Association of peripheral basophils with tumor M2 macrophage infiltration and outcomes of the anti-PD-1 inhibitor plus chemotherapy combination in advanced gastric cancer.
Although the anti-programmed death-1 (PD-1) inhibitor plus chemotherapy combination has been approved as the standard first-line treatment for advanced gastric cancer, a proportion of patients do not significantly benefit from this therapy. Who would respond poorly to this treatment and the underlying mechanisms of treatment failure are far from clear. We retrospectively analyzed the associations between the peripheral basophils at baseline and clinical outcomes in 63 advanced gastric cancer patients treated with anti-PD-1 plus chemotherapy and 54 patients treated with chemotherapy alone. Immunohistochemistry and immunofluorescence staining in gastric cancer samples were utilized to investigate the basophil-related immunophenotype. The optimal cutoff of basophil count to distinguish responders to anti-PD-1 plus chemotherapy from non-responders was 20.0/μL. Compared with the low basophil group (≤ 20.0/μL, n = 40), the high basophil group (> 20.0/μL, n = 23) had a significantly lower objective response rate (ORR 17.4% vs. 67.5%, p = 0.0001), worse progression-free survival (median PFS 4.0 vs. 15.0 months, p = 0.0003), and worse overall survival (median OS not reached, p = 0.027). Multivariate analyses identified a basophil count of > 20.0/μL as an independent risk factor for a worse ORR (OR 0.040, 95% CI 0.007-0.241, p = 0.0004), worse PFS (HR 3.720, 95% CI 1.823-7.594, p = 0.0003) and worse OS (HR 3.427, 95% CI 1.698-6.917, p = 0.001). In contrast, there was no significant association between peripheral basophil counts and tumor response or survival in the chemotherapy-alone group (p > 0.05). In primary gastric cancer samples, we observed a correlation between higher peripheral basophil counts and the accumulation of tumor-infiltrating basophils (r = 0.6833, p = 0.005). Tumor-infiltrating basophils were found to be spatially proximate to M2 macrophages within TME and positively correlated with tumor M2 macrophage infiltration (r = 0.7234, p = 0.0023). The peripheral basophil counts also had a significant positive correlation with tumor-infiltrating M2 macrophage counts (r = 0.6584, p = 0.003). Further validation in tumor samples treated with the neoadjuvant anti-PD-1 inhibitor plus chemotherapy combination suggests that the peripheral basophils, tumor infiltration of basophils, and M2 macrophages were significantly more abundant in non-responders than in responders (p = 0.0333, p = 0.0007, and p = 0.0066, respectively). The peripheral basophil count was observed to be a potential biomarker of anti-PD-1 efficacy for advanced gastric cancer. Moreover, basophils may induce an immune-evasive tumor microenvironment by increasing M2 macrophage infiltration, which could be a potential immunotherapeutic target for advanced gastric cancer.


A novel yeast silencer. the 2mu origin of Saccharomyces cerevisiae has HST3-, MIG1- and SIR-dependent silencing activity.
Silencing in Saccharomyces cerevisiae is found at the mating-type loci HMR and HML, in subtelomeric regions, and at the rDNA locus. Repressed chromatin is built up by the recruitment of the Sir proteins via their interaction with DNA-binding proteins that bind to silencers. Here, we have performed a genetic screen for novel sequence elements within the yeast genome that display silencing activity. We isolated as a novel silencer element the origin of replication from the endogenous 2mu plasmid (2mu ARS). 2mu ARS-mediated silencing was dependent upon the Sir proteins, the origin recognition complex (ORC), and Hst3, a Sir2 histone deacetylase homolog, suggesting that it constituted a novel class of silencing in yeast. Moreover, 2mu ARS carried a binding site for Mig1, a transcriptional repressor of glucose-regulated genes. Both the Mig1-binding site and the MIG1 gene were necessary for full silencing activity of 2mu ARS. Furthermore, Hst3 was physically present at 2mu ARS in a silencing context as well as at the endogenous 2mu plasmid. Also, Hst3 regulated the repression of the flipase gene, although this was likely an indirect effect of HST3 on FLP1 expression.


Phytochemical composition, and cytotoxic, antioxidant, and antibacterial activity of the essential oil and methanol extract of Semenovia suffruticosa.
In this study, our aim was to extract, and identify and quantify the chemical composition of essential oils of Semenovia suffruticosa grown in Kerman, Iran. Moreover, cytotoxic, antioxidant and antimicrobial activity of the essential oil and methanol extract of aerial parts of S. suffruticosa were reported. GC and GC/MS analysis were used for identifying and quantifying the essential oil components. Antioxidant and antibacterial activity were tested by 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and agar disc diffusion methods, respectively and MTT assay was used to determine the anti-proliferative potential of the oil against breast (MCF-7), colon (HT-29), neuroblastoma (SH-SY5Y), embryonal carcinoma (NCCIT) cancer cell relative to human umbilical vein endothelial cell (HUVEC) as a normal cell. Apoptosis induction was monitored by flow cytometry using PE annexin V apoptosis detection kit and cell cycle arrest was by with propidium iodide. Z-β-ocimene (25.1%), linalool (17.8%) and β-bisabolol (13.3%) were recognized as major components of the essential oil. Our study demonstrated apoptosis-inducing potential of essential oil on normal and cancer cells. However, methanol extract exerted cytotoxicity against a number of cancer cells and arrested cancer cells in G2/M phase; nevertheless, it did not exert strong cytotoxicity against normal cells. Furthermore, DPPH and disc diffusion results showed that while essential oil has considerable antiradical activity, methanol extract did not exert promising antioxidant and antimicrobial activity. Methanol extract of S. suffruticosa shows tumor-cell-specific cytotoxic properties and the essential oil demonstrated a strong antioxidant activity.


Specific PCR primers for Cryptosporidium parvum with extra high sensitivity.
One pair of high-sensitive polymerase chain reaction (PCR) primers for Cryptosporidium parvum was constructed based on the sequence of random amplified polymorphic DNA. PCR with this primer pair amplified only the DNA of C. parvum, not the control DNA including Cryptosporidium muris. This primer pair had most advantageous in its sensitivity over the six pairs of primers reported elsewhere. The minimum amount of template DNA required to produce visible bands after gel electrophoresis and ethidium bromide staining was 0.156 pg of C. parvum or just a single oocyst in the PCR tube.


Repair of tendon defect with dermal fibroblast engineered tendon in a porcine model.
Harvesting autologous tenocytes for tendon engineering may cause secondary tendon defect at the donor site. Dermal fibroblasts are an easily accessible cell source and do not cause major donor site defect. This study aims to explore the possibility of tendon engineering using dermal fibroblasts. A total of 45 hybrid pigs were randomly divided into three groups: experimental group (n = 15)--repair of tendon defect with a dermal fibroblast engineered tendon; control group 1 (n = 15)--repair of defect with a tenocyte engineered tendon; and control group 2 (n = 15)-repair of defect with a scaffold alone. Both autologous dermal fibroblasts and tenocytes were seeded on polyglycolic acid (PGA) unwoven fibers to form a cell-scaffold construct and cultured in vitro for 7 days before in vivo implantation to repair a defect of flexor digital superficial tendon. Specimens were harvested at weeks 6, 14, and 26 for gross, histological, and mechanical analyses. Microscopy revealed good attachment of both dermal fibroblasts and tenocytes on PGA fibers and matrix production. In vivo results showed that fibroblast and tenocyte engineered tendons were similar to each other in their gross view, histology, and tensile strength. At 6 weeks, parallel collagen alignment was observed at both ends, but not in the middle in histology, with more cellular components than natural tendons. At weeks 14 and 26, both engineered tendons exhibited histology similar to that of natural tendon. Collagens became parallel throughout the tendon structure, and PGA fibers were completely degraded. Interestingly, dermal fibroblast and tenocyte engineered tendons did not express type III collagen at 26 weeks, which remained observable in normal pig skin and control group 2 tissue using polarized microscopy, suggesting a possible phenotype change of implanted dermal fibroblasts. Furthermore, both fibroblast and tenocyte engineered tendons shared similar tensile strength, about 75% of natural tendon strength. At 6 weeks in control group 2, neo-tissue was formed only at the peripheral area by host cells. A cord-like tissue was formed at weeks 14 and 26. However, the formed tissue was histologically disorganized and mechanically weaker than both cell-engineered tendons (p < 0.05). These results suggest that dermal fibroblasts may have the potential as seed cells for tendon engineering.


Ethnomedicinal study of plants used in villages around Kimboza forest reserve in Morogoro, Tanzania.
An ethnomedicinal study was conducted to document medicinal plants used in the treatment of ailments in villages surrounding Kimboza forest reserve, a low land catchment forest with high number of endemic plant species. Ethnobotanical interviews on medicinal plants used to treat common illnesses were conducted with the traditional medical practitioners using open-ended semi -structured questionnaires. Diseases treated, methods of preparation, use and habitat of medicinal plants were recorded. A total of 82 medicinal plant species belonging to 29 families were recorded during the study. The most commonly used plant families recorded were Fabaceae (29%), Euphorbiaceae (20%), Asteraceae and Moraceae (17% each) and Rubiaceae (15%) in that order. The most frequently utilized medicinal plant parts were leaves (41.3%), followed by roots (29.0%), bark (21.7%), seeds (5.31%), and fruits (2.6%). The study revealed that stomach ache was the condition treated with the highest percentage of medicinal plant species (15%), followed by hernia (13%), diarrhea (12), fever and wound (11% each), and coughs (10%). Majority of medicinal plant species (65.9%) were collected from the wild compared to only 26.7% from cultivated land. A rich diversity of medicinal plant species are used for treating different diseases in villages around Kimboza forest reserve, with the wild habitat being the most important reservoir for the majority of the plants. Awareness programmes on sustainable utilization and active involvement of community in conservation programmes are needed.


Fragile site at Xq21 in Chinese hamster and its implications for the in vitro chromosomal aberration test.
Normal Chinese hamster primary fibroblasts were exposed to methotrexate, an antifolate agent known to induce fragile sites. In a total of 156 banded metaphases prepared from methotrexate-treated cells, 93 breaks and gaps were observed and mapped to the individual hamster chromosomes and their bands. About two-thirds (69%) of all breaks and gaps mapped to the band Xq21, which is significantly more than expected. Some other bands exhibited fragility but the effect was not significant. In 6% of cells, homozygous fragility of Xq21 was observed, suggesting that this is a common fragile site. It has been reported previously that various chemicals induce preferential localized fragility of Xq in Chinese hamster ovary (CHO) and V79 cell lines. Our results suggest that preferential fragility of Xq in the presence of chemical compounds represents examples of fragile-site induction. A tendency of the in vitro chromosomal aberration test to yield positive results in the absence of positive data in other test systems, such as the Ames test and the mouse bone marrow micronucleus test, might be due to fragile-site expression induced by chemical compounds under study.


