation at 45 °C for 20 h, respectively) than deglycosylated A277 N and T236 N (57.2 and 45.1% of initial activity was remained, respectively). These glycosylated mutants also showed higher remaining activity than wild-type BTL2 (56.0% of the initial activity were remained). Furthermore, the glycosylated mutant T236 N showed longer half-lives in the presence of 25% (v/v) ethylene glycol, DMSO, and DMF (161, 133, and 56.7 h at 45 °C, respectively) than deglycosylated mutant T236 N (107, 91.9, and 42.8 h, respectively). N-linked glycosylation may be a promising approach for preparing enzymes to retain their activity in the presence of organic solvents.


Fluoride retention kinetic and equilibrium studies on layered double hydroxides under ambient conditions: Implications on pond-stream-hot spring-well water remediation.
Fluoride deficiency and toxicity severely affect a large population globally. Hence, a low-cost geosorbent is in demand to overcome fluorosis hazards where in situ retardation is prioritized over pilot-scale waste water treatment. This study reports the fluoride removal potential of MgFe-type layered double hydroxide (HT-LDH) and its calcined form at 500 and 800°C for their usability for treatment of polluted streams, ponds, wells, and hot spring water. Rapid uptake with >33% removal in 24 h was found by the adsorptive method, whereas the co-precipitation process removed >16 mg/L (>83%) in 1 h. The efficiency was further enhanced upon calcination at 500°C with >95% removal up to five times regeneration, unlike that at 800°C. It was demonstrated that multilayer sorption onto heterogeneous surface sites is majorly controlled by surface adsorptive and ion exchange mechanisms. Acidic pH, low aqueous F - , and temperature >25°C favored greater uptake, whereas competitive anions slightly enhanced its potential in the order N O 3 - > S O 4 2 - > P O 4 3 - in adsorptive removal. In the co-precipitation process, competing anions slightly hindered F - retention, whereas high temperature and low aqueous F - led to greater F - retention. No F-bearing solid phases were evidenced upon its retention, except lowering the HT-LDH crystallinity and rearrangement of C O 3 2 - surface functional groups. The fluoride contents of natural water were lowered drastically up to 77% in 60 min upon precipitation of HT-LDH by maintaining alkalinity and a di-/trivalent cationic ratio of 2.0. PRACTITIONER POINTS: F^- uptake is rapid on heterogeneous surface sites with multilayer sorption mechanism Greater F^- removed by coprecipitation technique compared with adsorptive pathway Acidic medium and temperature >25°C favor greater F^- retention NO_3^-+PO_l4^(3-) slightly enhanced F^- uptake by adsorption but lowered in coprecipitation Formation of LDH from natural waters lowered F^- content up to <77.


Integrated Functional Neuroimaging, Monoamine Neurotransmitters, and Behavioral Score on Depressive Tendency in Intensive Care Unit Medical Staffs Induced by Sleep Deprivation After Night Shift Work.
Intensive care unit (ICU) medical staffs undergoing sleep deprivation with perennial night shift work were usually at high risk of depression. However, shift work on depression-related resting-state functional magnetic resonance imaging was still not fully understood. The objective of this study was to explore the effects of sleep deprivation in ICU medical staffs after one night of shift work on brain functional connectivity density (FCD) and Hamilton Depression Rating Scale (HAMD) scores. Also, serum neurotransmitter concentrations of serotonin (5-HT) and norepinephrine (NE) were obtained simultaneously. A total of 21 ICU medical staffs without psychiatric history were recruited. All participants received HAMD score assessment and resting-state functional magnetic resonance imaging scans at two time points: one at rested wakefulness and the other after sleep deprivation (SD) accompanied with one night of shift work. Global FCD, local FCD, and long-range FCD (lrFCD) were used to evaluate spontaneous brain activity in the whole brain. In the meantime, peripheral blood samples were collected for measurement of serum 5-HT and NE levels. All these data were acquired between 7:00 and 8:00 am to limit the influence of biological rhythms. The correlations between the FCD values and HAMD scores and serum levels of neurotransmitters were analyzed concurrently. Functional connectivity density mapping manifested that global FCD was decreased in the right medial frontal gyrus and the anterior cingulate gyrus, whereas lrFCD was decreased mainly in the right medial frontal gyrus. Most of these brain areas with FCD differences were components of the default mode network and overlapped with the medial prefrontal cortex. The lrFCD in the medial frontal gyrus showed a negative correlation with HAMD scores after SD. Compared with rested wakefulness, serum levels of 5-HT and NE decreased significantly, whereas HAMD scores were higher after SD within subjects. Our study suggested that sleep deprivation after night shift work can induce depressive tendency in ICU medical staffs, which might be related to alterative medial prefrontal cortex, raised HAMD scores, and varying monoamine neurotransmitters.


Does a vigorous feeding style influence early development of adiposity?
A prospective study of a cohort of healthy infants observed from birth to 2 years of age was carried out to investigate factors influencing the development of early adiposity. Infant suckling was measured in the laboratory twice during the first month of life. Multiple regression analyses revealed that parental educational level and a measure of feeding behavior, the interval between bursts of suckling, accounted for 18% of the variance in triceps skinfold measures at 1 year of age. A lower level of education and shorter interburst interval were associated with increased adiposity. Two feeding variables, pressure of suckling and the number of reported feeds per day, accounted for 21% of the variance in skinfold thickness at 2 years of age. Fewer, but larger, feeds and a higher sucking pressure were associated with a greater degree of adiposity. It seems that a vigorous infant feeding style, consisting of sucking more rapidly, at higher pressure, with a longer suck and burst duration, and a shorter interval between bursts of sucking, is associated with higher caloric intake and greater adiposity. The early development of this feeding style suggests that it may be a genetically endowed behavior. Breast-feeding protected against early adiposity only to the age of 6 months in this cohort of infants.


