Language Tasks and the Network Control Role of the Left Inferior Frontal Gyrus.
Recent work has combined cognitive neuroscience and control theory to make predictions about cognitive control functions. Here, we test a link between whole-brain theories of semantics and the role of the left inferior frontal gyrus (LIFG) in controlled language performance using network control theory (NCT), a branch of systems engineering. Specifically, we examined whether two properties of node controllability, boundary and modal controllability, were linked to semantic selection and retrieval on sentence completion and verb generation tasks. We tested whether the controllability of the left IFG moderated language selection and retrieval costs and the effects of continuous θ burst stimulation (cTBS), an inhibitory form of transcranial magnetic stimulation (TMS) on behavior in 41 human subjects (25 active, 16 sham). We predicted that boundary controllability, a measure of the theoretical ability of a node to integrate and segregate brain networks, would be linked to word selection in the contextually-rich sentence completion task. In contrast, we expected that modal controllability, a measure of the theoretical ability of a node to drive the brain into specifically hard-to-reach states, would be linked to retrieval on the low-context verb generation task. Boundary controllability was linked to selection and to the ability of TMS to reduce response latencies on the sentence completion task. In contrast, modal controllability was not linked to performance on the tasks or TMS effects. Overall, our results suggest a link between the network integrating role of the LIFG and selection and the overall semantic demands of sentence completion.


Predicting Risk of Type 2 Diabetes by Using Data on Easy-to-Measure Risk Factors.
Statistical models for assessing risk of type 2 diabetes are usually additive with linear terms that use non-nationally representative data. The objective of this study was to use nationally representative data on diabetes risk factors and spline regression models to determine the ability of models with nonlinear and interaction terms to assess the risk of type 2 diabetes. We used 4 waves of data (2005-2006 to 2011-2012) on adults aged 20 or older from the National Health and Nutrition Examination Survey (n = 5,471) and multivariate adaptive regression splines (MARS) to build risk models in 2015. MARS allowed for interactions among 17 noninvasively measured risk factors for type 2 diabetes. A key risk factor for type 2 diabetes was increasing age, especially for those older than 69, followed by a family history of diabetes, with diminished risk among individuals younger than 45. Above age 69, other risk factors superseded age, including systolic and diastolic blood pressure. The additive MARS model with nonlinear terms had an area under curve (AUC) receiver operating characteristic of 0.847, whereas the 2-way interaction MARS model had an AUC of 0.851, a slight improvement. Both models had an 87% accuracy in classifying diabetes status. Statistical models of type 2 diabetes risk should allow for nonlinear associations; incorporation of interaction terms into the MARS model improved its performance slightly. Robust statistical manipulation of risk factors commonly measured noninvasively in clinical settings might provide useful estimates of type 2 diabetes risk.


Clinical comparison of ibuprofen, fenoprofen calcium, naproxen and tolmetin sodium in rheumatoid arthritis.
After baseline aspirin therapy, 89 rheumatoid arthritis patients completed a double-blind, crossover trial comparing ibuprofen, fenoprofen, naproxen, and tolmetin. Initially, patients took the manufacturer's recommended starting dose; this could be increased by 50% within the first 2 weeks of therapy. Patients remained at the chosen dose for 4 weeks and then changed to the next drug. All 4 drugs were tolerated better than aspirin (p less than 0.001). There were no statistically significant differences among the 4 drugs for any efficacy measurements. However, patients' and physicians' rankings showed the same order of preferences: naproxen, ibuprofen, fenoprofen, tolmetin, and aspirin.


Gaps in Understanding the Experiences of Homecare Workers Providing Care for People with Dementia up to the End of Life: A Systematic Review.
This systematic review of the literature explores the perspectives and experiences of homecare workers providing care for people with dementia living at home up to the end of life. A search of major English language databases in 2016 identified 378 studies on the topic, of which 12 met the inclusion criteria. No empirical research was identified that specifically addressed the research question. However, synthesis of the findings from the broader literature revealed three overarching themes: value of job role, emotional labour and poor information and communication. The role of homecare workers supporting a person with dementia up to the end of life remains under-researched, with unmet needs for informational, technical and emotional support reported. The effective components of training and support are yet to be identified.


Evaluation of recommendations for replication-competent retrovirus testing associated with use of retroviral vectors.
With input from the gene therapy community, CBER is actively examining the recommendations for RCR testing during retroviral vector production, production of ex vivo-transduced cells, and in patients who receive such material. Our initial recommendations were made at a time when our experience with RCR detection assays and clinical use of retroviral vectors was limited. As the gene therapy field has matured, there is an increasing amount of data available on RCR detection assays and from monitoring of patients in clinical trials. The cumulative data give assurance that RCR detection assays in use are of sufficient sensitivity to provide a margin of safety to patients: no patients to date have evidence of RCR infection. However, CBER encourages members of the gene therapy community to continue to submit data to the FDA or to publish data that will enhance the cumulative data base on RCR testing assays, experience with different VPC, and patient monitoring. Based on the analysis of data accumulated to data, and ongoing discussions with members of the gene therapy community, CBER is proposing to discuss changes to the current RCR testing recommendations, as summarized below. RCR testing during production of retroviral vector and ex vivo-transduced cells. Development of characterized standards for RCR testing of supernatant and cells should allow comparison of assay sensitivity. One proposal under consideration is to apply statistical methods to determine how much material needs to be tested independent of the size of the production lot. Data and discussion are still needed to define a limit concentration and a value for probability of detection for RCR testing, while maintaining an appropriate margin of safety. These modifications of RCR testing strategies could lead to improvements in assay sensitivity. Additional discussion and data are also needed to evaluate the current recommendations of the testing for ex vivo-transduced cells: should both cells and supernatant be tested in all cases? RCR testing during patient follow-up. The time points required for RCR testing during patient follow-up need examination. One proposal under consideration is to sample and assay at three time points during the first year of treatment (e.g., 4-6 weeks, 3 months, and 1 year post-treatment). Further discussion is needed to define appropriate additional follow-up. Choice of assays to detect surrogate markers for RCR infection (i.e., serologic or PCR-based assays) should consider mode of vector administration and the patient population. Positive results with such assays should be pursued by direct culture assay to obtain and characterize the infectious viral isolate. These proposals will be the focal point for the discussion at the Retroviral Vector Breakout Session at the 1997 FDA/NIH Gene Therapy Conference. After the 1997 FDA/NIH Gene Therapy Conference, CBR plans to propose revised recommendations for RCR testing for public comment.


Preferred curricular activities and reduced problem behaviors in students with intellectual disabilities.
This research examined the relation between students' preferences for curricular activities and the occurrence of problem and desirable behaviors in 3 students with moderate intellectual disabilities. Activity preference was determined with a systematic assessment procedure. Subsequently, the influence of activity preference on student behavior was evaluated using a reversal design. Results showed that preferred activities were associated with reduced levels of problem behavior and increased levels of desirable behaviors. The findings of this investigation contribute to the applied literature on activity preference and suggest directions for future research in the areas of curriculum design, preference, and curricular modifications as a viable behavior-management strategy.


An Amino-Coordinated Metal-Organic Framework for Selective Gas Adsorption.
A novel 3D porous metal organic framework, JUC-141, constructed by 5-aminoisophthalic acid and Cu(NO3)2, has been synthesized successfully. The carboxyl groups in the ligand coordinate to Cu2+ to form the classic Cu2(COO)4 paddle wheel SBU, and the assembly of the SBUs with the isophthalic acid moieties leads to a kagome lattice. Interestingly, the amino groups in the ligand also take part in the coordination and link to the dipole of the paddle wheel as pillars, thus forming a 3D porous framework with eea topology. The sizes of the channels are 5.2 Å in the direction of [111] and 10.9 Å in the direction of [001]. Gas sorption tests show that the CO2 adsorption capacities of JUC-141 are 79.94 and 51.39 cm3 g-1 at 273 and 298 K under 1 atm pressure, respectively. However, the N2 adsorption capacities of JUC-141 are 13.90 and 6.76 cm3 g-1 at 273 and 298 K under 1 atm pressure, respectively. IAST calculations indicate that the selectivity values of CO2/N2 are 21.62 at 273 K and 27.60 at 298 K under 101 kPa, respectively. Good selective adsorption of CO2 over N2 makes JUC-141 possible for CO2 storage and separation.


Antidepressants in chronic neuropathic pain.
This review presents available clinical studies and new insights into mechanisms of analgesic effect and possible new routes of administration of antidepressant drugs. Older TCAs continue to be superior treatments. We focused on recent findings on newer antidepressants as analgesics. Their use should be supported by further controlled trials.


Characterization of the mitochondrial localization of the nuclear receptor SHP and regulation of its subcellular distribution by interaction with Bcl2 and HNF4α.
The nuclear receptor small heterodimer partner SHP was shown recently to translocate to the mitochondria, interact with Bcl2, and induce apoptosis in liver cancer cells. However, the exact mitochondrial localization of SHP remains to be determined. In addition, the detailed interaction domains between SHP and Bcl2 have not been characterized. Using biochemistry and molecular biology approaches, we demonstrate that SHP is localized to the mitochondrial outer membrane. Interestingly, compared with the full-length SHP, the N-terminal deleted protein exhibits increased expression in the mitochondria and decreased expression in the nucleus. GST pull-down assays demonstrate that the interaction domain of SHP shows the strongest interaction with Bcl2. Furthermore, the interaction of Bcl2 with SHP is completely abolished by deletion of the Bcl2 transmembrane domain (TM), whereas deletion of the Bcl2 BH1 domain enhances the interaction. As expected, AHPN, a synthetic SHP ligand, markedly augments the direct protein-protein interaction between Bcl2 and SHP. Ectopic expression of hepatocyte nuclear factor 4 alpha (HNF4α) results in exclusive nuclear translocation of SHP proteins that contain either the full-length or the N-terminal domain, but has a minimal effect on the subcellular distribution of SHP protein containing only the interaction domain or repression domain. These results indicate that the N-terminal domain of SHP is important for its nuclear translocation via HNF4α. Overall, this study provides novel insights into the domains of SHP that are critical for its shutting between different subcellular compartments.