Inverted Organic Solar Cells with Low-Temperature Al-Doped-ZnO Electron Transport Layer Processed from Aqueous Solution.
The aqueous-based Zn-ammine complex solutions represent one of the most promising routes to obtain the ZnO electron transport layer (ETL) at a low temperature in inverted organic solar cells (OSCs). However, to dope the ZnO film processed from the Zn-ammine complex solutions is difficult since the introduction of metal ions into the Zn-ammine complex is a nontrivial process as ammonium hydroxide tends to precipitate metal salts due to acid-base neutralization reactions. In this paper, we investigate the inverted OSCs with Al-doped-ZnO ETL made by immersion of metallic Al into the Zn-ammine precursor solution. The effects of ZnO layer with different immersion time of Al on film properties and solar cell performance have been studied. The results show that, with the Al-doped-ZnO ETL, an improvement of the device performance could be obtained compared with the device with the un-doped ZnO ETL. The improved device performance is attributed to the enhancement of charge carrier mobility leading to a decreased charge carrier recombination and improved charge collection efficiency. The fabricated thin film transistors with the same ZnO or AZO films confirm the improved electrical characteristics of the Al doped ZnO film.


Faceted monodomains of liquid crystal smectic blue phases.
Smectic blue phases (BP(Sm)) are mesophases of thermotropic liquid crystals, which exhibit both three-dimensional orientational order, such as classical blue phases, and smectic positional order. The BP(Sm) phases appear as the three-dimensional counterpart of the twist grain boundary phases. By growing large faceted monocrystals of BP(Sm) phase, we provide, for the first time at the length scale of the lattice parameter, information on the symmetry of the orientational unit cell. This study leads us to suggest an orthorhombic structure, contrary to the previous results obtained by x-ray scattering at the length scale of the smectic order.


Decoupling between Economic Development and Carbon Emissions and Its Driving Factors: Evidence from China.
Analyzing the relationship between economic development and carbon emissions is conducive to better energy saving and emission reduction. This study is based on the panel data of China's carbon emissions, from 2009 to 2019, and quantitative analysis of the relationship between carbon emissions and economic development through the Tapio decoupling model and the Logarithmic Mean Divisia Index (LMDI) decomposition model. The results show that: First, carbon emission and economic development are increasing year by year, and the development trend of economic growth rate and carbon emission growth rate presents the characteristics of consistency and stage. Second, China's carbon emissions and economic development are basically in a weak decoupling state, and carbon emissions and economic development are positively correlated. Third, there are significant differences in decoupling indices among the four regions, mainly in that the central region is better than the eastern region, the eastern region is better than the northeast region, the northeast region is better than the western region, and the development of provinces in the region is unbalanced. Fourth, from the perspective of driving factors, the elasticity of population size and economic intensity can restrain the decoupling of carbon emissions, while the elasticity of energy intensity and carbon intensity have a positive effect. Finally, according to the results of empirical analysis, this paper focuses on promoting China's emission reduction and energy sustainable development from the aspects of developing low-carbon and zero carbon technology, supporting new energy industries and promoting the construction of a carbon emission trading market.


[Urbanization in China. Data on the transformation of the urban system].
Recent trends in urbanization in China are analyzed. "This article presents new figures, as recently published in China, discusses their significance and draws some conclusions about the quality of modern urbanization in China. There are mainly three basic factors responsible for the present situation: 1. The tremendous increase in the rural population; 2. The influence of historical times from which two different city systems evolved (the traditional one and the colonial); 3. The planning strategies since 1949." The author notes that although the overall level of urbanization is low, there are considerable differences in regional urbanization levels. It is suggested that there have been profound changes in the Chinese urban system and urban spatial distribution patterns, which are not yet reflected in the available statistics. (SUMMARY IN ENG)


Contextualising migrants' health behaviour - a qualitative study of transnational ties and their implications for participation in mammography screening.
Lower participation rates in mammography screening are common among migrant women compared to native-born women. Explanations of these lower rates have mainly been based on behavioural theories investigating how lack of knowledge, access to services and culture influence the screening behaviour. The aim of the present study was to contextualise screening behaviour by exploring migrants' transnational ties and their influence on participation in mammography screening in Denmark. The study is based on the analysis of qualitative interviews with 29 women residing in greater Copenhagen, Denmark and born in Somalia, Turkey, India, Iran, Pakistan and Arab-speaking countries. We found that while women had knowledge about breast cancer and mammography screening, it was not prioritised. All women were embedded in transnational ties, which they struggled to retain through emotional and financial obligations, and these current struggles in their everyday life seemed to leave little room for concerns about breast cancer and therefore seemed to contribute to their lower participation in screening. The study emphasises the need to take into account the multi-layered and multi-sided factors in migrants' everyday life in order to further understand their health behaviour.


Generating comprehensive comparative evidence on various interventions for penile rehabilitation in patients with erectile dysfunction after radical prostatectomy: a systematic review and network meta-analysis.
We aim to present a comprehensive comparison of various treatments in the management of penile recovery after radical prostatectomy (RP) and provide recommendations for future research. Literature search of electronic databases including PubMed, the Cochrane Library, Embase, PsycInfo, and Web of Science, and manual retrieval were conducted from inception through March 2020. "Erectile dysfunction" and "prostatectomy" were used as the Mesh terms. The patients, intervention, comparison, outcome, and study design (PICOS) approach were used to define study eligibility. Two authors independently selected studies, evaluated the methodological quality, and extracted data using Cochrane Collaboration's tools. The data analysis was completed by STATA version 14.2. A total of 24 studies with 3,500 patients were incorporated in the final analysis after screening 6,131 records. Our findings indicated that vacuum constriction devices (VCD) ranked 1st which meant that patients in VCD group had the best effect regarding mean IIEF scores within 3 months after RP, and no significant difference was observed between VCD and VCD with 20 mg/day tadalafil (V20DT) (MD: 5.44; 95% CI: -0.81 to 11.69). VCD and 50 mg/day sildenafil (VC50DS) showed superiority over 50 mg/day sildenafil (50DS) (MD: 3.75; 95% CI: 2.74-4.76) and intraurethral alprostadil 125-250 µg (MD: 3.05; 95% CI: 0.38 to 5.72), respectively. Moreover, V20DT showed significant superiority over the other interventions for ≥6 months mean International Index Erectile of Function (IIEF) scores after RP. Monotherapy appeared to have similar efficacy in terms of mean IIEF scores and proportion of patients return to baseline, and the effect of phosphodiesterase type 5 inhibitors (PDE5is) did not seem to be affected by the patterns of administration (regular or on demand). The combination therapy showed certain advantages over monotherapy, and we recommended the combination of VCD and PDE5is to be considered in the clinical management of penile rehabilitation after RP.


Pleural malignant solitary fibrous tumor with sarcomatous overgrowth showing PDGFRbeta mutation.
Pleural malignant solitary fibrous tumors (SFTs) are uncommon, and little is known about their histogenesis and molecular features. We report a case of pleural SFT with sarcomatous overgrowth that showed expression for PDGFRbeta and a missense mutation on exon 18 of the PDGFRbeta gene. The involvement of the PDGFRbeta gene in SFT is compatible with a pericytic derivation, also supporting a possible role of this tyrosine kinase in malignant transformation and in the adoption of novel molecular therapies.


Discordance in Reporting of Maternal Aggression: Exploring Differences by Characteristics of Children, Mothers, and Their Environments.
This study investigated discordant reports of maternal aggression using the Fragile Families and Child Wellbeing Study (N = 1,606). Multinomial logistic regression models predicted discordant reports of hitting and shouting from child, mother, and environmental characteristics. Compared to dyads in which both mothers and children reported aggression, mothers with a college degree had higher child-only and mother-only reports of both hitting and shouting versus mothers with less than a high school diploma. High-income mothers had higher child-only reports of hitting, while families with past Child Protective Services involvement had higher child-only and mother-only reports of hitting. Additionally, children with lower reading test scores and whose fathers had history of incarceration had higher child-only reports of hitting. Families residing in neighborhoods for which mothers were scared to let children play outside also had higher child-only and mother-only reports of hitting and shouting.


Pre-versus postnatal presentation of posterior urethral valves: a multi-institutional experience.
To compare the outcomes of pre- vs postnatally diagnosed posterior urethral valves (PUV) at two large paediatric centres in North America to ascertain if the prenatal diagnosis of PUV is associated with better outcomes. All boys with PUV were identified at two large paediatric institutions in North America between 2000 and 2020 (The Hospital for Sick Children [SickKids, SK] and Children's Hospital of Philadelphia [CHOP]). Baseline characteristics and outcome measures were compared between those diagnosed pre- vs postnatally. Main outcomes of interest included progression of chronic kidney disease (CKD), the need for renal replacement therapy (RRT), and bladder function compromise, as determined by need for clean intermittent catheterisation (CIC). Time-to-event analyses were completed when possible. During the study period, 152 boys with PUV were treated at the SK (39% prenatal) and 216 were treated at the CHOP (71% prenatal). At the SK, there was no difference between the pre- and postnatal groups in the proportion of boys who required RRT, progressed to CKD Stage ≥3, or who were managed with CIC when comparing the timing of diagnosis. The time to event for RRT and CIC was significantly younger for prenatally detected PUV. At the CHOP, significantly more prenatal boys required RRT; however, there was no significant difference in the age this outcome was reached. The proportion of boys managed with CIC was not different but the time to event was significantly earlier in the prenatal group. This study represents the largest multi-institutional series of boys with PUV and failed to identify any difference in the outcomes of pre- vs postnatal detection of PUV. A multidisciplinary approach with standardisation of the treatment pathways will help in understanding the true impact of prenatal/early detection on outcomes of PUV.


Effect of chemopreventive agents on differentiation of mouse embryonic stem cells.
Chemopreventive agents are derived from edible plants and from ancient time is a part of daily intake for many humans and animals. There are several lines of compelling evidence from epidemiological, clinical and laboratory studies that these dietary constituents are associated in reducing cancer risks. However, developmental toxicity of these natural compounds cannot be excluded. In the present study, we examined the effect of chemopreventive agents on the differentiation of mouse embryonic stem cells (ESCs) as an in vitro embryotoxicity model. We assumed that inhibition of developmentally regulated genes in vitro might predict developmental toxicity also under in vivo conditions. We found that epigallocatechin gallate (EGCG) (20 microM) induced the expression of mesodermal and cardiomyocyte genes and a significant increase in the number and the percentage of cardiomyocytes. The increase of the subpopulation correlated with higher numbers of beating foci and beating frequencies. Curcumin on the other hand at 0.4 mM was seen to enhance expression of ectodermal transcripts. Quercetin (2.5 microM) was found to inhibit several developmentally regulated genes.