Influence of statins on postoperative wound complications after inguinal or ventral herniorrhaphy.
The lipid-lowering agents, statins, are the most commonly prescribed class of drugs in the western world. Because of their widespread use, many patients undergo surgical procedures while on statins. Statins, in addition to cholesterol-lowering effects, also have anticoagulant, immunosuppressive, and antiproliferative properties that may affect the risk of local wound complications. This study investigated the relationship between statins and postoperative wound complications in a large cohort of patients undergoing inguinal or ventral hernia repair. Data mining was performed in the Veterans Integrated Service Network (VISN)16 Data Warehouse. This database contains clinical and demographic information about all veterans cared for at the ten VA Medical Centers that comprise the South Central VA Healthcare Network in the mid-south region of the US. Aggregate data (age, body mass index, smoking history, gender, race, history of diabetes, statin use, and postoperative wound complications) were obtained for all patients who underwent inguinal or ventral hernia repair during the period October 1, 1996-November 30, 2004. During the period of the query, 10,782 patients (10,676 male, 106 female), 1,242 (11.5%) of whom received statins, underwent herniorrhaphy. Statin use did not affect the risk of wound infection or delayed wound healing. Statin use was, however, associated with an increased rate of local postoperative bleeding complications (P=0.01). When the type of hernia, age, smoking, diabetes, and body mass index were included in a multivariate analysis, statins remained borderline significant as an independent predictor of wound hematoma/postoperative bleeding (P=0.04), odds ratio 1.6 (95% CI 1.03-2.44). Patients who undergo inguinal herniorrhaphy while on statins have an increased risk of postoperative wound hematoma/hemorrhage. Focus on additional factors that may affect the propensity to postoperative bleeding and on meticulous intraoperative hemostasis are particularly important in such patients.


Response modalities and the cognitive architecture underlying action control: Intra-modal trumps cross-modal action coordination.
Performing two actions at the same time usually hampers performance. Previous studies have demonstrated a strong impact of the particular effector systems on performance in multiple action control situations. However, an open question is whether performance is generally better or worse in situations in which two actions within the same effector system are coordinated (intra-modal actions: e.g., two pedal or two manual actions) compared to situations requiring two different effector systems (cross-modal actions: e.g., a manual combined with a vocal action). Performance differences can be predicated, among others, in the light of encapsulation accounts. Encapsulation of modules on the output side of processing would suggest that actions in two different modules can be triggered simultaneously without significant interference between the actions. Thus, cross-modal actions should lead to better performance compared to intra-modal actions. We investigated this issue in two basic experiments, in which participants responded to a single stimulus (thereby maximizing control over input and central processing stages) with one or two either intra-modal or cross-modal responses (manual-manual vs. manual-oculomotor/manual-vocal in Experiment 1/2, respectively). The results represent clear evidence for a performance advantage of intra-modal over cross-modal action control across both effector system combinations and independent of the particular spatial compatibility relation between responses. The results suggest performance benefits by taking advantage of integrated, holistic representations of intra-modal action compounds.


Effect of adrenergic beta receptor blockade on ethanol elimination and on ethanol-induced changes in carbohydrate and lipid metabolism in man.
The effect of adrenergic beta receptor blockade on the elimination rate of ethanol was studied in seven healthy young men. The studies were performed before and after 14 days of propranolol 240 mg/day: the ethanol was given per-orally--0.8 mg/kg b.w. The blood concentration of ethanol, glucose, lactate and glycerol, and the plasma concentration of free fatty acids and triglycerides were followed in samples from the superior vena cava taken every 20 min for four hours. The splanchnic hepatic blood flow was estimated with a single i.v. injection of indocyanine green. The absorption rate, absorption fraction and elimination rate of ethanol were not changed by propranolol. The splanchnic hepatic blood flow was significantly reduced (mean 19 per cent) during beta receptor blockade. The ethanol-induced change in the concentration of glucose, lactate and free fatty acids was affected by propranolol, the time-concentration curves for glucose and lactate being significantly elevated and that for free fatty acids being significantly reduced. The time-concentration curves for glycerol and triglycerides did not differ in the two studies.


Breast MRI biopsy cancellation due to lesion nonvisualization.
It is a clinical dilemma when a finding reported as suspicious on a breast MRI is not visualized at the time of a scheduled MRI-guided breast biopsy. We retrospectively reviewed all canceled MRI-guided biopsies at our institution between 6/1/2009 and 9/20/2019 and found a cancellation rate of 6.9% (72/1051). In one case, a mastectomy was performed after the canceled biopsy revealing a focus of DCIS in the same quadrant as the original finding (malignancy rate 2.1%). Our results support the current practice of 6-month follow-up MRI recommendation after a canceled MRI-guided biopsy for lesion nonvisualization.


