Machine Learning-Based Integration Develops a Macrophage-Related Index for Predicting Prognosis and Immunotherapy Response in Lung Adenocarcinoma.
Macrophages play a critical role in tumor immune microenvironment (TIME) formation and cancer progression in lung adenocarcinoma (LUAD). However, few studies have comprehensively and systematically described the characteristics of macrophages in LUAD. This study identified macrophage-related markers with single-cell RNA sequencing data from the GSE189487 dataset. An integrative machine learning-based procedure based on 10 algorithms was developed to construct a macrophage-related index (MRI) in The Cancer Genome Atlas (TCGA), GSE30219, GSE31210, and GSE72094 datasets. Several algorithms were used to evaluate the associations of MRI with TIME and immunotherapy-related biomarkers. The role of MRI in predicting the immunotherapy response was evaluated with the GSE91061 dataset. The optimal MRI constructed by the combination of the Lasso algorithm and plsRCox was an independent risk factor in LUAD and showed a stable and powerful performance in predicting the overall survival rate of patients with LUAD. Those with low MRI scores had a higher TIME score, a higher level of immune cells, a higher immunophenoscore, and a lower Tumor Immune Dysfunction and Exclusion (TIDE) score, indicating a better response to immunotherapy. The IC50 value of common drugs for chemotherapy and target therapy with low MRI scores was higher compared to high MRI scores. Moreover, the survival prediction nomogram, developed from MRI, had good potential for clinical application in predicting the 1-, 3-, and 5-year overall survival rate of LUAD. Our study constructed for the first time a consensus MRI for LUAD with 10 machine learning algorithms. The MRI could be helpful for risk stratification, prognosis, and selection of treatment approach in LUAD.


Trauma center funding: time for an update.
Uncompensated care (UC) is healthcare provided with no payment from the patient or an insurance provider. UC directly contributes to escalating healthcare costs in the USA and potentially impacts patient care. In Texas, there has been a steady increase in the number of trauma centers and UC volumes without an increase in trauma funding of UC. The method of calculating UC trauma funds in Texas is imprecise as it is driven by Medicaid volumes and not actual trauma care costs. Five years of annual trauma UC disbursement reports from the Texas Department of State Health Services were used to determine changes in UC economic considerations for level I, II, and III trauma centers in the largest urban trauma service areas (TSAs). Data for UC costs, compensation, and TSA demographics were used to assess variations. Statistical significance was determined using a Kruskal-Wallis test with Dunn's pairwise comparison post-hoc analysis and logistic regression. TSA-E (Dallas-Fort Worth area) has 33% of the level I trauma centers in Texas (n=6) and yet serves only 27% of the total state population across 14 metropolitan and 5 non-metropolitan counties. Since 2015, TSA-E has shown higher UC costs (p<0.02) and lower reimbursement (p<0.01) than the second largest urban hub, TSA-Q (Houston area). TSA-E level I trauma centers trended towards decreased UC reimbursements. The unregulated expansion of trauma centers in Texas has led to an unprecedented increase in hospitals participating in trauma care. The unbalanced allocation of UC funding could lead to further economic instability, compromise resource allocation, and negatively impact patient care in an already fragile healthcare environment. Level IV; Retrospective economic analysis and evaluation.


Transection of Nasolacrimal Duct in Endoscopic Medial Maxillectomy: Implication on Epiphora.
Management of the nasolacrimal system is usually recommended during medial maxillectomy via external approach because of reported higher rates of postoperative epiphora. Association of the endoscopic medial maxillectomy (EMM) with epiphora, however, is not clearly stated. In this study, we attempted to evaluate whether patients develop epiphora after simple transection of the nasolacrimal duct during EMM. Medical records of 26 patients who underwent endoscopic tumor resection for inverted papilloma (IP) were retrospectively reviewed. Patients who underwent EMM with nasolacrimal canal transection were included and recalled for lacrimal system evaluation. Twelve patients were eligible for inclusion and fluorescein dye disappearance test (FDDT) was performed for each patient. Patient demographics, tumor data, surgical procedures, and follow-up time were recorded. Of the 12 patients included in the study, 6 underwent canine fossa transantral approach concurrently with EMM. The mean duration of follow-up was 21.1 months (range, 6-84 months). Eight patients were graded as 0, whereas 4 patients were graded as 1 according to FDDT. All test results were interpreted as negative for epiphora. All patients were completely symptom free of epiphora. Epiphora after EMM with nasolacrimal canal transection among patients with sinonasal tumors appears to be uncommon. Therefore, prophylactic concurrent management of nasolacrimal system including stenting, dacryocystorhinostomy (DCR), or postoperative lacrimal lavage are not mandatory for all patients.


Theory and practical impact of binding of antimicrobials to serum proteins and tissue.
Binding of antimicrobials to serum proteins and tissue affects their distribution, elimination and antimicrobial activity. Penetration of drugs into most tissues and interstitial and inflammatory fluids correlates with level of free drug in serum. Serum protein binding can increase or decrease the rate of drug elimination depending on whether total or free drug is available to the excretory or metabolic routes of elimination. Binding to soluble intracellular proteins (ligandin and fatty acid binding protein) appears to be important in the cellular transport and elimination of antimicrobials by renal tubular secretion and hepatic extraction. Although only free, unbound drug is antimicrobially active, the lack of well designed studies has prevented precise quantitation of the influence of binding on therapeutic efficacy in vivo. Pharmacokinetic considerations predict that serum binding greater than 80% would be necessary to significantly reduce free levels of drug in the body. However, extensive protein binding is often compensated for by greater intrinsic activity of lipophilic antimicrobials.


The development and evaluation of a measure to assess cancer survivors' unmet supportive care needs: the CaSUN (Cancer Survivors' Unmet Needs measure).
Many cancer survivors experience ongoing morbidity over the survivorship continuum and their supportive care needs have yet to be comprehensively assessed. This study aimed to develop and empirically evaluate a self-report measure of cancer survivors' supportive care needs. In Phase I, questionnaire items were generated based upon previous qualitative research that identified both unique and shared needs in survivors and their partners; items were constructed into the Cancer Survivors' Unmet Needs measure (CaSUN). In Phase 2, the CaSUN was completed by 353 cancer survivors who had been diagnosed with cancer between 1 and 15 years earlier and were currently disease-free. After modification, the CaSUN included 35 unmet need items, 6 positive change items and an open-ended question. Good acceptability, internal consistency and validity were demonstrated, although test-retest reliability was low. Maximum likelihood factor analysis identified five discrete factors: Existential Survivorship, Comprehensive Care, Information, Quality of Life and Relationships. Preliminary data indicates that the CaSUN meets the majority of psychometric criteria for assessment measures, although its low test-retest reliability awaits further investigation. The CaSUN will facilitate the evaluation of supportive care services and generation of service delivery recommendations for cancer survivors.


Evaluating multiplexed quantitative phosphopeptide analysis on a hybrid quadrupole mass filter/linear ion trap/orbitrap mass spectrometer.
As a driver for many biological processes, phosphorylation remains an area of intense research interest. Advances in multiplexed quantitation utilizing isobaric tags (e.g., TMT and iTRAQ) have the potential to create a new paradigm in quantitative proteomics. New instrumentation and software are propelling these multiplexed workflows forward, which results in more accurate, sensitive, and reproducible quantitation across tens of thousands of phosphopeptides. This study assesses the performance of multiplexed quantitative phosphoproteomics on the Orbitrap Fusion mass spectrometer. Utilizing a two-phosphoproteome model of precursor ion interference, we assessed the accuracy of phosphopeptide quantitation across a variety of experimental approaches. These methods included the use of synchronous precursor selection (SPS) to enhance TMT reporter ion intensity and accuracy. We found that (i) ratio distortion remained a problem for phosphopeptide analysis in multiplexed quantitative workflows, (ii) ratio distortion can be overcome by the use of an SPS-MS3 scan, (iii) interfering ions generally possessed a different charge state than the target precursor, and (iv) selecting only the phosphate neutral loss peak (single notch) for the MS3 scan still provided accurate ratio measurements. Remarkably, these data suggest that the underlying cause of interference may not be due to coeluting and cofragmented peptides but instead from consistent, low level background fragmentation. Finally, as a proof-of-concept 10-plex experiment, we compared phosphopeptide levels from five murine brains to five livers. In total, the SPS-MS3 method quantified 38 247 phosphopeptides, corresponding to 11 000 phosphorylation sites. With 10 measurements recorded for each phosphopeptide, this equates to more than 628 000 binary comparisons collected in less than 48 h.


Addressing Hereditary Cancer Risk at the End of Life.
Oncology guidelines clearly outline evidence-based recommendations for patients with newly diagnosed cancer to help oncologists determine which patients are appropriate for a genetic assessment. Ideally, patients with newly diagnosed cancer, who have personal or family histories suggestive of hereditary cancer predisposition, are referred for genetics work up in the nonurgent setting. However, in some cases, a genetics work up is delayed until the end of life. This is a time of heightened stress and additional obstacles, including discordance between family members regarding the obtainment of genetic information, paying for testing, selecting a surrogate to receive and disperse information in the case of a patient's death, and the use of DNA banking for future evaluation. To meaningfully participate and support patients, family members, and our colleagues facing requests at the end of life for genetic testing, we provide a practical approach and highlight resources to effectively engage in this rising challenge.


Basal cell carcinoma in young women: an evaluation of the association of tanning bed use and smoking.
Basal cell carcinomas (BCCs) typically occur in middle-aged to elderly patients but less commonly in younger ones. In our experience, most BCCs seen in patients younger than 40 years are found in women. We evaluated 30 women with biopsy-proven BCC and 30 control patients matched for sex, age, and skin type to determine potential risk factors for this population. Tanning bed visits, pack-years of cigarette smoking, recreational sun exposure, number of blistering sunburns, and use of sunscreens were determined for both groups. Among patients with a BCC, the histologic type of tumor, site of involvement, method of treatment, follow-up period, incidence of recurrence, and presence of actinic keratoses were also evaluated. Patients with a BCC had a statistically greater number of pack years of smoking (P =.045), and a greater percentage of these women had experienced blistering sunburns (P =.028). Although women with a BCC had, on average, almost twice as many tanning salon visits (152.2 vs 83.1), this was not statistically significant. Sunscreen use and amount of recreational ultraviolet light exposure were essentially equal between the two groups. Young women with a BCC are more likely to have a past or current history of cigarette smoking and blistering sunburns. Repeated exposure to tanning beds may also be a contributory factor.


