A Female Career in Research.
After a long career at the National Center for Health Statistics, I retired and joined the Stanford Prevention Research Center as an unpaid associate. I was once described by a former US Food and Drug Administration commissioner as "one of the great epidemiologists." The chair of the Harvard nutrition department, speaking on National Public Radio, once described my research as "rubbish." Both may be exaggerations. Here I address some of the events that led to these contrasting descriptions. I also address the extent to which the so-called Matilda effect may have influenced my career. Are women in science on an equal footing with men? The Matilda effect suggests not. Unlike the Matthew effect for scientists, whereby those of higher prestige accrue a disproportionate share of recognition and rewards, the Matilda effect proposes that women scientists are systematically undervalued and underrecognized. I could never get a faculty job and was often treated like an underling. Nonetheless I persevered to publish highly cited research on several high-profile and sometimes controversial topics. Though overt sexism in science and workplaces has diminished over the course of my career, progress toward eliminating unconscious bias has been slower. The Matthew and Matilda effects are still powerful forces that distort incentives and rewards in science.


Theodor Billroth: A Surgeon for the 21st Century.
This perspective article describes unique aspects of Theodor Billroth's personality and life, which enabled him to succeed and become a leading figure of 19th century medicine. These qualities are discussed with today's developing surgeon in mind.


Functional arterial and venous fate is determined by graded VEGF signaling and notch status during embryonic stem cell differentiation.
The aim of this work was to develop a mouse embryonic stem (ES) cell system addressing the early specification of the developing vasculature into functional arteries and veins. ES cells were differentiated 4 days on collagen-type IV coated dishes to obtain Flk1+ endothelial precursors. Sub-culture of these precursors for additional 4 days robustly generated, in a VEGF dose-dependent manner, mature endothelial cells. Arterial marker genes were specifically expressed in cultures differentiated with high VEGF concentration whereas the venous marker gene COUP-TFII was upregulated in endothelial cells induced through low and intermediate VEGF concentrations. This VEGF-dependent arterialization could be blocked by inhibition of Notch resulting in an arterial to venous fate switch. Functional and morphological studies, ie, measurement of sprout length, pericyte recruitment, and interleukin-I-induced leukocyte adhesion, further confirmed their arterial and venous identity. We conclude that endothelial cells with distinct molecular, morphological, and functional characteristics of arteries and veins can be derived through in vitro differentiation of ES cells in a VEGF dose-dependent and Notch-regulated manner.


TFEB Overexpression in the P301S Model of Tauopathy Mitigates Increased PHF1 Levels and Lipofuscin Puncta and Rescues Memory Deficits.
Transcription factor EB (TFEB) was recently shown to be a master regulator of autophagy lysosome pathway. Here, we successfully generated and characterized transgenic mice overexpressing flag-TFEB. Enhanced autophagy in the flag-TFEB transgenic mice was confirmed by an increase in the cellular autophagy markers, as determined by both immunoblots and transmission electron microscopy. Surprisingly, in the flag-TFEB mice we observed increased activity of senescence-associated β-galactosidase by ∼66% of neurons in the cortex (p < 0.001) and 73% of neurons in the hippocampus (p < 0.001). More importantly, flag-TFEB expression remarkably reduced the levels of paired-helical filament (PHF)-tau from 372% in the P301S model of tauopathy to 171% (p < 0.001) in the cortex, and from 436% to 212% (p < 0.001) in the hippocampus. Significantly, reduced levels of NeuN in the cortex (38%, p < 0.001) and hippocampus (25%, p < 0.05) of P301S mice were almost completely restored to WT levels in the P301S/flag-TFEB double-transgenic mice. Also, levels of spinophilin in both the cortex (p < 0.001) and hippocampus (p < 0.001) were restored almost to WT levels. Most importantly, the age-associated lipofuscin granules, which are generally presumed to be nondegradable, were reduced by 57% (p < 0.001) in the cortex and by 55% (p < 0.001) in the hippocampus in the double-transgenic mice. Finally, TFEB overexpression in the P301S mice markedly reversed learning deficits in terms of spatial memory (Barnes maze), as well as working and reference memories (T maze). These data suggest that the overexpression of TFEB can reliably enhance autophagy in vivo, reduce levels of PHF-tau, and thereby reverse the deposition of lipofuscin granules and memory deficits.


Electric field-controlled water permeation coupled to ion transport through a nanopore.
We report molecular dynamics simulations of a generic hydrophobic nanopore connecting two reservoirs which are initially at different Na(+) concentrations, as in a biological cell. The nanopore is impermeable to water under equilibrium conditions, but the strong electric field caused by the ionic concentration gradient drives water molecules in. The density and structure of water in the pore are highly field dependent. In a typical simulation run, we observe a succession of cation passages through the pore, characterized by approximately bulk mobility. These ion passages reduce the electric field, until the pore empties of water and closes to further ion transport, thus providing a possible mechanism for biological ion channel gating.


Minimally invasive preimplantation genetic testing using blastocyst culture medium.
Is minimally invasive chromosome screening (MICS) using blastocyst culture medium (BCM) sufficiently fast and accurate for preimplantation genetic testing (PGT). A new assay for MICS, named MICS-Inst achieved high-resolution, comprehensive chromosome ploidy detection using BCM. BCM is a viable source of genomic DNA for use in PGT. Forty-one vitrified blastocysts donated by 22 couples known to carry a chromosome rearrangement and 21 vitrified blastocysts donated from 8 couples with normal karyotypes were used in this study. Good-quality blastocysts, defined as Day 5 and Day 6 embryos ≥ BB (AA, AB, BA, BB) based on the Gardner system were used for analysis. Recruitment took place from May 2018 to August 2018. We performed PGT for structural rearrangements (PGT-SR) on 41 BCM, trophectoderm (TE) biopsy and blastocyst-stage embryo (BE) samples as well as PGT for aneuploidies (PGT-A) on 21 BCM, TE biopsy and BE samples. We made several significant modifications to the BCM composition (mixing blastocoel fluid and spent blastocyst medium) as well as the pre-existing multiple annealing and looping-based amplification cycles (MALBAC) techniques and library generation procedures. The design of a quasilinear preamplification (Pre-AMP) primer and AMP primers 1 and 2 enables the preparation of a next-generation sequencing library after the exponential amplification stage by introducing the Illumina P5 and P7 primers into the final products, which are then ready for sequencing. Sequencing was performed on the Illumina Hiseq 2500 platform with 2.0 Mb raw reads generated for each sample. For PGT-A, BCM and TE biopsy samples showed 90% and 86% clinical concordance with the corresponding BE samples, respectively. In addition, both BCM and TE biopsy samples showed 76% karyotype concordance with the corresponding BE samples. For PGT-SR, we successfully obtained ploidy information for all 23 chromosomes with the exception of any rearrangements involving the Y chromosome. Both BCM and TE biopsy samples showed 100% clinical concordance with the corresponding BE samples in detecting chromosomal rearrangements. BCM and TE biopsy samples showed 90% and 100% karyotype concordance with the corresponding BE samples, respectively. Additionally, no statistically significant differences were detected in the aforementioned values of the BCM and TE biopsy samples in either PGT-A or PGT-SR (P > 0.05). Moreover, we achieved accurate quantification of segmental abnormalities using BCM samples. In addition, MICS-Inst reduced the number of steps required for library preparation through the use of new primer designs, resulting in an overall time reduction of 7.5 h. This time reduction allows for the performance of fresh blastocyst transfers. The main limitation is that BE, rather the inner cell mass, was used as the standard to evaluate the chromosome screening results. These results show that MICS-Inst is effective in procedure and precision for PGT, and that it is possible to achieve fresh blastocyst transfer following PGT. The implications are significant, as these findings may lead to minimally invasive PGT methods in the future. This work was supported by the National Natural Science Foundation of China (No. 81671423 and No. 81402130), the National Key Research and Development Program of China (No. 2018YFC1003100), Liaoning Provincial Key Research and Development Program (No. 2018225090), the Fok Ying Tung Education Foundation (No. 151039) and Distinguished Talent Program of Shengjing Hospital (No. ME76). No competing interests declared.


Effect of long-term tacrolimus immunosuppression on renal function in liver transplant recipients.
To describe changes in renal function occurring after long-term treatment with tacrolimus in clinically stable liver transplant recipients, and to identify risk factors for a clinically significant decline in renal function in these patients. Retrospective cohort study. Setting. University medical center. Patients. Four hundred thirty-two patients aged 18 years or older who underwent liver transplantation between January 1, 1996, and December 31, 2000, and received tacrolimus as part of their immunosuppressive treatment regimen. Six hundred patients were identified from an electronic records review. Those who received multiorgan transplants, were not receiving their first liver transplant, or died during the hospitalization were excluded from the study. Outcomes measured were change in mean glomerular filtration rate (GFR) up to 5 years after transplantation, and proportion of patients with a decline in GFR of 30% or greater from baseline to the last recorded serum creatinine level. Covariates that affected this decline were identified using a logistic regression model. Patients were followed for a mean +/- SD of 3.7 +/- 2.0 years. Mean GFR showed a statistically significant decline from baseline to end of follow-up (67.7 +/- 25.6 vs 58.4 +/- 26.5 ml/min/1.73 m(2), p<0.001). The GFR declined by 30% or more in 154 (35.6%) patients. Increasing age (odds ratio [OR] = 1.03, p=0.020), female sex (OR = 1.92, p=0.006), higher baseline GFR (OR = 1.03, p<0.001), and diagnosis of diabetes mellitus (OR = 1.74, p=0.059) were identified as predictors of this outcome. After the acute posttransplantation period, liver transplant recipients given long-term treatment with tacrolimus experienced only small changes in GFR over time. Patients with diabetes and women had the highest risk of experiencing a clinically significant decline in renal function.


Perioperative confocal microscopy of the nail matrix in the management of in situ or minimally invasive subungual melanomas.
Although dermoscopy of the nail plate is helpful to discriminate between benign and malignant causes of nail pigmentations, there remain ambiguous cases in which a matricial biopsy is required. When a subungual melanoma is diagnosed histopathologically, a complementary surgical treatment is performed secondarily, the duration of postoperative disability being accordingly prolongated. The purpose of our study was to evaluate the feasibility of an intraoperative diagnosis by reflectance confocal microscopy (RCM). Our series included nine consecutive patients who underwent a matricial biopsy for an acquired melanonychia (one benign lentigo and eight melanomas). RCM examination was performed in vivo on the nail matrix after reclination of the nail plate, and/or ex vivo on the fresh tissue biopsy. RCM data were compared with histopathology. There was a good correlation between confocal and histopathological features. Seven melanoma cases were unequivocally diagnosed intraoperatively according to the confocal features, whereas the lentigo was correctly classified as a benign lesion according to RCM. The remaining lesion could not be unequivocally classified by RCM and corresponded histopathologically to an early melanoma that required immunostaining to be diagnosed. Intraoperative RCM examination of the nail matrix is an efficient diagnostic approach of melanonychia striata that permits an extemporaneous diagnosis of malignancy and therefore a one-step surgical treatment of in situ or minimally invasive melanoma, reducing dramatically the duration of postoperative disability.


