Vascular Health in Adults Born After Using Assisted Reproductive Technologies.
An increasing number of children are conceived by assisted reproductive technologies (ART). Several studies indicated vascular alterations in ART children. However, limited data is available within the adult ART population. Therefore, this study investigated the overall vascular health of young ART adults in comparison to spontaneously conceived peers. In total, 16 ART subjects and 22 spontaneously conceived peers (22.06 ± 2.21 years vs. 22.00 ± 2.14 years, p = 0.194) were enrolled for the assessment of endothelial function, brachial blood pressure, central blood pressure, pulse wave velocity, carotid intima-media thickness, and blood lipids. No significant differences in vascular function were detected between the in vitro fertilization subgroup (n = 9), the intracytoplasmic sperm injection subgroup (n = 7) and spontaneously conceived peers. This pilot study suggests an unimpaired vascular function in young ART adults. In the future, multi-centric studies with a greater sample size are required to confirm the results of the current study and enable precise cardiovascular risk stratification of the adult ART population.


Carbon Sequestration Potential in Stands under the Grain for Green Program in Southwest China.
The Grain for Green Program (GGP) is the largest afforestation and reforestation project in China in the early part of this century. To assess carbon sequestration in stands under the GGP in Southwest China, the carbon stocks and their annual changes in the GGP stands in the region were estimated based on the following information: (1) collected data on the annually planted area of each tree species under the GGP in Southwest China from 1999 to 2010; (2) development of empirical growth curves and corresponding carbon estimation models for each species growing in the GPP stands; and (3) parameters associated with the stands such as wood density, biomass expansion factor, carbon fraction and the change rate of soil organic carbon content. Two forest management scenarios were examined: scenario A, with no harvesting, and scenario B, with logging at the customary rotation followed by replanting. The results showed that by the years 2020, 2030, 2040, 2050 and 2060, the expected carbon storage of the GGP stands in Southwest China is 139.58 TgC, 177.50-207.55 TgC, 196.86-259.65 TgC, 240.45-290.62 TgC and 203.22-310.03 TgC (T = 1012), respectively. For the same years, the expected annual change in carbon stocks is 7.96 TgCyr-1, -7.95-5.95 TgCyr-1, -0.10-4.67 TgCyr-1, 4.31-2.24 TgCyr-1 and -0.02-1.75 TgCyr-1, respectively. This indicates that the stands significantly contribute to forest carbon sinks in this region. In 2060, the estimated carbon stocks in the seven major species of GGP stands in Southwest China are 4.16-13.01 TgC for Pinus armandii, 6.30-15.01 TgC for Pinus massoniana, 11.51-13.44 TgC for Cryptomeria fortunei, 15.94-24.13 TgC for Cunninghamia lanceolata, 28.05 TgC for Cupressus spp., 5.32-15.63 TgC for Populus deltoides and 5.87-14.09 TgC for Eucalyptus spp. The carbon stocks in these seven species account for 36.8%-41.4% of the total carbon stocks in all GGP stands over the next 50 years.


[Skeletal age determination from the elbow during pubertal growth].
The Sauvegrain et al. method of assessing skeletal age from elbow radiographs is useful during the 2 years of the pubertal growth spurt: between 11 and 13 years in girls and between 13 and 15 years in boys. This method uses four ossification centers of the elbow: lateral condyle, trochlea, olecranon apophysis, and proximal radial epiphysis. It is based on a 27-point scoring system. The scores of these structures are summed, a total score is determined, and a graph is then used to determine the skeletal age. This simple, reliable, and reproducible method complements the Greulich and Pyle atlas, which does not allow assessment of skeletal age in 6-month intervals during the phase of accelerating growth velocity. In clinical practice, maturity can best be evaluated by associating skeletal age, annual growth rate, and Tanner stages. Skeletal age assessment from the elbow is useful to plan the timing of epiphysiodesis in limb length inequality or to evaluate the progression risk of idiopathic scoliosis.


Fatty acids present in commercial albumin preparations differentially affect development of murine embryos before and during implantation.
To characterize fatty acid (FA) profile of commercially available albumin products and determine their effect on embryonic development. Research study. Private research facility. Outbred mice aged 4-8 weeks. Gas chromatography-mass spectrometry was used to quantify the FA content of 15 commercial albumins. Embryos were produced in media containing different albumin products, with or without carnitine or exogenous FA supplementation, to determine their effect on embryo development in vitro. Total micrograms of FA per milligram of albumin for the 15 albumin products, blastocyst development, cell number, allocation to the trophectoderm (TE) or inner cell mass (ICM), and evaluation of morphology during implantation. The albumin products contained 0.07-16.77 μg total FA/mg albumin. Compared to media with with >1.4 μg FA/mg albumin, media with <0.5 μg FA/mg albumin supported improved blastocyst development, and addition of carnitine mitigated this difference. Addition of palmitoleic acid or oleic acid individually did not improve blastocyst development and decreased ICM:TE ratio. However, in the presence of carnitine, there was improved blastocyst development and maintenance of the ICM:TE ratio. Embryos cultured in Vitrolife human serum albumin with supplementation of carnitine, palmitoleic acid, and oleic acid were more likely to develop cells positive for POU5F1 in an extended embryo culture than embryos cultured in Origio serum protein substitute. Commercial albumin products contain FAs, which vary in abundance. These FAs have different effects on embryo development and quality before and during the implantation stage. Several of these albumin preparations are routinely used for human-assisted reproductive technologies; therefore, serious consideration is warranted when selecting a product for clinical use.


Retinal astrocytes are immigrants from the optic nerve.
The retina in most mammals contains two types of macroglial cells--Müller cells, which span the entire thickness of the retina, and astrocytes, which are mainly confined to the nerve fibre layer. Whereas Müller cells are diffusely distributed in all vertebrate retinae, the presence and distribution of retinal astrocytes correlate with the presence and distribution of retinal blood vessels: retinae that are avascular contain no astrocytes; those that are diffusely vascularized contain diffusely distributed astrocytes; and those that are vascularized in a restricted region contain astrocytes only in the vascularized region. This striking correlation between vascularization and the presence of astrocytes led Stone and Dreher to postulate that retinal astrocytes are immigrants that enter the retina with its vasculature, although others have suggested that they derive from Müller cells. Here we provide strong evidence that astrocytes in the diffusely vascularized rat retina are immigrants from the optic nerve.


Examining the effects of social and cash transfer programs for homeless adults: Evidence from the Samaritan pilot.
To conduct a program evaluation of a technology-based intervention for a housing insecure population. We conduct a quantitative analysis of Samaritan pilot administrative records. Samaritan conducted an initial single-arm pilot of their technology platform among a housing insecure population (N = 500). Administrative records containing basic demographics and social determinants of health were analyzed as part of this evaluation. Our analysis revealed that among the participants, roughly 60% reported one or more improvements in unmet social determinants of health, showing the greatest improvements in the areas of utilities and nutrition. A gender subgroup analysis also revealed a differential pattern of platform use to address social determinant needs, with women more likely to report improvements in housing and nutrition while men report improvements in income and hope categories. Samaritan, a technology-based intervention targeted at housing insecure individuals, aims to connect users to the financial and social capital necessary to improve their current situations. The results of the pilot demonstrate the potential role the Samaritan platform could play in addressing social determinant needs and insights on potentially useful technology-based intervention features for housing insecure populations.


Excessive branched-chain amino acid accumulation restricts mesenchymal stem cell-based therapy efficacy in myocardial infarction.
Mesenchymal stem cells (MSCs) delivered into the post-ischemic heart milieu have a low survival and retention rate, thus restricting the cardioreparative efficacy of MSC-based therapy. Chronic ischemia results in metabolic reprogramming in the heart, but little is known about how these metabolic changes influence implanted MSCs. Here, we found that excessive branched-chain amino acid (BCAA) accumulation, a metabolic signature seen in the post-ischemic heart, was disadvantageous to the retention and cardioprotection of intramyocardially injected MSCs. Discovery-driven experiments revealed that BCAA at pathological levels sensitized MSCs to stress-induced cell death and premature senescence via accelerating the loss of histone 3 lysine 9 trimethylation (H3K9me3). A novel mTORC1/DUX4/KDM4E axis was identified as the cause of BCAA-induced H3K9me3 loss and adverse phenotype acquisition. Enhancing BCAA catabolic capability in MSCs via genetic/pharmacological approaches greatly improved their adaptation to the high BCAA milieu and strengthened their cardioprotective efficacy. We conclude that aberrant BCAA accumulation is detrimental to implanted MSCs via a previously unknown metabolite-signaling-epigenetic mechanism, emphasizing that the metabolic changes of the post-ischemic heart crucially influence the fate of implanted MSCs and their therapeutic benefits.


High-Detectivity Non-Fullerene Organic Photodetectors Enabled by a Cross-Linkable Electron Blocking Layer.
The anode interlayer plays a critical role in the performance of organic photodetectors, which requires sufficient electron-blocking ability to simultaneously attain a high photocurrent and low dark current. Here, we developed two cross-linkable polymers, which can be deposited on the top of the widely used poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) and form a robust layer that can effectively suppress the electron injection from the anode under reverse bias. The optimized device with the resulting cross-linkable XP2 exhibited the lowest dark current density of 5.81 × 10-9 A cm-2 at -0.1 V, which is about 2 orders of magnitude lower than the control devices. A remarkable responsivity of 0.5 A W-1 and a detectivity of >1 × 1013 Jones at a near-infrared wavelength of 800 nm were achieved. Of particular importance is that the resulting device exhibited a linear dynamic range of >135 dB associated with a high working frequency that is shorter than typical commercial digital imagers. The planar heterojunction devices demonstrate that the dark current is closely correlated to the charge generation, which relied on the highest occupied molecular orbital energy levels of the developed cross-linked interlays. The Mott-Schottky analysis revealed that the optimized cross-linked interlayer increased the depletion width of the devices.


Visceral leishmaniasis in infancy and childhood epidemiology and clinicopathological study of 63 cases in Al-Baha Province, Saudi Arabia.
The epidemiology, clinicopathological features, and response to therapy of 63 Saudi patients with visceral leishmaniasis are described. The clinical features in our cases were similar to those described from Asir province, India, and Ethiopia, except for the presence of lymphadenopathy. Fever, hepatosplenomegaly, pancytopenia, and liver dysfunction were common findings. The unusual feature is the seasonal variation in the distribution of the disease. The response to sodium stibogluconate was excellent and the mortality rate was low (less than 1 per cent).


