The effects of radiation on the expression of a newly cloned and characterized rat cyclin B mRNA.
To evaluate the hypothesis that the radiation induced G2 delay in the cell cycle is associated with radiation induced effects on cyclin B expression in a rodent cell system. Two rodent, rat and Chinese hamster, cyclin B cDNAs were cloned and characterized. The two rodent species were 85% and 86% identical, respectively, when compared to the human cyclin B, indicating that they are the rodent homologous of cyclin B. 3.7 cells (rat embryo cells transformed by H-ras and v-myc) were synchronized and then irradiated. Flow cytometry and Northern blots were performed to evaluate the effects of radiation on cyclin expression in relation to phase of the cell cycle. Examination of the rodent cyclin B sequences revealed only two regions with significant divergence to the human sequence, one in the lysine rich region adjacent to the cyclin destruction box, which is the putative site for ubiquitination, and one at the C terminal end. Although many of the amino acids diverged in the lysine rich region, the positions of the lysines themselves were virtually invariant suggesting their potential importance in ubiquitination. Both rodent species were also noted to have a PEST-like sequence which occurs in the human, but not in non-mammalian cyclins cloned to date and could also potentially contribute to rapid destruction. The rat and Chinese hamster mRNAs contain much longer 3' untranslated regions than the published human sequence with multiple AUUUA and AUUU motifs which are seen in other mRNAs with rapid turnover times. This feature has not been previously found in cyclin mRNAs. In addition we have found that in the 3' region of the rodent cDNAs we find two potential polyadenylation sites suggesting that this gene may have several transcripts. Our studies suggest that multiple mechanisms of control of mammalian cyclin B destruction exist, both at the mRNA and protein level. Evidence is also provided that the levels of rat cyclin B mRNA peaks during G2/M. Irradiation is shown to induce a G2 delay in synchronized 3.7 cells, compared to unirradiated controls, and the delay is temporally related to decreased levels of cyclin B mRNA expression. Since the G2 delay induced by ionizing radiation may contribute to the ability of cells to survive irradiation, cyclin B expression may be a key component in the determination of sensitivity or resistance to radiation therapy. The isolation and characterization of two rodent cyclin B's confirm that multiple mechanisms of control of mammalian cyclin B destruction exist. Our studies show that rat cyclin B expression is influenced by radiation and is temporally related to the delay in the G2 phase induced by radiation.


Antitrypanosomal activity of new semi-synthetic bergenin derivatives.
Bergenin and 11-O-(4'-O-methyl galloyl)-bergenin, previously isolated from Crassula capitella extract, were used as starting materials for the synthesis of eight derivatives; four derivatives 2a-2d were synthesized from bergenin through the formation of ester derivatives and four alkyl derivatives 4a-4d were synthesized from 11-O-(4'-O-methyl galloyl)-bergenin. The structures of the synthesized analogues were confirmed upon 1 H and 13 C NMR spectroscopic elucidation. Antileishmanial and antitrypanosomal activities of the synthesized derivatives were evaluated, compounds 11-O-(3',5' di-benzyl, 4'-O-methyl galloyl)-8,10-di-O-benzyl-bergenin (4c) and 11-O-(3',5'di-4-chlorobenzyl,4'-O-methyl galloyl)-8,10di-O-4-chlorobenzyl bergenin (4d) showed potent antitrypanosomal activity with IC50 values of 0.52 and 0.5 μM, respectively and IC90 values of 0.66 μM against T. brucei compared with IC50 and IC90 values of 21.7 and 50.3 μM for the positive control difluoromethylornithine.


Azide-Terminated RAFT Polymers for Biological Applications.
Reversible addition-fragmentation chain-transfer (RAFT) polymerization is a commonly used polymerization methodology to generate synthetic polymers. The products of RAFT polymerization, i.e., RAFT polymers, have been widely employed in several biologically relevant areas, including drug delivery, biomedical imaging, and tissue engineering. In this article, we summarize a synthetic methodology to display an azide group at the chain end of a RAFT polymer, thus presenting a reactive site on the polymer terminus. This platform enables a click reaction between azide-terminated polymers and alkyne-containing molecules, providing a broadly applicable scaffold for chemical and bioconjugation reactions on RAFT polymers. We also highlight applications of these azide-terminated RAFT polymers in fluorophore labeling and for promoting organelle targeting capability. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Synthesis of the azide derivatives of chain transfer agent and radical initiator Basic Protocol 2: Installation of an azide group on the α-end of RAFT polymers Alternate Protocol: Installation of an azide group on the ω-end of RAFT polymers Basic Protocol 3: Click reaction between azide-terminated RAFT polymers and alkyne derivatives.


The late-onset psychoses. Possible risk factors.
Schizophrenia and depressive illness can manifest for the first time in late life. Similarities to the early-life forms of the illnesses appear to outweigh the differences. Disparities in symptoms and risk factors in the elderly likely stem from biologic and social changes that are part of the aging process.


Mutations in the stromal antigen 3 (STAG3) gene cause male infertility due to meiotic arrest.
Are sequence variants in the stromal antigen 3 (STAG3) gene a cause for non-obstructive azoospermia (NOA) in infertile human males? Sequence variants affecting protein function of STAG3 cause male infertility due to meiotic arrest. In both women and men, STAG3 encodes for a meiosis-specific protein that is crucial for the functionality of meiotic cohesin complexes. Sequence variants in STAG3 have been reported to cause meiotic arrest in male and female mice and premature ovarian failure in human females, but not in infertile human males so far. The full coding region of STAG3 was sequenced directly in a cohort of 28 men with NOA due to meiotic arrest. In addition, a larger group of 275 infertile men that underwent whole-exome sequencing (WES) was screened for potential STAG3 sequence variants. Furthermore, meiotic spreads, immunohistochemistry, WES and population sampling probability (PSAP) have been conducted in the index case. This study included 28 infertile but otherwise healthy human males who underwent Sanger sequencing of the full coding region of STAG3. Additionally, WES data of 275 infertile human males with different infertility phenotypes have been screened for relevant STAG3 variants. All participants underwent karyotype analysis and azoospermia factor (AZF) screening in advance. In the index patient, segregation analysis, WES data, PSAP, lab parameters, testis histology and nuclear spreads have been added to suplort the findings. Two compound-heterozygous variants in STAG3 (c.[1262T>G];[1312C>T], p.[(Leu421Arg)];[(Arg438Ter)]) have been found to cause male infertility due to complete bilateral meiotic arrest in an otherwise healthy human male. Compound heterozygosity was confirmed by Sanger sequencing of the parents and the patient's brother. Other variants which may affect spermatogenesis have been ruled out through analysis of the patient's WES data and application of the PSAP pipeline. As expected from Stag3 knockout-mice meiotic spreads, germ cells did not develop further than zygotene and showed drastic chromosome aberrations. No rare variants in STAG3 were found in the 275 infertile males with other phenotypes. Our results indicate that STAG3 variants that negatively affect its protein function are a rare cause of NOA (<1% of cases). We identified only one patient with compound-heterozygous variants in STAG3 causing NOA due to meiotic arrest. Future studies should evaluate STAG3 variants in larger cohorts to support this finding. Identification of STAG3 sequence variants in infertile human males should improve genetic counselling as well as diagnostics and treatment. Especially before testicular sperm extraction (TESE) for ICSI, STAG3 variants should be ruled out to prevent unnecessary interventions with frustrating outcomes for both patients and clinicians. This work was carried out within the frame of the German Research Foundation (DFG) Clinical Research Unit 'Male Germ Cells: from Genes to Function' (CRU326). Work in the laboratory of R.J. is supported by a grant of the European Union H2020 program GermAge. The authors declare no conflicts of interest. Not applicable.


Dosimetry of 70 MeV proton beams from the NIRS cyclotron.
Dosimetry of 70 MeV proton beams for radiotherapy was carried out using various ionization chambers. The beam irradiation conditions, dose estimation with an ionization chamber, measurement of dose distributions, and calculation of isodose curves for the proton beams will be discussed.


Cataract wound closure with polyglactin 910 following insertion of a 4-loop Binkhorst lens: preliminary report.
In this preliminary report our results with 8-0 braided polyglactin 910 suture for cataract wound closure after insertion of a 4-loop Binkhorst lens were encouraging. However, more experience is required before valid conclusions can be reached regarding its safety. Early experience indicates that the surgeon should approach the use of 9-0 monofilament polyglactin 910 suture for cataract wound closure following insertion of an intraocular lens with extreme caution.


Effect of pressure drop on solute retention and column efficiency in supercritical fluid chromatography.
The effect of pressure drop on the performance of supercritical fluid chromatographic systems is studied. Experiments have been conducted at different pressures and at 55 and 65 degrees C. Experiments at conditions leading to large and small pressure drops have been performed. Parameters to describe the pressure drop, retention time and efficiency have been extracted from these experiments. Using these parameters the dynamics of the chromatographic column have been modeled. Darcy's law was used to describe the pressure drop. The efficiency was modeled by considering the contributions from axial dispersion, resistance to mass transfer from the fluid film, and to diffusion in the pores. Good description of the pressure drop, retention time and mass transfer characteristics under normal operating conditions was obtained. The parameters extracted were used to predict the elution profile by numerical simulations. Considerable loss in column efficiency was observed when operating the column at lower values of the back pressure.


Impact of one HF-rTMS session on fine motor function in right-handed healthy female subjects: a comparison of stimulation over the left versus the right dorsolateral prefrontal cortex.
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive tool to investigate neural conduction in motor processes. Most rTMS research has been conducted by targeting the primary motor cortex. Several studies have also found increased psychomotor speed after rTMS of the dorsolateral prefrontal cortex (DLPFC). However, these studies were mainly performed in psychiatric patients, only targeting the left DLPFC, and often without sham control. Moreover, psychomotor speed is mostly measured based on tasks that also require higher executive functions. Here, we examined the lateralized effect of one sham-controlled high-frequency rTMS session applied to the left or right DLPFC on fine motor function in 36 healthy right-handed females, using the Fitts' paradigm. We found a significant improvement in psychomotor speed only after actively stimulating the right DLPFC. Our results support the assumption of a right prefrontal neural network implicated in visuomotor behavior and performance processes, and that the improvement in psychomotor speed is not a secondary effect of decreased mood.


Lipid-lowering therapy in high-risk persons.
Randomized, double-blind, placebo-controlled studies and observational studies have demonstrated that statins reduce mortality and major cardiovascular events in high-risk persons with hypercholesterolemia. The Heart Protection Study showed that statins reduced mortality and major cardiovascular events in high-risk persons, regardless of the initial level of serum lipids, age, or gender. Lipid-lowering therapy reduces cardiovascular morbidity and mortality in high-risk persons, forming the basis for the updated National Cholesterol Education Program (NCEP) III guidelines.