Enhancing bioactivity, physicochemical, and pharmacokinetic properties of a nano-sized, anti-VEGFR2 Adnectin, through PASylation technology.
The crucial role of VEGF receptor 2 (VEGFR2) signaling in the angiogenesis and metastasis of solid tumors has prompted the development of inhibitors with minimal bystander effects. Recently, Adnectin C has attracted attention for cancer treatment. To overcome the problematic properties of Adnectin, a novel form of Adnectin C has been designed by its fusion to a biodegradable polymeric peptide containing Pro/Ala/Ser (PAS) repetitive residues. E. coli-expressed recombinant fused and unfused proteins were compared in terms of bioactivity, physicochemical, and pharmacokinetic properties using standard methods. Dynamic light scattering (DLS) analysis of PASylated adnectin C revealed an approximate 2-fold increase in particle size with a slight change in the net charge. Additionally, fusion of the PAS sequence improved its stability against the growth of thermo-induced aggregated forms. The high receptor-binding and improved binding kinetic parameters of PASylated Adnectin C was confirmed by ELISA and surface plasmon resonance assays, respectively. Pharmacokinetic studies showed a noticeable increase in the terminal half-life of Adnectin C-PAS#1(200) by a factor of 4.57 after single dose by intravenous injection into female BALB/c mice. The results suggest that PASylation could offer a superior delivery strategy for developing Adnectin-derived drugs with improved patient compliance.


High-throughput printing of combinatorial materials from aerosols.
The development of new materials and their compositional and microstructural optimization are essential in regard to next-generation technologies such as clean energy and environmental sustainability. However, materials discovery and optimization have been a frustratingly slow process. The Edisonian trial-and-error process is time consuming and resource inefficient, particularly when contrasted with vast materials design spaces1. Whereas traditional combinatorial deposition methods can generate material libraries2,3, these suffer from limited material options and inability to leverage major breakthroughs in nanomaterial synthesis. Here we report a high-throughput combinatorial printing method capable of fabricating materials with compositional gradients at microscale spatial resolution. In situ mixing and printing in the aerosol phase allows instantaneous tuning of the mixing ratio of a broad range of materials on the fly, which is an important feature unobtainable in conventional multimaterials printing using feedstocks in liquid-liquid or solid-solid phases4-6. We demonstrate a variety of high-throughput printing strategies and applications in combinatorial doping, functional grading and chemical reaction, enabling materials exploration of doped chalcogenides and compositionally graded materials with gradient properties. The ability to combine the top-down design freedom of additive manufacturing with bottom-up control over local material compositions promises the development of compositionally complex materials inaccessible via conventional manufacturing approaches.


Multipotent antioxidants: from screening to design.
Free-radicals play an important role in the pathogenesis of many diseases, accounting for continuing interest in the identification and development of novel antioxidants that prevent radical-induced damage. To develop more-powerful weapons that address complex diseases in which free-radicals might be significant, but not exclusive drivers, antioxidants that also have other pharmacological effects are desired. To obtain multipotent antioxidants, one can screen drug collections and/or natural-product libraries, or couple an antioxidant group with other pharmacophores. It is interesting to note that most rationally designed multifunctional antioxidants are structurally different from their naturally occurring counterparts. Therefore, nature's design strategy provides important clues as to how the design concept for multipotent antioxidants can be improved.


Light microscopic histology of supraspinatus tendon ruptures.
We analysed the morphological features of the human surgical specimens of supraspinatus tendon from patients with rotator cuff tears. Tendon samples were harvested from 31 subjects (21 men and 10 women; mean age 51 years, range 38-64) who underwent arthroscopic repair of a rotator cuff tear, and from five male patients who died of cardiovascular events (mean age, 69.6 years). Histological examination was performed using Haematoxylin and Eosin, Masson's Trichrome and Van Gieson's connective tissue stain. The specimens were examined twice by the same examiner under white light and polarized light microscopy. Particular effort was made to assess any evidence of the changes associated with tendinopathy. Within each specific category of tendon abnormalities, the chi-square test showed significant differences between the control and ruptured tendons (P < 0.05). Using the kappa statistics, the agreement between the two readings ranged from 0.57 to 0.84. We found thinning and disorientation of collagen fibres and chondroid metaplasia to be more pronounced on the articular side of the specimens from patients with rotator cuff tear (P < 0.05). The present study provides a description of the histological architecture of human surgical specimens of normal supraspinatus tendon from patients with rotator cuff tears and demonstrates more frequent tendon changes on the articular side of the rotator cuff.


Basic immunologic principles underlying vaccination procedures.
Mass immunization programs and routine immunization of infants and children have significantly reduced the incidence of several serious diseases. This article describes the immunologic principles that guide the use of vaccines and explains the mechanisms of protective immunity, adverse side reactions associated with immunization, and new molecular approaches for producing vaccines.


New guidelines on ethical considerations in HIV preventive vaccine research.
In March 2000, UNAIDS released annotated guidance points on the ethical considerations of HIV vaccine research (the "Guidance Document"). The guidance points, reproduced at the end of the article, are the product of two years' consultation and debate around the world, yet key questions remain unsettled. This article reviews the process, the outcomes, and the challenges that remain.


Encoding of rat working memory by power of multi-channel local field potentials via sparse non-negative matrix factorization.
Working memory plays an important role in human cognition. This study investigated how working memory was encoded by the power of multi-channel local field potentials (LFPs) based on sparse nonnegative matrix factorization (SNMF). SNMF was used to extract features from LFPs recorded from the prefrontal cortex of four Sprague-Dawley rats during a memory task in a Y maze, with 10 trials for each rat. Then the power-increased LFP components were selected as working memory-related features and the other components were removed. After that, the inverse operation of SNMF was used to study the encoding of working memory in the time-frequency domain. We demonstrated that theta and gamma power increased significantly during the working memory task. The results suggested that postsynaptic activity was simulated well by the sparse activity model. The theta and gamma bands were meaningful for encoding working memory.