Intraaortic balloon pumping for prolonged circulatory support.
Prolonged circulatory support with an intraaortic balloon pump (IABP) is controversial, in part because it has not been performed frequently enough to base treatment policy on adequate data. To help clarify this problem, 733 cases of consecutive patients who were supported by IABP between 1967 and 1982 were analyzed. Twenty-seven patients were supported for 20 days or more (range 20 to 71). Twelve (44%) had prior histories of chronic congestive heart failure. Complications were more frequent in prolonged-support patients than in those assisted for less than 20 days (vascular, 37% vs 15%, p = 0.001; infectious, 67% vs 25%, p = 0.0001; and bleeding, 26% vs 15%, p = 0.04, respectively). The survival rate of prolonged-support patients, however, was 63% (17 of 27), essentially the same as that of the controls (57%, p = 0.5). Of 17 prolonged-pumping patients discharged alive from the hospital, 9 died within 6 months but 8 survived greater than 2 years. Among congestive heart failure patients, none was a long-term survivor. Prolonged IABP support in congestive heart failure patients lacking surgically correctable lesions can extend life while arrangements for definitive therapy are made (transplant, permanent mechanical assistance). Where definitive therapy is unavailable, IABP may provide additional months of life.


Comparative proteome analysis identified CD44 as a possible serum marker for docetaxel resistance in castration-resistant prostate cancer.
Baseline or acquired resistance to docetaxel (DOC) represents a significant risk for patients with metastatic prostate cancer (PC). In the last years, novel therapy regimens have been approved providing reasonable alternatives for DOC-resistant patients making prediction of DOC resistance of great clinical importance. We aimed to identify serum biomarkers, which are able to select patients who will not benefit from DOC treatment. DOC-resistant PC3-DR and DU145-DR sublines and their sensitive parental cell lines (DU145, PC3) were comparatively analyzed using liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS). Results were filtered using bioinformatics approaches to identify promising serum biomarkers. Serum levels of five proteins were determined in serum samples of 66 DOC-treated metastatic castration-resistant PC patients (mCRPC) using ELISA. Results were correlated with clinicopathological and survival data. CD44 was subjected to further functional cell culture analyses. We found at least 177 two-fold significantly overexpressed proteins in DOC-resistant cell lines. Our bioinformatics method suggested 11/177 proteins to be secreted into the serum. We determined serum levels of five (CD44, MET, GSN, IL13RA2 and LNPEP) proteins in serum samples of DOC-treated patients and found high CD44 serum levels to be independently associated with poor overall survival (p = 0.001). In accordance, silencing of CD44 in DU145-DR cells resulted in re-sensitization to DOC. In conclusion, high serum CD44 levels may help identify DOC-resistant patients and may thereby help optimize clinical decision-making regarding type and timing of therapy for mCRPC patients. In addition, our in vitro results imply the possible functional involvement of CD44 in DOC resistance.


Molecular monitoring of causative viruses in child acute respiratory infection in endemo-epidemic situations in Shanghai.
Numerous viruses are responsible for respiratory infections; however, both their distribution and genetic diversity, in a limited area and a population subgroup, have been studied only rarely during a sustained period of time. A 2-year surveillance program of children presenting with acute respiratory infections (ARIs) was carried out to characterize the viral etiology and to assess whether using gene amplification and sequencing could be a reliable approach to monitor virus introduction and spread in a population subgroup. Using multiplex RT-PCR, 15 different respiratory viruses were detected within the 486 nasopharyngeal positive samples collected among 817 children aged <9-year old who presented with ARI during October 2006 to September 2008. A single virus was detected in 373 patients (45.7%), and two to four viruses in 113 patients (13.8%). The most frequent causative viruses were respiratory syncytial virus (RSV) (24.7%), human bocavirus (24.5%), and human rhinovirus (HRV) (15%). RSV was more prevalent in winter and among young infants. Cases of seasonal influenza A and B viruses were reported mainly in January and August. An increase in adenovirus infection was observed during the spring of the second year of the study. Sequence analyses showed multiple introductions of different virus subtypes and identified a high prevalence of the newly defined HRV-C species. A higher viral incidence was observed during the winter of 2008, which was unusually cold. This study supports the usefulness of multiplex RT-PCR for virus detection and co-infection, and for implementation of a molecular monitoring system for endemic and epidemic viral respiratory infections.


Endocrine hormone imbalance in heart failure with reduced ejection fraction: A cross-sectional study.
Sustained neurohormonal activation plays a central role in the progression of heart failure (HF). Other endocrine axes may also be affected. It was the aim of this study to examine the endocrine profile (thyroid, parathyroid, glucocorticoid, and sex hormones) in a contemporary sample of patients with HF and reduced ejection fraction (EF) on established disease-modifying therapy. This study prospectively measured morning fasting hormones in 52 ambulatory and stable HF patients with EF < 50% on disease-modifying therapy (mean age 63 ± 11 years, 29% female, mean LVEF 32 ± 9.6%) and compared them to 54 patients at elevated risk for HF (61 ± 12 years, 28% female) and 62 healthy controls (HC; 61 ± 13 years, 27% female). Main comparisons were performed using one-way analysis of variance. Associations with biomarkers were studied with linear regression. HF patients showed a reduced free triiodothyronine (fT3)/free thyroxine (fT4) ratio compared to HC (0.30 ± 0.06 vs. 0.33 ± 0.05, p = 0.046). Parathyroid hormone (PTH) and cortisol were increased in HF compared to both HC (median [IQR] 59 [50-84] vs. 46 [37-52] ng/L, p < 0.001 and 497 ± 150 vs. 436 ± 108 nmol/L, p = 0.03, respectively) and patients at risk (both p < 0.001). Total testosterone was reduced in male HF compared to HC (14.4 ± 6.6 vs. 18.6 ± 5.3 nmol/L; p = 0.01). No differences in TSH, estradiol, progesterone, and prolactin were found. Lower fT3 levels were found in HF with EF < 40% versus EF 40%-49% (4.6 ± 0.3 vs. 5.2 ± 0.7 pmol/L, p = 0.009). In HF patients, fT3 was an independent predictor of NT-proBNP and high-sensitivity troponin T in multiple regression analysis. PTH was positively associated with NT-proBNP. There is evidence of endocrine hormonal imbalance in HF with reduced EF beyond principal neurohormones and despite the use of disease-modifying therapy.


Propelling pride to promote healthy food choices among entity and incremental theorists.
Past research suggests that people's beliefs about the malleability of their body weight influence their motivation to engage in healthful behaviors: people who perceive their body weight as fixed (entity theorists) engage less in healthful behaviors than people who perceive their body weight as changeable (incremental theorists). Accordingly, current health interventions frequently aim at shifting entity theorists' beliefs about the malleability of their body weight. Instead of trying to change these beliefs, we test whether the elicitation of pride from past achievements can serve as an intervention to promote healthful behaviors among entity theorists. In addition, we contrast the effect of pride recall among entity theorists with the effect among incremental theorists. Specifically, we find that entity theorists chose healthier behaviors upon the recall of pride related and unrelated to the health domain - the source of pride does not seem to matter. For incremental theorists, however, the source of pride does matter. While health-related pride led them to persist in making healthy food choices, health-unrelated pride instilled reward-seeking behavior among incremental theorists. Prompting health-related pride might be a viable motivational tool to promote healthy food choices, as it is beneficial for entity theorists without thwarting the motivation of incremental theorists.


Putative hormetic mechanisms and effects of atypical antipsychotic agents: Implications for study design and clinical psychopharmacotherapeutics.
This paper addresses a novel putative mechanism by which atypical antipsychotic agents induce clinically significant neuroprotective effects that may be viable in the treatment of schizophrenia - and perhaps other neuropsychiatric disorders. Based upon experimental studies with multiple in vitro models (i.e., PC 12 cells, NSC-34 hybrid cells, SH-SY5Y cells, the immune cell line U-937) and several rodent in vivo models, six atypical antipsychotic drugs, within direct experimental comparisons and/or preconditioning protocol studies with six different stressor/toxic agents (i.e. rotenone, hydrogen peroxide, MPP+, serum withdrawal, beta-amyloid, and corticosterone) were demonstrated to induce neuroprotective effects with consistently hormetic dose response patterns. These findings suggest that some of the reported neuroprotective effects of atypical human antipsychotic agents are likely to be mediated by hormetic mechanisms. These findings may have important implications for both experimental study design and clinical therapeutics.


Ashamed Caregivers: Self-Stigma, Information, and Coping among Dementia Patient Families.
The number of people living with dementia increases almost every year, and the majority of the care system for these individuals is often made up of close family members. This study investigates the relationship between family caregivers' cross-checking of information with healthcare providers and patient health outcomes. Specifically, we examined whether this relationship was mediated by caregivers' enhanced coping efficacy. We also tested the moderation effect of family caregivers' affiliate stigma on information cross-checking, coping efficacy, and coping outcomes. Using a survey of 226 family caregivers of dementia patients in South Korea, this study tested the moderated mediation model with the PROCESS macro. Results indicate that low affiliate stigma moderates coping efficacy on the relationship between information cross-checking and dementia patients' health outcomes. Further implications for family caregiving and general dementia care are discussed.


Fim3-dependent autoagglutination of Bordetella pertussis.
Autoagglutination (Agg) of Bordetella pertussis is often observed in clinical laboratory. However, its causal factors and frequency in circulating strains are unknown. Repeated single colony isolation enabled us to detect an Agg- mutant in the supernatant of an Agg+ strain of B. pertussis. Whole-genome sequencing and immunoblot analysis disclosed that the Agg- mutant had a single C-deletion in its fim3 promoter region (Pfim3) which abolished Fim3 fimbriae production. A B. pertussis fim3-knock out mutant also lacked the Agg+ phenotype. Agg+ clinical isolates were detected a higher production of Fim3 than Fim3-producing Agg- isolates. B. pertussis is known to harbor multiple Pfim3 poly(C) lengths within a single strain culture and our newly developed PCR/LDR assay revealed that Agg+ isolates harbor the highest Pfim3 poly-14C abundance. We evaluated the frequency of autoagglutination in clinical B. pertussis isolates collected in Japan between 1994 and 2018 (n = 203). Fim3 production was confirmed for 190 isolates and 74.7% of them displayed the Agg+ phenotype. The Agg+ phenotype was strongly associated with Pfim3 poly-14C abundance. Taken together, our findings demonstrated that B. pertussis autoagglutination occurs in response to high Fim3 levels and the Agg+ strain has predominated in Japan over the past two decades.