Up-regulation of HER2 by gemcitabine enhances the antitumor effect of combined gemcitabine and trastuzumab emtansine treatment on pancreatic ductal adenocarcinoma cells.
Although pancreatic ductal adenocarcinomas (PDAs) widely express HER2, the expression level is generally low. If HER2 expression in PDA cells could be enhanced by treatment with a given agent, then combination therapy with that agent and trastuzumab emtansine (T-DM1), a chemotherapeutic agent that is a conjugate of trastuzumab, might lead to significant antitumor effects against PDA. Cell proliferation was examined by spectrophotometry. HER2 expression was examined by flow cytometry, immunoblot and quantitative reverse transcription polymerase chain reaction. T-DM1 binding to cells was examined by flow cytometry and enzyme-linked immunosorbent assay. Out of 5 tested human PDA cell lines, including MIA PaCa-2, three showed increases in HER2 expression after gemcitabine (GEM) treatment. The binding of T-DM1 to GEM-treated MIA PaCa-2 cells was higher than to untreated MIA PaCa-2 cells. Treatment with GEM and T-DM1 showed synergic cytotoxic effects on MIA PaCa-2 cells in vitro. Cells in the G2M phase of the cell cycle were retained after GEM treatment and showed higher levels of HER2 expression, possibly contributing to the synergic effect of GEM and T-DM1. Combined treatment with GEM and T-DM1 might confer a potent therapeutic modality against PDA as a result of GEM-mediated HER2 up-regulation.


Measuring psychosocial work quality and health: development of health care measures of measurement.
Demands on workload and work efficiency have increased because of ongoing global changes in health care organizations. Assessing and evaluating effects of changes on organizational and individual well-being require valid and reliable methods. Questionnaires from 3 large health care studies were used to develop instruments for work quality and health. Variable fields of work quality, health and well-being, and modifying factors were factor analyzed with replicated structures in new samples, including 6 factors of work quality, 5 health factors, and 2 modifying factors. All except 2 factors had high internal consistency (Cronbach's alpha = .69-.84) and low factor intercorrelations within areas. Social climate (but not individual resources) had, according to our model, a modifying effect on the work-health interaction.


Bioinformatics Identification of Candidate Biomarkers in Endomyocardial Biopsy and Peripheral Blood for Cardiac Allograft Rejection.
BACKGROUND Cardiac allograft rejection is still a crucial barrier to achieving satisfactory outcomes after surgery. In this study, we propose to find candidate biomarkers from endomyocardial biopsy (EMB) and peripheral blood (PB) samples for efficient diagnosis and treatment of cardiac allograft rejection. MATERIAL AND METHODS Microarray datasets were obtained from the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) of cardiac allograft rejection patients and control subjects from EMB and PB samples were screened using the online tool GEO2R. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of all samples' DEGs were performed with the DAVID online tool. Protein-protein interaction (PPI) networks were constructed and visualized using Cytoscape and the top 10 hub genes were selected. Finally, the most highly enriched GO and KEGG pathways of the top 10 hub genes were determined. RESULTS A total of 57 502 genes from EMB samples and 131 624 genes from PB samples were identified. Gene characteristics and enrichment analysis indicated that both EMB and PB samples contained DEGs involved in antigen presentation, immune cells activation, inflammatory process, and cellular injuries. In EMB samples, there were some DEGs related to heart tissue injury and cardiac malfunction. Moreover, DEGs that regulates hypoxia-induced factors and erythrocyte function in response of ischemia and hypoxia stress were present in PB samples but were absent in EMB samples. CONCLUSIONS The screened differentially expressed genes (DEGs) from EMB and PB samples of patients with cardiac graft rejection are potential candidate biomarkers of diagnosis and treatment.


Clinically unsuspected disseminated intravascular coagulation (DIC): an autopsy survey.
In a review of 768 consecutive autopsies, 21 (2.7%) clinically unsuspected cases of disseminated intravascular coagulation (DIC) syndrome were diagnosed by histologic examination. DIC was diagnosed by the presence of fibrin thrombi in arterioles, capillaries, venules, and medium-sized veins. Fibrin thrombi were found, in the descending order of frequency, in the brain, heart, lungs, kidneys, adrenals, spleen and liver. Most patients had multiple visceral involvement, with three showing fibrin thrombi in as many as ten organs. The density of fibrin thrombi was greatest in the spleen, followed by kidneys, liver, lungs, adrenals, brain, and heart. A review of clinical data showed that infections were the most common underlying conditions in 13 cases, including nine with positive bacterial cultures from blood or cerebrospinal fluid, or both. The results suggest that, despite increasing clinical recognition of DIC, a great number of patients remain unsuspected of having the DIC syndrome prior to postmortem examination.


Electron transfer-initiated epoxidation and isomerization chain reactions of β-caryophyllene.
The abundant sesquiterpene β-caryophyllene can be epoxidized by molecular oxygen in the absence of any catalyst. In polar aprotic solvents, the reaction proceeds smoothly with epoxide selectivities exceeding 70 %. A mechanistic study has been performed and the possible involvement of free radical, spin inversion, and electron transfer mechanisms is evaluated using experimental and computational methods. The experimental data-including a detailed reaction product analysis, studies on reaction parameters, solvent effects, additives and an electrochemical investigation-all support that the spontaneous epoxidation of β-caryophyllene constitutes a rare case of unsensitized electron transfer from an olefin to triplet oxygen under mild conditions (80 °C, 1 bar O2 ). As initiation of the oxygenation reaction, the formation of a caryophyllene-derived radical cation via electron transfer is proposed. This radical cation reacts with triplet oxygen to a dioxetane via a chain mechanism with chain lengths exceeding 100 under optimized conditions. The dioxetane then acts as an in situ-formed epoxidizing agent. Under nitrogen atmosphere, the presence of a one-electron acceptor leads to the selective isomerization of β-caryophyllene to isocaryophyllene. Observations indicate that this isomerization reaction is a novel and elegant synthetic pathway to isocaryophyllene.


Steric effects in the aerobic oxidation of pi-allylnickel(II) complexes with N-heterocyclic carbenes.
Pi-allylchloro(NHC)nickel(II) complexes were synthesized and their reactions with O2 were studied. Ligand steric effects were found to determine the difference between rapid oxidation of the allyl group to produce bis-mu-hydroxonickel complexes and no observable reaction. The ability of the metal-NHC bond to rotate correlates with the ability of the complex to react with O2. In the limiting cases, conformationally restricted complexes are stable to O2 and complexes with rapid Ni-NHC bond rotation react rapidly with O2. Complexes with intermediate conformational flexibility were found to exhibit lesser reactivity with O2. On the basis of the observed inertness of complexes with saddle-shaped ligands to O2, we propose the adoption of a nonplanar geometry upon reaction with O2 to be required. The issue of conformational flexibility versus rigidity is expected to directly impact the catalytic behavior of metal-NHC complexes.


Posteromedial approach to the distal humerus for fracture fixation.
The authors report their experience with the posteromedial surgical approach of the humeral shaft for internal fixation of fractures by plating. Sixteen patients were treated for humeral shaft fractures (14 for recent fractures and two for nonunion) below the mid-diaphysis, all without injury of the radial nerve. Patients were operated in the prone position. Plate and screw fixation on the medial side was used in all cases. Fourteen fractures healed without delay, and two after revision with bone grafting. There were no surgical complications. The posteromedial approach allows the surgeon to avoid dissection of the radial nerve, and is an interesting alternative to lateral approaches especially in cases of re-operation or nonunion. Preoperative lesion of the radial nerve is however a relative contraindication to selecting this posteromedial approach, as it does not give access to the radial nerve.


De novo synthesis of 2-substituted syn-1,3-diols via an iterative asymmetric hydration strategy.
The enantioselective syntheses of several protected 4-substituted syn-3,5-dihydroxy carboxylic esters have been achieved from the corresponding achiral (E,E)- or (E,Z)-1,3-dienoates. The route relies upon an enantio- and regioselective Sharpless dihydroxylation and a palladium-catalyzed reduction to form gamma-substituted delta-hydroxy-1-enoates. The resulting delta-hydroxy-1-enoates are subsequently converted into benzylidene-protected 4-substituted syn-3,5-dihydroxy carboxylic esters in one step. The benzylidene-protected 3,5-dihydroxy carboxylic esters are produced in good overall yields (20-54%) and high enantiomeric excess (73-97% ee).


Temperature effect on leaf water deuterium enrichment and isotopic fractionation during leaf lipid biosynthesis: results from controlled growth of C3 and C4 land plants.
The hydrogen isotopic ratios ((2)H/(1)H) of land plant leaf water and the carbon-bound hydrogen of leaf wax lipids are valuable indicators for climatic, physiological, metabolic and geochemical studies. Temperature will exert a profound effect on the stable isotopic composition of leaf water and leaf lipids as it directly influences the isotopic equilibrium (IE) during leaf water evaporation and cellular water dissociation. It is also expected to affect the kinetics of enzymes involved in lipid biosynthesis, and therefore the balance of hydrogen inputs along different biochemical routes. We conducted a controlled growth experiment to examine the effect of temperature on the stable hydrogen isotopic composition of leaf water and the biological and biochemical isotopic fractionations during lipid biosynthesis. We find that leaf water (2)H enrichment at 20°C is lower than that at 30°C. This is contrary to the expectation that at lower temperatures leaf water should be more enriched in (2)H due to a larger equilibrium isotope effect associated with evapotranspiration from the leaf if all other variables are held constant. A hypothesis is presented to explain the apparent discrepancy whereby lower temperature-induced down-regulation of available aquaporin water channels and/or partial closure of transmembrane water channel forces water flow to "detour" to a more convoluted apoplastic pathway, effectively increasing the length over which diffusion acts against advection as described by the Péclet effect (Farquhar and Lloyd, 1993) and decreasing the average leaf water enrichment. The impact of temperature on leaf water enrichment is not reflected in the biological isotopic fractionation or the biochemical isotopic fractionation during lipid biosynthesis. Neither the biological nor biochemical fractionations at 20°C are significantly different from that at 30°C, implying that temperature has a negligible effect on the isotopic fractionation during lipid biosynthesis.