Forensic use of a subtropical blowfly: the first case indicating minimum postmortem interval (mPMI) in southern Brazil and first record of Sarconesia chlorogaster from a human corpse.
Southern Brazil is unique due to its subtropical climate. Here, we report on the first forensic entomology case and the first record of Sarconesia chlorogaster (Wiedemann) in a human corpse in this region. Flies' samples were collected from a body indoors at 20°C. Four species were found, but only Chrysomya albiceps (Wiedemann) and S. chlorogaster were used to estimate the minimum postmortem interval (mPMI). The mPMI was calculated using accumulated degree hour (ADH) and developmental time. The S. chlorogaster puparium collected was light in color, so we used an experiment to establish a more accurate estimate for time since initiation of pupation where we found full tanning after 3 h. Development of C. albiceps at 20°C to the end of the third instar is 7.4 days. The mPMI based on S. chlorogaster (developmental time until the third instar with no more than 3 h of pupae development) was 7.6 days.


Effects of autologous serum eye drops on corneal wound healing after superficial keratectomy in rabbits.
: To study the effects of topically applied autologous serum on the wound healing process of mechanically produced corneal ulcers. : A superficial keratectomy was done in 1 eye from each of 28 rabbits, using a corneal trephine. Four groups of 7 rabbits were treated topically 4 times a day with nondiluted autologous serum; diluted autologous serum (20%); unpreserved pharmaceutical tear substitute; and physiologic saline. The saline-treated group served as a control. The healing of the ulcers was followed on a slit-lamp biomicroscope regarding its size, infiltration, and neovascularization on alternate days up to day 10 with and without fluorescein staining. : Autologous serum significantly accelerated the corneal wound healing process in both concentrations compared with either the unpreserved pharmaceutical tear substitute or physiologic saline solutions, but the process was faster with the nondiluted concentration. : Autologous serum eye drops could be used as a corneal wound healing adjuvant in mechanical corneal ulcers. To accelerate the wound healing process, the blood-derived factors were brought externally to the avascular cornea through autologous serum eye drops. The importance of the vascular supply on the wound healing process of vascular tissues is well known, and this study considers the benefit of blood-derived factors on the healing process of cornea.


Surgery alone versus post-operative radiotherapy for sinonasal malignant melanoma: a meta-analysis.
Sinonasal malignant melanoma is a relatively rare malignancy with poor prognosis, and effective treatments remain elusive. This analysis aimed to explore whether post-operative radiotherapy conferred any survival advantages in patients with this disease when compared with surgery alone. Published studies were identified by searching four electronic databases. The endpoints evaluated were: rates of overall survival, disease-free survival and local control. Twenty-eight studies including 1392 patients were identified. The results indicated that post-operative radiotherapy led to a significantly better three-year overall survival rate (p = 0.02), and suggested a borderline significant benefit for five-year overall survival (p = 0.05), when compared with surgery alone. However, no statistical advantage was found for disease-free survival, local control or one-year overall survival. This meta-analysis indicated that adjuvant radiotherapy prolonged survival, but showed no benefit for disease-free survival or local control.


Vasoactive Intestinal Peptide Tumor as the Cause of Persistent Diarrhea: A Diagnostic Challenge.
Although chronic diarrhea is frequent, some of its causes are rare, namely, neuroendocrine tumors (NETs). Due to their rarity and non-specific symptoms, such as diarrhea, they are often underdiagnosed. An 80-year-old woman presented to the emergency department due to emesis and watery diarrhea. Blood tests showed acute kidney injury, hypokalemia, and metabolic acidosis. An abdominal computed tomography revealed a 51 mm pancreatic lesion. An endoscopic ultrasound-guided biopsy raised the hypothesis of a NET. The patient refused surgery and was lost to follow-up. At the eighth hospitalization, 11 months later, the suspicion of a vasoactive intestinal peptide tumor (VIPoma) was raised and confirmed by assessing the vasoactive intestinal peptide (VIP) levels (>100 pmol/L). Octreotide was started with the resolution of the symptoms. 68Ga-DOTANOC positron emission tomography/computed tomography excluded metastatic disease. After six months of octreotide therapy, the tumor shrunk 13 mm in maximum diameter. At the last follow-up, one year later, she remained asymptomatic. The delayed diagnosis of VIPoma led to multiple life-threatening episodes. This case highlights the importance of considering all potential differential diagnoses of common symptoms such as diarrhea. Although VIPomas are rare, clinicians should be aware of this entity and suspect this diagnosis in patients with chronic diarrhea with a poor response to standard antidiarrheal agents. Somatostatin analogs should be promptly prescribed for symptom control and tumor progression prevention in patients who refuse surgery or have unresectable tumors. Tumor shrinkage might also be observed in these cases.


Effects of some prostaglandins and leukotrienes on lymphocytes, monocytes and their activity in vitro.
The effect of some prostaglandins (PGs) and leukotrienes (LTs) on lymphocytes and monocytes was tested in vitro. Overnight incubation with PGD2 reduces the expression of Leu-2 antigen (suppressor/cytotoxic phenotype) and of Fc receptors for IgG. PGA2, PGD2 and to a lesser extent PGE2 inhibit PHA reactivity of lymphocytes. LTB4 does not have any inhibitory activity. Preincubation of lymphocytes with PGD2 and PGE2 decreases their NK activity. LTB4, but not the PGs tested, stimulates monocyte metabolism as assessed by chemiluminescence.


Application of workplace correction factors to dosemeter results for the assessment of personal doses at nuclear facilities.
Ratios of H(p)(10) and H*(10) were determined with reference instruments in a number of workplace fields within the nuclear industry and used to derive workplace-specific correction factors. When commercial survey meter results together with these factors were applied to the results of the locally used personal dosemeters their results improved and became within 0.7 and 1.7 of the reference values or better depending on the response of the survey meter. A similar result was obtained when a correction was determined with a prototype reference instrument for H(p)(10) after adjustment of its response. Commercially available survey instruments both for photon and neutron H*(10) measurements agreed with the reference instruments in most cases to within 0.5-1.5. Those conclusions are derived from results reported within the EC supported EVIDOS contract.


Circular RNA regulation and function in drug seeking phenotypes.
Drug overdoses have increased dramatically in the United States over the last decade where they are now the leading cause of accidental death. To develop efficient therapeutic options for decreasing drug consumption and overdose risk, it is critical to understand the neurobiological changes induced by drug exposure. Chronic systemic exposure to all drug classes, including opioids, psychostimulants, nicotine, cannabis, and alcohol, induces profound molecular neuroadaptations within the central nervous system that may reveal crucial information about the lasting effects that these substances impart on brain cells. Transcriptome analyses of messenger RNAs (mRNAs) have identified gene patterns in the brain that result from exposure to various classes of drugs. However, mRNAs represent only a small fraction of the RNA within the cell, and drug exposure also impacts other classes of RNA that are largely understudied, especially circular RNAs. Circular RNAs (circRNAs) are a naturally occurring RNA species formed from back-splicing events during mRNA processing and are enriched in the nervous system. circRNAs are a pleiotropic class of RNAs and have a diverse impact on cellular function, with putative functions including regulation of mRNA transcription, protein translation, microRNA sponging, and sequestration of RNA-binding proteins. Recent studies have demonstrated that circRNAs can modulate cognition and are regulated in the brain in response to drug exposure, yet very few studies have explored the contribution of circRNAs to drug seeking phenotypes. In this review, we will provide an overview of the mechanisms of circRNA function in the cell to highlight how drug-induced circRNA dysregulation may impact the molecular substrates that mediate drug seeking behavior and the current studies that have reported drug-induced dysregulation of circRNAs in the brain. Furthermore, we will discuss how principles of circRNA biology can be adapted to study circRNAs in models of drug exposure and seek to provide further insight into the neurobiology of addiction.


Graft-versus-leukemia effects of transplantation and donor lymphocytes.
Allogeneic transplantation of hematopoietic cells is an effective treatment of leukemia, even in advanced stages. Allogeneic lymphocytes produce a strong graft-versus-leukemia (GVL) effect, but the beneficial effect is limited by graft-versus-host disease (GVHD). Depletion of T cells abrogates GVHD and GVL effects. Delayed transfusion of donor lymphocytes into chimeras after T cell-depleted stem cell transplantation produces a GVL effect without necessarily producing GVHD. Chimerism and tolerance provide a platform for immunotherapy using donor lymphocytes. The allogeneic GVL effects vary from one disease to another, the stage of the disease, donor histocompatibility, the degree of chimerism, and additional treatment. Immunosuppressive therapy before donor lymphocyte transfusions may augment the effect as well as concomitant cytokine treatment. Possible target antigens are histocompatibility antigens and tumor-associated antigens. Immune escape of tumor cells and changes in the reactivity of T cells are to be considered. Durable responses may be the result of the elimination of leukemia stem cells or the establishment of a durable immune control on their progeny. Recently, we have learned from adoptive immunotherapy of viral diseases and HLA-haploidentical stem cell transplantation that T-cell memory may be essential for the effective treatment of leukemia and other malignancies.


[Paroxysmal nocturnal hemoglobinuria revealed by hepatic vein thrombosis (Budd-Chiari syndrome) during Infliximab therapy].
We report the case of a 41-Year-old man presenting with hepatic vein thrombosis (Budd-Chiari syndrome) during Infliximab therapy for ankylosing spondylitis. The systematic work-up revealed paroxysmal nocturnal hemoglobinuria. One Year later the patient was receiving anticoagulation therapy and was in good condition. The role of Infliximab in the development of thrombosis in this patient with rare underlying thrombophilia is discussed.


Targeting multiple chorismate-utilizing enzymes with a single inhibitor: validation of a three-stage design.
Chorismate-utilizing enzymes are attractive antimicrobial drug targets due to their absence in humans and their central role in bacterial survival and virulence. The structural and mechanistic homology of a group of these inspired the goal of discovering inhibitors that target multiple enzymes. Previously, we discovered seven inhibitors of 4-amino-4-deoxychorismate synthase (ADCS) in an on-bead, fluorescent-based screen of a 2304-member one-bead-one-compound combinatorial library. The inhibitors comprise PAYLOAD and COMBI stages, which interact with active site and surface residues, respectively, and are linked by a SPACER stage. These seven compounds, and six derivatives thereof, also inhibit two other enzymes in this family, isochorismate synthase (IS) and anthranilate synthase (AS). The best binding compound inhibits ADCS, IS, and AS with K(i) values of 720, 56, and 80 microM, respectively. Inhibitors with varying SPACER lengths show the original choice of lysine to be optimal. Lastly, inhibition data confirm the PAYLOAD stage directs the inhibitors to the ADCS active site.