A Highly Stable Yttrium Organic Framework as a Host for Optical Thermometry and D2 O Detection.
The yttrium organic framework (Y0.89 Tb0.10 Eu0.01 )6 (BDC)7 (OH)4 (H2 O)4 (BDC=benzene-1,4-dicarboxylate) is hydrothermally stable up to at least 513 K and thermally stable in air in excess of 673 K. The relative intensities of luminescence of Tb3+ and Eu3+ are governed by Tb3+ -to-Eu3+ phonon-assisted energy transfer and Tb3+ -to-ligand back transfer and are responsible for the differing temperature-dependent luminescence of the two ions. This provides a ratiometric luminescent thermometer in the 288-573 K temperature range, not previously seen for MOF materials, with a high sensitivity, 1.69±0.04 % K-1 at 523 K. In aqueous conditions, loosely bound H2 O can be replaced by D2 O in the same material, which modifies decay lifetimes to yield a quantitative luminescent D2 O sensor with a useful sensitivity for practical application.


Landscape transformation of an urban wetland in Kashmir Himalaya, India using high-resolution remote sensing data, geospatial modeling, and ground observations over the last 5 decades (1965-2018).
Wetlands are among the most vulnerable and dynamic ecosystems of the world. Any change in the anthropogenic footprint or climate affects the health of these pristine ecologically and socioeconomically important ecosystems. In the present study, land use land cover changes (LULCC) and fragmentation of natural landscape changes in an urban wetland, Khushalsar, located in the heart of the Srinagar City, were assessed using high-resolution satellite data, geospatial modeling approach, and ground observations over the last ~ 5 decades (1965 and 2018). The spatiotemporal changes in LULC of the wetland were assessed for 3 time periods that include 1965-1980, 1980-2018, and 1965-2018. Additionally, landscape fragmentation tool (LFT) was used to quantify fragmentation of land cover. The analysis of LULCC indicated that built-up areas in the vicinity of the wetland increased by 510% between 1965 and 2018. The aquatic vegetation and marshy lands increased by 150% and 33% respectively. The area under agriculture, plantation, open water, and barren lands decreased mostly taken over by built-up areas. Within the wetland, the area under open water spread reduced by 75% while the aquatic vegetation increased by 150% from 1965 to 2018. The built-up areas including roads also showed a substantial increase. The LFT analysis revealed four categories of landscapes i.e., patch, edge, perforated, and core areas. Since the natural land cover types were taken over by land use predominantly built-up areas, the core natural areas and perforated landscapes in the Khushalsar shrunk by 34% and 94% respectively indicating fragmentation of natural environment. The lack of sewage treatment facility, reckless unplanned urbanization within and in the vicinity of the wetland, is responsible for the degradation of the Khushalsar wetland.


Identification of a peptide antagonist for platelet-derived growth factor.
A series of peptides derived from the primary sequence of the B-chain of platelet-derived growth factor (PDGF) was analyzed for their ability to inhibit the binding of 125I-PDGF-AA and 125I-PDGF-BB to PDGF alpha-receptors and PDGF beta-receptors, respectively. A 13-amino acid peptide (ANFLVWEIVRKKP), corresponding to amino acids 116-121 and 157-163 in PDGF B-chain, was found to compete with binding to both alpha- and beta-receptors. Modification of this peptide on the tryptophan residue increased its receptor competing activity. The peptide was found to be a receptor antagonist, since it inhibited dimerization and autophosphorylation of PDGF receptors. When analyzed on intact cells, the peptide was found to have, in addition to the specific inhibitory effect at the receptor level, a nonspecific inhibitory effect on [3H]thymidine incorporation. Our study has identified two regions in PDGF that are of importance for receptor interaction.


Phase 1 multicenter, dose-expansion study of ARX788 as monotherapy in HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma.
ARX788 is an anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate with AS269 as cytotoxic payload. In this phase 1 multicenter dose-expansion clinical trial, patients with HER2-positive advanced gastric/gastroesophageal junction adenocarcinoma failing to respond to prior trastuzumab-based standard treatment were enrolled. Between July 15th, 2019, and March 14th, 2022, 30 participants were enrolled. Twenty-eight (93.3%) patients experienced at least one drug-related adverse event (AE) and 13.3% experienced grade 3 ARX788-related AEs. The confirmed objective response rate is 37.9% (95% confidence interval [CI]: 20.7%-57.7%) and the disease control rate is 55.2% (95% CI: 35.7%-73.6%). With a median follow up of 10 months, the median progression-free survival and overall survival are 4.1 (95% CI: 1.4-6.4) and 10.7 months (95% CI: 4.8-not reached), respectively. The median duration of response is 8.4 (95% CI: 2.1-18.9) months. ARX788 is well tolerated and has promising anti-tumor activity in patients with HER2-positive advanced gastric adenocarcinoma (ChinaDrugTrials.org.cn: CTR20190639).


The metabolic syndrome, depression, and cardiovascular disease: interrelated conditions that share pathophysiologic mechanisms.
This article introduces the metabolic syndrome as a clinical phenotype with consequences for diagnosis and treatment that go beyond the different clinical specialties involved. A life-course approach is suggested as a means of understanding the complex interrelations between the metabolic syndrome, depression, and cardiovascular disease. Pathophysiologic mechanisms that these conditions share are discussed in detail. These considerations provide arguments for a more integrative approach to patients in general that surpass the current disease-centered services such as endocrinology, psychiatry, and cardiology.


Diverse aspidosperma-type alkaloids from the leaves of Tabernaemontana bovina with anti-hepatoma activity.
Seventeen undescribed Aspidosperma-type alkaloids (ASPs), along with nine known ones were isolated from the leaves of Tabernaemontana bovina. Taberbovermines A and B were assigned to tabersonine-type with a contracted A- and E-ring, respectively. Taberbovermine C was attributed to tabersonine without D ring. These structures of the ASPs were established on the basis of comprehensive spectroscopic data, electronic circular dichroism calculations and X-ray diffraction. The summaries of structure-activity relationship of tabersonine class were discussed based on hepatoma cells screening.


[L forms of Streptococcus in the cultures of blood from patients with rheumatic fever in the active and inactive phases].
It was shown that L-forms of streptococci were constantly isolated by means of the method used by the authors from patients with rheumatism, irrespective of the activity and the course of the disease. The data obtained pointed to the presence of septicemia caused by the L-forms of streptococci in patients with rheumatism both at the active and inactive phase. In this connection it should be noted that modern clinical criteria of the activity of rheumatic process are unreliable.


The Bulla ocular circadian pacemaker. I. Pacemaker neuron membrane potential controls phase through a calcium-dependent mechanism.
In an effort to understand the cellular basis of entrainment of circadian oscillators we have studied the role of membrane potential changes in the neurons which comprise the ocular circadian pacemaker of Bulla gouldiana in mediating phase shifts of the ocular circadian rhythm. We report that: 1. Intracellular recording was used to measure directly the effects of the phase shifting agents light, serotonin, and 8-bromo-cAMP on the membrane potential of the basal retinal neurons. We found that light pulses evoke a transient depolarization followed by a smaller sustained depolarization. Application of serotonin produced a biphasic response; a transient depolarization followed by a sustained hyperpolarization. Application of a membrane permeable analog of the intracellular second messenger cAMP, 8-bromo-cAMP, elicited sustained hyperpolarization, and occasionally a weak phasic depolarization. 2. Changing the membrane potential of the basal retinal neurons directly and selectively with intracellularly injected current phase shifts the ocular circadian rhythm. Both depolarizing and hyperpolarizing current can shift the phase of the circadian oscillator. Depolarizing current mimics the phase shifting action of light, while hyperpolarizing current produces phase shifts which are transposed approximately 180 degrees in circadian time to depolarization. 3. Altering BRN membrane potential with ionic treatments, depolarizing with elevated K+ seawater or hyperpolarizing with lowered Na+ seawater, produces phase shifts similar to current injection. 4. The light-induced depolarization of the basal retinal neurons is necessary for phase shifts by light. Suppressing the light-induced depolarization with injected current inhibits light-induced phase shifts. 5. The ability of membrane potential changes to shift oscillator phase is dependent on extracellular calcium. Reducing extracellular free Ca++ from 10 mM to 1.3 X 10(-7) M inhibits light-induced phase shifts without blocking the photic response of the BRNs. The results indicate that changes in the membrane potential of the pacemaker neurons play a critical role in phase shifting the circadian rhythm, and imply that a voltage-dependent and calcium-dependent process, possibly Ca++ influx, shifts oscillator phase in response to light.


Influence of somatostatin analogue (SMS 201-995, octreotide) on blood pressure in adrenocorticotrophin (ACTH) treated rats: role of hyperinsulinaemia in ACTH hypertension.
1. The hypothesis that adrenocorticotrophin (ACTH)-induced hypertension is a consequence of steroid-induced hyperinsulinaemia was tested using the somatostatin analogue (sandostatin, octreotide) to inhibit insulin release in Sprague-Dawley (SD) rats (n = 41). 2. Octreotide (20 micrograms, twice daily) did not modify blood pressure, plasma glucose, bodyweight, water and electrolyte balance, or organ weights but inhibited insulin secretion in the SD rat. 3. Compared with sham injection, ACTH-treated (0.5 mg/kg per day) SD rats showed an increase in blood pressure (sham 111 +/- 4 mmHg; ACTH 140 +/- 5 mmHg on treatment day 10 (P < 0.01), organ weights, water intake, urine volume, plasma glucose, insulin and sodium concentrations, and decrease of bodyweight and plasma potassium concentration. 4. Systolic blood pressure in rats treated with combined octreotide and ACTH was similar to that in rats on ACTH alone. Plasma insulin concentration was lower in octreotide + ACTH treated rats than with ACTH treatment alone. There were no differences in body or organ weights, plasma glucose, water or electrolyte balance. 5. Octreotide lowered plasma insulin concentration to the normal range but did not modify ACTH-induced hypertension in SD rats. These data do not support the notion that insulin-mediated alterations in blood pressure are a major mechanism for ACTH-induced hypertension in the rat.


