The phenotype of recovery VIII: Association among delay discounting, recovery capital, and length of abstinence among individuals in recovery from substance use disorders.
Research defines recovery capital as the amount of tangible and intangible resources (e.g., human/personal, physical, social, and cultural) available to initiate and sustain recovery from substance use disorders (SUDs). An individual's amount of recovery capital is dynamic over time and influenced by a number of factors such as baseline amount at initiation of recovery/treatment, length of abstinence, access/availability of resources, and individual factors such as the decision to utilize available resources. Research has been proposed delay discounting (DD), which reflects an individual's relative preference for immediate versus delayed rewards, as a candidate behavioral marker for SUDs but has not yet examined it in the context of recovery capital, and DD may be an important aspect of human capital. Thus, the aim of the current study was to examine associations among recovery capital, DD, and length of abstinence. The study included in its analysis data from 111 individuals in recovery from SUDs from the International Quit and Recovery Registry, an ongoing data collection program used to further scientific understanding of recovery. The study assessed recovery capital using the Assessment of Recovery Capital (ARC) and assessed discounting rates using an adjusting-delay task. The study team performed univariate linear regression to examine the relationship between total ARC score and demographic variables, length of abstinence, and DD. The research team performed a mediation analysis to understand the role of length of abstinence in mediating the relationship between DD and ARC score. Total ARC score was significantly negatively associated with DD and positively associated with length of abstinence, even after adjusting for covariates. Mediation analysis indicated that length of abstinence significantly partially mediated the relationship between DD and ARC score. These findings support the characterization of DD as an important aspect of human capital and a candidate behavioral marker for SUDs. Future research may wish to investigate whether interventions designed to increase the value of future rewards also increase recovery capital.


Moxibustion for medical personnel with negative emotion and insomnia during COVID-19 pandemic: A randomized, controlled trial.
We conducted this randomized controlled trial (RCT) to evaluate the effectiveness and safety of moxibustion at Sanyinjiao (SP6) acupoint for treatment of negative mood and sleep quality in healthcare workers during the 2019 coronavirus disease (COVID-19). A total of 180 participants were divided in a 1:1 ratio into two groups, the treatment group (for moxibustion) and the control group (for no treatment). The treatment group had a 30-minute moxibustion therapy once a day for two weeks, followed by a two-week follow-up. The Hamilton Anxiety Scale (HAMA) was used to assess the degree of the participants' anxiety, and the Patient Health Questionnaire-9 (PHQ-9) was utilized to examine their depressed condition. The Maslach Burnout Inventory-General Survey (MBI-GS) was used to measure the level of burnout among healthcare workers. To determine the severity of insomnia, the Sleep Dysfunction Rating Scale (SDRS) was utilized. At baseline, week 2, and week 4, all scales were evaluated. Compared to the control group, The treatment group improved more significantly in the HAMA at week 2 (MD = -19.01, 95% CI: -21.89 to -16.14; P<0.001) and at week 4 follow-up visits (MD = -8.96, 95% CI: -11.19 to -6.73; P<0.001). A subgroup study of HAMA scores revealed that position and education had significant impact on treatment effectiveness. During the 2-week intervention period, the treatment group showed more significant improvements in depressive symptoms measured by PHQ-9 (13.00±2.41 vs. 15.60±3.65; P<0.001), work burnout symptoms measured by MBI-GS (MD = -11.88, 95% CI, -15.73 to -8.03; P<0.001), and insomnia symptoms measured by SDRS (MD = -2.45, 95% CI, -4.24 to -0.66; P<0.01). There were no significant adverse effects reported. Moxibustion at SP6 may be an effective treatment to improve anxiety, depression, sleep quality, and quality of life for healthcare workers during COVID-19. Chinese Clinical Trial Registry (ChiCTR): ChiCTR-2200059327.


Two new N-acetyldopamine tetrapolymers from periostracum Cicadae.
Two new N-acetyldopamine tetrapolymers, cicadamide A (1) and cicadamide B (2), were isolated from periostracum Cicadae, and their structures were elucidated as 3-acetylamino-7-(3″-acetylamino-7″-(N-acetyl-2‴-aminoethyl)-1″,4″-benzodioxan-2″-yl)-2-(2'-(3″″,4″″-dihydroxyphenyl)-3'-acetylamino-1',4'-benzodioxan-7'-yl)-1,4-benzodioxane (1) and 3-acetylamino-7-(3″-acetylamino-6″-(N-acetyl-2‴-aminoethyl)-1″,4″-benzodioxan-2″-yl)-2-(2'-(3″″,4″″-dihydroxyphenyl)-3'-acetylamino-1',4'-benzodioxan-7'-yl)-1,4-benzodioxane (2), by the combined analysis of 1D NMR and 2D NMR, and mass spectrometry. Pharmacological investigation on two compounds obtained in this study showed that part of them had anti-inflammatory activities.


Exposure to ambient gaseous pollutant and daily hospitalizations for Sjögren's syndrome in Hefei: A time-series study.
Increasing evidence suggested that gaseous pollutants were associated with the development of autoimmune diseases, while there were few studies on the association between gaseous pollutants and Sjögren's syndrome (SS). This study sought to assess the relationship between exposure to several gaseous pollutants and the hospitalizations for SS. The data regarding SS hospitalizations, gaseous pollutants, and meteorological factors in Hefei from 2016 to 2021 were collected. A distributed lag non-linear model combined with a generalized linear model were adopted to analyze the association between gaseous pollutants and SS hospitalizations, and stratified analyses were also conducted. We detected significant associations between gaseous pollutants (NO2, SO2, O3, CO) and SS hospitalizations. Exposure to NO2 was linked with the elevated risk of hospitalizations for SS (RR=1.026, lag1 day). A positive correlation between CO exposure and hospitalizations for SS was found (RR=1.144, lag2 day). In contrast, exposure to SO2, O3 was respectively related to the decreased risk of hospitalizations for SS (SO2: RR=0.897, lag14 day; O3: RR=0.992, lag9 day). Stratified analyses found that female patients were more vulnerable to these gaseous pollutants. SS patients ≥ 65 years were more susceptible to NO2, CO exposure, and younger patients were more vulnerable to O3 exposure. In addition, exposure to O3, CO in cold season were more likely to affect hospitalizations for SS. Our results demonstrated a significant association between exposure to NO2, CO and elevated risk of hospitalizations for SS, and SO2, O3 exposure might be linked to reduced risk of SS hospitalizations.


Systems Biology on Acetogenic Bacteria for Utilizing C1 Feedstocks.
With a presence of the Wood-Ljungdahl pathway, acetogenic bacteria are capable of converting C1 feedstocks into biomass and various metabolites, receiving industrial interest in microbial production of biochemicals derived from C1 substrates. To understand C1 feedstock fermentation using acetogenic bacteria, most of the studies have focused on revealing their carbon assimilation and energy conservation systems. Despite the determination of the essential mechanisms, a fundamental understanding of acetogenic bacteria and the associated complex regulatory systems remains unclear and is needed for rational strain design. For this purpose, systems biology is a suitable approach for investigating genome, transcription, translation, regulation systems, and metabolic flux, providing a glimpse of the relationship between the genotype and phenotype of the organisms. This chapter will cover recent systems biology applications on acetogenic bacteria and discuss the cellular responses during C1 feedstock fermentation along with the regulatory systems that orchestrate cellular processes.


Sesquiterpene lactones from Sonchus palustris L. (Asteraceae, Cichorieae).
Seven previously undescribed sesquiterpene lactones, three known sesquiterpene lactones (ixerin D, 15-p-hydroxyphenylacetyllactucin, and 15-p-hydroxyphenylacetyllactucin-8-sulfate), and two known quinic acid derivatives (3-O-feruloylquinic acid and 3,5-di-O-caffeoylquinic acid) were isolated from Sonchus palustris L. roots. Four formerly undescribed compounds were elucidated to be 3β,14-dihydroxycostunolide-3-O-β-D-glucopyranosyl-(2-O-p-hydroxyphenylacetyl)-14-O-p-hydroxyphenylacetate, 15-p-methoxyphenylacetyllactucin, 15-p-methoxyphenylacetyllactucin-8-sulfate, and 8-p-hydroxyphenylacetyllactucin-15-sulfate. Additionally, three undescribed conjugates of lactucin and a eudesmanolide type sesquiterpenic acid, sonchpalustrin, 4″-O-methylsonchpalustrin, and isosonchpalustrin, were characterized. The structures of the newly discovered natural products were elucidated using 1D and 2D NMR spectroscopy and UHPLC-HRMS. 15-p-Hydroxyphenylacetyllactucin and 15-p-methoxyphenylacetyllactucin showed significant in vitro cytotoxicity against CEM and BJ cells with IC50 values ranging from 3.9 to 9.8 μM. Compounds 3 and 4 showed also strong anti-inflammatory activity in vitro.


Pancreas transplantation for treatment of generalized allergy to human insulin in type 1 diabetes.
We report the case of a 29-year-old man with a 14-year history of type 1 diabetes, normal renal function, and mild diabetic retinopathy. The patient progressively developed a generalized allergic reaction to two insulin excipients--protamine and metacresol--with systemic manifestations of tremor, tachycardia, vertigo, shortness of breath, and short episodes of unconsciousness causing him to be out of work. In June 2003, he received a vascularized cadaveric pancreas transplant using induction with polyclonal antibodies along with tacrolimus and sirolimus but without steroids. A hyperglycemic episode following corticosteroid therapy for rejection treatment required reintroduction of insulin therapy with prompt reappearance of allergic manifestations. Now, the patient is euglycemic without insulin or allergic manifestations and a glycated hemoglobin of 6.4%.


Springs and zippers: coiled coils in SNARE-mediated membrane fusion.
A conserved molecular machinery based on SNARE proteins catalyzes most, if not all, cellular membrane fusion events. A flurry of recent biophysical studies have established a detailed molecular picture of the core SNARE complex. Structural and biochemical analysis of the SNARE machinery is rapidly advancing our understanding of the specificity, regulation and protein catalysis of membrane fusion.


Directional Clustering of Slanted Nanopillars by Elastocapillarity.
The unidirectional clustering induced by capillary force of drying liquids between pillars is investigated and a theoretical model to set a criterion of the unidirectional clustering of the slanted nanopillars is proposed.