Identification of crucial genes of pediatric inflammatory bowel disease in remission by protein-protein interaction network and module analyses.
Although the main treatments of inflammatory bowel disease (IBD) aim at the induction and maintenance of clinical remission, several studies have demonstrated inflammation still present in clinical remission. The goal of this study was to analyze the gene expression profiles between the pediatric IBD and control samples, aiming to further investigate the underlying therapeutic target in remission. Gene expression profiles data of GSE33943 were downloaded from Gene Expression Omnibus, which included 45 pediatric IBD samples and 13 control samples. The differentially expressed genes (DEGs) between IBD and control samples were identified by LIMMA package in R and the function of DEGs were predicted by Gene Ontology and KEGG pathway enrichment analyses using GeneAnswer package. Furthermore, a protein-protein interaction (PPI) network was constructed through the STRING database and functional module was obtained using ClusterONE. A total of 224 DEGs were screened between IBD and control samples. These DEGs (e.g. up-regulated FAS and down-regulated CCL5) were mainly enriched in cytokine‒cytokine receptor interaction and chemokine signaling pathway. In addition, some hub genes (e.g. up-regulated PSMA2 and PSMA6) were obtained through PPI network and functional module. These two genes were involved in Proteasome alpha-subunit and conserved site by functional module analysis. The immune and Proteasome mechanisms are still active during remission and FAS, PMSF6 and PMSF2 may be underlying targets for therapy of this disease.


Epidemiology and genetics of ankylosing spondylitis.
The spondyloarthropathies represent a group of disorders characterized by the presence of inflammatory peripheral and axial arthritis with sacroiliac involvement and a tendency to familial aggregation; prototype clinical syndromes are ankylosing spondylitis (AS) and Reiter's syndrome. The descriptive epidemiology of AS, including course and prognosis in patients cohorts, is reviewed. Particular attention is focused on the genetic epidemiology of AS, especially the evidence supporting causal association of disease with the class I histocompatibility antigen HLA-B27. In addition, analytical studies that support associations of infectious agents are reviewed. The spondyloarthropathies, especially AS and Reiter's syndrome, clearly illustrate the epidemiologic concept of host-environment interaction in the development and expression of disease.


[Sexual medicine in Lausanne : past, present and future].
Sexuality is a natural function, part of global health and has to be evaluated in every patient. When difficulties or dyfunctions happen in this domain, a specific mangement should be proposed. Sexual medicine is a « young » transversal discipline developping these last years in the french-speaking area of Switzerland. We present in this article a short history of sexual medicine in Lausanne and the recent activity in the Sexual Medicine Consultation of the Maternity in the CHUV.


[Change in the ratio of blood saturated to unsaturated fatty acids is a universal marker of lipid metabolic disorder in patients with cholelithiasis].
To study the spectrum of serum fatty acids (SSFA) and the composition of blood lipids in cholelithiasis (CL) in various ethnic groups of East Siberia. A clinical and epidemiological study was conducted, during which ultrasonography and oral cholecystography were used to examine 991 Khakases and 934 Europoids in Khakassia and 652 Evenks and 996 Europoids in Evenkia. Biochemical tests were performed to determine serum lipids in 20% of the random sample. Gas liquid chromatography was applied to investigate ASSFA in 220 patients in Khakassia and 157 people in Evenkia. The manifestations of hyperlipidemia were detected in the Europoids with CL in Evenkia and Khakassia. These changes were less pronounced in the Evenks with CL and absent in the Khakases with CL. In all populations, the blood levels of saturated FAs and ratios of saturated to unsaturated FAs were considerably higher in the patients with CL than in the healthy individuals. The higher levels of saturated FAs and the lower proportion of serum unsaturated FAs are a universal marker of lipid metabolic disturbances in patients with CL in genetically different populations.


Analysis of the Reasons for Medical Malpractice Litigation Due to Facet Injections.
Introduction As the use of facet joint injections (FJI) increases, practitioners performing FJI may be at increased risk of legal liability. Malpractice claim analysis is performed by several specialties as it provides valuable insight into patient values and methods to mitigate the risk of malpractice litigation pertaining to a specific procedure or treatment. Malpractice analysis regarding FJI may provide clinicians with a better understanding of the reasons that lead to malpractice due to FJI, thereby allowing practitioners to improve the quality of care delivered to patients whilst mitigating the incidence of malpractice. The aim of our study was to analyze the reasons for malpractice litigation due to FJI by querying Westlaw and VerdictSearch, two well-established legal databases widely used in medicolegal research. Methods We queried the Westlaw Edge and VerdictSearch legal databases utilizing the terms "facet injection" and "spine". Our database queries yielded 1026 results on Westlaw Edge and 545 results on VerdictSearch. Cases were reviewed and categorized by two independent reviewers based on the grievance(s) levied by the plaintiff. Discrepancies between reviewers were resolved by a third reviewer. Inclusion criteria for case relevance were defined as a basis of litigation resting on malpractice claims filed between the years 2000-2022 directly pertaining to FJI. Additional data collected included the date of the case hearing, verdict ruling, location of filed claim, payment or settlement amount, and sustained injuries. Results Of all 1571 cases reviewed, 1568 cases were excluded due to a basis of litigation unrelated to FJI. Of the three cases pertaining to FJI, the first case involved an alleged procedural error on the part of the anesthesiologist, whereby the anesthesiologist misplaced the needle during FJI, resulting in quadriplegia due to a cervical spine infarction. The plaintiff also contended that the pre-procedural timeout was improperly conducted as the practitioner utilized iohexol as the injected contrast material despite the patient's well-documented allergy to iohexol. The jury deemed both the practitioner and hospital negligent, and a plaintiff verdict was issued. The second case was filed under a basis of litigation alleging delayed diagnosis and treatment on the part of an emergency medicine physician. The court acquitted the physician, and a defense verdict was issued. The third case was filed under a basis of litigation of alleged deviation from the standard of care on the part of the anesthesiologist, whereby the anesthesiologist performing the FJI did not use fluoroscopy. The court affirmed fluoroscopy is not dictated as the standard of care for FJI and issued a defendant verdict. Conclusion This study provides insight into the risk of medical malpractice suits brought on by facet joint injection. Our findings suggest that despite the high prevalence of facet joint injections performed annually, there is limited legal liability associated with the procedure. Nevertheless, there are certain reasons a malpractice claim may be filed due to facet injection, including gross procedural error resulting in patient paralysis, delay in treatment or diagnosis, and deviation from the established standard of care. As such, treatment decisions regarding facet joint injection should not be influenced by medicolegal concerns and remain predicated on patient care needs and standard of care.


Inhibition of GPR91 Reduces Inflammatory Mediators Involved in Active Labor in Myometrium.
GPR91 mRNA expression was significantly higher in myometrium from women during term spontaneous labor compared to no labor. Likewise, in mice, GPR91 mRNA expression was significantly upregulated in myometrium during inflammation-induced preterm labor compared to preterm no labor. In myometrial cells, IL1B and TNF significantly increased GPR91 mRNA expression. Knockdown of GPR91 by siRNA in myometrial cells significantly suppressed the secretion and/or expression of IL1B- and TNF-induced proinflammatory cytokines (GM-CSF, IL1A, IL1B, and IL6) and chemokines (CXCL8 and CCL2), myometrial contractility (expression of the contraction-associated proteins PTGFR and CX43, secretion of the uterotonic PGF2α , and in situ collagen gel contraction), and the transcription factor NF-κB. Our findings demonstrate that GPR91 is involved in the genesis of proinflammatory and prolabor mediators induced by IL1B or TNF and collectively suggest that GPR91 may contribute to augmentation of the labor processes.


Outcome of operable oral cavity cancer and impact of maintenance metronomic chemotherapy: A retrospective study from rural India.
Oral cavity cancer is the most common cancer among rural India. There is a paucity of data for outcomes of operable oral cavity cancer from rural India. Use of maintenance metronomic may delay or avoid relapse. To evaluate outcomes of operable oral cavity carcinoma and evaluate impact of maintenance metronomic chemotherapy. To evaluate disease-free survival (DFS), overall survival (OS), and factors affecting the outcome in operable oral cavity cancer. Data of patients diagnosed with oral cavity cancer registered between May 2008 and May 2014 were retrieved. Only those patients with operable oral cavity cancer and upfront definitive surgery were included in the study. Demographic profile, stage, tobacco consumption, adjuvant therapy, and pattern of failure were collected. Kaplan-Meir survival analysis was used to determine DFS and OS. Log-rank test was used to evaluate factors affecting outcome. Median follow-up is 24 months. Out of 335 patients, 225 (67%) had advanced operable cancer with 42/225 (18%) and 183/225 (82%) as Stages III and IVA, respectively. Buccal mucosa was the most common subsite (178/335, 53%) followed by tongue (63/335, 19%). Ninety-two percent patients were addicted to smokeless tobacco, whereas 27% were smokers. Median DFS is 13 months with 2 years relative DFS 32%. Median OS is 30 months, with 2 years OS of 54%. Metronomic adjuvant oral chemotherapy was given in 130/225 (58%); Stage III and IVA patients with median of 14 months (3-18 months). Use of metronomic chemotherapy improved DFS (8 vs. 14 months, P = 0.22) and OS (14 vs. 26 months, P = 0.04). Oral cavity cancer is a major health care problem in rural India. Presentation at advanced stage leads to suboptimal outcomes. Benefit of metronomic maintenance chemotherapy in locally advanced oral cavity needs to be further evaluated prospectively.


Case Report: Primary Duodenal Melanoma with Brain Metastasis.
Malignant duodenal tumors can be primary or secondary. Although the most common primary tumor involving the duodenum is an adenocarcinoma, primary malignant melanomas arising in the small intestine are exceedingly rare and remain a controversial clinical entity. In this report, we present a unique case of primary duodenal melanoma with brain metastasis managed successfully by surgical excision, stereotactic radiation, and adjuvant immunotherapy.


Panitumumab-Conjugated and Platinum-Cored pH-Sensitive Apoferritin Nanocages for Colorectal Cancer-Targeted Therapy.
Apoferritin (AF) is a natural nontoxic iron carrier and has a natural hollow structure that can be used to deliver small molecules. The surface of AF has many amine functional groups that can be modified to create targeted ligands. We loaded oxaliplatin onto AF, which was then used as a template to conjugate with panitumumab via a polyethylene glycol linker. The oxaliplatin-loaded AF conjugated with panitumumab (AFPO) was designed to specifically target cell lines expressing epidermal growth factor receptor (EGFR). AFPO efficiently released oxaliplatin and suppressed tumor cell growth. Furthermore, the novel AFPO nanocages showed significant inhibition and greater accumulation in tumor models with high EGFR expression in vivo. Our study revealed that combining panitumumab and oxaliplatin into one formulation (AFPO nanocage) could be a promising shortcut in clinical applications.