Replication study of candidate genes associated with type 2 diabetes based on genome-wide screening.
The present study was conducted to confirm possible associations between candidate genes from genome-wide association studies and type 2 diabetes in Japanese diabetic patients and a community-based general population. A total of 11 previously reported single-nucleotide polymorphisms (SNPs) from the TCF7L2, CDKAL1, HHEX, IGF2BP2, CDKN2A/B, SLC30A8, and KCNJ11 genes were analyzed. Candidate SNPs were genotyped in 506 type 2 diabetic patients and 402 control subjects and meta-analyzed with six previous association studies in Japanese patients. Associations with fasting plasma insulin levels were investigated in a general population sample (n = 1,963, 61 +/- 13 years). In our case-control subjects, susceptibility to type 2 diabetes was replicated in TCF7L2 (rs12255372), CDKAL1 (rs7756992, rs7754840), HHEX (rs7923837), IGF2BP2 (rs4402960 and rs1470579), CDKN2A/B (rs10811661), and SLC30A8 (rs13266634). In addition to these polymorphisms, meta-analysis confirmed the association of type 2 diabetes susceptibility with KCNJ11 rs5219, TCF7L2 rs7903146, and HHEX rs1111875. The TCF7L2 rs12255372 polymorphism showed the highest odds ratio (OR) for type 2 diabetes (OR 1.714 [1.298-2.263]). Odds ratio of other polymorphisms ranged from 1.13 to 1.41. The risk allele of CDKAL1 rs7756992 was significantly associated with lower insulin levels in type 2 diabetic patients after adjustment for other confounding factors. Type 2 diabetes susceptibility of seven candidate genes was confirmed in Japanese. Conservation of susceptible loci for type 2 diabetes was independent of ethnic background.


Use of expansion factors to estimate the burden of dengue in Southeast Asia: a systematic analysis.
Dengue virus infection is the most common arthropod-borne disease of humans and its geographical range and infection rates are increasing. Health policy decisions require information about the disease burden, but surveillance systems usually underreport the total number of cases. These may be estimated by multiplying reported cases by an expansion factor (EF). As a key step to estimate the economic and disease burden of dengue in Southeast Asia (SEA), we projected dengue cases from 2001 through 2010 using EFs. We conducted a systematic literature review (1995-2011) and identified 11 published articles reporting original, empirically derived EFs or the necessary data, and 11 additional relevant studies. To estimate EFs for total cases in countries where no empirical studies were available, we extrapolated data based on the statistically significant inverse relationship between an index of a country's health system quality and its observed reporting rate. We compiled an average 386,000 dengue episodes reported annually to surveillance systems in the region, and projected about 2.92 million dengue episodes. We conducted a probabilistic sensitivity analysis, simultaneously varying the most important parameters in 20,000 Monte Carlo simulations, and derived 95% certainty level of 2.73-3.38 million dengue episodes. We estimated an overall EF in SEA of 7.6 (95% certainty level: 7.0-8.8) dengue cases for every case reported, with an EF range of 3.8 for Malaysia to 19.0 in East Timor. Studies that make no adjustment for underreporting would seriously understate the burden and cost of dengue in SEA and elsewhere. As the sites of the empirical studies we identified were not randomly chosen, the exact extent of underreporting remains uncertain. Nevertheless, the results reported here, based on a systematic analysis of the available literature, show general consistency and provide a reasonable empirical basis to adjust for underreporting.


Parental Satisfaction towards Care Given at Neonatal Intensive Care Unit and Associated Factors in Comprehensive and Referral Hospitals of Southern Ethiopia.
Patient satisfaction is an important aspect of the quality of care in the inpatient setting. In neonatal intensive care units, parents' satisfaction and their experiences are fundamental to assessing clinical practice and improving the quality of care delivered to infants. Hence then, it reduces infant mortality rates globally. In Ethiopia, few studies address the level of parental satisfaction towards care given at neonatal intensive care unit and no single study was done in the study area. Therefore, this study is aimed at assessing parental satisfaction towards care given at neonatal intensive care unit and associated factors in comprehensive and referral hospitals of southern Ethiopia. An institutional-based cross-sectional study was conducted among 401 parents who visited neonatal intensive care from March 28 to April 28, 2022. The data were assorted via a structured interviewer-administered questionnaire using ODK collect version and exported to SPSS window version 25 for further cleaning and analysis. Bivariate and multivariate logistic regressions were used to identify factors associated with parental satisfaction with care given at the neonatal intensive care unit. The adjusted odds ratio with 95% CI was used to show the strength of the association, and a P value < 0.05 was used to declare the cutoff point to determine the level of significance. In this study, 63% (95% CI: 58%, 68%) of the parents were satisfied with the care given at the neonatal intensive care unit. Factors associated with parental satisfaction towards care given at neonatal intensive care unit were parents with no formal education (AOR: 0.15; 95% CI: 0.07-0.31), availability of necessary information using direction indicator (AOR: 3.14; 95% CI: 1.85-5.31), and availability of enough chairs in waiting area (AOR: 3.26; 95% CI: 1.81-5.87). Nearly two-thirds of the parents were satisfied with the care given at the neonatal intensive care unit. The availability of enough chairs in the waiting area and the creation of direction indicators are key issues to improve parental satisfaction towards their neonatal care.


Procedures for chemical fixation in immunohistochemical analyses of PIN proteins regulating polar auxin transport: Relevance to spaceflight experiments.
The mechanism by which gravity controls the polar transport of auxin, a plant hormone regulating multiple physiological processes in higher plants, remains unclear, although an important role of PIN proteins as efflux carriers/facilitators in polar auxin transport is suggested. We are going to study the effect of microgravity on the polar transport of auxin, focusing on the cellular localization of its efflux carrier, PsPIN1 in etiolated pea seedlings and ZmPIN1a in etiolated maize seedlings grown under microgravity conditions on the International Space Station (ISS) using immunohistochemical analyses according to space experimental plans (Ueda, 2016). To obtain adequate results regarding the cellular localization of functional proteins, prolonged chemical fixation processes as well as chemical fixatives should be well-matched to the properties of functional proteins as antigens since experimental analyses will be performed on the ground after keeping samples for a long duration on the ISS. As a result of ground verification, clear detection of the cellular localization of PsPIN1 and ZmPIN1a immunohistochemically was successful based on the results of several kinds of chemical fixation tested, even when etiolated pea and maize seedlings were fixed by immersion in chemical fixative for a long duration. The addition of 0.1% (w/v) Nonidet P-40 to chemical fixative composed of 50% (v/v) ethanol and 5% (v/v) acetic acid or that of 50% (v/v) methanol and 5% (v/v) acetic acid has led to a significant improvement in the immunohistochemical detection of PsPIN1 or ZmPIN1a. These chemical fixatives were also shown to be storage-stable for a long time before use. In this study, adequate chemical fixatives and fixation protocols were developed, which can be used to detect localization of PsPIN1 and ZmPIN1a proteins in young etiolated pea and maize seedlings, respectively, using anti PsPIN1 and ZmPIN1a antibodies. These protocols can be used in spaceflight experiments to investigate the effects of the microgravity environment on the ISS on PIN protein localization in pea and maize seedlings.


Successful treatment of restless leg syndrome with the traditional herbal medicines Dangguijakyak-san and Shihogyeji-tang: A case report (CARE-compliant).
Dopamine replacement is currently the standard treatment for restless leg syndrome (RLS); however, various adverse effects are associated with long-term therapy, and the benefits disappear upon discontinuation. To overcome these limitations, interest in traditional East Asian medicine has increased. A 72-year-old Asian woman originally admitted for an intracerebral hemorrhage presented with complaints of an unpleasant sensation throughout the body that appeared at night. The patient was diagnosed with chronic persistent RLS based on the 2012 Revised International Restless Leg Syndrome Study Group Diagnostic Criteria. The patient was treated with extracts of the traditional herbal medicines Dangguijakyak-san (DS) and Shihogyeji-tang (ST). After 47 days of therapy, all herbal medicines were discontinued, and symptoms had not returned by the last follow-up 244 days after the initial treatment. One week after initiating herbal treatment with DS and ST, the RLS symptoms began to improve, and the total hours of sleep had increased from 2 to 9 hours by day 21, with a Korean version of the international restless legs scale score of 11 points. On day 36, ST was discontinued, given the continued improvement of symptoms. On day 47, symptoms had disappeared (Korean version of the international restless legs scale score: 0), and sleep disturbances caused by RLS had completely resolved. After day 47, DS was also discontinued. There were no adverse effects associated with the administration of DS and ST, and the symptoms had not recurred by the last follow-up on day 244. In this case, RLS related symptoms, which had been present for approximately 60 years, were improved using only the traditional herbal medicines DS and ST (without dopamine replacement), and no symptoms recurred for 244 days. This case suggests that if replacement therapy is difficult or not desired, herbal medicinal therapies may be an effective alternative. This also suggests that the effect of herbal medicine on RLS might be semi-permanent. Further investigations, including clinical trials, are needed to confirm these effects.


Neuroleptic treatment of HIV-associated psychosis. HNRC group.
The aim of this rater-blinded randomized study was to evaluate the efficacy and side effects of haloperidol and thioridazine in the treatment of new-onset psychosis in HIV-positive individuals. Participants were 13 men who had no history of psychosis prior to infection with HIV, and whose psychosis was not attributable to delirium or to non-HIV-related organic factors. Participants were evaluated at baseline after at least one month without neuroleptic treatment and then weekly for six weeks of the experimental treatment using several rating scales. The mean daily dose in chlorpromazine equivalents was 124 mg. Both neuroleptics produced modest but significant reduction in overall level of psychosis and in positive symptoms, but not in negative symptoms. All the haloperidol-treated patients developed extrapyramidal side effects and required treatment with anticholinergic medication, whereas three of the five thioridazine-treated patients had noticeable side effects. We make recommendations for the treatment of HIV-associated psychosis with neuroleptics.


Paracetamol: a cause for analgesic nephropathy and end-stage renal disease.
180 patients with end-stage renal disease (ESRD) on maintenance dialysis and those who had undergone renal transplantation were questioned retrospectively. 14 patients had consumed excessive quantities of analgesics (greater than 1 kg) prior to the institution of long-term dialysis or transplantation. Sonographic examination done on these patients indicated that 7 had renal papillary necrosis (RPN). The sonographic features were renal papillary calcifications surrounding the central sinus in a complete or incomplete garland pattern. In 5 of these patients RPN is attibutable to the excessive consumption of paracetamol. We have earlier reported 10 cases of RPN due to excessive consumption of paracetamol. Thus 15 cases of RPN attributable to paracetamol consumption (1.0-15.3 kg over a period ranging from 3 to 23 years) have been documented. It is concluded that paracetamol may assume an increasingly important role in the causation of analgesic nephropathy (AN) and ESRD.