Efficacy of three treatment schedules in severe meconium aspiration syndrome.
To compare three different schedules in severe meconium aspiration syndrome (MAS) treatment: standard, bronchoalveolar lavage (BAL) with diluted surfactant, and diluted surfactant BAL plus a single early dexamethasone dose. Twenty-four full-term newborns with severe MAS (needing mechanical ventilation and with oxygenation index > or = 15) were divided into three groups: group I (historical control group; n = 6) treated with standard therapy; group II (n = 7) treated in the first hours of life with one BAL using diluted surfactant (beractant 5 mg/mL) in a volume of 15 mL/kg in four aliquots; and group III (n = 11) treated with one diluted surfactant BAL and a previous single dose of intravenous dexamethasone (0.5 mg/kg). At 12 h, groups II and III showed a significant improvement in oxygenation index (OI) compared with group I (14.7% and 27.0% vs -19.6% respectively; p = 0.012). Group III also showed a significantly lower OI than group I at 24 h (63.6% vs -27.9%) and at 48 h (87.1% vs 49.6%). Group III, in comparison to group I, showed a lower FiO2 requirement at 12 h (0.66 vs 1), at 24 h (0.4 vs 0.87) and at 48 h (0.35 vs 0.67), and a decrease in the number of days of inhaled nitric oxide administration, mechanical ventilation, oxygen therapy and hospitalisation period. All patients from groups II and III survived and none developed pneumothorax or respiratory infections. Diluted surfactant BAL in the first hours of life combined with an intravenous single dose of dexamethasone may be an effective treatment for severe MAS.


Sequential appearance of cytoskeletal components during the early stages of neurite outgrowth from cerebellar granule cells in vitro.
Cerebellar granule cells derived from one-week-old rat pups have been placed into culture to examine the expression of microfilament, microtubular and neurofilament proteins in developing neurites up to 2 days in vitro. Immunofluorescence and rhodamine-phalloidin studies have shown that the first cytoskeletal element to appear in the developing neurite was the microfilament network which was present in cell processes and expansions from at least 8 minutes in vitro. Rhodamine-phalloidin fluorescence was maintained in the developing neurite over 2 days and was enriched in some growth cones. At between 30 and 60 min in culture microtubules (reacting with anti alpha-tubulin antibodies) appeared in the neurites but did not ramify throughout the growth cone at this or later time points. The expression of tyrosylated alpha-tubulin in microtubules of the developing neurite appeared to precede that of acetylated alpha-tubulin. Only one of the neurofilament subunits, the 200 kDa subunit, could be positively identified in granule cell processes in these cultures. The developmental pattern of cytoskeletal protein expression in granule cell neurites in vitro may reflect a process of stabilisation of the growing neurite behind an active, motile growth cone.


[It is necessary to do psychological intervention for patients with cleft lip and palate].
Psychological intervention is one of the most important parts in cleft lip/palate team approach. However, the psychological intervention has not been taken into deep consideration until now in China, and thus practical experience has not been obtained in this field. Based on a profound analysis of the reason of psychological abnormality and the psychological characteristics of cleft patients, we suggest that the psychological healthy should be the final destination of cleft lip/palate team approach. We further suggest that, based on the practical condition and experience in China, some therapies like psychological counseling should be feasible at the present time.


Diencephalic syndrome following cervical spinal cord trauma.
The authors discuss about five cases of diabetes insipidus observed in patients affected by traumatic cervical spine fractures and/or dislocations, without either evident lesions of the cerebral structures at CT scan examination, or important craniocerebral trauma. In all patients polyuria and hyperthermia arose some days after the traumatic accident and regressed spontaneously or after exogeneous vasopressin administration. Vasopressin urinary levels confirmed the presence of a true diabetes insipidus, the origin of which is in largely obscure. A central medullary vasopressin mediated pathway, demonstrated only in experimental animals, may be responsible for such a finding.


Reduced Circumferential Resection Margin Involvement in Rectal Cancer Surgery: Results of the Dutch Surgical Colorectal Audit.
The circumferential resection margin (CRM) is a significant prognostic factor for local recurrence, distant metastasis, and survival after rectal cancer surgery. Therefore, availability of this parameter is essential. Although the Dutch total mesorectal excision trial raised awareness about CRM in the late 1990s, quality assurance on pathologic reporting was not available until the Dutch Surgical Colorectal Audit (DSCA) started in 2009. The present study describes the rates of CRM reporting and involvement since the start of the DSCA and analyzes whether improvement of these parameters can be attributed to the audit. Data from the DSCA (2009-2013) were analyzed. Reporting of CRM and CRM involvement was plotted for successive years, and variations of these parameters were analyzed in a funnelplot. Predictors of CRM involvement were determined in univariable analysis and the independent influence of year of registration on CRM involvement was analyzed in multivariable analysis. A total of 12,669 patients were included for analysis. The mean percentage of patients with a reported CRM increased from 52.7% to 94.2% (2009-2013) and interhospital variation decreased. The percentage of patients with CRM involvement decreased from 14.2% to 5.6%. In multivariable analysis, the year of DSCA registration remained a significant predictor of CRM involvement. After the introduction of the DSCA, a dramatic improvement in CRM reporting and a major decrease of CRM involvement after rectal cancer surgery have occurred. This study suggests that a national quality assurance program has been the driving force behind these achievements.


Co-delivery of docetaxel and chloroquine via PEO-PPO-PCL/TPGS micelles for overcoming multidrug resistance.
The combination of two or more drug is a promising strategy to suppress the multidrug resistance (MDR) through different action mechanisms. Co-delivery drugs via polymeric micelle can minimize the amount of each drug and reduce toxic side effects. Here we co-encapsulate anticancer drug docetaxel (DTX) and autophagy inhibitor chloroquine (CQ) in complex micelles based on poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ϵ-caprolactone) (PEO-PPO-PCL) and D-α-tocopheryl poly(ethylene glycol) (TPGS) for enhancing anticancer effects. Two series copolymer with different length of hydrophobic chain were synthesized (PEO68-PPO34-PCL18 and PEO68-PPO34-PCL36) in our lab. The dual-drug micelles possessed nanosize and sustained release profile in vitro. Drug-loaded micelles have low hemolysis rate (<5%), indicating that they are safe for use in vivo. Studies on cellular uptake demonstrate that the micelles can effectively accumulate in cancer cells. Furthermore, in vitro cytotoxicity with different DTX/CQ mass ratio are studied and the sample with a DTX/CQ ratio of 0.8/0.2 is found to have the strongest synergism effect. The co-delivery micelles have obviously higher therapeutic effects against MCF-7 and MCF-7/ADR cells than either free drug or individually DTX-loaded micelles. The IC50 values of DTX/CQ-loaded PEO68-PPO34-PCL18/TPGS and PEO68-PPO34-PCL36/TPGS micelles are 134.16 and 194.74 fold smaller than that of free DTX after 48 h treatment with MCF-7/ADR cells, respectively. Therefore, the as-prepared co-delivery of DTX and CQ based on PEO-PPO-PCL/TPGS micelles can provide a promising combined therapeutic strategy for enhanced antitumor therapy.


The Addition of Pinto Bean Flour and Margarine in the Development of Red Rice-Based Novel Gluten-Free Cookies to Improve the Technological, Sensory and Physicochemical Properties.
This study aimed to understand how the addition of pinto bean flour (PBF) and margarine affected the technological, sensory, and physicochemical properties of red rice-based gluten-free cookies. PBF addition (25-75 g/100 g) and margarine content (13.3-19.3 g/100 g dough) were varied according to a central composite rotatable design. Cookies selection was performed by overlaid contour and principal component analysis (PCA) for technological properties and sensory evaluation, respectively. Chemical composition analyses, bioactive compounds, and microstructure were carried out in the selected formulations. In addition, other physicochemical analyses were carried out during storage time. PBF addition affected the technological properties and increased the nutritional content of proteins (up to 13%), fibers (8.28%), iron (2.13%), zinc (1.54%), and phenolic compounds (139.46 mg gallic acid equivalent/100 g), but it negatively affected sensory acceptance. However, margarine's addition improved all the sensory attributes in all the trials, showing an acceptance greater than 70%. Cookies with 50 g PBF, 50 g red rice flour, and 16.3 g margarine/100 g dough showed better technological, nutritional characteristics, and physicochemical quality up to 60 days of storage. This work contributed to the incorporation of mixtures of red rice and pinto bean for developing more nutritious cookies for celiac patients or even those who wish to consume gluten-free products.


Isolation of sulfited oligosaccharides from glycoproteins treated with alkaline sulfite.
The oligosaccharide products resulting from treatment of mucin-type glycoproteins with alkali in the presence of the sulfite anion have been investigated. Treatment of fetuin and of tryptic glycopeptides from the human erythrocyte with this reagent resulted in the release of sulfited oligosaccharides identified as N-acetylsulfohexosamine (HexNAcSO3), alpha-NeuAc-(2----6)-HexNAcSO3, and alpha-NeuAc-(2----3)-Gal-(1----3 or 4)-[GlcNAc-(1----6)]-HexNAcSO3. In addition, 2.7 moles of sialic acid were released per mole of alpha-NeuAc-(2----6)-HexNAcSO3 from fetuin. The sulfohexosamine moiety is formed via unsaturated intermediates from a 3-O-substituted 2-acetamido-2-deoxy-D-galactosyl residue at the carbohydrate-peptide linkage site when this residue is not substituted at O-4 by another sugar residue. A reaction mechanism accounting for the release of the sulfited oligosaccharides from a 3-O- and 6-O-substituted hexosamine is proposed in which the oligosaccharide branch attached to O-6 is obtained as a specific fragment terminating in sulfohexosamine.


In-depth Correlation Analysis of SARS-CoV-2 Effective Reproduction Number and Mobility Patterns: Three Groups of Countries.
Many governments have imposed-and are still imposing-mobility restrictions to contain the coronavirus disease 2019 (COVID-19) pandemic. However, there is no consensus on whether policy-induced reductions of human mobility effectively reduce the effective reproduction number (Rt) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several studies based on country-restricted data reported conflicting trends in the change of the SARS-CoV-2 Rt following mobility restrictions. The objective of this study was to examine, at the global scale, the existence of regional specificities in the correlations between Rt and human mobility. We computed the Rt of SARS-CoV-2 using data on worldwide infection cases reported by the Johns Hopkins University, and analyzed the correlation between Rt and mobility indicators from the Google COVID-19 Community Mobility Reports in 125 countries, as well as states/regions within the United States, using the Pearson correlation test, linear modeling, and quadratic modeling. The correlation analysis identified countries where Rt negatively correlated with residential mobility, as expected by policymakers, but also countries where Rt positively correlated with residential mobility and countries with more complex correlation patterns. The correlations between Rt and residential mobility were non-linear in many countries, indicating an optimal level above which increasing residential mobility is counterproductive. Our results indicate that, in order to effectively reduce viral circulation, mobility restriction measures must be tailored by region, considering local cultural determinants and social behaviors. We believe that our results have the potential to guide differential refinement of mobility restriction policies at a country/regional resolution.