The Role of Iron, Its Metabolism and Ferroptosis in Traumatic Brain Injury.
Traumatic brain injury (TBI) is a structural and physiological disruption of brain function caused by external forces. It is a major cause of death and disability for patients worldwide. TBI includes both primary and secondary impairments. Iron overload and ferroptosis highly involved in the pathophysiological process of secondary brain injury. Ferroptosis is a form of regulatory cell death, as increased iron accumulation in the brain leads to lipid peroxidation, reactive oxygen species (ROS) production, mitochondrial dysfunction and neuroinflammatory responses, resulting in cellular and neuronal damage. For this reason, eliminating factors like iron deposition and inhibiting lipid peroxidation may be a promising therapy. Iron chelators can be used to eliminate excess iron and to alleviate some of the clinical manifestations of TBI. In this review we will focus on the mechanisms of iron and ferroptosis involving the manifestations of TBI, broaden our understanding of the use of iron chelators for TBI. Through this review, we were able to better find novel clinical therapeutic directions for further TBI study.


The regulation of liver cell survival by complement.
Complement effectors are known to contribute to host cell injury in several inflammatory diseases. Contrary to this paradigm, in this study utilizing surgical liver resection (partial hepatectomy) in various complement-deficient mice as a model, we have demonstrated that complement anaphylatoxins C3a and C5a are required for the survival of liver cells during regeneration. The mechanisms of these cytoprotective functions of complement were related to the regulation of IL-6 and TNF production or release after liver resection. Disturbances in the cytokine milieu, induced by a loss of complement activity, were found to alter prosurvival signaling, including the IL-6/STAT3 and PI3K/Akt/mammalian target of rapamycin pathways. In conclusion, this study documents functions of complement proteins as prosurvival factors that, through their interactions with cytokines, inhibit apoptotic signaling in proliferating cells of epithelial origin.


A possible mechanism of action of thyrotropin-releasing hormone (TRH) and its analog DN-1417 on the release of dopamine from the nucleus accumbens and striatum in rats.
Slices of the nucleus accumbens, the terminus of the mesolimbic dopaminergic system and the striatum, the terminus of the nigrostriatal dopaminergic system obtained from rats, were used for analyzing the dopamine releasing effects of TRH and its analog DN-1417 (gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate). (1) Dopamine release: The addition of DN-1417 (5 X 10(-5) M) or TRH (5 X 10(-4) M) stimulated the release of prelabelled [3H]-dopamine (DA) from the superfused nucleus accumbens slices, and 100 or 20 times higher concentrations of each compound stimulated DA release from the striatal slices. The omission of Ca2+ from the superfusion medium or the addition of ouabain (5 X 10(-3) M), a (Na+ + K+) stimulated adenosine triphosphate (ATP) phosphohydrolase [(Na+ + K+)-ATPase] inhibitor, almost completely abolished the DN-1417- or TRH-induced DA releasing effect. (2) 45Ca2+ uptake: The addition of DN-1417 (10(-4) M) or TRH (10(-4) M) stimulated 45Ca2+ uptake into the nucleus accumbens slices in a time-dependent manner from 1 to 5 min at 30 degrees C. On the other hand, both drugs (10(-4) M) had no effect on 45Ca2+ uptake into the striatal slices. A Ca2+ ionophore, A-23187 (10(-6) M), stimulated 45Ca2+ uptake into slices of the nucleus accumbens and striatum. Ouabain abolished the DN-1417-, TRH- and A-23187-induced effects. (3) Cyclic AMP formation: The addition of DN-1417 (10(-4) M) or TRH (10(-4) and 10(-3) M) accelerated cyclic AMP formation in the nucleus accumbens, but not in the striatal slices. A Ca2+ antagonist, methoxyverapamil (D-600, 10(-6) M) almost completely abolished the DN-1417- and TRH-effects. (4) (Na+ + K+)-ATPase activity: The addition of DN-1417 (10(-5) and 10(-4) M) or TRH (10(-4) M) activated (Na+ + K+)-ATPase in the P1 fraction (cell debris, nuclei) of the nucleus accumbens, but had little effect on the same activity in the striatum. (5) [3H]-TRH binding: The addition of 10(-6) to 10(-4) M of DN-1417 and TRH inhibited concentration-dependently [3H]-TRH binding in the nucleus accumbens and striatal slices. Ouabain (5 X 10(-3) M) almost completely abolished [3H]-TRH binding in both types of slices.(ABSTRACT TRUNCATED AT 400 WORDS)


Potential of asphericity as a novel diagnostic parameter in the evaluation of patients with 68Ga-PSMA-HBED-CC PET-positive prostate cancer lesions.
The aim of this study was to evaluate the diagnostic value of the asphericity (ASP) as a novel quantitative parameter, reflecting the spatial heterogeneity of tracer uptake, in the staging process of patients with 68Ga-PSMA-HBED-CC positron emission tomography (PET)-positive prostate cancer (PC). In this study, 37 patients (median age 72 years, range 52-82 years) with newly diagnosed PC, who received a 68Ga-PSMA-HBED-CC PET fused with computed tomography (68Ga-PSMA-PET/CT), a magnetic resonance imaging (MRI) of the prostate, and a core needle biopsy (within 74.2 ± 80.2 days) with an available Gleason score (GSc) were extracted from the local database. The ASP and the viable tumor volume (VTV) was calculated using the rover software (ABX GmbH, Radeberg, Germany), a segmentation tool for automated tumor volume delineation. Additionally, parameters including total lesion binding rate (TLB), maximum, mean and peak standardized uptake value (SUVmax/mean/peak), prostate-specific antigen (PSA), D'Amico classification, and prostate imaging reporting and data system (PI-RADS) were analyzed. The ASP mean differed significantly (p ≤ 0.05) between the different GSc groups: GSc 6-7: 11.9 ± 4.8%, GSc 8: 25.5 ± 4.8%, GSc 9-10: 33.3 ± 6.8%. A significant correlation between ASP and GSc (rho = 0.88; CI 0.78-0.94; p < 0.05) was measured. The ASP enabled an independent (p > 0.05) prediction of the GSc. A moderate correlation was measured between ASP and the D'Amico classification (rho = 0.6; CI 0.32-0.78; p < 0.05). The VTV showed a moderate correlation with the SUVmax (rho = 0.58; CI 0.32-0.76; p < 0.05) and the GSc (rho = 0.51; CI 0.23-0.72; p < 0.05). The asphericity in 68Ga-PSMA-PET could represent a promising novel quantitative parameter for an improved non-invasive tumor staging of patients with PC.


A-current modifies the spike of C-type neurones in the rabbit nodose ganglion.
1. In the rabbit nodose ganglion, C-type fibre neurones (C neurones) can be divided into two subtypes according to their after-hyperpolarizing potential (AHP) i.e. those with a fast AHP only and those with a fast AHP and a subsequent slow AHP produced by a slow calcium-dependent potassium current. In addition we have shown that some C neurones can be divided into two groups according to the effect of membrane hyperpolarization on their spikes i.e. type 1 in which duration and amplitude do not change and type 2 in which duration and amplitude decrease significantly. 2. In the present report we studied the effect of A-current (IA) on spike duration, amplitude and slow AHP using intracellular recording techniques. 3. To detect the presence of IA, we first applied a series of increasing rectangular hyperpolarizing pulses to remove IA inactivation and then a short depolarizing pulse to trigger a spike. In type 1 C neurones the lag time of the spike in relation to hyperpolarization remains constant whereas in type 2 C neurones the spike only appears after IA inactivation and lag time in relation to hyperpolarization is lengthened. Thus, type 2 C neurones have an IA while type 1 C neurones do not. The fact that addition of cadmium did not change the lag time in type 2 C neurones shows that the IA is not calcium dependent. 4. Nodose neurones can be orthodromically activated by stimulation of the vagal peripheral process. In this way, after a hyperpolarizing pulse, IA can be fully activated by the orthodromic spike itself. Under these conditions it is possible to analyse the effects of IA on the spike. This was done by increasing either the hyperpolarizing potential, pulse duration, or the delay of the spike after the end of the pulse. We observed that maximum IA inactivation removal was always associated with the lowest duration and amplitude of the spike. 5. When IA inhibitors, 4-aminopyridine (4-AP) or catechol, were applied to type 2 C neurones, the delay of the spike after the hyperpolarization-depolarization test was no longer observed. In addition 4-AP abolished the shortening of the duration of the spike induced by steady hyperpolarization. 6. In type 2 C neurones with slow AHP, the IA-related decrease in spike duration was associated with a disappearance of the slow AHP. This indicates that IA decreases the calcium influx during the spike.(ABSTRACT TRUNCATED AT 400 WORDS)


Acute plasma ghrelin and leptin responses to oral feeding or intraperitoneal hypertonic glucose-based dialysate in patients with chronic renal failure.
Chronic renal failure (CRF) is associated with increased plasma levels of ghrelin and leptin, but the regulation of the secretion of these hormones has been insufficiently studied, in this setting. The aim of this study was to analyze the acute effects of oral feeding or intraperitoneal 3.86% glucose-based dialysate infusion on plasma ghrelin and leptin levels in patients with CRF undergoing peritoneal dialysis (PD). Following a crossover design, 10 patients and eight healthy controls underwent a standardized oral intake, a 3.86% glucose-based dialysate PD exchange (patients) and placebo oral intake. We scrutinized acute changes in plasma ghrelin, leptin, glucose, insulin, and growth hormone (GH) levels. In patients, total ghrelin decreased modestly immediately after oral feeding (nadir 90.6% of baseline, range 85.1, 94.5, P= 0.03) or the PD exchange test (92.2%, range 58.7, 101.9, P= 0.05) (median). Response to oral feeding was markedly blunted when compared with healthy individuals (73.8%, range 56.1, 89.1, P= 0.007) (P < 0.005 vs. patients). Plasma acyl-ghrelin had a less marked but more persistent decay after the PD exchange test (nadir 80.4%, range 55.1, 96.3, P= 0.02) than after oral intake (64.4%, range 45.6, 82.3, P= 0.005); again, changes were more intense in normal controls (47.4%, range 32.1, 67.3, P= 0.01) (P < 0.05 vs. patients). Leptin levels decreased slightly (P < 0.05) after the PD exchange in patients, but did not respond acutely to oral feeding in patients or controls. Ghrelin secretion is partially refractory to the acute inhibitory effect of oral feeding in patients with CRF undergoing PD therapy. A 3.86% glucose-based PD exchange results in a significant decrease of plasma ghrelin levels. Plasma leptin levels are not acutely affected by oral feeding in patients with CRF or healthy individuals.