Laryngeal tuberculosis: review of twenty cases.
Despite a dramatic reduction in incidence of laryngeal tuberculosis over the last three decades, tuberculous involvement still has to be considered in the differential diagnosis of laryngeal lesions. The majority of the 20 cases in our series consists of patients in whom the working diagnosis of carcinoma of the larynx was initially made. These patients presented with the chief complaint of hoarseness of several months duration, frequently associated with dysphagia, but in most cases with chest symptoms that were not prominent despite the fact that most of these patients had far advanced pulmonary tuberculosis. This presentation consists of a detailed analysis of 20 cases, and a discussion of the incidence, pathogenesis, clinical presentation and management of laryngeal tuberculosis.


Postnatal aversive experience impairs sensitivity to natural rewards and increases susceptibility to negative events in adult life.
Evidence shows that maternal care and postnatal traumatic events can exert powerful effects on brain circuitry development but little is known about the impact of early postnatal experiences on processing of rewarding and aversive stimuli related to the medial prefrontal cortex (mpFC) function in adult life. In this study, the unstable maternal environment induced by repeated cross-fostering (RCF) impaired palatable food conditioned place preference and disrupted the natural preference for sweetened fluids in the saccharin preference test. By contrast, RCF increased sensitivity to conditioned place aversion (CPA) and enhanced immobility in the forced swimming test. Intracerebral microdialysis data showed that the RCF prevents mpFC dopamine (DA) outflow regardless of exposure to rewarding or aversive stimuli, whereas it induces a strong and sustained prefrontal norepinephrine (NE) release in response to different aversive experiences. Moreover, the selective mpFC NE depletion abolished CPA, thus indicating that prefrontal NE is required for motivational salience attribution to aversion-related stimuli. These findings demonstrate that an unstable maternal environment impairs the natural propensity to seek pleasurable sources of reward, enhances sensitivity to negative events in adult life, blunts prefrontal DA outflow, and modulates NE release in the reverse manner depending on the exposure to rewarding or aversive stimuli.


Mechanisms of cisplatin ototoxicity and progress in otoprotection.
This review presents exciting new data published in the past year that help to elucidate the mechanisms of cisplatin ototoxicity. Recent research findings on otoprotection could lead to the development of novel protective agents. Cisplatin ototoxicity is a frequent and serious problem in patients. Strategies to ameliorate ototoxicity without interfering with the desired therapeutic effects are urgently needed. Cisplatin ototoxicity appears to involve the production of reactive oxygen species in target tissues in the inner ear by activating an enzyme unique to the cochlea. This leads to a cascade resulting in oxidation of lipids and cell death. The upregulation of endogenous protective mechanisms in the cochlea or treatment with exogenous compounds reduces ototoxicity in cisplatin-treated animals. The only clinical trials reported to date with the putative protective agent, amifostine, have been disappointing. The data summarized in this paper could lead to important clinical trials to determine whether the findings in experimental animals can translate into effective treatments to prevent cisplatin ototoxicity.


[Effects of prenatal maternal cold stress on spontaneous, exploratory and anxious behaviors in offspring].
To study the effects of prenatal cold stress on the behavior and mood of offspring in pregnant rats. Six SPF-class Wister pregnant rats were randomly divided into normal temperature control group and cold stress group with 3 rats in each group. The pregnant female rats in the normal temperature control group were kept in the environment of (22 ±2)℃, and the pregnant female rats in the cold stress group were placed in the artificial intelligence climate chamber at(4 ±0.1)℃ for 7 days before the birth, and the young rats were divided into normal temperature after the young rats were born. After the young rats were born, they were divided into normal temperature control group of male rats (MR, 22), normal temperature control group of mother rats (FR, 15), cold stress group of male rats (MC, 15), and cold stress group of female rats (FC, 15) .In the fourth generation of the offspring, the open field experiment and the elevated cross maze test were carried out. In the open field experiment, there was no significant difference in spontaneous activity and exploration behavior between the normal temperature control group and the cold stress group (P>0.05). In the elevated plus maze experiment, the retention time of the open arms, the number of open arms and the distance of the male and female rats in the cold stress group were significantly higher than those in the normal temperature control group (P<0.05). Prenatal maternal cold stress has no significant effect on spontaneous activity, exploration behavior and activity level of offspring, but the offspring have obvious abnormal behaviors with reduced anxiety behavior.


Cigarette smoke-induced airway hyperresponsiveness is not dependent on elevated immunoglobulin and eosinophilic inflammation in a mouse model of allergic airway disease.
Epidemiologic studies suggest that children raised in homes of cigarette smokers have a higher incidence of asthma than children who are raised in homes of nonsmokers. We sought to develop an experimental model to understand the mechanisms involved. Female BALB/c mice were paired with male DO11.10 ovalbumin (OVA)-T cell receptor hemizygous (+/-) mice such that the offspring were either transgene positive (+/-) or negative (-/-). Mice were exposed to either air or mainstream cigarette smoke (100 mg/m(3) total particulate matter, 6 hours/day, 7 days/week) during pregnancy. Immediately after birth, newborn mice were exposed for 4 weeks to either air or sidestream cigarette smoke (SS; 5 mg/m(3) total particulate matter, 6 hours/day, 5 days/week) and then exposed for the following 6 weeks to either air, SS, OVA (5 mg/m(3), 6 hours/day, 5 days/week) or a combination of OVA-SS. DO11.10 +/- offspring exposed to OVA had increased airway hyperresponsiveness (AHR) to methacholine challenge, total IgE, OVA-specific IgE and IgG(1), lymphocytes, and neutrophils in bronchoalveolar lavage and perivascular and peribronchiolar inflammation. Exposure to SS alone caused a significant increase in AHR in both +/- and -/- mice. Transgene -/- mice did not exhibit AHR after OVA exposure unless it was delivered in combination with SS. When compared with OVA-only exposure, OVA-SS exposure decreased total IgE, OVA-specific IgE, and IgG(1) amounts in +/- mice. These results indicate that exposure to SS after birth enhanced AHR in offspring that are both predisposed (+/-) and nonpredisposed (-/-) to develop an allergic response to OVA, but this AHR was not associated with elevated lung eosinophilia or OVA-specific Ig amounts.


Non-coding RNAs in Kawasaki disease: Molecular mechanisms and clinical implications.
Kawasaki disease (KD) is an acute self-limiting vasculitis with coronary complications, usually occurring in children. The incidence of KD in children is increasing year by year, mainly in East Asian countries, but relatively stably in Europe and America. Although studies on KD have been reported, the pathogenesis of KD is unknown. With the development of high-throughput sequencing technology, growing number of regulatory noncoding RNAs (ncRNAs) including microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA) have been identified to involved in KD. However, the role of ncRNAs in KD has not been comprehensively elucidated. Therefore, it is significative to study the regulatory role of ncRNA in KD, which might help to uncover new and effective therapeutic strategies for KD. In this review, we summarize recent studies on ncRNA in KD from the perspectives of immune disorders, inflammatory disorders, and endothelial dysfunction, and highlight the potential of ncRNAs as therapeutic targets for KD.


Mapping Novel Metabolic Nodes Targeted by Anti-Cancer Drugs that Impair Triple-Negative Breast Cancer Pathogenicity.
Triple-negative breast cancers (TNBCs) are estrogen receptor, progesterone receptor, and HER2 receptor-negative subtypes of breast cancers that show the worst prognoses and lack targeted therapies. Here, we have coupled the screening of ∼400 anticancer agents that are under development or in the clinic with chemoproteomic and metabolomic profiling to identify novel metabolic mechanisms for agents that impair TNBC pathogenicity. We identify 20 anticancer compounds that significantly impaired cell survival across multiple types of TNBC cells. Among these 20 leads, the phytoestrogenic natural product licochalcone A was of interest, since TNBCs are unresponsive to estrogenic therapies, indicating that licochalcone A was likely acting through another target. Using chemoproteomic profiling approaches, we reveal that licochalcone A impairs TNBC pathogenicity, not through modulating estrogen receptor activity but rather through inhibiting prostaglandin reductase 1, a metabolic enzyme involved in leukotriene B4 inactivation. We also more broadly performed metabolomic profiling to map additional metabolic mechanisms of compounds that impair TNBC pathogenicity. Overlaying lipidomic profiling with drug responses, we find that deubiquitinase inhibitors cause dramatic elevations in acyl carnitine levels, which impair mitochondrial respiration and contribute to TNBC pathogenic impairments. We thus put forth two unique metabolic nodes that are targeted by drugs or drug candidates that impair TNBC pathogenicity. Our results also showcase the utility of coupling drug screens with chemoproteomic and metabolomic profiling to uncover unique metabolic drivers of TNBC pathogenicity.


Genomics-aided structure prediction.
We introduce a theoretical framework that exploits the ever-increasing genomic sequence information for protein structure prediction. Structure-based models are modified to incorporate constraints by a large number of non-local contacts estimated from direct coupling analysis (DCA) of co-evolving genomic sequences. A simple hybrid method, called DCA-fold, integrating DCA contacts with an accurate knowledge of local information (e.g., the local secondary structure) is sufficient to fold proteins in the range of 1-3 Å resolution.


Systemic infantile complex I deficiency with fatal outcome in two brothers.
A male infant presented at 5 months of age with vomiting, developmental stagnation and convulsions. Complex I activity was in skeletal muscle 0.025 mU/mU CS (N 0.044-0.265) and in fibroblasts 0.046 mU/mU CS (N 0.100-0.307). Despite riboflavine supplementation progressive neurological deterioration occurred and he died at 14 months of age. During the mother's following pregnancy complex I activity was measured in chorionic villi and found mildly reduced, pregnancy was continued. A male infant was born who presented at 7 months of age with vomiting, developmental stagnation and hypotonia. Complex I activity was in skeletal muscle 0.031 mU/mU CS and in fibroblasts 0.100 mU/mU CS. There was progressive neurological deterioration and he died at 17 months of age. Complex I activity in autopsy liver of both patients was normal. Apparently, complex I deficiency presenting in infancy can have a fatal outcome despite only mild reduction of enzyme activity in skeletal muscle and/or fibroblasts, and chorionic villi and normal activity in liver.