The cGAS-STING pathway is a therapeutic target in a preclinical model of hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and the incidence of HCC is increasing. Recently, cancer immunotherapy has emerged as an efficient treatment against some cancers. Here we have used a mouse model of mutagen-induced HCC to explore the therapeutic usefulness of targeting the DNA-activated STING pathway in HCC. STING-deficient mice exhibited unaltered initial development of HCC, but had higher number of large tumors at late stages of disease. In the liver of STING-deficient HCC mice, we observed reduced levels of phospho-STAT1, autophagy, and cleaved caspase3. These responses were activated in the liver by treatment with a cyclic dinucleotide (CDN) STING agonist. Importantly, CDN treatment of mice after HCC development efficiently reduced tumor size. Initiation of CDN treatment at an even later stage of disease to allow HCC detection by MR scanning revealed that the majority of tumors regressed in response to CDN, but new tumors were also detected, which were unresponsive to CDN treatment. Overall, the modulation of the STING pathway affects the development of HCC, and holds promise for a use as a treatment of this disease, most likely in combination with other immunomodulatory treatments such as PD1 inhibitors or with standard of care.


[Anterior gastropexy using the Boerma method in gastroesophageal reflux].
The results obtained in 38 patients with gastro-oesophageal reflux who had been submitted to operation by Boerema's method are presented. Twenty-nine (76%) became entirely symptomfree and eight (21%) experienced reduction of symptoms. Postoperative oesophageal stenosis was demonstrated in five patients.


A full-fledged overhaul is needed for a risk and value-based regulation of medical devices in Europe.
The unacceptably high incidence of clinical adverse events caused by medical devices (MDs), their high recall rates, and the frequent phase out of some of the devices that pose a greater risk to health have triggered alarm concerning the long-standing weaknesses of their regulatory processes. It has long been known that regulation is not strongly associated with the existence of market failures. In this article the deficient approval process and postmarketing surveillance of MDs in the United States and Europe, as well as the causes and effects of their very serious failings, that put patient safety at serious risk, are critically reviewed. Solutions to address the urgent need to develop new regulation in the European Union are set forth as well. The fragmented MD industry is plagued with externalities. It seems that regulation is more being supplied in response to industry's demand (legislation and agencies capture) than for redistributing health and wealth. Severe adverse events associated with MD are spurring demand for regulation. Governments should promote the most risked-based, cost-effective regulations, those that pursue the interests of individuals affected, by using public and unbiased estimates of their costs and benefits, maximizing net health gains through legislation, applying clear rules of the game, and braking up the effects of the influence of interest groups.


Incidence of infectious mononucleosis at the Universities of California and Hawaii.
The observed rates of heterophil-positive infectious mononucleosis at the University of California at Davis and the University of Hawaii at Manoa were 1,212 and 37 per 100,000 students per academic year, respectively. The data collected suggest that the extraordinarily low incidence at the University of Hawaii may be due to the following factors: (1) underutilization of the student health service by students with infectious mononucleosis; (2) low proportion of Epstein-Barr virus-seronegative students; (3) high proportion of Asian students who appear to be less likely to develop heterophil-positive infectious mononucleosis; and (4) possible low efficiency in the transmission of primary Epstein-Barr virus infections.


Periplasmic expression and recovery of human interferon gamma in Escherichia coli.
A synthetic human interferon gamma (hIFN-gamma) gene was fused to SP1 and SP3, two Sec-dependent artificial signal peptides to transport the hIFN-gamma to the periplasm of Escherichia coli BL21-SI. The processing efficiency of both SP1-hIFN-gamma and SP3-hIFN-gamma was dependent on the culture medium as well as the post-induction temperature. Both precursors were processed completely when cells were cultured using minimal medium and a post-induction temperature of 32.5 degrees C, and only the processed hIFN-gamma was detected. The SP3 signal peptide was more efficient than SP1 for the secretion of hIFN-gamma. Sixty percent of the total hIFN-gamma was secreted to the periplasm using the SP3 signal peptide and a post-induction temperature of 20 degrees C. Using Tris-sucrose-dithiothreitol (TSD) hypertonic buffer, the periplasmic soluble hINF-gamma was recovered with a purity of 85%.


Type I interferons impair BDNF-induced cell signaling and neurotrophic activity in differentiated human SH-SY5Y neuroblastoma cells and mouse primary cortical neurons.
Type I interferons (IFNs) have been shown to act on neurons and to cause neuronal damage through mechanisms not completely defined. Here, we investigated the effects of type I IFNs on brain-derived neurotrophic factor (BDNF)-induced TrkB receptor signaling and neurotrophic activity. In retinoic acid-treated human SH-SY5Y neuroblastoma cells and mouse primary cortical neurons, long-term exposure to IFNs curtailed BDNF-induced activation of phosphatidylinositol 3-kinase, phospholipase Cγ and extracellular-regulated kinases 1 and 2 signaling. Moreover, IFN-β inhibited BDNF-induced cell survival, neurite outgrowth, and expression of neuronal markers, such as neurofilament proteins, growth-associated protein-43 and glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor subunit GluR1. The IFN inhibitory effects were associated with down-regulation of TrkB and inhibition of TrkB autophosphorylation. In SH-SY5Y cells, blockade of either Janus kinase with pyridone 6 or signal transducer and activator of transcription (STAT) 1 with siRNA transfection attenuated IFN-β-induced TrkB down-regulation. Quantitative real time RT-PCR indicated that IFN-β significantly reduced TrkB mRNA levels. Moreover, blockade of protein kinase R counteracted IFN-β-induced inhibition of TrkB expression and signaling. These data indicate that in neuronal cells IFNs negatively regulate BDNF signaling and neurotrophic activity through inhibition of TrkB activation and Janus kinase/Signal transducer and activator of transcription-dependent down-regulation of TrkB.


Microbial associations enabling nitrogen acquisition in plants.
Large flows of nitrogen between the atmosphere, terrestrial and aquatic ecosystems contribute to the global cycle on Earth. When balanced, this cycle ensures that life at every level can flourish and diversify. However, in the past 50 years, humans have had a large, negative influence on nitrogen cycle pushing it beyond safe boundaries at the global level. Alternative, wholesome strategies are needed for the agricultural systems to achieve sustainability without compromising crop yields. Decades of research in the field of biological nitrogen fixation in symbiotic root nodules paved the way for ambitious bioengineering projects aiming to meet the nitrogen request in a sustainable manner. Parallel studies of the other microbes that associate with healthy plants in nature unveiled a tremendous, untapped resource for biostimulants. Many of these interactions are now worth investigating in detail to enable understanding at the molecular and ecological level and facile transfer into agricultural settings.


The geochemistry of mercury in central Amazonian soils developed on the Alter-do-Chão formation of the lower Tapajós River Valley, Pará state, Brazil.
In an oxisol-spodosol system developed on the terrestrial surface of the lower Tapajós Valley, the determination of total mercury (Hg), organic carbon (C), iron and aluminum oxy-hydroxide (Fe(cdb) and Al(cdb)) concentrations in the surface soil horizons are used to characterise the geochemical processes controlling the accumulation of Hg in soils under natural vegetation cover and in deforested and cultivated sites. Oxisols from the plateau have homogeneous and relatively high background Hg contents and burdens constituting an important natural reservoir of Hg for the region (90-210 ng/g dry wt. and 19-33 mg/m2 for the first 20 cm). The Fe(cdb) and Al(cdb) contents associated with the fine fraction (< 63 microns) of the soil suggest that oxy-hydroxides and, particularly Al-substituted Fe oxy-hydroxides, control the Hg concentrations observed in all of the soils of the study region. Consequently, the geochemistry of these minerals along the slopes governs the accumulation or the release of the Hg according to the natural evolution of the soil cover and/or following the degradation of soils by erosion after deforestation and cultivation. These observations have important implications for the interpretation of Hg contamination patterns observed in Amazonian aquatic systems that could be linked to different drainage sources of Hg from the terrestrial surface. The sandification and podzolisation that is characteristic of the evolution of numerous pedological systems in the equatorial Amazon could be responsible for exportation of the naturally accumulated Hg, as for other metals, by acidic complexation and migration to the black waters of the Amazon. In the central Amazon region, as a result of the fragility of the soil cover, deforestation and cultivation, affecting principally the superficial soil, promote the selective erosion of fine particles enriched in oxides and Hg. The erosion of soil could be responsible for an important release of Hg, transported in particulate form by drainage waters.


Phenomenological characterization of blood's intermediate shear rate: a new concept for hemorheology.
The phenomena of aggregation, breakdown, and disaggregation of the rouleaux of red blood cells (RBCs) in addition to deformability affect the human blood viscosity at different shear rates. In this study, the intermediate shear rate is introduced and defined when the effect of aggregation on the change of blood viscosity is diminished; and afterwards, the alteration in the blood viscosity is dominantly affected by the deformation of RBCs. With this respect, modeling the effective parameters on the blood shear-thinning behavior including hematocrit and plasma viscosity was performed for the two different shear regions discriminated by the proposed intermediate shear rates. The presented rheological model reflects a phenomenological approach to assess the human blood viscosity with an average error of ± 5% compared to experimental data for hematocrits between 0.299 and 0.702, subjected to various shear rates from 0.2 to 680 1/s. The temperature changes as well as biochemical effects on whole blood viscosity are characterized by the introduced plasma viscosity-dependent model. The presented comprehensive model could be used for better understanding of blood flow hemodynamics and analyzing the shear dependence of aggregation and deformability behaviors of RBCs.