Increased release of free oxygen radicals from peripheral neutrophils in adult periodontitis after Fc delta-receptor stimulation.
The release of free oxygen radicals and degranulation was studied in neutrophils from 14 patients with adult periodontitis and 14 age- and sex-matched healthy controls. The neutrophils were activated by Fc gamma-receptor stimulation, using Staphylococcus aureus opsonized with gamma globulin. Release of oxygen radicals was measured as luminol-enhanced chemiluminescence. Degranulation was assessed as release of elastase, measured with a specific substrate and as release of lactoferrin measured with ELISA. The neutrophils from the patients showed a significantly higher chemiluminescence and a slightly higher release of elastase, whereas the release of lactoferrin was the same in both groups. In contrast, the ratio between the 2 degranulation products, elastase and lactoferrin, was significantly higher in the group with periodontitis. A flow cytometric analysis of the membrane expression of the adhesion molecules CD 11a, CD 11b, CD 15, CD 16, CD 35 and Mel 14 showed no differences in the median immunofluorescence between the 2 groups. This study showed a more than 2-fold higher release of free oxygen radicals from Fc-gamma-receptor stimulated neutrophils compared with healthy controls, which indicates a specific neutrophil-associated host response in adult periodontitis.


Imbalanced plasminogen system in lymphangioleiomyomatosis: potential role of serum response factor.
Pulmonary lymphangioleiomyomatosis (LAM) is characterized by abnormal smooth muscle-like cell (LAM cell) proliferation leading to tissue destruction. We previously demonstrated that serum response factor (SRF), a critical smooth muscle transcription factor, is highly expressed in LAM cells. Here we show that a high SRF level alters the plasminogen (Plg) system. Specifically, overexpression of SRF in human lung fibroblasts upregulated urokinase-type plasminogen activator (uPA) and its substrate Plg, whereas it downregulated plasminogen activator inhibitor (PAI)-1. Because uPA cleaves Plg into plasmin, which activates matrix metalloproteinases (MMP), the end result was an increase in MMP activity. To determine whether uPA, Plg, and PAI-1 were abnormally expressed in LAM in vivo, we immunostained 12 LAM cases. In all cases, the LAM lesions showed stronger immunoreaction for uPA and Plg than the surrounding normal lung parenchyma. On the contrary, PAI-1 was absent in LAM lesions, whereas it was ubiquitous in normal lung parenchyma. Microdissection-based reverse transcriptase/polymerase chain reaction further confirmed upregulation of uPA and Plg and downregulation of PAI-1 message in LAM. Altogether, our findings suggest that the high SRF level seen in LAM contributes to extracellular matrix degradation and progressive LAM cell infiltration of the lung.


Clinical and immunological evaluation of oral ribavirin administration in recurrent herpes simplex infections.
A total of 38 out-patients with recurrent oral or genital Herpes simplex virus infections received either oral ribavirin (800-1600 mg/day for 7 days) or placebo following a randomized and balanced protocol. Clinical and laboratory parameters, including haematological, metabolic and immunological tests, were checked in order to estimate tolerance to and efficacy of ribavirin on recurrent Herpes simplex virus infection and on the number of recurrences during the 12 months following treatment. Ribavirin showed definite superiority in the treatment of recurrent Herpes simplex virus 1, when compared to placebo, its efficacy being enhanced if treatment is started as soon as possible after infection has started. No significant modification of the parameters used to assess tolerance was noted; moreover there was no modification of the immunological parameters evaluated.


Dopaminergic activity and water-sodium handling in the kidneys of essential hypertensive subjects: is renal dopaminergic activity suppressed at the prehypertensive stage?
To investigate whether the suppression of the renal dopaminergic system in hypertension is primary or secondary, renal dopaminergic activity was compared between young healthy normotensive subjects without a family history of hypertension [FH(-)] and those with a family history of hypertension [FH(+)]. A significant decrease in urinary dopamine excretion was recognized, and the responses of urine volume, urinary sodium excretion, fractional excretion of sodium, and urinary kallikrein and kinin activity to infused dopamine were significantly augmented in FH(+) subjects. In addition, a normal level of L-dopa delivery into the kidney and at the renal proximal tubules and a significant reduction of the conversion from L-dopa to dopamine in the kidney were found in FH(+) subjects. These findings suggest that renal dopaminergic activity is already suppressed at the prehypertensive stage, and a reduction in the conversion from L-dopa to dopamine in the proximal tubules may contribute to the attenuation of renal dopaminergic activity in FH(+) subjects.


Comparison between intralesional injection of zinc sulfate 2 % solution and intralesional meglumine antimoniate in the treatment of acute old world dry type cutaneous leishmaniasis: a randomized double-blind clinical trial.
Zinc sulfate (ZS) has been used for the treatment of acute cutaneous leishmaniasis (CL) in both forms of in vivo and in vitro recently. The aim of the present study was to compare the efficacy of intralesional injection of ZS 2 % solution with intralesional glucantime in the treatment of acute CL. In this double-blind randomized clinical trial, 80 cases with acute old world dry type CL were enrolled in the study. The treatment protocol in the first group consisted of intralesional injection of ZS 2 % vials once a week for 10 weeks or sooner in case of complete resolution of the lesions. In the second group, intralesional glucantime once a week for 10 weeks or sooner in case of complete resolution of the lesions were used. In both groups cryotherapy was performed once every other week for 10 weeks. In ZS versus second group, partial and complete clinical response was observed with fewer injections although this difference was not statistically significant. In addition, we found that the trend of treatment in second group was faster but again it was not significant [partial treatment: hazard ratio (HR) 1.4, 95 % CI 0.7-2.9; complete treatment: HR 1.3, 95 % CI 0.6-2.8]. The results of this study showed that the intralesional injection of ZS 2 % solution was as effective as glucantime on the healing of the acute old world dry type CL.


Epithelial Hic-5/ARA55 expression contributes to prostate tumorigenesis and castrate responsiveness.
Stromal-epithelial interactions dictate prostate tumorigenesis and response to castration. Hydrogen peroxide-inducible clone 5 (Hic-5/ARA55) is a transforming growth factor-beta (TGF-β)-induced coactivator of androgen receptor (AR) expressed in the prostate stroma. Interestingly, following castration, we identified epithelial expression of Hic-5/ARA55 in mouse and human prostate tissues. To determine the role of epithelial Hic-5 in prostate cancer progression and castration responsiveness, we compared LNCaP cells having Hic-5 stably expressed with the parental LNCaP cells following tissue recombination xenografts with mouse prostate stromal cells. We previously identified knocking out prostate stromal TGF-β signaling potentiated castrate-resistant prostate tumors, in a Wnt-dependent manner. The LNCaP chimeric tumors containing prostate fibroblasts conditionally knocked out for the TGF-β type II receptor (Tgfbr2-KO) resulted in larger, more invasive, and castration-resistant tumors compared those with floxed (control) stromal cells. However, the LNCaP-Hic5 associated with Tgfbr2-KO fibroblasts generated chimeric tumors with reduced tumor volume, lack of invasion and restored castration dependence. Neutralization of canonical Wnt signaling is shown to reduce prostate tumor size and restore regression following castration. Thus, we hypothesized that epithelial Hic-5/ARA55 expression negatively regulated Wnt signaling. The mechanism of the Hic-5/ARA55 effects on castration was determined by analysis of the c-myc promoter. C-myc luciferase reporter activity suggested Hic-5/ARA55 expression inhibited c-myc activity by β-catenin. Sequential ChIP analysis indicated β-catenin and T-cell-specific 4 (TCF4) bound the endogenous c-myc promoter in the absence of Hic-5 expression. However, the formation of a TCF4/Hic-5 repressor complex inhibited c-myc promoter activity, by excluding β-catenin binding with TCF4 on the promoter. The data indicate Hic-5/ARA55 expression in response to castration-enabled epithelial regression through the repression of c-myc gene at the chromatin level.


[The transrectus sheath preperitoneal procedure: a safe, effective and cheap surgical approach to inguinal hernia?].
The main complication of surgery for inguinal hernia is chronic postoperative pain. This is often reported following the Lichtenstein procedure. A new, open surgical technique for the repair of inguinal hernia has been developed. This procedure is called the transrectus sheath preperitoneal procedure (TREPP). At TREPP a lightweight mesh with a ring made of memory metal is introduced into the preperitoneal space through the transrectus sheath. The first results of this operative technique are very promising: short operation time, short learning curve and not many patients with chronic postoperative pain. In a randomised, multi-centre study which will start mid-2013 (ISRCTN18591339), the TREPP procedure is compared with the transinguinal preperitoneal procedure. The primary outcome measure of this study is chronic postoperative pain.


Active Surveillance of Engineered Stone Workers Facilitates Early Identification of Silicosis: A Discussion of Surveillance of Occupational Lung Diseases.
Silicosis in workers exposed to respirable crystalline silica while fabricating engineered stone products is an emerging respiratory health issue. We describe silicosis in engineered stone workers in California and examine clinical features by the source of identification. Cases were identified passively using hospital-based patient discharge data or actively through outreach and medical testing following enforcement investigation. Outcomes were examined based on the source of case identification. We identified 18 cases diagnosed between 2006 and 2020. Cases identified passively compared to other identification methods were associated with lower percent predicted forced vital capacity (FVC) (P ≤ .01), forced expiratory volume in 1 s (FEV1) (P ≤ .01), and diffusing capacity of the lungs for carbon monoxide (DLCO) (P < .01) at the time of diagnosis and were more likely to be identified following death or lung transplant (P = .01). Our experience demonstrates delays in diagnosis and case identification when relying on passive surveillance methods. Enhanced public health surveillance systems can improve the early detection of occupational lung disease and inform future prevention policies.