Rapid determination of 5-hydroxymethylfurfural by DART ionization with time-of-flight mass spectrometry.
DART (direct analysis in real time), a novel technique with wide potential for rapid screening analysis, coupled with high-resolution time-of-flight mass spectrometry (TOF-MS) has been used for quantitative analysis of 5-hydroxymethylfurfural (5-HMF), a typical temperature marker of food. The DART/TOF-MS method was optimised and validated. Quantification of 5-HMF was achieved by use of a stable isotope-labelled 5-HMF standard prepared from glucose. Formation of 5-HMF from saccharides, a potential source of overestimation of results, was evaluated. Forty-four real samples (honey and caramelised condensed sweetened milk) and 50 model samples of heated honey were analysed. The possibility of using DART for analysis of heated samples of honey was confirmed. HPLC and DART/TOF-MS methods for determination of 5-HMF were compared. The correlation equation between these methods was DART = 1.0287HPLC + 0.21340, R(2) = 0.9557. The DART/TOF-MS method has been proved to enable efficient and rapid determination of 5-HMF in a variety of food matrices, for example honey and caramel.


Flies developed smaller cells when temperature fluctuated more frequently.
Changes in cell size might be an important component of adaptation to thermal heterogeneity. Although Drosophila melanogaster develops smaller cells at fluctuating temperatures, we do not know whether this response depends on the frequency or amplitude of thermal change. In a laboratory experiment, we exposed flies to either frequent or infrequent fluctuations between 17 and 27 °C, while controlling the total exposure to each temperature. Flies emerged from these treatments with similar body sizes, but flies at more frequent fluctuations emerged earlier and had smaller epidermal cells for a given body size. Tissue built from small cells has more nuclei for transcription, shorter distances between cell compartments, and a larger surface area for transport across membranes. Therefore, we hypothesize that physiological effects of small cells reduce lags in metabolic activity and enhance performance of flies during warming. For plasticity of cell size to confer a fitness advantage, this hypothetical benefit must outweigh the cost of maintaining a greater area of plasma membrane.


Transient osteoporosis of the hip in the first trimester of pregnancy. A case report and review of Japanese literature.
A patient with transient osteoporosis of the hip in her first trimester of pregnancy is reported in this study. Rapid symptomatic improvement after artificial abortion was observed. These findings exclude pressure on the obturator nerve, Sudeck's osteodystrophy, venous obstruction, and excessive demand of proteins and calcium in the etiology of this condition. Rather it is here suggested that chemical or hormonal factors related to pregnancy play an important role in the etiology.


A numerical taxonomic study of the strains of three types of Corynebacterium renale.
Numerical analysis has been carried out on 100 features of 55 strains of Corynebacterium renale. Three phena were formed, which respectively corresponded to three immunological types of C. renale.


Methane emissions from cypress knees in a southeastern floodplain swamp.
Methane emissions were observed from knees of baldcypress (Taxodium distichum) in floodplain swamps of the Ogeechee river, a blackwater river in the lower coastal plain of Georgia, USA Emissions were sampled on 10 dates from March 1988 to September 1989, with small chambers placed over single knees. Methane emission rates from individual knees averaged 0.90 mg/d, corresponding to an average of 0.14 mg m-2 d-1 for the whole floodplain. In the habitat with the highest knee density (0.42 knees/m2), the average rate was 0.55 mg m-2 d-1. Spatial patterns in emissions from knees were similar to those of overall methane emissions from the swamp surface, though because of their low density were a minor contribution (0.42%) to total methane emissions from this system.


The adsorption process during inorganic phosphorus removal by cultured periphyton.
To explain the detailed process involved in phosphorus removal by periphyton, the periphyton dominated by photoautotrophic microorganisms was employed in this study to remove inorganic phosphorus (Pi) from wastewater, and the removal kinetics and isotherms were then evaluated for the Pi removal process. Results showed that the periphyton was capable of effectively removing Pi that could completely remove the Pi in 24 h at an initial Pi concentration of 13 mg P L(-1). Furthermore, the Pi removal process by the periphyton was dominated by adsorption at initial stage (~24 h), which involved physical mechanistic process. However, this Pi adsorption process was significantly influenced by environmental conditions. This work provides an insight into the understanding of phosphorus adsorption by periphyton or similar microbial aggregates.


The effect of cationic charge on release of eosinophil mediators.
In patients with atopic diseases, cationic-charged eosinophil proteins are deposited in inflamed tissues. Although the role of cytokines in cell activation is well established, the presence of cationic-charged tissue can also be an important factor in inflammatory cell function. We sought to determine whether increased cationic charge seen in an atopic microenvironment plays a role in the activation of eosinophils. Human eosinophils were incubated with Sepharose beads coated with cationic or anionic compounds in the presence and absence of a cytokine cocktail (IL-3, IL-5, and GM-CSF) to simulate the milieu of inflammation. Eosinophil peroxidase and eosinophil-derived neurotoxin (EDN) release were compared with eosinophil morphology and expression of CD18, as determined by means of confocal microscopy. Cytokines with positively charged beads caused greater eosinophil peroxidase release (lysine coated, 44.2 nmol/L; compound 48/80, 40.0 nmol/L; or EDN coated, 49.1 nmol/L) than cytokines alone (14.9 nmol/L). Beads coated with heparin, dextran sulfate, and aspartic acid did not show this effect. EDN release was also induced by lysine-coated beads with cytokines (67.1 ng/100 microL) and blocked by heparin. Eosinophil incubation with wortmannin, genistein, and the src kinase inhibitor PP1 blocked cationic signaling. Eosinophils adherent to cationic-charged beads but not anionic-charged beads show polarization of CD18 expression toward the bead's surface. Cationic-charged surfaces induce increased eosinophil mediator release by increasing the density of CD18 expression available at the target surface.


Fully-automated functional region annotation of liver via a 2.5D class-aware deep neural network with spatial adaptation.
Automatic functional region annotation of liver should be very useful for preoperative planning of liver resection in the clinical domain. However, many traditional computer-aided annotation methods based on anatomical landmarks or the vascular tree often fail to extract accurate liver segments. Furthermore, these methods are difficult to fully automate and thus remain time-consuming. To address these issues, in this study we aim to develop a fully-automated approach for functional region annotation of liver using deep learning based on 2.5D class-aware deep neural networks with spatial adaptation. 112 CT scans were fed into our 2.5D class-aware deep neural network with spatial adaptation for automatic functional region annotation of liver. The proposed model was built upon the ResU-net architecture, which adaptively selected a stack of adjacent CT slices as input and, generating masks corresponding to the center slice, automatically annotated the liver functional region from abdominal CT images. Furthermore, to minimize the problem of class-level ambiguity between different slices, the anatomy class-specific information was used. The final algorithm performance for automatic functional region annotation of liver showed large overlap with that of manual reference segmentation. The dice similarity coefficient of hepatic segments achieved high scores and an average dice score of 0.882. The entire calculation time was quite fast (~5 s) compared to manual annotation (~2.5 hours). The proposed models described in this paper offer a feasible solution for fully-automated functional region annotation of liver from CT images. The experimental results demonstrated that the proposed method can attain a high average dice score and low computational time. Therefore, this work should allow for improved liver surgical resection planning by our precise segmentation and simple fully-automated method.


A study of skin characteristics with long-term sleep restriction in Korean women in their 40s.
Previous studies have demonstrated increased pore size and darkening skin color with total sleep deprivation. There are many studies of skin characteristics with short-term sleep restriction, but there are few studies on skin characteristics when sleep is restricted more than three consecutive days. This study evaluated skin changes with sleep limited to 4 hours per night for six nights. The study included 32 Korean women in their 40s. Skin hydration, desquamation, barrier recovery, texture, gloss, transparency, elasticity, crow's feet, frown lines, and color were measured. Individual sleep time was monitored by smartwatches. Subjects slept 8 hours per night for six nights in week one and 4 hours per night for six nights in week two. Skin hydration was significantly reduced after 1 day of sleep deprivation, and it continued to decrease. Skin gloss, desquamation, transparency, elasticity, and wrinkles were significantly aggravated after 1 day of sleep deprivation. Skin texture was significantly aggravated on the fourth day of sleep restriction. Elasticity was most affected by reduced sleep, with a standardized coefficient of -.320, indicating a significant decrease over time as compared to other characteristics. Skin hydration was gradually decreased with sleep restriction. Skin texture did not change after only 1 day of sleep restriction. It is a new finding that elasticity decreases more than other skin characteristics with prolonged sleep restriction.


Barium proctography vs magnetic resonance proctography for pelvic floor disorders: a comparative study.
Accurate and reliable imaging of pelvic floor dynamics is important for tailoring treatment in pelvic floor disorders; however, two imaging modalities are available. Barium proctography (BaP) is widely used, but involves a significant radiation dose. Magnetic resonance (MR) proctography allows visualization of all pelvic midline structures but patients are supine. This project investigates whether there are measurable differences between BaP and MR proctography. Patient preference for the tests was also investigated. Consecutive patients referred for BaP were invited to participate (National Research Ethics Service approved). Participants underwent BaP in Poole and MR proctography in Dorchester. Proctograms were reported by a consultant radiologist with pelvic floor subspecialization. A total of 71 patients were recruited. Both tests were carried out on 42 patients. Complete rectal emptying was observed in 29% (12/42) on BaP and in 2% (1/42) on MR proctography. Anismus was reported in 29% (12/42) on BaP and 43% (18/42) on MR proctography. MR proctography missed 31% (11/35) of rectal intussusception detected on BaP. In 10 of these cases no rectal evacuation was achieved during MR proctography. The measure of agreement between grade of rectal intussusception was fair (κ=0.260) although MR proctography tended to underestimate the grade. Rectoceles were extremely common but clinically relevant differences in size were evident. Patients reported that they found MR proctography less embarrassing but harder to empty their bowel. The results demonstrate that MR proctography under-reports pelvic floor abnormalities especially where there has been poor rectal evacuation.


Management of frontal sinus fractures.
The traditional treatment of frontal sinus fractures is undergoing a review by many clinicians. This review will undoubtedly contribute to the existing controversy surrounding the management of patients with this condition. This article seeks to further the review and suggest the authors' perspective on a more appropriate approach to the care of patients with frontal sinus injuries.


