Opioid receptor activation is involved in neuroprotection induced by TRPV1 channel activation against excitotoxicity in the rat retina.
Recently, we reported that capsaicin, a transient receptor potential vanilloid type1 (TRPV1) agonist, protected against excitotoxicity induced by intravitreal N-methyl-D-aspartic acid (NMDA) in the rats in vivo. It has been reported that morphine, an opioid receptor agonist, ameliorated excitotoxicity induced by ischemia-reperfusion in the retina, and that capsaicin-induced neuroprotection was reduced by naloxone, an opioid receptor antagonist in the brain. The aim of the present study is to clarify whether activation of opioid receptors is involved in the capsaicin-induced neuroprotection in the retina. Under ketamine/xylazine anesthesia, male Sprague-Dawley rats were subjected to intravitreal NMDA injection (200nmol/eye). Capsaicin (5.0nmol/eye), calcitonin gene-related peptide (CGRP; 0.05pmol/eye), β-endorphin (0.5 pmol/eye), substance P (5nmol/eye), and naloxone (0.5nmol/eye) were intravitreally administered simultaneously with NMDA. Morphometric evaluation 7 days after NMDA injection showed that intravitreal NMDA injection resulted in ganglion cell loss. Capsaicin, CGRP, β-endorphin, and substance P prevented this damage. Treatment with naloxone (0.5nmol/eye) almost completely negated the protective effects of capsaicin, CGRP, β-endorphin, and substance P in the NMDA-injected rats. These results suggested that activation of opioid receptors is possibly involved in the protective effect of capsaicin.


Colonic Ileus, Distension, and Ischemia Due to COVID-19-Related Colitis: A Case Report and Literature Review.
Coronavirus disease 2019 (COVID-19) predominantly presents with respiratory symptoms, however, the involvement of the gastrointestinal system has also been reported. Isolated gastrointestinal manifestation due to COVID-19 presenting as colonic distension is uncommon. Colonic ileus from COVID-19 infection presents as dilatation on imaging, with the risk of subsequent ischemia and perforation if not recognized and treated promptly. There is no consensus on the treatment modality for COVID-19-related colitis, however, COVID-19-targeted medications in conjunction with surgical intervention have been performed for management. We present a case of a 73-year-old man who presented with abdominal pain, distention, and diarrhea. He tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and was found to have marked dilatation of the colon on imaging. He was initially given convalescent plasma to reduce inflammatory markers, as tocilizumab was contraindicated due to suspected bowel obstruction. Once more stable, he underwent surgical intervention followed by tocilizumab infusion. Pathological specimens of the colon demonstrated hemorrhagic colitis with microthrombi suggestive of COVID-19-related colitis. Recognizing COVID-19-related colitis allows for timely diagnosis and management with targeted interventions in addition to surgery, which may prevent perforation. We suggest convalescent plasma followed by the formation of colostomy and finally infusion of tocilizumab as a feasible option for the treatment of COVID-19-related colitis. However, further research is needed in order to fully understand this entity and provide guidance for its management.


Total synthesis and biological evaluation of the antibiotic lysocin E and its enantiomeric, epimeric, and N-demethylated analogues.
Lysocin E, a macrocyclic peptide, exhibits potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) through a novel mechanism. The first total synthesis of lysocin E was achieved by applying a full solid-phase strategy. The developed approach also provides rapid access to the enantiomeric, epimeric, and N-demethylated analogues of lysocin E. Significantly, the antibacterial activity of the unnatural enantiomer was comparable to that of the natural isomer, suggesting the absence of chiral recognition in its mode of action.