Van der Waals complexes of polar aromatic molecules: unexpected structures for dimers of azulene.
Full geometry optimizations at the dispersion corrected DFT-BLYP/TZV2P level of theory have been performed for dimers of azulene that may serve as a model system for the van der Waals complexes of polar pi systems. The structures and binding energies for 11 dimers are investigated in detail. The DFT-D interaction energies have been successfully checked against results from the accurate SCS-MP2/aug-cc-pVTZ approach. Out of the nine investigated stacked complexes, eight have binding energies larger than 7.4 kcal/mol (SCS-MP2) that exceed the value of 7.1 kcal/mol for the best naphthalene dimer. T-shaped arrangements (CH...pi) are significantly less stable. Two out of the three best structures have an antiparallel alignment of the monomer dipole moments in the complex, although the best ones with a parallel orientation are only about 0.5 kcal/mol less strongly bound which points to a minor importance of dipole-dipole interactions to binding. Quite surprisingly, the energetically lowest structure (DeltaE = -9.2 kcal/mol) corresponds to a situation where the two seven-membered rings are located almost on top of each other (7-7) and the long molecular axes are rotated against each other by 130 degrees. The 7-7 structural motif is found also in other energetically low-lying structures, and the expected 5-7 (two-side) arrangement is less strongly bound by about 2 kcal/mol. This can be explained by the electrostatic potential of azulene that only partially reflects the charge separation according to the common 4n + 2 pi electron rule. General rules for predicting stable van der Waals complexes of polar pi systems are discussed.


Scaling up the Manufacturing Process of Adoptive T Cell Immunotherapy.
Adoptive T cell immunotherapy, involving the reprogramming of immune cells to target specific cancer or virus-infected cells, has been recognized as a promising novel approach for the treatment of complex diseases. The impressive global momentum of this therapeutic approach has highlighted the urgent need for establishing it as an effective and standardized onco-therapeutic approach in a large manufacturing scale. However, given its heterogeneity and uncertainty in nature, adoptive T cell immunotherapy is associated with a high failure rate that restricts its manufacturing to a limited number of institutions worldwide. It is undoubted that quite a few major challenges must be met before engineered T cells can be considered as a reliable, safe, and effective remedy for a broad range of diseases with global-wise patient benefits. Here, the fundamental challenges that as yet remain unsolved in the manufacturing process before adoptive T cell therapy can be considered as a key element in the next generation of precision medicine is reviewed. It is proposed that it is necessary to adopt a closed system, automation, cost-effective manufacturing model, and quality-by-design (QbD) strategy to enable scaled up manufacturing of adoptive T cell immunotherapy; and it is challenging to choose appropriate bioreactors, parameters, and infrastructure in this process.


[Morphological parameters for endothelial cells under shear stress].
Shear stresses acting on vascular endothelial cells due to blood fluid flow play an vital role in regulating their morphology, structure, growth rate and functions. The change in morphology is an instinctive response to biomechanical environment and is an indicator for the functional changes in the cells. In this paper, the morphological research literatures of endothelial cells in the recent years are reviewed and the common morphological parameters are described in detail. At the end, the difficulties of quantitative study of endothelial cell morphology and the future direction of morphological parameters research are also discussed.


Preschool foundations of early reading acquisition.
The present paper describes research on the skills and processes associated with word and text reading acquisition in preschool children and during the first years of school. The aim is to provide an overview that gives a sense of the important milestones in language and literacy acquisition. A comparison of children's performances against these milestones may thus guide effective intervention for health professionals, parents and other professionals. Also summarized and explored are the role of speech perception and production, grammatical and syntactic skills, and metacognitive skills, including phonological awareness.


Slow photoelectron velocity-map imaging spectroscopy of cold thiozonide (S3(-)).
We report high-resolution anion photoelectron spectra of thiozonide (S3(-)) acquired by slow electron velocity-map imaging (SEVI). The ions were cryogenically cooled within an ion trap before photodetachment. We measure an electron affinity of 2.3630(9) eV, resolving discrepancies in previously reported photoelectron spectra that resulted from the presence of vibrational hot bands. The SEVI spectrum shows well-resolved, extended vibrational progressions in the symmetric stretch and bending modes of S3, yielding accurate frequencies for both.


Presence of circulating tumor cells in a patient with multiple invasive basal cell carcinoma - a case report.
Basal cell carcinoma (BCC) is the most frequent skin cancer worldwide, however, its metastatic spreading is extremely rare. We present a case of advanced BCC with rapid growth of new tumor lesions in a patient who was later diagnosed with Gorlin syndrome. Due to the advanced disease stage, the patient was examined for circulating tumor cells (CTCs), which are used as a prognostic marker in some metastatic malignancies. To date, no studies have been found that could assess the BCC tumor and the presence of CTCs in peripheral blood. CTCs were obtained after each surgical excision and during systemic oncological therapy from the peripheral venous blood by size-based isolation method (Metacell®) and cultured in vitro for 7 days. CTCs were enriched by size-based separation and examined using vital fluorescence microscopy. Cytomorphological comparison of CTCs with cells from the tumor lesions was provided. In the course of the treatment, the CTCs count in the blood decreased after surgical removal of the tumorous mass, but finally, the sustained and persisting decrease in CTCs was achieved with a hedgehog pathway inhibitor treatment. The detection of CTCs points a systematic disease behavior in this case.


Prosurvival and prodeath effects of hypoxia-inducible factor-1alpha stabilization in a murine hippocampal cell line.
Hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator involved in adaptation to hypoxic stress. Previous studies from our laboratory demonstrated that pharmacological activators of HIF-1 (e.g. deferoxamine, cobalt chloride) could also protect cultured primary neurons or an immortalized hippocampal neuroblast line (HT22) from oxidative stress-induced death. However, whether HIF-1 activation is sufficient to abrogate neuronal death resulting from oxidative stress or other hypoxia-independent death inducers remains unclear. To address this question we utilized a HIF-1alpha fusion protein that partially lacks the domain required for oxygen-dependent degradation of HIF-1alpha and that has a VP16 transcriptional activation domain from herpes simplex virus. HT22 cells were infected with a retrovirus encoding either the HIF-1alpha-VP16 fusion protein or the activation domain of the VP16 protein alone as a control. Expression of HIF-1alpha-VP16, but not VP16 alone, increased luciferase activity driven by a canonical hypoxia response element, increased mRNA of established HIF-1 target genes, and increased activity of one of these HIF-1 target genes. Unexpectedly, enhanced HIF-1 activity in HT22 cells enhanced sensitivity to oxidative death induced by glutathione depletion. Accordingly, suppression of HIF-1alpha expression using RNA interference prevented oxidative death. By contrast, HIF-1alpha-VP16-expressing HT22 cells were more resistant to DNA damage (induced by camptothecin) or endoplasmic reticulum stress (induced by thapsigargin and tunicamycin) than were VP16-expressing cells, and suppression of HIF-1alpha expression using RNA interference rendered HT22 cells more sensitive to death induced by DNA damage or endoplasmic reticulum stress. Together, these data demonstrate that HIF-1 can mediate prodeath or prosurvival responses in the same cell type depending on the injury stimulus.


Late-onset and classic phenotypes of Fabry disease in males with the GLA-Thr410Ala mutation.
To present phenotypic characteristics and biomarkers of a family with the rare mutation Thr410Ala of the α-galactosidase A gene (T410A/GLA) causing Fabry disease (FD). In a woman in her 60s with hypertrophic cardiomyopathy, T410A/GLA was found in screening for variants in 59 cardiomyopathy-related genes. Her son in his 40s, two granddaughters and two great grandsons carried T410A/GLA. The son had a history of hypertension and paroxysmal AF but no microalbuminuria or classic symptoms or signs of FD. Baseline α-galactosidase A enzyme (α-Gal A) activity varied from 0% to 26.5%. Cardiac MRI showed mild Fabry cardiomyopathy (FC). During 11 years of enzyme replacement therapy (ERT), FC progressed and he suffered sudden cardiac death in his 50s. The great grandsons with T410A/GLA had no active α-Gal A, high lyso-Gb3 levels and normal cardiac imaging. They suffered from neuropathic pain and gastrointestinal symptoms and were started with ERT at the age under 10. Granddaughters with T410A/GLA had α-Gal A activities of 8-18 and 10% of normal. The older granddaughter in her 30s was diagnosed with incipient FC. Plasma lyso-Gb3 analogues were elevated, markedly in the elder male with FC and moderately in the elder granddaughter. In young males with classic phenotype, plasma lyso-Gb3 analogues were only slightly elevated. The T410A/GLA mutation caused late-onset FD with progressive cardiomyopathy in elder male, and classic FD in young males of the same family. Varying levels of α-Gal A and lyso-Gb3 analogues reflected variable phenotype of FD in the family.


The effects of kinase modulation on in vitro maturation according to different cumulus-oocyte complex morphologies.
Successful production of transgenic pigs requires oocytes with a high developmental competence. However, cumulus-oocyte complexes (COCs) obtained from antral follicles have a heterogeneous morphology. COCs can be classified into one of two classes: class I, with five or more layers of cumulus cells; and class II, with one or two layers of cumulus cells. Activator [e.g., epidermal growth factor (EGF)] or inhibitors (e.g., wortmannin and U0126) are added to modulate kinases in oocytes during meiosis. In the present study, we investigated the effects of kinase modulation on nuclear and cytoplasmic maturation in COCs. Class I COCs showed a significantly higher developmental competence than class II COCs. Moreover, the expression of two kinases, AKT and ERK, differed between class I and class II COCs during in vitro maturation (IVM). Initially, inhibition of the PI3K/AKT signaling pathway in class I COCs during early IVM (0-22 h) decreased developmental parameters, such as blastocyst formation rate, blastomere number, and cell survival. Conversely, EGF-mediated AKT activation in class II COCs enhanced developmental capacity. Regarding the MAPK signaling pathway, inhibition of ERK by U0126 in class II COCs during early IVM impaired developmental competence. However, transient treatment with U0126 in class II COCs increased oocyte maturation and AKT activity, improving embryonic development. Additionally, western blotting showed that inhibition of ERK activity negatively regulated the AKT signaling pathway, indicative of a relationship between AKT and MAPK signaling in the process underlying meiotic progression in pigs. These findings may help increase the developmental competence and utilization rate of pig COCs with regard to the production of transgenic pigs and improve our understanding of kinase-associated meiosis events.