Vaccines and vaccine resistance: Past, present and future.
Edward Jenner, by any definition would be considered the father of vaccinology. His use of cow pox virus for vaccinating against small pox is the prime example of a live vaccine. Using a virus that has very low virulence for humans and therefore, fits the definition of attenuated. Hesitancy towards a vaccine of this type, much before the science of microbiology and immunology were established, would have been justifiable. In the first half of 20th century, large number of vaccines became available for childhood diseases with significant morbidity and mortality. Around the same time global travel and trade led to escalation in the widespread transmission of diseases caused by microbes. The objective of this narrative is to offer a balanced view of science behind vaccines, their current status and advances expected in the near future. At the same time the various types of reactions from public at large towards vaccines over past decades are reviewed. This narrative provides a historical perspective of vaccine development, reviews mechanisms of vaccine induced protection, currently available vaccine technologies and vaccines. The focus is on newer vaccines including those utilizing viral vectors and gene based vaccines. Based on the times during which this narrative is being written, messenger RNA vaccines are discussed in detail. The content and review of literature offered in this review makes the impact of vaccines on human life clear. It is also to be accepted that resistance and hesitation towards vaccines is nothing new or limited to vaccines being used during the ongoing pandemic of Covid 19. The continued development of science and products of vaccinology is necessary for further impact on human life. The development of a strong public health infrastructure by nations around the world is the key to improve upon current efforts at public awareness, proactive interventions and appropriate vaccine utilization during all times. Preparedness for epidemics and pandemics would then become more and more efficient than currently in existence.


A system for reporting and evaluating adverse drug reactions of herbal medicine in Taiwan from 1998 to 2016.
The Taiwan Adverse Drug Reaction Reporting System for Herbal Medicine (TADRRS-HM) has systematically documented suspected adverse events from adverse drug reaction (ADR) reports from 1998 (prior to its formal establishment in 2001) and evaluates safety profiles of herbal medicines. This article describes findings from 2079 ADR reports filed between 1998 and 2016: 941 reports involved single herbs and 87 involved folk herbals; 842 were generated from clinical trials, while 209 ADR reports involving foods, health foods, dietary supplement foods and herbal cuisine were grouped as Other. Severity assessments using the Modified Hartwig and Siegel scale classified 72.4% of ADRs as mild, 17.4% as moderate and 6.5% as severe. System Organ Class classification of the ADRs identified gastrointestinal system disorders as the most common (33.4%), followed by skin and subcutaneous tissue disorders (21.2%). The TADRRS-HM records indicate that herbal medicines may cause a wide range of ADRs. Aconiti Radix, Xiao-Qing-Long-Tang, and Datura suaveolens were the most commonly reported single herb, herbal formula, and folk herbal, respectively. The data indicate that herbal medicines may cause a wide range of ADRs. This system will confer long-term benefits for the development of Taiwan's herbal medicines adverse reaction database and facilitate epidemiological analysis.


Effect of purified scorpion toxin (tityustoxin) on the pancreatic secretion of the rat.
Intravenous injection, in anesthetized rats, of a single dose of purified scorpion toxin (tityustoxin, TsTX), obtained from the venom of the Brazilian scorpion Tityus serrulatus, causes a striking increase in flow rate, protein content, kallikrein and amylase activities of the pancreatic juice. The flow rate and protein content of the juice remain significantly higher than in control rats, for at least one hour, whereas the kallikrein activity returns to control values 30 min after tityustoxin injection. Sub-diaphragmatic bilateral vagotomy does not prevent the pancreatic secretion induced by tityustoxin; moreover, vagotomy potentiates the flow rate and kallikrein secretion produced by the toxin. Pre-treatment of the rats with atropine blocks the pancreatic secretion evoked by tityustoxin. It is suggested that the pancreatic secretion induced by tityustoxin is due to actions of acetylcholine, released from postganglionic nerve fibers, on muscarinic receptors. The mechanism by which vagotomy potentiates the pancreatic secretion evoked by tityustoxin is under investigation.


Biomarkers for Allergen Immunotherapy: A "Panoromic" View.
Biomarkers (BMKs) are biological parameters that can be measured to predict or monitor disease severity or treatment efficacy. The induction of regulatory dendritic cells (DCs) concomitantly with a downregulation of proallergic DC2s (ie, DCs supporting the differentiation of T-helper lymphocyte type 2 cells) in the blood of patients allergic to grass pollen has been correlated with the early onset of allergen immunotherapy efficacy. The combined use of omics technologies to compare biological samples from clinical responders and nonresponders is being implemented in the context of nonhypothesis-driven approaches. Such comprehensive "panoromic" strategies help identify completely novel candidate BMKs, to be subsequently validated as companion diagnostics in large-scale clinical trials.


Consolidating food safety measures against COVID-19.
The world is facing an extraordinarily unprecedented threat from the COVID-19 pandemic triggered by the SARS-CoV-2 virus. Global life has turned upside down, and that several countries closed their borders, simultaneously with the blockage of life cycle as a result of the shutdown of the majority of workplaces except the food stores and some few industries. In this review, we are casting light on the nature of COVID-19 infection and spread, the persistence of SARS-CoV-2 virus in food products, and revealing the threats arising from the transmission of COVID-19 in food environment between stakeholders and even customers. Furthermore, we are exploring and identifying some practical aspects that must be followed to minimize infection and maintain a safe food environment. We also present and discuss some World Health Organization (WHO) guidelines-based regulations in food safety codes, destined to sustain the health safety of all professionals working in the food industry under this current pandemic. The information compiled in this manuscript is supporting and consolidating the safety attributes in food environment, for a prospective positive impact on consumer confidence in food safety and the citizens' public health in society. Some research is suggested on evaluating the use and potentiality of native and chemical modified basic proteins as possible practices aiming at protecting food from bacterial and viral contamination including COVID-19.


Protein distribution of the orexin-2 receptor in the rat central nervous system.
Orexin-A and -B are neuropeptides mainly expressed in the lateral hypothalamic area (LHA). A role for orexins was first demonstrated in the regulation of feeding behaviour. Subsequently, the peptides have been implicated in the control of arousal. To date, two receptors for orexins have been characterised: orexin-1 and -2 receptors (OX-R1 and OX-R2). Both receptor genes are widely expressed within the rat brain. Particularly high expression of both receptor genes in certain hypothalamic and pons nuclei could be responsible for the orexigenic and arousal properties of the peptides. It is, however, presently unclear if one given receptor subtype or both subtypes may mediate a specific biological effect of orexins such as an increase in food intake. We have recently reported the distribution of the OX-R1 protein in the rat nervous system. In this study, we report the distribution of the OX-R2 protein in the rat brain and spinal cord using specific anti-peptide antisera raised against the OX-R2 protein. We also assess the expression profile of the OX-R2 gene in different brain regions. Immunolabelling for the OX-R2 protein was observed in brain regions that exhibited OX-R1-like immunoreactivity (cerebral neocortex, basal ganglia, hippocampal formation, and many other regions in the hypothalamus, thalamus, midbrain and reticular formation). Differences in the OX-R1 and OX-R2 distribution were, however, noticed in the hippocampus, hypothalamus and dorso-lateral pons.


Gentamicin pharmacokinetics in neonates undergoing therapeutic hypothermia.
To identify whether therapeutic hypothermia in newborns with hypoxic ischemic encephalopathy affects gentamicin pharmacokinetics. Retrospective case-control study consisting of 16 neonates who underwent therapeutic hypothermia and received gentamicin with interpretable peak and trough serum levels obtained during the period of cooling and at steady state; comparator group consisting of 7 neonates met the criteria but did not undergo therapeutic hypothermia. Significant differences in gentamicin pharmacokinetics were noted between the therapeutic hypothermia group and the comparator group in elimination rate constant (0.08/h versus 0.11/h; P < 0.01), elimination half-life (9.16 hours versus 6.56 hours; P < 0.01), and clearance (0.04 L/kg.h(-1) versus 0.05 L/kg.h(-1); P < 0.01), respectively. Higher gentamicin trough serum concentrations were seen with the therapeutic hypothermia group (1.68 mcg/mL versus 0.77 mcg/mL; P < 0.01). Therapeutic hypothermia is associated with alterations in gentamicin pharmacokinetics, reducing gentamicin clearance by 25.5% in neonates with hypoxic ischemic encephalopathy, which may result in increased trough serum concentrations.


Access to social services for undiagnosed rare disease patients in France: A pilot study.
Although the challenge of access to care for undiagnosed rare disease patients is well documented in the literature, little is known about lack of diagnosis preventing access to social services. Yet this has serious consequences for patients and their families because disability associated with rare disease requires frequent and costly multi-disciplinary support. The aim of this research is to explore, in the French context, access to social assistance for rare disease patients. We investigate the link between diagnosis and access to social services to identify potential barriers and unmet needs for patients. Our study is based on a self-administered online questionnaire, adressed to parents or legal representatives of a child under ten years old with a rare disease and development disorders. The survey has been carried out between November 2019 and the end of January 2020 and includes 103 respondents. While our data does not show any differences in the possibility of obtaining a social benefit depending on the diagnosis status, there are differences in the length of time they are granted and in the satisfaction of families with the assistance obtained. Families with an undiagnosed child obtained social assistance for a shorter period on average. They were also more likely to be dissatisfied with the amount of benefit they received. The results of this pilot study need to be confirmed by further extended studies.


[Effect of chromatographic fractions of blood ultrafiltrates of patients with chronic uremia on the fibrinolytic activity]].
Ultrafiltrates obtained from the patients with chronic uremia were chromatographically separated in the column filled with Sephadex A25. "Middle" molecular weight substances were localized mainly in a single peak. Dialysis decreased their contents. Determination of the fibrinolytic activity of each chromatographic fractions with caseinolytic and fibrinplate techniques has shown activating effect of the fractions 10-12. Dialysis decreased fibrinolytic activity statistically significantly.


Effective prevention of lethal acute graft-versus-host disease by combined immunosuppressive therapy with prodigiosin and cyclosporine A.
Prodigiosin (PDG), a bacterial metabolite, is a known T cell-specific immunosuppressant. Here, we compared its inhibitory potency and mode of action with cyclosporine A (CsA) in a mouse model. PDG efficiently inhibited T cell proliferation with an IC(50) of 3.37 ng/ml, a similar dose to that of CsA (IC(50) of 2.71 ng/ml). PDG inhibited only IL-2Ralpha expression, but not IL-2 expression, whereas CsA inhibited both. Exogenously added IL-2 reversed the suppressive activity of CsA, but not that of PDG. Moreover, although both PDG and CsA markedly reduced mortality rates in lethal acute graft-versus-host disease (GVHD), the combined treatment was more effective than either drug alone. These results demonstrate that PDG and CsA have similar inhibitory potencies, but different modes of action, and suggest that PDG has potential use as a supplementary immunosuppressant in combination with CsA for the treatment of GVHD.