Docetaxel as neoadjuvant chemotherapy in patients with advanced cervical carcinoma.
The purpose of this study was to evaluate the efficacy and toxicity of docetaxel as single-agent neoadjuvant chemotherapy in locoregionally advanced cervical carcinoma. Between April 1998 and August 2000, 38 untreated patients with International Federation of Gynecology and Obstetrics stages IIB to IVA were entered onto this study. The median age was 44 years (range: 25-66 years). Stages: IIB 22 patients, IIIB 15 patients, and IVA 1 pt. Treatment consisted of docetaxel 100 mg/m2 IV infusion during 1 hour. Standard premedication with dexamethasone, diphenhydramine, and ranitidine was used. Cycles were repeated every 3 weeks for three courses, followed by radical surgery when it was judged appropriate, or definitive radiotherapy. Both staging and response assessment were performed by a multidisciplinary team. 106 cycles of therapy were administered; all patients were evaluable for TX, whereas 35 were evaluable for response (3 patients refused further treatment after the first cycle of therapy). Complete response (CR): 1 patient (3%); partial response: 11 patients (31%), for an overall objective response rate of 34% (95% CI: 15-53%); no change (NC): 16 patients (46%); and progressive disease: 7 patients (20%). Six patients (17%) underwent surgery and a pathologic CR was confirmed in 1 of them. The median time to treatment failure and the median survival have not been reached yet. The limiting toxicity was leukopenia in 25 patients (69%) (G1-G2: 14 patients, G3: 10 patients, and G4: 1 patient). Neutropenia: 28 patients (78%) (G1-G2: 10 patients, G3: 8 and G4: 10). Myalgias: 17 patients (47%) (G1-G2: 15 patients and G3: 2 patients). Emesis: 21 patients (55%) (G1-G2: 19 patients and G3: 2 patients). Alopecia G3: 13 patients (36%); rash cutaneous 26 patients (68%) (G1-G2: 22 patients and G3: 4 patients). There were no hypersensitivity reactions or fluid-retention syndrome. The received dose intensity was 91% of that projected. Docetaxel is an active drug against advanced cervical carcinoma with moderate toxicity. Further evaluation in association with other agents is clearly justified.


Triplet-triplet annihilation upconversion followed by FRET for the red light activation of a photodissociative ruthenium complex in liposomes.
Upconversion is a promising way to trigger high-energy photochemistry with low-energy photons. However, combining upconversion schemes with non-radiative energy transfer is challenging because bringing several photochemically active components in close proximity results in complex multi-component systems where quenching processes may deactivate the whole assembly. In this work, PEGylated liposomes were prepared that contained three photoactive components: a porphyrin dye absorbing red light, a perylene moiety emitting in the blue, and a light-activatable ruthenium prodrug sensitive to blue light. Time-dependent spectroscopic studies demonstrate that singlet perylene excited states are non-radiatively transferred to the nearby ruthenium complex by Förster resonance energy transfer (FRET). Under red-light irradiation of the three-component membranes, triplet-triplet annihilation upconversion (TTA-UC) occurs followed by FRET, which results in a more efficient activation of the ruthenium prodrug compared to a physical mixture of two-component upconverting liposomes and liposomes containing only the ruthenium complex. This work represents a rare example where TTA-UC and Förster resonance energy transfer are combined to achieve prodrug activation in the phototherapeutic window.


Genetic variation and phylogeography of free-living mouse species (genus Mus) in the Balkans and the Middle East.
This work presents a study of the distribution and pattern of variation throughout the ranges of three free-living mouse species of the genus Mus-M. macedonicus, M. spicilegus, and a M. cypriacus - based on sequencing of two segments of the mitochondrial DNA (mtDNA) control region. The study shows a similar level of variability in the three species and suggests their recent population expansion. The highest proportion of variation is found within populations indicating low genetic structuring. Phylogenetic analysis confirms the significant divergence of a mitochondrial lineage of M. macedonicus from Israel, recently described as a new subspecies, M. macedonicus spretoides. Conversely, no genetic hiatus is revealed between European and Asian populations of M. macedonicus macedonicus. Although phylogenetic relationships among M. spicilegus populations could not be unravelled precisely, the results suggest a recent westward expansion of the species. The mtDNA divergence between M. macedonicus and M. spicilegus is 7.3%, suggesting their split between c. 700,000 and 1 million years ago. These dates correspond with a coalescent estimate about 720,000 years ago. On the other hand, M. cypriacus appeared almost twice as divergent from the former species (4.5%) as from the latter (8.8%) suggesting a divergence of c. 430,000-610,000 years ago (coalescent approximately 490,000 years ago) and 830,000-1.2 million years ago (coalescent approximately 780,000 years ago), respectively. Approximate times of population expansion have also been estimated for all taxa and groups of populations. Existence of several glacial refuges and various colonization scenarios are discussed; since all estimated divergence times fall within interglacial periods it seems that climatic oscillations did not play a crucial role in the evolution of the three species.


One-Pot Two-Step Synthesis of 2-Aryl benzimidazole N-oxides Using Microwave Heating as a Tool.
A methodology is reported for the preparation of 2-aryl-benzimidazole-3-oxide derivatives. By means of a one-pot two-step protocol, a library of 42 new compounds has been prepared. Reactions were performed in a total time of 40 min using microwave heating as a tool. A streamlined work-up process was also developed, allowing for facile isolation of the products. The methodology offers a more sustainable approach than previous routes, with only water and ethanol being used as solvents, and the products being isolated by means of a simple filtration without the need for any further purification.


Smart nanodevice combined tumor-specific vector with cellular microenvironment-triggered property for highly effective antiglioma therapy.
Malignant glioma, a highly aggressive tumor, is one of the deadliest types of cancer associated with dismal outcome despite optimal chemotherapeutic regimens. One explanation for this is the failure of most chemotherapeutics to accumulate in the tumors, additionally causing serious side effects in periphery. To solve these problems, we sought to develop a smart therapeutic nanodevice with cooperative dual characteristics of high tumor-targeting ability and selectively controlling drug deposition in tumor cells. This nanodevice was fabricated with a cross-linker, containing disulfide linkage to form an inner cellular microenvironment-responsive "-S-S-" barrier, which could shield the entrapped drug leaking in blood circulation. In addition, dehydroascorbic acid (DHA), a novel small molecular tumor-specific vector, was decorated on the nanodevice for tumor-specific recognition via GLUT1, a glucose transporter highly expressed on tumor cells. The drug-loaded nanodevice was supposed to maintain high integrity in the bloodstream and increasingly to specifically bind with tumor cells through the association of DHA with GLUT1. Once within the tumor cells, the drug release was triggered by a high level of intracellular glutathione. When these two features were combined, the smart nanodevice could markedly improve the drug tumor-targeting delivery efficiency, meanwhile decreasing systemic toxicity. Herein, this smart nanodevice showed promising potential as a powerful platform for highly effective antiglioma treatment.


Inducements revisited.
The paper defends the permissibility of paying inducements to research subjects against objections not covered in an earlier paper in Bioethics. The objections are that inducements would cause inequity, crowd out research, and undesirably commercialize the researcher-subject relationship. The paper shows how these objections presuppose implausible factual and/or normative claims. The final position reached is a qualified defence of freedom of contract which not only supports the permissibility of inducements but also offers guidance to ethics committees in dealing with practical problems that might arise if inducements are offered.


Initial dose cascade of TTS fentanyl with proper adjuvant medications in cancer pain.
According to the three step-ladder analgesics in patients with cancer pain, adjuvant drugs are required for pain relief according to the pain character and also to reduce side effects of opioids. Pain clinicians sometimes want to decide to jump directly from naive and mild opioid to transdermal therapeutic system (TTS) fentanyl with less side effects. We investigated the safety, efficacy, and satisfaction of the patients of TTS fentanyl converting from opioid-naive and mild-opioid with adjuvant drug medications in related to dose cascade of TTS fentanyl. Both opioid-naive (n=3) and opioid-using (n=34) patients started with TTS fentanyl in the lowest available delivery rate (25 microg/hr) with rescue medication. A numeric rating scale (NRS, from 0=no pain to 10=worst pain imaginable), satisfaction of the patients with the transdermal therapy and side effects were recorded everyday during 29 days. Average reductions of NRS scores were 1.79 and 2.77, and the mean doses were 35.14 and 44.12 microg/hr on the 15th and 29th day, respectively. Reported level of satisfaction with the transdermal patch and generalized pain management were 'completely satisfied' and 'satisfied'. Frequent side effects were nausea, vomiting, and constipation. In conclusion, initial application of TTS fentanyl with proper adjuvant medications is effective, safe, and well tolerated.


Silicon diode detectors used in radiological physics measurements. Part II: Measurement of dosimetry data for high-energy photons.
Initial calibration of a linear accelerator requires physics instruments to measure accurately central axis depth-dose and off-axis data, both in and out of the beam. These data for an 8- MeV unit were first measured using film, a Farmer 0.6-cm3 ion chamber, a 0.3-cm3 ion chamber, and a 0.1-cm3 silicon diode. Both small probes and film gave a high response compared to the Farmer probe, which has a uniform energy response. Measurements with the diode interfaced to an X-Y recorder required only a fraction of the time required with the chambers, minimizing error due to change in machine output, and permitted resolution of isodose lines in the penumbra. However, corrections required at points in depth due to nonuniform energy response of the unshielded diode were laborious. Construction of a partially shielded diode which duplicates the response of the Farmer probe eliminated the necessity for corrections, permitting rapid accumulation of a wide range of depth-dose and off-axis data.


Temperamental characteristics of 3--4-year-olds and mother-child interaction.
Comparisons are presented between the temperamental characteristics of preschool-age children from two-child families and aspects of mother-child interaction observed in the home. The data were collected when the children were 42 months old (n = 45) and 50 months old (n = 37). Although few behavioural items were directly relevant to temperament, several temperamental characteristics (Moody, Intense, Shy, Assertive) had behavioural correlates of a type that might be expected. Active and Irregular also showed meaningful patterns of correlations. Unmalleable, Dependent and Attention span did not. However, although there were no sex differences in the ratings of temperamental characteristics, the correlations between particular characteristics and behavioural items sometimes differed markedly between boys and girls, and also between firstborns and secondborns. Thus comparisons between temperamental characteristics and the behavioural data involving the whole sample were sometimes less revealing than those concerning each sex or sibling-status group separately.