Expression of 1-cys peroxiredoxin in the corneal wound-healing process.
To study the regulation by mitomycin C (MMC) of 1-cys peroxiredoxin (Prx) expression during the corneal wound-healing process and its induction pathway in cultured bovine keratocytes (BKs). Rat corneas were excised at 4 hours, 12 hours, 1 day, 3 days, and 7 days after photorefractive keratectomy (PRK). Expression of 1-cys Prx in the corneas was examined by Northern blot and immunoblot analyses. Cultured BKs were exposed to 0.02% MMC for 5 minutes and maintained under normal culture conditions for different time periods. Subsequently, levels of 1-cys Prx and extracellular signal-regulated kinase (ERK)1/2 expression were measured by immunoblot analysis using polyclonal 1-cys Prx, ERK1/2, or phospho-ERK1/2 antibodies. To inhibit ERK1/2 activation, the BKs were pretreated with 50 micromol/mL PD98059 for 1 hour before MMC exposure and incubated in complete medium with or without PD98059 for 24 hours. MMC-induced cytotoxicity was determined by colorimetric cell-counting kit-8 assay. Increased levels of 1-cys Prx expression were seen in wounded rat corneas at 12 hours after injury and reached the highest level between 1 and 3 days, during which time active proliferation occurred. Induction of 1-cys Prx expression was obvious in proliferating BKs stimulated by growth factors. MMC treatment in cultured BKs resulted in increased expression of 1-cys Prx and phospho-ERK1/2 in a time-dependent manner. Treatment with 50 micromol/mL PD98059 significantly inhibited the active ERK1/2 and 1-cys Prx expression induced by MMC, leading to synergistic cytotoxicity in the BKs. 1-Cys Prx may function as an important enzyme in cell proliferation during the postinjury corneal wound-healing process. Furthermore, the induction of 1-cys Prx expression through the ERK1/2 signaling pathway may contribute to cellular defense against cytotoxic agents, thus playing an important role in cell survival.


A case of feline primary duodenal carcinoid with intestinal hemorrhage.
A 15-year-old neutered male Persian cat was presented with recurrent hematemesis and melena. Abdominal ultrasonography and computed tomography revealed a mass in the proximal descending duodenal wall. Endoscopic examination revealed hemorrhage on the luminal side of the mass. Fine-needle aspiration of the mass was performed. Microscopic analysis revealed a cluster of cells with oval nuclei and indistinct cell borders, suggesting a neoplastic disease of neuroendocrine origin. The mass located near the major duodenal papilla was partially resected, and the bleeding was stopped by cauterization. However, the surgical procedures could not control the hemorrhage from the tumor mass, and the cat died of severe anemia. Immunohistopathological analysis revealed that the tumor was a duodenal carcinoid.


Nonmedical use of prescription stimulants in college students: Attitudes, intentions, and vested interest.
Research on vested interest theory (VIT) indicates that the importance and hedonic relevance of attitudes moderates the link between attitudes and attitude-congruent behavior. Though largely untested in prevention research, this relationship may prove crucial in determining the success or failure of prevention efforts. The current study was designed to determine if subjectively perceived vested interest maximized the association between attitudes and intentions regarding the nonmedical use of prescription stimulants (NUPS). A cross-sectional survey was conducted with college student respondents (N=162) using Amazon's MTurk. Participant age ranged from 19 to 49years old. A subsample analysis (n=129) was also conducted with younger respondents, as the typical college student is usually under the age of 30. Four-step hierarchical regression analysis indicated that both attitudes and perceived vested interest were significantly associated with NUPS behavioral intentions (p<.001). Further, vested interest moderated the relationship between stimulant-related attitudes and usage intentions (p<.001). Attitudes were significantly associated with intentions of moderately and highly vested respondents (p<.001), but not those of participants expressing low levels of perceived vested interest. Findings support the proposition that vested interest may be a useful target for attenuating NUPS. Rather than attempting to weaken positive attitudes toward NUPS, campaigns may prove more successful if designed to convince receivers that NUPS is not in their best interest.