Experimental alcoholism and pathogenesis of prostatic diseases in UChB rats.
Previous studies have shown that long-term alcohol treatment has negative effects on prostatic stromal-epithelial interaction. Thus, the aim of the present study was to analyze the histochemical, immunohistochemical and ultrastructural alterations that occur in the prostatic stroma and epithelium of rats submitted to chronic alcohol ingestion and alcohol abstinence, as well as to establish the relationship between these changes and prostatic diseases. Thirty male rats (10 Wistar and 20 UChB rats) were divided into three experimental groups: the control group received tap water, the alcoholic group received ethanol diluted to 10 degrees G.L. for 150 days, and the abstinent group received the same liquid diet as the alcoholic group up to 120 days of treatment and only tap water for 30 days thereafter. At the end of treatment, all animals were sacrificed and the ventral lobe of the prostate was removed and processed for histochemical, immunohistochemical and ultrastructural analyses. In addition, plasma testosterone levels were measured. The results showed prostatic intraepithelial neoplasia, infolding of the epithelium towards the stroma, stromal hypertrophy and the presence of inflammatory cells in alcoholic animals. In the abstinent group, alterations were noted mainly in the stromal area. In conclusion, ethanol triggers alterations in prostatic epithelial and stromal compartments, affecting the stromal microenvironment and predisposing the organ to pathological processes.


Two novel glycosidic triterpene alkaloids from the stem barks of Machilus yaoshansis.
[structure: see text] Two unusual glycosidic triterpene alkaloids, machilaminosides A (1) and B (2), have been isolated from the stem barks of Machilus yaoshansis. Their structures were elucidated by detailed spectroscopic analysis. A possible biogenetic origin of 1 and 2 mediated by the coupling of 2-O-beta-D-glucopyranosyl-cucurbitacin I, respectively, with urea and adenosine was postulated. 1 and 2 showed nonselective cytotoxic activities against several human cancer cell lines as well as TNF-alpha secretion inhibitory activities.


Orthodontic treatment needs among 12-15 year-olds in Moshi, Tanzania.
To assess malocclusion and orthodontic treatment needs among 12-15-year-olds in Moshi municipality, Tanzania. A cross-sectional study. Moshi municipality, Tanzania. Two hundred and eighty nine randomly selected primary school children in Moshi municipality in the year 2003. Maxillary median diastema occurred in 20.1% of the children. Crowding and spacing in the incisor segments occurred in 41.2% and 28.4% respectively with significantly more crowding in males than in females (p = 0.009). Anterior irregularities occurred in 46% of the sample in the maxilla and 51.6% in the mandible. These irregularities were significantly more common in the females than in males in the maxilla and mandible (p = 0.014, p = 0.037 respectively). Reverse overjet was extremely rare (0.3%). Anterior openbite and antero-posterior molar relation discrepancies occurred in 6.2% and 32.5% of the sample, respectively. Crowding, irregularities in the incisor segments and antero-posterior molar relation discrepancies were dominant malocclusion traits in this population. The sample mean DAI score was 24.6 points (CI 95% 23.86-25.36). There was no statistically significant gender difference of DAI scores (p = 0.473). About 65% of the subjects had either no need or had slight need for treatment whereas 35.3% were found with orthodontic treatment needs ranging from elective (21.5%), highly desirable (6.9%) to mandatory (6.9%). There was no significant gender difference in the categories of treatment need (p = 0.942). Unmet orthodontic treatment needs were present in this population with a very small proportion of subjects exhibiting handicapping malocclusion. The information from this study forms part of the basis not only for further research, but also for planning orthodontic care in this community where unmet orthodontic treatment needs are present.


Aspergillus cholangitis: A late complication after Kasai portoenterostomy.
Ascending bacterial cholangitis can be a recurring complication in older children and adolescents who have undergone successful surgery for biliary atresia. The authors describe a 19-year-old girl with a history of recurrent late-onset, febrile cholangitis in whom persistent jaundice developed. Aspergillus terreus was isolated from her biliary fluid obtained at percutaneous transhepatic cholangiography. Despite prolonged external biliary drainage and systemic amphotericin B therapy, the fungus was not eliminated from her biliary system. Aspergillus cholangitis can occur in the portoenterostomy patient and may be highly resistant to conventional therapy.


Kinetics of the "on-off" change in regulatory state of the muscle thin filament.
The excimer fluorescence of pyrene iodoacetamide-labeled tropomyosin bound to actin is a probe of the regulatory state change of the muscle thin filament associated with the cooperative binding of myosin subfragment 1 (S1) (Y. Ishii and S. S. Lehrer, Biochemistry 29, 1160, 1990). In this study, the excimer fluorescence was used to monitor the kinetics of the "on-off" state change due to the ATP-induced dissociation of S1 from actin-tropomyosin. A lag in the fluorescence change indicated that the thin filament was maintained in the "on-state" until more than half of the S1s dissociate. The on-off transition rate was slower than the dissociation of the remaining S1s. These delays in relaxation to the "off-state" may explain some observed kinetic and cooperative effects during tension measurements.


Trypan blue staining of the anterior capsule: the one-drop technique.
Capsule staining is usually a two- or three-stage procedure in which trypan blue is injected under air, a viscoelastic device, viscoelastic mixed with dye, or compartmentalized viscoelastic and balanced salt solution. In these techniques, the consequent irrigation of the anterior chamber with balanced salt solution may lead to a less stable anterior chamber, a decrease of pupil diameter, and damage of the corneal endothelium. A modification of current injection techniques for staining the anterior capsule under a dispersive viscoelastic device with 1 drop of trypan blue by an ordinary 27-gauge anterior chamber cannula is described.


The DEAD box protein Dhh1 stimulates the decapping enzyme Dcp1.
An important control step in the regulation of cytoplasmic mRNA turnover is the removal of the m(7)G cap structure at the 5' end of the message. Here, we describe the functional characterization of Dhh1, a highly conserved member of the family of DEAD box-containing proteins, as a regulator of mRNA decapping in Saccharomyces cerevisiae. Dhh1 is a cytoplasmic protein and is shown to be in a complex with the mRNA degradation factor Pat1/Mtr1 and with the 5'-3' exoribonuclease Xrn1. Dhh1 specifically affects mRNA turnover in the deadenylation-dependent decay pathway, but does not act on the degradation of nonsense-containing mRNAs. Cells that lack dhh1 accumulate degradation intermediates that have lost their poly(A) tail but contain an intact 5' cap structure, suggesting that Dhh1 is required for efficient decapping in vivo. Furthermore, recombinant Dhh1 is able to stimulate the activity of the purified decapping enzyme Dcp1 in an in vitro decapping assay. We propose that the DEAD box protein Dhh1 regulates the access of the decapping enzyme to the m(7)G cap by modulating the structure at the 5' end of mRNAs.


Impact of spontaneous prophage induction on the fitness of bacterial populations and host-microbe interactions.
Bacteriophages and genetic elements, such as prophage-like elements, pathogenicity islands, and phage morons, make up a considerable amount of bacterial genomes. Their transfer and subsequent activity within the host's genetic circuitry have had a significant impact on bacterial evolution. In this review, we consider what underlying mechanisms might cause the spontaneous activity of lysogenic phages in single bacterial cells and how the spontaneous induction of prophages can lead to competitive advantages for and influence the lifestyle of bacterial populations or the virulence of pathogenic strains.


Thyroid hormone receptor-alpha inhibits retinoic acid-responsive gene expression and modulates retinoic acid-stimulated neural differentiation in mouse embryonic stem cells.
Thyroid hormone (T3) and retinoic acid (RA) are essential for normal vertebrate development and are known to coregulate several genes. Early development is predominantly retinoic acid sensitive, yet thyroid hormone receptor-alpha (T3R alpha) is expressed along with retinoic acid receptors (RAR)-alpha, -beta, and -gamma. To determine the role of unliganded T3R alpha in early development and on RA-stimulated neural development, we used homologous recombination techniques to inactivate both T3R alpha gene alleles in mouse embryonic stem (ES) cells. Loss of both T3R alpha alleles resulted in an increase in basal and RA-induced expression of the endogenous RA-responsive genes, RAR beta and alkaline phosphatase, which demonstrates that T3R alpha has an inhibitory effect on the RA response. A similar magnitude of T3R inhibition of the RA response was seen in transient transfection assays of RA response elements in both ES and assays of RA response elements in both ES and JEG cells. Cotransfection experiments were used to demonstrate that inhibition of the RA response could be mediated by T3R alpha 1. The addition of T3R alpha 1, but not the T3R alpha variant c-erbA alpha 2, to T3R alpha-null ES cells restored the inhibitory effect on RA-induced gene expression. RA-stimulated neural differentiation was seen in the wild-type, but not in T3R alpha-null ES, cells, consistent with reports of abnormal neural development as a consequence of premature RA stimulation. Our results demonstrate that the early expression of unliganded T3R alpha functions to modulate the RA response and RA-stimulated neural differentiation.


Randomly ordered addressable high-density optical sensor arrays.
Array-based sensors provide an architecture for multianalyte sensing. In this paper, we report a new approach for array fabrication. Sensors are made by immobilizing different reactive chemistries on the surfaces of microspheres. Sensor arrays are prepared by randomly distributing a mixture of microsphere sensors on an optical substrate containing thousands of micrometer-scale wells. The sensors occupy a different location from array to array; thus the identity of each sensor is ascertained and registered on the detector using encoding schemes, rather than by a predetermined location in the array. The approach thereby shifts the demand from fabrication to signal processing. The availability of commercial image analysis software makes such a shift both cost-effective and time efficient.


Hunger and the temporal lobe.
A boy experienced two episodes of intracerebral hemorrhage in the region of the right anterior temporal lobe. On both occasions, the bleeding was ushered in by an exclamation of intense hunger. The patient provides further evidence for the temporal lobe localization of the sensation of hunger. We describe a model of the neural system subserving feeding that incorporates the cortical locus of hunger.