Effects of leukocyte-depleted warm blood cardioplegia on cardiac and endothelial function.
It has been reported that neutrophils and platelets have deleterious effects on myocardium and endothelium during and after ischemia. In this study we evaluated the effects of a leukocyte-depleting filter (Sepacell PLX, Asahi medical, Tokyo) during warm blood cardioplegia and early reperfusion on cardiac and endothelial function in the blood-perfused rat heart. Hearts (n = 7 per group) from donor rats were excised and perfused with blood at 37 degrees C from a support rat. After 10 min of stabilization, the hearts were arrested for 60 min with warm blood cardioplegia given at 20 min intervals. This was followed by 60 min of reperfusion. A leukocyte-depleting filter was used during the cardioplegia and the initial 10 min of reperfusion in the experimental group (Group F) and it was not used in the control group (Group N). Left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), maximum rate of left ventricular pressure rise (+dp/dt) and maximum rate of left ventricular pressure fall (-dp/dt) were measured as indices of left ventricular function before and after cardioplegic arrest. Coronary sinus effluent was obtained and the levels of MB isozyme of creatine kinase (CKMB), malondialdehide (MDA), elastase and thromboxane B2 (TXB2) were measured as indices of myocardial and endothelial injury. After 60 min of reperfusion, acetylcholine (Ach.) was administered to the coronary perfusate and the difference of nitric oxide (NO) concentration between inflow and outflow, and coronary blood flow were measured as an indication of endothelial function. Group F showed significantly lower LVEDP than Group N at 10 min of reperfusion. The elastase levels were significantly (p < 0.05) lower and the CKMB levels tended (p < 0.1) to be lower in Group F at 60 min of reperfusion. The administration of Ach. to the coronary perfusate showed significantly (p < 0.05) greater coronary blood flow and NO production in Group F. The results suggested that the use of a leukocyte-depleting filter during warm blood cardioplegia and early reperfusion preserves endothelial function and left ventricular diastolic compliance. The technique may provide beneficial effects by reducing reperfusion injury in patients undergoing cardiac surgery.


Bi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2.
Neutralizing agents against SARS-CoV-2 are urgently needed for the treatment and prophylaxis of COVID-19. Here, we present a strategy to rapidly identify and assemble synthetic human variable heavy (VH) domains toward neutralizing epitopes. We constructed a VH-phage library and targeted the angiotensin-converting enzyme 2 (ACE2) binding interface of the SARS-CoV-2 Spike receptor-binding domain (Spike-RBD). Using a masked selection approach, we identified VH binders to two non-overlapping epitopes and further assembled these into multivalent and bi-paratopic formats. These VH constructs showed increased affinity to Spike (up to 600-fold) and neutralization potency (up to 1,400-fold) on pseudotyped SARS-CoV-2 virus when compared to standalone VH domains. The most potent binder, a trivalent VH, neutralized authentic SARS-CoV-2 with a half-maximal inhibitory concentration (IC50) of 4.0 nM (180 ng ml-1). A cryo-EM structure of the trivalent VH bound to Spike shows each VH domain engaging an RBD at the ACE2 binding site, confirming our original design strategy.


Evaluation of Children's Thermal Environment in Nursery School: Through the Questionnaire and Measurement of Wearable Sensors Approach.
Due to psychological and physical differences, children are more vulnerable to the influence of the surrounding environment than adults. A nursery school in Japan was selected as the research object. The actual thermal environment of children aged 1 to 5 in the classroom was evaluated based on measured data in winter and summer. Through a questionnaire survey of nursery teachers, this paper analyzed and compared the relationship between teachers' thermal adaptation behavior and children's thermal sensation. Compared with the traditional fixed-points measurement method, a method of wearable sensors for children was proposed to measure the indoor temperature distribution. The traditional measurement results showed that 73% of classroom indoor temperatures and humidity do not meet the thermal comfort standard stipulated by the government. The method proposed in this paper indicates that: (1) nursery teachers' thermal adaptation behavior may not be based on children's thermal sensations; (2) solar radiation and weather context could lead to uneven indoor horizontal temperature distribution, hence, specific attention should be paid to the thermal environment when children move to the window side; and (3) the density of occupants causes the temperature around the human body to be relatively high. We suggest that teachers improve the thermal comfort of gathered children through thermal adaptive behaviors. The results of the study provide valuable information for nursery managers to formulate effective indoor thermal environment strategies from the perspective of children.


Optimal dilutions of S-PRG filler eluate for experiments on human gingival fibroblasts in vitro.
The present study attempted to identify the optimal dilution at which at which the effects of surface reaction-type pre-reacted glass-ionomer (S-PRG) filler eluate on human gingival fibroblasts (HGF) may be safely examined in vitro. S-PRG filler is a material that releases six ions and exerts strong caries-suppressing effects. We prepared S-PRG filler eluate in which S-PRG filler and α-MEM were mixed as a medium for HGF. This eluate contains six ions that are released from S-PRG filler. All cells died in proliferation experiments on HGF using S-PRG filler eluate, which demonstrated that unless S-PRG filler eluate was diluted, the ion concentration was strongly cytotoxic. S-PRG filler eluate diluted by 1/100 or more with the addition of 2% or more of FBS was safe for use. We herein successfully established the optimal dilution of S-PRG filler eluate at which HGF may be safely examined in vitro.


Differences in infant mortality and their implications for policy.
"This note tries to identify a few social and environmental factors that explain variation in infant mortality among some of the developing and developed countries of the world. Using the data of the Population Reference Bureau's World's Children Wall Chart, the authors have shown that access to drinking water supply is important as a single factor in reducing infant mortality. But adult female literacy and percentage of the labour force engaged in agriculture are more important. Female literacy has turned out to be the most crucial factor irrespective of the development status of the countries."


Using point cloud data to improve three dimensional gaze estimation.
This paper addresses the problem of estimating gaze location in the 3D environment using a remote eye tracker. Instead of relying only on data provided by the eye tracker, we investigate how to integrate gaze direction with the point-cloud-based representation of the scene provided by a Kinect sensor. The algorithm first combines the gaze vectors for the two eyes provided by the eye tracker into a single gaze vector emanating from a point in between the two eyes. The gaze target in the three dimensional environment is then identified by finding the point in the 3D point cloud that is closest to the gaze vector. Our experimental results demonstrate that the estimate of the gaze target location provided by this method is significantly better than that provided when considering gaze information alone. It is also better than two other methods for integrating point cloud information: (1) finding the 3D point closest to the gaze location as estimated by triangulating the gaze vectors from the two eyes, and (2) finding the 3D point with smallest average distance to the two gaze vectors considered individually. The proposed method has an average error of 1.7 cm in a workspace of 25 × 23 × 24 cm located at a distance of 60 cm from the user.


Aortic valve imaging using 18F-sodium fluoride: impact of triple motion correction.
Current 18F-NaF assessments of aortic valve microcalcification using 18F-NaF PET/CT are based on evaluations of end-diastolic or cardiac motion-corrected (ECG-MC) images, which are affected by both patient and respiratory motion. We aimed to test the impact of employing a triple motion correction technique (3 × MC), including cardiorespiratory and gross patient motion, on quantitative and qualitative measurements. Fourteen patients with aortic stenosis underwent two repeat 30-min PET aortic valve scans within (29 ± 24) days. We considered three different image reconstruction protocols; an end-diastolic reconstruction protocol (standard) utilizing 25% of the acquired data, an ECG-gated (four ECG gates) reconstruction (ECG-MC), and a triple motion-corrected (3 × MC) dataset which corrects for both cardiorespiratory and patient motion. All datasets were compared to aortic valve calcification scores (AVCS), using the Agatston method, obtained from CT scans using correlation plots. We report SUVmax values measured in the aortic valve and maximum target-to-background ratios (TBRmax) values after correcting for blood pool activity. Compared to standard and ECG-MC reconstructions, increases in both SUVmax and TBRmax were observed following 3 × MC (SUVmax: Standard = 2.8 ± 0.7, ECG-MC = 2.6 ± 0.6, and 3 × MC = 3.3 ± 0.9; TBRmax: Standard = 2.7 ± 0.7, ECG-MC = 2.5 ± 0.6, and 3 × MC = 3.3 ± 1.2, all p values ≤ 0.05). 3 × MC had improved correlations (R2 value) to the AVCS when compared to the standard methods (SUVmax: Standard = 0.10, ECG-MC = 0.10, and 3 × MC = 0.20; TBRmax: Standard = 0.20, ECG-MC = 0.28, and 3 × MC = 0.46). 3 × MC improves the correlation between the AVCS and SUVmax and TBRmax and should be considered in PET studies of aortic valves using 18F-NaF.


Outcomes of endoscopy in patients with iron deficiency anemia after Billroth II partial gastrectomy.
To determine the frequency of gastrointestinal lesions detected by upper endoscopy and colonoscopy in patients who developed iron deficiency anemia after Billroth II surgery. The authors reviewed the medical records of 116 consecutive patients with a Billroth II partial gastrectomy and 232 age- and gender-matched controls without gastric surgery who were referred for endoscopy to evaluate iron deficiency anemia over a 5-year period. Clinically important lesions were detected in 22.4% of the patients with gastric surgery and in 59.5% of those with intact stomachs (p < 0.001). In the gastric surgery group, clinically important lesions were found more often in the upper gastrointestinal tract than in the colon (19.0% vs. 3.4%, p < 0.001). In the nonsurgical group, the diagnostic yields of upper endoscopy and colonoscopy were not significantly different (38.4% vs. 32.8%, p = 0.24). Synchronous lesions in the upper and lower gastrointestinal tract were significantly less common in the group of patients with gastric surgery compared with those without gastric surgery (0.0% vs. 11.6%, p < 0.001). Small bowel biopsies and small bowel follow-through did not identify any additional lesions. In the gastric surgery group, multivariate analysis identified abdominal symptoms (OR = 11.2, 95% CI 3.2-39.2, p < 0.001), a positive result on fecal occult blood testing (OR = 6.4, 95% CI 2.0-20.3, p = 0.002), and Billroth II surgery at least 10 years before evaluation (OR = 5.4, 95% CI 1.7-16.7, p = 0.004) as independent predictors of identifying a clinically important lesion by endoscopy. Upper endoscopy had a significantly higher diagnostic yield than colonoscopy in patients who developed iron deficiency anemia after Billroth II surgery. Prospective studies are necessary to determine the role and cost-effectiveness of colonoscopy in the evaluation of iron deficiency anemia in this patient population.


Action-Specific Perception & Performance on a Fitts's Law Task in Virtual Reality: The Role of Haptic Feedback.
While user's perception and performance are predominantly examined independently in virtual reality, the Action-Specific Perception (ASP) theory postulates that the performance of an individual on a task modulates this individual's spatial and time perception pertinent to the task's components and procedures. This paper examines the association between performance and perception and the potential effects that tactile feedback modalities could generate. This paper reports a user study (N=24), in which participants performed a standardized Fitts's law target acquisition task by using three feedback modalities: visual, visuo-electrotactile, and visuo-vibrotactile. The users completed 3 Target Sizes × 2 Distances × 3 feedback modalities = 18 trials. The size perception, distance perception, and (movement) time perception were assessed at the end of each trial. Performance-wise, the results showed that electrotactile feedback facilitates a significantly better accuracy compared to vibrotactile and visual feedback, while vibrotactile provided the worst accuracy. Electrotactile and visual feedback enabled a comparable reaction time, while the vibrotactile offered a substantially slower reaction time than visual feedback. Although amongst feedback types the pattern of differences in perceptual aspects were comparable to performance differences, none of them was statistically significant. However, performance indeed modulated perception. Significant action-specific effects on spatial and time perception were detected. Changes in accuracy modulate both size perception and time perception, while changes in movement speed modulate distance perception. Also, the index of difficulty was found to modulate all three perceptual aspects. However, individual differences appear to affect the magnitude of action-specific effects. These outcomes highlighted the importance of haptic feedback on performance, and importantly the significance of action-specific effects on spatial and time perception in VR, which should be considered in future VR studies.