α1 and α2-adrenoceptors in the medial amygdaloid nucleus modulate differently the cardiovascular responses to restraint stress in rats.
Medial amygdaloid nucleus (MeA) neurotransmission has an inhibitory influence on cardiovascular responses in rats submitted to restraint, which are characterized by both elevated blood pressure (BP) and intense heart rate (HR) increase. In the present study, we investigated the involvement of MeA adrenoceptors in the modulation of cardiovascular responses that are observed during an acute restraint. Male Wistar rats received bilateral microinjections of the selective α1-adrenoceptor antagonist WB4101 (10, 15, and 20 nmol/100 nL) or the selective α2-adrenoceptor antagonist RX821002 (10, 15, and 20 nmol/nL) into the MeA, before the exposure to acute restraint. The injection of WB4101 reduced the restraint-evoked tachycardia. In contrast, the injection of RX821002 increased the tachycardia. Both drugs had no influence on BP increases observed during the acute restraint. Our findings indicate that α1 and α2-adrenoceptors in the MeA play different roles in the modulation of the HR increase evoked by restraint stress in rats. Results suggest that α1-adrenoceptors and α2-adrenoceptors mediate the MeA-related facilitatory and inhibitory influences on restraint-related HR responses, respectively.


Perseverance of exploration in novel environments predicts morphine place conditioning in rats.
Reactivity to novelty has been related to operant drug self-administration but does not seem involved in the conditioned place preference (CPP). To further assess this issue our aims were to investigate: (1) the importance of the initial versus delayed activity in the novel environment to predict the CPP induced by morphine; (2) the separate contribution of trait anxiety in morphine CPP. Male Sprague-Dawley rats were exposed to a circular corridor for 30 min to assess reactivity to novelty and to the elevated plus-maze and the light-dark tests as measures of anxiety and morphine CPP was then studied (three pairings with 5 mg/kg s.c. morphine and three with saline). Delayed activity in the corridor (16-30 min) correlated positively with CPP score, whereas the initial activity (0-15 min) did not. High-responders (HR), those more active during the second half of the corridor, developed morphine CPP in contrast to low-responders (LR). Also, HR and LR did not differ in anxiety nor any plus-maze or light-dark test measure correlated with CPP behaviour. Enhanced vulnerability to develop morphine CPP is predicted by a higher delayed activity in a novel environment, regardless of anxiety.


An integrated deep-learning and multi-level framework for understanding the behavior of terrorist groups.
Human security is threatened by terrorism in the 21st century. A rapidly growing field of study aims to understand terrorist attack patterns for counter-terrorism policies. Existing research aimed at predicting terrorism from a single perspective, typically employing only background contextual information or past attacks of terrorist groups, has reached its limits. Here, we propose an integrated deep-learning framework that incorporates the background context of past attacked locations, social networks, and past actions of individual terrorist groups to discover the behavior patterns of terrorist groups. The results show that our framework outperforms the conventional base model at different spatio-temporal resolutions. Further, our model can project future targets of active terrorist groups to identify high-risk areas and offer other attack-related information in sequence for a specific terrorist group. Our findings highlight that the combination of a deep-learning approach and multi-scalar data can provide groundbreaking insights into terrorism and other organized violent crimes.


A time-series analysis of the association between alcohol and suicide in Australia.
800,000 people die by suicide every year according to World Health Organisation data. Studies have shown associations between alcohol consumption and suicide, with most demonstrating that alcohol consumption increases suicide risk. However, some studies from high consumption countries show results in the opposite direction. This present study examines the association between per capita (PC) alcohol consumption and same year suicide mortality in Australia, and tests for lag effects, between 1910 and 2017. Age and gender-specific autoregressive integrated moving average (ARIMA) models were used to examine associations between alcohol consumption PC and suicide mortality rates. Associations between unemployment, divorce, barbiturates access, and the Great Depression and World War II, and suicide were examined. A 10% increase in PC alcohol consumption was associated with a 5% and 5.1% decrease in overall and male suicide mortality respectively in the same year. However, a 10% increase in PC alcohol consumption was associated with an 5.1% and 5.4% increase in overall and male suicide mortality respectively 12 years later. This association differed among age groups and was significant in the male population only. Unemployment, divorce, the Great Depression and WW2, and barbiturates access were significantly associated with same year suicide mortality. Contemporaneous alcohol consumption was associated with decreased suicide mortality, but was also associated with an increased risk of suicide 12 years later. Unemployment and barbiturates access were associated with an increased risk of suicide. Interventions and policies that address chronic alcohol consumption and support the unemployed may reduce suicide mortality.


Epitope mapping of human immunoglobulin-specific murine monoclonal antibodies with domain-switched, deleted and point-mutated chimeric antibodies.
27 engineered chimeric antibodies possessing human gamma, epsilon, mu or alpha constant regions and V region specificity for nitrophenyl or dansyl were used to study the isotype specificity of 29 murine monoclonal antibodies (MAbs) specific for human immunoglobulins (IgG1-4, IgE, IgM, IgA or secretory piece). The isotype-restricted immunoreactivity observed with wild-type chimeric antibodies paralleled the pattern of each MAb's reactivity with purified human myeloma proteins. 16 mutant IgG anti-dansyl chimeric antibodies with genetically engineered domain switches, deletions or point-mutations were used as antigens to further characterize the epitopes recognized by the human IgG subclass-specific MAbs. The binding of three human IgG1-specific MAbs (HP6069, HP6070 and HP6091) was mapped to similar epitopes on the CH2 domain of human IgG1. Of the two anti-human IgG2 MAbs tested, HP6002 reacted with the CH2 of IgG2 while HP6014 bound to the CH1 domain. Both anti-human IgG3 MAbs (HP6047, HP6050) reacted with different regions of the IgG3 hinge. The anti-human IgG4 MAbs (HP6023, HP6025) bound to a similar epitope on the carboxyl terminus of CH2 or the CH3 of human IgG4. The three exclusion antibodies (HP6019, HP6030 and HP6058) bound to different epitopes in the CH2 domain of three of four IgG subclasses. The domain mapping was confirmed by competitive inhibition experiments. These results were used to select a group of IgG-reactive MAbs for construction of a poly-monoclonal anti-IgG capture and detection reagent that uniformly bound all four subclasses of human IgG. This study provides support for the use of engineered chimeric human chimeric antibodies as replacements for increasingly rare, purified human paraproteins in the specificity analysis of immunochemical reagents used in clinical and research laboratories for the detection and quantitation of human antibodies. Moreover, these studies demonstrate how the MAbs can serve as effective probes for examining conformational differences among the four human IgG subclasses.


Human Dystrophin Structural Changes upon Binding to Anionic Membrane Lipids.
Scaffolding proteins play important roles in supporting the plasma membrane (sarcolemma) of muscle cells. Among them, dystrophin strengthens the sarcolemma through protein-lipid interactions, and its absence due to gene mutations leads to the severe Duchenne muscular dystrophy. Most of the dystrophin protein consists of a central domain made of 24 spectrin-like coiled-coil repeats (R). Using small angle neutron scattering (SANS) and the contrast variation technique, we specifically probed the structure of the three first consecutive repeats 1-3 (R1-3), a part of dystrophin known to physiologically interact with membrane lipids. R1-3 free in solution was compared to its structure adopted in the presence of phospholipid-based bicelles. SANS data for the protein/lipid complexes were obtained with contrast-matched bicelles under various phospholipid compositions to probe the role of electrostatic interactions. When bound to anionic bicelles, large modifications of the protein three-dimensional structure were detected, as revealed by a significant increase of the protein gyration radius from 42 ± 1 to 60 ± 4 Å. R1-3/anionic bicelle complexes were further analyzed by coarse-grained molecular dynamics simulations. From these studies, we report an all-atom model of R1-3 that highlights the opening of the R1 coiled-coil repeat when bound to the membrane lipids. This model is totally in agreement with SANS and click chemistry/mass spectrometry data. We conclude that the sarcolemma membrane anchoring that occurs during the contraction/elongation process of muscles could be ensured by this coiled-coil opening. Therefore, understanding these structural changes may help in the design of rationalized shortened dystrophins for gene therapy. Finally, our strategy opens up new possibilities for structure determination of peripheral and integral membrane proteins not compatible with different high-resolution structural methods.


Comparison of the Effects of Spreader Graft Versus Spreader Flap on Nasal Valve Angle in Open Approach Rhinoplasty.
This study aimed to compare the spreader graft and flap techniques, which are used in nasal valve surgery, based on measurements of nasal valve angles using computed tomography. In this retrospective study, all patients' right and left internal nasal valve angles were measured from coronal computed tomography images taken preoperatively and in the third postoperative month. A paired t-test and independent t-test were used to compare continuous numerical variables. There were 52 patients with 104 valves in the spreader flap group and 54 patients with 108 valves in the spreader graft group, with a mean age of 27.76 ± 8.16 years. The angles were found to be statistically significantly higher in the postoperative period (p<0.001) in all patients. While the angles did not differ significantly between the flap and graft groups in the preoperative period, they were significantly higher in the flap group in the postoperative period (p<0.001). It is essential to preserve nasal valve function in rhinoplasty. The findings show that a spreader flap is superior to a spreader graft, although both techniques increase internal nasal valve function. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


Biological, immunological and biochemical characterization of cleaved prolactin generated by lactating mammary gland.
We have previously shown that rat prolactin is proteolytically cleaved in its loop by peripheral tissues of the rat. Of the tissues examined to date, lactating mammary gland exhibits the highest prolactin-cleaving activity. The objective of this study was to characterize cleaved prolactin, biologically, immunologically and chemically. By modifying an established analytical method, we were able to generate large (micrograms) amounts of cleaved rat prolactin from cell fractions of rat mammary gland which could then be assayed for biological and immunological activity relative to intact hormone. The cleaved product showed no significant difference relative to the intact rat prolactin when assayed for its ability to compete with 125I-labelled ovine prolactin for the prolactin receptor and for its ability to stimulate the proliferation of rat Nb2 lymphoma cells. Cleaved rat prolactin, however, did show a 50-60% reduction in activity relative to intact rat prolactin when assayed by radioimmunoassay. Using Edman degradation and partial amino acid analysis, we determined that the second N-terminus of the cleaved rat prolactin begins at amino acid 149. The divergence of biological and immunological activity produced by proteolytic cleavage in the loop of rat prolactin suggests that biological and immunological sites differ in location. The possible physiological implications of a cleaved rat prolactin molecule generated by target tissue with maintained biological activity and reduced immunological activity are discussed.