Sex-linked gene traffic underlies the acquisition of sexually dimorphic UV color vision in Heliconius butterflies.
The acquisition of novel sexually dimorphic traits poses an evolutionary puzzle: How do new traits arise and become sex-limited? Recently acquired color vision, sexually dimorphic in animals like primates and butterflies, presents a compelling model for understanding how traits become sex-biased. For example, some Heliconius butterflies uniquely possess UV (ultraviolet) color vision, which correlates with the expression of two differentially tuned UV-sensitive rhodopsins, UVRh1 and UVRh2. To discover how such traits become sexually dimorphic, we studied Heliconius charithonia, which exhibits female-specific UVRh1 expression. We demonstrate that females, but not males, discriminate different UV wavelengths. Through whole-genome shotgun sequencing and assembly of the H. charithonia genome, we discovered that UVRh1 is present on the W chromosome, making it obligately female-specific. By knocking out UVRh1, we show that UVRh1 protein expression is absent in mutant female eye tissue, as in wild-type male eyes. A PCR survey of UVRh1 sex-linkage across the genus shows that species with female-specific UVRh1 expression lack UVRh1 gDNA in males. Thus, acquisition of sex linkage is sufficient to achieve female-specific expression of UVRh1, though this does not preclude other mechanisms, like cis-regulatory evolution from also contributing. Moreover, both this event, and mutations leading to differential UV opsin sensitivity, occurred early in the history of Heliconius. These results suggest a path for acquiring sexual dimorphism distinct from existing mechanistic models. We propose a model where gene traffic to heterosomes (the W or the Y) genetically partitions a trait by sex before a phenotype shifts (spectral tuning of UV sensitivity).


Exposure levels of organophosphate pesticides in Japanese diapered children: Contributions of exposure-related behaviors and mothers' considerations of food selection and preparation.
Organophosphate (OP) pesticide exposure is a public health issue due to its potential link to neurodevelopmental problems in children. This study aimed to examine the exposure levels of OP pesticides in Japanese toddlers and explore the possible contributions of their exposure-related behaviors and their mothers' considerations of food selection and preparation to their exposure levels to OP pesticides. We recruited diapered children participating in the Japan Environment and Children's Study and collected used disposable diapers from 1037 children between June 2015 and August 2016. Six dialkylphosphates (DAPs) were measured in the urine extracted from the diapers. The geometric means of urinary creatinine (Cr)-unadjusted and Cr-adjusted concentrations of the sum of the six DAPs (ΣDAP) were 120 nmol/L and 243 nmol/g Cr, respectively. A receiver operating characteristic curve analysis for propensity scores of exposure-related factors revealed that discriminatory powers determining whether Cr-unadjusted and Cr-adjusted ΣDAP concentrations exceeded the 95th percentile values were lower for the exposure-related behaviors (areas under the curve, 0.72 and 0.69, respectively) and the mothers' considerations of food selection and preparation (0.55 and 0.57, respectively) than those for the foodstuffs ingested on the survey day (0.75 and 0.81, respectively). Some exposure-related behaviors, namely the use of insecticides, herbicides, and insect repellent sprays, were found to be associated with increased Cr-unadjusted ΣDAP concentrations (odds ratio, 2.0-2.6) via multivariate analysis. In contrast, only the use of a fragrance or deodorant was associated with increased Cr-adjusted ΣDAP concentrations (odds ratio, 2.3). This is the first report on the exposure levels of OP pesticides in a large number of Japanese toddlers. Some household chemical product use was related to OP common metabolite DAP levels. Japanese toddlers were widely exposed to OP pesticide.


Antecedents of cell aging research.
Our observation that normal human and animal cells have a limited capacity to divide and function in vitro overturned a dogma held since the turn of the century. The dogma held that cultured normal cells are immortal and gerontologists interpreted this to mean that aging, therefore, could not be the result of intracellular events. We concluded that longevity and aging do result from intracellular events, and, in the subsequent 30 years, the validity of our finding has been widely confirmed. Other major findings have been made: (a) The number of population doublings and functional events that a cultured normal cell can undergo is inversely proportional to donor age and, probably, directly proportional to species longevity; (b) the limit on cell division and function also occurs in vivo when normal cells are transplanted seriatim; (c) as cell doublings or functional events reach their limit, changes occur in hundreds of variables from the molecular to the whole cell. Most importantly, many of these changes are identical to those seen in intact humans and animals as they age; (d) WI-38, the first widely distributed normal human cell strain has retained its memory of population doubling level during 27 years of cryogenic storage. This is the longest time that any normal human cell has ever been preserved. Evidence that longevity is determined by genetic events is overwhelming but evidence that age changes are the result of gene expression is not. Normal age changes must be distinguished from disease. Because few feral animals ever become old, natural selection could not have favored the development of a genetically programmed aging process. In the 2 or 3 million years of human existence, too few old humans existed to have provided a selective advantage favoring the development of a genetic program that would determine age changes. The selective advantage of maintaining physiological vigor for as long as possible in order to insure maximum reproductive success may be the essential indirect determinant of longevity. Natural selection has provided sexually mature animals with extraordinary reserve capacities in virtually all organs. After sexual maturation, animals continue to function by utilizing the reserve capacity that evolved to insure that they would attain reproductive success. The magnitude of reserve capacity is the essential element in determining postdevelopmental longevity. Thus "Why do we age?" may be the wrong question. The right question may be "Why do we live as long as we do?"


The epidemiology of adverse and unexpected events in the long-term care setting.
To describe the adverse and unexpected events reported by staff over a 1-year period in a large, long-term care institution. A retrospective review of resident incident reports. A 703-bed, academically oriented, long-term care facility. Residents of the facility have a mean age of 88.5 years, are 76% female, and have an average length of stay of 4.3 years. Of the 3,390 adverse and unexpected events reports over the 1-year study period, falls (with and without associated injury) were the most frequently reported incidents, followed by non-fall-related injuries, medication-related events, and wandering episodes. While a large proportion of falls occurred in ambulating residents (47%), the majority occurred under different circumstances including falls from bed, wheelchair, and commode/toilet. Bruises and skin tears were the most frequently reported fall- and non-fall-related injuries. The annual incidence rates for falls, fall-related injuries, and non-fall-related injuries varied according to resident care unit level, with semi-dependent residents experiencing the highest rates of falls and dependent residents experiencing the highest rates of non-fall-related injuries. Circadian patterns in the incidence of these events varied according to resident care level. Information regarding adverse and unexpected events in the long-term care setting can be organized into databases that allow analysis of patterns and trends. The results of these analyses may be helpful in targeting limited resources to areas of greatest need within an individual institution and for comparing quality of care across different long-term care facilities.


Investigation on utility of some novel terpenes on transungual delivery of fluconazole for the management of onychomycosis.
Onychomycosis, the most prevailing affliction of the nail, accounts for approximately 90% of the toenail infection worldwide. Owing to this infection, the affected patients experience reduced quality of their life as its awful appearance undermines their daily activities and social interactions. Onychomycosis is notoriously strenuous to cure. Systemic therapy, though effective, possess severe complication of toxicities, contra-indication, and drug-drug interaction. Albeit topical therapy is favorable to its localized effect, its potency relates to the effective concentration of the antifungal drugs achieved at the infection site. An approach to accomplish this goal would be acquiring benefits from the terpenes as penetration enhancers from natural sources. This investigation aimed to study the effectiveness of six terpenes, namely safranal, lavandulol, rose oxide, 3-methyl-2-butene-1-ol, linalool, and limonene, as potential penetration enhancers for improved nail permeation of fluconazole through the human nail. Ex vivo permeation experiments were carried out by soaking the nail clippings of human volunteers in control and working solutions containing fluconazole (5 mg/ml) per se and fluconazole (5 mg/ml) with 6% of each terpene, including safranal, lavandulol, rose oxide, 3-methyl-2-butene-1-ol, linalool, and limonene, respectively, for 48 h. The amount of fluconazole in nail clippings was quantified using an HPLC method. Statistical analysis showed that fluconazole transungual permeation was influenced by the studied terpenes in the following order: safranal >lavandulol acetate >limonene > rose oxide (p-value >0.05) while the other terpenes showed no significant difference with the control group and safranal represents as the most effective permeation enhancer for the transungual delivery of fluconazole. It is concluded that the safranal can be successfully used as a safe and potential permeation enhancer to enhance the transungual delivery of fluconazole for the treatment of onychomycosis.


Prevalence and associations of dry eye disease and meibomian gland dysfunction in the ural eye and medical study.
To assess the prevalence of dry eye disease (DED) and Meibomian gland dysfunction (MGD) in a population in Russia. The population-based Ural Eye and Medical Study was conducted in an urban and rural region in Bashkortostan/Russia and included 5899 (80.5%) out of 7328 eligible persons, aged 40 + years. DED and MGD were assessed by Schirmer´s test, slit-lamp based examination of the Meibomian glands, and an interview with DED-related questions. The study included 5153 (87.4%) individuals with DED and MGD assessments (mean age: 58.5 ± 10.5 years). The mean Schirmer´s test result was 11.8 ± 6.8 mm and 12.5 ± 7.1 mm for the right/left eye, with a result of ≤ 5 mm measured in 1098 (21.3%; 95% confidence intervals (CI) 20.2, 22.4) of the worse eyes. The mean subjective dry eye symptoms score was 1.37 ± 1.82. MGD grade 1 (telangiectasia at the lid margin), 2, 3, 4 or any grade in the worse eye was diagnosed in 901 (21.1%), 1161 (27.1%), 158 (3.7%), 32 (0.7%), and 2252 (52.6%; 95% CI 51.1, 54.1) eyes respectively. The prevalence of DED diagnosis #1, #2 and #3 (Schirmer´s test ≤ 5 mm, and dry eye score ≥ 1, ≥ 2, and ≥ 3, respectively), #4 (dry eye score ≥ 1, Schirmer test ≤ 5 mm, MGD grade 1 +), and #5 (dry eye score ≥ 1, Schirmer test ≤ 5 mm, MGD grade 2 +) were 598/5142 (11.6%), 426/5153 (8.3%), 273/5142 (5.3%), 335/5142 (6.5%), and 186/5142 (3.6%), respectively. Mean depression score as applied was 5.1 ± 3.8. Higher DED prevalence (definition #4) was associated (multivariable analysis) with female sex (odds ratio (OR) 1.71; 95% CI 1.31, 2.22; P < 0.001), higher depression score (OR 1.04; 95% CI 101, 1.07; P = 0.009), and higher prevalence of thyroid disease history (OR 1.63; 95% CI 1.19, 2.24; P = 0.006). DED and MGD were common in this rural and urban population, and their prevalence was associated with female sex, thyroid disease, and depression.