Addition of a Vascular Bundle Accelerates Bone Union in Femoral Bone Defects.
The Masquelet method has become increasingly popular for the treatment of bone defects in recent years. In this method, an induced membrane (IM) with abundant blood circulation, stem cells, and osteogenesis-promoting factors is formed by implanting bone cement during the first surgery. This IM stimulates bone formation in the bone defect after implantation of the bone graft during the second surgery. However, the Masquelet method requires two surgeries and thus a longer treatment period. In the present study, we investigated whether bone defects could be reconstructed in a single surgery by introducing a vascular bundle into the bone defect as an alternative to the IM, in addition to bone grafting. Thirty-six 12-week-old female Sprague-Dawley rats were used. After creating a 5-mm long bone defect in the femur, a mixture of autologous and artificial bone was grafted into the defect, and a saphenous arteriovenous vascular bundle was introduced. The animals were divided into three groups: the control group (bone defect only), the BG group (bone grafting only), and the BG + V group (bone grafting + vascular bundle introduction). After surgery, radiological and histological evaluations were performed to assess osteogenesis and angiogenesis in bone defects. In the BG + V group, significant bone formation was observed in the bone defect on radiological and histological evaluations, and the amount of bone formation was significantly higher than that in the other two groups. Furthermore, cortical bone continuity was observed in many specimens in the BG + V group. On histological evaluation, the number of blood vessels was also significantly higher in the BG + V group than in the other two groups. Our results suggest that the introduction of a vascular bundle in addition to bone grafting can promote bone formation in bone defects and allow for complete bone defect reconstruction in a single surgery.


In vitro recombination catalyzed by bacterial class 1 integron integrase IntI1 involves cooperative binding and specific oligomeric intermediates.
Gene transfer via bacterial integrons is a major pathway for facilitating the spread of antibiotic resistance genes across bacteria. Recently the mechanism underlying the recombination catalyzed by class 1 integron recombinase (IntI1) between attC and attI1 was highlighted demonstrating the involvement of a single-stranded intermediary on the attC site. However, the process allowing the generation of this single-stranded substrate has not been determined, nor have the active IntI1*DNA complexes been identified. Using the in vitro strand transfer assay and a crosslink strategy we previously described we demonstrated that the single-stranded attC sequences could be generated in the absence of other bacterial proteins in addition to IntI. This suggests a possible role for this protein in stabilizing and/or generating this structure. The mechanism of folding of the active IntI*DNA complexes was further analyzed and we show here that it involves a cooperative binding of the protein to each recombination site and the emergence of different oligomeric species specific for each DNA substrate. These findings provide further insight into the recombination reaction catalyzed by IntI1.


Evaluating the identity and diiron core transformations of a (μ-oxo)diiron(III) complex supported by electron-rich tris(pyridyl-2-methyl)amine ligands.
The composition of a (μ-oxo)diiron(III) complex coordinated by tris[(3,5-dimethyl-4-methoxy)pyridyl-2-methyl]amine (R(3)TPA) ligands was investigated. Characterization using a variety of spectroscopic methods and X-ray crystallography indicated that the reaction of iron(III) perchlorate, sodium hydroxide, and R(3)TPA affords [Fe(2)(μ-O)(μ-OH)(R(3)TPA)(2)](ClO(4))(3) (2) rather than the previously reported species [Fe(2)(μ-O)(OH)(H(2)O)(R(3)TPA)(2)](ClO(4))(3) (1). Facile conversion of the (μ-oxo)(μ-hydroxo)diiron(III) core of 2 to the (μ-oxo)(hydroxo)(aqua)diiron(III) core of 1 occurs in the presence of water and at low temperature. When 2 is exposed to wet acetonitrile at room temperature, the CH(3)CN adduct is hydrolyzed to CH(3)COO(-), which forms the compound [Fe(2)(μ-O)(μ-CH(3)COO)(R(3)TPA)(2)](ClO(4))(3) (10). The identity of 10 was confirmed by comparison of its spectroscopic properties with those of an independently prepared sample. To evaluate whether or not 1 and 2 are capable of generating the diiron(IV) species [Fe(2)(μ-O)(OH)(O)(R(3)TPA)(2)](3+) (4), which has previously been generated as a synthetic model for high-valent diiron protein oxygenated intermediates, studies were performed to investigate their reactivity with hydrogen peroxide. Because 2 reacts rapidly with hydrogen peroxide in CH(3)CN but not in CH(3)CN/H(2)O, conditions that favor conversion to 1, complex 1 is not a likely precursor to 4. Compound 4 also forms in the reaction of 2 with H(2)O(2) in solvents lacking a nitrile, suggesting that hydrolysis of CH(3)CN is not involved in the H(2)O(2) activation reaction. These findings shed light on the formation of several diiron complexes of electron-rich R(3)TPA ligands and elaborate on conditions required to generate synthetic models of diiron(IV) protein intermediates with this ligand framework.


Temporal variations of metallothionein and metal concentrations in the digestive gland of oysters (Crassostrea gigas) from a clean and a metal-rich site.
The concentrations of metallothionein (MT) in bivalves, a potential biomarker of metal pollution, are variable according to specific organs, the highest concentrations being encountered in the digestive glands of oysters. Thus, the present study has been focussed on this organ with a view to validate the use of MT as a biomarker in the field, the temporal changes of metal and metallothionein concentrations have been examined from March to October 1997 in the digestive gland of resident oysters from a clean site (Bay of Bourgneuf, France) and a metal-rich site, the Gironde estuary which has been shown as the most Cd-contaminated marine area in France but is also enriched with Cu and Zn. Moreover, oysters from the clean site have been translocated to the Gironde estuary over the same period. Taking into account all the samples collected over the 7 months of the study, MT concentrations in the digestive gland were positively correlated with weight whereas metal levels were negatively correlated with weight. However, considering monthly samples including specimens from both sites (resident or translocated oysters), a positive correlation was shown between MT and metal concentrations in autumn (September and October) but not in spring and summer. These findings limit the interest of using the digestive gland of oysters as the preferred tissue for the determination of MT concentration as a biomarker.The alternative use of gills should be considered.


Primary Indicators to Systematically Monitor COVID-19 Mitigation and Response - Kentucky, May 19-July 15, 2020.
State and local health departments in the United States are using various indicators to identify differences in rates of reported coronavirus disease 2019 (COVID-19) and severe COVID-19 outcomes, including hospitalizations and deaths. To inform mitigation efforts, on May 19, 2020, the Kentucky Department for Public Health (KDPH) implemented a reporting system to monitor five indicators of state-level COVID-19 status to assess the ability to safely reopen: 1) composite syndromic surveillance data, 2) the number of new COVID-19 cases,* 3) the number of COVID-19-associated deaths,† 4) health care capacity data, and 5) public health capacity for contact tracing (contact tracing capacity). Using standardized methods, KDPH compiles an indicator monitoring report (IMR) to provide daily analysis of these five indicators, which are combined with publicly available data into a user-friendly composite status that KDPH and local policy makers use to assess state-level COVID-19 hazard status. During May 19-July 15, 2020, Kentucky reported 12,742 COVID-19 cases, and 299 COVID-19-related deaths (1). The mean composite state-level hazard status during May 19-July 15 was 2.5 (fair to moderate). IMR review led to county-level hotspot identification (identification of counties meeting criteria for temporal increases in number of cases and incidence) and facilitated collaboration among KDPH and local authorities on decisions regarding mitigation efforts. Kentucky's IMR might easily be adopted by state and local health departments in other jurisdictions to guide decision-making for COVID-19 mitigation, response, and reopening.


Short-range control of cell differentiation in the Arabidopsis root meristem.
Meristems are distinctive regions of plants that have capacity for continuous growth. Their developmental activity generates the majority of plant organs. It is currently unknown how cell division and cell differentiation are orchestrated in meristems, although genetic studies have demonstrated the relevance of a proper balance between the two processes. Root meristems contain a distinct central region of mitotically inactive cells, the quiescent centre, the function of which has remained elusive until now. Here we present laser ablation and genetic data that show that in Arabidopsis thaliana the quiescent centre inhibits differentiation of surrounding cells. Differentiation regulation occurs within the range of a single cell, in a manner strikingly similar to examples in animal development, such as during delamination of Drosophila neuroblasts. Our data indicate that pattern formation in the root meristem is controlled by a balance between short-range signals inhibiting differentiation and signals that reinforce cell fate decisions.


Complete mitochondrial genome of the pseudobream, Pseudobrama simoni (Teleostei:Cypriniformes:Cyprinidae).
The Pseudobrama simoni (Bleeker) is the only one species within the genus Pseudobrama of the subfamily Xenocyprinae. In this study, we first determined the complete mitochondrial genome sequence of the P. simoni. The whole mitogenome is 16,618 bp in size, consisting of 13 protein-coding genes, 22 transfer RNA (tRNA) genes, 2 ribosomal RNA (rRNA) genes and 1 control region. The gene order and molecule structure are similar to most vertebrates. The complete mitogenome of P. simoni provides the valuable information for the biogeographic and phylogenetic studies on the subfamily Xenocyprinae.


Serum and intratesticular sex steroids in azoospermic men: how do they correlate?
Five intratesticular sex steroids (testosterone, dihydrotestosterone, androstenedione, estradiol and epitestosterone) along with six serum hormones (LH, FSH, prolactin, SHBG, testosterone and estradiol) were determined in 84 non-obstructive azoospermic men, in order to evaluate to what extent serum and testicular tissue as well as individual hormones in the same material mutually correlate. With exception of androstenedione, tight correlations were found among tissue content of sex steroids, while only weak correlation was recorded between serum and testicular concentrations of major sex steroids testosterone and estradiol. It points to importance of measurement of intratesticular steroids in combination with examination of sperm parameters for assessment of testicular function and spermatogenesis.