[The study of peri-operative chemotherapy in stage I-IIIa NSCLC].
A number of studies had evaluated the benefit of neoadjuvant chemotherapy combined surgery on stage IIIa-IIIb NSCLC, survival benefit was found in several papers. We attempt to evaluate the survival and prognosis of cisplatinum-based schedule as peri-operative CT for resectable stage I-IIIa NSCLC. A prospective, randomized, multicenter study was conducted by Shanghai Lung Cancer Team (supported by Shanghai Branch of Discipline Foundation) since 1995-1997 for 211 cases of stage I-IIIa NSCLC with curative resection (99 stage I, 47 stage II, 65 stage III), age of <or= 75, KPS >or= 80, staged by 1997 AJC TNM Criteria. They were randomized to be 103 cases with 1 - 2 cycles of pre-operative CT and 108 cases with no pre-operative CT, 2 - 4 cycles of post-operative CT were used for stage II and stage IIIa NSCLC, it was totally 4 cycles of MVP or MOP CT schedule each case. Follow-up team had been trained, the follow-up rate should be >or= 95%, last follow-up date was March of 2002. Lobectomy was performed for most patients. Accumulated survival, log rank, MST, Cox uni-variance and multi-variance analyses were used as statistics for evaluation. The two arms were well balanced for baseline demographic and clinical characteristics (P > 0.05 for all). Stage I NSCLC had the best year-survival in whole patients. No statistical survival difference was found between the group with pre-op CT and with no pre-op CT, P = 0.074, 0.087 and 0.097, respectively, 5-year survival rates were of 31.98%:36.68%. In various stage, a statistical survival difference was only shown in stage IINSCLC, P = 0.042, 5-year survival rates and MST were worse in the group with pre-operation CT, 20%:65.2% and 24 months:48 months, respectively, but no difference was seen in stage I and stage IIIa NSCLC. Stage and post-operation CT were the only two meaningful parameters with statistical survival difference calculated by multi-variance analyses, P = 0.000 all, but no difference was found in others 4 parameters (age, sex, type and pre-operation CT). The response rate of pre-operation CT was of 50%. Though there was no statistical difference, the responders were with slightly better year-survival rates than MR + NR patients, 38.9% and 33.3%, respectively. In the cases with pathological "T" down stage and "T" unchanged after pre-operation CT had a better yr-survival rates than "T" up-stage, P = 0.03, 5-year survival rates were of 41.67%, 40.51% and 11.76%, respectively, thus, effective chemotherapy might be beneficial to survival. Besides, in the cases with >or= 3 cycles of post-operation CT have better survival rates than less cycles. A prospective, randomized, multicenter peri-operation CT study for stage I-IIIa NSCLC conducted in Shanghai, China., it showed there had no benefit in survival between with pre-operation CT arm and with no pre-operation CT arm. In stage II NSCLC, pre-operation CT cases had a worse year-survival than with no pre-operation CT, P = 0.042, but no difference was seen in stage I and stage IIIa NSCLC. The responder of CT and "T" down stage, "T" unchanged had better survival rates than those of not response and "T" up-stage. From multivariate analyses, stage and post-operation CT were the two meaningful parameters to year-survival, >or= 3 - 4 cycles of post-operation CT had a better statistical higher year-survival than less cycles. Nutrition, supportive treatment, immunity status and prevention of toxicity might be the next study worthy to conduct, for CT combined with OP.


Childhood maltreatment and decision-making autonomy in adulthood: The mediating roles of self-esteem and social support.
Childhood maltreatment (CM) is connected with a large number of maladaptive long-term outcomes. Effective prevention and intervention hinges partly on our understanding of the key mediating mechanisms that help account for the relationship between child maltreatment and its long-term consequences. We know the consequences of CM can extend into adulthood, including the intergenerational transmission of violence, re-victimization, high-risk behavior, and persisting mental health problems. We argue that CM also likely affects decision-making autonomy in adulthood, limiting their independence and exaggerating their risk for other poor outcomes. We suggest that the effects of CM on self-esteem and access to social support mediate this relationship, helping to explain how and why CM impacts autonomy in the long term. This study aimed to examine these relationships using a cross-sectional sample of currently married women of Bangladesh aged 15-49 years (N = 426). A multi-stage random sampling technique was employed for data collection and a multivariate logistic regression technique was applied for data analysis. Results from the multivariate logistic regression model revealed a direct effect of a history of CM on limited decision-making autonomy in adulthood and a full mediating effect of self-esteem and social support on the associations between CM and decision-making autonomy in women, even after adjusting for theoretically and empirically relevant covariates. The study findings provide insight into the mechanisms by which early childhood experiences impact autonomous decision-making. However, causality cannot be determined because of the cross-sectional design. Finally, our findings suggest that the influence of CM on autonomy could be augmented by self-esteem recovery through social support from family, friends, and peers.


Asymmetric aerobic oxidation of secondary alcohols catalyzed by poly(N-vinyl-2-pyrrolidone)-stabilized gold clusters modified with cyclodextrin derivatives.
Surface modification of poly(N-vinyl-2-pyrrolidone)-stabilized gold clusters (1.8 ± 0.6 nm) with aminated cyclodextrins induced aerobic oxidative kinetic resolution of racemic secondary alcohols (krel = 1.2).


Self-expandable metallic stent for unresectable malignant strictures in the esophagus and cardia.
Self-expandable metallic stent (EMS) placement has been the first choice for dysphagia because of the certainty over its safety, low invasiveness, and immediate efficacy. However, there still remain some problems in relation to the EMS placement site and anticancer therapies before and after EMS placement. Consecutive 78 patients in whom EMS was placed due to the unresectable malignant stricture in the esophagus or cardia from July 1995 to August 2003 in our department were studied. Gastroesophageal reflux was found in 5 of 8 patients after placement of conventional EMS for the stricture in the gastroesophageal junction. Meanwhile, acid and bile reflux into the esophagus were not detected by pH and bilirubin monitoring, respectively, in 6 patients after placement of the EMS with an anti-reflux mechanism for the stricture in the gastroesophageal junction. The median survival period of all patients after EMS placement was 123 days. The median survival period of 7 patients with radiotherapy only after EMS placement was 138 days and that of 17 patients with radiotherapy before EMS placement was 60 days, which was shorter than that of the former (p<0.05). On the other hand, the median survival period after hospital admission due to dysphagia of these 7 patients was longer than that of 17 patients with radiotherapy only before EMS placement, although, the difference was not significant. EMS with an antireflux mechanism is not commercially available in Japan and approval is urgently required. The indication of radiotherapy associated with EMS placement is to be studied further.


Analysis of skin dose distribution for the prediction of severe radiation dermatitis in head and neck squamous cell carcinoma patients treated with concurrent chemo-radiotherapy.
We investigated whether the pattern of intensity-modulated radiotherapy (IMRT) dose distribution to the skin can be correlated with the development of G3/G4 radiation dermatitis (RD). A frequency-matched cohort analysis was perfomed on patients treated with IMRT and concurrent cisplatin or cetuximab. Risk ratios were obtained by fitting Poisson regression models. The incidence of G3/G4 RD was 41.1% in 90 patients included (50% vs 36.6% in the cetuximab and cisplatin cohorts, respectively). In multivariate analysis, PS ≥ 1 and weight loss at RT completion >10 kg were the only factors that retained significance. The best dosimetric predictive accuracy was provided by 19.9 cc and 5.8 cc of skin ring 2 mm V50 and V60, respectively (AUC: 0.61 for both). Along with clinical factors, the pattern of dose distribution to a ring structure localized 2 mm below the patient's surface may help predict the development of severe RD.


Parotid masses: evaluation, analysis, and current management.
Two hundred thirty-one sequential parotid masses seen from January 1982 to July 1986 were reviewed for their clinical presentation, diagnostic evaluation, pathologic findings, and therapeutic approach. The results were compared with the previously reported findings on parotid masses. There were 146 (63.2%) benign tumors, 50 (21.6%) malignancies, and 35 (15.2%) nonmalignant lesions. Tumors were classified according to their histopathologic diagnosis. An asymptomatic mass was the most common presentation. Radiological evaluation was mainly with computed tomography. The primary surgical procedure was parotidectomy with facial nerve preservation. A selected group of patients was referred for radiation therapy. Our study demonstrated that non-neoplastic lesions contribute a significant number of masses in the differential diagnosis of parotid tumors. Metastatic squamous cell carcinoma was the most frequently encountered malignancy. Deep lobe tumors were twice as common as previously reported.


HTLV-1 seroprevalence in AIDS patients and in HIV-1 seropositive and seronegative subjects at risk for AIDS in northern Italy.
Sera of 1023 subjects belonging to categories at risk for AIDS, positive for HIV-1, were tested for antibodies to human T-cell leukemia virus (HTLV-1) by ELISA, Western blotting, and radioimmunoprecipitation (RIP) assay. Sera of these subjects were positive for antibodies to HTLV-1 in a percentage of 18.54%. Nine out of 18 sera from patients with AIDS had antibodies to HTLV-1 (50%). Sera of 207 intravenous drug abusers and 64 homosexual males, seronegative for HIV-1, were tested for antibodies to HTLV-1 and 6.7% of intravenous drug abusers and 7.8% of homosexual males were found to be HTLV-1 antibody positive, showing that HTLV-1 infection occurred independently of HIV-1 and HIV-2 infections. In fact the same HIV-1 seronegative patients were also tested for the presence of antibodies to HIV-2 and none of them was found to be positive.


Recombinant human antithrombin expressed in Chinese hamster ovary cells shows in vivo efficacy on rat DIC model similarly to plasma-derived antithrombin regardless of different N-glycosylation.
Plasma-derived human antithrombin (pAT) is used for the treatments of disseminated intravascular coagulation (DIC) and hereditary antithrombin deficiencies. We expressed recombinant human antithrombin (rAT) in Chinese hamster ovary (CHO) cells. The purified rAT is composed of 55% alpha-isoform and 45% beta-isoform. The structure of the N-linked oligosaccharides of rAT is the same biantennary complex type as previously found in pAT with less sialylated on the non-reducing ends. Most of the oligosaccharides of rAT are fucosylated at the reducing ends of N-acetylglucosamine, while those of pAT are not fucosylated. Despite of the difference in sialylation and fucosylation of the oligosaccharide units, rAT and pAT showed indistinguishable heparin cofactor and progressive activities, and they bound to thrombin in a one-to-one stoichiometric manner. In lipopolysaccharide (LPS)-induced and thromboplastin-induced DIC rat models, rAT reduced fibrinogen and platelet consumption to a similar extent with pAT. In LPS-induced DIC model, both ATs similarly restrained the increase of alanine aminotransferase and aspartate aminotransferase activities. Finally, pharmacokinetic analysis showed that both ATs had similar half-lives in the circulation of normal rats. Together, the present study demonstrated that rAT prepared in CHO cells has potential for a substitute of pAT in therapeutic use.