Palliative chemotherapy with or without anti-EGFR therapy for de novo metastatic nasopharyngeal carcinoma: a propensity score-matching study.
We aimed to investigate the efficacy and safety of cetuximab (CTX) or nimotuzumab (NTZ) on the addition of palliative chemotherapy (PCT) in patients with de novo metastatic nasopharyngeal carcinoma (NPC). From 2007 to 2016, 451 eligible patients with de novo metastatic NPC were enrolled in the study. With propensity score matching technique, we created a well-balanced cohort by matching patients who received CTX/NTZ plus PCT (62 patients) with those receiving PCT alone (248 patients) in a ratio of 1:4. The primary endpoint was overall survival (OS). All potential prognostic factors were involved in the multivariate analysis with the Cox regression hazards model. Kaplan-Meier curves were used to compare the survival status, and log-rank test to measure the significance. The median follow-up time was 27.7 months (range, 1-126 months). No significant difference in survival was observed between the CTX/NTZ plus PCT group and PCT group. (3-year OS: 63.0% vs 58.1%; P=0.485). The administration of CTX/NTZ was not found to be an independent prognostic factor in multivariate analysis. With regard to toxicity, the development of a G3-4 skin reaction and mucositis was more common in patients receiving CTX plus PCT. Interaction effects analysis did not show any significant interaction effects on OS between the treatment regimen and prognostic factors (P>0.05). The efficacy of CTX/NTZ and PCT is comparable to single PCT treatment in terms of survival outcomes among de novo metastatic NPC patients. Moreover, the application of CTX exacerbated skin reactions and mucositis.


[Automated complex for registering and analysing evoked potentials of the human auditory system].
A complex setup for diagnosing affections involving the auditory system of man is described. The algorhythm of the setup functioning is depicted in detail, its main task consisting in segregation of the signal produced by the potential from the noise--the background activity of the human brain cortex. The functioning of the complex setup in dynamics by following the given algorhythm is shown.


Mechanism of sappanchalcone-induced growth inhibition and apoptosis in human oral cancer cells.
Sappanchalcone, a flavonoid extracted from Caesalpinia sappan, exhibits cytoprotective activity, but the molecular basis for the anticancer effect of sappanchalcone has not been reported. In this study, we examined whether sappanchalcone could inhibit the growth of human primary and metastatic oral cancer cells, and we analyzed the signaling pathway underlying the apoptotic effects of the compound in this process using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide (MTT) assays, fluorescence microscopy, flow cytometry, and Western blotting. Sappanchalcone-treated oral cancer cells showed an increased cytosolic level of cytochrome c, downregulated Bcl-2 expression, upregulated Bax and p53 expression, caspase-3 and -9 activation, and poly (ADP-ribose) polymerase cleavage. Furthermore, sappanchalcone induced activation of p38, extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK), and Nuclear factor k B (NF-κB), as demonstrated by the phosphorylation of each mitogen-activated protein kinases (MAPKs), the degradation of inhibitor of NF-κα (IκB-α), increased expression of nuclear p65, and NF-κB-DNA binding. Inhibition of the expression of p38, ERK, JNK, and NF-κB by pharmacological inhibitors reversed sappanchalcone-induced growth inhibition and apoptosis. These results provide the first evidence that sappanchalcone suppresses oral cancer cell growth and induces apoptosis through the activation of p53-dependent mitochondrial, p38, ERK, JNK, and NF-κB signaling. Thus, it has potential as a chemotherapeutic agent for oral cancer.


Muscarinic receptors, leukotriene B4 production and neutrophilic inflammation in COPD patients.
Acetylcholine (ACh) plays an important role in smooth muscle contraction and in the development of airway narrowing; preliminary evidences led us to hypothesize that ACh might also play a role in the development of airways inflammation in chronic obstructive pulmonary disease (COPD). We evaluated the concentrations of leukotriene B4 (LTB4) in induced sputum, and the expression of Ach M1, M2, and M3 receptors in sputum cells (SC) obtained from 16 patients with COPD, 11 smokers, and 14 control subjects. The SC were also treated with ACh and the production of LTB4 assessed in the presence or absence of a muscarinic antagonist (oxitropium). In blood monocytes, we evaluated LTB4 release and activation of the extracellular signal-regulated kinases (ERK) pathway after treatment with Ach. The LTB4 concentrations were higher in COPD than in controls (P < 0.01) and correlated with the number of neutrophil (P < 0.01). The M3 receptors expression was increased in COPD subjects when compared to smokers and control (P < 0.05 and 0.0001, respectively), while M2 expression resulted decreased (P < 0.05 and 0.01). The ACh-induced LTB(4) production was observed in peripheral blood monocytes, and was sensitive to ERK inhibition. Similarly, ACh significantly increased neutrophil chemotactic activity and LTB4 released from SC of COPD patients only, and these effects were blocked by pretreatment with the inhibitor of ERK pathway PD98059. The results obtained show that muscarinic receptors may be involved in airway inflammation in COPD subjects through ACh-induced, ERK1/2-dependent LTB4 release. Muscarinic antagonism may contribute to reduce neutrophil infiltration and activation in COPD.


Formation of bicyclic ethers from Lewis acid promoted cyclizations of cyclic oxonium ions.
Oxacycles carrying a vinyl group and an acetal were extended with a cyclization terminator (vinyl silane or vinyl sulfide) by Suzuki coupling. Treatment with Lewis acid induced cyclization to provide bicyclic ethers in reasonable yields. In the case of the vinyl silane, an ene-like mechanism is preferred, whereas the thioenol ether enters into a Prins-type reaction channel. In one instance, the bicyclic compound was opened to give the ten-membered functionalized enone 24. [reaction: see text]


Incidence, Clinical Manifestations, and Severity of Juvenile Idiopathic Arthritis Among Maori and Pacific Island Children.
To describe the incidence, demographics, diagnostic clinical manifestations, and severity of juvenile idiopathic arthritis (JIA) in Maori and Pacific Island children compared to European children. A chart review was conducted of all children with JIA seen by Auckland pediatric and rheumatology services between the years 2000 and 2015. Demographic data and diagnostic clinical manifestations, including poor prognostic features, were collated. The incidence, diagnostic, clinical manifestations, and severity of JIA were determined and compared between ethnic groups, in particular Maori, Pacific Island, and European children. The overall incidence in a New Zealand cohort of children with JIA was 5.1/100,000 children per year, which was significantly higher among European children (7.2/100,000 children per year) compared to all other ethnic groups. Poor prognostic features at diagnosis were present in 36% of children with JIA, with significantly more Maori and Pacific Island children presenting with poor prognostic features compared to European children (58% versus 27%; P = 0.0001). Maori and Pacific Island children had significantly more poor prognostic features per child associated with JIA (1.10 versus 0.37; P < 0.0001) and in oligoarticular and polyarticular JIA (1.28 versus 0.40; P < 0.0001), which was independent of socioeconomic status. Significant features included cervical involvement (25% versus 9%; P = 0.03), erosive changes (22% versus 8%; P = 0.05), joint space narrowing (13% versus 2%; P = 0.02), and positive rheumatoid factor polyarticular disease (47% versus 14%; P = 0.01). Maori and Pacific Island children were more likely to present with poor prognostic features at diagnosis, although the incidence of JIA was demonstrated to be significantly higher among European children compared to all ethnic groups.


Job strain and early atherosclerosis: the Cardiovascular Risk in Young Finns study.
The purpose of this study was to determine whether job strain and social support are associated with early atherosclerosis measured by carotid intima-media thickness (IMT) in young adults. The subjects were 478 men and 542 women (mean age 32.3) who were participating in the ongoing prospective Cardiovascular Risk in Young Finns study. Job strain was defined as a joint effect of job demands and job control. Early atherosclerosis was determined with IMT ultrasound. The associations between job strain, social support, and IMT were evaluated using multiple linear regressions. In men, job strain was associated with increased IMT after adjustment for age. This association was not attenuated by additional adjustment for established risk factors of coronary heart disease. In women, job strain was not associated with IMT. No 3-way interaction of job demand, job control, and social support on IMT was found. These findings suggest that job strain may be related to atherosclerosis already in its early nonsymptomatic stages in men.


Responses of promyelocytic leukemia HL60 cells as an inflammatory cell lineage model to silica microparticles used to coat blood collection tubes.
The preparation of platelet-rich fibrin (PRF) requires glass blood collection tubes, and thus, the shortage or unavailability of such tubes has driven clinicians to search for suitable substitutes, such as silica-coated plastic tubes. However, we have previously demonstrated the cytotoxicity of silica microparticles (MPs) used in plastic tubes to cultured human periosteal cells. To further establish the effects of silica MPs on inflammation, we examined silica MP-induced changes in a human promyelocytic cell model in vitro. Human promyelocytic HL60 cells were used either without chemical induction or after differentiation induced using phorbol myristate acetate (PMA) or dimethyl sulfoxide. HL60 cells, osteoblastic MG63, and Balb/c mouse cells were treated with silica MPs, and their surface ultrastructure and numbers were examined using a scanning electron microscope and an automated cell counter, respectively. Differentiation markers, such as acid phosphatase, non-specific esterase, and CD11b, were visualized by cytochemical and immunofluorescent staining, and superoxide dismutase (SOD) activity was quantified. Regardless of SOD activity, silica cytotoxicity was observed in MG63 and Balb/c cells. At sub-toxic doses, silica MPs slightly or moderately upregulated the differentiation markers of the control, PMA-induced monocytic, and dimethyl sulfoxide-induced granulocytic HL60 cells. Although SOD activity was the highest (P < 0.05) in PMA-induced cells, a silica-induced reduction in cell adhesion was observed only in those cells (P < 0.05). Silica MP contamination of PRF preparations can potentially exacerbate inflammation at implantation sites. Consequently, unless biomedical advantages can be identified, silica-coated plastic blood collection tubes should not be routinely used for PRF preparations.


Clustering of low usage codons in the translation initiation region of hepatitis C virus.
The adaptation of the overall codon usage pattern of hepatitis C virus (HCV) to that of human is estimated by the synonymous codon usage value (RSCU). The synonymous codon usage biases for the translation initiation region (TIR) of this virus are also analyzed by calculation of usage fluctuation of each synonymous codon along the TIR (the first 30 codon sites of the whole coding sequence of HCV). As for the overall codon usage pattern of HCV, this virus has a significant tendency to delete the codons with CpG or TpA dinucleotides. Turning to the adaptation of the overall codon usage of HCV to that of human, over half part of codons has a similar usage pattern between this virus and human, suggesting that the host cellular environment of the overall codon usage pattern influences the formation of codon usage for HCV. In addition, there is no obvious phenomenon that the codons with relatively low energy tend to be highly selected in the TIR of HCV, suggesting that the synonymous codon usage patterns for the TIR of HCV might be not affected by the secondary structure of nucleotide sequence, however, the formation of synonymous codons usage in the TIR of HCV is influenced by the overall codon usage patterns of human to some degree.