Juvenile hormone suppresses aggregation behavior through influencing antennal gene expression in locusts.
Animals often exhibit dramatically behavioral plasticity depending on their internal physiological state, yet little is known about the underlying molecular mechanisms. The migratory locust, Locusta migratoria, provides an excellent model for addressing these questions because of their famous phase polyphenism involving remarkably behavioral plasticity between gregarious and solitarious phases. Here, we report that a major insect hormone, juvenile hormone, is involved in the regulation of this behavioral plasticity related to phase change by influencing the expression levels of olfactory-related genes in the migratory locust. We found that the treatment of juvenile hormone analog, methoprene, can significantly shift the olfactory responses of gregarious nymphs from attraction to repulsion to the volatiles released by gregarious nymphs. In contrast, the repulsion behavior of solitarious nymphs significantly decreased when they were treated with precocene or injected with double-stranded RNA of JHAMT, a juvenile hormone acid O-methyltransferase. Further, JH receptor Met or JH-response gene Kr-h1 knockdown phenocopied the JH-deprivation effects on olfactory behavior. RNA-seq analysis identified 122 differentially expressed genes in antennae after methoprene application on gregarious nymphs. Interestingly, several olfactory-related genes were especially enriched, including takeout (TO) and chemosensory protein (CSP) which have key roles in behavioral phase change of locusts. Furthermore, methoprene application and Met or Kr-h1 knockdown resulted in simultaneous changes of both TO1 and CSP3 expression to reverse pattern, which mediated the transition between repulsion and attraction responses to gregarious volatiles. Our results suggest the regulatory roles of a pleiotropic hormone in locust behavioral plasticity through modulating gene expression in the peripheral olfactory system.


Combined laparoscopic near-total gastrectomy and colectomy.
Synchronous gastrointestinal lesions of the abdomen are uncommon. Although laparoscopic gastric resection and colonic resection have been previously described, the combined laparoscopic resection of these 2 organs is unique. We report a case of a 72-year-old man with in situ gastric cancer and high-grade dysplasia of a colon polyp who underwent successful laparoscopic resection of both lesions. This report highlights the importance of preoperative planning and port placement in combined laparoscopic procedures.


Impact of anesthetic factors on prognosis of patients with non-small cell lung cancer after surgery.
Nowadays, the influence of anesthesia management on the prognosis of cancer patients has been widely concerned. The goal of this study is to assess the association between anesthetic factors and the prognosis of patients with non-small cell lung cancer (NSCLC) after surgery. Patients with NSCLC who underwent surgery from January 1, 2006, to December 31, 2009 were selected. Cox proportional hazards model and Logistic regression analysis model were used to screen the independent predictors of prognosis of patients. The primary endpoint was postoperative overall survival (OS), and the secondary endpoint was postoperative recurrence-free survival (RFS) and postoperative pulmonary complications (PPCs). A total of 588 patients were included into the final analysis. The overall RFS was 4.4 [interquartile range (IQR), 1.1-10.1] years, and the OS was 6.2 (IQR, 2.4-10.2) years. Age ≥60 years, advanced tumor stage, and maximal tumor size >3 cm were associated with shortened survival, whereas high BMI grade, mediastinal lymph node dissection, perioperative fentanyl equivalents >28.2 µg/kg, and high tumor grade were associated with prolonged survival (P<0.05); perioperative glucocorticoid administration delayed recurrence (P<0.05); advanced tumor stage and perioperative fentanyl equivalents >28.2 µg/kg were associated with an increased PPCs risk (P<0.05). The findings from this study revealed that perioperative anesthetic factors may impact the prognosis of patients with NSCLC after surgery. Perioperative opioid and glucocorticoid exposure were independent predictors for outcomes. However, perioperative fentanyl equivalents over 28.2 µg/kg seemed to be beneficial to OS, but contribute to the occurrence of PPCs.


Fluid structure interaction with contact surface methodology for evaluation of endovascular carotid implants for drug-resistant hypertension treatment.
Drug-resistant hypertensive patients may be treated by mechanical stimulation of stretch-sensitive baroreceptors located in the sinus of carotid arteries. To evaluate the efficacy of endovascular devices to stretch the carotid sinus such that the induced strain might trigger baroreceptors to increase action potential firing rate and thereby reduce systemic blood pressure, numerical simulations were conducted of devices deployed in subject-specific carotid models. Two models were chosen--a typical physiologic carotid and a diminutive atypical physiologic model representing a clinically worst case scenario--to evaluate the effects of device deployment in normal and extreme cases, respectively. Based on the anatomical dimensions of the carotids, two different device sizes were chosen out of five total device sizes available. A fluid structure interaction (FSI) simulation methodology with contact surface between the device and the arterial wall was implemented for resolving the stresses and strains induced by device deployment. Results indicate that device deployment in the carotid sinus of the physiologic model induces an increase of 2.5% and 7.5% in circumferential and longitudinal wall stretch, respectively, and a maximum of 54% increase in von Mises arterial stress at the sinus wall baroreceptor region. The second device, deployed in the diminutive carotid model, induces an increase of 6% in both circumferential and longitudinal stretch and a 50% maximum increase in von Mises stress at the sinus wall baroreceptor region. Device deployment has a minimal effect on blood-flow patterns, indicating that it does not adversely affect carotid bifurcation hemodynamics in the physiologic model. In the smaller carotid model, deployment of the device lowers wall shear stress at sinus by 16% while accelerating flow entering the external carotid artery branch. Our FSI simulations of carotid arteries with deployed device show that the device induces localized increase in wall stretch at the sinus, suggesting that this will activate baroreceptors and subsequently may control hypertension in drug-resistant hypertensive patients, with no consequential deleterious effects on the carotid sinus hemodynamics.


Laboratory tests for live attenuated poliovirus vaccines.
A new generation of tests to control live attenuated poliovirus vaccines are under development based on major advances in our understanding of the molecular basis of attenuation and reversion to virulence of polioviruses. These include an alternative in vivo neurovirulence test in transgenic mice that express the human poliovirus receptor and a new in vitro test, the MAPREC (mutant analysis by polymerose chain reaction and restriction enzyme cleavage assay, that assesses consistency of production at a molecular level. Excellent progress is being made with both methods but neither is sufficiently developed yet for regulatory use. Critical review of existing control tests shows that the WHO neurovirulence test is well standardized and contributes significantly to the assessment of each batch. On the other hand, the current rct40 test is neither standardized nor particularly informative, though improvements could be made in both areas. The continued relevance of other marker tests such as the d or antigenic marker is doubtful. Potency, identity and thermal stability tests are crucial for control of the final trivalent vaccine.


Feasibility of a smartphone app for prescribed exercise tutoring in patients with stable coronary heart disease.
Digital health technologies have potential to address the challenges associated with traditional cardiac rehabilitation (CR). However, it is not complete enough for prescribed exercise guidance and remote monitoring. We aimed to evaluate the feasibility of a smartphone app for prescribed exercise tutoring by exercise videos combined with wearable devices to monitor heart rate in patients with stable coronary heart disease (CHD). The study is a quasi-experimental design study with a single group. A total of 31 patients were included with an average age of 56.2 years (SD 13.4). They participated in a 12-week remote digital CR program. We employed a wearable heart rate monitoring device connected with an app to monitor the patients' exercise intensity. The app can display the videos corresponding to an exercise prescription to guide the exercise. Cardiorespiratory endurance, blood pressure, blood glucose, cholesterol, blood uric acid, left ventricular ejection fraction and quality of life (QoL) were assessed at the beginning and end of the intervention. Compliance and safety events were recorded as well. Completion rate reached 90.3%. Average daily effective exercise time was 39.4 min (SD 17.8), and 92.9% of the patients could exercise in the prescribed intensity for at least 20 min per day. Average effective exercise days per week were 4.6 days (SD 2.2), and 67.9% of the patients could exercise in the prescribed intensity for at least 3 days per week. Patients' peak VO2 (P = 0.041) and peak metabolic equivalents (P = 0.018) were significantly increased, low-density lipoprotein (P = 0.036) and diastolic blood pressure at rest (P = 0.044) were significantly decreased, and depression (GAD-7, P = 0.014) and anxiety (PHQ-9, P = 0.013) were significantly improved. It is feasible, safe, and helpful for stable CHD patients to use the app for prescribed exercise tutoring with videos combined with wearable devices to monitor heart rate. ChiCTR1800019144.


Genetic association analysis of serotonin and signal transduction pathways in suicide attempters from an Italian sample of psychiatric patients.
Genetic factors have been reported to contribute to the liability of suicide. We aimed to investigate functional polymorphisms in eight genes (serotonin transporter, SLC6A4; receptors, 5HTR1A, 1B, 5HTR2A; Tryptophan Hydroxylase, TPH1, TPH2; Monoamine Oxidase, MAOA and G Protein Subunit Beta 3, GNB3) to investigate their predictive value for suicide. The possible confounding effects of gender and phenotypic patients dissection were also valued. A sample of 111 consecutive psychiatric inpatients was recruited and assessed using specific psychometric instruments. Genomic DNA was isolated from peripheral white blood cell samples and polymorphisms were genotyped by pyrosequencing technology. Although no differences were observed between allele and genotype frequencies for all polymorphisms and suicide attempt (SA), a polygenic risk score was detected for three genes HTR2A (A-1438G), TPH1 and TPH2 increasing the prediction of SA risk (Thresh=0.43, p=0.038, R2=0.053). Moreover some nominal associations were obtained after gender and phenotypic dissection stratification (TEMPS-A, TEMPs-H, GSMD, SHSS, GAF, CGI) for SLC6A4 (5-HTTLPR), HTR1A (C-1019G), HTR2A (A-1438G), TPH1 (A799C) and GNB3 (C825T) genes, that were lost after Bonferroni correction. This is a first evidence that specific additive combinations of genes could increase the prediction of SA risk and that gender and phenotypic dissection could influence the association of the genes with SA. This could represent a further study also for future meta-analyses on larger samples.