Reverse vaccinology and immunoinformatics approaches to design multi-epitope based vaccine against oncogenic KRAS.
Mutant KRAS-induced tumorigenesis is highly involved in the progression of pancreatic, lung, and breast cancer. Comparatively, KRAS G12D and KRAS G12C are the most frequent mutations that promote cancer progression and aggressiveness. Although KRAS mutant inhibitors exhibit significant therapeutic potential, day by day, they are becoming resistant among patients. Multi-epitope based cancer vaccines are a promising alternative strategy that induces an immune response against tumor antigens. In the present study, we have designed, constructed, and validated a novel multi-epitope vaccine construct against KRAS G12D and G12C mutants using reverse vaccinology and immunoinformatics approaches. In addition, the vaccine construct was structurally refined and showed significant physiochemical properties, and could induce an immune response. Furthermore, the optimized vaccine construct was cloned into a pET‑28a (+) expression vector through in silico cloning. Conclusively, the multi-epitope vaccine construct is structurally stable, soluble, antigenic, non‑allergic, and non‑toxic. Further, it has to be studied in in vitro and in vivo to evaluate its therapeutic efficacy against KRAS-mutated cancers in the near future.


Anatomic study of lateral pelvic lymph nodes: implications in the treatment of rectal cancer.
Lateral pelvic lymphadenectomy remains a controversial issue in rectal cancer surgery. Beyond clinical results, disagreement includes surgical anatomy aspects and definitions, as wells as lack of information about location, groups, and number of lymph nodes, all of which makes comparison of results difficult. We performed a systematic examination of the number and distribution of lateral pelvic lymph nodes using cadaveric dissection. Sixteen formalin-fixed cadavers were dissected (14 males). Dissection fields were divided according to the three surgical groups of pelvic wall lymph nodes: presacral, obturator, and hypogastric. Number and site of excised lymph nodes was recorded, noting neurovascular relationships. A total of 458 lymph nodes were found, with a mean of 28.6 nodes per pelvis (range, 16-46). Lymph node size ranged from 2 to 13 mm. The highest number of lymph nodes was found in the obturator fossa group (mean, 7; range, 2-18). Hypogastric lymph nodes were found lying predominantly above the inferior hypogastric nerve plexus but reaching the deep pelvic veins. The mean number of lymph nodes found in lateral pelvic wall compartments was 28.6 per specimen. The group containing most lymph nodes lies in the obturator fossa. Complete excision of hypogastric lymph nodes demands a deep pelvic dissection of neurovascular structures.


Resilience in Nurses: The Reliability and Validity of the Resilience Scale.
Background and Purpose: The Resilience Scale (RS) RS-25 and shortened RS-14 have measured resilience but not with nurses. Our purpose was to investigate both for nurses. Methods: A random sample of 345 RNs from the North Carolina Board of Nursing completed an online questionnaire. Parallel analysis, factor analysis, and receiver operating characteristic analysis were performed. Results: Previous RS factor models had poor confirmatory factor analysis fit. Exploratory factor analysis and item analyses suggested removing items. Good fit was found for an "RS-13" using a bifactor approach. Adequate internal consistency was demonstrated (omega = 0.77-0.90). The RS-13 general factor gave similar accuracy for bullying, physical and mental quality of life, stress, and intent to leave. Conclusions: A shortened RS is comparable in reliability, construct, and convergent validity. It measures nurse resilience well.


Ankle mobility in relation to chronic venous insufficiency in HIV-positive persons with and without a history of injection drug use.
The purpose of this study was to examine ankle mobility in relation to chronic venous insufficiency (CVI) in HIV-positive persons with and without a history of injection drug use (IDU) and to examine the extent to which peripheral neuropathy further reduced ankle mobility. A cross-sectional, stratified design with quota sampling was used to recruit 27 persons with no history of IDU and 46 with a history of IDU from an infectious diseases clinic. Goniometric measurements of forefoot inversion-eversion and dorsiflexion-plantar flexion were obtained. CVI was assessed on a clinical scale. Peripheral neuropathy was identified from chart review and self-report. Injection drug users had less ankle flexion-extension right, inversion-eversion left and right, and total ankle motion than those who did not inject drugs (p < .05). Neuropathy was not associated with less mobility of the ankle joint (p < .01). A causal model supported the hypothesis of ankle mobility as a mediator of the effect of IDU on CVI.


SPectroscOpic prediction of bRain Tumours (SPORT): study protocol of a prospective imaging trial.
The revised 2016 WHO-Classification of CNS-tumours now integrates molecular information of glial brain tumours for accurate diagnosis as well as for the development of targeted therapies. In this prospective study, our aim is to investigate the predictive value of MR-spectroscopy in order to establish a solid preoperative molecular stratification algorithm of these tumours. We will process a 1H MR-spectroscopy sequence within a radiomics analytics pipeline. Patients treated at our institution with WHO-Grade II, III and IV gliomas will receive preoperative anatomical (T2- and T1-weighted imaging with and without contrast enhancement) and proton MR spectroscopy (MRS) by using chemical shift imaging (MRS) (5 × 5 × 15 mm3 voxel size). Tumour regions will be segmented and co-registered to corresponding spectroscopic voxels. Raw signals will be processed by a deep-learning approach for identifying patterns in metabolic data that provides information with respect to the histological diagnosis as well patient characteristics obtained and genomic data such as target sequencing and transcriptional data. By imaging the metabolic profile of a glioma using a customized chemical shift 1H MR spectroscopy sequence and by processing the metabolic profiles with a machine learning tool we intend to non-invasively uncover the genetic signature of gliomas. This work-up will support surgical and oncological decisions to improve personalized tumour treatment. This study was initially registered under another name and was later retrospectively registered under the current name at the German Clinical Trials Register (DRKS) under DRKS00019855.


Alterations in nigral NMDA and GABAA receptor control of the striatal dopamine level after repetitive exposures to nitrogen narcosis.
Nitrogen pressure exposure in rats results in decreased dopamine (DA) release at the striatal terminals of the substantia nigra pars compacta (SNc) dopaminergic neurons, demonstrating the narcotic potency of nitrogen. This effect is attributed to decreased excitatory and increased inhibitory inputs to dopaminergic neurons, involving a change in NMDA and GABA(A) receptor function. We investigated whether repetitive exposures to nitrogen modify the excitatory and inhibitory control of the dopaminergic nigro-striatal pathway. We used voltammetry to measure dopamine levels in freely-moving rats, implanted with dopamine-sensitive electrodes in the striatum. NMDA/GABA(A) receptor agonists (NMDA/muscimol) and antagonists (AP7/gabazine) were administered through a guide-cannula into the SNc, and their effects on striatal dopamine levels were measured under normobaric conditions, before and after five repetitive exposures to 1 MPa nitrogen. NMDA-mediated dopamine release was greater following repetitive exposures, AP7-mediated inhibition of glutamatergic input was blocked, suggesting that NMDA receptor sensitivity was increased and glutamate release reduced. Muscimol did not modify dopamine levels following repetitive exposures, whereas the effect of gabazine was greater after exposures than before. This suggested that interneuronal GABA(A) receptors were desensitized, leading to an increased GABAergic input at dopaminergic cells. Thus, repetitive nitrogen exposure induced persistent changes in glutamatergic and GABAergic control of dopaminergic neurons, resulting in decreased activity of the nigrostriatal pathway.


Primary postpartum haemorrhage in Tasmania 1982-1986.
Primary postpartum haemorrhage remains a significant problem in modern obstetric practice. The incidence and factors associated with postpartum haemorrhage in Tasmania over a 5-year period were studied. The mode of delivery, anaesthesia, birth-weight, induction and augmentation of labour, multiple pregnancy, antepartum haemorrhage and hypertension were found to be important factors. The incidence of retained placenta was not considered in this study.


Disruption of gap junctional intercellular communication in human renal cancer cell lines.
Gap junctional intercellular communication (GJIC) is believed to play an important role in the maintenance of cell homeostasis, and its disruption may be associated with carcinogenesis. However, GJIC has not been detected in many human cancers. We therefore studied the regulation of GJIC in human renal cancer cell lines. We examined the human renal cancer cell lines, ACHN and NT, as well as Madin-Darby canine kidney (MDCK) cells as a positive control, using GJIC assays, Northern blotting to detect connexin 43 mRNA, immunofluorescent staining, and Western blotting of connexin 43 protein. GJIC of ACHN and NT was completely blocked. In ACHN cells, connexin 43 mRNA was not altered. However, connexin 43 protein was aberrantly localized and phosphorylated connexin 43 protein had disappeared. Both connexin 43 protein and its mRNA were undetectable in NT cells. GJIC in human renal cancer cell lines is impaired and various pathways may inhibit this mechanism in renal cancer. We believe that connexin plays an important role in renal carcinogenesis.


An Evaluation of Six Brief Interventions that Target Drug-Related Problems in Correctional Populations.
Finding brief effective treatments for criminal justice populations is a major public need. The CJ-DATS Targeted Intervention for Corrections (TIC), which consists of six brief interventions (Communication, Anger, Motivation, Criminal Thinking, Social Networks, and HIV/Sexual Health), were tested in separate federally-funded randomized control studies. In total, 1,573 criminal justice-involved individuals from 20 correction facilities participated (78% males; 54% white). Multi-level repeated measures analyses found significant gains in knowledge, attitudes, and psychosocial functioning (criteria basic to Knowledge, Attitude, and Practices (KAP) and TCU Treatment Process Models). While improvements were less consistent in criminal thinking, overall evidence supported efficacy for the TIC interventions.


Occupant-centric robotic air filtration and planning for classrooms for Safer school reopening amid respiratory pandemics.
Coexisting with the current COVID-19 pandemic is a global reality that comes with unique challenges impacting daily interactions, business, and facility maintenance. A monumental challenge accompanied is continuous and effective disinfection of shared spaces, such as office/school buildings, elevators, classrooms, and cafeterias. Although ultraviolet light and chemical sprays are routines for indoor disinfection, they irritate humans, hence can only be used when the facility is unoccupied. Stationary air filtration systems, while being irritation-free and commonly available, fail to protect all occupants due to limitations in air circulation and diffusion. Hence, we present a novel collaborative robot (cobot) disinfection system equipped with a Bernoulli Air Filtration Module, with a design that minimizes disturbance to the surrounding airflow and maneuverability among occupants for maximum coverage. The influence of robotic air filtration on dosage at neighbors of a coughing source is analyzed with derivations from a Computational Fluid Dynamics (CFD) simulation. Based on the analysis, the novel occupant-centric online rerouting algorithm decides the path of the robot. The rerouting ensures effective air filtration that minimizes the risk of occupants under their detected layout. The proposed system was tested on a 2 × 3 seating grid (empty seats allowed) in a classroom, and the worst-case dosage for all occupants was chosen as the metric. The system reduced the worst-case dosage among all occupants by 26% and 19% compared to a stationary air filtration system with the same flow rate, and a robotic air filtration system that traverses all the seats but without occupant-centric planning of its path, respectively. Hence, we validated the effectiveness of the proposed robotic air filtration system.