Comparison of the Vitek 2 yeast susceptibility system with CLSI microdilution for antifungal susceptibility testing of fluconazole and voriconazole against Candida spp., using new clinical breakpoints and epidemiological cutoff values.
A commercially available, fully automated yeast susceptibility test system (Vitek 2; bioMérieux, Marcy d'Etoile, France) was compared in 3 different laboratories with the Clinical and Laboratory Standards Institute (CLSI) reference microdilution (BMD) method by testing 2 quality control strains, 10 reproducibility strains, and 425 isolates of Candida spp. against fluconazole and voriconazole. Reference CLSI BMD MIC endpoints and Vitek 2 MIC endpoints were read after 24 hours and 9.1-27.1 hours incubation, respectively. Excellent essential agreement (within 2 dilutions) between the reference and Vitek 2 MICs was observed for fluconazole (97.9%) and voriconazole (96.7%). Categorical agreement (CA) between the 2 methods was assessed using the new species-specific clinical breakpoints (CBPs): susceptible (S) ≤2 μg/mL, susceptible dose-dependent (SDD) 4 μg/mL, and resistant (R) ≥8 μg/mL for fluconazole and Candida albicans, Candida tropicalis, and Candida parapsilosis and ≤32 μg/mL (SDD), ≥64 μg/mL (R) for Candida glabrata; S ≤0.12 μg/mL, SDD 0.25-0.5 μg/mL, R ≥1 μg/mL for voriconazole and C. albicans, C. tropicalis, and C. parapsilosis, and ≤0.5 μg/mL (S), 1 μg/mL (SDD), ≥2 μg/mL (R) for Candida krusei. The epidemiological cutoff value (ECV) of 0.5 μg/mL for voriconazole and C. glabrata was used to differentiate wild-type (WT; MIC ≤ ECV) from non-WT (MIC > ECV) strains of this species. Due to the lack of CBPs for the less common species, the ECVs for fluconazole and voriconazole, respectively, were used for Candida lusitaniae (2 μg/mL and 0.03 μg/mL), Candida dubliniensis (0.5 μg/mL and 0.03 μg/mL), Candida guilliermondii (8 μg/mL and 0.25 μg/mL), and Candida pelliculosa (4 μg/mL and 0.25 μg/mL) to categorize isolates of these species as WT and non-WT. CA between the 2 methods was 96.8% for fluconazole and 96.5% for voriconazole with less than 1% very major errors and 1.3-3.0% major errors. The Vitek 2 yeast susceptibility system remains comparable to the CLSI BMD reference method for testing the susceptibility of Candida spp. when using the new (lower) CBPs and ECVs.


No abatement of steroid injections for tennis elbow in Australian General Practice: A 15-year observational study with random general practitioner sampling.
Evaluate general practitioner (GP) management of tennis elbow (TE) in Australia. Data about the management of TE by GPs from 2000 to 2015 were extracted from the Bettering the Evaluation of Care of Health program database. Patient and GP characteristics and encounter management data were classified by the International Classification of Primary Care, version 2, and reported using descriptive statistics with point estimates and 95% confidence intervals. TE was managed by GPs 242,000 times per year on average. Patients were mainly female (52.3%), aged between 35 and 64 years (mean: 49.3 yrs), had higher relative risks of concomitant disorders (e.g. carpal tunnel syndrome and other tendonitis) and their TE was 10 times more likely to be work related than problems managed for patients who did not have TE. Use of diagnostic tests was low, implying a clinical examination based diagnosis of TE. Management was by procedural treatments (36 per 100 TE problems), advice, education or counselling (25 per 100), and referral to other health care providers (14 per 100, mainly to physiotherapy). The rate of local injection did not change over the 15 years and was performed at similar rates as physiotherapy referral. The high risk of comorbidities and work relatedness and no abatement in the reasonably high rate of local injections (which is contrary to the evidence from clinical trials) provides support for the development and dissemination of TE clinical guidelines for GPs.


Long-term effects of ACTH combined with angiotensin II on steroidogenesis and adrenal zona glomerulosa morphology in the rat.
To test the hypothesis that the trophic action of angiotensin II on the adrenal zona glomerulosa may allow a sustained stimulation of aldosterone by ACTH by preventing the morphological changes of the zona glomerulosa cells into zona fasciculata-like elements we investigated the effects in rats of a 6-day treatment with ACTH (100 micrograms/kg/day) alone or combined with angiotensin II (300 ng/kg/day) on corticosterone and aldosterone production and adrenal morphology. The responsiveness of both steroids to an acute ACTH dose was also studied on the last day of long-term treatment. Morphologic data showed that prolonged ACTH treatment stimulated the growth of zona glomerulosa cells, though it transformed the tubulo-lamellar cristae of mitochondria into a homogeneous population of vesicles. Angiotensin II furthered the trophic effects of ACTH but prevented the mitochondrial transformation. Despite its ability to conserve the well differentiated aspect of the zona glomerulosa cells, the administration of angiotensin II was unable to prevent the fall in the secretion of aldosterone caused by chronic ACTH treatment and its subsequent unresponsiveness to ACTH stimulation.


A hierarchical biology concept framework: a tool for course design.
A typical undergraduate biology curriculum covers a very large number of concepts and details. We describe the development of a Biology Concept Framework (BCF) as a possible way to organize this material to enhance teaching and learning. Our BCF is hierarchical, places details in context, nests related concepts, and articulates concepts that are inherently obvious to experts but often difficult for novices to grasp. Our BCF is also cross-referenced, highlighting interconnections between concepts. We have found our BCF to be a versatile tool for design, evaluation, and revision of course goals and materials. There has been a call for creating Biology Concept Inventories, multiple-choice exams that test important biology concepts, analogous to those in physics, astronomy, and chemistry. We argue that the community of researchers and educators must first reach consensus about not only what concepts are important to test, but also how the concepts should be organized and how that organization might influence teaching and learning. We think that our BCF can serve as a catalyst for community-wide discussion on organizing the vast number of concepts in biology, as a model for others to formulate their own BCFs and as a contribution toward the creation of a comprehensive BCF.