Antiproliferative effects of selective cyclooxygenase-2 inhibitor modulated by nimotuzumab in estrogen-dependent breast cancer cells.
Breast cancer is the most common malignancy in women, and many breast cancer patients fail conventional treatment strategies of chemotherapy, radiation, and antiestrogen therapy. Research into the molecular pathways and biomarkers involved in the development of breast cancer should yield information that will guide therapeutic decisions. Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) are involved in the carcinogenesis of breast cancer and exist tight crosstalk with estrogen receptor (ER) pathway. Combination of EGFR and COX-2 inhibitors, therefore, could be an effective strategy for reducing cell growth in estrogen-dependent breast cancer. In order to verify the effects of EGFR and COX-2 inhibitors, breast cancer cells MCF-7 and SKBR-3 were characterized for receptors status and then treated with respective inhibitors (nimotuzumab and celecoxib) alone and in combination. Both cell lines were sensitive to celecoxib, but not to nimotuzumab. However, combination of two drugs demonstrated synergistic effects on cell killing. Moreover, association of two drugs resulted in SKBR-3 cells, a further G0/G1 phase arrest than one drug alone. Downregulation of p-EGFR, p-Akt, p-mTOR, and amplified in breast cancer 1 (AIB1) were observed in both cell lines, and upregulation of E-cadherin was only found in MCF-7, after treatment with single agent or in combination. These studies suggest that nimotuzumab and celecoxib exert synergistic antiproliferation effects in breast cancer, which partly correlates with ER status. Due to Akt/mTOR, EMT and AIB1 pathways participate in this process, therefore, E-cadherin and AIB1 may be considered as possible biomarkers to predict response in ER-positive breast cancer cells treated with EGFR and COX-2 inhibitors.


Association of Adiponectin gene polymorphisms and nonalcoholic fatty liver disease.
To investigate the correlation between Adiponectin gene polymorphisms and the genetic susceptibility of nonalcoholic fatty liver disease (NAFLD). 357 NAFLD patients from January 2005 to December 2013 and 357 cases of healthy controls among the Han population were collected; polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to detect three tagSNPs (Rs2241767, rsl501299 and rs3774261) of Adiponectin. Risk factors were analyzed by multivariate logistic regression and haplotype analysis was performed using SHEsis software. Rs2241767, rsl501299 and rs3774261 polymorphisms were associated with the risk of NAFLD. Haplotype analysis showed that, A-T-A haplotype was a protective factor of NAFLD (OR: 0.154, 95% CI: 0.011-0.576, P = 0.004) and G-G-A (OR: 4.012, 95% CI: 2.118-10.324, P < 0.001) and G-T-G (OR: 5.219, 95% CI: 2.751-12.651, P < 0.001) haplotype was risk factors of NAFLD. There was an association between Adiponectin gene polymorphisms and the genetic susceptibility of NAFLD.


Acetylcholinesterase inhibitors in the giant goldenrod root.
Eight bioactive clerodane diterpenes from the root extract of Solidago gigantea Ait. (giant goldenrod) were quantified by high-performance thin-layer chromatography (HPTLC) and two newly developed hyphenated methods. One uses vanillin sulphuric acid derivatization and densitometry, and the other an inhibition assay of acetylcholinesterase (AChE) and video densitometry. Both methods gave figures of merit for quantification including 5.8-33.9 ng and 175.5-448.7 ng LOQs and 2.7-6.9 RSD% and 8.8-13.9 RSD% inter-day precisions, respectively. Based on the diterpenes' content of 14 root samples collected over a year from the same plant population, the fully flowering plant is suggested to collect the root as a source of these compounds. Excepting one diterpene (with the lowest retardation factor), the quantitative results for the richest sample obtained by the two methods were in harmony. The difference could be due to a matrix effect.


Comparative behavioral, biochemical and pigmentary effects of MPTP, MPP+ and paraquat in Rana pipiens.
We demonstrate that injections of 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP), 1-methyl-4-phenyl-pyridinium ion (MPP+) and Paraquat (PQ+) produce in Rana Pipiens different behavioral, biochemical and skin pigmentation changes. MPTP causes in frogs the main symptoms of Parkinsonism (rigidity, akinesia and tremor) and it darkens the skin of animals. It also decreases brain and, less so, adrenal medulla dopamine. These effects are blocked by Pargyline. MPP+ causes the same symptoms but more rapidly. In contrast, skin pigmentation is clearly lightened. Brain and particularly adrenal dopamine reserves are nearly abolished. Pargyline increases these effects. Paraquat, in a cumulative fashion, eventually causes the same behavioral changes and a slight increase in pigmentation. It initially produces an increase in brain and adrenal dopamine concentrations, but later a significant dopamine concentration decrease. Pargyline potentiates these long term effects, blocks the dopamine increase, but reverses the PQ+ effect upon melanin, producing the same depigmentation as MPP+ alone.


Mapping human brain charts cross-sectionally and longitudinally.
Brain scans acquired across large, age-diverse cohorts have facilitated recent progress in establishing normative brain aging charts. Here, we ask the critical question of whether cross-sectional estimates of age-related brain trajectories resemble those directly measured from longitudinal data. We show that age-related brain changes inferred from cross-sectionally mapped brain charts can substantially underestimate actual changes measured longitudinally. We further find that brain aging trajectories vary markedly between individuals and are difficult to predict with population-level age trends estimated cross-sectionally. Prediction errors relate modestly to neuroimaging confounds and lifestyle factors. Our findings provide explicit evidence for the importance of longitudinal measurements in ascertaining brain development and aging trajectories.


Food waste composting based on patented compost bins: Carbon dioxide and nitrous oxide emissions and the denitrifying community analysis.
Mature compost and rice bran were used as bulking agents to perform Food Waste Rapid Composting (FWRC) in a patented composting bin. The characteristics of CO2 and N2O emission and the denitrifying community were investigated. The release of CO2 and N2O concentrated in the early composting stage and reduced greatly after 28 h, and the N2O emission peak of the treatment with mature compost was 8.5 times higher than that of rice bran. The high N2O generation resulted from massive denitrifying bacteria and NOx--N in the composting material. The relative abundances of denitrifiers, correspondingly genes of narG and nirK were much higher in the treatment with mature compost, which contributed to the N2O emission. Moreover, the correlation matrices revealed that N2O fluxes correlated well with moisture, pH, temperature, and the abundances of nirK and nosZ genes during FWRC.


[MR urography in the diagnosis of upper urinary tract obstruction].
To evaluate the role of magnetic resonance urography (MRU) in the diagnosis of upper urinary tract obstruction. MRU was performed for 35 patients suspicious of upper urinary tract obstruction. MRU provided high resolution images of the urinary tract. The site of upper urinary tract obstruction and hydronephrosis could be clearly shown. MRU, a nontraumatic technique, needs no iodinated contrast medium. It might be widely adopted in the diagnosis of upper urinary diseases.


Is working in a cold environment associated with musculoskeletal complaints 7-8 years later? A longitudinal analysis from the Tromsø Study.
Exposure to a cold environment at work is associated with a higher prevalence of musculoskeletal pain and chronic pain in cross-sectional studies. This study aims to determine the association between working in a cold environment ≥ 25% of the time and musculoskeletal complaints (MSC) 7-8 years later. We followed participants from the sixth survey (Tromsø 6, 2007-2008) to the seventh survey (Tromsø 7, 2015-2016) of the Tromsø Study. Analyses included 2347 men and women aged 32-60 years who were not retired and not receiving full-time disability benefits in Tromsø 6. Three different binary outcomes were investigated in Tromsø 7: any MSC, severe MSC, and MSC in ≥ 3 anatomical regions. We excluded participants with severe MSC, MSC in ≥ 3 regions, or missing values in Tromsø 6. The association between working in a cold environment and future MSC were examined using Poisson regression and adjusted for age, sex, number of moderate MSC, education, physical activity at work, smoking status, body mass index, and self-reported health in Tromsø 6. 258 participants reported to work in a cold environment ≥ 25% of the time in Tromsø 6. They had an increased risk of having any MSC in Tromsø 7 (incidence rate ratio 1.15; 95% confidence interval 1.03-1.29). There was no significantly increased risk of severe MSC or MSC in ≥ 3 regions. Working in a cold environment was associated with future MSC, but not with future severe MSC or future MSC in ≥ 3 regions.


Effects of clinician behaviors on acceptability of patients' responses in aphasia treatment sessions.
Records of the content of 40 videotaped samples of aphasia treatment sessions were prepared. These records were analyzed to determine (a) whether certain clinician behaviors and task characteristics are related to the occurrence of patient error responses in speech and language treatment sessions for aphasic individuals, and (b) whether "errors generate errors"; that is, whether error responses tend to occur in clusters rather than being distributed uniformly throughout the treatment session. The results of these analyses indicated that a number of event categories were significantly related to the occurrence of unacceptable patient responses. These results suggest that certain clinician behaviors generate patient error responses and also that clinicians tend to response to patient errors in characteristic ways. An analysis of these results also confirmed that unacceptable patient responses tended to occur in clusters.


Performance evaluation of a full-scale innovative swine waste-to-energy system.
Intensive monitoring was carried out to evaluate the performance of a full-scale innovative swine waste-to-energy system at a commercial swine farm with 8640 heads of swine. Detailed mass balances over each unit of the system showed that the system, which includes a 7600m(3) anaerobic digester, a 65-kW microturbine, and a 4200m(3) aeration basin, was able to remove up to 92% of the chemical oxygen demand (COD), 99% of the biological oxygen demand (BOD), 77% of the total nitrogen (TN), and 82% of the total phosphorous (TP) discharged into the system as fresh pig waste. The overall biogas yield based on the COD input was 64% of the maximum theoretical, a value that indicates that even greater environmental benefits could be obtained with process optimization. Overall, the characterization of the materials fluxes in the system provides a greater understanding of the fate of organics and nutrients in large scale animal waste management systems.


Effects of socioeconomic status on cancer patient survival: counterfactual event-based mediation analysis.
This study investigated the direct and indirect effects of socioeconomic status (SES) on the survival time of cancer patients by using cancer stage to create a pathway from SES to health outcomes and facilitate a mechanistic inference. Both a traditional mediation analysis and a counterfactual event-based mediation analysis were applied to SEER (The Surveillance, Epidemiology, and End Results) data from the National Cancer Institute of the United States. A Cox proportional hazards model for survival analysis was performed in the mediation analysis. The counterfactual event-based mediation analysis showed that the effect of SES on survival time was partially mediated by stage at diagnosis in lung (12%), liver (14.33%), and colorectal (9%) cancers. Investigation of the fundamental mechanism involved thus established the direct effect of SES on survival time and the indirect effect of SES on survival time through stage at diagnosis. Moreover, the mediation analysis also revealed that the disparity in timely diagnosis (i.e., stage at diagnosis) caused by SES was slightly significant. SES can either affect cancer survival directly or indirectly through stage at diagnosis. Opportunities to reduce cancer disparity exist in the design of early detection policies or mechanisms for patients with varying resources.