Mechanisms of deoxynivalenol (DON) degradation during different treatments: a review.
Deoxynivalenol (DON) is one of the main trichothecenes, that causes health-related issues in humans and animals and imposes considerable financial loss to the food industry each year. Numerous treatments have been reported in the literature on the degradation of DON in food products. These treatments include thermal, chemical, biological/enzymatic, irradiation, light, ultrasound, ozone, and atmospheric cold plasma treatments. Each of these methods has different degradation efficacy and degrades DON by a distinct mechanism, which leads to various degradation byproducts with different toxicity. This manuscript focuses to review the degradation of DON by the aforementioned treatments, the chemical structure and toxicity of the byproducts, and the degradation pathway of DON. Based on the type of treatment, DON can be degraded to norDONs A-F, DON lactones, and ozonolysis products or transformed into de-epoxy deoxynivalenol, DON-3-glucoside, 3-acetyl-DON, 7-acetyl-DON, 15-acetyl-DON, 3-keto-DON, or 3-epi-DON. DON is a major problem for the grain industry and the studies focusing on DON degradation mechanisms could be helpful to select the best method and overcome the DON contamination in grains.


Anti-idiotypic antibodies: powerful tools in diagnosis and therapy.
Mouse x mouse hybridomas secreting monoclonal anti-idiotypic antibodies have been prepared from BALB/c mice immunized with syngeneic monoclonal antibodies specific for IgE, AFP, CEA and TSH respectively. The hybridomas were selected on the basis that the secreted antibodies competed with antigen for binding to the immunizing idiotope. Using IgE and AFP as a model it could be shown that syngeneic antigen inhibitable monoclonal anti-idiotypic antibodies can act well as antigen surrogate. Thus a complementary idiotype-anti-idiotype antibody pair could be used in a competitive assay wherein the extend of idiotype-anti-idiotype complex formation is inversely proportional to the amount of antigen in the sample. Apart from this a lot of human and animal studies have shown that this interaction between idiotype and anti-idiotype could be utilized to prevent certain infectious diseases and to treat some kinds of cancers.


Mortality associated with benzodiazepines and benzodiazepine-related drugs among community-dwelling older people in Finland: a population-based retrospective cohort study.
To investigate the association between the use of benzodiazepines (BDZs) and BDZ-related drugs and mortality among community-dwelling people aged 65 years and older in Finland. This was a population-based retrospective cohort study. Records of all reimbursed drugs purchased by all 2224 residents of Leppävirta, Finland, aged 65 years and older in 2000 were extracted from the Finnish National Prescription Register. Diagnostic data were extracted from the Special Reimbursement Register. All-cause mortality was assessed after 9 years using national registers. Cox proportional hazards models were used to compute unadjusted and adjusted hazard ratios (HRs) and 95% confidence intervals for mortality among prevalent users of BDZs and BDZ-related drugs in 2000 (n = 325), compared with nonusers of BDZs and BDZ-related drugs between 2000 and 2008 (n = 1520). BDZs and BDZ-related drugs were used by 325 out of the 2224 residents (14.6%) in 2000. The 9-year mortality was 50.2% among BDZ and BDZ-related drug users in 2000 and 36.3% among BDZ and BDZ-related drug nonusers between 2000 and 2008 (HR 1.53; 95% CI 1.28 to 1.82). After adjusting for baseline age, sex, antipsychotic drug use, and diagnostic confounders, the HR was 1.01 (95% CI 0.84 to 1.21). Use of BDZs and BDZ-related drugs was associated with an increased mortality hazard in unadjusted analyses. However, after adjusting for age, sex, antipsychotic drug use, and diagnostic confounders, the use of BDZs and BDZ-related drugs was not associated with excess mortality.


Policy Making to Build Relationships: A Grounded Theory Analysis of Interviews and Documents Relating to H1N1, Ebola, and the U.S. Public Health Preparedness Network.
In the last five years, the American public health emergency preparedness and response system has been tested by two significant threats, H1N1 and Ebola. While neither proved as dangerous as initially feared, these viruses highlighted on-going issues with collaborations in the field of public health and health care. Strengths were identified within the network, but also challenges that must be resolved before the U.S. faces a major pandemic. Employing interview data from public health emergency response practitioners and documentary evidence from the H1N1 and Ebola responses, this qualitative analysis uses the grounded theory approach to identify key areas for collaborative improvement. The grounded theory developed calls for a stronger policy framework at the federal level to facilitate more collaboration between U.S. agencies and facilitate more collaboration at the state and local level.


Quantification of an external motion surrogate for quality assurance in lung cancer radiation therapy.
The purpose of this work was to validate the stability of the end exhale position in deep expiration breath hold (DEBH) technique for quality assurance in stereotactic lung tumor radiation therapy. Furthermore, a motion analysis was performed for 20 patients to evaluate breathing periods and baseline drifts based on an external surrogate. This trajectory was detected using stereo infrared (IR) cameras and reflective body markers. The respiratory waveform showed large interpatient differences in the end exhale position during irradiation up to 18.8 mm compared to the global minimum. This position depends significantly on the tumor volume. Also the baseline drifts, which occur mostly in posterior direction, are affected by the tumor size. Breathing periods, which depend mostly on the patient age, were in a range between 2.4 s and 7.0 s. Fifteen out of 20 patients, who showed a reproducible end exhale position with a deviation of less than 5 mm, might benefit from DEBH due to smaller planning target volumes (PTV) compared to free breathing irradiation and hence sparing of healthy tissue. Patients with larger uncertainties should be treated with more complex motion compensation techniques.


A valentine-shaped cardiac silhouette in feline thoracic radiographs is primarily due to left atrial enlargement.
Conflicting information has been published regarding the cause of a valentine-shaped cardiac silhouette in dorsoventral or ventrodorsal thoracic radiographs in cats. The purpose of this retrospective, cross-sectional study was to test the hypothesis that the valentine shape is primarily due to left atrial enlargement. Images for cats with a radiographic valentine-shaped cardiac silhouette and full echocardiography examination were retrieved and independently reviewed. A subjective scoring system was used to record severity of radiographic valentine shape. Subjective radiographic evidence of left atrial enlargement in a radiographic lateral projection and a final diagnosis based on medical records were also recorded. A total of 81 cats met inclusion criteria. There was a strong positive correlation (P < 0.001) between echocardiographic left atrial size and severity of radiographic valentine shape. There was no effect of echocardiographic right atrial size on the severity of valentine shape, except when concurrent with severe left atrial enlargement. In this situation, right atrial enlargement increased the likelihood of observing a severe valentine shape. There was no effect of right atrial enlargement on the shape of the cardiac silhouette when left atrial enlargement was absent or only mild to moderate. There was no correlation between the category of final diagnosis of cardiac disease and the severity of valentine shape. Findings from this study supported the hypothesis that a valentine-shaped cardiac silhouette in radiographs is due primarily to left atrial enlargement in cats, with right atrial enlargement only impacting the shape if concurrent with severe left atrial enlargement.


Microorganisms isolated in patients with post-cardiac surgery mediastinitis at a cardiology hospital of Mexico City.
Mediastinitis after cardiovascular surgery gives rise to prolonged hospital stay and increased medical care costs, and is associated with high in-hospital mortality. To describe the clinical characteristics of patients with post-surgical mediastinitis, including the isolated microorganisms, resistance profile, and in-hospital survival. Cross-sectional study of patients with bacteriologically-confirmed post-surgical mediastinitis cared for at a cardiology hospital in Mexico City between January 2017 and March 2019. Fifty-eight cases of mediastinitis were included. Median age was 67 years. Most subjects were males who underwent myocardial revascularization. During in-hospital follow-up, all-cause and mediastinitis-related mortality were 27.6% and 20.7%, respectively. Staphylococcus aureus, Staphylococcus epidermidis and Escherichia coli were the most commonly isolated microorganisms. High resistance to methicillin was found in coagulase-negative staphylococci, as well as high expression of extended-spectrum beta-lactamases in Escherichia coli and Klebsiella pneumoniae strains. High mortality and significant antimicrobial resistance were found in patients with post-cardiac surgery mediastinitis.


In vivo microdialysis/liquid chromatography/tandem mass spectrometry for the on-line monitoring of melatonin in rat.
Liquid chromatography/tandem mass spectrometry (LC/MS/MS) has been coupled to in vivo microdialysis for on-line monitoring of melatonin in a freely moving rat for a period of 15 hours. A microdialysis probe was surgically implanted into the jugular vein of the rat, and deionized water was used as the perfusion medium at a flow rate of 1.0 microL/min. Microdialysis samples were collected in an on-line injector with sample injection every 30 minutes. Melatonin was dosed by intraperitoneal (i.p.) injection and then monitored by microdialysis/LC/MS/MS. The whole experiment, including the microdialysis sampling and sample injection into the LC/MS system, was fully automated. Metabolites of melatonin were identified off-line by LC/MSn experiments. Two metabolites were identified as 6-hydroxymelatonin and cyclic 2-hydroxymelatonin, consistent with ones found previously in the literature.


AXL Downstream Targeting Unravels Synergistic Drug Combinations in Ovarian Carcinoma Cells.
Platinum-based therapy represents the main pharmacological treatment for ovarian carcinoma. Since molecular targeting of receptor tyrosine kinases (RTK) affects factors that may modulate drug response, the aim of this study was to examine whether downstream targets of AXL RTK could be exploited to improve cell response to cisplatin. Inhibitors of p38 (SB203580) and of signal transducer and activator of transcription 3 (stattic) were employed in combination with cisplatin in ovarian carcinoma cell lines. Apoptosis assay and western blot analysis were performed to evaluate cell response after treatment. SB203580 produced a synergistic effect in combination with cisplatin in cisplatin-resistant IGROV-1/Pt1 cells. In addition, a favorable drug interaction was observed in A2780 cells when pre-incubated with cisplatin prior to stattic. The analysis of cell response after combined treatment showed down-regulation of the pro-apoptotic protein BCL2-associated agonist of cell death (BAD). Our results support the notion that downstream targets of AXL in ovarian carcinoma cells can be exploited to increase cisplatin activity in ovarian carcinoma models.


Percutaneous thrombectomy for pulmonary embolism.
The current treatment of massive pulmonary embolism (PE) has been either thrombolysis or surgical embolectomy. Percutaneous rheolytic thrombectomy, however, has emerged as an alternative treatment in patients with contraindications to thrombolysis. This case illustrates the usefulness of the AngioJet(R) thrombectomy catheter in patients with contraindications to thrombolytics. Three-dimensional computed tomography imaging demonstrated the effectiveness of treatment in this patient with massive PE.