Tissue engineering of ligaments.
Tissue engineering is emerging as a significant clinical option to address tissue and organ failure by implanting biological substitutes for the compromised tissues. As compared to the transplantation of cells alone, engineered tissues offer the potential advantage of immediate functionality. Engineered tissues can also serve as physiologically relevant models for controlled studies of cells and tissues designed to distinguish the effects of specific signals from the complex milieu of factors present in vivo. A high number of ligament failures and the lack of adequate options to fully restore joint functions have prompted the need to develop new tissue engineering strategies. We discuss the requirements for ligament reconstruction, the available treatment options and their limitations, and then focus on the tissue engineering of ligaments. One representative tissue engineering system involving the integrated use of adult human stem cells, custom-designed scaffolds, and advanced bioreactors with dynamic loading is described.


Dendritic cells revisited in human allergic rhinitis and asthma.
The role of dendritic cells (DCs) in airway allergy has been studied for 15 years; recent data has highlighted the cross talk with airway epithelial cells and environmental factors (allergens, virus) during the inception and exacerbation of allergic asthma. Although murine models have provided key information, it remains uncertain to what extent these basic mechanisms take place in human allergic disease, notably with regard to different clinical phenotypes. In the present review, we discuss new evidence regarding mechanisms of DC regulation in the mouse which could be important in human asthma. Finally, after discussing the effects of current therapies on DC biology, we focus on pathways that could represent targets for future therapies.


Do those who cannot speak really have a voice?
Joseph Finelli, after a heart transplant, is being artificially maintained by medications and a gastrostomy tube (G-tube). He is not brain dead nor in a persistent vegetative state. In my role as court-appointed Guardian ad Litem (GAL-court investigator), it appears to me that Mr. Finelli is being treated against his stated goals and values. After applying the substituted judgment factors, I recommend the withdrawal of the medication which sustains his life. His family adamantly opposes my position.


The intravascular magnetic suspension of a test device for in vivo hemocompatibility evaluation of biomaterials.
To advance hemocompatibility evaluation techniques, a new in vivo method has been developed for the dynamic testing of candidate biomaterials in suitably-sized experimental animals. One of the salient features this method is that the material to be evaluated constitutes the blood contact surface of a slender body of revolution which is coaxially suspended in a large canine vessel by electromagnetic forces only. The insertion site of the specimen is distal and downstream to the test region, reducing the influence of thrombotic tissue substances. These experimental conditions also insure that the only chronically exposed foreign surface is that of the test material, whose interactions with blood components are not affected by contact with the vessel intima. As demonstrated in simulated Circulation Model experiments, macroscopic thromboembolic phenomena induced by the test material can be continuously monitored. Preliminary in vivo trials have verified the validity of the underlying principles; the feasibility of the required surgical techniques, and the adequate performance of the suspension system.


Proteomics and lipidomics reveal the protective mechanism of dietary n-3 PUFA supplementation for photoaging.
Chronic ultraviolet radiation exposure could induce photoaging, and even carcinogenesis. Dietary omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation has proved to alleviate photoaging and cutaneous carcinoma. Although the exact mechanism remains poorly elucidated, accumulated evidence suggests that the alleviation effect of n-3 PUFA for photoaging is a multifactorial procession characterized by different pathways. Here, we performed a whole-genome proteomics and lipidomics analyses using a self-constructed photoaging mouse model with n-3 PUFA or n-6 PUFA supplementation. Significant alleviation of photoaging was observed, and a total of 88 differentially expressed proteins and 152 differentially expressed lipids were identified in mice with n-3 PUFA supplementation. We found that n-3 PUFA may alleviate photoaging by upregulating Hmmr (hyaluronic acid receptor) expression, which can decrease Mmp9 expression, reducing collagen degradation. As most proteins were associated with lipogenesis and lipid metabolism, we further analyzed the lipidomics data, finding that most triglycerides (93%) showed a significant increase in the n-3 PUFA supplementation group. Our proteomics and lipidomics results indicate that the protective mechanism of n-3 PUFA for photoaging is complicated. Furthermore, the effect of elevated triglycerides by n-3 PUFA supplementation in counteracting skin photoaging cannot be ignored, which will become a new prime target in anti-photoaging.