After the double helix: Rosalind Franklin's research on Tobacco mosaic virus.
Rosalind Franklin is best known for her informative X-ray diffraction patterns of DNA that provided vital clues for James Watson and Francis Crick's double-stranded helical model. Her scientific career did not end when she left the DNA work at King's College, however. In 1953 Franklin moved to J. D. Bernal's crystallography laboratory at Birkbeck College, where she shifted her focus to the three-dimensional structure of viruses, obtaining diffraction patterns of Tobacco mosaic virus (TMV) of unprecedented detail and clarity. During the next five years, while making significant headway on the structural determination of TMV, Franklin maintained an active correspondence with both Watson and Crick, who were also studying aspects of virus structure. Developments in TMV research during the 1950s illustrate the connections in the emerging field of molecular biology between structural studies of nucleic acids and of proteins and viruses. They also reveal how the protagonists of the "race for the double helix" continued to interact personally and professionally during the years when Watson and Crick's model for the double-helical structure of DNA was debated and confirmed.


Long-term MRI and clinical follow-up of symptomatic and presymptomatic carriers of dysferlin gene mutations.
We report the results of a longitudinal study involving MRI and clinical follow-up in nine siblings from four families with Miyoshi myopathy (MM). All individuals carried pathogenic dysferlin gene (DYSF) mutations with six of them suffering from symptomatic disease and three being presymptomatic. In presymptomatic subjects, MRI was sensitive to detect alterations in muscle tissue years before disease onset. The first MRI alteration to disclose was evidence for myoedema in dorsal compartment muscles of the legs followed by fatty degeneration. Moreover, MRI changes anticipated the topography of subsequent clinical muscle involvement and progressed from distal to proximal dorsal leg muscles. In symptomatic subjects, MRI changes reflected the pattern and severity of clinical muscle involvement. MRI evidence, however, suggests that muscle involvement is much more prominent in early disease stages than clinically seen. Clinical follow-up up to 8 years made evident that MM onset occurs at a mean age of 18.4 years. The most prominent initial deficit was impaired tiptoe gait due to muscle plantarflexor dysfunction followed by impaired dorsiflexor function. Dorsal compartments were predominantly affected not only in distal but also in proximal leg muscles, and a more rapid progression was noticed during the early phase of the disease. Our data suggest that MRI is a helpful diagnostic tool for an early diagnosis of MM and other distal myopathies since it provides sensitive and topographic information about initial and even preclinical muscle involvement. This is of particular relevance in Miyoshi myopathy because distinct CK elevation is present long before its clinical onset and often misdiagnosed as "idiopathic".


[Target and therapeutic microbubbles].
Because ultrasound microbubbles lower the threshold for cavitation by ultrasound energy, they may be used as cavitation nuclei for drug and gene delivery. By tailoring the physical properties of microbubbles and coating materials, drugs and genetic drugs can be incorporated into ultrasound contrast agents. As the microbubbles enter the region of insonation, the microbubbles cavitate, locally releasing the therapeutic agents.


[Modern methods of surgical treatment of hallux valgus deformity].
Hallux valgus is the most common deformity of the foot, affecting 2-4% of the population. The disease is mostly genetic, but there are also exogenous factors. Conservative treatment for the use of orthotics is usually ineffective and only surgery leads to a complete cure. The indications for surgery are pain and/or problems with shoe choosing. AP and lateral foot standing X-ray film is necessary for the proper qualifications. Depending on the size of the hallux valgus angle (HVA) and intermetatarsal angle (IMA) deformations are divided into mild, moderate, advanced and severe. In addition, we assess congruency of the first metatarsophalangeal joint (MTP I). Depending on the degree of deformation and the ascertained pathology we combine different procedures, such as: bunionectomy with medial capsulorrhaphy, osteotomy of basal phalanx of the great toe, distal, midshaft or proximal osteotomy of the first metatarsal, double osteotomy of the first metatarsal, MTP I joint arthrodesis and arthrodesis of medial cuneiform-first metatarsal I joint. In non-congruent MTP I joint we usually perform lateral release. In some indications we also use arthroplasty and minimally invasive techniques. Only the proper qualification for surgery provides a good clinical effect.


Chaplaincy research: its value, its quality, and its future.
The article is divided into four major sections, the first of which presents and discusses various reasons given by major researchers in the field why chaplains should do research. The second section summarizes findings on the sophistication of research on religion and health published in (a) medical and other healthcare journals, and (b) specialty journals on religion and health, chaplaincy, and pastoral care and counseling. The third section revisits suggestions that have been made by prominent chaplain researchers to increase and improve research by chaplains. The last section offers some suggestions for expanding several lines of current research in the future, including research: (1) to elucidate the nature of spiritual care chaplains provide to different populations, including patients, families and staff; (2) to assess the prevalence and intensity of patients' spiritual needs and the degree to which they are being met; (3) to identify that subset of patients who are spiritually at risk in terms of having high needs and slow religious resources; (4) to identify the biological causal mechanisms by which religion influences health; and (5) to measure the effectiveness of chaplain interventions.


Increase in lymphocyte subsets following treatment of HIV-associated neutropenia with granulocyte colony-stimulating factor.
Recombinant human granulocyte colony-stimulating factor (G-CSF) has been used to treat neutropenia in patients with cancer and HIV disease. Since lymphocyte counts have been reported to increase with G-CSF therapy, we studied the effect of G-CSF on lymphocyte subsets in HIV-infected patients. Six patients with HIV-associated neutropenia were treated with G-CSF and had significant increases in white blood cell counts. G-CSF induced a significant rise in total lymphocytes, total T-cells, CD8 T-cells, and natural killer cells. A smaller but statistically significant increase in CD4 T-cells and cytotoxic CD8 T-cells was also noted. We conclude that G-CSF has the ability to raise lymphocyte subset levels in patients with HIV disease. The potential immunologic benefit of G-CSF therapy merits further investigation.


Monitoring of Yersinia enterocolitica strains from free-living animals using different methods.
The aim of the study was to monitor Y. enterocolitica strains from free-living animals captured during 2011-2014 hunting seasons in Poland using warm (ITC) and cold (PSB) enrichment and molecular examination. Over 1600 samples have been cultured. After ITC/PSB enrichment 237 strains presenting features characteristic for Y. enterocolitica were isolated. Molecular examination using multiplex PCR revealed 140 isolates from PSB and 78 from ITC. The concentration of pathogenic Yersinia in asymptomatic carriers is low and the PCR detection should be preceded by bacteriological examination.


Alendronate-functionalized double network hydrogel scaffolds for effective osteogenesis.
Development of artificial bone substitutes mimicking the extracellular matrix is a promising strategy for bone repair and regeneration. In views of the actual requirement of biomechanics, biodegradability, and bioactivity, herein, a double-network (DN) hydrogel was constructed by interspersing a methacrylated gelatin (GelMA) network into alendronate (ALN)-modified oxidized alginate (OSA) network via Schiff base reaction and photo-crosslinking process to promote in situ bone regeneration. This GelMA@OSA-ALN DN hydrogel possessed favorable network and pores, good biocompatibility, and enhanced biomechanics. Notably, the introduction of Schiff base furnished the ND hydrogel scaffold with pH-responsive biodegradation and sustained ALN drug release delivery, which could provide effective bioactivity, upregulate osteogenesis-related genes, and promote the cell viability, growth, proliferation, and osteogenesis differentiation for bone regeneration. Therefore, we provide a new insight to develop functional DN hydrogel scaffold toward governing the on-demand drug release and achieving the stem cell therapy, which will be developed into the minimally invasive gelling system to prolong local delivery of bisphosphonates for the bone-related diseases.


Modified kloen approach treatment for acetabular fractures.
To evaluate the feasibility and efficacy of modified Kloen approach for the treatment of ace tabular fractures through lateral window exposure beneath fascia iliaca with superior ramus of pubis exposure by internal small incision. Matta radiological criteria was employed to evaluate the post operation recovery, and modified D'Aubigne-Postel evaluation system was adopted for demonstration of hip joint function condition. There is no incision infection, neurovascular trauma or postoperative lymphorrhagia. 42 patients cooperated with the following up of 11.2 months. The average bone healing time was 13 weeks. Matta radiological criteria was to evaluate the postoperative fracture quality, 18 case with excellent recovery, 16 cases with good recovery, 4 cases with normal recovery and 1 case with bad recovery. Modified D'Aubigne-Postel evaluation was taken 6 months after surgery, 17 cases with excellent recovery, 22 cases with good recovery, 2 cases with normal recovery and 1 case with bad recovery. There was no internal fixation loosening, breakage or inguinal hernia. The modified Kloen approach can improve iliofemoral vascular activity, expense exposure range for restoration and fixation. Besides, the exposure of articular surface could ensure the condition of restoration quality, and avoid the incidence of postoperative hernia.


Heritable variation and evolution under favourable and unfavourable conditions.
Genetic variability in quantitative traits can change as a direct response to the environmental conditions in which they are expressed. Consequently, similar selection in different environments might not be equally effective in leading to adaptation. Several hypotheses, including recent ones that focus on the historical impact of selection on populations, predict that the expression of genetic variation will increase in unfavourable conditions. However, other hypotheses lead to the opposite prediction. Although a consensus is unlikely, recent Drosophila and bird studies suggest consistent trends for morphological traits under particular conditions.


Optical-Clock-Based Time Scale.
A time scale is a procedure for accurately and continuously marking the passage of time. It is exemplified by Coordinated Universal Time (UTC) and provides the backbone for critical navigation tools such as the Global Positioning System. Present time scales employ microwave atomic clocks, whose attributes can be combined and averaged in a manner such that the composite is more stable, accurate, and reliable than the output of any individual clock. Over the past decade, clocks operating at optical frequencies have been introduced that are orders of magnitude more stable than any microwave clock. However, in spite of their great potential, these optical clocks cannot be operated continuously, which makes their use in a time scale problematic. We report the development of a hybrid microwave-optical time scale, which only requires the optical clock to run intermittently while relying upon the ensemble of microwave clocks to serve as the flywheel oscillator. The benefit of using a clock ensemble as the flywheel oscillator instead of a single clock can be understood by the Dick-effect limit. This time scale demonstrates for the first time subnanosecond accuracy over a few months, attaining a fractional frequency stability of 1.45 × 10-16 at 30 days and reaching the 10-17 decade at 50 days, with respect to UTC. This time scale significantly improves the accuracy in timekeeping and could change the existing time-scale architectures.