Functional characteristics improvement by structural modification of hydroxypropyl methylcellulose modified polyvinyl alcohol films incorporating roselle anthocyanins for shrimp freshness monitoring.
A novel indicator film incorporating roselle anthocyanin extracts (RAE) was prepared to monitor shrimp freshness. Hydroxypropyl methylcellulose (HPMC) modified polyvinyl alcohol (PVA) was applied as film-forming substrates to obtain better functions. Structural characterization results suggested compositions were well dispersed and confirmed the structural modification. The addition of HPMC would improve film functions through generation of new interactions. The films with a ratio (HPMC-to-PVA) of 3:1 exhibited stronger tensile strength (91.88 ± 0.13 MPa), hydrophobic (moisture content of 10.44 ± 0.65%, water contact angle of 56.40 ± 3.11°), barrier properties and larger color variations in response to pH changes, demonstrating positive influences of physical functions on indication properties. Thus, a relationship among structural, physical and indication functions was proposed. Furthermore, the films were applied for shrimp freshness real-time monitoring. The film color changed from rose-red to light green at 4 d, corresponding to the onset of spoilage, and then turned into yellow at 8 d, when the shrimp was severely spoilage. The strong correlation between total color difference and chemical spoilage indexes (P < .05) was observed. Therefore, the incorporation of HPMC could improve film functional characteristics by structural modification of new interaction formation, and the PVA/HPMC/RAE films could be applied as intelligent packaging for real-time shrimp freshness monitoring.


Cerebral enzyme antioxidant system. Influence of aging and phosphatidylcholine.
To obtain a comprehensive profile of the age-related changes of the antioxidant enzyme system in discrete brain regions (cortex, caudate-putamen, substantia nigra, thalamus), the present study involved practically the total life span of male Wistar rats (from 5 to 35 months of age). The activities of both glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase increase from 5 to 25 months of life and remain relatively constant or decrease scantily thereafter. In thalamus, the activity of total superoxide dismutase (SOD) increases from 5 to 20 months of rat life and decreases thereafter. Conversely, in both substantia nigra and caudate-putamen, enzyme activity declines steadily with age, while in parietotemporal cortex enzyme activity deteriorates from the 25th month onward. In both caudate-putamen and parietotemporal cortex, the activity of glutathione peroxidase increases from 5 to 20 months of life and remains relatively constant thereafter, while in substantia nigra the enzyme activity is practically unmodified during the life span. Furthermore, the activity of glutathione reductase in parietotemporal cortex declines from the 20th month onward, while in caudate-putamen and thalamus, enzyme activity deteriorates after an increase from 5 to 20 months of life. The interference of phosphatidylcholine and/or its metabolite(s) with the cerebral enzyme antioxidant system shows a characteristic specificity as regards both the time of onset and the enzyme activities involved, namely, SOD and glutathione reductase. The interference with SOD is related to the cytosolic form of the enzyme and affects the cortex only of 5-month-old animals and also extends to the thalamus of 15-month-old rats and all regions in 25-month-old ones.(ABSTRACT TRUNCATED AT 250 WORDS)


Sisters in Birth: Improving Birth Outcomes in Mississippi.
Mississippi has the poorest birth outcomes in the United States. Sisters in Birth (SIB) is a community-based nonprofit, charitable organization program that links community and clinical health to improve birth outcomes in Mississippi. This article describes the community and clinical health variables that influence birth outcomes and the organization's work or mission. The overwhelmingly positive outcomes of the first 50 women in the program are presented as well as snapshots of individual women's experiences.


Tyrosine residues initiated photopolymerization in living organisms.
Towards intracellular engineering of living organisms, the development of new biocompatible polymerization system applicable for an intrinsically non-natural macromolecules synthesis for modulating living organism function/behavior is a key step. Herein, we find that the tyrosine residues in the cofactor-free proteins can be employed to mediate controlled radical polymerization under 405 nm light. A proton-coupled electron transfer (PCET) mechanism between the excited-state TyrOH* residue in proteins and the monomer or the chain transfer agent is confirmed. By using Tyr-containing proteins, a wide range of well-defined polymers are successfully generated. Especially, the developed photopolymerization system shows good biocompatibility, which can achieve in-situ extracellular polymerization from the surface of yeast cells for agglutination/anti-agglutination functional manipulation or intracellular polymerization inside yeast cells, respectively. Besides providing a universal aqueous photopolymerization system, this study should contribute a new way to generate various non-natural polymers in vitro or in vivo to engineer living organism functions and behaviours.


Vascular anatomy relevant to distal biceps tendon repair.
Avoiding bleeding and vascular complications in open repair of distal biceps tendon rupture requires knowledge of the local vascular anatomy. This study examined the vascular anatomy relevant to distal biceps tendon repair. The antecubital regions of 17 cadaveric upper extremities were dissected using ×2.5 loupe magnification to identify the brachial artery, the radial artery and its recurrent branches, and venous branches crossing the distal biceps tendon. With the elbow in full extension and supination, the position of each vascular structure was measured relative to the most proximal aspect of the bicipital tuberosity. The most common pattern (13 of 17 specimens) was a single radial recurrent artery (RRA) crossing volar to the tendon at a mean of 4 mm proximal to the tuberosity and positioned 15.4 mm volar to the tuberosity. The RRA bifurcated 2 to 9 mm from its origin in 6 arms and demonstrated a single bifurcation. In 8 of 17 specimens, an additional recurrent branch off the brachial artery traveled dorsal to the intact biceps tendon 16 mm proximal to the RRA. Two arms demonstrated a high brachial artery bifurcation. The crossing veins were venae comitantes of the RRAs and radial and ulnar arteries. They connected to the superficial veins by way of a perforating branch. Most often, 3 transverse veins positioned on average 0.2 mm proximal and 16 mm volar to the tuberosity were seen. The vascular anatomy encountered during distal biceps repair is variable, and RRAs occasionally travel dorsal to the biceps tendon. Most often, a single RRA on average 4 mm proximal to the tuberosity will branch once.


The affinity of cytochrome P-450 for ethyl isocyanide: an explanation of double soret spectra.
The 2 pH dependent peaks formed in the Soret region by the treatment of reduced hepatic microsomes or purified cytochrome P-448 with ethyl isocyanide do not exhibit identical dependence on ethyl isocyanide concentration. This behavior and other facts regarding double Soret spectra can be explained by a simple expostulation involving lipophilic and corrdinate binding of pi-acceptor ligands.


Phase I study of KRP-116D, a 50% w/w dimethyl sulfoxide aqueous solution, on the systemic absorption from bladder by intravesical instillation in healthy Japanese subjects.
This was a single-institution, single-dose, single-arm phase 1 study in healthy adult males to evaluate the safety and absorption of dimethyl sulfoxide (DMSO) from the bladder into the body when KRP-116D (a 50% w/w DMSO solution) was intravesically administered and allowed to remain in the bladder for 15 minutes. Six healthy adult males were enrolled in this study. KRP-116D (50 mL) was instilled directly into the bladder via a catheter where it was allowed to remain for 15 minutes under lidocaine anesthesia in accordance with the usage of RIMSO-50 (50% w/w DMSO solution) approved in the USA. The residual DMSO solution in the bladder was collected 15 minutes after instillation. The concentrations of DMSO in the plasma and the recovered solution were analyzed by a validated high-performance liquid chromatography (HPLC) method. The concentration in the residual DMSO solution was multiplied by the solution volume and divided by the dosage to calculate the recovery rate of DMSO. Plasma DMSO was detected in one of six subjects, and in the remaining five subjects DMSO was not detected (<19.6 μg/mL). The recovery rate of DMSO from the bladder was 60.7% to 93.7%. The only drug-related adverse event was breath odor (garlic-like breath) observed in four of six subjects (66.7%). Absorption of DMSO from the bladder was low (16.3%), and the systemic exposure was limited. Most of the DMSO was recovered from the bladder. KRP-116D 50 mL was well tolerated and safe.


Strongyloides ratti: 1. parasitological observations on primary and secondary infections in the small intestine of rats.
Adult Strongyloides ratti were expelled from the small intestine of rats starting 14-18 days after a primary infection. In a secondary infection very few adult worms developed and most of these were expelled before day 14. At the time of expulsion the worms migrated posteriorly in the intestine and their size decreased.


Gender differences in affective response to acute nicotine administration and deprivation.
Men and women may differ in their sensitivity to the mood-modulating properties of nicotine. Male and female adult smokers were exposed to four sessions crossing two nicotine deprivation conditions (12-h deprived vs. nondeprived) with two drug conditions (nicotine vs. placebo nasal spray). Acoustic probes elicited startle eyeblink responses while viewing affective and cigarette-related slides. In-session mood ratings were collected to gauge self-reported negative affect, positive affect, and craving. Nicotine nasal spray reduced startle amplitude in both men and women following 12-h deprivation compared with smoking nondeprivation. During nondeprivation, nicotine nasal spray increased startle amplitude in women compared with placebo spray, whereas no difference was found for men. The startle results suggest that both men and women are responsive to the hedonic properties of nicotine.


Modified mRNA as a Therapeutic Tool for the Heart.
Despite various clinical modalities available for patients, heart disease remains among the leading causes of mortality and morbidity worldwide. Genetic medicine, particularly mRNA, has broad potential as a therapeutic. More specifically, mRNA-based protein delivery has been used in the fields of cancer and vaccination, but recent changes to the structural composition of mRNA have led the scientific community to swiftly embrace it as a new drug to deliver missing genes to injured myocardium and many other organs. Modified mRNA (modRNA)-based gene delivery features transient but potent protein translation and low immunogenicity, with minimal risk of insertional mutagenesis. In this review, we compared and listed the advantages of modRNA over traditional vectors for cardiac therapy, with particular focus on using modRNA therapy in cardiac repair. We present a comprehensive overview of modRNA's role in cardiomyocyte (CM) proliferation, cardiac vascularization, and prevention of cardiac apoptosis. We also emphasize recent advances in modRNA delivery strategies and discuss the challenges for its clinical translation.