Transcriptomics-Guided Design of Synthetic Promoters for a Mammalian System.
Despite recent advances in improving titers for therapeutic proteins such as antibodies to the 10 g/L scale, these high yields can only be achieved in select mammalian hosts. Regardless of the host or product, strong promoters are required to obtain high levels of transgene expression. However, the promoters employed to drive this expression are rather limited in variety and are usually either viral-derived or screened empirically during vector design. To begin to move away from viral parts, we employed a more systematic approach to identify and design new synthetic promoters using endogenous elements. To do so, we established a workflow to design these elements by (1) analyzing the transcriptomics profile of a specific cell line under a desired, representative cell culture condition, (2) identifying key genetic motifs using bioinformatics that can be used to rationally construct synthetic promoters, (3) building synthetic promoters using conventional DNA synthesis and molecular biology techniques, and (4) evaluating the performance of these synthetic promoters using model proteins. The resulting promoters perform comparably to the hCMV IE promoter variants tested, but with endogenous components. During this design-build-test cycle we also investigated the underlying design rules for transcription factor binding site arrangement in synthetic promoters. Overall, this approach of using an "omics-guided" workflow for designing synthetic promoters facilitates the construction of high expression vectors for immediate use in current production hosts.


Progressive neurologic deterioration and renal failure due to storage of glutamyl ribose-5-phosphate.
A six-year-old boy presented with a history of seizures, progressive neurologic deterioration, and proteinuria. Physical examination revealed mildly coarse facies, failure to thrive, generalized hypotonia with muscle wasting, and optic atrophy; there was no organomegaly. The family history suggested an X-linked recessive inheritance. The electroencephalogram, electroretinogram, evoked potentials, and computed axial tomography of the brain were abnormal. Urine oligosaccharide chromatography, urine amino acids and organic acids, and results of leukocyte and fibroblast lysosomal-enzyme assays for the known storage diseases were normal; however, conjunctival and renal biopsy specimens contained enlarged lysosomes on electron microscopy. The patient had progressive neurologic deterioration and died of renal failure at eight years of age. A compound identified as glutamyl ribose-5-phosphate was purified from the brain (0.96 mumol per gram, wet weight) and kidney (0.60 mumol per gram, wet weight). This compound is the linkage group in ADP-ribosylation of proteins, an important regulatory process in gene expression and DNA repair. We believe this new disorder represents a glycoproteinosis that results in the cytoplasmic storage of glutamyl ribose-5-phosphate.


Prospective study on Trilucent soybean oil-filled breast prosthesis.
The use of Trilucent breast implants dates back to 1995. These implants were produced in an attempt to overcome the perceived shortcomings of other implants filled with saline and silicone gel. The filler material, which was derived from soybean oil, was said to be biodegradable and biocompatible. When this prosthesis was subsequently found to be prone to rapid aging and rupture of the silicone shell, the company that manufactured this implant decided to withdraw it from the market and offered to remove or replace all Trilucent prostheses. The authors present a clinical study of the Trilucent implant in which 36 patients received a total of 63 implants and 33 patients had 58 implants removed. The authors also examined the implant shell of the removed prostheses to investigate the possible cause of silicone implant aging and rupture. Each of the implants removed was carefully inspected visually, and samples of the implant shell were analyzed by scanning electron microscopy. All the implants removed had a very bizarre appearance; they were variegated in color, with shades of yellow and brown, and were studded with whitish yellow nodules whose number grew in proportion to the time the prosthesis was implanted. Scanning electron microscopic analysis of the implant shell revealed a heterogeneous inner surface of the implant together with fissures and globoid deposits on the cut surface. The authors' findings on Trilucent implants are similar to those reported in previously published studies for other types of breast implants for the first 2 years after implantation, after which a progressive, rapid deterioration was observed.