Electron-microscopic imaging of single-walled carbon nanotubes grown on silicon and silicon oxide substrates.
Direct imaging of single-walled carbon nanotubes (SWNTs) suspended on pillar-patterned Si or SiO2 substrates is investigated using transmission electron microscopy (TEM) and scanning electron microscopy (SEM). The suspended nanotubes are successfully observed by direct TEM imaging and it is seen that they have either individual or bundles of SWNTs. Low energy (< or =2 keV) SEM produces high contrast images of suspended SWNTs. On the contrary, when SWNTs contact a SiO2 substrate, they are imaged using electron-beam induced current. The image brightness depends on the length of SWNTs.


Hospital dietetics and food service in developing countries: III. Bangladesh.
A survey of 11 hospitals in Bangladesh revealed that most heads of hospital food service had little or no training in nutrition and dietetics, hospital diets were usually inadequate, therapeutic diets were seldom used, and kitchen sanitation was poor. However, in three hospitals in which the heads of food service had some education in nutrition, conditions were markedly better. Even though the results of this survey suggest that major improvements are needed in hospital food service and dietetics in Bangladesh, extensive training programs are probably unrealistic because of the limited economic base of the country. Short-term inservice training programs could result in marked improvement in the quality of food service, sanitation, and the use of therapeutic diets.


CT-Guided Chemical Thoracic Sympathectomy versus Botulinum Toxin Type A Injection for Palmar Hyperhidrosis.
The present study aimed to evaluate and compare the efficacy of botulinum toxin type A (BTX-A) injection versus thoracic sympathectomy for idiopathic palmar hyperhidrosis. Fifty-one patients with idiopathic palmar hyperhidrosis were treated with either BTX-A injection or thoracic sympathectomy between March 2013 and April 2016. The severity of palmar hyperhidrosis was qualitatively measured via the Hyperhidrosis Disease Severity Scale (HDSS). All patients completed a questionnaire that detailed the time taken for the treatment to work, local or systemic adverse effects, and pre- and post-treatment severity of hyperhidrosis. The efficacy and adverse effects of the two treatments were compared and analyzed. Hyperhidrosis-related quality of life improved quickly and significantly in the BTX-A group (26 patients) and the sympathectomy group (25 patients). Compared with pre-treatment, the HDSS score significantly reduced after treatment in both groups (p < 0.05). All patients in the sympathectomy group had cessation of sweating of the hands after treatment, and this curative effect lasted for 12 months. In contrast, the treatment took more time to work in the BTX-A group, and the curative effect lasted for a much shorter period (3 months). The sympathectomy group had a significantly lesser mean HDSS score than the BTX-A group at 1 week, 3 months, 6 months, 9 months, and 12 months after treatment (p < 0.05). The sympathectomy group experienced more complications than the BTX-A group. For palmar hyperhidrosis, thoracic sympathectomy is more effective and has a longer lasting curative effect than BTX-A injection, but thoracic sympathectomy has more complications.


Agitated saline contrast echocardiography reveals cor triatriatum dexter.
We present the case of a 54-year-old man who had an unusual finding in contrast echocardiography with agitated saline. Partition of the right atrium in two compartments, an opacified and a non-opacified one, was noted. Further assessment with a transesophageal echocardiogram revealed the presence of a membrane in the right atrium, with the final diagnosis being cor triatriatum dexter.


A pathologic study of allergic bronchopulmonary aspergillosis.
A lung biopsy specimen was obtained from a 10-year-old boy with cystic fibrosis and allergic bronchopulmonary aspergillosis. Light microscopy revealed a marked inflammatory process that was largely bronchocentric. Infiltrating cells included lymphocytes, plasma cells, monocytes, and numerous eosinophils. Elastin layers were intact in blood vessels and markedly disrupted in bronchioles. By immunofluorescent, major basic protein was demonstrated in eosinophils, was freely deposited outside of eosinophils, especially in the interlobular septum, and was taken up by macrophages. A number of lymphocytes stained positively for IgE. Through an immunoperoxidase stain, septate hyphae of Aspergillus were clearly observed in the lung parenchyma. A significant increase in interleukin-2 positive-staining T cells was observed with an approximate 2:1 ratio of helper to suppressor cells. The use of newer immunohistologic techniques has enabled us to gain additional insights into the pathogenesis of allergic bronchopulmonary aspergillosis.


Decidual cell-expressed tissue factor in human pregnancy and its involvement in hemostasis and preeclampsia-related angiogenesis.
During extravascular trophoblast (EVT) invasion of the decidua, thrombin generated from decidual cell-expressed tissue factor (TF) forms a "hemostatic envelope" that protects against hemorrhage during the initial breaching of capillaries by EVTs and subsequent invasion and remodeling of the spiral arteries and arterioles. Preeclampsia, the world's leading cause of fetal and maternal morbidity and mortality, stems from shallow trophoblast invasion leading to incomplete vascular remodeling that impairs uteroplacental blood flow. A considerable subset of cases of preeclampsia is associated with decidual hemorrhage and maternal thrombophilias, which form excess thrombin from decidual cell-expressed TF. Thrombin affects several cell functions by binding to protease-activated receptors. In first-trimester decidual cells, thrombin enhances expression of sFlt-1, which can block the angiogenic effects of vascular endothelial growth factor (VEGF) and placental growth factor. By contrast, thrombin does not affect decidual cell VEGF expression. Thrombin-enhanced sFlt-1 expression by decidual cells, the predominant cell type encountered by invading cytotrophoblasts, could promote preeclampsia by interfering with angiogenesis-dependent vascular remodeling to reduce uteroplacental blood flow.


Benzodiazepine, z-drug and pregabalin prescriptions and mortality among patients in opioid maintenance treatment-A nation-wide register-based open cohort study.
Use of sedatives may increase risk of death in opioid users. The aim of the study was to assess whether prescription of sedatives may be associated with mortality in patients in opioid maintenance treatment. This retrospective register-based open cohort study included nation-wide register data including all individuals who were dispensed methadone or buprenorphine as opioid maintenance treatment for opioid dependence between July, 2005 and December, 2012 (N=4501). Outcome variables were overdose mortality and non-overdose mortality, respectively. Extended Cox regression analyses examined associations between type of sedative prescriptions and death, controlling for sex, age, previous overdoses and suicide attempts, psychiatric in-patient treatment and opioid maintenance treatment status. Opioid maintenance was assumed to last for 90days (or 30days in a sensitivity analysis) after the last methadone or buprenorphine prescription. Benzodiazepine prescriptions were associated with non-overdose death (HR: 2.02, 95% CI: 1.29-3.18) but not significantly associated with overdose death (1.49, 0.97-2.29). Z-drug (1.60, 1.07-2.39) and pregabalin prescriptions (2.82, 1.79-4.43) were associated with overdose death. In the sensitivity analysis, all categories of sedatives, including benzodiazepines, were significantly associated with overdose death. Caution is advised when prescribing sedative drugs, including benzodiazepines, z-drugs and pregabalin, to patients in opioid maintenance treatment.


Structural insights into regulation of the PEAK3 pseudokinase scaffold by 14-3-3.
PEAK pseudokinases are molecular scaffolds which dimerize to regulate cell migration, morphology, and proliferation, as well as cancer progression. The mechanistic role dimerization plays in PEAK scaffolding remains unclear, as there are no structures of PEAKs in complex with their interactors. Here, we report the cryo-EM structure of dimeric PEAK3 in complex with an endogenous 14-3-3 heterodimer. Our structure reveals an asymmetric binding mode between PEAK3 and 14-3-3 stabilized by one pseudokinase domain and the SHED domain of the PEAK3 dimer. The binding interface contains a canonical phosphosite-dependent primary interaction and a unique secondary interaction not observed in previous structures of 14-3-3/client complexes. Additionally, we show that PKD regulates PEAK3/14-3-3 binding, which when prevented leads to PEAK3 nuclear enrichment and distinct protein-protein interactions. Altogether, our data demonstrate that PEAK3 dimerization forms an unusual secondary interface for 14-3-3 binding, facilitating 14-3-3 regulation of PEAK3 localization and interactome diversity.


Metabolism and regulation of canonical histone mRNAs: life without a poly(A) tail.
The canonical histone proteins are encoded by replication-dependent genes and must rapidly reach high levels of expression during S phase. In metazoans the genes that encode these proteins produce mRNAs that, instead of being polyadenylated, contain a unique 3' end structure. By contrast, the synthesis of the variant, replication-independent histones, which are encoded by polyadenylated mRNAs, persists outside of S phase. Accurate positioning of both histone types in chromatin is essential for proper transcriptional regulation, the demarcation of heterochromatic boundaries and the epigenetic inheritance of gene expression patterns. Recent results suggest that the coordinated synthesis of replication-dependent and variant histone mRNAs is achieved by signals that affect formation of the 3' end of the replication-dependent histone mRNAs.


Optimal time interval between pretreatment with alcuronium and suxamethonium during anaesthetic induction.
Alcuronium 0.03 mg/kg was studied in a double-blind randomized fashion as a pretreatment before suxamethonium using different time intervals between the administration of the drugs in 78 patients (ASA I-II) undergoing otolaryngological surgery. Alcuronium was given 1, 2 or 3 min before suxamethonium 1.5 mg/kg. The control group received saline as a pretreatment and suxamethonium 1 mg/kg. Anaesthesia was induced with thiopental 5.5 mg/kg over 60 s. Muscle fasciculations, intubating conditions, cardiovascular responses to endotracheal intubation and duration of neuromuscular block were assessed. Muscle fasciculations were statistically and similarly inhibited (P less than 0.01) at all time intervals between alcuronium and suxamethonium. Intubating conditions were worse (P less than 0.05) in the 3-min group than in the other groups. Cardiovascular responses to endotracheal intubation were similar in all groups. The neuromuscular block after suxamethonium was significantly shorter (P less than 0.05) in the 2- and 3-min groups than in the other groups. In conclusion, from the clinical point of view the 1-min time interval between alcuronium and suxamethonium is optimal since muscle fasciculations are inhibited and intubating conditions are satisfactory.


Metabolomics Analysis of Urinary Extracellular Vesicles by Nuclear Magnetic Resonance and Liquid Chromatography-Mass Spectrometry.
Extracellular vesicle (EV) release and their content are influenced by diverse clinical conditions. EVs participate in inter-cellular communication and have been postulated as reflectors of the pathophysiology of the cells, tissues, organs or the whole system with which they are in contact. Urinary EVs have been proved to reflect pathophysiology not only of renal system related diseases constituting an additional source of potential biomarkers easily accessible in a non-invasive way. The interest in EVs cargo has been mostly focused on proteins and nucleic acids and more recently it has been extended to metabolites. Metabolites represent the downstream changes in the genome, transcriptome, and proteome as a reflection of processes occurring in living organisms. For their study, nuclear magnetic resonance (NMR) and mass spectrometry in tandem (LC-MS/MS) are widely used. NMR is a reproducible and non-destructive technique and we show here methodological protocols for the metabolomics analysis of urinary EVs by NMR. Additionally, we also describe the workflow for a targeted LC-MS/MS analysis that is extensible to untargeted studies.