Deforestation and Malaria on the Amazon Frontier: Larval Clustering of Anopheles darlingi (Diptera: Culicidae) Determines Focal Distribution of Malaria.
We performed bimonthly mosquito larval collections during 1 year, in an agricultural settlement in the Brazilian Amazon, as well as an analysis of malaria incidence in neighboring houses. Water collections located at forest fringes were more commonly positive for Anopheles darlingi larvae and Kulldorff spatial analysis pinpointed significant larval clusters at sites directly beneath forest fringes, which were called larval "hotspots." Remote sensing identified 43 "potential" hotspots. Sampling of these areas revealed an 85.7% positivity rate for A. darlingi larvae. Malaria was correlated with shorter distances to potential hotpots and settlers living within 400 m of potential hotspots had a 2.60 higher risk of malaria. Recently arrived settlers, usually located closer to the tip of the triangularly shaped deforestation imprints of side roads, may be more exposed to malaria due to their proximity to the forest fringe. As deforestation progresses, transmission decreases. However, forest remnants inside deforested areas conferred an increased risk of malaria. We propose a model for explaining frontier malaria in the Amazon: because of adaptation of A. darlingi to the forest fringe ecotone, humans are exposed to an increased transmission risk when in proximity to these areas, especially when small dams are created on naturally running water collections.


Gentamicin and tobramycin resistant gram-negative bacilli in a community hospital.
The incidence and spectrum of resistance to gentamicin and tobramycin among gram-negative bacilli (GNB) isolated in a community hospital over a one-year period were studied. The overall incidence of resistance was 3.7%. Pseudomonads constituted almost half of the resistant organisms. The majority of resistant GNB was isolated from the respiratory and urinary tracts. Acquisition of resistance was correlated with both the total use of gentamicin in the hospital and recent treatment of individual patients with gentamicin plus tobramycin. The overall incidence of resistant isolates (3.7%) and the incidence of resistance for the enterobacteriaceae (1.9%) were lower than rates reported by comparable studies at several university or municipal hospitals.


Outer hair cells: the inside story.
The neurobiology of hair cells is reviewed, including their transduction apparatus, the production and nature of receptor potentials, and the similarities and differences between inner hair cells and outer cells (OHCs). Intracellular recordings from hair cells in vivo are discussed. This is followed by a consideration of effects of OHC lesions and consequent notions about OHC functions. Feedback in the cochlea is then considered, and the role of OHCs as the feedback element is examined, along with putative means of producing the feedback.


Functional Characterization of Novel Faecalibacterium prausnitzii Strains Isolated from Healthy Volunteers: A Step Forward in the Use of F. prausnitzii as a Next-Generation Probiotic.
Faecalibacterium prausnitzii is a major member of the Firmicutes phylum and one of the most abundant bacteria in the healthy human microbiota. F. prausnitzii depletion has been reported in several intestinal disorders, and more consistently in Crohn's disease (CD) patients. Despite its importance in human health, only few microbiological studies have been performed to isolate novel F. prausnitzii strains in order to better understand the biodiversity and physiological diversity of this beneficial commensal species. In this study, we described a protocol to isolate novel F. prausnitzii strains from feces of healthy volunteers as well as a deep molecular and metabolic characterization of these isolated strains. These F. prausnitzii strains were classified in two phylogroups and three clusters according to 16S rRNA sequences and results support that they would belong to two different genomospecies or genomovars as no genome sequencing has been performed in this work. Differences in enzymes production, antibiotic resistance and immunomodulatory properties were found to be strain-dependent. So far, all F. prausnitzii isolates share some characteristic such as (i) the lack of epithelial cells adhesion, plasmids, anti-microbial, and hemolytic activity and (ii) the presence of DNAse activity. Furthermore, Short Chain Fatty Acids (SCFA) production was assessed for the novel isolates as these products influence intestinal homeostasis. Indeed, the butyrate production has been correlated to the capacity to induce IL-10, an anti-inflammatory cytokine, in peripheral blood mononuclear cells (PBMC) but not to the ability to block IL-8 secretion in TNF-α-stimulated HT-29 cells, reinforcing the hypothesis of a complex anti-inflammatory pathway driven by F. prausnitzii. Altogether, our results suggest that some F. prausnitzii strains could represent good candidates as next-generation probiotic.


Mechanistic understanding of the correlation between structure and dynamics of liquid carbonate electrolytes: impact of polarization.
Liquid electrolyte design and modelling is an essential part of the development of improved lithium ion batteries. For mixed organic carbonates (ethylene carbonate (EC) and ethyl-methyl carbonate (EMC) mixtures)-based electrolytes with LiPF6 as salt, we have compared a polarizable force field with the standard non-polarizable force field with and without charge rescaling to model the structural and dynamic properties. The result of our molecular dynamics simulations shows that both polarizable and non-polarizable force fields have similar structural factors, which are also in agreement with X-ray diffraction experimental results. In contrast, structural differences are observed for the lithium neighborhood, while the lithium-anion neighbourhood is much more pronounced for the polarizable force field. Comparison of EC/EMC coordination statistics with Fourier transformed infrared spectroscopy (FTIR) shows the best agreement for the polarizable force field. Also for transport quantities such as ionic conductivities, transference numbers, and viscosities, the agreement with the polarizable force field is by far better for a large range of salt concentrations and EC : EMC ratios. In contrast, for the non-polarizable variants, the dynamics are largely underestimated. The excellent performance of the polarizable force field is explored in different ways to pave the way to a realistic description of the structure-dynamics relationships for a wide range of salt and solvent compositions for this standard electrolyte. In particular, we can characterize the distinct correlation terms between like and unlike ions, relate them to structural properties, and explore to which degree the transport in this electrolyte is mass or charge limited.


Abolishment of metastasis formation by murine tumor cells transfected with "foreign" H-2K genes.
High metastatic, low immunogenic Lewis lung carcinoma clones express low levels of H-2Kb major histocompatibility complex antigens. These cells metastasize spontaneously in mice with C57BL/6 genetic background possessing the H-2Db locus. Transfection of different H-2K genes abrogates metastasis in H-2K, H-2D compatible mice and in C57BL/6 recipients. The transfected cells are potent inducers of H-2K-restricted and alloreactive cytotoxic lymphocytes that kill H-2K-positive cells and cross-react with parental nontransfected cells.


[Research progress on identification and quality evaluation of glues medicines].
Glues medicines is a special kind of traditional Chinese medicine.As the market demand is large, the raw materials are in short supply and lacks proper quality evaluation technology, which causes inconsistent quality of products on the market. Its authentic identification and evaluation stay a problem to be solved. In this paper, the research progress of the methods and techniques of the evaluation of the identification and quality of glues medicines were reviewed. The researches of medicinal glue type identification and quality evaluation mainly concentrated in four aspects of medicinal materials of physical and chemical properties, trace elements, organic chemicals and biological genetic methods and techniques. The methods of physicochemical properties include thermal analysis, gel electrophoresis, isoelectric focusing electrophoresis, infrared spectroscopy, gel exclusion chromatography, and circular dichroism. The methods including atomic absorption spectrometry, X-ray fluorescence spectrometry, plasma emission spectrometry and visible spectrophotometry were used for the study of the trace elements of glues medicines. The organic chemical composition was studied by methods of composition of amino acids, content detection, odor detection, lipid soluble component, organic acid detection. Methods based on the characteristics of biogenetics include DNA, polypeptide and amino acid sequence difference analysis. Overall, because of relative components similarity of the glues medicines (such as amino acids, proteins and peptides), its authenticity and quality evaluation index is difficult to judge objectively, all sorts of identification evaluation methods have different characteristics, but also their limitations. It indicates that further study should focus on identification of evaluation index and various technology integrated application combining with the characteristics of the production process.


A Tibetan with chronic mountain sickness followed by high altitude pulmonary edema on reentry.
Chronic mountain sickness (CMS) and high altitude pulmonary edema (HAPE) each occur rarely in Tibetans, and they have previously not been reported in the same person. Here we describe a 37-year-old native Tibetan man with CMS at 4300 m, who developed HAPE after his return home from a 12-day visit to sea level. Possible common pathogenetic factors included a poor ventilatory response to hypoxia, accentuated hypoxemia, pulmonary hypertension, and increased blood volume. In addition, strenuous exercise and high levels (to approximately 1000 ng/L) of plasma atrial natriuretic peptide may have contributed to HAPE.


AhR activation promotes Treg cell generation by enhancing Lkb1-mediated fatty acid oxidation via the Skp2/K63-ubiquitination pathway.
Several aryl hydrocarbon receptor (AhR) agonists have been reported to promote the generation of regulatory T cells (Treg cells), and the action mechanisms need to be identified. In this study, we addressed the underlying mechanism of AhR activation to induce the generation of Treg cells in the view of cellular metabolism. Naïve CD4+ T cells were purified with mouse CD4+ CD62L+ T Cells Isolation Kits. The proportions of Treg cells were detected by flow cytometry. The value of oxygen consumption rate (OCR) of CD4+ T cells was detected by the Seahorse XFe 96 analyzer. The activation of fatty acid oxidation (FAO)-related metabolic pathways was detected by Western blotting. Intracellular localization of Lkb1 was detected by immunofluorescence. The Strad-Mo25-Lkb1 complex formation and K63 chain ubiquitination modification of Lkb1 were detected by co-immunoprecipitation. The binding of AhR to the Skp2 promoter was detected by constructing luciferase reporter gene. AhR or carnitine palmitoyltransferases 1 was knockdown in dextran sulphate sodium (DSS)-induced colitis or collagen-induced arthritis (CIA) mice by infecting mice with adeno-associated virus via the tail vein injection. Compared to the control group, exogenous and endogenous AhR agonists 3,3'-diindolylmethane (DIM) and 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) were shown to preferentially upregulate the mRNA expression of FAO-related enzymes and the value of OCR. Consistently, pharmacological or genetic inhibition of FAO markedly diminished the induction of DIM and ITE on the differentiation of Treg cells. DIM and ITE functioned mainly through activating the liver kinase B1 (Lkb1)-AMPK pathway via promotion of Lkb1-Strad-Mo25 complex formation and Lkb1 K63 ubiquitination. DIM and ITE were also shown to upregulate the mRNA expression of Skp2, a ubiquitination-related enzyme, and facilitate the binding of AhR to the xenobiotic responsive element of Skp2 promoter region by luciferase reporter gene assay. Furthermore, the contribution of Skp2/K63 ubiquitination/Lkb1/FAO axis was verified in (DSS)-induced colitis or CIA mice. In summary, these findings indicate that AhR activation promotes Treg cell generation by enhancing Lkb1-mediated FAO via the Skp2/K63-ubiquitination pathway, and AhR agonists may be used as inducers of Treg cells to prevent and treat autoimmune diseases.