The study of NADPH-dependent flavoenzyme-catalyzed reduction of benzo[1,2-c]1,2,5-oxadiazole N-oxides (benzofuroxans).
The enzymatic reactivity of a series of benzo[1,2-c]1,2,5-oxadiazole N-oxides (benzofuroxans; BFXs) towards mammalian single-electron transferring NADPH:cytochrome P-450 reductase (P-450R) and two-electron (hydride) transferring quinone oxidoreductase (NQO1) was examined in this work. Since the =N+ (→O)O- moiety of furoxan fragments of BFXs bears some similarity to the aromatic nitro-group, the reactivity of BFXs was compared to that of nitro-aromatic compounds (NACs) whose reduction mechanisms by these and other related flavoenzymes have been extensively investigated. The reduction of BFXs by both P-450R and NQO1 was accompanied by O2 uptake, which was much lower than the NADPH oxidation rate; except for annelated BFXs, whose reduction was followed by the production of peroxide. In order to analyze the possible quantitative structure-activity relationships (QSARs) of the enzymatic reactivity of the compounds, their electron-accepting potency and other reactivity indices were assessed by quantum mechanical methods. In P-450R-catalyzed reactions, both BFXs and NACs showed the same reactivity dependence on their electron-accepting potency which might be consistent with an "outer sphere" electron transfer mechanism. In NQO1-catalyzed two-electron (hydride) transferring reactions, BFXs acted as more efficient substrates than NACs, and the reduction efficacy of BFXs by NQO1 was in general higher than by single-electron transferring P-450R. In NQO1-catalyzed reactions, QSARs obtained showed that the reduction efficacy of BFXs, as well as that of NACs, was determined by their electron-accepting potency and could be influenced by their binding mode in the active center of NQO1 and by their global softness as their electronic characteristic. The reductive conversion of benzofuroxan by both flavoenzymes yielded the same reduction product of benzofuroxan, 2,3-diaminophenazine, with the formation of o-benzoquinone dioxime as a putative primary reductive intermediate, which undergoes a further reduction process. Overall, the data obtained show that by contrast to NACs, the flavoenzyme-catalyzed reduction of BFXs is unlikely to initiate their redox-cycling, which may argue for a minor role of the redox-cycling-type action in the cytotoxicity of BFXs.


The effect of rTMS on auditory processing in adults with chronic, bilateral tinnitus: a placebo-controlled pilot study.
On the basis that tinnitus may result from neural hyperactivity in the auditory cortex, researchers have investigated the use of low frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) as a potential modulator of this hyperactivity. While these investigations show promise, investigations to date have neglected to consider the possible effect of 1 Hz rTMS on other functions of the auditory cortex of these individuals, such as auditory processing. This placebo-controlled pilot study aimed to determine whether 1 Hz rTMS applied to the primary auditory cortex (PAC), specifically Brodmann Area 41 (BA41), of adults with chronic, bilateral tinnitus would influence their auditory processing abilities. Eight participants with bilateral, chronic tinnitus were randomized to receive a 10-day course of neuronavigationally guided active rTMS (n = 4) or placebo rTMS (n = 4) treatment applied to a focal region of the left PAC (BA41). Participants' auditory processing was measured using Time Compressed Reverberant Speech and three-pair Dichotic Digits (DD). Their tinnitus was measured using the Tinnitus Handicap Inventory (THI) and a psychoacoustic measure of tinnitus perception. All outcome measures were administered at baseline (1 week prior to rTMS), 1 week, 1, 2 and 3 months post-rTMS. All four participants in the active rTMS (A) group, and none of the participants in the sham (placebo) rTMS (S) group, showed improved auditory processing scores at multiple assessment points post-stimulation, with the group differences in median normalized gain scores reaching significance at the 5% level from 1 week or 1 month post-stimulation onwards. Three of the four participants in the active rTMS (A) group, and none of the participants in the sham rTMS (S) group, showed improved tinnitus scores at multiple assessment points post-stimulation, with some of the group differences in median normalized gain scores reaching significance at the 5% level. The results of this preliminary study suggest that 1 Hz rTMS applied to the PAC (BA41) has the capacity to improve both auditory processing and tinnitus perception in some adults with chronic, bilateral tinnitus.


Application of a diphasic dialysis technique to the extraction of aflatoxins in dairy products.
A new method is described for the extraction of aflatoxins from milk and milk products based on a diphasic dialysis technique, followed by detection and quantification of aflatoxins by TLC. Recovery was 65 to 99% for aflatoxins B1, G1, and M1, and the detection limit in milk and yogurt was .01 to .02 ppb for all aflatoxins studied. In cheese, the detection limit was .03 to .04 ppb for aflatoxins B1 and G1 and .1 ppb for aflatoxin M1. The main advantages of this technique are its simplicity; sensitivity; very economical use of reagents, thereby minimizing environmental pollution; efficiency, allowing the quick processing of a high number of samples; use by laboratories with little equipment; and a sensitivity comparable with that of much more sophisticated techniques.