Age-related changes in total DNA and RNA and incorporation of uridine and thymidine in rat liver, kidney and spleen.
Total content of DNA and RNA in liver, kidney and spleen were measured in young and aged rats. At the same time the incorporation of [14C]thymidine, a DNA precursor, and [3H]uridine, an RNA precursor, were also determined. Changes in total organ DNA and RNA correlated with sexual maturation as did incorporation of precursors. Young animals have more DNA per organ relative to RNA, with kidney and spleen DNA showing a decrease between maturity and senescence. However, liver RNA increases with age, a change probably due to decreased catabolism of RNA since [3H]urine uptake decreases. Liver polyploid differentiation, and [14C]thymidine and [3H]uridine uptake, are correlated. In kidney, incorporation of [3H]uridine is inversely related to [14C]thymidine incorporation.


Evidence for N⁷ guanine methyl transferase activity encoded within the modular domain of RNA-dependent RNA polymerase L of a Morbillivirus.
Post-transcriptional modification of viral mRNA is essential for the translation of viral proteins by cellular translation machinery. Due to the cytoplasmic replication of Paramyxoviruses, the viral-encoded RNA-dependent RNA polymerase (RdRP) is thought to possess all activities required for mRNA capping and methylation. In the present work, using partially purified recombinant RNA polymerase complex of rinderpest virus expressed in insect cells, we demonstrate the in vitro methylation of capped mRNA. Further, we show that a recombinant C-terminal fragment (1717-2183 aa) of L protein is capable of methylating capped mRNA, suggesting that the various post-transcriptional activities of the L protein are located in independently folding domains.


New small proteinase inhibitors from Capsicum annuum seeds: Characterization, stability, spectroscopic analysis and a cDNA cloning.
Recent results from our laboratory have previously shown the purification of a small serine proteinase inhibitor (PI), named CaTI1, from Capsicum annuum seeds. This work demonstrated the characterization of CaTI now named CaTI1, and the identification of two other small serine PIs, named CaTI2 and CaTI3, also present in these seeds. CaTI1 presented molecular mass of 6 kDa and pI value of ∼9.0. CaTI1 inhibited both trypsin and chymotrypsin with inhibition constants (Ki and Ki') of 14 and 2.8 nM for trypsin and 4.3 and 0.58 nM for chymotrypsin, respectively. Circular dichroism analysis suggested the predominance of both disordered and β-strands regions in the secondary structure. CaTI1 presented striking physico-chemical stability. In an attempt to get the entire sequence of CaTI1 we found another PI called CaTI2. The discussion of this finding is in the main text. A degenerate primer was designed based on the sequence of trypsin inhibitor CaTI1 in an attempt to achieve the cloning of this PI. Surprisingly, the alignment of the predicted peptide derived from the cDNA with the protein database showed similarity with other C. annuun PIs, and thus it was called CaTI3.


Influence of presensitization with allogeneic lymphoma cells on the growth and response to therapy of radiation-induced lymphomas in mice.
Congenic mice were sensitized with viable H-2-incompatible radiation-induced lymphomas (RIL), challenged with syngeneic RIL and treated with bis-chloroethyl-nitrosourea. Either enhancement or inhibition of RIL was found in presensitized mice, depending on the tumor-host system used.


A novel DNMT1 mutation associated with early onset hereditary sensory and autonomic neuropathy, cataplexy, cerebellar atrophy, scleroderma, endocrinopathy, and common variable immune deficiency.
DNA methyltransferase 1 (DNMT1) is an enzyme which has a role in methylation of DNA, gene regulation, and chromatin stability. Missense mutations in the DNMT1 gene have been previously associated with two neurological syndromes: hereditary sensory and autonomic neuropathy type 1 with dementia and deafness (HSAN1E) and autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN). We report a case showing overlap of both of these syndromes plus associated clinical features of common variable immune deficiency, scleroderma, and endocrinopathy that could also be mutation associated. Our patient was found to be heterozygous for a previously unreported frameshift mutation, c.1635_1637delCAA p.(Asn545del) in the DNMT1 gene exon 20. This case displays both the first frameshift mutation described in the literature which is associated with a phenotype with a high degree of overlap between HSAN1E and ADCA-DN and early age of onset (c. 8 years). Our case is also of interest as the patient displays a number of new non-neurological features, which could also be DNMT1 mutation related.


Applying linear mixed models to estimate reliability in clinical trial data with repeated measurements.
Repeated measures are exploited to study reliability in the context of psychiatric health sciences. It is shown how test-retest reliability can be derived using linear mixed models when the scale is continuous or quasi-continuous. The advantage of this approach is that the full modeling power of mixed models can be used. Repeated measures with a different mean structure can be used to usefully study reliability, correction for covariate effects is possible, and a complicated variance-covariance structure between measurements is allowed. In case the variance structure reduces to a random intercept (compound symmetry), classical methods are recovered. With more complex variance structures (e.g., including random slopes of time and/or serial correlation), time-dependent reliability functions are obtained. The methodology is motivated by and applied to data from five double-blind randomized clinical trials comparing the effects of risperidone to conventional antipsychotic agents for the treatment of chronic schizophrenia. Model assumptions are investigated through residual plots and by investigating the effect of influential observations.


Diametrical Effects of Glucose Levels on Microvascular Permeability of Peripheral Nerves in Patients With Type 2 Diabetes With and Without Diabetic Neuropathy.
Clinical studies investigating the benefit of glucose control on the progression of diabetic neuropathy (DN) have come to controversial results in patients with type 2 diabetes (T2D). This study aimed to assess associations of HbA1c levels with parameters of nerve perfusion in patients with T2D with and without DN using dynamic contrast-enhanced magnetic resonance neurography (DCE-MRN) at 3 Tesla. A total of 58 patients with T2D (20 with DN and 38 without DN) took part in this cross-sectional single-center study. Groups were matched for age, BMI, HbA1c, duration of T2D, and renal function. All patients underwent DCE-MRN with subsequent electrophysiologic and serologic testing. The extended Tofts model was used to quantify the sciatic nerve's microvascular permeability (Ktrans), volume fraction of the extracapillary extracellular space, and volume fraction of the plasma space. As a main result, we found that Ktrans correlated positively with HbA1c in patients with DN, while a negative correlation between the two parameters was found in patients without DN. Our results indicate that the effect of glucose control on the capillary permeability of peripheral nerves differs between patients with T2D with and without DN.


Cerium(III) chloride promoted highly regioselective ring opening of epoxides and aziridines using NaN(3) in acetonitrile: a facile synthesis of 1,2-azidoalcohols and 1,2-azidoamines.
A convenient and efficient synthesis of 1,2-azidoalcohols and 1,2-azidoamines has been achieved by ring opening of epoxides and aziridines using cerium(III) chloride and sodium azide in acetonitrile. The reaction is highly regioselective and afforded the corresponding products in good to excellent yields under mild and neutral reaction conditions. The method is very rapid and equally compatible for both epoxides and aziridines.


Knowledge and attitudes of nurses on a regional neurological intensive therapy unit towards brain stem death and organ donation.
The study aimed to explore nurses knowledge and attitudes towards brain stem death and organ donation. An ex post facto research design was used to determine relationships between variables. A 16 item questionnaire was used to collect data. Statistical analysis revealed one significant result. The limitations of the sample size is acknowledged and the conclusion suggests a larger study is required.


Conservation of a pseudomonad-like hydrocarbon degradative ferredoxin oxygenase complex involved in rhizopine catabolism in Sinorhizobium meliloti and Rhizobium leguminosarum bv. viciae.
In Sinorhizobium meliloti the mocCABR genes have previously been shown to be required for rhizopine (3-O-methyl-scyllo-inosamine, 3-O-MSI) catabolism. We show that the mocDE(F) gene cluster is also needed. MocDE(F), which is involved in the catabolism of 3-O-MSI to its demethylated form scyllo-inosamine (SI) has homology to components that would comprise a ferredoxin-oxygenase system. The mocCABRDE(F) suite of genes is required for 3-O-MSI catabolism in both S. meliloti and R. leguminosarum bv. viciae. However, SI catabolism in S. meliloti requires mocCABR, whereas only mocCA are required for its catabolism in R. leguminosarum suggesting the two species require different chromosomal genes which act in concert with moc genes for the catabolism of rhizopine.


Using electrical impedance detection to evaluate the viability of biomaterials subject to freezing or thermal injury.
This paper is aimed at comprehensively investigating the dynamic low-frequency electrical impedance (DLFI) of biological materials during the processes of freezing, thawing and heating, and combinations of them. Electrical impedance detection (EID) was proposed as a means of rapidly evaluating the viability of biological materials subject to freezing or thermal injury (processes expected to be significant in the practices of cryobiology and hyperthermia). Using two experimental setups, the DLFI for selected biological materials (fresh pork and fish) under various freezing and heating conditions was systematically measured and analyzed. Preliminary results demonstrate that damage that occurs to a biological material due to freezing or heating could result in a significant deviation in its electric impedance value from that of undamaged biomaterials. Monitoring impedance change ratios under various freezing and heating conditions may offer an alternative strategy for assessing the amount of damage sustained by biomaterials subject to cryosurgery, cryo-preservation and hyperthermia. Implementation of the present method in order to develop a new micro-analysis or biochip system is also suggested.


Functional MR Imaging in Gynecologic Cancer.
Dynamic-contrast enhanced (DCE) and diffusion-weighted (DW) MR imaging are invaluable in the detection, staging, and characterization of uterine and ovarian malignancies, for monitoring treatment response, and for identifying disease recurrence. When used as adjuncts to morphologic T2-weighted (T2-W) MR imaging, these techniques improve accuracy of disease detection and staging. DW-MR imaging is preferred because of its ease of implementation and lack of need for an extrinsic contrast agent. MR spectroscopy is difficult to implement in the clinical workflow and lacks both sensitivity and specificity. If used quantitatively in multicenter clinical trials, standardization of DCE- and DW-MR imaging techniques and rigorous quality assurance is mandatory.