An upflow microbial fuel cell with an interior cathode: assessment of the internal resistance by impedance spectroscopy.
An upflow microbial fuel cell (UMFC) system with a U-shaped cathode inside the anode chamber was developed and produced a maximum volumetric power of 29.2 W/m3 at a volumetric loading rate of 3.40 kg COD/(m3 day) and an operating temperature of 35 degrees C while feeding sucrose continuously. The Coulombic efficiency decreased from 51.0% to 10.6% with the increase in the volumetric loading rate from 0.57 to 4.29 kg COD/(m3 day). In addition, the lab-scale UMFC maintained soluble chemical oxygen demand (COD) removal efficiencies exceeding 90% and volatile fatty acid concentrations of approximately 40 mg/L, indicating efficient wastewater treatment. The analysis of impedance spectroscopy, generated by fitting experimental data into an equivalent circuit, revealed that at a volumetric loading rate of 3.40 kg COD/(m3 day) the overall internal resistance was 17.13 omega. This internal resistance was composed of electrolyte resistance (8.62 omega), charge-transfer resistance (7.05 omega), and diffusion resistance (1.46 omega). Electrolyte resistance dominated throughout the entire range of loading rates. In addition, impedance spectroscopy demonstrated that both the anodic and the cathodic charge-transfer resistances were important limiting factors. To further improve the power output of the UMFC, we must reduce the electrolyte resistance by optimizing reactor configuration, reduce the anode charge-transfer resistances by selecting superior anodic microbiota, and reduce the cathodic charge-transfer resistance by exploring sustainable and efficient catalysts.


Detection of fraud in ginger powder using an automatic sorting system based on image processing technique and deep learning.
Ginger is a well-known product in the food and pharmaceutical industries. Ginger is one of the spices which are adulterated for economic gain. The lack of marketability of grade 3 chickpeas (small and broken chickpeas) and their very low price have made them a good choice to be mixed with ginger in powder form and sold in the market. Demand for non-destructive methods of measuring food quality, such as machine vision and the growing need for food and spices, were the main motives to conduct this study. This study classified ginger powder images to detect fraud by improving convolutional neural networks (CNN) through a gated pooling function. The main approach to improving CNN is to use a pooling function that combines average pooling and max pooling. The Batch normalization (BN) technique is used in CNN to improve classification results. We show empirically that the combining operation used increases the accuracy of ginger powder classification compared to the baseline pooling method. For this purpose, 3360 image samples of ginger powder were prepared in 7 categories (pure ginger powder, chickpea powder, 10%, 20%, 30%, 40%, and 50% fraud in ginger powder). Moreover, MLP, Fuzzy, SVM, GBT, and EDT algorithms were used to compare the proposed CNN results with other classifiers. The results showed that using batch normalization based on gated pooling, the proposed CNN was able to grade the images of ginger powder with 99.70% accuracy compared to other classifiers. Therefore, it can be said that the CNN method and image processing technique effectively increase marketability, prevent ginger powder fraud, and promote traditional methods of ginger powder fraud detection.


A new mutation in the hMSH2 gene in a Spanish Lynch syndrome family.
We report a new germline mutation in exon 13 of the hMSH2 gene (c.2081T>C; F694S) in a patient diagnosed with colorectal carcinoma. The patient's family fulfilled the clinical criteria of the Bethesda guidelines for Lynch syndrome. The segregation analysis determined the presence of the mutation in the proband's mother (breast cancer younger than 40 years old) and in two healthy daughters. The mutation was not present in 116 normal controls screened. The medical implications for the carrier relatives are discussed.


Accelerated fractionation of heavy metals in contaminated soils and sediments using rotating coiled columns.
A new approach to performing an accelerated sequential extraction of trace elements from solid samples has been proposed. It has been shown that rotating coiled columns (RCC) earlier used in counter-current chromatography can be successfully applied to the dynamic leaching of heavy metals from soils and sediments. A solid sample was retained in the rotating column as the stationary phase under the action of centrifugal forces while different eluents (aqueous solutions of complexing reagents, mineral salts and acids) were continuously pumped through. The procedure developed is time saving and requires only 4-5 h instead of the several days needed for traditional sequential extraction (TSE), complete automation being possible. Losses of solid sample are minimal. In most cases the recoveries of readily bioavailable and leachable forms of Pb, Zn, and Cd are higher, if a dynamic extraction in RCC is used. Since naturally occurring processes are always dynamic, continuous extraction in RCC may help to estimate the contents of leachable forms and their potential risk for the environment more correctly than batch TSE. The Kersten-Foerstner and McLaren-Crawford leaching schemes have been compared, the former has been found to be preferable.


Pharmacological interventions for clozapine-induced sinus tachycardia.
Clozapine is an efficacious treatment for treatment-resistant schizophrenia; however its use can be limited by side effect intolerability. Sinus tachycardia is a common adverse event associated with clozapine treatment. Various pharmacological treatments are used to control heart rate increase due to clozapine use and can include a decreased rate of clozapine titration, a switch to a different antipsychotic, or treatment with negative chronotropic drugs. To assess the clinical effects and efficacy of pharmacological interventions for clozapine-induced sinus tachycardia.To systematically review the adverse events associated with pharmacological interventions for clozapine-induced sinus tachycardia. On 23 March 2015, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials, which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO and registries of clinical trials. There are no language, date, document type or publication status limitations for inclusion of records in the register. Randomised controlled trials comparing pharmacological interventions, at any dose and by any route of administration, for clozapine-induced tachycardia. We independently screened and assessed studies for inclusion using pre-specified inclusion criteria. The electronic searches located three references. However, we did not identify any studies that met our inclusion criteria. With no studies meeting the inclusion criteria, it is not possible to arrive at definitive conclusions. There are currently insufficient data to confidently inform clinical practice. We cannot, therefore, conclude whether specific interventions, such as beta-blockers, are less effective or more effective than standard courses of alternative treatments for tachycardia. This lack of evidence for the treatment of clozapine-induced tachycardia has implications for research and practice. Well-planned, conducted and reported randomised trials are indicated. One trial is currently underway. Current practice outside of well-designed randomised trials should be clearly justified.


Characteristics of visual fatigue under the effect of 3D animation.
Visual fatigue is commonly encountered in modern life. Clinical visual fatigue characteristics caused by 2-D and 3-D animations may be different, but have not been characterized in detail. This study tried to distinguish the differential effects on visual fatigue caused by 2-D and 3-D animations. A total of 23 volunteers were subjected to accommodation and vergence assessments, followed by a 40-min video game program designed to aggravate their asthenopic symptoms. The volunteers were then assessed for accommodation and vergence parameters again and directed to watch a 5-min 3-D video program, and then assessed again for the parameters. The results support that the 3-D animations caused similar characteristics in vision fatigue parameters in some specific aspects as compared to that caused by 2-D animations. Furthermore, 3-D animations may lead to more exhaustion in both ciliary and extra-ocular muscles, and such differential effects were more evident in the high demand of near vision work. The current results indicated that an arbitrary set of indexes may be promoted in the design of 3-D display or equipments.


Cellular Uptake of Gold Nanoparticles Triggered by Host-Guest Interactions.
We describe an approach to regulate the cellular uptake of small gold nanoparticles using supramolecular chemistry. The strategy relies on the functionalization of AuNPs with negatively charged pyranines, which largely hamper their penetration in cells. Cellular uptake can be activated in situ through the addition of cationic covalent cages that specifically recognize the fluorescent pyranine dyes and counterbalance the negative charges. The high selectivity and reversibility of the host-guest recognition activates cellular uptake, even in protein-rich biological media, as well as its regulation by rational addition of either cage or pyranine.


MicroRNA variants increase the risk of HPV-associated squamous cell carcinoma of the oropharynx in never smokers.
Both microRNAs and human papillomavirus (HPV) infection play an important role in the development and progression of oral squamous cell carcinoma (OSCC). In addition, microRNAs affect all facets of the immune/inflammation responses to infection, which may control HPV clearance. We thus hypothesized that microRNA polymorphisms modify the association between HPV16 seropositivity and OSCC risk. Four single-nucleotide polymorphisms in microRNAs were genotyped and HPV16 serology was determined in 325 cases and 335 matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using univariate and multivariable logistic regression models. Overall, each polymorphism had no significant main effect on OSCC risk. Compared with the risk among individuals with both miR146 rs2910164 GG genotype and HPV16 seronegativity, risk of OSCC was increased among those with CG or CC genotype and HPV16 seronegativity (OR, 1.2; 95% CI, 0.9-1.8), GG genotype and HPV16 seropositivity (OR, 3.0; 95% CI, 1.8-5.0), and CG or CC genotype and HPV16 seropositivity (OR, 4.7; 95% CI, 2.3-9.4). Similar results were found for miR149 rs2292832, miR196 rs11614913, and miR499 rs3746444. Analyses stratified by tumor sites and smoking status showed that each polymorphism significantly increased the risk of HPV16-associated squamous cell carcinoma of the oropharynx (SCCOP), and such effect modification was particularly prominent in never smokers. Our results indicate that microRNA polymorphisms modify the risk of OSCC associated with HPV16 seropositivity, particularly in patients with SCCOP and never smokers. Larger studies are needed to verify our findings.


Surfing parameter hyperspaces under climate change scenarios to design future rice ideotypes.
Growing food crops to meet global demand and the search for more sustainable cropping systems are increasing the need for new cultivars in key production areas. This study presents the identification of rice traits putatively producing the largest yield benefits in five areas that markedly differ in terms of environmental conditions in the Philippines, India, China, Japan and Italy. The ecophysiological model WARM and sensitivity analysis techniques were used to evaluate phenotypic traits involved with light interception, photosynthetic efficiency, tolerance to abiotic stressors, resistance to fungal pathogens and grain quality. The analysis involved only model parameters that have a close relationship with phenotypic traits breeders are working on, to increase the in vivo feasibility of selected ideotypes. Current climate and future projections were considered, in the light of the resources required by breeding programs and of the role of weather variables in the identification of promising traits. Results suggest that breeding for traits involved with disease resistance, and tolerance to cold- and heat-induced spikelet sterility could provide benefits similar to those obtained from the improvement of traits involved with canopy structure and photosynthetic efficiency. In contrast, potential benefits deriving from improved grain quality traits are restricted by weather variability and markedly affected by G × E interactions. For this reason, district-specific ideotypes were identified using a new index accounting for both their productivity and feasibility.