Expression of transforming growth factor-β1 (TGF-β1) and E-cadherin in glioma.
Gliomas are the most common tumors in the central nervous system. This study aims to investigate the expressions of transforming growth factor-β1 (TGF-β1) and epithelial cadherin (E-cadherin) in human brain glioma tissues and the correlation between their expressions with clinical pathological features and clinical significance. The expressions of mRNA or protein of TGF-β1 and E-cadherin were detected by using reverse transcription polymerase chain reaction (RT-PCR) and Western blot in these tissues. Positive rates of the expression of TGF-β1 and E-cadherin were 62.9 % and 38.6 % in brain tissues of glioma patients. The expressions of mRNA or protein for TGF-β1 in brain glioma tissues were significantly higher than that in normal brain tissues (p < 0.01). Their expressions in well-differentiated glioma brain tissues were lower than those in poorly differentiated glioma brain tissues (p < 0.01). A negative correlation was found between TGF-β1 and E-cadherin in brain glioma tissues (r = -0.302, p < 0.011). The cell numbers of C6 glioma through Transwell chambers were decreased significantly (p < 0.01), and the expression of TGF-β1 was downregulated significantly (p < 0.01). However, the expression of E-cadherin was upregulated significantly (p < 0.01) after transfecting TGF-β1 siRNA. The expression changes of TGF-β1 and E-cadherin may be related to the emergence and the development of glioma. Downregulation of TGF-β1 expression using siRNA can decrease the invasive capability of C6 glioma cells.


Rearrangement of the MLL gene and a region proximal to the RARalpha gene in a case of acute myelocytic leukemia M5 with a t(11;17)(q23;q21).
A case of acute myelocytic leukemia (AML) M5 subtype (French-American-British classification), in a 13-year-old girl showed the abnormal karyotype 46,XX,t(11;17)(q23;q21) in all bone marrow cells analyzed. Rearrangements involving 11q23 are frequent in cases of AML M5 and often involve the MLL gene. Nevertheless, t(11;17)(q23;q21) is very rare in this type of leukemia. In acute promyelocytic leukemia, the RARalpha gene, located at 17q21, is involved in almost all cases. Fluorescence in situ hybridization studies revealed a deletion of the C-terminal part of the MLL gene and a translocation of the RARalpha gene on the derivative chromosome 11, proximal to the remaining part of the MLL gene. However, hybridization with the LSI RARA dual color break-apart rearrangement probe showed that the RARalpha gene was not rearranged in this translocation. This is the first study reporting a t(11;17)(q23;q21) with a deletion distal to MLL gene exon 6 in a case of AML M5. Furthermore, this is the second study that strongly suggests the implication of a gene proximal and close to the RARalpha locus in a case of AML M5. According to these results, the discovery of new fusion partner genes of MLL and the precise characterization of t(11;17) will be important for the understanding of neoplastic cell differentiation in AML M5.


Some properties of mitochondrial glutathione.
1. The presence of GSH in rat liver mitochondria is confirmed. GSH diffuses from the suspended particles in the presence of phosphate but respiratory inhibitors inhibit the diffusion. 2. GSH is oxidised in situ by oxidants including t-butyl hydroperoxide. The products formed include GSSG and GSS-protein mixed disulphides. The oxidation occurs at lower oxidant concentrations if phosphate or oxaloacetate are also present. Respiratory inhibitors abolish their effect. 3. With phosphate, the GSSG produced is found chiefly outside the mitochondria whereas with oxaloacetate, it is found chiefly inside. 4. The GSSG formed by the oxidation is reduced by Krebs-cycle acids with the exception of the ketoacids. Exogenous GSSG is reduced by these substrates only after lysis. Intact particles, however, catalyse the reduction of GSSG by either NADH2 or NADPH2.


[Efferent activity in the phrenic nerve during the startle reflex in chloralose-anesthetized cats].
Reflex activity in the phrenic nerve was studied in chloralose anesthetized cats during development of somatic startle reflexes in limb and lower intercostal nerves. It was shown that the main component of this activity during low-threshold reflexes evoked by acoustic, tactile and low-threshold somatic afferent stimulation was depression of phrenic inspiratory activity. The following reflex discharges were prevalent components of phrenic responses to high-threshold afferent stimulation: early, propriospinal (intercostal-to-phrenic reflex) and late, suprasegmental ones. The latter were of two types: inspiratory (observed mainly during inspiration in about 75% of experiments) and expiratory (observed during expiration in 25% of experiments) which could be classified as "phrenic startle reflexes". Modulation of all responses during the respiratory cycle was described. Structural characteristics of reflex responses evoked in the phrenic nerve by stimulation of various respiratory and nonrespiratory bulbar sites as well as their respiratory modulation have been analyzed. Organization of possible neurophysiological mechanisms of phrenic responses during startle reflexes is discussed.


A smooth test in proportional hazard survival models using local partial likelihood fitting.
Proportional hazard models for survival data, even though popular and numerically handy, suffer from the restrictive assumption that covariate effects are constant over survival time. A number of tests have been proposed to check this assumption. This paper contributes to this area by employing local estimates allowing to fit hazard models in which covariate effects are smoothly varying with time. A formal test is derived to check for proportional hazards against smooth hazards as alternative. The test proves to possess omnibus power in that it is powerful against arbitrary but smooth alternatives. Comparative simulations and two data examples accompany the presentation. Extensions are provided to multiple covariate settings, where the focus of interest is to decide which of the covariate effects vary with time.