Characterizing the morphologic changes in collagen crosslinked-treated corneas by Fourier transform-second harmonic generation imaging.
To evaluate the efficacy of using forward second harmonic generation (SHG) and 2-dimensional fast Fourier-transform (2D-FFT) analysis for the label-free characterization and quantification of morphologic changes in the corneal stroma after collagen crosslinking (CXL). Department of Physics, National Taiwan University, Taipei, Taiwan. Experimental study. En face forward SHG imaging and 2D-FFT analysis were performed on ex vivo porcine corneas at the depths of 100, 200, 400, and 800 μm. Morphologic changes in stromal collagen fiber in control, ultraviolet-A (UVA), riboflavin, and riboflavin-UVA treated porcine corneas were assessed. Hematoxylin-eosin staining and Sirius red staining were performed for comparison. Corneas after CXL treatment tended to have collagen fibers that were wavy compared with the linear pattern in normal corneas. Quantitative 2D-FFT analysis of forward SHG images also showed an increase in the standard deviations of the distribution of stromal collagen fiber orientations, which is indicative of the changed pattern of crosslinked stromal collagen fibers. Second harmonic generation imaging showed the morphologic changes in stromal collagen after CXL treatment. The linear collagen fibers in normal corneal stroma became wavy after treatment. With the introduction of 2D-FFT analysis, the morphologic changes can be quantified.


Conditioned suppression of behavior maintained by cocaine self-administration.
Shock-paired stimuli have produced conditioned suppression of behavior maintained by a variety of reinforcers such as food, water, sucrose, and intracranial self-stimulation. With the ongoing pursuit of animal models for drug abuse treatment, it is surprising that this procedure for suppressing positively reinforced behavior has never been applied to drug-maintained behavior. The present study applied the conditioned suppression paradigm to behavior maintained by cocaine self-administration in rats. If shock-paired stimuli suppress ongoing cocaine self-administration, this would contrast with recent studies reporting that aversive stimuli can enhance the acquisition and reinstatement of behavior reinforced by cocaine. Rats were trained to bar-press for intravenous cocaine infusions on a variable-interval schedule. Then, a tone conditioned stimulus (CS) and a light CS were each paired with foot-shock while the rats were bar-pressing for cocaine. These CSs each came to reliably suppress responding in all subjects, just as shock-paired CSs suppressed responding by the positive reinforcers mentioned above. When the tone and the light were presented simultaneously in testing, suppression was significantly enhanced over that controlled by the single CSs. These results demonstrate that (1) cocaine-maintained behavior can be suppressed by environmental stimuli associated with non-drug reinforcers; and (2) combining stimuli that decrease drug self-administration can enhance their suppressive effects. Thus, the present findings can have implications for drug treatment.


In vivo toxicology of excipients commonly employed in drug discovery in rats.
Toxicology and pharmacology studies conducted in the early stages of drug discovery often require formulation strategies involving the use of excipients with limited knowledge regarding their preclinical safety liabilities. The use of excipients is vital to efforts to solubilize and deliver small molecules in drug discovery. Whilst excipients can have a significant impact on pharmacology and toxicology studies by enabling solubility to maximize systemic exposure, they also have the potential to obscure clinical pathology endpoints. In this article, we report on the in vivo safety in rats for 18 excipients commonly employed in formulations for preclinical pharmacology and toxicology studies. The test articles were administered once daily for five days, by oral gavage to male Sprague Dawley rats, and the animals monitored for visible clinical signs. At the end of the study, routine necropsy and clinical pathology endpoints were investigated. None of the excipients tested were acutely toxic. However, there were effects on parameters commonly evaluated as indicators of health and/or toxicological response in regulated preclinical safety studies. While the excipients tested were generally well tolerated, several were found to affect common clinical pathology endpoints in a manner that might confound or conceivably mask the interpretation of compound mediated adverse/pharmacological effects.


Evidence for the presence of immunoreactive acetylcholine receptors on human thymus cells.
Triton extracts from thymuses and thymomas from either normal subjects or MG patients specifically bind [125I] alpha-bungarotoxin (alpha Bgt). This binding is saturable (apparent Ks = 5.9 X 10(-9) M) and can be inhibited by cold alpha Bgt, acetylcholine or nicotinic agonists. These results demonstrate the presence on human thymus cells of acetylcholine receptor (ACh.R), 2.8% for normal human thymus in regard of ACh.R concentration in human muscle. Normal human thymic extracts were used as an antigen source in the radioimmunoassay for the detection of anti-ACh.R antibodies in positive MG patients' sera. 72% of these sera were also positive with the thymic antigen. The demonstration of ACh.R in human thymus brings further support to the hypothesis of intrathymic autosensitivity against ACh.R as a major factor in MG pathogenesis.


Relationship between cystic duct diameter and the presence of cholelithiasis.
We sought to measure cystic duct diameter in patients without biliary calculi and in those with cholelithiasis or choledocholithiasis. Using endoscopic retrograde cholangiopancreatography (ERCP), we visualized the cystic duct in 168 patients referred to our unit. These patients were distributed into three groups based on findings at ERCP: Group I (N = 57), no calculi in the gallbladder or common bile duct; group II (N = 27), stones found in the gallbladder but absent from the common bile duct; and group III (N = 34), stones present in the common bile duct with or without gallbladder stones. The diameter of the cystic duct was measured at its widest and narrowest dimensions. The largest diameter measured was greater in group III (7.72 +/- 2.29 mm) than in groups I (2.63 +/- 0.67 mm) and II (4.59 +/- 1.13 mm) (P < 0.001). The same differences were found in measurement of the smallest diameter (5.00 +/- 0.99 mm, 3.10 +/- 0.62 mm, and 1.83 +/- 0.53 mm, for groups III, II, and I, respectively) (P < 0.001). Maximal and minimal cystic duct diameter show a progressive increase at each level of disease. This increase in cystic duct size may facilitate the migration of gallstone fragments after lithotripsy and facilitate the instrumentation of the cystic duct during ERCP and laparoscopic cholecystectomy.


Communication technologies in health care environments.
A successful implementation of hierarchical health care networks is dependent on a number of different technical and non technical factors. This paper investigates how the networking technologies, both 'traditional' and broadband, can support the communication requirements of medical environments. The general purpose is to implement communication infrastructures and services, which will improve the collaboration between the different partners in the health sector in offering better healthcare services at affordable costs.


Identification of epitope expression on the internal proteins of rinderpest virus which is dependent upon virion maturation events.
Monoclonal antibodies (MAb) identified the existence of both maturation-dependent and maturation-independent epitopes on rinderpest virus antigens. The former were divided into (i) post-maturation antigenic determinants, which were dependent upon the maturation of viral antigen into complete virions; and (ii) pre-maturation antigenic determinants, which were only expressed on what appeared to be immature particles before 'budding' into the extracellular environment. Epitope expression could be related to the kinetics of virus production, with the 'post-maturation' sites requiring the production of mature/infectious virions, but the 'pre-maturation' sites being lost when mature virus was formed (these 'pre-maturation' determinants were strongly cell-associated). MAb against the different virion proteins of measles virus, when reacting with rinderpest virus did not demonstrate the same relationship to virion maturation as did the anti-rinderpest virus MAb: the anti-measles virus MAb detected maturation-independent epitopes. This work demonstrates the caution which should be taken when preparing antigens for diagnostic and epidemiological purposes, especially when MAb are being used to identify antigenic differences between isolates, and/or to compare antigenically isolates with vaccine viruses.


Identification of nucleotide patterns enriched in secreted RNAs as putative cis-acting elements targeting them to exosome nano-vesicles.
Exosomes are nanoscale membrane vesicles released by most cells. They are postulated to be involved in cell-cell communication and genetic reprogramming of their target cells. In addition to proteins and lipids, they release RNA molecules many of which are not present in the donor cells implying a highly selective mode of their packaging into these vesicles. Sequence motifs targeting RNA to the vesicles are currently unknown. Ab initio approach was applied for computational identification of potential RNA secretory motifs in the primary sequences of exosome-enriched RNAs (eRNAs). Exhaustive motif analysis for the first time revealed unique sequence features of eRNAs. We discovered multiple linear motifs specifically enriched in secreted RNAs. Their potential function as cis-acting elements targeting RNAs to exosomes is proposed. The motifs co-localized in the same transcripts suggesting combinatorial organization of these secretory signals. We investigated associations of the discovered motifs with other RNA parameters. Secreted RNAs were found to have almost twice shorter half-life times on average, in comparison with cytoplasmic RNAs, and the occurrence of some eRNA-specific motifs significantly correlated with this eRNA feature. Also, we found that eRNAs are highly enriched in long noncoding RNAs. Secreted RNAs share specific sequence motifs that may potentially function as cis-acting elements targeting RNAs to exosomes. Discovery of these motifs will be useful for our understanding the roles of eRNAs in cell-cell communication and genetic reprogramming of the target cells. It will also facilitate nano-scale vesicle engineering and selective targeting of RNAs of interest to these vesicles for gene therapy purposes.


Symmetry-Induced Structuring of Ultrathin FeO and Fe₃O₄ Films on Pt(111) and Ru(0001).
Iron oxide films epitaxially grown on close-packed metal single crystal substrates exhibit nearly-perfect structural order, high catalytic activity (FeO) and room-temperature magnetism (Fe₃O₄). However, the morphology of the films, especially in the ultrathin regime, can be significantly influenced by the crystalline structure of the used support. This work reports an ultra-high vacuum (UHV) low energy electron/synchrotron light-based X-ray photoemission electron microscopy (LEEM/XPEEM) and electron diffraction (µLEED) study of the growth of FeO and Fe₃O₄ on two closed-packed metal single crystal surfaces: Pt(111) and Ru(0001). The results reveal the influence of the mutual orientation of adjacent substrate terraces on the morphology of iron oxide films epitaxially grown on top of them. On fcc Pt(111), which has the same mutual orientation of adjacent monoatomic terraces, FeO(111) grows with the same in-plane orientation on all substrate terraces. For Fe₃O₄(111), one or two orientations are observed depending on the growth conditions. On hcp Ru(0001), the adjacent terraces of which are 'rotated' by 180° with respect to each other, the in-plane orientation of initial FeO(111) and Fe₃O₄(111) crystallites is determined by the orientation of the substrate terrace on which they nucleated. The adaptation of three-fold symmetric iron oxides to three-fold symmetric substrate terraces leads to natural structuring of iron oxide films, i.e., the formation of patch-like magnetite layers on Pt(111) and stripe-like FeO and Fe₃O₄ structures on Ru(0001).