[Persons living with HIV/AIDS: factors associated with adherence to antiretroviral treatment].
This study aimed to describe the adherence of persons living with HIV/AIDS to antiretroviral therapy (ART) and to investigate adherence predictors among the following: level of schooling, presence of side effects, current or previous interruption of ART by the persons themselves, self-esteem, self-efficacy expectation, coping strategies, social support, and satisfaction with the health professional-patient relationship. Adherence was measured by self-reported number of ART pills/capsules missed during the previous week and previous month, evaluated as satisfactory when less than 5%. 101 HIV+ adults took part in this study, 60.4% males, ranging from 20 to 71 years of age (mean = 37.9 years), and 73.3% symptomatic. Data procedures included interviews and the use of validated instruments. The majority of participants (n = 73; 72.3%) reported adherence of > 95%. Logistic regression showed that a history of self-reported ART interruption and self-efficacy expectations were significant adherence predictors. Upgrading of care with interdisciplinary teams is needed to develop an appropriate approach to the medical and psychosocial difficulties of ART adherence by persons with HIV/AIDS.


Increased Prevalence of Autoimmune Rheumatologic Diseases in Patients With Primary Hyperparathyroidism.
Background Parathyroid hormone (PTH) and Dickkopf-related protein 1 (DKK-1) have been mentioned together at the intersection of autoimmune rheumatologic diseases (ARDs) and osteoimmunology. However, few studies have evaluated the association between primary hyperparathyroidism (PHPT) and ARDs. Methodology This retrospective study included 225 PHPT patients and 386 patients with thyroid nodules as a control group. The electronic hospital records of all patients were screened going back nine years for the presence of ARDs. Patients who were diagnosed at least three months ago, had complete serologic tests, and were continuing with rheumatologic follow-up were included. Results The prevalence of ARDs in the PHPT group was 9.77% (22/225), while the prevalence of ARDs in the CG was 1.04% (4/386, p < 0.001). The prevalence of rheumatoid arthritis in the PHPT group was 4.4% (10/225), ankylosing spondylitis 3.1% (7/225), systemic lupus erythematosus 0.88% (2/225), Behçet's disease 0.88% (2/225), and mixed connective tissue disease 0.44% (1/225). Of the 22 patients with ARDs, 21 (95.45%) were diagnosed before they were diagnosed with PHPT, and the median time from diagnosis with ARD to the onset of PHPT was 36 months (interquartile range = 61.5). Logistic regression analysis showed a positive correlation between the duration of PHPT and ARDs (odds ratio (OR) = 1.06; 95% confidence interval (CI) = 1.02-1.09, p < 0.001) and a negative correlation between ARDs and calcium levels (OR = 0.26; 95% CI = 0.09-0.79, p = 0.018). Conclusions The prevalence of ARDs increased in PHPT patients and PHPT accompanying ARDs developed after rheumatologic disease. ARDs with PHPT are cases with a prolonged duration of PHPT and mildly elevated calcium, probably preceded by parathyroid hyperplasia. Therefore, the factors that cause ARDs may trigger a process that leads to mild PHPT.


Patient satisfaction of emergency nursing care in the United States, Slovenia, and Australia.
Patient satisfaction with nursing care in the emergency department (ED) was measured in 616 patients in California and Kentucky in the United States, Slovenia, and rural and urban Victoria in Australia. Patients were almost equally divided between men and women, primarily white, with a mean age of 44. They responded to the caring and teaching subscales of the Consumer Emergency Care Satisfaction Scale (CECSS). While scores indicated no differences in caring, the US and Slovenian groups reported greater satisfaction with teaching than did the Australian group. The subscale alpha coefficients were .87 for the caring subscale and .92 for the teaching subscale.


Anterior single implants with different neck designs: 5 Year results of a randomized clinical trial.
The design of the implant neck might be significant for preservation of marginal bone. To compare the 5-year radiographic and clinical outcome of single anterior implants provided with a smooth neck, a rough neck or a scalloped rough neck. 93 Patients with a missing anterior tooth in the maxilla were included. At random, patients received an implant with a 1.5 mm smooth neck ("smooth group"), a rough neck with grooves ("rough group") or a scalloped rough neck with grooves ("scalloped group"). Implants were installed in healed sites. Follow-up visits were conducted after final crown delivery and 1 year and 5 years later. Scalloped implants showed significantly more initial marginal bone resorption. The total amount of bone loss was 1.26 ± 0.90 mm in the smooth group, 1.20 ± 1.1 mm in the rough group and 2.28 ± 0.97 mm in the scalloped group (P < .05). Survival rates were 96.2% for the smooth and scalloped group and 100% for the rough group. Scalloped implants showed deeper pocket depths, more bleeding and more technical complications. There were no differences in esthetic outcome nor in patient satisfaction. For anterior single tooth replacements, scalloped implants show less favorable radiographic and clinical outcome compared to regular implants with a smooth neck or rough neck.


Immunoradiometric assay of succinylated corticotropin: an improved method for quantification of ACTH.
In this paper we describe the development and the evaluation of a new type of immunoassay for human corticotropin (ACTH). We succeeded, by using an original approach based upon immunization with ACTH derivatized with succinic anhydride, in raising monoclonal antibodies against this poorly immunogenic peptide. Three of the antibodies were selected to develop an immunoassay for ACTH. The assay requires the prior succinylation of the plasma samples for optimal sensitivity and specificity. This acylation treatment is fast, reproducible, and, in addition, improves the stability of the ACTH molecule in plasma, thus facilitating sample handling. The assay is performed in only 3 h with a detection limit of 0.7 ng/L. Analytical evaluation showed excellent specificity, reproducibility, and reliability. A comparison with two commonly used but time-consuming ACTH IRMAs was carried out by assaying several plasma samples in parallel and gave in both cases very good correlation.


Genomics in Primary and Secondary Prevention of Pancreatic Cancer.
Pancreatic cancer (PC) is one of the deadliest cancers worldwide for which little clinical progress has been made in the last decades. Furthermore, increased trends of PC mortality rates have been reported in Westernised countries. PC is usually diagnosed in advanced stages, precluding patients of an effective treatment. Identifying high-risk populations and early detection markers is the first and crucial step to impact on these figures and change the PC horizon. To discuss the published body of evidence on host and tumor genomics promising markers for primary and/or secondary personalised PC prevention, as well as the future perspectives in the field. A review of the literature was performed to identify germline and tumor DNA and RNA markers that showed potential usefulness in defining the high-risk population, diagnosing the disease early, and identifying new carcinogens associated with PC. Only high-penetrance inherited mutations are used, at present, to define the high-risk PC population. Although there are some promising genomics markers to be used as early detection tests, none has been validated adequately to be integrated into the clinics routine. Despite of important efforts made in the recent time, little progress has been made to better characterise high-risk PC populations and to identify genomics-based markers for its early diagnosis. PC rates continue to rise, and this disease is becoming a real public health problem in the Westernised world. International and multidisciplinary strategies to identify new markers and properly validate the promising ones are urgently needed to implement cost-efficient primary and secondary prevention interventions in PC.


Calcium ion stimulated endogenous protein kinase catalyzed phosphorylation of basic proteins in myelin subfractions and myelin-like membrane fraction from rat brain.
Polypeptide composition and endogenous phosphorylation were investigated in the subfractions of rat brain myelin isolated by either discontinuous or continuous sucrose density gradient centrifugation of myelin. Similarly, a myelin-like membrane fraction (SN4) was also studied. Observations were made that strongly indicated the presence of a calcium-stimulated protein kinase in a highly purified myelin preparation and which exclusively phosphorylated myelin basic proteins of the membrane preparation. Adenosine cyclic 3',5'-phosphate (cAMP) stimulated kinase on the other hand was found to be considerably enriched in the myelin-like membrane fraction. Although this latter enzyme is also capable of phosphorylating the basic proteins, its effect was at least 5 times weaker compared to the calcium-stimulated myelin protein kinase. Within the gradient subfractions there appeared a close relation between the amount of basic proteins and their calcium-stimulated phosphorylation; a similar relationship, however, was not obtained in the case of cAMP-dependent phosphorylation of myelin basic proteins. The former (i.e., Ca2+-stimulated phosphorylation) was found to require a protein factor that functionally resembled calmodulin. The results thus raises an interesting possibility of the presence of calmodulin-like proteins and a calcium-stimulated protein kinase in adult myelin membrane from mammalian brain, both of which have been hitherto unrecognized constituents of myelin membranes.


Overdose of atypical antipsychotics: clinical presentation, mechanisms of toxicity and management.
Historically, treatment for schizophrenia focused on sedation. The advent of the typical antipsychotics resulted in treatment aimed specifically at the underlying disease, but these agents were associated with numerous adverse effects, and were not particularly effective at treatment of the negative symptoms of schizophrenia. As a result, numerous atypical agents have been developed over the past 2 decades, including several agents within the past 5 years. Overdose of antipsychotics remains quite common in Western society. In 2010, poison control centres in the US received nearly 43,000 calls related to atypical antipsychotics alone. Due to underreporting, the true incidence of overdose with atypical antipsychotics is likely much greater. Following overdose of an atypical antipsychotic, the clinical effects observed, such as CNS depression, tachycardia and orthostasis are largely predictable based on the unique receptor binding profile of the agent. This article, which focuses on the atypical antipsychotics commonly used in the treatment of schizophrenia, discusses the features commonly encountered in overdose. Specifically, agents that result in QT prolongation and the corresponding potential for torsades de pointes, as well as unique features encountered with the various medications are discussed. The diagnosis of this overdose is largely based on history. Routine use of drug screens is unlikely to be beneficial. The primary goal of management is aggressive supportive care. Patients with significant CNS depression with associated loss of airway reflexes and respiratory failure need advanced airway management. Hypotension should be treated first with intravenous fluids, with the use of direct acting vasopressors reserved for persistent hypotension. Benzodiazepines should be used for seizures, with barbiturates used for refractory seizures. Intravenous magnesium can be administered for patients with a corrected QT interval exceeding 500 milliseconds.