Effect of parathyroid hormone fragments on calcium transport in toad bladder.
Parathyroid hormone (PTH) has a variety of biologic effects which are both dependent and independent on activation of adenylate cyclase. We studied the effects of intact PTH and PTH fragments on water flow and Ca transport in isolated toad bladder sacs. As reported previously by us, PTH (1-84) significantly stimulated basal water flow in isolated toad bladder sacs. Synthetic PTH 1-34, 44-68, 53-84 and 65-84 (1 microgram/ml) had no effect on basal water flow after a 60-min incubation period. Intact PTH (1-84) and synthetic 1-34 PTH significantly inhibited both arginine-vasopressin and cyclic AMP-stimulated water flow. Synthetic PTH 44-68, 53-84 and 65-84 (1 microgram m/ml) had no effect on arginine-vasopressin or cyclic AMP-stimulated water flow after a 60-min incubation. Intact PTH (1-84) and synthetic 1-34 PTH significantly stimulated 45Ca uptake without affecting 45Ca efflux. Synthetic PTH 44-68, 53-84 and 65-84 had no effect on either 45Ca uptake or 45Ca efflux. Although these results suggest that the intact hormone is required for the maximal effect of PTH on water flow, substantial activity resides in the amino terminal fragment of the hormone. No activity per se resides in the carboxy terminal portion of the hormone as regards water flow. Alterations in Ca transport appear to mediate the effect of PTH on water flow. These effects are independent of activation of adenylate cyclase because these hormones also inhibit cyclic AMP-stimulated water flow.


Respiratory findings in art and medical students. Effects of the art environment.
Art students are exposed to many noxious agents during their training, in contrast to medical students, who are not exposed to known environmental pollutants. In order to investigate the potential effects of toxic agents in the art students' environment, we studied respiratory findings in a cohort of 117 art students and 128 medical students, matched for age, sex and smoking. Acute and chronic respiratory symptoms were evaluated by modifying the British Medical Research Council questionnaire. Lung function studies were performed with a spirometer (Jaeger, Germany) measuring maximum expiratory flow-volume (MEFV) curves. On these curves we calculated the forced vital capacity (FVC), one second forced expiratory volume (FEV1) and the maximal expiratory flow at 50% and the last 25% of the FVC (FEF50, FEF25). Significantly higher prevalences of most of the chronic respiratory symptoms were recorded in art students compared to medical students (p < 0.05). Art students who were smokers had significantly higher prevalences of many of the chronic respiratory symptoms than nonsmoking art students. Among medical students these differences were not statistically significant (NS). High prevalences of acute symptoms related to the study environment were recorded for art students. Odds ratios in male and female art students were significant for chronic cough, chronic phlegm and chronic bronchitis for the risk factor of smoking. Significantly decreased lung function values compared to predicted values were recorded mostly for FEF50 and FEF25 in male and female art students. Smoking and non-smoking art students had similar reductions of lung function. Lung function data in medical students were within predicted values. Our data indicate that art students may be at risk of developing chronic respiratory symptoms and lung function changes as a result of their environmental exposure and their smoking habits.


Range of validity of the Rayleigh hypothesis.
The parameter range over which the Rayleigh hypothesis (RH) for optical gratings might be validly applied to analysis of high power backward wave oscillators has been investigated numerically. It had been pointed out that from a rigorous mathematical viewpoint, RH was only valid for a shallow corrugation of slow wave structure (SWS) such that h K0 <0.448; here, h and K0 are, respectively, the amplitude and wave number of the periodicity in a sinusoidal planar grating. We numerically analyze the electromagnetic fields in the axisymmetric SWS with and without use of RH. The field patterns and eigenfrequency for the SWS are solved numerically for a given k(z) by using the code HIDM (higher order implicit difference method) that is free from the RH. It is found that, for a deep corrugation, h K0 =5 x 0.448, using RH is still valid for obtaining the dispersion relation, although the Floquet harmonic expansion (FHE) fails to correctly represent the field patterns inside the corrugation. Accordingly, there exists a discrepancy between the validity of using RH for obtaining dispersion relations and for an exact convergence of FHE everywhere in the SWS.