Enteral nutrition improves the prognosis and immune nutritional status of patients in the cardiothoracic surgery recovery unit: A propensity score-matched analysis.
It remains unclear whether enteral nutrition (EN) has an impact on prognosis and immune nutritional status for patients in the cardiothoracic surgery recovery unit (CSRU). We hypothesized that only patients with specific characteristics would benefit from EN and aimed to distinguish that specific population by examining a large database. Propensity-score matching (PSM) was used to eliminate the baseline imbalances between the EN and non-EN groups. The modified nutritional risk in the critically ill (mNUTRIC) score was used to assess the severity of patients' disease as well as their nutritional risk. Kaplan-Meier curves were used to compare the differences in 28- and 1000-day overall survival in the two groups after PSM. Generalized additive mixed models (GAMMs) were used to show dynamic changes in neutrophil-to-lymphocyte ratios (NLRs) and platelet-to-lymphocyte ratios (PLRs) in the two groups. Subgroup analysis was used to identify the specific population that could benefit from EN. A total of 1823 patients (EN group, n = 395; non-EN group, n = 1428) were enrolled; after PSM, 320 pairs of patients remained. EN was found to reduce the 28-day mortality rate (adjusted hazard ratio [HR] = .56; 95% CI, .35-.91; P = .019) of patients, whereas it had no effect on 1000-day survival (adjusted HR = .97; 95% CI, .75-1.25; P = .797). Subgroup analyses indicated that patients with mNUTRIC equal to or greater than 4, body mass index (BMI) 25-30 kg/m2, and vasopressor support were more likely to benefit from EN. NLR and PLR in the EN group decreased progressively over time compared with the non-EN group, suggesting that EN might improve clinical outcomes by regulating immune and inflammatory responses. EN may improve the prognosis and immune nutritional status of patients in the CSRU. Patients who might benefit should be actively treated with EN.


The investigation of Helicobacter pylori in the dental biofilm and saliva samples of children with dyspeptic complaints.
The oral cavity can be an extra-gastric reservoir for Helicobacter pylori (H.pylori). This can play a role in the pathogenesis of halitosis, glossitis, recurrent aphthous stomatitis, and dental caries. The present study was conducted to detect the presence of H.pylori within the dental biofilm and in saliva samples collected from children suffering from dyspepsia and children without any gastrointestinal complaints. Associations with gastric infection, halitosis, and some oral parameters were also evaluated. Seventy children (aged between 5-16) with dyspepsia were selected for the study group and control group composed of 30 healthy children without dyspepsia were also included in the study. After detailed oral and clinical examinations for oral parameters, saliva, and supragingival dental biofilm samples were collected for 16S rRNA and 23S rRNA genes detection by real-time polymerase chain reaction (RT-PCR). The presence of gastric H.pylori was evaluated in endoscopic biopsy specimens histopathologically. Halitosis was evaluated by benzoyl-DL-arginine-naphthylamid (BANA) test. Salivary S.mutans and Lactobacilli sp. counts were also carried out by commercial kits. H.pylori was histopathologically detected amongst 83% of the children with the dyspeptic condition. The detection rate of this bacteria in dental biofilm and saliva samples and halitosis were found relatively higher in the dyspeptic children rather than the control group (p < 0.01). Halitosis was not significantly different between dyspeptic children and those detected with H.pylori (p > 0.05). In the gastric H.pylori positive group with dyspepsia, DMFT/S and dmft/s numbers and plaque indices were found higher than the control group (p < 0.01). Only plaque indices of gastric H.pylori negative group with dyspepsia were found higher than the control group (p < 0.01). S.mutans and Lactobacilli sp. counts were not significantly different between gastric H.pylori positive and negative groups (p > 0.05). Comparing to those with negative for both genes, in children whose dental biofilm and saliva samples were positive for both 16S rRNA and 23S rRNA genes, significantly higher results for halitosis, and DMFS numbers and significantly lower results for dmfs numbers and pH values were found (p < 0.01). Helicobacter pylori can occur in the oral cavity aside and independently from the stomach. However, the high number of bacteria in the oral cavities of children with gastric H.pylori, an association between the presence of H.pylori and halitosis, DMFS, and pH were found.


Anastasis: cell recovery mechanisms and potential role in cancer.
Balanced cell death and survival are among the most important cell development and homeostasis pathways that can play a critical role in the onset or progress of malignancy steps. Anastasis is a natural cell recovery pathway that rescues cells after removing the apoptosis-inducing agent or brink of death. The cells recuperate and recover to an active and stable state. So far, minimal knowledge is available about the molecular mechanisms of anastasis. Still, several involved pathways have been explained: recovery through mitochondrial outer membrane permeabilization, caspase cascade arrest, repairing DNA damage, apoptotic bodies formation, and phosphatidylserine. Anastasis can facilitate the survival of damaged or tumor cells, promote malignancy, and increase drug resistance and metastasis. Here, we noted recently known mechanisms of the anastasis process and underlying molecular mechanisms. Additionally, we summarize the consequences of anastatic mechanisms in the initiation and progress of malignancy, cancer cell metastasis, and drug resistance. Video Abstract.