In vivo localization and biological effect of anti-yolk sac monoclonal antibodies.
Two monoclonal antibodies directed against rat yolk sac antigen 1 (mab 6D1) and yolk sac antigen 2 (mab 3C3) were injected i.v. into pregnant or tumor-bearing rats. Immunofluorescent examination of the different organs from animals killed, 2, 24, or 48 hours after inoculation showed the specific binding of mab 6D1 to the free surface of visceral endoderm cells in pregnant animals and on visceral cells of yolk sac carcinoma. The mab 3C3 reacted only with the endoderm of parietal yolk sac and with a distinctive parietal pattern of the tumor. The reaction was strong after 2 and 24 hours following injection and much weaker after 48 hours. The 3C3 mab had an embryotoxic effect, whereas the 6D1 mab did not influence the development of the fetus.


Displacement imposition scale assesses reactions of cigarette and e-cigarette users impacted by a campus-wide smoking ban.
The present study developed a measure assessing the emotional responses, "Displacement Imposition," of cigarette and e-cigarette users on a college campus with a smoking/vaping ban. It also examined the relationship between Displacement Imposition and readiness to quit smoking/vaping, and how this relationship differed between cigarette and e-cigarette users. Participants (N = 297) were from a large, Midwestern university. Participants completed online questionnaires assessing demographics, cigarette and e-cigarette use, Displacement Imposition, and readiness to quit. All six Displacement Imposition items loaded onto a single factor. A significant interaction emerged between Displacement Imposition and product use in predicting readiness to quit. At high levels of Displacement Imposition, cigarette users were less ready to quit than e-cigarette users. Findings suggest restrictions imposed on cigarette and e-cigarette users were associated with reduced readiness to quit. Findings inform tobacco control policies as tobacco denormalization may increase the burden placed on tobacco users.


[Lines of research in the treatment of HIV infection].
Antiretroviral treatment have completely modified the face of HIV infection. Research of new therapeutic approaches during infection focus on the use of antiretroviral drugs and on new targets, treatment of immune activation and viral eradication. Recommendations for c-ART initiation are now broader. Future development in the area of antiretroviral therapy concern their use for prevention and the design of long-acting drugs. Extensive research efforts have led to the proposal of strategies that aim to treat immune activation which favor the occurrence of non AIDS defining disease and to eradicate HIV through the use of several different strategies (therapeutic vaccines, anti latency compounds). Results of these new approaches remain preliminary and antiretroviral treatment remain the only weapon to fight HIV infection.


[Congenital trans-mesenteric hernia with incarceration in a five-year-old boy].
This is a case report of a five-year-old boy, presenting with abdominal pain and signs of gastrointestinal emergency imitating appendicitis. Diagnostic laparoscopy revealed an incarcerated internal hernia involving 50 cm of ischaemic small bowel. Bowel resection and primary anastomosis was performed. The post-operative outcome was uneventful. We wish to shed light on a seldom but important differential diagnosis to appendicitis in children, and raise attention to internal hernias in patients presenting with acute abdomen, whether it is due to congenital defects or a post-operative complication.


The clinical profile of cerebral small vessel disease: Toward an evidence-based identification of cognitive markers.
There is no consensus on which test is more suited to outline the cognitive deficits of cerebral small vessel disease (cSVD) patients. We explored the ability of eight cognitive tests, selected in a previous systematic review as the most commonly used in this population, to differentiate among cSVD patients, controls, and other dementing conditions performing a meta-analysis of 86 studies. We found that cSVD patients performed worse than healthy controls in all tests while data on the comparison to neurodegenerative diseases were limited. We outlined a lack of data on these tests' accuracy on the diagnosis. Cognitive tests measuring processing speed were those mostly associated with neuroimaging cSVD markers. There is currently incomplete evidence that a single test could differentiate cSVD patients with cognitive decline from other dementing diseases. We make preliminary proposals on possible strategies to gain information about the clinical definition of cSVD that currently remains a neuroimaging-based one.


Reduced elimination of cyclosporine A in elderly (>65 years) kidney transplant recipients.
Physiologic functions that may affect pharmacokinetics of drugs are altered in elderly patients. The current study was performed to elucidate the effect of age on cyclosporine A (CsA) pharmacokinetics in renal transplant recipients. Twenty-five renal transplant recipients on CsA treatment were included in the study. CsA doses were adjusted by C2 monitoring. The patients were divided into two groups based on age; elderly: more than 65 years (n=11, mean 73 years) and younger: 18 to 64 years (n=14, mean 43 years). A full 12-hr pharmacokinetic profile was performed during stable phase. CsA whole blood and intracellular T-lymphocytes concentrations (first 6 hr) were measured. Genotyping of the CYP3A5*1/*3 and ABCB1 (C1236T, G2677T, C3435T) polymorphisms and quantification of whole blood mRNA ABCB1 expression were performed in all patients. Elderly patients achieved target C2 levels with lower CsA doses than the younger patients (4.3+/-0.8 vs. 6.1+/-2.1 mg/day/kg, P=0.025) because of lower clearance of CsA (22.7+/-5.1 vs. 30.5+/-11.1 L/hr, P=0.031). Elderly patients also showed 44% higher intracellular-to-whole blood CsA ratio than younger patients (P=0.02). Neither the CYP3A5*1, the ABCB1 genotypes nor mRNA ABCB1 expression revealed any significant influence on CsA pharmacokinetics. The clearance of CsA decreased with increasing age. In addition, elderly patients had a significant larger proportion of the whole blood CsA concentration located at the site of action (within T lymphocytes). This indicates that in elderly recipients it might be safe to aim for an even lower whole blood target levels than current guidelines propose.


[Speech perception. The basis for speech audiometry examinations].
Speech recognition measurements are widely used in clinical applications. Usually, either a speech recognition threshold is determined, being defined as the speech level or signal-to-noise ratio that enables the patient to understand 50% of the target words or target sentences. In other cases, a discrimination curve, describing speech recognition as function of the presentation level, is recorded. For the interpretation of these findings, it is important to keep in mind that speech perception is affected by many interacting sensory, perceptual and cognitive processes.Here, our current knowledge of these processes is outlined and theories that model speech perception in general are briefly reviewed.


Parasite-Parasite Interactions in the Wild: How To Detect Them?
Inter-specific interactions between parasites impact on parasite intra-host dynamics, host health, and disease management. Identifying and understanding interaction mechanisms in the wild is crucial for wildlife disease management. It is however complex because several scales are interlaced. Parasite-parasite interactions are likely to occur via mechanisms at the within-host level, but also at upper levels (host population and community). Furthermore, interactions occurring at one level of organization spread to upper levels through cascade effects. Even if cascade effects are important confounding factors, we argue that we can also benefit from them because upper scales often provide a way to survey a wider range of parasites at lower cost. New protocols and theoretical studies (especially across scales) are necessary to take advantage of this opportunity.


Protocols and dollars.
A protocol is part of the process which translates a research question into a feasible project. It must be specific and include all relevant circumstances under which the research will be conducted (for example, the patient's age, sex, time of presentation, pre existing conditions) with an appropriate decision about each. As the examples show, preparation of a protocol (Table 2) can be a painstaking process and, even after acceptance by a funding organisation, it might require modification.


Luminescent lanthanide cryptates: from the bench to the bedside.
The design and application of luminescent lanthanide cryptates for sensing biological interactions is highlighted through the review of the work performed in our laboratory and with academic collaborations. The path from the initial applications probing biochemical interaction in vitro to "state-of-the-art" cellular assays toward clinical applications using homogeneous time-resolved fluorescence technology is described. An overview of the luminescent lanthanide macrocyclic compounds developed at Cisbio in the recent past is given with an emphasis on specific constraints required by specific applications. Recent assays for drug-discovery and diagnostic purposes using both antibody-based and suicide-enzyme-based technology are illustrated. New perspectives in the field of molecular medicine and time-resolved microscopy are discussed.


Clinical perspectives of drugs inhibiting acid secretion--H+K+-ATPase inhibitors.
The H+K+-ATPase is supposed to be the terminal step in the acid-secreting pathway in the parietal cell. Omeprazole blocks this enzyme, resulting in a marked inhibition of basal and stimulated acid secretion. With omeprazole 20 mg daily, 24-hour intragastric acidity is decreased by about 90%. Several clinical studies have now been published in which omeprazole has been compared with the H2-receptor antagonists cimetidine and ranitidine. Omeprazole in doses between 20 and 40 mg daily resulted in healing rates between 65% and 82% after treatment for 2 weeks and between 90% and 100% after treatment for 4 weeks. Treatment with omeprazole also gave faster and more pronounced pain relief. One comparative study in gastric ulcer has also been published showing healing rates equal to those with ranitidine. Placebo-controlled trials have also shown very pronounced therapeutic effect in reflux esophagitis. Omeprazole seems to be the drug of choice in Zollinger-Ellison syndrome, giving beneficial clinical effects and pronounced and long-lasting reduction in gastric acid secretion.


[Impact of ideal cardiovascular health behaviors and factors on resting heart rate in individuals without cardiovascular diseases].
To investigate the impact of ideal cardiovascular health behaviors and factors on resting heart rate (RHR). A cross-sectional study method was used in our study.83 824 workers who had participated in the 2006-2007 Kailuan health examination were included, individuals with arrhythmia, hemoglobin ≤ 90g/L, taking drugs which might affect RHR, history of cerebral infarction or myocardial infarction or cancer were excluded.Related information was obtained from the unified questionnaire, blood biochemistry was performed. Multivariate logistic regression was used to analyze the impact of ideal cardiovascular health behaviors and factors on the RHR. (1) The RHR was (76.4 ± 10.3), (75.2 ± 10.3), (74.3 ± 9.9), (73.6 ± 10.0), (72.6 ± 9.9), (72.1 ± 9.7) and (71.8 ± 9.2) beats/min in workers whose number of ideal cardiovascular health behaviors and factors was 1, 2, 3, 4, 5 and ≥ 6 respectively (P < 0.01). (2) Multivariate logistic regression showed that, after adjusted by gender, age, triglyceride, high density lipoprotein cholesterol, high-sensitive C-reactive protein, tea drinking, alcohol drinking, the risk of RHR ≥ 80 beats/min gradually reduces along with the increasing of number of ideal cardiovascular health behaviors and factors (1, 2, 3, 4, 5 and ≥ 6) compared with those who did not have ideal cardiovascular health behaviors and factors, the value of OR (95%CI) was 0.79 (0.71-0.87), 0.68 (0.62-0.75), 0.61 (0.55-0.67), 0.52 (0.47-0.58), 0.50 (0.44-0.56), 0.49 (0.40-0.60) respectively. Ideal cardiovascular health behavior and factors is related to lower RHR in individuals without cardiovascular diseases.