Comparative study of composition of methanolic extracts of the paratoid gland secretions (PGS) of Rhinella jimi (cururu toad) from northeastern Brazil: Gender, seasonality and geographic occurrence.
Toads belonging to the Bufonidae family have a pair of paratoid glands that store highly toxic a biological secretion with varied chemical composition, that act as a chemical defense against microbial infections and predators. The paratoid gland secretion (PGS) of bufonids is rich in bioactive steroids, alkaloids, proteins, bufadienolides and bufotoxins. In the present investigation we performed a systematic analysis of the chemical profile of PGS obtained from the Bufonidae toad Rhinella jimi ("Cururu" toad) collected at three different regions of Piauí state, Northeastern Brazil. Our aim was to investigate the PGS variation related to the season of animals collection, geographic distribution and gender of the animals. The methanolic extracts of PGS were analyzed by UPLC-QToF-MS/MS. Principal component analysis (PCA) were applied to the data set obtained by the UPLC-QToF-MS/MS analyses. Among 23 compounds identified, dehydrobufotenine, suberoyl arginine, 3-(N-suberoyl-argininyl) telocinobufagin, 3-(N-suberoyl-argininyl) marinobufagin, telocinobufagin, marinobufagin and 3-(N-suberoyl-argininyl) bufalin were detected in all PGS. Minimal variations in the composition of paratoid secretions of R. jimi were observed related to distinct geographical and seasonal parameters. R. jimi female animals presented the most diverse chemical composition in its PGS. With this comparative study, unprecedented for the species, it was possible to observe that the secretions of the paratoid glands produced by R. jimi from different regions of the state of Piauí, at different times of the year, presented consistent chemical composition, with discrete particularities in the number and nature chemistry of its constituents.


Efficient PCNA complex formation is dependent upon both transcription coupled repair and genome overall repair.
The protein proliferating cell nuclear antigen (PCNA) is an auxiliary factor for DNA polymerase delta and is involved in the resynthesis step of nucleotide excision repair (NER). After UV irradiation of quiescent cells, PCNA forms an insoluble complex with nuclear substructures. We have investigated associations between NER and its subcomponent pathway, transcription coupled repair (TCR) on PCNA complex formation using genetically related hamster cell lines with different repair characteristics. In DNA repair proficient cells, the PCNA complex was readily detectable within 30 min after UV irradiation by both immunofluorescence and western blot analyses. This complex formation after UV occurs efficiently in quiescent cells. In UV5 (human XP-D homolog) and UV 24 (human XP-B homolog) cells, which are totally deficient in NER, the PCNA complex was not detectable at 30 min after UV. The PCNA complex formation is restored to normal levels in UV5 cells after transfection with the human XPD gene, encoding a subunit of the basal transcription factor, TFIIH. In UV61 (Human CS-B homolog) cells, that are defective only in transcription coupled repair (TCR) of cyclobutane pyrimidine dimers (CPDs), the rate of PCNA complex formation was 2-fold slower than in repair proficient cells. This defect was complemented by transfection of the CSB gene into the UV61 cells. We thus conclude that efficient PCNA complex formation after UV is dependent upon both the NER and TCR pathways in hamster cells. The association of several other DNA repair proteins including XPA, RPA, TFIIH and p53 with the insoluble PCNA complex in UV treated cells suggests a central role for PCNA in different steps of NER.


Evaluation of the Differences Between Conventional and Digitally Developed Models Used for Prosthetic Rehabilitation in a Case of Untreated Palatal Cleft.
The virtual cone beam computed tomography-derived 3-dimensional model was compared with the scanned conventional model used in the fabrication of a palatal obturator for a patient with a large palatal defect. A digitally derived 3-dimensional maxillary model incorporating the palatal defect was generated from the patient's existing cone beam computerized tomography data and compared with the scanned cast from the conventional impression for linear dimensions, area, and volume. The digitally derived cast was 3-dimensionally printed and the obturator fabricated using traditional techniques. Similarly, an obturator was fabricated from the conventional cast and the fit of both final obturator bulbs were compared in vivo. The digitally derived model produced more accurate volumes and surface areas within the defect. The defect margins and peripheries were overestimated which was reflected clinically. The digitally derived model provided advantages in the fabrication of the palatal obturator; however, further clinical research is required to refine consistency.


Satisfaction of Search in Chest Radiography 2015.
Two decades have passed since the publication of laboratory studies of satisfaction of search (SOS) in chest radiography. Those studies were performed using film. The current investigation tests for SOS effects in computed radiography of the chest. Sixty-four chest computed radiographs half demonstrating various "test" abnormalities were read twice by 20 radiologists, once with and once without the addition of a simulated pulmonary nodule. Receiver-operating characteristic detection accuracy and decision thresholds were analyzed to study the effects of adding the nodule on detecting the test abnormalities. Results of previous studies were reanalyzed using similar modern techniques. In the present study, adding nodules did not influence detection accuracy for the other abnormalities (P = .93), but did induce a reluctance to report them (P < .001). Adding nodules did not affect inspection time (P = .58) so the reluctance to report was not associated with reduced search. Reanalysis revealed a similar decision threshold shift that had not been recognized in the early studies of SOS in chest radiography (P < .01) in addition to reduced detection accuracy (P < .01). The nature of SOS in chest radiography has changed, but it is not clear why. SOS may be changing as a function of changes in radiology education and practice.


Activation of eNOS in rat portal hypertensive gastric mucosa is mediated by TNF-alpha via the PI 3-kinase-Akt signaling pathway.
Activation of endothelial nitric oxide synthase (eNOS) in portal hypertensive (PHT) gastric mucosa leads to hyperdynamic circulation and increased susceptibility to injury. However, the signaling mechanisms for eNOS activation in PHT gastric mucosa and the role of TNF-alpha in this signaling remain unknown. In PHT gastric mucosa we studied (1) eNOS phosphorylation (at serine 1177) required for its activation; (2) association of the phosphatidylinositol 3-kinase (PI 3-kinase), and its downstream effector Akt, with eNOS; and, (3) whether TNF-alpha neutralization affects eNOS phosphorylation and PI 3-kinase-Akt activation. To determine human relevance, we used human microvascular endothelial cells to examine directly whether TNF-alpha stimulates eNOS phosphorylation via PI 3-kinase. PHT gastric mucosa has significantly increased (1) eNOS phosphorylation at serine 1177 by 90% (P <.01); (2) membrane translocation (P <.05) and phosphorylation (P <.05) of p85 (regulatory subunit of PI 3-kinase) by 61% and 85%, respectively; (3) phosphorylation (P <.01) and activity (P <.01) of Akt by 40% and 52%, respectively; and (4) binding of Akt to eNOS by as much as 410% (P <.001). Neutralizing anti-TNF-alpha antibody significantly reduced p85 phosphorylation, phosphorylation and activity of Akt, and eNOS phosphorylation in PHT gastric mucosa to normal levels. Furthermore, TNF-alpha stimulated eNOS phosphorylation in human microvascular endothelial cells. In conclusion, these findings show that in PHT gastric mucosa, TNF-alpha stimulates eNOS phosphorylation at serine 1177 (required for its activation) via the PI 3-kinase-Akt signal transduction pathway.


Ridge Augmentation in a Site of a Previous Implant Failure Using Tenting Screws With Allograft and Collagen Membrane.
As digital workflows become increasingly common in dentistry, clinicians are able to quickly demonstrate esthetic possibilities to their patients and easily implement the digitally designed outcome. In this case presentation of a young patient, it was critical to maintain maximum tooth structure and alveolar bone when treating her esthetic concerns. Chairside confirmation of the proposed treatment plan, coupled with careful multidisciplinary consultations, led to improved oral health and an excellent esthetic outcome without increasing the patient's risk for future disease.


In situ Nanopore sequencing reveals metabolic characteristics of the Qilian glacier meltwater microbiome.
Nanopore metagenomic sequencing enables rapid annotating microbiological ecosystems, and the previous glacier-related sequencing applications (e.g., targeted ice sheets, ice lake, and cryoconite holes) inspire us to explore high-altitude glacier meltwater at Qilian Mountain, China (3000 to 4000 m above sea level, MASL). Our findings suggest that (1) despite only several hundred meters apart, the microbial communities and functionalities are quite different among vertical alpine distributions; (2) the high-altitude Qilian meltwater microbiome serve several main metabolic functions, including sulfur oxidation, selenite decomposing, photosynthesis, energy production, enzymic, and UV tolerant activities. Meanwhile, our Nanopore metagenomic results indicate that the microbial classifications and functionalities (e.g., chaperones, cold-shock, specific tRNA species, oxidative stress, and resistance to toxic compounds) of Qilian meltwater are highly consistent with the other glacial microbiome, emphasizing that only certain microbial species can survive in the cold environment and the molecular adaptions and lifestyles remain stable all over the world. Besides, we have shown Nanopore metagenomic sequencing can provide reliable prokaryotic classifications within or among studies, which therefore can encourage more applications in the field given faster turnaround time. However, we recommend accumulating at least 400 ng nucleic acids (after extraction) and maximizing Nanopore library preparation efficiency before on-site sequencing to obtain better resolutions.


PF4 antagonizes retinal neovascularization via inhibiting PRAS40 phosphorylation in a mouse model of oxygen-induced retinopathy.
Retinal neovascularization (RNV) is a common pathology of blinding proliferative retinopathies. The current treatments to RNV, however, are hindered by limited efficacy, side effects, and drug resistance. A naturally-occurring cytokine in retina that is amicable to immune system and possesses robust anti-neovascular function would facilitate to overcome the hurdles. In this study, retinas from a mouse model of oxygen-induced retinopathy (OIR) underwent a protein array to screen the naturally-occurring cytokines that may antagonize RNV. Among the 62 angiogenesis-associated cytokines, platelet factor 4 (Pf4) stood out with the most prominent upregulation and statistical significance. Moreover, an intravitreal injection of mouse Pf4 demonstrated dramatic anti-vaso-obliteration and anti-neovascularization effects dose dependently in the OIR model; whereas human PF4 inhibited the proliferation, migration, and tubulogenesis of monkey retinal vascular endothelial cells treated with VEGF and TNF-α. These previously undescribed angiostatic effects of PF4 in OIR retinas and retinal vascular endothelial cells support translation of this naturally-occurring chemokine into a therapeutic modality to RNV supplementary to the anti-VEGFs. Mechanistically, a phosphorylation array and western blots indicated that downregulation of proline-rich Akt substrate of 40 kDa (Pras40) and its phosphorylation were necessary for Pf4's anti-neovascular effects in the OIR retinas. Indeed, overexpression of the wildtype Pras40 and the mutant version with deficient phosphorylation abolished and mimicked the Pf4's angiostatic effects in the OIR retinas, respectively. The similar effects were also observed in vitro. This study, for the first time, links PF4's anti-RNV function to an intracellular signaling molecule PRAS40 and its phosphorylation.