Inhibitory action of auxin on root elongation not mediated by ethylene.
The inhibitory effects of indole-3-acetic acid (IAA) and 1-aminocyclopropane-1-carboxylic acid (ACC) on elongation growth of pea (Pisum sativum L.) seedling roots were investigated in relation to the effects of these compounds on ethylene production by the root tips. When added to the growth solution both compounds caused a progressively increasing inhibition of growth within the concentration range of 0.01 to 1 micromolar. However, only ACC increased ethylene production in root tips excised from the treated seedlings after 24 hours. High auxin concentrations caused a transitory increase of ethylene production during a few hours in the beginning of the treatment period, but even in 1 micromolar IAA this increase was too low to have any appreciable effect on growth. ACC, but not IAA, caused growth curvatures, typical of ethylene treatment, in the root tips. IAA caused conspicuous swelling of the root tips while ACC did not. Cobalt and silver ions reversed the growth inhibitory effects induced by ACC but did not counteract the inhibition of elongation or swelling caused by IAA. The growth effects caused by the ACC treatments were obviously due to ethylene production. We found no evidence to indicate that the growth inhibition or swelling caused by IAA is mediated by ethylene. It is concluded that the inhibitory action of IAA on root growth is caused by this auxin per se.


Do treatment effects vary among differing baseline depression criteria in depression in Alzheimer's disease study ± 2 (DIADS-2)?
To determine if the effect of sertraline in the depression in Alzheimer's disease study - 2 (DIADS-2) differed in subgroups of patients defined by baseline depression criteria. DIADS-2 was a randomized, parallel, placebo-controlled, multicenter trial designed to evaluate the efficacy and safety of sertraline (target dose of 100 mg/day) for the treatment of depression in patients with Alzheimer's disease. DIADS-2 enrolled 131 patients who met criteria for the depression of Alzheimer's disease (dAD). Analyses reported here examined if the effect of sertraline differed in various subgroups, including those meeting criteria for major depressive episode (MaD), minor depressive episode (MiD), and Alzheimer's-associated affective disorder (AAAD) at baseline. At baseline, 52 of 131 participants (39.7%) met criteria for MaD, 54 (41.2%) for MiD, and 90 (68.7%) for AAAD. For the primary outcome of modified Alzheimer's Disease Cooperative Study Clinical Global Impression of Change (mADCS-CGIC) scores at 12 weeks of follow-up, the odds of being at or better than a given mADCS-CGIC category did not significantly differ between the two treatment groups for those patients with MaD at baseline (OR(sertraline) = 0.66 [95% CI: 0.24, 1.82], p = 0.42); tests for interactions between treatment group and baseline depression diagnostic subgroup were not significant for MaD versus MiD versus neither (χ(2) = 1.05 (2df), p = 0.59) or AAAD versus no AAAD (χ(2) = 0.06 (1df), p = 0.81). There was no evidence that sertraline treatment was more efficacious in those patients meeting baseline criteria for MaD compared to MiD or to neither.


Differential adaptations to eccentric versus conventional resistance training in older humans.
We hypothesized that training with eccentric contractions only (therefore using higher loads) would yield greater muscle structural and strength gains compared with conventional resistance training. Nine older adults (mean +/- s.d. age, 74 +/- 3 years) were assigned to a conventional (CONV) resistance training group performing both concentric and eccentric contractions and 10 (age, 67 +/- 2 years) to an eccentric-only (ECC) resistance training group. Both groups trained three times per week for 14 weeks at 80% of the five-repetition maximum, specific to each training mode. Maximal knee extensor torque was assessed during isometric, concentric and eccentric contractions across a range of angular velocities (0-3.49 rad s(-1)). Vastus lateralis muscle architecture (fascicle length, pennation angle and muscle thickness) was assessed in vivo at rest using ultrasonography. Training increased fascicle length in both groups, but the increase was significantly greater in the ECC (20% increase) than the CONV group (8% increase). Conversely, pennation angle significantly increased in the CONV (35% increase) but not in the ECC group (5% increase). Muscle thickness increased to a similar extent in both groups (approximately 12% increase). In the ECC group, eccentric knee extensor torque increased by 9-17% across velocities, but concentric torque was unchanged. Conversely, in the CONV group, concentric torque increased by 22-37% across velocities, but eccentric torque was unchanged. Instead, isometric torque increased to a similar extent in both groups (approximately 8% increase). Thus, the two training regimens resulted in differential adaptations in muscle architecture and strength. These results suggest that the stimulus for adding sarcomeres in-series and in-parallel may be different, which implies that different myogenic responses were induced by the two different training methods.


Hydroxyurea (hydroxycarbamide) for sickle cell disease.
Sickle cell disease (SCD) is one of the most common inherited diseases worldwide. It is associated with lifelong morbidity and a reduced life expectancy. Hydroxyurea (hydroxycarbamide), an oral chemotherapeutic drug, ameliorates some of the clinical problems of SCD, in particular that of pain, by raising foetal haemoglobin (HbF). This is an update of a previously published Cochrane Review. The aims of this review are to determine through a review of randomised or quasi-randomised studies whether the use of hydroxyurea in people with SCD alters the pattern of acute events, including pain; prevents, delays or reverses organ dysfunction; alters mortality and quality of life; or is associated with adverse effects. In addition, we hoped to assess whether the response to hydroxyurea in SCD varies with the type of SCD, age of the individual, duration and dose of treatment, and healthcare setting. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Haemoglobinopathies Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries. The date of the most recent search was 17 February 2022. Randomised and quasi-randomised controlled trials (RCTs and quasi-RCTs), of one month or longer, comparing hydroxyurea with placebo or standard therapy in people with SCD. Authors independently assessed studies for inclusion, carried out data extraction, assessed the risk of bias and assessed the quality of the evidence using GRADE. We included nine RCTs recruiting 1104 adults and children with SCD (haemoglobin SS (HbSS), haemoglobin SC (HbSC) or haemoglobin Sβºthalassaemia (HbSβºthal) genotypes). Studies lasted from six to 30 months. We judged the quality of the evidence for the first two comparisons below as moderate to low as the studies contributing to these comparisons were mostly large and well-designed (and at low risk of bias); however, the evidence was limited and imprecise for some outcomes such as quality of life, deaths during the studies and adverse events, and the results are applicable only to individuals with HbSS and HbSβºthal genotypes. We judged the quality of the evidence for the third and fourth comparisons to be very low due to the limited number of participants, the lack of statistical power (both studies were terminated early with approximately only 20% of their target sample size recruited) and the lack of applicability to all age groups and genotypes. Hydroxyurea versus placebo Five studies (784 adults and children with HbSS or HbSβºthal) compared hydroxyurea to placebo; four recruited individuals with only severe disease and one recruited individuals with all disease severities. Hydroxyurea probably improves pain alteration (using measures such as pain crisis frequency, duration, intensity, hospital admissions and opoid use) and life-threatening illness, but we found no difference in death rates (10 deaths occurred during the studies, but the rates did not differ by treatment group) (all moderate-quality evidence). Hydroxyurea may improve measures of HbF (low-quality evidence) and probably decreases neutrophil counts (moderate-quality evidence). There were no consistent differences in terms of quality of life and adverse events (including serious or life-threatening events) (low-quality evidence). There were fewer occurrences of acute chest syndrome and blood transfusions in the hydroxyurea groups. Hydroxyurea and phlebotomy versus transfusion and chelation Two studies (254 children with HbSS or HbSβºthal also with risk of primary or secondary stroke) contributed to this comparison. There were no consistent differences in terms of pain alteration, death or adverse events (low-quality evidence) or life-threatening illness (moderate-quality evidence). Hydroxyurea with phlebotomy probably increased HbF and decreased neutrophil counts (moderate-quality evidence), but there were more occurrences of acute chest syndrome and infections. Quality of life was not reported. In the primary prevention study, no strokes occurred in either treatment group but in the secondary prevention study, seven strokes occurred in the hydroxyurea and phlebotomy group (none in the transfusion and chelation group) and the study was terminated early. Hydroxyurea versus observation One study (22 children with HbSS or HbSβºthal also at risk of stoke) compared hydroxyurea to observation. Pain alteration and quality of life were not reported. There were no differences in life-threatening illness, death (no deaths reported in either group) or adverse events (very low-quality evidence). We are uncertain if hydroxyurea improves HbF or decreases neutrophil counts (very low-quality evidence). Treatment regimens with and without hydroxyurea One study (44 adults and children with HbSC) compared treatment regimens with and without hydroxyurea. Pain alteration, life-threatening illness and quality of life were not reported. There were no differences in death rates (no deaths reported in either group), adverse events or neutrophil levels (very low-quality evidence). We are uncertain if hydroxyurea improves HbF (very low-quality evidence). There is evidence to suggest that hydroxyurea may be effective in decreasing the frequency of pain episodes and other acute complications in adults and children with sickle cell anaemia of HbSS or HbSβºthal genotypes and in preventing life-threatening neurological events in those with sickle cell anaemia at risk of primary stroke by maintaining transcranial Doppler velocities. However, there is still insufficient evidence on the long-term benefits of hydroxyurea, particularly with regard to preventing chronic complications of SCD, or recommending a standard dose or dose escalation to maximum tolerated dose. There is also insufficient evidence about the long-term risks of hydroxyurea, including its effects on fertility and reproduction. Evidence is also limited on the effects of hydroxyurea on individuals with the HbSC genotype. Future studies should be designed to address such uncertainties.


Type 2 diabetes is not a risk factor for asymptomatic ischemic brain lesion--the Funagata study.
The purpose of this study is to clarify whether type 2 diabetes (DM) is a risk factor for asymptomatic (silent) ischemic brain lesion, which is controversial at present. The subjects (n=187), who showed normal results on both neurological and neuropsychological examinations, underwent a 75-g OGTT and were examined by brain MRI on T1-weighted, T2-weighted, and FLAIR (fluid-attenuated inversion recovery) images. Their brain MRIs were evaluated quantitatively with the ischemia rating scale defined here. The subjects were grouped based on their glucose tolerance: normal glucose tolerance (NGT) (n=48), impaired glucose tolerance (IGT) (n=62), and DM (n=65). The subjects with DM were further divided based on their duration of illness: 20 with short duration (short DM: 1.3+0.8 years) and 45 with long duration (long DM; 8.9+/-5.4 years). Ages were matched among the groups. The percentages of individuals with asymptomatic ischemic brain lesion were 81% in NGT, 74% in IGT, 65% in short DM, and 78% in long DM. No significant difference was observed among the groups in terms of the percentage. Namely, even in individuals with a long history of DM without clinical stroke, the prevalence of asymptomatic ischemic brain lesion was not different from that of the other groups. Multiple regression and multiple logistic regression analyses showed that age and hypertension were significant independent risk factors for asymptomatic ischemic brain lesion, whereas hypercholesterolemia, smoking, and glucose intolerance, including IGT, short DM and long DM, were not. DM is not a risk factor for asymptomatic ischemic brain lesion.