Lack of an association between a functional polymorphism in the neuropeptide Y gene promoter and the presence of coronary artery disease in an Iranian population.
Several genetic factors have been identified that may contribute to the risk of coronary artery disease (CAD). Variants of the neuropeptide Y (NPY) gene, whose products play an important role in regulating several physiological functions, have been associated with the risk of CAD in some populations. The purpose of this study was to investigate the relationship between the NPY gene rs16147 polymorphism and the presence of CAD in an Iranian population. DNA samples of 922 subjects, including 433 with angiographically defined CAD (CAD+), 196 without angiographically defined significant CAD (CAD-) and 293 controls, were genotyped using polymerase chain reaction based on the amplification-refractory mutation system. Logistic regression analyses were performed to assess the association of rs16147 genotypes with the presence of significant CAD. Although logistic regression analysis indicated that the NPY polymorphism rs16147 was nominally associated with an increased risk of CAD (p < 0.05), after adjustment for confounding factors, there was no evidence for any significantly increased or decreased risk of CAD with this polymorphism. However, in stratified analyses, the C allele was significantly associated with a reduced risk of CAD in males and subjects who were <50 years of age. This study suggests that the rs16147 polymorphism in the NPY gene may not be a potential contributor to the risk of CAD in an Iranian population.


[Memory disorders after unilateral cerebral lesions].
In contrast to the amnestic syndrome, unilateral hemispheric lesions are mostly connected with selective memory deficits, which are related to either verbal or visual-spatial information. Clinical studies concerning this are mostly about patients with temporal lobe epilepsy. Almost all studies found that significantly worse verbal memory deficits appeared before or after left temporal lobectomy. In contrast to these outcomes, the results concerning right temporal lobectomy (RTL) are nonuniform. There are studies that cannot prove figurative memory deficits before or after RTL and others that ascertain a correlation between RTL and figurative memory deficits. Mean values are always compared with random samples of left and right hemispheric patients. In contrast, the presented study assumes a clinical isolated case and analyses a random sample of neurological patients with different genesis with a standardized memory test (Berlin Amnesia Test, or BAT). As a result, a significant correlation between left hemispheric lesions and verbal memory deficits as well as right hemispheric lesions and visual-spatial memory deficits can be proven. Possible reasons for these differing results with visual-spatial memory deficits are still under discussion.


Association between sarcopenia and survival in patients with gynecologic cancer: A systematic review and meta-analysis.
Despite prior attempts to evaluate the effects of sarcopenia on survival among patients with gynecologic cancer, the results of these studies have not been consistent. The present study evaluated the association between sarcopenia and survival among patients with gynecologic cancer by aggregating multiple studies. We performed a literature search using computerized databases and identified additional studies included in the bibliographies of retrieved articles. The quality of each study was evaluated using the Newcastle-Ottawa Scale, and meta-analyses were performed to evaluate overall survival (OS) and progression-free survival (PFS). We constructed a forest plot for each outcome and assessed publication bias using Begg's test. Heterogeneity was assessed using I2 statistics. From the 5,933 initially identified articles, 16 studies describing 2,031 participants with a mean age of 60.34 years were included in the meta-analysis. We found that compared with patients with gynecologic cancer but without sarcopenia, patients with sarcopenia had worse OS, with a pooled hazard ratio (HR) of 2.61 (95% confidence interval [CI]:1.52-4.46), and worse PFS (HR: 1.37, 95% CI: 1.09-1.73). The quality of studies was generally good, and no publication bias was detected among studies for either OS or PFS. Although 4 of 12 studies were of fair quality, we conducted a sensitivity analysis excluding studies or fair quality and obtained similar results. These meta-analysis results suggest that sarcopenia is associated with worse OS and PFS among patients with gynecologic cancer. The use of different case definitions appeared to be a major source of heterogeneity among the studies. Further studies remain necessary to confirm our findings, especially those examining OS and PFS, because publication bias was identified.


[An uncommon trichoepithelioma: the giant solitary trichoepithelioma].
A case of giant solitary trichoepithelioma of the perianal region is described so to draw attention to this rare benign neoplasme and to discuss its clinical and histopathological chracteristics.


Joint Attention in Human and Chimpanzee Infants in Varied Socio-Ecological Contexts.
Joint attention (JA) is an early manifestation of social cognition, commonly described as interactions in which an infant looks or gestures to an adult female to share attention about an object, within a positive emotional atmosphere. We label this description the JA phenotype. We argue that characterizing JA in this way reflects unexamined assumptions which are, in part, due to past developmental researchers' primary focus on western, middle-class infants and families. We describe a range of cultural variations in caregiving practices, socialization goals, and parenting ethnotheories as an essential initial step in viewing joint attention within inclusive and contextualized perspectives. We begin the process of conducting a decolonized study of JA by considering the core construct of joint attention (i.e., triadic connectedness) and adopting culturally inclusive definitions (labeled joint engagement [JE]). Our JE definitions allow for attention and engagement to be expressed in visual and tactile modalities (e.g., for infants experiencing distal or proximal caregiving), with various social partners (e.g., peers, older siblings, mothers), with a range of shared topics (e.g., representing diverse socialization goals, and socio-ecologies with and without toys), and with a range of emotional tone (e.g., for infants living in cultures valuing calmness and low arousal, and those valuing exuberance). Our definition of JE includes initiations from either partner (to include priorities for adult-led or child-led interactions). Our next foundational step is making an ecological commitment to naturalistic observations (Dahl, 2017, Child Dev Perspect, 11(2), 79-84): We measure JE while infants interact within their own physical and social ecologies. This commitment allows us to describe JE as it occurs in everyday contexts, without constraints imposed by researchers. Next, we sample multiple groups of infants drawn from diverse socio-ecological settings. Moreover, we include diverse samples of chimpanzee infants to compare with diverse samples of human infants, to investigate the extent to which JE is unique to humans, and to document diversity both within and between species. We sampled human infants living in three diverse settings. U.K. infants (n = 8) were from western, middle-class families living near universities in the south of England. Nso infants (n = 12) were from communities of subsistence farmers in Cameroon, Africa. Aka infants (n = 10) were from foraging communities in the tropical rain forests of Central African Republic, Africa. We coded behavioral details of JE from videotaped observations (taken between 2004 and 2010). JE occurred in the majority of coded intervals (Mdn = 68%), supporting a conclusion that JE is normative for human infants. The JA phenotype, in contrast, was infrequent, and significantly more common in the U.K. (Mdn = 10%) than the other groups (Mdn < 3%). We found significant within-species diversity in JE phenotypes (i.e., configurations of predominant forms of JE characteristics). We conclude that triadic connectedness is very common in human infants, but there is significant contextualization of behavioral forms of JE. We also studied chimpanzee infants living in diverse socio-ecologies. The PRI/Zoo chimpanzee infants (n = 7) were from captive, stable groups of mixed ages and sexes, and included 4 infants from the Chester Zoo, U.K. and 3 from the Primate Research Institute, Kyoto University, Japan. The Gombe chimpanzee infants (n = 12) were living in a dynamically changing, wild community in the Gombe National Park, Tanzania, Africa. Additionally, we include two Home chimpanzee infants who were reared from birth by a female scientist, in the combined U.S., middle-class contexts of home and university cognition laboratory. JE was coded from videotaped observations (taken between 1993 and 2006). JE occurred during the majority of coded intervals (Mdn = 64%), consistent with the position that JE is normative for chimpanzee infants. The JA phenotype, in contrast, was rare, but more commonly observed in the two Home chimpanzee infants (in 8% and 2% of intervals) than in other chimpanzee groups (Mdns = 0%). We found within-species diversity in the configurations comprising the JE phenotypes. We conclude that triadic connectedness is very common in chimpanzee infants, but behavioral forms of joint engagement are contextualized. We compared JE across species, and found no species-uniqueness in behavioral forms, JE characteristics, or JE phenotypes. Both human and chimpanzee infants develop contextualized social cognition. Within-species diversity is embraced when triadic connectedness is described with culturally inclusive definitions. In contrast, restricting definitions to the JA phenotype privileges a behavioral form most valued in western, middle-class socio-ecologies, irrespective of whether the interactions involve human or chimpanzee infants. Our study presents a model for how to decolonize an important topic in developmental psychology. Decolonization is accomplished by defining the phenomenon inclusively, embracing diversity in sampling, challenging claims of human-uniqueness, and having an ecological commitment to observe infant social cognition as it occurs within everyday socio-ecological contexts. It is essential that evolutionary and developmental theories of social cognition are re-built on more inclusive and decolonized empirical foundations.


Studies of cellular immunity in Graves' disease.
Cell immunity aspects were studied in patients with untreated Graves' disease or thyreotoxicosis relapsing after anti-thyroid drug therapy interruption. The peripheral blood T-lymphocyte count was significantly low (p less than 0.05) in the untreated patients. The leucocyte inhibition factor (LIF) test showed only a slight sensibilization of lymphocytes to thyroglobulin in the untreated patients, whereas in those with relapsed thyreotoxicosis there was a marked sensitization to thyroglobulin and microsomal antigen. Our observations suggest that part of the untreated patients have some abnormalities in the function of their lymphocytes. All the relapsed cases showed an intense sensitization of lymphocytes in the direct LIF test. The possibility of using the LIF test as an indicator of thyreotoxicosis release after interruption of the anti-thyroid drug therapy is suggested.


The gel-forming polysaccharide of psyllium husk (Plantago ovata Forsk).
The physiologically active, gel-forming fraction of the alkali-extractable polysaccharides of Plantago ovata Forsk seed husk (psyllium seed) and some derived partial hydrolysis products were studied by compositional and methylation analysis and NMR spectroscopy. Resolving the conflicting claims of previous investigators, the material was found to be a neutral arabinoxylan (arabinose 22.6%, xylose 74.6%, molar basis; only traces of other sugars). With about 35% of nonreducing terminal residues, the polysaccharide is highly branched. The data are compatible with a structure consisting of a densely substituted main chain of beta-(1-->4)-linked D-xylopyranosyl residues, some carrying single xylopyranosyl side chains at position 2, others bearing, at position 3, trisaccharide branches having the sequence L-Araf-alpha-(1-->3)-D-Xylp-beta-(1-->3)-l-Araf. The presence of this sequence is supported by methylation and NMR data, and by the isolation of the disaccharide 3-O-beta-D-xylopyranosyl-L-arabinose as a product of partial acid hydrolysis of the polysaccharide.


Analysis of the control of citrulline synthesis in isolated rat-liver mitochondria.
The amount of control of the various steps involved in the citrulline synthesizing pathway in isolated rat-liver mitochondria incubated with saturating concentrations of ammonia and ornithine has been measured. The flux control coefficient of carbamoyl-phosphate synthase (ammonia) was close to one. Control exerted by other steps in the pathway, including ornithine transcarbamoylase, carbonic anhydrase. ATP production and transport of ornithine, was negligible. The high flux control coefficient of carbamoyl-phosphate synthetase is due to the low elasticity coefficient of this enzyme towards its product, intramitochondrial carbamoyl phosphate, in combination with a high elasticity coefficient of ornithine transcarbamoylase towards carbamoyl phosphate.