Polymyositis and pemphigus vulgaris in a patient: successful treatment with rituximab.
Rituximab has been documented to be an effective treatment for autoimmune diseases with contribution of B cells. We report a case of antisynthetase syndrome with a history of EBV-induced lymphoma which developed a pemphigus vulgaris. Rituximab was effective both on polymyositis and on pemphigus. Fifteen months later, the patient died from a septic shock after the first cyclophosphamide infusion for amyloidosis while the B cell population remained depleted. Rituximab may be a good alternative to immunosuppressive drugs in polymyositis and pemphigus especially in lymphoma-risk patients. However, it did not prevent progression to secondary amyloidosis and the fatal infection developed in this patient raises the question of whether a prolonged B cell depletion with rituximab contributes to a greater risk of infection.


Hormone producing pancreatic islet cell carcinoma: changing clinical presentation.
A patient with pancreatic islet cell carcinoma demonstrated spontaneous remission and recurrence of hyperinsulinism and disappearance of elevated plasma motilin levels. Despite evidence for gastrin production by the tumor initially, the Zollinger-Ellison syndrome was not diagnosed until three years after initial presentation. Diarrhea and steatorrhea could be attributed to hyperchlorhydria rather than to direct intestinal effects of elevated cirulating gastrin, gastric inhibitory peptide or motilin. Pancreatic islet cell carcinomas, considered as a type a APUD cell proliferation, frequently produce more than one hormone; the pattern of hormone secretion may differ with time and clinical manifestations may change accordingly.


FISH is better than BIOMED-2 PCR to detect IgH/BCL2 translocation in follicular lymphoma at diagnosis using paraffin-embedded tissue sections.
The most common genetic aberration in follicular lymphoma (FL) is the t(14;18)(q32;q21) translocation that juxtaposes the antiapoptotic BCL2 gene with the promoter of the immunoglobulin heavy chain (IgH) gene. Our aim was to test the usefulness of two different techniques, fluorescence in situ hybridization (FISH) and PCR to detect t(14;18) in FL at diagnosis in paraffin-embedded tissue sections. A total of 51 patients diagnosed of FL were analyzed. FISH was performed with dual color dual fusion commercial probes (VYSIS) and in PCR experiments, the BIOMED-2 primers covering MBR, mcr and 3'MBR regions were applied. FISH showed positivity for the IgH/BCL2 translocation in 96% of patients and PCR in 59% of patients. FISH was able to detect variant translocations involving light chain Ig, or showing variant patterns such as deletions of the IgH portion involved in translocation. In 4% of cases, the IgH/BCL2 translocation was not detected by any of the two techniques tested. Our results show that FISH represents the best technique to detect t(14;18) at diagnosis.


Pharmacokinetic Evaluation of CYP3A4-Mediated Drug-Drug Interactions of Isavuconazole With Rifampin, Ketoconazole, Midazolam, and Ethinyl Estradiol/Norethindrone in Healthy Adults.
This report describes the phase 1 trials that evaluated the metabolism of the novel triazole antifungal isavuconazole by cytochrome P450 3A4 (CYP3A4) and isavuconazole's effects on CYP3A4-mediated metabolism in healthy adults. Coadministration of oral isavuconazole (100 mg once daily) with oral rifampin (600 mg once daily; CYP3A4 inducer) decreased isavuconazole area under the concentration-time curve (AUCτ ) during a dosing interval by 90% and maximum concentration (Cmax ) by 75%. Conversely, coadministration of isavuconazole (200 mg single dose) with oral ketoconazole (200 mg twice daily; CYP3A4 inhibitor) increased isavuconazole AUC from time 0 to infinity (AUC0-∞ ) and Cmax by 422% and 9%, respectively. Isavuconazole was coadministered (200 mg 3 times daily for 2 days, then 200 mg once daily) with single doses of oral midazolam (3 mg; CYP3A4 substrate) or ethinyl estradiol/norethindrone (35 μg/1 mg; CYP3A4 substrate). Following coadministration, AUC0-∞ increased 103% for midazolam, 8% for ethinyl estradiol, and 16% for norethindrone; Cmax increased by 72%, 14%, and 6%, respectively. Most adverse events were mild to moderate in intensity; there were no deaths, and serious adverse events and adverse events leading to study discontinuation were rare. These results indicate that isavuconazole is a sensitive substrate and moderate inhibitor of CYP3A4.


Characteristics of maltase activity in amniotic fluid.
The nature and origin of maltase activity present in amniotic fluid, and used as a marker enzyme in the prenatal monitoring of cystic fibrosis, has been studied. Using monoclonal antibodies against human intestinal disaccharidases and via heat inactivation experiments it is shown that the maltase activity found in amniotic fluids from pregnancies of 16-24 wk of gestational age originates completely from sucrase-isomaltase; no maltase-glucoamylase could be detected. With various monospecific antibodies the possible contribution of non-intestinal brush border enzymes to the total maltase pool could be excluded: neither renal nor lysosomal maltase appeared to be present.


The impact of secondhand smoke on the development of kidney stone disease is not inferior to that of smoking: a longitudinal cohort study.
Tobacco use and secondhand smoke (SHS) are risk factors of kidney stone disease (KSD). The hypothesis is that tobacco produces chemicals that increase oxidative stress and vasopressin, which leads to decreased urine output, and contributes to stone formation. The aim of this study was to examine the effects of smoking and SHS on the development of KSD. We analyzed a total of 25,256 volunteers with no history of KSD participated in the Taiwan Biobank. The presence of underlying and follow-up KSD was surveyed by a self-administrated questionnaire. They were classified into three groups on the basis of smoking and SHS exposure, accessed with survey questionnaires; never-smokers with no SHS exposure, never-smokers with SHS exposure and ever-smokers groups. KSD was noted in 352 (2.0%), 50 (3.3%) and 240 (4.1%) subjects in the never-smokers with no SHS exposure, never-smokers with SHS exposure and ever-smokers groups, respectively, with a mean follow-up of 4 years. The odds ratio (OR) of KSD was higher in the never-smokers with SHS exposure (OR, 1.622; 95% confidence interval [95% CI], 1.225 to 2.255) and ever-smokers groups (OR, 1.282; 95% CI, 1.044 to 1.574) than in the never-smokers with no SHS exposure group after adjustment of confounders. In addition, never-smokers with SHS exposure had similar effects on the development of KSD than ever-smokers (OR, 1.223; 95% CI, 0.852 to 1.756). Our study suggests that both smoking and SHS are a risk factor for developing KSD and that the impact of SHS is not inferior to that of smoking. The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Kaohsiung Medical University Hospital (KMUHIRB-E(I)-20,210,058).


Gram positive and Gram negative bacteria differ in their sensitivity to cold plasma.
Cold atmospheric-pressure plasma (CAP) is a relatively new method being investigated for antimicrobial activity. However, the exact mode of action is still being explored. Here we report that CAP efficacy is directly correlated to bacterial cell wall thickness in several species. Biofilms of Gram positive Bacillus subtilis, possessing a 55.4 nm cell wall, showed the highest resistance to CAP, with less than one log10 reduction after 10 min treatment. In contrast, biofilms of Gram negative Pseudomonas aeruginosa, possessing only a 2.4 nm cell wall, were almost completely eradicated using the same treatment conditions. Planktonic cultures of Gram negative Pseudomonas libanensis also had a higher log10 reduction than Gram positive Staphylococcus epidermidis. Mixed species biofilms of P. aeruginosa and S. epidermidis showed a similar trend of Gram positive bacteria being more resistant to CAP treatment. However, when grown in co-culture, Gram negative P. aeruginosa was more resistant to CAP overall than as a mono-species biofilm. Emission spectra indicated OH and O, capable of structural cell wall bond breakage, were present in the plasma. This study indicates that cell wall thickness correlates with CAP inactivation times of bacteria, but cell membranes and biofilm matrix are also likely to play a role.


Cofilin 1 promotes the aggregation and cell-to-cell transmission of α-synuclein in Parkinson's disease.
The histopathological hallmark of Parkinson's disease (PD) is the presence of fibrillar aggregates referred to as Lewy bodies (LBs), in which α-synuclein is the major component. Converging evidence supports the prion-like transmission of α-synuclein aggregates in the onset and progression of PD. Intracellular α-synuclein aggregates into pathological fibrils, which can be transferred from aggregate-producing cells to aggregate-free cells, triggering neuronal injury and the progression of pathology. However, the specific mechanisms mediating the aggregation and transmission of pathological α-synuclein remain unknown. Here we show that cofilin 1 binds to α-synuclein and promotes its aggregation. The mixed fibrils consist of cofilin 1 and α-synuclein are more compact and more potent than pure α-synuclein fibrils in seeding α-synuclein aggregation. Cofilin 1 also facilitates the uptake of α-synuclein fibrils and finally induces neuronal dysfunction. Together, these observations indicate that cofilin 1 acts as a crucial mediator in the aggregation and propagation of pathological α-synuclein, contributing to the pathogenesis of PD.


Clinical and Brain Magnetic Resonance Imaging Features in a Cohort of Chinese Patients with Kearns-Sayre Syndrome.
Kearns-Sayre syndrome (KSS) is a mitochondrial DNA (mtDNA) deletion disorder characterized by a triad of onset before 20 years of age, ophthalmoplegia, and pigmentary retinopathy. The heart and central nervous system are commonly involved. We summarized clinical and brain magnetic resonance imaging (MRI) features of a cohort of Chinese KSS patients. Nineteen patients confirmed by muscle biopsy and mtDNA analysis were enrolled. We examined clinical profiles, mainly focusing on changes in electrocardiogram (ECG) and brain MRI. The correlation between genotype and phenotype was statistically analyzed. The mean age of onset was 9.6 ± 4.3 years, with all developing the classic triad at the time of diagnosis. Heart conduction block was detected in 63.2%, with four initially presenting as bundle branch block and developing into complete atrioventricular block over 3-72 months. Brain MRI showed symmetric high-T2 signals in 100% of cerebral and cerebellar white matter, as well as brainstem, 46.7% of basal ganglia, and 53.3% of thalamus. There were two patterns of cerebral white matter involvements, one with selective subcortical U-fibers and the other with periventricular white matter. The size of mtDNA deletion did not significantly correlate with age of onset or percentage of ragged blue fibers on muscle pathology. The clinical features of KSS evolve dynamically, affecting the cardiac conduction system predominantly, highlighting the significance of ECG monitoring. Brain MRI showed changes involving both the white matter and deep gray nuclei. Clinical presentation or severity of muscle pathological changes is not related to the size of mtDNA deletions.