Identification of Cytokinin Biosynthesis Genes in Arabidopsis: A Breakthrough for Understanding the Metabolic Pathway and the Regulation in Higher Plants.
The primary biosynthetic reaction of cytokinin is thought to be the isopentenylation of an adenine nucleotide such as AMP with dimethylallylpyrophosphate. For many years, the nature of the enzyme catalyzing this reaction in higher plants had not been identified despite the physiological importance of these compounds. However, the completion of the genomic sequence of Arabidopsis thaliana, a model plant for genetic research, has provided us with new opportunities to solve these problems. Recent studies have revealed the cytokinin biosynthesis enzyme is encoded by a small multigene family that is structurally related to both bacterial adenylate isopentenyltransferase and tRNA isopentenyltransferase. Interestingly, biochemical studies of some of the gene products indicate that ADP and ATP, rather than AMP, are preferentially used as substrates for this biosynthetic reaction. These findings require reconsideration of the currently accepted cytokinin biosynthetic pathway. In addition, there is an increasing body of evidence suggesting that the expression of these cytokinin synthesis genes is affected by the availability of nutrients.


[Establishment of 2-dE map of human low differentiation nasopharyngeal carcinoma cell line CNE-2 proteome].
To establish a two-dimensional polyacrylamide gel electrophoresis (2-DE) map of human low differentiation nasopharyngeal carcinoma (NPC) cell line CNE-2 proteome. Immobilized pH gradient 2-DE was applied to separate the total proteins of CNE-2 cells, matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS) and database searching were used to indentify proteins. A good 2-DE pattern with high resolution and reproducibility was obtained. Seventy-eight protein spots were incised from sliver staining gel and digested in gel by trypisin. Of them 77 maps of peptide mass fingerprints (PMF) were obtained and 48 proteins were identified. A reference 2-DE map of CNE-2 proteome has been established and the data coupled with similar proteome analysis of other NPC cell lines will expand the human nasopharyngeal carcinoma proteome database.


Freshwater salinization reduces vertical movement rate and abundance of Daphnia: Interactions with predatory stress.
Contaminants in human-dominated landscapes are changing ecological interactions. The global increase in freshwater salinity is likely to change predator-prey interactions due to the potential interactive effects between predatory stress and salt stress. We conducted two experiments to assess the interactions between the non-consumptive effects of predation and elevated salinity on the abundance and vertical movement rate of a common lake zooplankton species (Daphnia mendotae). Our results revealed an antagonism rather than a synergism between predatory stress and salinity on zooplankton abundance. Elevated salinity and predator cues triggered a >50% reduction in abundance at salt concentrations of 230 and 860 mg Cl-/L, two thresholds designed to protect freshwater organisms from chronic and acute effects due to salt pollution. We found a masking effect between salinity and predation on vertical movement rate of zooplankton. Elevated salinity reduced zooplankton vertical movement rate by 22-47%. A longer exposure history only magnified the reduction in vertical movement rate when compared to naïve individuals (no prior salinity exposure). Downward movement rate under the influence of predatory stress in elevated salinity was similar to the control, which may enhance the energetic costs of predator avoidance in salinized ecosystems. Our results suggest antagonistic and masking effects between elevated salinity and predatory stress will have consequences for fish-zooplankton interactions in salinized lakes. Elevated salinity could impose additional energetic constraints on zooplankton predator avoidance behaviors and vertical migration, which may reduce zooplankton population size and community interactions supporting the functioning of lake ecosystems.


Association of polycyclic aromatic hydrocarbons and asthma among children 6-19 years: NHANES 2001-2008 and NHANES 2011-2012.
Polycyclic aromatic hydrocarbons (PAHs) are a group of chemicals that can induce oxidative stress and related cytotoxicity. Whether environmental exposure of PAHs has effects on asthma in the general population is still unclear. This study investigated the association of urinary PAHs with asthma in U.S. children. 15 447 children who participated in the US National Health and Nutrition Examination Survey 2001-2008 and 2011-2012 were studied. Ten urinary PAHs were analyzed for their association with asthma or asthma related symptoms. Multivariate logistic regression was applied to assess associations between urinary PAHs and asthma adjusted for age, gender, ethnicity, body mass index and the poverty income ratio. When stratified by age and sex, we found a remarkable association between urinary 2-phenanthrene and diagnosed asthma in boys (OR: 2.353, 95% CI: 1.156-4.792; P = 0.021) aged 13-19 years old. Positive association was observed between ever wheeze and 4-phenanthrene among girls aged 13-19 years (OR: 4.086, 95% CI: 1.326-12.584, P = 0.043). Moreover, an overall positive association between 1-pyrene and diagnosed asthma was observed. However, no association existed between levels of 1-napthol, 2-napthol, 3-fluorene, 2-fluorene, 3-phenanthrene, 1-phenanthrene or 9-fluorene with asthma or asthma symptom in this population. This data provide epidemiological evidences that urinary PAHs are positively associated with asthma in children aged 6-19 years. However, the underlying mechanisms still need further exploration.


A family of main-chain polymeric Lewis acids: synthesis and fluorescent sensing properties of boron-modified polythiophenes.
A new family of main-chain organoborane polymeric Lewis acids (PTh-BAr) that contain Lewis acidic boron groups embedded into a polythiophene backbone has been prepared under mild conditions through tin-boron exchange reaction. When phenyl and pentafluorophenyl groups are attached to boron, blue and green luminescence is observed, respectively, while the attachment of ferrocenyl substituents leads to a characteristic red color. The incorporation of readily accessible highly Lewis acidic groups into the conjugated polymer backbone provides an opportunity for sensing of Lewis basic substrates. For instance, treatment of the polymer containing phenyl substituents on boron with pyridine leads to efficient quenching of the fluorescence, while the polymer containing ferrocenyl groups changes color from dark red to light orange.