Comparing Microfluidic Performance of Three-Dimensional (3D) Printing Platforms.
Three-dimensional (3D) printing has emerged as a potential revolutionary technology for the fabrication of microfluidic devices. A direct experimental comparison of the three 3D printing technologies dominating microfluidics was conducted using a Y-junction microfluidic device, the design of which was optimized for each printer: fused deposition molding (FDM), Polyjet, and digital light processing stereolithography (DLP-SLA). Printer performance was evaluated in terms of feature size, accuracy, and suitability for mass manufacturing; laminar flow was studied to assess their suitability for microfluidics. FDM was suitable for microfabrication with minimum features of 321 ± 5 μm, and rough surfaces of 10.97 μm. Microfluidic devices >500 μm, rapid mixing (71% ± 12% after 5 mm, 100 μL/min) was observed, indicating a strength in fabricating micromixers. Polyjet fabricated channels with a minimum size of 205 ± 13 μm, and a surface roughness of 0.99 μm. Compared with FDM, mixing decreased (27% ± 10%), but Polyjet printing is more suited for microfluidic applications where flow splitting is not required, such as cell culture or droplet generators. DLP-SLA fabricated a minimum channel size of 154 ± 10 μm, and 94 ± 7 μm for positive structures such as soft lithography templates, with a roughness of 0.35 μm. These results, in addition to low mixing (8% ± 1%), showed suitability for microfabrication, and microfluidic applications requiring precise control of flow. Through further discussion of the capabilities (and limitations) of these printers, we intend to provide guidance toward the selection of the 3D printing technology most suitable for specific microfluidic applications.


Deterioration of muscle function after 21-day forearm immobilization.
Although it is well known that immobilization causes muscle atrophy, most immobilization models have examined lower limbs, and little is known about the forearm. The purpose of this study was to determine whether forearm immobilization produces changes in muscle morphology and function. Six healthy males (age: 21.5 +/- 1.4, mean +/- SD) participated in this study. The nondominant arm was immobilized with a cast (CAST) for 21 d, and the dominant arm was measured as the control (CONT). The forearm cross-sectional area (CSA) and circumference were measured as muscle morphology. Maximum grip strength, forearm muscle oxidative capacity, and dynamic grip endurance were measured as muscle function. Magnetic resonance (MR) imaging was used to measure CSA, and 31phosphorus MR spectroscopy was used to measure time constant (Tc) for phosphocreatine (PCr) recovery after submaximal exercise (PCr-Tc). Grip endurance was expressed by the number of handgrip contractions at 30% maximum grip strength load. All measurements were taken before and after the immobilization. After the 21-d forearm immobilization, no changes were seen for each measurement in CONT. CSA and the circumference showed no significant changes in CAST. However, maximum grip strength decreased by 18% (P < 0.05), PCr-Tc was prolonged by 45% (P < 0.05), and the grip endurance at the absolute load was reduced by 19% (P < 0.05) for CAST. In this model, 21-d forearm immobilization caused no significant changes in forearm muscle morphology, but the muscle function showed remarkable deterioration ranging from 18 to 45%.


Defective thrombus formation in mice lacking endogenous factor VII activating protease (FSAP).
Factor VII (FVII) activating protease (FSAP) is a circulating protease with a putative function in blood coagulation and fibrinolysis. Genetic epidemiological studies have implied a role for FSAP in carotid stenosis, stroke and thrombosis. To date, no in vivo evidence is available to support these claims. We have, for the first time, used FSAP-/- mice to define its role in thrombosis and haemostasis in vivo and to characterise the molecular mechanisms involved. FeCl3-induced arterial thrombosis in carotid and mesenteric artery revealed that the occlusion time was significantly increased in FSAP-/- mice (p< 0.01) and that some FSAP-/- mice did not occlude at all. FSAP-/- mice were protected from lethal pulmonary thromboembolism induced by collagen/ epinephrine infusion (p< 0.01). Although no spontaneous bleeding was evident, in the tail bleeding assay a re-bleeding pattern was observed in FSAP-/- mice. To explain these observations at a mechanistic level we then determined how haemostasis factors and putative FSAP substrates were altered in FSAP-/- mice. Tissue factor pathway inhibitor (TFPI) levels were higher in FSAP-/- mice compared to WT mice whereas FVIIa levels were unchanged. Other coagulation factors as well as markers of platelet activation and function revealed no significant differences between WT and FSAP-/- mice. This phenotype of FSAP-/- mice could be reversed by application of exogenous FSAP. In conclusion, a lack of endogenous FSAP impaired the formation of stable, occlusive thrombi in mice. The underlying in vivo effect of FSAP is more likely to be related to the modulation of TFPI rather than FVIIa.


[Functional differentiation of residual volume changes and problems of evaluation from the physiopathologic viewpoint].
The ascertainment of the residual volume is a very important method for pulmonary emphysema diagnosis. But there are problems of estimation on the basis of this residual volume. The usual relation (RV/TLC) greater than 0,35 as measure for an emphysema will be considered critically. In this way functional relations will be given which allow a more secure emphysema diagnosis. They use as measure comparisons between RV and fit reference volumes, such as normal values of RV, VC or TLC. These equations make it possible to differentiate between structural and functional disturbances.


BMP signaling turns up in fragile X syndrome: FMRP represses BMPR2.
Fragile X syndrome is the most common inherited form of intellectual disability and results from a loss of function of the translational repressor FMRP. In this issue of Science Signaling, Kashima et al find that FMRP binds to and represses a specific isoform of BMPR2, a type II bone morphogenetic protein (BMP) receptor. Reducing signaling through this BMP pathway reverses neuroanatomical defects observed in fragile X models.


Thermoset Shape-Memory Polyurethane with Intrinsic Plasticity Enabled by Transcarbamoylation.
Thermoset polymers are known for their superior thermomechanical properties, but the chemical crosslinking typically leads to intractability. This is reflected in the great differences between thermoset and thermoplastic shape-memory polymers; the former exhibit a robust shape memory but are not capable of redefining the permanent shape. Contrary to current knowledge, we reveal here that a classical thermoset shape-memory polyurethane is readily capable of permanent reshaping (plasticity) after a topological network rearrangement that is induced by transcarbamoylation. By employing the Jianzhi technique (also known as kirigami), unexpected shape-shifting versatility was observed for this otherwise classical material. As the essential carbamate moiety in polyurethanes is one of the most common polymer building units, we anticipate that our finding will have significant benefits beyond shape shifting.


Mild Impairment of Mitochondrial OXPHOS Promotes Fatty Acid Utilization in POMC Neurons and Improves Glucose Homeostasis in Obesity.
Mitochondrial oxidative phosphorylation (OXPHOS) and substrate utilization critically regulate the function of hypothalamic proopiomelanocortin (POMC)-expressing neurons. Here, we demonstrate that inactivation of apoptosis-inducing factor (AIF) in POMC neurons mildly impairs mitochondrial respiration and decreases firing of POMC neurons in lean mice. In contrast, under diet-induced obese conditions, POMC-Cre-specific inactivation of AIF prevents obesity-induced silencing of POMC neurons, translating into improved glucose metabolism, improved leptin, and insulin sensitivity, as well as increased energy expenditure in AIFΔPOMC mice. On a cellular level, AIF deficiency improves mitochondrial morphology, facilitates the utilization of fatty acids for mitochondrial respiration, and increases reactive oxygen species (ROS) formation in POMC neurons from obese mice, ultimately leading to restored POMC firing upon HFD feeding. Collectively, partial impairment of mitochondrial function shifts substrate utilization of POMC neurons from glucose to fatty acid metabolism and restores their firing properties, resulting in improved systemic glucose and energy metabolism in obesity.


Effects of Polyester Fibers and Car Tire Particles on Freshwater Invertebrates.
Microplastic ingestion has been shown for various organisms, but knowledge of the potential adverse effects on freshwater invertebrates remains limited. We assessed the ingestion capacity and the associated effects of polyester fibers (26-5761 µm) and car tire particles (25-75 µm) on freshwater invertebrates under acute and chronic exposure conditions. A range of microplastic concentrations was tested on Daphnia magna, Hyalella azteca, Asellus aquaticus, and Lumbriculus variegatus using water only (up to 0.15 g/L) or spiked sediment (up to 2 g/kg dry wt), depending on the habitat of the species. Daphnia magna did not ingest any fibers, but low levels of fibers were ingested by all tested benthic invertebrate species. Car tire particle ingestion rose with increasing exposure concentration for all tested invertebrates and was highest in D. magna and L. variegatus. In most cases, no statistically significant effects on mobility, survival, or reproductive output were observed after acute and chronic exposure at the tested concentrations. However, fibers affected the reproduction and survival of D. magna (no-observed-effect concentration [NOEC]: 0.15 mg/L) due to entanglement and limited mobility under chronic conditions. Car tire particles affected the reproduction (NOEC: 1.5 mg/L) and survival (NOEC: 0.15 mg/L) of D. magna after chronic exposure at concentrations in the same order of magnitude as modeled river water concentrations, suggesting that refined exposure and effect studies should be performed with these microplastics. Our results confirm that microplastic ingestion by freshwater invertebrates depends on particle shape and size and that ingestion quantity depends on the exposure pathway and the feeding strategy of the test organism. Environ Toxicol Chem 2022;41:1555-1567. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.


Symptomatic relapse of HIV-associated cryptococcal meningitis after initial fluconazole monotherapy: the role of fluconazole resistance and immune reconstitution.
Cryptococcal meningitis (CM) in South Africa is often treated with fluconazole as initial therapy. Surveillance data suggest that the prevalence of fluconazole-resistant CM is increasing, and expanding access to antiretroviral therapy is resulting in increasing recognition of immune reconstitution inflammatory syndrome. Therefore, we conducted a study to assess the contribution of these factors to CM relapse in this context. Patients with symptomatic relapse of CM were prospectively identified at 2 hospitals in Cape Town, South Africa, during the period of 2003-2005. Patients met the following criteria: (1) a previous laboratory-confirmed episode of CM, with resolution of symptoms after treatment; (2) reported adherence to fluconazole treatment; (3) recurrence of typical CM symptoms; (4) cerebrospinal fluid antigen test and/or culture positive for Cryptococcus neoformans; and (5) no alternative diagnosis. Data on patients' human immunodeficiency virus (HIV) and CM infections and treatment were collected and analyzed. Thirty-two episodes of relapse occurred among 27 patients. Episodes were classified into 3 groups: culture-positive episodes in antiretroviral therapy-naive patients (6 episodes), culture-positive episodes in patients receiving antiretroviral therapy (15 episodes), and culture-negative episodes in patients receiving antiretroviral therapy (11 episodes). Seventy-six percent of culture-positive relapses were associated with isolates that had reduced susceptibility to fluconazole. Drug-resistant cases required prolonged intravenous therapy with amphotericin B, and despite this treatment, the mortality rate was high (54% at a median of 6 months of follow-up). Despite a long interval between initiation of antifungal therapy and initiation of antiretroviral therapy (median interval, 144 days), immune reconstitution inflammatory syndrome contributed to at least one-third of relapses. After initial treatment with fluconazole, relapses of symptomatic CM are often associated with fluconazole resistance and immune reconstitution inflammatory syndrome. These data add to concern about the efficacy of fluconazole, compared with amphotericin B, for initial treatment of HIV-associated CM.