Spinal cord injury and co-occurring traumatic brain injury: assessment and incidence.
To examine prospectively the incidence and severity of co-occurring traumatic brain injury (TBI) in persons with traumatic spinal cord injury (SCI) and to describe a TBI assessment process for SCI rehabilitation professionals. A prospective, cohort design to collect and analyze clinical variables relevant for diagnosing co-occurring TBI. An urban, single-center National Institute of Disability and Rehabilitation Research Model Spinal Cord Injury System in the Southeastern United States. People (N=198) who met inclusion criteria and provided consent within an 18-month recruitment window. Not applicable. FIM cognitive scale. Based on participants' presence and duration of posttraumatic amnesia, initial Glasgow Coma Scale total score, and presence of cerebral lesion documented by neuroimaging, 60% of our traumatic SCI sample also sustained a TBI (n=118). Most co-occurring TBIs were mild (34%). Co-occurring mild complicated (10%), moderate (6%), and severe TBI (10%) were less common but still occurred in a significant percentage (26%) of persons with traumatic SCI. Persons with traumatic SCI who were injured in motor vehicle collisions and falls were more likely to sustain a co-occurring TBI. Cervical level traumatic SCI was associated with greater rates of TBI but not more severe injuries. Tree analyses established a practical algorithm for classifying TBI severity associated with traumatic SCI. Analysis of variance established criterion validity for the algorithm's TBI severity classifications. Findings from our prospective study provide strong support that TBI is a common co-occurring injury with traumatic SCI. Incomplete acute care medical record documentation of TBI in the traumatic SCI population remains a considerable issue, and there is a significant need to educate emergency department and acute care personnel on the TBI clinical data needs of acute rehabilitation providers. A systematic algorithm for reviewing acute care medical records can yield valid estimates of TBI severity in the traumatic SCI population.


Biodegradation of short-chain n-alkanes in oil sands tailings under methanogenic conditions.
The biodegradation of a mixture of low molecular weight n-alkanes (C6, C7, C8, and C10) was assessed under methanogenic conditions using mature fine tailings (MFT) produced by the oil sands industry in Alberta, Canada. Microorganisms present in the MFT mineralized the added n-alkane mixture, producing 16.2 (+/- 0.3) or 20.5 (+/- 0.1) mmol of methane in the headspace of microcosms spiked with 0.2% or 0.5% w/v n-alkanes, respectively, during 29 weeks of incubation. The spiked n-alkanes biodegraded in the sequence C10 > C8 > C7 > C6. Degradation of 100% C10, 97% C8, 74% C7, and 44% C6 occurred in a mixture of n-alkanes in the MFT spiked at 0.2% after 25 weeks of incubation. The same pattern of biodegradation was also observed in the MFT spiked with 0.5% n-alkanes. Stoichiometric calculations confirmed the mineralization of the degraded n-alkanes to methane. This study showed that the short-chain n-alkanes, which comprise a significant portion of the unrecovered naphtha used in bitumen extraction and released into the settling basins, can be biodegraded into methane. These findings may influence decisions regarding extraction processes and long-term management of MFT, and they suggest that intrinsic, methanogenic metabolism of these n-alkanes may occur in other anoxic environments.


The metabolic, stress axis, and hematology response of zilpaterol hydrochloride supplemented beef heifers when exposed to a dual corticotropin-releasing hormone and vasopressin challenge.
The objective of this study was to determine the metabolic, stress, and hematology response of beef heifers supplemented with zilpaterol hydrochloride (ZH) when exposed to an endocrine stress challenge. Heifers ( = 20; 556 ± 7 kg BW) were randomized into 2 treatment groups: 1) control (CON), no ZH supplementation, and 2) zilpaterol (ZIL), supplemented with ZH at 8.33 mg/kg (DM basis). The ZIL group was supplemented ZH for 20 d, with a 3-d withdrawal period. On d 24, heifers received an intravenous bolus of corticotropin-releasing hormone (CRH; 0.3 µg/kg BW) and arginine vasopressin (VP; 1.0 µg/kg BW) to activate the stress axis. Blood samples were collected at 30-min intervals for serum and 60-min intervals for plasma and whole blood, from -2 to 8 h relative to the challenge at 0 h (1000 h). Samples were analyzed for glucose, insulin, NEFA, blood urea nitrogen (BUN), cortisol, epinephrine, norepinephrine, and complete blood cell counts. Following the challenge, cattle were harvested over a 3-d period. Liver, LM, and biceps femoris (BF) samples were collected and analyzed for glucose, lactate, and glycolytic potential (GP). There was a treatment ( ≤ 0.001) effect for vaginal temperature (VT), with ZIL having a 0.1°C decrease in VT when compared with CON. A treatment × time effect ( = 0.002) was observed for NEFA. A treatment effect was observed for BUN; ZIL had decreased BUN concentrations compared with CON ( < 0.001) prior to the challenge; however, no treatment × time effect was observed. There was also a treatment effect for cortisol ( ≤ 0.01) and epinephrine ( = 0.003); ZIL had decreased cortisol and epinephrine during the CRH/VP challenge when compared with CON. There was a time effect for total white blood cells, lymphocytes, and monocytes; each variable increased ( ≤ 0.01) 2 h postchallenge. Additionally, neutrophil counts decreased ( ≤ 0.01) in response to CRH/VP challenge in both treatment groups. Glucose concentrations within the LM were greater ( = 0.03) in CON when compared with ZIL. Lactate concentrations and GP within the BF were greater in CON ( = 0.05) when compared with ZIL. These data suggest there are some variations observed between treatments in terms of response to the CRH/VP challenge; however, in the environmental conditions of this trial, none of the variations observed suggest that the supplementation of ZH detrimentally alters the ability of cattle to effectively respond to stressful stimuli.


Protective effects of folic acid on PM2.5-induced cardiac developmental toxicity in zebrafish embryos by targeting AhR and Wnt/β-catenin signal pathways.
Our previous observations indicated that extractable organic matter (EOM) from PM2.5 induced malformations in the heart of zebrafish embryos by activating AhR and inhibiting canonical Wnt/β-catenin signal pathway. As a nutritional factor, folic acid (FA) is reported to prevent cardiac defects during embryo development. Hence, we hypothesize that FA may prevent PM2.5-induced heart defects by interfering with AhR and Wnt/β-catenin signaling pathways. Our results showed that FA supplementation alleviated the EOM-induced heart defects in zebrafish embryos, and both AhR inhibitor CH223191 and Wnt activator CHIR99021 enhanced the protective efficiency of FA. Furthermore, FA supplementation attenuated the EOM-induced upregulation of AhR and its target genes including Cyp1a1, Cyp1b1, Ahrra, and Ahrrb. EROD assay confirmed that the EOM agonized Cyp1a1 activity was diminished by FA. The EOM-induced downregulation of β-catenin and its target genes including Nkx2.5, Axin2, Sox9b, and Cox2b were recovered or even overexpressed in embryos exposed to EOM plus FA. In conclusion, our study suggested that FA supplementation protected against PM2.5 cardiac development toxicity by targeting AhR and Wnt/β-catenin signal pathways.


Influence of acetonylgeraniin, a hydrolyzable tannin from Euphoria longana, on orthostatic hypotension in a rat model.
Acetonylgeraniin, an active principle isolated from the seeds of Euphoria longana Lam. (Sapindaceae), reversed the fall in arterial blood pressure in conscious hypertensive rats (SHRs) with orthostatic hypotension induced by injection of hexamethonium into animals subjected to 90 degrees head-up tilts for 60 seconds. However, acetonylgeraniin failed to affect prazosin-induced orthostatic hypotension. Plasma noradrenaline (NA) and mean blood pressure were elevated dose-dependently by an intravenous injection of acetonyl-geraniin into the rats; this increase in blood pressure was totally abolished by prazosin. Failure of hexamethonium or pentolinium, the blockers of ganglionic nicotinic receptors, to influence the NA releasing action of acetonylgeraniin ruled out the participation of ganglionic stimulation. This NA-releasing action of acetonylgeraniin was, however, totally abolished by the inhibitors of noradrenergic nerve terminals, guanethidine or bretylium. Also, the activity of this tannin was not modified by adrenalectomy. Thus, a direct release of NA from the noradrenergic nerve terminals by acetonylgeraniin seems responsible for the reversing of orthostatic hypotension.


Metoclopramide (Primperan) in the treatment of ureterolithiasis. A prospective double-blind study of metoclopramide compared with morphatropin on ureteral colic.
A prospective double-blind study was performed to compare metoclopramide (Primperan) with morphatropin in the treatment of ureteral colic. Twenty-one patients (10 in the morphatropin group and 11 in the metoclopramide group) entered the study and diagnosis was confirmed radiologically. Using the Mann-Whitney rank sum test, no significant difference was found in the pain-relieving effect 10, 20, or 30 min after treatment with either 1 ml morphatropin s.c. or 20 mg metoclopramide i.v. Two patients in the morphatropin group developed nausea and giddiness, respectively, and 1 patient from this group was omitted due to the development of urticaria. No side effects occurred in the metoclopramide group. Thus metoclopramide seems to be an alternative to the traditional treatment of ureteral colic with morphia.


Validation of the short version of the obsessive compulsive spectrum questionnaire.
In the recent years, a rising amount of research has stressed the importance of a dimensional perspective on mental disorders. In particular, the conceptualization of an obsessive-compulsive spectrum appears to be in line with the very first descriptions of Obsessive-Compulsive Disorder and has been partially acknowledged by the inclusion of the "OCD-spectrum related syndromes and disorders" section in the DSM-5. The goal of the current study is to ascertain the psychometric characteristics of the Obsessive-Compulsive Spectrum-Short Version (OBS-SV), a novel questionnaire designed to measure the complete range of obsessive-compulsive symptoms, from severe full blown to subthreshold ones. Forty three subjects with a clinical diagnosis of OCD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5); 42 subjects with a clinical diagnosis of social anxiety disorder (SAD), and 60 individuals without current or lifetime mental disorders (HC) were recruited from the Psychiatric Clinic of the University of Pisa. Subjects were assessed with the SCID-5, the Yale Brown Obsessive Compulsive Scale (Y-BOCS) and the OBS-SV. OBS-SV showed strong test-retest reliability for both the total and the domains scores, as well as a high level of internal consistency. The Pearson's coefficients for the OBS-SV domain scores ranged from 0.771 to 0.943, and they were positively and strongly linked with one another (p < 0.001). The OBS-SV total score had a strong correlation with each of the OBS-SV domain scores. All correlation coefficients between OBS-SV and additional measures of OCS were observed to be strong, significant and positive. Both OBS-SV domain and overall score differences between diagnostic groups were found to be statistically significant. From HCs, to the SAD, up to the OC group, which had the highest values, the OBS-SV total score grew dramatically and progressively. The OBS-SV demonstrated significant convergent validity with other dimensional OCD measures, excellent internal consistency, and test-retest reliability. Across the three diagnostic categories, the questionnaire functioned differently, with a rising score gradient from healthy controls through SAD patients to OCD subjects.