Short-term effects of glucocorticoid therapy on biochemical markers of bone metabolism in Japanese patients: a prospective study.
Glucocorticoid (GC) therapy induces rapid bone loss, but the early changes in calcium and bone metabolism in patients treated with GC have not been clarified. To investigate the changes in calcium and bone metabolism during the early stage of GC therapy, we analyzed various biochemical markers of bone metabolism. The serum levels of calcium (Ca), phosphorus, parathyroid hormone (PTH), osteocalcin (OC), bone alkaline phosphatase (BAP), and type I collagen cross-linked N-telopeptide (NTx), as well as the urinary levels of Ca, creatinine, and NTx, were measured on days 0, 3, 7, and 28 of GC therapy. The subjects were divided into the following four groups: 9 patients receiving pulse therapy (P), 18 patients receiving prednisolone (PSL) at doses > or =40 mg/day (H), 9 patients receiving PSL at doses > or =20 mg/day (M), and 11 patients receiving PSL at doses < or =10 mg/day (S). The serum OC level showed a marked decrease on day 3 of GC therapy (-41.2% +/- 6.6%, P < 0.01), while the BAP level decreased gradually. Both serum and urinary NTx levels significantly increased on day 7 of GC therapy (9.9% +/- 4.5%, P < 0.05, and 42.2% +/- 10.6%, P < 0.01, respectively). Urinary Ca excretion was increased on day 3 of GC therapy and continued to increase until 4 weeks, while intact PTH showed an increase on day 3 and then remained constant until 4 weeks. In groups P and H, there were significant early changes in OC, BAP, NTx, and intact PTH levels, as well as urinary Ca excretion. Even a PSL dose of <10 mg/day caused a decrease in the serum OC level. In conclusion, the biochemical markers of Ca and bone metabolism showed different kinetics depending on the dose of GC, and it is important for patients on high-dose GC therapy to receive prophylaxis for bone loss from the start of GC treatment.


Overexpression of HOXA10 is associated with unfavorable prognosis of acute myeloid leukemia.
HOXA family genes were crucial transcription factors involving cell proliferation and apoptosis. While few studies have focused on HOXA10 in AML. We aimed to investigate the prognostic significance of HOXA10. We downloaded datasets from GEO and BeatAML database, to compare HOXA expression level between AML patients and controls. Kaplan-Meier curves were used to estimate the impact of HOXA10 expression on AML survival. The differentially expressed genes, miRNAs, lncRNAs and methylated regions between HOXA10-high and -low groups were obtained using R (version 3.6.0). Accordingly, the gene set enrichment analysis (GSEA) was accomplished using MSigDB database. Moreover, the regulatory TFs/microRNAs/lncRNAs of HOXA10 were identified. A LASSO-Cox model fitted OS to clinical and HOXA10-associated genetic variables by glmnet package. HOXA10 was overexpressed in AML patients than that in controls. The HOXA10-high group is significantly associated with shorter OS and DFS. A total of 1219 DEGs, 131 DEmiRs, 282 DElncRs were identified to be associated with HOXA10. GSEA revealed that 12 suppressed and 3 activated pathways in HOXA10-high group. Furthermore, the integrated regulatory network targeting HOXA10 was established. The LASSO-Cox model fitted OS to AML-survival risk scores, which included age, race, molecular risk, expression of IKZF2/LINC00649/LINC00839/FENDRR and has-miR-424-5p. The time dependent ROC indicated a satisfying AUC (1-year AUC 0.839, 3-year AUC 0.871 and 5-year AUC 0.813). Our study identified HOXA10 overexpression as an adverse prognostic factor for AML. The LASSO-COX regression analysis revealed novel prediction model of OS with superior diagnostic utility.


Mortality Reduction Associated With β-Adrenoceptor Inhibition in Chronic Heart Failure Is Greater in Patients With Diabetes.
Diabetes increases mortality in patients with chronic heart failure (CHF) and reduced left ventricular ejection fraction. Studies have questioned the safety of β-adrenoceptor blockers (β-blockers) in some patients with diabetes and reduced left ventricular ejection fraction. We examined whether β-blockers and ACE inhibitors (ACEIs) are associated with differential effects on mortality in CHF patients with and without diabetes. We conducted a prospective cohort study of 1,797 patients with CHF recruited between 2006 and 2014, with mean follow-up of 4 years. β-Blocker dose was expressed as the equivalent dose of bisoprolol (mg/day) and ACEI dose as the equivalent dose of ramipril (mg/day). Cox regression analysis was used to examine the interaction between diabetes and drug dose on all-cause mortality. Patients with diabetes were prescribed larger doses of β-blockers and ACEIs than were patients without diabetes. Increasing β-blocker dose was associated with lower mortality in patients with diabetes (8.9% per mg/day; 95% CI 5-12.6) and without diabetes (3.5% per mg/day; 95% CI 0.7-6.3), although the effect was larger in people with diabetes (interaction P = 0.027). Increasing ACEI dose was associated with lower mortality in patients with diabetes (5.9% per mg/day; 95% CI 2.5-9.2) and without diabetes (5.1% per mg/day; 95% CI 2.6-7.6), with similar effect size in these groups (interaction P = 0.76). Increasing β-blocker dose is associated with a greater prognostic advantage in CHF patients with diabetes than in CHF patients without diabetes.