Development of 32-channel silicon drift detectors and digital electronics for X-ray spectroscopy.
The performance of silicon-drift-detector (SDD) arrays and digital electronics designed for X-ray absorption spectroscopy in the fluorescence excitation mode is reported. Different detectors have been manufactured and tested: two single-channel SDDs with different active areas (10 mm(2) and 1 cm(2)) and a monolithic 2 cm(2) SDD with eight readout anodes. The energy resolution varies between 160 and 170 eV FWHM. A new digital multichannel shaping amplifier has been produced. Its performance is presented in comparison with that of a standard commercial shaper.


Determination of prostate-specific antigen in serum by immunoradiometric assay.
A better understanding is needed of the role of pre-analytical factors if prostate-specific antigen (PSA) is to be reliably used as a tumor marker. Reports on the analytical performance of TANDEM-R PSA (Hybritech, Inc., San Diego, CA) differ considerably with respect to detection limit and imprecision, differences that might be due (e.g.) to the use of different control matrices, to between-batch variations in reagent composition, or to nonrobustness of the assay. During nine months we determined PSA in 986 serum samples from 728 male urology patients and 54 samples from women (25 assay runs). As controls we used two serum pools with low PSA concentration and two widely used commercial controls. The within-assay CV for patients' samples was similar to that found with the commercial controls: 2.6% to 3.4% in the upper part of the normal reference interval. Precision was worse at lower concentrations (CVs 5-10% at about 0.5 micrograms/L). Imprecision tended to be higher at the end of runs. Assay drift for 100-tube runs was -4%. PSA was stable at -20 degrees C during six months. Neither the polyester polymer in SST tubes nor a hemolysate had any detectable effect on PSA values. Clinical analysis of the first 322 patients and all patients with PSA less than or equal to 0.20 micrograms/L highlighted the requirements for strict adherence to sampling instructions and to stringent quality control also at low analyte concentrations (analyte-free sera and sera with PSA concentrations 0.2-0.5 micrograms/L). Values with TANDEM-R PSA and IRMA-Count PSA (Diagnostic Products Corp., Los Angeles, CA) correlated well with no difference in detection limit or with samples from women. Within-assay precision was better with IRMA-Count PSA in the upper part of the normal reference interval and above. The designs of the two assays were compared in a format that is generally applicable for immunoassay kits (NORDKEM kit group, unpublished), and subjective impressions were recorded.


Is multi-infarct dementia representative of vascular dementias? A retrospective study.
Multi-infarct dementia (MID) indicates a dementia disorder primarily caused by multiple cerebral infarcts. Since other pathogenetic mechanisms cause vascular dementia we evaluated clinical, CT scan and CSF neurochemical parameters of 134 MID and 67 PVD (probable vascular dementia) patients. We found no differences with regard to the presence of major risk factors. Only TIA/stroke episodes and focal neurological signs were significantly more frequent in MID than in PVD cases, an anticipable result on the basis of MID definition. CT scan findings showed a prevalence of subcortical with respect to cortical lesions in both groups, with a higher frequency in MID patients. Subjects with deep infarcts more frequently showed TIA/stroke episodes and diabetes mellitus. No differences were detectable in CSF monoamine metabolite levels. We conclude that in the majority of vascular dementias subcortical damage seems to have a major pathogenetic role.


Core-in-cup/liquisol dual tackling effect on azelnidipine buccoadhesive tablet micromeritics, in vitro release, and mucoadhesive strength.
Reduced bioavailability of azelnidipine is related to its poor aqueous solubility and extensive first-pass metabolism, which hinder its efficacy. These problems were addressed by implementing (1) a liquisol technique for promoting the dissolution rate in a controlled-release manner and (2) a core-in-cup bucco-adhesive drug delivery system as an alternative to the oral route. A 33 factorial design was used to study the effects of polymer type (sodium carboxymethyl cellulose (CMC Na), chitosan, or Carbomer P940) concentration (5, 10 or 15 %) and preparation technique (simple mix, liquisol or wet granulation) on the dissolution and mucoadhesion of core-in-cup azelnidipine buccoadhesive tablets. Tablet micromeritics, swelling index, mucoadhesive strength and in vitro release were characterized. Statistical analyses of these factors show ed significant effects on the studied responses, where F#16 prepared by the liquisol technique and containing 15 % CMC Na was chosen with an overall desirability of 0.953.


Killing of human lung cancer cells using a new [111In]bleomycin complex [111In]BLMC.
The ability of a [111In]bleomycin complex [( 111In]BLMC) to kill five cell lines of human lung cancer (small cell lung cancer) was investigated. Cells were exposed to either 0.9% NaCl, [111In]Cl3, BLM, [111In]BLMC, nonradioactive InCl3, or In-BLMC for 60 minutes, plated in soft agarose, and assessed for colony formation. [111In]BLMC (40-200 microCi carried by 15-25 micrograms BLM/ml) was more cytotoxic than BLM (15-25 micrograms BLM/ml) by a factor of 1.6-5.3 for five cell lines. The percent survival of N417 cells was 28.4 for [111In]BLMC (40 microCi/15 micrograms BLM/ml) and 54.3 for BLM (15 micrograms/ml); 1.9 for [111In]BLMC (200 microCi/25 micrograms BLM/ml), and 10.0 for BLM (25 micrograms/ml). 111InCl3 (200 microCi/ml) and nonradioactive InCl3 failed to inhibit colony formation. The new [111In]BLMC may be useful for therapy of some lung cancer patients.


A pro-survival role for the intracellular granzyme B inhibitor Serpinb9 in natural killer cells during poxvirus infection.
Intracellular serpins are proposed to inactivate proteases released from lysosome-related organelles into the host cell interior, preventing cell death. Serpinb9 opposes the immune cytotoxic protease, granzyme B, and in a number of settings protects cells against granzyme B-mediated cell death. Using a knockout mouse line engineered to express green fluorescent protein under the serpbinb9 promoter, we demonstrate that serpinb9 is vital for host survival during Ectromelia virus infection by maintaining both mature natural killer NK) cells, and activated CD8+ T cells. Serpinb9 expression parallels granzyme B expression within both populations during infection. Maturing serpinb9-null NK cells exhibit higher levels of granzyme B-mediated apoptosis during infection; hence there are fewer mature NK cells, and these cells also have lower cytotoxic potential. Thus the serpinb9-granzyme B axis is important for homeostasis of both major cytotoxic effector cell populations.


[Effects of sex hormones on the expression of placenta form glutathione S-transferase (GST-P) in rat induced hepatocarcinoma].
Using Solt-Farber method for the induction of rat hepatocarcinoma, the changes of the activity of glutathione S-transferase (GST) and the content of placenta form GST (GST-P) were studied during hepatocarcinogenesis, then the effects of sex hormones on the hepatic expression of GST-P were observed using immunohistochemical method. The results showed that both GST activity and GST-P content began to increase at the 3rd week, and reached the highest level at the 5th week (Table 1). Therefore, the 5th week was selected for the study of GST-P expression in the livers of rats treated with different protocol (Fig. 1). It was found that GST-P was highly expressed in the livers of sham-castrated male rats after chemically induced hepatocarcinoma (PLATE I, Fig. 1A, Table 2). When estradiol was administrated to these rats, both the number and area of GST-P positive(+) foci decreased significantly (PLATE I, Fig. 1B, Table 2). While testosterone was administrated instead of estradiol, the decrease of the area but slight increase of the number of GST-P positive foci were found (PLATE I, Fig. 1C, Table 2). After orchiectomy, the areas of GST-P (+) foci in carcinogen treated liver of male rats were smaller than those in rats with sham-orchiectomy and same carcinogen treatment (PLATE I, Fig. 2A, B, Table 3). When the orchiectomized male rats were administrated with estradiol, the areas of GST-P (+) foci decreased further (PLATE I, Fig. 2C, Table 3). In contrast, after ovariectomy of the female rats, the areas of GST-P (+) foci in carcinogen treated livers were slightly increased as compared with those in the rats with sham-ovariectomy and same carcinogen treatment (PLATE I, Fig. 2D, E, Table 3). While the ovariectomized female rats were administrated with testosterone, the areas of GST-P (+) foci increased further (PLATE I, Fig. 2F, Table 3). Regardless of whether castrations were done or not, GST-P expression in livers of male rats induced hepatocarcinoma was higher than in livers of female rats (PLATE I, Fig. 2A, B, D, E, Table 3). These results indicated that estrogen may inhibit but androgen may promote the GST-P expression in the rat liver during hepatocarcinogenesis. This may be related to the higher incidence of liver carcinoma in male than in female.


The emergency department in a 2000-bed teaching hospital: saving open ward and intensive care facilities.
Providing emergency medicine at the entrance to the hospital proves to be a sufficient link between pre- and inhospital medical care. The aim of our study is to investigate how many open ward and intensive care facilities can be saved within the hospital by the emergency department. Therefore, the data of our emergency department within a 2000-bed teaching hospital are retrospectively analysed. Unstable life-threatening emergencies for acute care, stable for immediate care and non-life-threatening emergencies are defined. Patients were discharged, admitted to an open ward, intensive care unit, the operation theatre or died. According to the level of care needed in the emergency department the continuing medical management is investigated. Over a 2-year period, 102,411 patients entered our emergency department. Overall 1498 (1%) needed acute care, 3652 (4%) immediate care and 97,261 (95%) delayed care. Of the acute care patients, 29 (2%) were discharged, 573 (38%) were admitted to an open ward, 551 (37%) to an intensive care unit, 67 (4%) needed surgery and 278 (19%) died. Of the immediate care patients, 1611 (44%) were discharged, 1755 (48%) were admitted to an open ward, 551 (37%) to an intensive care unit, and 286 (8%) needed surgery. Of the delayed care patients, 93061 (96%) were discharged and 4200 (4%) were admitted to an open ward. Of 5150 patients with life-threatening diseases, 551 (11%) needed an intensive care unit and 2328 (45%) an open ward. Providing acute and immediate care in our emergency department saves both intensive care and open ward facilities of the hospital.