Regulation of the movement of solutes across tight junctions.
The intercellular tight junction is the rate-limiting barrier in the paracellular pathway for permeation by ions and larger solutes. A variety of widely used electrical and flux approaches are used in the analyses of solute permeation through this pathway; however, each has limitations in practice. It is now clear that solute permeation across tight junctions is dynamically regulated by intracellular events with a common effector mechanism apparently tied to the cytoskeleton. These pathways, which regulate tight junction solute permeability, are targets that produce epithelial barrier dysfunction in a variety of disease states. However, regulation of solute permeation across the junctional barrier may also represent a potential means to improve bioavailability of orally administered bioactive solutes.


DNA methylation mediated down-regulation of ANGPTL4 promotes colorectal cancer metastasis by activating the ERK pathway.
Background: Colorectal cancer (CRC) imposes significant health burden and is increasing in incidence. NGPTL4 has been implicated in the development of CRC. The present study aimed to investigate the molecular mechanisms by which ANGPTL4 expression might regulate epithelial-mesenchymal transition (EMT) and the tumor microenvironment in CRC. Methods: CRC and para-carcinoma tissues were collected from 67 CRC patients. ANGPTL4 expression levels and DNA methylation of ANGPTL4 promoter region were determined. Next, the migration and invasion capacities of CRC cells were assessed. Immunofluorescence and Western blot were used to identify the signaling pathways by which ANGPTL4 mediated tumor metastasis. A tumorigenesis mice model with transplanted fibroblast cells and ANGPTL4 overexpressed CRC cells was established to investigate the effects of ANGPTL4 on the metastasis of cancer cells in vivo. Results: ANGPTL4 was significantly decreased in CRC tissues and DNA hypermethylation was involved in the regulation of ANGPTL4. Mechanistically, ANGPTL4 induced activation of cancer-associated fibroblasts in the tumor microenvironment and promoted EMT in CRC cells through the ERK signaling pathway. In vivo, the overexpression of ANGPTL4 was found to inhibit the metastasis of tumor cells in lung tissues. Conclusion: DNA hypermethylation induced ANGPTL4 downregulation promoted the activation of cancer-associated fibroblasts and epithelial mesenchymal transformation of CRC cells via the ERK signaling pathway, thereby promoting invasion and metastasis in CRC.


First principles centroid molecular dynamics simulation of high pressure ices.
The nuclear quantum effects (NQEs) on the structural, elastic, electronic, and vibrational properties of high pressure ices (HPIs) VIII, VII, and X at 270 K were investigated via first principles centroid molecular dynamics (CMD). Our simulations clearly show that even at relatively high temperature of 270 K, the NQEs play a definite role in the pressure-induced proton order (ice VIII)-disorder (ice VII) transition occurring at ∼30 GPa in our H2O ice and the subsequent transition to the symmetric phase ice X suggested to occur at ∼80 GPa. The internal pressure computed at constant NVT conditions shows that the NQEs manifest themselves in the equation of state of HPIs. Our employed approach based on first principles CMD for computing vibrational spectra is proved to be able to reproduce well the overall features of the measured infrared and Raman spectra.


Gender-related biases in evaluations of sex discrimination allegations: is perceived threat the key?
Hypotheses derived from defensive attribution theory and social identity theory were tested in 3 laboratory experiments examining the effects of plaintiff and observer gender on perceived threat, plaintiff identification, and sex discrimination. In Study 1, women differentiated plaintiffs on the basis of gender, whereas men did not. Study 2 showed that this bias occurred because employment discrimination was personally threatening to women but not to men. In Study 3, the bias was reversed in a child custody context. As predicted, men found this context to be significantly more threatening than did women and subsequently exhibited a similarity bias. Mediation analyses suggested that responsibility attributions explained most of the variance in discrimination judgments associated with the plaintiff gender by observer gender interactions.


Role of oxidative stress and the microenvironment in breast cancer development and progression.
Breast cancer is a highly complex tissue composed of neoplastic and stromal cells. Carcinoma-associated fibroblasts (CAFs) are commonly found in the cancer stroma, where they promote tumor growth and enhance vascularity in the microenvironment. Upon exposure to oxidative stress, fibroblasts undergo activation to become myofibroblasts. These cells are highly mobile and contractile and often express numerous mesenchymal markers. CAF activation is irreversible, making them incapable of being removed by nemosis. In breast cancer, almost 80% of stromal fibroblasts acquire an activated phenotype that manifests by secretion of elevated levels of growth factors, cytokines, and metalloproteinases. They also produce hydrogen peroxide, which induces the generation of subsequent sets of activated fibroblasts and tumorigenic alterations in epithelial cells. While under oxidative stress, the tumor stroma releases high energy nutrients that fuel cancer cells and facilitate their growth and survival. This review describes how breast cancer progression is dependent upon oxidative stress activated stroma and proposes potential new therapeutic avenues.


Primary care and population factors associated with NHS Health Check coverage: a national cross-sectional study.
High and equitable coverage of systematic cardiovascular disease (CVD) prevention programmes, such as the NHS Health Check programme in England, is essential if they are to effectively reduce the population CVD burden. We conducted a cross-sectional study using data from 151 English primary care trusts (PCTs) on NHS Health Check coverage during 2011-12. We examined the associations between programme coverage and primary care and population factors, including patient demographics, primary care workforce and cardiovascular health need. Median coverage of NHS Health Checks was 8.2%, with wide PCT-level variation (range = 0-29.8%). Coverage was significantly higher in PCTs in the most deprived areas compared with the least deprived (P = 0.035), adjusting for covariates. Significant negative associations between coverage and a higher proportion of PCT population aged 40-74 years-the eligible Health Check age group, a larger total population size and higher practice staffing levels were found in the unadjusted analyses. NHS Health Check coverage during 2011-12 was lower than the government projection of 18% coverage. Coverage must be increased through concerted multi-disciplinary strategies, for the programme to improve cardiovascular health in England. Considerable variation in participation between PCTs warrants attention, with enhanced support for poor performers.


Cerebral microembolisation during radiofrequency ablation of lung tumours: detection by carotid duplex ultrasound.
The aim of this study was to investigate the appearance of microbubbles during radiofrequency ablation (RFA) of lung tumours. Eight consecutive patients (mean age, 73.1 years; 3 men and 5 women; 10 malignant lesions; mean lesion size, 24.8 mm) who underwent RFA of lung tumours using internally cooled single electrodes were enrolled. During the RFA procedure, the right internal carotid artery was continuously monitored by duplex ultrasound. High-intensity transient signals (HITS) that occurred in the Doppler blood flow waveform were taken to indicate microbubbles. 21 RFA applications were performed for the 10 lesions. HITS were observed in 19 of 21 RFA applications; the mean frequency in a single application was 10+/-13.3. A statistical correlation was seen between the duration of energy deposition and the number of HITS, and between tumour size and the number of HITS. Microbubbles were detected in all patients in the late phase of the first session of RFA.


Relationship between epicardial adipose tissue, systemic inflammatory diseases, and subclinical atheromatosis: A systematic review.
Systemic inflammatory diseases could act as an unfavorable condition in which epicardial adipose tissue (EAT) becomes harmful to cardiovascular health. The objectives were: (a) to quantitatively compare the presence of EAT between patients with systemic inflammatory diseases and controls; (b) to analyze the association between EAT and subclinical atheromatosis in individuals with systemic inflammatory diseases. Studies that have quantified EAT in a population with systemic inflammatory diseases compared to a control group, or that describe the association between EAT and the presence of subclinical atheromatosis in patients with systemic inflammatory diseases were included. A quantitative analysis was performed for the first objective. This systematic review was performed according to PRISMA guidelines. Twenty-one studies including 1448 patients with systemic inflammatory diseases, were considered eligible for this study. Patients with systemic inflammatory disease have a higher volume (MD: 10.4cm3 [1.8-19.1]; p<0.01), higher thickness (MD: 1.0mm [0.8-1.2]; p<0.01), and a statistically non-significant higher area (MD: 3.1cm2 [1.0-5.2]; p=0.46) of EAT compared to the control group. Most studies reported a significant association between EAT and subclinical atheromatosis in patients with different systemic inflammatory diseases. This study demonstrated that EAT is increased in patients with systemic inflammatory diseases compared with healthy controls, and that EAT measurement is closely correlated with subclinical atherosclerosis in these patients. The causality of this association should be tested in prospective studies.


Reduced prefrontal activation during working and long-term memory tasks and impaired patient-reported cognition among cancer survivors postchemotherapy compared with healthy controls.
Patients who receive adjuvant chemotherapy have reported cognitive impairments that may last for years after the completion of treatment. Working memory-related and long-term memory-related changes in this population are not well understood. The objective of this study was to demonstrate that cancer-related cognitive impairments are associated with the under recruitment of brain regions involved in working and recognition memory compared with controls. Oncology patients (n = 15) who were receiving adjuvant chemotherapy and had evidence of cognitive impairment according to neuropsychological testing and self-report and a group of age-matched, education group-matched, cognitively normal control participants (n = 14) underwent functional magnetic resonance imaging. During functional magnetic resonance imaging, participants performed a nonverbal n-back working memory task and a visual recognition task. On the working memory task, when 1-back and 2-back data were averaged and contrasted with 0-back data, significantly reduced activation was observed in the right dorsolateral prefrontal cortex for oncology patients versus controls. On the recognition task, oncology patients displayed decreased activity of the left-middle hippocampus compared with controls. Neuroimaging results were not associated with patient-reported cognition. Decreased recruitment of brain regions associated with the encoding of working memory and recognition memory was observed in the oncology patients compared with the control group. These results suggest that there is a reduction in neural functioning postchemotherapy and corroborate patient-reported cognitive difficulties after cancer treatment, although a direct association was not observed. Cancer 2016;122:258-268. © 2015 American Cancer Society.