Targeting mailed nicotine patch distribution interventions to rural regions of Canada: protocol for a randomized controlled trial.
Quitting smoking is the most effective way of reducing the risk of cancer among smokers. One way of helping people stop smoking is to provide them with free Nicotine Replacement Therapy (NRT), such as when NRT is sent to people by postal mail as part of a mass distribution initiative. Our previous research indicated that there may be a substantial impact on increasing quit rates of a mailed NRT intervention in rural areas. The current research seeks to confirm this finding and to understand the social determinants of health driving these anticipated large effects. Telephone numbers will be randomly selected from across rural regions of Canada in order to recruit adult smokers interested in completing a smoking survey and willing to be interviewed again in 6 months. The survey will ask participants about their smoking history, demographic characteristics, and a hypothetical question: would they be interested in receiving nicotine patches if they were provided to them free of charge? Half of the smokers interested in receiving nicotine patches will be selected by chance and offered the NRT package. The other half of smokers will not be offered the nicotine patches. In addition, the municipality where each participant lives will be identified and, once the relevant general population data becomes available, attempts will be made to link participant data to relevant municipal characteristics (e.g., smoking rates, availability of health services). Characteristics of the participants and the municipalities in which they live will be used to explain why the nicotine patch intervention may have a larger impact in some rural regions compared to others. The findings from the proposed RCT are timely and of high relevance as the distribution of nicotine patches has substantial potential to combat the public health problem of cigarette related cancer, other diseases, and premature death from tobacco use. Targeting such tobacco cessation initiatives to rural regions may substantially increase the impact of this intervention, helping to optimize the use of limited prevention resources while aiming to save the maximum number of lives. ClinicalTrials.gov NCT04606797 , October, 27, 2020.


Retinoic acid suppression of human leukocyte interferon production.
Retinoic acid (RA) suppressed the production of interferon (IFN) alpha and IFN gamma of human peripheral blood leukocytes in response to stimulation with lectin mitogens, bacterial products, synthetic polynucleotides, viruses, and tumor cell lines in vitro. Virus-induced secretion of IFN alpha of human lymphoblastoid cells was also inhibited. RA-mediated suppression was dose-dependent and required the near-concurrent addition of RA and inducers to human leukocyte cultures, thus suggesting that RA affects an early cellular function in the generation of IFN. Implications of these findings for the use of retinoids in the treatment of human malignancies are discussed.


Modeling and simulation of the novel coronavirus in Caputo derivative.
The Coronavirus disease or COVID-19 is an infectious disease caused by a newly discovered coronavirus. The COVID-19 pandemic is an inciting panic for human health and economy as there is no vaccine or effective treatment so far. Different mathematical modeling approaches have been suggested to analyze the transmission patterns of this novel infection. this paper, we investigate the dynamics of COVID-19 using the classical Caputo fractional derivative. Initially, we formulate the mathematical model and then explore some the basic and necessary analysis including the stability results of the model for the case when R 0 < 1 . Despite the basic analysis, we consider the real cases of coronavirus in China from January 11, 2020 to April 9, 2020 and estimated the basic reproduction number as R 0 ≈ 4.95 . The present findings show that the reported data is accurately fit the proposed model and consequently, we obtain more realistic and suitable parameters. Finally, the fractional model is solved numerically using a numerical approach and depicts many graphical results for the fractional order of Caputo operator. Furthermore, some key parameters and their impact on the disease dynamics are shown graphically.


Esophageal carcinoma: surgery without preoperative adjuvant chemotherapy.
Our experience with 100 consecutive patients with esophageal carcinoma treated with surgical intervention as the primary method of therapy between 1967 and 1987 was reviewed. Preoperative chemotherapy was not administered by us. Follow-up was complete for all 100 patients. Twelve percent of tumors were in the proximal third of the esophagus, 21% were in the middle third, and 67% were in the distal third. Adenocarcinoma accounted for 44% of all tumors, squamous cell for 55%, and adenosquamous for 1%. Six patients were in stage I, 14 were in stage II, and 80 were in stage III; no patient was in stage IV. Surgical procedures included 85 esophagogastrectomies with primary anastomoses, 11 with colon interposition, and 4 with Roux-en-Y small-bowel interposition. Six patients had radical laryngopharyngo-esophagectomy with gastric or colopharyngeal anastomosis. Operative mortality was 3%. The mean survival of stage I patients was 182 months; stage II patients, 25 months; and stage III patients, 18 months. Our data show that surgical resection without preoperative adjuvant chemotherapy remains the cornerstone of therapy for patients with carcinoma of the esophagus.


Control of protein quality and stoichiometries by N-terminal acetylation and the N-end rule pathway.
N(α)-terminal acetylation of cellular proteins was recently discovered to create specific degradation signals termed Ac/N-degrons and targeted by the Ac/N-end rule pathway. We show that Hcn1, a subunit of the APC/C ubiquitin ligase, contains an Ac/N-degron that is repressed by Cut9, another APC/C subunit and the ligand of Hcn1. Cog1, a subunit of the Golgi-associated COG complex, is also shown to contain an Ac/N-degron. Cog2 and Cog3, direct ligands of Cog1, can repress this degron. The subunit decoy technique was used to show that the long-lived endogenous Cog1 is destabilized and destroyed via its activated (unshielded) Ac/N-degron if the total level of Cog1 increased in a cell. Hcn1 and Cog1 are the first examples of protein regulation through the physiologically relevant transitions that shield and unshield natural Ac/N-degrons. This mechanistically straightforward circuit can employ the demonstrated conditionality of Ac/N-degrons to regulate subunit stoichiometries and other aspects of protein quality control.


Sex difference in the turnover of GABA in the rat substantia nigra.
The turnover of GABA (estimated from the post-mortem accumulation of GABA), and the activity of glutamic acid decarboxylase and GABA transaminase, along with the saturation of both enzymes by cofactor pyridoxal phosphate, were studied in the substantia nigra of rats of both sexes. Although no sex differences were found in the in vitro measured characteristics of both enzymes involved in GABA metabolism, the turnover of GABA was greater in males. This finding is consistent with our previous reports showing the greater resistance of male rats to GABA-related convulsions.


Microbial ultraviolet sunscreens.
Exposure to the shortest wavelengths in sunlight, ultraviolet light, constitutes a deleterious ecological factor for many microorganisms. The use of secondary metabolites as sunscreens has emerged as an important photoprotective mechanism in certain groups of large-celled microorganisms, such as cyanobacteria, fungi and many protists. In this Review, we describe our current understanding of microbial 'sunscreen' compounds, including scytonemin, the mycosporines and the naphthalene-based melanins. Study of these sunscreens has led to the discovery of new classes of compounds, new metabolic pathways, a deeper understanding of microbial photobiology and the potential for dermatological or biomedical applications.


Intraocular lenses with surface aspherization: Interferometric study.
To accurately evaluate in an optical laboratory 2 different types of intraocular lenses (IOLs). Department of Oto-Neuro-Ophthalmological Surgical Sciences and CNR-Institute for Applied Optics, Florence Italy. In this study, optical testing facilities based on interferometry were used. The IOLs were inspected with laser light, and interference patterns were acquired and processed, obtaining the physical parameters accounting for the lens behavior. Comparison of the respective performances within the pseudophakic eye was provided in terms of modulation transfer function (MTF) using lens diameters from 3.0 mm to 5.0 mm. The data were inserted in a mathematical model of the eye, and the relevant merit functions were computed with a ray-tracing program. Sample sets of both all-spherical IOLs and IOLs with aspherical surfaces were inspected. The interferometric maps showed clear evidence of the opposite wave aberration introduced by the different IOL types. With a 3.0 mm pupil diameter, both IOL types performed as almost ideal lenses, while with a 5.0 mm diameter, IOLs with aspherical surfaces effectively compensated for the spherical aberration of the cornea and had a significantly higher MTF. The interferometric approach to IOL testing provided accurate data on the physical parameters of the IOL. With a measuring and computing chain that includes eye modeling and ray tracing, it was possible to analyze in detail the process by which IOLs with aspherical surfaces compensate for the spherical aberration of the cornea under photopic, mesopic, and scotopic conditions.


Scientific Hepatectomy for Hepatocellular Carcinoma.
With advances in imaging technology and surgical instruments, hepatectomy can be perfectly performed with technical precision for hepatocellular carcinoma (HCC). However, the 5-year tumor recurrence rates remain greater than 70%. Thus, the strategy for hepatectomy needs to be reappraised based on insights of scientific advances. Scientific evidence has suggested that the main causes of recurrence after hepatectomy for HCC are mainly related to underlying cirrhosis and the vascular spread of tumor cells that basically cannot be eradicated by hepatectomy. Liver transplantation and systemic therapy could be the solution to prevent postoperative recurrence in this regard. Therefore, determining the severity of liver cirrhosis for choosing the appropriate surgical modality, such as liver transplantation or hepatectomy, for HCC and integrating newly emerging immune-related adjuvant and/or neoadjuvant therapy into the strategy of hepatectomy for HCC have become new aspects of exploration to optimize the strategy of hepatectomy. In this new area, hepatectomy for HCC has evolved from a pure technical concept emphasizing anatomic resection into a scientific concept embracing technical considerations and scientific advances in underlying liver cirrhosis, vascular invasion, and systemic therapy. By introducing the concept of scientific hepatectomy, the indications, timing, and surgical techniques of hepatectomy will be further scientifically optimized for individual patients, and recurrence rates will be decreased and long-term survival will be further prolonged.


Validating the clinical assessment of eustachian tube dysfunction: The Eustachian Tube Dysfunction Questionnaire (ETDQ-7).
Eustachian tube dysfunction (ETD) is a common condition that is associated with otologic and rhinologic symptoms. The complete assessment of ETD is limited without a valid symptom score. We developed and conducted initial validation of the seven-item Eustachian Tube Dysfunction Questionnaire (ETDQ-7), a disease-specific instrument to assess symptoms with respect to ETD. Validation study. The ETDQ-7 was developed using standard survey methodology. The ETDQ-7 was completed by a group of 50 consecutive adult patients diagnosed with ETD and 25 non-ETD patients who served as a control group. Tympanometry was used as a criterion standard to distinguish the two groups. A subset of respondents repeated the ETDQ-7 at a time point 4 weeks later. Content validity for the ETDQ-7 was established by focus group and review of the literature. Reliability testing indicated acceptable internal consistency for the entire instrument (Cronbach α = .71). The test-retest reliability indicated good correlation between the two questionnaires completed by the same patient 4 weeks apart (r = 0.78). The ETDQ-7 was able to discriminate between patients with ETD and those without (P < .001), indicating excellent discriminant validity. The ETDQ-7 is a valid and reliable symptom score for use in adult patients with ETD that may facilitate clinical practice by highlighting the impact of ETD. Further testing is needed to determine its usefulness in assessing treatment response.