Genotoxicological effects of some phenoxyherbicides and their metabolites on Bacillus subtilis M45 Rec- and H17 Rec+ strains.
Because they are used in a number of commercial preparations phenoxyacetic acids and their salts can occur in wastewater. During their degradation genotoxic substances may be created. The results of investigations of biodegradability and genotoxicity of some phenoxyherbicides are presented. Commercial formulations of 2,4-D (Aminopielik 720) and MCPA (Chwastox Extra) were the substrates studied. Biodegradation tests were conducted according to OECD guidelines for testing of chemicals--confirmatory test (OECD Method 303 A). Genotoxicity tests were conducted with Bacillus subtilis strains according to the method of [Chemical Mutagens, vol. 6, Plenum Press. New York, 1980, p. 149]. Genotoxicity of biodegradation products was also studied. Both commercial formulations were biodegradable. Aminopielik 720 was potentially genotoxic but only at great concentrations while Chwastox Extra was not genotoxic. Biodegradation products of neither compound were genotoxic.


Peptide π-Electron Conjugates: Organic Electronics for Biology?
Highly ordered arrays of π-conjugated molecules are often viewed as a prerequisite for effective charge-transporting materials. Studies involving these materials have traditionally focused on organic electronic devices, with more recent emphasis on biological systems. In order to facilitate the transition to biological environments, biomolecules that can promote hierarchical ordering and water solubility are often covalently appended to the π-electron unit. This review highlights recent work on π-conjugated systems bound to peptide moieties that exhibit self-assembly and aims to provide an overview on the development and emerging applications of peptide-based supramolecular π-electron systems.


No association between HLA-DRB1 alleles and susceptibility to advanced stage endometriosis in a Korean population.
The aetiological factors of endometriosis still remain poorly understood. While there is growing evidence that genetic and immunological factors play important roles in the pathogenesis of the disease, HLA-DRB1 alleles have been reported to be associated with the risk of endometriosis in Japanese populations. This study was performed to determine whether susceptibility to advanced endometriosis is also associated with HLA-DRB1 alleles in a Korean population, which is the closest ethnic group to Japanese. We recruited 100 Korean patients with advanced endometriosis confirmed by surgical and histolological examinations. HLA-DRB1 genotyping was carried out in two steps. Low to intermediate resolution typing was performed by PCR sequence-specific oligonucleotide hybridization method, followed by high resolution typing utilizing group-specific amplification and PCR-single strand conformation polymorphism method. Distribution of HLA-DRB1 alleles was compared with that of 800 unrelated ethnically matched individuals as well as 108 healthy female subjects. Genotyping revealed that the distribution of HLA-DRB1 alleles in patients with advanced endometriosis was not different from that in the two control groups. The findings of the present study suggest that susceptibility of advanced endometriosis is not associated with HLA-DRB1 alleles in a Korean population, which is apparently not the case in the Japanese population.


Effect of sodium-glucose co-transporter-2 inhibitor empagliflozin on disease progression in a patient with heart failure and preserved ejection fraction.
Sodiumglucose co-transporter 2 inhibitors - gliflozins - have a scientific evidence on efficacy in patients with heart failure regardless left ventricular ejection fraction. Gliflozins They reduced combined endpoint of cardiovascular mortality and heart failure hospitalization also in patients with heart failure and left ventricular ejection fraction above 40 %. We report a case study of a patient with new onset heart failure. Early initiation of therapy with empagliflozin was associated with an improvement of symptoms and laboratory parameters including NT-proBNP level.


Evaluation of noise attenuation and verbal communication capabilities using three ear insert hearing protection systems among airport maintenance personnel.
The goal of this project was to determine whether one type of earplug would allow a user to hear communication in a noisy environment better than two other types of earplugs. The three types of earplugs studied are newly available on the market. Sonomax SonoCustoms are custom fitted to the user. E-A-R Push-Ins are the newest form of foam earplugs, and Howard Leight SmartFits have an adaptable shape. One of the earplug manufacturers claimed to have improved verbal communications due to the design of the earplug. We hypothesized that the type of earplug providing better communication properties would have lower attenuation around the communication frequencies compared with the other types. To test this hypothesis, we used speech intelligibility and attenuation tests in the laboratory on 26 subjects, and real-time video exposure monitoring in the field (airport maintenance personnel) for visual communication cues. ANCOVA was used to analyze the data from the laboratory study. The type of earplug worn was not significant in the model (p-value 0.0849), nor was attenuation of the earplug (p-value 0.2379). Further analysis showed that attenuation did not differ significantly among earplugs (p-value 0.5903). Logistic regression was used to analyze the data from the field study. Again, the type of earplug was not significant in the model (p-value 0.0965). A comfort questionnaire determined that Howard Leight SmartFits and the E-A-R Push-Ins were more comfortable and easier to use than the Sonomax HPDs (p-value <0.0001). We found a definite difference between manufacturers' attenuation data and our attenuation data, especially in the frequencies for 125-1000 Hz. Also, there was no difference in frequency and overall attenuation among the HPDs. This resulted in no difference in communication abilities among the types of HPDs.


Open port placement of the first laparoscopic port: a safe technique.
Blind insertion of the Veress needle and of the first trocar is a significant cause of complications in laparoscopic surgery. Despite this risk, the closed technique is still more popular than the open one. Our aim is to report the results of our experience with the routine use of the modified open technique in laparoscopic surgery and to describe the technical details of the creation of pnuemoperitoneum by the open technique that we used. A prospective study was conducted in the department of surgery at Maulana Azad Medical College and associated Lok Nayak Hospital, New Delhi. A modified method of open laparoscopy was performed on 755 consecutive patients requiring laparoscopy or laparoscopic surgery over a 5-year period from August 1998 to February 2003 in 1 surgical unit. The mean time taken was 4 minutes (range, 2 to 10). No intraoperative complications occurred during trocar insertion. Forty-nine (6.49%) patients had minor umbilical sepsis, 22 (2.91%) had periumbilical hematoma, but none had umbilical hernia during 3 months of follow-up after surgery. Based on our own experience, we recommend open laparoscopy as a safe and easy approach for routine laparoscopic interventions.


Involving patients in service improvement.
This article describes the experiences of two multidisciplinary teams that took part in a national initiative to improve care through the implementation of research evidence. Both teams worked with patients with chronic illnesses. The patients required regular admissions to hospital for treatment and care, and had reported difficulties when moving between different services.


[The Current Issues of Crime Victim Support from a Clinical Point of View].
This paper reviews part of an educational lecture at the 111th Annual Meeting of the Jap- anese Society of Psychiatry and Neurology (JSPN), under the identical title by the author. First, current victim support and treatment for victims at psychiatric services in Japan are reviewed. Second, introducing a case report of a rape victim diagnosed as PTSD, comments are made on symptoms, such as avoidance and emotional numbing as part of dissociation. It is common for clinicians, even for patients themselves, to fail to notice these symptoms. How to detect and treat these covert symptoms appropriately are discussed.


In pursuit of "growth with equity": the limits of Chile's free-market social reforms.
The economic and social strategy developed by the democratic governments in Chile since 1990 has been based on the premise that free-market policies promoting growth and economic stability must continue, but should be combined with social policies designed to promote greater equality. This new set of policies produced quick and positive results in the context of strong economic growth. The reduction of poverty was its crowning achievement. However, not all the Concertación's redistributive efforts have enjoyed the same level of success. Inequalities in income distribution are again increasing. Significant segments of society, such as subsistence farmers, rural migrants to cities, women and youth who lack vocational training--as well as an important segment of the middle class that had been impoverished during the military regime--are being systematically marginalized from the benefits of economic growth and social policy. The fundamental problems of current Chilean social policy are rooted in the privatization of social sectors under the military government and the resulting dual model of social welfare.


Dysregulation of circadian rhythm in zebrafish (Danio rerio) by thifluzamide: Involvement of positive and negative regulators.
Thifluzamide as a fungicide is toxic to brain of zebrafish embryos. Brain can regulate biological rhythms. To clarify whether thifluzamide would influence circadian rhythms, zebrafish embryos were treated with thifluzamide (0, 0.19, 1.90 and 2.85 mg/L) for 4 days. Exposure to thifluzamide induced pronounced changes in embryo brain and melatonin levels. The mRNA levels of genes related to circadian rhythms were apparently altered. Among these, the transcripts of cry1ba and clock1 were extremely correlated with exposure concentrations. Importantly, the content of cry1 showed no apparent changes, but the clock level was dramatically increased. Moreover, consistent with the inhibition of development and behavior, the levels of GH and DA were significantly inhibited. In addition, the expression levels of genes related to development, behavior and reproduction were significantly changed by thifluzamide. Therefore, we speculated that circadian disruption due to thifluzamide exposure were primarily attributed to increases in expression of clock1a and contents of clock, which might be at least in part responsible for abnormal development and behavior of zebrafish. In addition, our research will provide important insights into the grouped assessment of SDHI pesticides in future.


Proceedings of the First Curing Coma Campaign NIH Symposium: Challenging the Future of Research for Coma and Disorders of Consciousness.
Coma and disorders of consciousness (DoC) are highly prevalent and constitute a burden for patients, families, and society worldwide. As part of the Curing Coma Campaign, the Neurocritical Care Society partnered with the National Institutes of Health to organize a symposium bringing together experts from all over the world to develop research targets for DoC. The conference was structured along six domains: (1) defining endotype/phenotypes, (2) biomarkers, (3) proof-of-concept clinical trials, (4) neuroprognostication, (5) long-term recovery, and (6) large datasets. This proceedings paper presents actionable research targets based on the presentations and discussions that occurred at the conference. We summarize the background, main research gaps, overall goals, the panel discussion of the approach, limitations and challenges, and deliverables that were identified.


High School Dropout in Proximal Context: The Triggering Role of Stressful Life Events.
Adolescents who drop out of high school experience enduring negative consequences across many domains. Yet, the circumstances triggering their departure are poorly understood. This study examined the precipitating role of recent psychosocial stressors by comparing three groups of Canadian high school students (52% boys; Mage = 16.3 years; N = 545): recent dropouts, matched at-risk students who remain in school, and average students. Results indicate that in comparison with the two other groups, dropouts were over three times more likely to have experienced recent acute stressors rated as severe by independent coders. These stressors occurred across a variety of domains. Considering the circumstances in which youth decide to drop out has implications for future research and for policy and practice.