Can Intraoperative Processed EEG Predict Postoperative Cognitive Dysfunction in the Elderly?
Postoperative cognitive dysfunction (POCD) is a serious and costly complication of the elderly; even mild impairment has the potential to impact overall well being. Anesthesiologists continue to search for ways to manipulate intraoperative technique to optimize postoperative cognition in the elderly. Depth of anesthesia during surgery is an area that has shown some promise for short-term outcomes, such as delirium. However, excessive depth has both positive and negative associations with longer-term POCD. We hypothesize that this uncertainty is due to the inability of median depth to capture the amount of burst suppression or electrical silence. In this study, our purpose was to identify the intraoperative processed EEG parameters that are most closely correlated with POCD. To explore the association of several processed EEG parameters with POCD, we performed a retrospective analysis of a cohort of 105 patients aged >68 years scheduled for major surgery under general anesthesia. Intraoperative medications, hemodynamics, processed EEG and cerebral oxygen saturation were recorded. All patients had a cognitive battery before surgery and repeated at 3 months afterward. One hundred and five patients enrolled and 77 (73.3%) patients completed the 3-month cognitive testing. The incidence of POCD was 27%; the median Bispectral Index value for patients who developed POCD was similar to patients who did not (46 vs 42 minutes). However, patients who developed POCD spent less time with Bispectral Index <45 minutes (82.8 vs 122.5 minutes, P = 0.01) and burst suppression (35 vs 96 minutes, P = 0.04). Hypotension, cerebral desaturation, and use of total intravenous anesthesia were similar between patients with and without POCD. Patients who developed POCD spent less time in EEG burst suppression and less time in deep states. Burst suppression may be protective for POCD. Further work is needed to definitively identify the role of burst suppression in the context of other patient and intraoperative variables to prevent POCD.


Mass isolation of cell surface membrane fragments from pigeon heart.
Cell surface membrane fragments were isolated and purified by successive rate zonal and isopycnic centrifugation of calcium oxalate-loaded pigeon heart microsomes in sucrose density gradients. The most highly purified cell membrane fraction sediments at a buoyant density of 1.105 g/ml. Some of the membrane pieces are present as open fragments and leaky vesicles, while others form tightly sealed vesicles of both inside-in and inside-out membrane orientation. The pigeon heart cell membrane preparation exhibits high (Na+ + K+ + Mg2+)-ATPase and adenylate cyclase activities. Additional activity of these enzymes is uncovered by sodium dodecyl sulfate and alamethicin, respectively. Electron microscopic inspection of the cell surface membrane preparation revealed (a) a predominance of thick-walled vesicles with smooth surfaces on negative staining and (b) binding of concanavalin A to the bulk of isolated membrane pieces following their incubation with the lectin.


An active optical sensor for monitoring mixed venous oxygen-saturation for an implantable rate-regulating pacing system.
Presently available physiologic pacing systems do not fully restore rate regulation, especially in respect to little or no atrial response to activity. Other biologic parameters, detected by sensors, may provide the physiologic responsiveness necessary to rate-regulating pacemakers. An optical sensor using mixed venous oxygen saturation may be the ideal parameter for such a pacing system. At present, further research is necessary to elaborate a suitable algorithm for optimal rate control.


The significance of post-mortem vitreous calcium concentration in forensic practice.
Calcium, as one of the main extracellular ions, maintains a key role in numerous biologic functions. For forensic purposes, it was analyzed mostly for estimation of postmortem interval (PMI). We have designed our experiment with the concept that the repetitive withdrawal of vitreous humor (VH) might clarify the postmortem metabolism of calcium in greater detail to estimate the PMI. Accordingly, 248 samples of VH from 31 autopsy cases were evaluated over three years; samples (0,1 mL of VH) were taken and analyzed at equal time intervals after death-every three hours until 24 h after death. Each sample was centrifuged and analyzed using the ARCHITECT C SYSTEM 8000. Moreover, functional relationship between PMI and calcium concentration was established: PMI (hours) = [Ca2+] × 13.696-7.843. Although the concentration of calcium in VH in the analyzed group increases with time, the coefficient of variation for the regression (CVreg = 46.8%) indicates that this correlation is not so strong, meaning that the level of predictiveness of calcium for estimation of time since death is poor when is not used in combination with other relevant substances.


Expression of the proteolysis-inducing factor core peptide mRNA is upregulated in both tumour and adjacent normal tissue in gastro-oesophageal malignancy.
Gastro-oesophageal cancer is associated with a high incidence of cachexia. Proteolysis-inducing factor (PIF) has been identified as a possible cachectic factor and studies suggest that PIF is produced exclusively by tumour cells. We investigated PIF core peptide (PIF-CP) mRNA expression in tumour and benign tissue from patients with gastro-oesophageal cancer and in gastro-oesophageal biopsies for healthy volunteers. Tumour tissue and adjacent benign tissue were collected from patients with gastric and oesophageal cancer (n=46) and from benign tissue only in healthy controls (n=11). Expression of PIF-CP mRNA was quantified by real-time PCR. Clinical and pathological information along with nutritional status was collected prospectively. In the cancer patients, PIF-CP mRNA was detected in 27 (59%) tumour samples and 31 (67%) adjacent benign tissue samples. Four (36%) gastro-oesophageal biopsies from healthy controls also expressed PIF-CP mRNA. Expression was higher in tumour tissue (P=0.031) and benign tissue (P=0.022) from cancer patients compared with healthy controls. In the cancer patients, tumour and adjacent benign tissue PIF-CP mRNA concentrations were correlated with each other (P<0.0001, r=0.73) but did not correlate with weight loss or prognosis. Although PIF-CP mRNA expression is upregulated in both tumour and adjacent normal tissue in gastro-oesophageal malignancy, expression does not relate to prognosis or cachexia. Post-translational modification of PIF may be a key step in determining the biological role of PIF in the patient with advanced cancer and cachexia.