Identification and characterization of functional CD154 (CD40 ligand) in the Pekin duck.
Binding of CD154, a member of the TNF ligand superfamily, to its receptor CD40 is essential for the development and regulation of adaptive immune responses in mammals. The duck CD154 (DuCD154) encoding gene was isolated from activated splenocytes using RT-PCR. Sequence analysis of the cloned DuCD154 gene revealed an open reading frame of 819 base pairs encoding a 272 amino acid protein. The extracellular domain of DuCD154 was identified and expressed for characterization and generation of antibodies. DuCD154 mRNA was predominantly expressed in spleen, thymus and duodenum. DuCD154 protein generated in cell culture was secreted and formed dimers. DuCD154 markedly enhanced proliferative responses in duck splenocytes when used alone or in conjunction with LPS or PHA. These observations suggest that DuCD154 has functional equivalence with mammalian CD154 and that the central role of CD154 as an immunoregulatory protein had already evolved before the divergence of birds and mammals.


Association between elevated coffee consumption and daily chocolate intake with normal liver enzymes in HIV-HCV infected individuals: results from the ANRS CO13 HEPAVIH cohort study.
We used longitudinal data from the ANRS CO13 HEPAVIH cohort study of HIV-HCV co-infected individuals to investigate whether polyphenol rich food intake through coffee and/or daily chocolate consumption could play a role in reducing liver enzymes levels. Longitudinal data collection included self-administered questionnaires and medical data (aspartate aminotransferase (AST) and alanine aminotransferase (ALT) liver enzymes). Two analyses were performed to assess the association between coffee (≥3 cups a day) and daily chocolate intake and abnormal values of AST and ALT (AST or ALT >2.5 × upper normal limit (UNL)) (N=990) over time, after adjustment for known correlates. Logistic regression models based on generalized estimating equations were used to take into account the correlations between repeated measures and estimate adjusted odds ratio. After adjustment, patients reporting elevated coffee consumption and daily chocolate intake were less likely to present abnormal ALT (OR=0.65; p=0.04 and OR=0.57; p=0.04, for coffee and chocolate respectively), while only patients reporting elevated coffee consumption were less likely to have abnormal AST values (p=0.05). Nevertheless, the combined indicator of coffee and chocolate intake was most significantly associated with approximately 40% reduced risk of abnormal liver enzymes (p=0.003 for AST; p=0.002 for ALT). Elevated coffee consumption and daily chocolate intake appear to be associated with reduced levels of liver enzymes in HIV-HCV co-infected patients. Further experimental and observational research is needed to better understand the role that polyphenol intake or supplementation can play on liver disease and liver injury.


Parents' Educational Anxiety Under the "Double Reduction" Policy Based on the Family and Students' Personal Factors.
Educational anxiety is a true portrayal of Chinese parents. As an endogenous problem in the development of modern education system, the pressure of students' entrance examination continues to rise. Based on the empirical survey data of education in 3298 families, this study uses the analysis method of multiple linear regressions to analyze the influencing factors of parental education anxiety and finds that educational anxiety has become a common social emotion. After the regression analysis of the four-layer model was established, it was found that different school segments, school priorities, and student achievements had a significant impact on parents' educational anxiety, and factors such as annual family income, educational satisfaction and family parenting style had a significant impact on parental educational anxiety. It is worth noting that the gap in parental expectations has a significant positive effect on educational anxiety, and the greater the expectation gap, the higher the educational anxiety of parents. Therefore, it is suggested that governments at all levels should conscientiously implement the task of "reducing burdens" and rationally allocate high-quality educational resources; parents and teachers should start from the needs of children to establish a scientific concept of education and the concept of becoming a talent; the whole society should put forward reasonable educational expectations in education, and be good at adjusting expectations on time so that education can return to a rational natural growth state and eliminate parents' educational anxiety.


In vitro glycation and glycoxidation of phosphatidylethanolamines.
Formation and accumulation of advanced glycation end products (AGEs) appear to correlate with many human diseases, such as atherosclerosis and inflammation. Whereas AGE-modified proteins relatively well studied, aminophospholipid AGE-adducts have been less intensively investigated. At elevated concentrations, glucose can react with amino groups of phosphatidylethanolamines (PE) to form Schiff bases or Amadori products, which can be further converted, under oxidative conditions, to various AGEs. Many of these products such as carboxymethylamine (CMA) and carboxyethylamine (CEA) can be formed by oxidative degradation of Amadori-products. The aim of this work was to investigate the different glycation and glycoxidation PE-adducts and to elucidate the most prominent mechanisms of AGE-PE formation. Four different aminophospholipids,[dipalmitoyl-(DPPE), palmitoyl-oleoyl-(POPE), palmitoyl-linoleoyl-(PLPE) or palmitoyl-arachidonoyl-phosphatidylethanolamine(PAPE); all 1mmol/L] were glycated in vitro (5mmol/L glucose) and oxidized by the Fenton reaction (80µmol/L FeSO4, 50mmol/L H2O2) or using electrochemical oxidation (Roxy EC System, Antec, Leiden, Netherlands). High resolution mass spectrometry (MS) in combination with MS(n) fragmentation allowed the identification of major products, such as CMA, CEA and oxo-glucuronic acid. The mechanism of CMA/CME formation by oxidative degradation of the Amadori product was confirmed by co-oxidation (Fenton reaction) of purified glycated (gPOPE) with nonglycated DPPE (Fenton reaction) and by electrochemical oxidation of purified gPOPE, whereas the reaction with glyoxal/methylglyoxal formed by glucose oxidation was excluded. In both cases CMA/CEA-POPE adducts were detected. When glycated with 1,2-(13)C glucose, DPPE-CMA/CME adducts contained two (13)C atoms further confirming the proposed mechanism. Finally, the ability of glycated PE when co-incubated with cells (HeLa) to induce Nrf2 activation was also addressed.


Developing Capacity in Dissemination and Implementation Research in the Eastern Mediterranean Region: Evaluation of a Training Workshop.
As the demand for dissemination and implementation (D&I) research grows globally, there is a need for D&I capacity building in regions where D&I science is underrepresented. The Workshop on Dissemination and Implementation Research in Health (WONDIRH) was aimed for participants in the Eastern Mediterranean region to (1) appreciate the complex process of bridging research and practice in a variety of real-world settings, and (2) develop research that balances rigor with relevance and employs study designs and methods appropriate for the complex processes involved in D&I. The present exploratory study investigates participants' satisfaction with the workshop, the enhancement of their self-rated confidence in D&I skills, as well as their intention to apply the learned content into practice. The workshop included four weekly 90-min virtual interactive training sessions in conjunction with open access content from the National Cancer Institute Training Institute in Implementation and Dissemination Research in Cancer (TIDIRC). We applied a one-group pre-post design for the evaluation of workshop. Participants were invited to self-rate their confidence in D&I competencies (15 items, pre and post workshop). At the end of the workshop, participants additionally were asked to rate their satisfaction (5 items, 1-5 scales), and their intention to apply the learned content into practice (4 items, 1-5 scales). Of the 77 workshop participants, 34 completed the evaluation. Confidence improved between pre- and post-workshop assessments in all 15 self-rated D&I competencies. Respondents were generally satisfied with the workshop (mean satisfaction range 3.82-4.26 across the 5 items) and endorsed intentions to apply workshop topics (mean intention range 4.03-4.35 across the 4 items). This initial workshop demonstrated the ability to attract and engage participants to enhance their confidence in D&I research competencies and skills and to build capacity in D&I research. Future efforts should consider offering targeted training for researchers at different stages and to clearly articulate learning objectives. The online version contains supplementary material available at 10.1007/s43477-022-00067-y.


Computer-assisted femoral head reduction osteotomies: an approach for anatomic reconstruction of severely deformed Legg-Calvé-Perthes hips. A pilot study of six patients.
Legg-Calvé-Perthes (LCP) is a common orthopedic childhood disease that causes a deformity of the femoral head and to an adaptive deformity of the acetabulum. The altered joint biomechanics can result in early joint degeneration that requires total hip arthroplasty. In 2002, Ganz et al. introduced the femoral head reduction osteotomy (FHRO) as a direct joint-preserving treatment. The procedure remains one of the most challenging in hip surgery. Computer-based 3D preoperative planning and patient-specific navigation instruments have been successfully used to reduce technical complexity in other anatomies. The purpose of this study was to report the first results in the treatment of 6 patients to investigate whether our approach is feasible and safe. In this retrospective pilot study, 6 LCP patients were treated with FHRO in multiple centers between May 2017 and June 2019. Based on patient-specific 3D-models of the hips, the surgeries were simulated in a step-wise fashion. Patient-specific instruments tailored for FHRO were designed, 3D-printed and used in the surgeries for navigating the osteotomies. The results were assessed radiographically [diameter index, sphericity index, Stulberg classification, extrusion index, LCE-, Tönnis-, CCD-angle and Shenton line] and the time and costs were recorded. Radiologic values were tested for normal distribution using the Shapiro-Wilk test and for significance using Wilcoxon signed-rank test. The sphericity index improved postoperatively by 20% (p = 0.028). The postoperative diameter of the femoral head differed by only 1.8% (p = 0.043) from the contralateral side and Stulberg grading improved from poor coxarthrosis outcome to good outcome (p = 0.026). All patients underwent acetabular reorientation by periacetabular osteotomy. The average time (in minutes) for preliminary analysis, computer simulation and patient-specific instrument design was 63 (±48), 156 (±64) and 105 (±68.5), respectively. The clinical feasibility of our approach to FHRO has been demonstrated. The results showed significant improvement compared to the preoperative situation. All operations were performed by experienced surgeons; nevertheless, three complications occurred, showing that FHRO remains one of the most complex hip surgeries even with computer assistance. However, none of the complications were directly related to the simulation or the navigation technique.


Indocyanine green plasma disappearance rate during the anhepatic phase of orthotopic liver transplantation.
Non-invasive pulse spectrophotometry to measure indocyanine green (ICG) elimination correlates well with the conventional invasive ICG clearance test. Nevertheless, the precision of this method remains unclear for any application, including small-for-size liver remnants. We therefore measured ICG plasma disappearance rate (PDR) during the anhepatic phase of orthotopic liver transplantation using pulse spectrophotometry. Measurements were done in 24 patients. The median PDR after exclusion of two outliers and two patients with inconstant signal was 1.55%/min (95% confidence interval [CI]=0.8-2.2). No correlation with patient age, gender, body mass, blood loss, administration of fresh frozen plasma, norepinephrine dose, postoperative albumin (serum), or difference in pre and post transplant body weight was detected. In conclusion, we found an ICG-PDR different from zero in the anhepatic phase, an overestimation that may arise in particular from a redistribution into the interstitial space. If ICG pulse spectrophotometry is used to measure functional hepatic reserve, the verified average difference from zero (1.55%/min) determined in our study needs to be taken into account.