Hypertension after clonidine overdose. A case report.
A hypertensive reaction is described in a 28-year-old woman with renal failure who took 30-70 clonidine tablets (150 micrograms each) with suicidal intent. She became increasingly drowsy. Her blood pressure on admission was 210/150 mmHg and gradually fell to 140/100 mmHg during the next 16 hours, at which time her plasma clonidine concentration was 4.7 ng/ml. This interesting hypertensive reaction was probably due to excessive stimulation of peripheral postsynaptic alpha-adrenoceptors.


Finite-element modelling of elastic wave propagation and scattering within heterogeneous media.
The scattering treated here arises when elastic waves propagate within a heterogeneous medium defined by random spatial fluctuation of its elastic properties. Whereas classical analytical studies are based on lower-order scattering assumptions, numerical methods conversely present no such limitations by inherently incorporating multiple scattering. Until now, studies have typically been limited to two or one dimension, however, owing to computational constraints. This article seizes recent advances to realize a finite-element formulation that solves the three-dimensional elastodynamic scattering problem. The developed methodology enables the fundamental behaviour of scattering in terms of attenuation and dispersion to be studied. In particular, the example of elastic waves propagating within polycrystalline materials is adopted, using Voronoi tessellations to randomly generate representative models. The numerically observed scattering is compared against entirely independent but well-established analytical scattering theory. The quantitative agreement is found to be excellent across previously unvisited scattering regimes; it is believed that this is the first quantitative validation of its kind which provides significant support towards the existence of the transitional scattering regime and facilitates future deployment of numerical methods for these problems.


Structure-activity relationship studies of gomesin: importance of the disulfide bridges for conformation, bioactivities, and serum stability.
Gomesin is an antimicrobial peptide isolated from hemocytes of the Brazilian spider Acanthoscurria gomesiana that contains two disulfide bridges Cys(2-15)/Cys(6-11) and presents a beta-hairpin structure. To investigate the role of the disulfide bridges on gomesin conformation, bioactivities, and serum stability, structure-activity relationship (SAR) studies were conducted. Initially, gomesin and variants lacking one or both disulfide bridges were synthesized. CD studies showed that the gomesin structure is very rigid independently of the solvent environment. On the other hand, the linearized analogues adopted secondary structures according to the environment, while the monocyclic disulfide-bridged peptides had a tendency to adopt a turn structure. The absence of one or both bridges resulted in a decrease in the antimicrobial and hemolytic activities. In addition, serum stability studies revealed that, contrasting to gomesin that was stable even after 48 h of incubation, the linearized analogues were rapidly degraded. The replacement of the disulfide bounds by lactam bridges led to monocyclic and bicyclic compounds. SAR studies indicated that the monocyclic lactam-bridged analogues tend to assume a alpha-helical structure being less potent, hemolytic, and serum stable than the wild-type gomesin. On the other hand, the bicyclic lactam/disulfide-bridged analogues displayed a similar conformation and degradation kinetics identical to gomesin. However, the antimicrobial activity appeared to be dependent on the lactam bridge position and size. These findings indicated that (i) the secondary structure plays a pivotal role for the full activity of gomesin; (ii) the antimicrobial and hemolytic activities of gomesin are correlated events; (iii) while at least one of the disulfide bridges is needed for the maintenance of a significant antimicrobial activity of gomesin, both bridges are required for high serum stability and optimal conformation; and finally (iv) the best analogue obtained was the bicyclo (2-15,6-11)[Glu2, Cys(6,11), Lys15]-Gm since it is as stable and potent as gomesin.


Age- and Gender-Specific Prevalence of Frailty and Its Outcomes in the Longevous Population: The Chinese Longitudinal Healthy Longevity Study.
Background: Frailty is an epidemic age-related syndrome addressing heavy burden to the healthcare system. Subject to the rarity, age-, and gender-specific prevalence of frailty and its prognosis among the longevous population remains under-investigated. Methods: Based on the Chinese Longitudinal Healthy Longevity Study (CLHLS, 2008-2018), individuals aged ≥ 65 years having complete data of frailty were recruited. Modified Fried criteria (exhaustion, shrink, weakness, low mobility, and inactivity) were adopted to define pre-frailty (1-2 domains) and frailty (≥3 domains), respectively. The association between pre-frailty/frailty and adverse outcomes (frequent hospitalization, limited physical performance, cognitive decline, multimorbidity, and dependence) was analyzed using logistic regression models. The association between pre-frailty/frailty and mortality was analyzed using Cox proportional hazards models. Age- and gender-stratified analyses were performed. Results: Totally, 13,859 participants aged 85.8 ± 11.1 years, including 2,056 centenarians, were recruited. The overall prevalence of pre-frailty and frailty were 54.1 and 26.3%, respectively. Only 5.0% of centenarians were non-frailty whereas 59.9% of the young-old (65-79 years) showed pre-frailty. Both pre-frailty and frailty were associated with the increased risk of multiple adverse outcomes, such as incident limited physical performance, cognitive decline and dependence, respectively (P < 0.05). Frail males were more vulnerable to the risk of mortality (hazard ratio [HR] = 2.3, 95% confidence interval [CI], 2.1-2.6) compared with frail females (HR = 1.9, 95%CI, 1.7-2.1). The strongest association between frailty and mortality was observed among the young-old (HR = 3.6, 95%CI, 2.8-4.5). Exhaustion was the most common domain among patients with pre-frailty (74.8%) or frailty (83.2%), followed by shrink (32.3%) in pre-frailty and low mobility (83.0%) in frailty. Inactivity among females aged 65-79 years showed the strongest association with the risk of mortality (HR = 3.50, 95%CI, 2.52-4.87). Conclusion: A huge gap exists between longer life and healthy aging in China. According to the age- and gender-specific prevalence and prognosis of frailty, the strategy of frailty prevention and intervention should be further individualized.


Phosphorylation of histone H2A.X by DNA-dependent protein kinase is not affected by core histone acetylation, but it alters nucleosome stability and histone H1 binding.
Phosphorylation of the C-terminal end of histone H2A.X is the most characterized histone post-translational modification in DNA double-stranded breaks (DSB). DNA-dependent protein kinase (DNA-PK) is one of the three phosphatidylinositol 3 kinase-like family of kinase members that is known to phosphorylate histone H2A.X during DNA DSB repair. There is a growing body of evidence supporting a role for histone acetylation in DNA DSB repair, but the mechanism or the causative relation remains largely unknown. Using bacterially expressed recombinant mutants and stably and transiently transfected cell lines, we find that DNA-PK can phosphorylate Thr-136 in addition to Ser-139 both in vitro and in vivo. Furthermore, the phosphorylation reaction is not inhibited by the presence of H1, which in itself is a substrate of the reaction. We also show that, in contrast to previous reports, the ability of the enzyme to phosphorylate these residues is not affected by the extent of acetylation of the core histones. In vitro assembled nucleosomes and HeLa S3 native oligonucleosomes consisting of non-acetylated and acetylated histones are equally phosphorylated by DNA-PK. We demonstrate that the apparent differences in the extent of phosphorylation previously observed can be accounted for by the differential chromatin solubility under the MgCl(2) concentrations required for the phosphorylation reaction in vitro. Finally, we show that although H2A.X does not affect nucleosome conformation, it has a de-stabilizing effect that is enhanced by the DNA-PK-mediated phosphorylation and results in an impaired histone H1 binding.


Prenatal paracetamol exposure and asthma: further evidence against confounding.
Observational studies have reported an association between maternal use of paracetamol in pregnancy and childhood asthma, which was not explained by measured confounding factors. However, it is possible that this relation might be confounded by unmeasured behavioural factors linked to paracetamol usage; if that were the case, effects of similar magnitude of partner's paracetamol use and/or postnatal maternal use would be expected. In the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based birth cohort, we compared the univariate effects of maternal use of paracetamol in pregnancy on risk of doctor-diagnosed asthma, wheeze and elevated immunoglobulin E (IgE) in the offspring at 7 years of age, with the univariate effects of partner's use and postnatal maternal use on these phenotypes. Maternal use of paracetamol in pregnancy was strongly associated with all outcomes. Partner's use was very weakly associated with asthma but not associated with wheezing or IgE. Postnatal maternal use was associated with asthma and wheezing, though less strongly than was prenatal use, and was not associated with IgE. On mutual adjustment, the effects of maternal use in pregnancy on all outcomes were not substantially attenuated, whereas the effects of partner's use on asthma, and of postnatal maternal use on asthma and wheezing, were reduced. These findings suggest that the relation between maternal use of paracetamol in pregnancy and childhood asthma is unlikely to be confounded by unmeasured behavioural factors linked to paracetamol use.


[Amino liberation in Brown-Norway rats].
When injected intravenously with dextran or O-hydroxyethyl derivatives of rutoside, rat Brown Norway BN/Mai Pfd f exhibit a fall in the blood pressure and an increase of vascular permeability with oedema formation. As the rat is genetically deprived of plasmatic prekallikrein an of kininogens, activation of the kinin system is not necessary neither for mast-cell degranulation nor for amine release.


Magnetic dipole with a flexible tail as a self-propelling microdevice.
By numerical simulations, it is illustrated that a magnetic dipole with a flexible tail behaves as a swimmer in AC magnetic fields. The behavior of the swimmer on long time scales is analyzed and it is shown that due to the flexibility of the tail two kinds of torques arise, the first is responsible for the orientation of the swimmer perpendicularly to the AC field and the second drags the filament in the direction of the rotating field. Due to this, circular trajectories of the swimmer are possible; however, these are unstable. The self-propulsion velocity of this swimmer is higher than the velocities of other magnetic microdevices for comparable values of the magnetoelastic number.


Optimized free-form phase mask for extension of depth of field in wavefront-coded imaging.
To achieve a further extension of the depth of field in wavefront-coded imaging by reducing the impact of focus error in the optical transfer function, we propose the use of a free-form phase mask (FPM) instead of a conventional cubic phase mask (CPM). We optimized the shape of the FPM using the simulated annealing algorithm and confirmed that the optimized FPM provides a much larger focal tolerance and better final images than the CPM in the noise-free case.


Effect of electromechanical coupling on static deformations and natural frequencies.
A two-way coupled electromechanical theory is used to study static deformations and free vibrations of a laminated hybrid rectangular plate comprised of either piezoceramic (PZT) layers or patches embedded at arbitrary locations in graphite/epoxy layers. A first-order shear deformation theory is used to develop equations for the plate which are solved by the finite-element method (FEM) using eight-node isoparametric elements. Static deflections and natural frequencies computed with open-circuited PZT layers are found to differ significantly from those of grounded PZT layers.