[Novel scaffold materials for tissue engineering].
In this paper, the resorbable and degradable biomaterials often used in recent years are reviewed. These materials include natural and synthetical ones such as collagen, protein fiber, chitosan, polylactic acid (PLA), polyglycolic acid(PGA), polyanlydrides, etc.


Heterotopic ossification associated with myelopathy following cervical disc prosthesis implantation.
This case report presents a 37-year-old man with clinical signs of myelopathy almost 9 years after implantation of a Bryan disc prosthesis (Medtronic Sofamor Danek, Memphis, TN, USA) for C5/C6 soft disc herniation. As demonstrated on MRI and CT scan, spinal cord compression was caused by bony spurs due to heterotopic ossification posterior to the still moving prosthesis. The device, as well as the ectopic bone deposits, had to be removed because of myelopathy and its imminent aggravation. Conversion to anterior spondylodesis was performed.


Can armrests improve comfort and task performance in laparoscopic surgery?
The study sought to determine whether the support provided by armrests influenced task quality, task efficiency, and surgeon comfort during laparoscopic surgery. Complex laparoscopic surgery requires precise movements, and usually long execution times and an uncomfortable stance. Discomfort in the shoulders, back, and neck is an established complaint among laparoscopic surgeons and is related to the unnatural postures adopted during laparoscopic interventions. Discomfort, and the associated fatigue, is a contributory factor in the execution of errors. Nineteen subjects completed a bimanual simulated laparoscopic task both with and without the aid of bilateral armrests. The task was completed in both an ideal unstressed posture and an uncomfortable, stressed elevated posture that more closely represents real laparoscopic operating conditions. Task duration was prolonged sufficiently to precipitate muscular fatigue. The participants also completed a visual analogue scale instrument on level of discomfort symptoms experienced in every part of the upper limbs and vertebral spine. Execution errors (task quality) and completion times (task efficiency) were recorded automatically by the laparoscopic simulator. Error rates and discomfort measures were significantly improved when the armrests were used, but there was no significant change in task completion time. The use of armrests in simulated laparoscopic surgery brings measurable comfort and task performance benefits, which could transfer to actual surgical procedures.


An oligosaccharide-tetanus toxoid conjugate vaccine against type III group B Streptococcus.
We have developed an oligosaccharide-tetanus toxoid conjugate vaccine against type III group B Streptococcus. Purified group B streptococcal type III capsular polysaccharide was depolymerized by enzymatic digestion using endo-beta-galactosidase produced by Citrobacter freundii. Following enzymatic digestion, oligosaccharides were fractionated by gel filtration chromatography on Sephadex G-75. An oligosaccharide pool of average Mr = 14,500 (corresponding to 13.6 repeating units of the type III polysaccharide) was used for conjugation to tetanus toxoid. Tetanus toxoid was covalently coupled via a synthetic spacer molecule to the reducing end of the oligosaccharide by reductive amination. The oligosaccharide-tetanus toxoid conjugate elicited type III-specific anticapsular antibodies (measured in enzyme-linked immunosorbent assay) in three out of three rabbits whereas the unconjugated native type III polysaccharide was nonimmunogenic. Antiserum from rabbits vaccinated with the oligosaccharide-protein conjugate protected mice against lethal challenge with live group B streptococci (16 out of 16 mice survived) and opsonized group B streptococci for phagocytosis in vitro. No protection was conferred by preimmune serum nor by serum from rabbits vaccinated with unconjugated native type III polysaccharide. An oligosaccharide-protein conjugate vaccine of this design may prove to be an effective immunogen for protection against group B streptococcal infection in humans. In addition, the approach to vaccine design utilized in these studies will facilitate further definition of the structural parameters that determine immune response to glycoconjugate vaccines.


The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration?
The diagnosis of anemia is an important aspect of the practice of hematology. The first step is to decide whether the patient is, in fact, anemic. Unless earlier blood counts are available, and they often are not, the physician must make his or her decision on the basis of the population distribution of hemoglobin values. How likely is it that the patient's hemoglobin value lies below the normal distribution; that is, "the lower limit"?


Bacterial lipids: metabolism and membrane homeostasis.
Membrane lipid homeostasis is a vital facet of bacterial cell physiology. For decades, research in bacterial lipid synthesis was largely confined to the Escherichia coli model system. This basic research provided a blueprint for the biochemistry of lipid metabolism that has largely defined the individual steps in bacterial fatty acid and phospholipids synthesis. The advent of genomic sequencing has revealed a surprising amount of diversity in the genes, enzymes and genetic organization of the components responsible for bacterial lipid synthesis. Although the chemical steps in fatty acid synthesis are largely conserved in bacteria, there are surprising differences in the structure and cofactor requirements for the enzymes that perform these reactions in Gram-positive and Gram-negative bacteria. This review summarizes how the explosion of new information on the diversity of biochemical and genetic regulatory mechanisms has impacted our understanding of bacterial lipid homeostasis. The potential and problems of developing therapeutics that block pathogen phospholipid synthesis are explored and evaluated. The study of bacterial lipid metabolism continues to be a rich source for new biochemistry that underlies the variety and adaptability of bacterial life styles.


Neuronal projections to the guinea pig stellate ganglion investigated by retrograde tracing.
Previous electrophysiological studies have revealed a peripheral sensory input to the stellate ganglion which does not originate from the dorsal root ganglia. The present retrograde tracing study aimed at evaluating whether the parent cell bodies are located in the periphery, i.e. in mediastinal ganglia. Following injection of Fast blue or wheat germ agglutinin-horseradish peroxidase into the right stellate ganglion of the guinea pig, retrogradely labelled cell bodies were observed in the intermediolateral and intercalated nuclei of the spinal cord as well as in dorsal root ganglia at segmental levels C8 to T6. In another case, the stellate ganglion was resected and replaced by a sponge soaked with 10 microliters of Fast blue. Labelling of preganglionic and sensory neurons parallelled that obtained by tracer injections. In neither case, however, were retrogradely labelled neurons found within or around the thoracic viscera (thymus, trachea, bronchi, esophagus, heart, great vessels of upper mediastinum) when these were cut serially en bloc. Controls performed by injection of Fast blue into the inferior mesenteric ganglion and investigation of the distal colon showed that our experimental protocol was able to visualize a peripheral projection towards a sympathetic ganglion--in this case from myenteric ganglia to the inferior mesenteric ganglion. We conclude that, in contrast to the circuitry connecting prevertebral sympathetic ganglia with the gut, the neuronal cell bodies providing peripheral sensory input from thoracic viscera to the right stellate ganglion most likely are not located within the mediastinal ganglia. Instead, they may reside within the stellate ganglion itself.


Diptoindonesin G is a middle domain HSP90 modulator for cancer treatment.
HSP90 inhibitors can target many oncoproteins simultaneously, but none have made it through clinical trials due to dose-limiting toxicity and induction of heat shock response, leading to clinical resistance. We identified diptoindonesin G (dip G) as an HSP90 modulator that can promote degradation of HSP90 clients by binding to the middle domain of HSP90 (Kd = 0.13 ± 0.02 μM) without inducing heat shock response. This is likely because dip G does not interfere with the HSP90-HSF1 interaction like N-terminal inhibitors, maintaining HSF1 in a transcriptionally silent state. We found that binding of dip G to HSP90 promotes degradation of HSP90 client protein estrogen receptor α (ER), a major oncogenic driver protein in most breast cancers. Mutations in the ER ligand-binding domain (LBD) are an established mechanism of endocrine resistance and decrease the binding affinity of mainstay endocrine therapies targeting ER, reducing their ability to promote ER degradation or transcriptionally silence ER. Because dip G binds to HSP90 and does not bind to the LBD of ER, unlike endocrine therapies, it is insensitive to ER LBD mutations that drive endocrine resistance. Additionally, we determined that dip G promoted degradation of WT and mutant ER with similar efficacy, downregulated ER- and mutant ER-regulated gene expression, and inhibited WT and mutant cell proliferation. Our data suggest that dip G is not only a molecular probe to study HSP90 biology and the HSP90 conformation cycle, but also a new therapeutic avenue for various cancers, particularly endocrine-resistant breast cancer harboring ER LBD mutations.


Cross-cultural differences in driver self-assessment.
This study investigated differences in driver self-assessment among U.S., Spanish, and West German drivers. Subjects responded to 14 questions that used five-point semantic scales dealing with driver performance and abilities. Pairs of questions, concerning the same driving-related aspects, differed by requesting a self-assessment on an absolute basis and in relation to the average driver. The subjects in all three countries included younger, middle-aged, and older drivers of both sexes. The following are the main findings: (1) a majority of drivers in each country rated themselves positively on all driving-related scales studied; (2) significant effects of country, age group, and sex of the subjects were present for several of the scales; (3) some of these effects remained significant even after controlling for the differential driving experience. For example, U.S. drivers assessed themselves as safer than did West German and Spanish subjects, younger subjects less wise than middle-aged and older subjects, and males more relaxed than females.


Polychromatic full-polarization control in mid-infrared light.
Objects with different shapes, materials and temperatures can emit distinct polarizations and spectral information in mid-infrared band, which provides a unique signature in the transparent window for object identification. However, the crosstalk among various polarization and wavelength channels prevents from accurate mid-infrared detections at high signal-to-noise ratio. Here, we report full-polarization metasurfaces to break the inherent eigen-polarization constraint over the wavelengths in mid-infrared. This recipe enables to select arbitrary orthogonal polarization basis at individual wavelength independently, therefore alleviating the crosstalk and efficiency degradation. A six-channel all-silicon metasurface is specifically presented to project focused mid-infrared light to distinct positions at three wavelengths, each with a pair of arbitrarily chosen orthogonal polarizations. An isolation ratio of 117 between neighboring polarization channels is experimentally recorded, exhibiting detection sensitivity one order of magnitude higher than existing infrared detectors. Remarkably, the high aspect ratio ~30 of our meta-structures manufactured by deep silicon etching technology at temperature -150 °C guarantees the large and precise phase dispersion control over a broadband from 3 to 4.5 μm. We believe our results would benefit the noise-immune mid-infrared detections in remote sensing and space-to-ground communications.