Estrogen and progesterone receptors in normal and malignant vulvar tissue.
Cytoplasmic receptors for 17 beta-estradiol (ER) and progesterone (PR) were measured in vulvar carcinomas. Tissues from 12 patients were examined. 5 of the vulvar carcinomas had detectable amounts of ER of whom 1 also had positive PR. Tissue samples from normal vulvar skin in 9 of the same patients were also examined for ER and PR activity. 3 had positive ER only and 1 had both ER and PR activity. The concentration of ER in cancer tissue showed a binding capacity of 2-23 pmol/g cytosol protein. In receptor-positive normal vulvar skin the binding capacity of ER ranged between 4 and 10 pmol/g cytosol protein. The binding capacity or PR, positive in 1 vulvar carcinoma and in 1 normal skin sample, was 12 and 10 pmol/g cytosol protein, respectively.


Selective upregulation of Per1 mRNA expression by ATP through activation of P2X7 purinergic receptors expressed in microglial cells.
Clock genes are believed to play a pivotal role in the generation and oscillation of circadian rhythm as a central clock in the hypothalamic suprachiasmatic nucleus in the mammalian brain. In this study, mRNA expression was for the first time demonstrated with clock genes in both cultured murine microglia and microglial cell line BV-2 cells. Exposure to ATP transiently increased Period-1 (Per1) mRNA expression without affecting that of other clock genes in BV-2 cells, while a similarly transient increase was shown in Per1 mRNA expression in a manner sensitive to P2X7 purinergic receptor antagonists in cultured microglia exposed to ATP. In BV-2 cells transfected with a Per1 promoter luciferase reporter plasmid, ATP significantly increased luciferase activity in a manner sensitive to a P2X7-receptor antagonist. In both microglia and BV-2 cells, a significant increase by ATP was seen in the immunocytochemical fluorescence intensity of cells expressing Per1 protein, with mRNA expression of different P2 receptors including P2X7. Per1 siRNA significantly decreased the number of cells with processes in BV-2 cells exposed to ATP. These results suggest that ATP selectively promotes Per1 expression through gene transactivation after stimulation of P2X7 purinergic receptors in microglial cells.


New directions for telemental health research.
Although telemental healthcare has been available for many years, is generally accepted as effective, and has steadily growing numbers of consumers and providers, more and better research in this area needs to be done in order to convince insurers, policymakers, and funding agencies that mental healthcare delivered from a distance is at least as good as that delivered face-to-face. Because there is a wide spectrum of potential mental health disorders that might be encountered, there are significant gaps in telemental health research that need to be addressed before payment for services or funding for large-scale studies of this application can be expected. This white paper will review the current state of telemental health research and will offer suggestions for future directions necessary for telemental research to take in order to firmly establish its effectiveness.


Correlated dynamics in aqueous proton diffusion.
The aqueous proton displays an anomalously large diffusion coefficient that is up to 7 times that of similarly sized cations. There is general consensus that the proton achieves its high diffusion through the Grotthuss mechanism, whereby protons hop from one molecule to the next. A main assumption concerning the extraction of the timescale of the Grotthuss mechanism from experimental results has been that, on average, there is an equal probability for the proton to hop to any of its neighboring water molecules. Herein, we present ab initio simulations that show this assumption is not generally valid. Specifically, we observe that there is an increased probability for the proton to revert back to its previous location. These correlations indicate that the interpretation of the experimental results need to be re-examined and suggest that the timescale of the Grotthuss mechanism is significantly shorter than was previously thought.


Identification of Hub Genes Related to Carcinogenesis and Prognosis in Colorectal Cancer Based on Integrated Bioinformatics.
The high mortality of colorectal cancer (CRC) patients and the limitations of conventional tumor-node-metastasis (TNM) stage emphasized the necessity of exploring hub genes closely related to carcinogenesis and prognosis in CRC. The study is aimed at identifying hub genes associated with carcinogenesis and prognosis for CRC. We identified and validated 212 differentially expressed genes (DEGs) from six Gene Expression Omnibus (GEO) datasets and the Cancer Genome Atlas (TCGA) database. We investigated functional enrichment analysis for DEGs. The protein-protein interaction (PPI) network was constructed, and hub modules and genes in CRC carcinogenesis were extracted. A prognostic signature was developed and validated based on Cox proportional hazards regression analysis. The DEGs mainly regulated biological processes covering response to stimulus, metabolic process, and affected molecular functions containing protein binding and catalytic activity. The DEGs played important roles in CRC-related pathways involving in preneoplastic lesions, carcinogenesis, metastasis, and poor prognosis. Hub genes closely related to CRC carcinogenesis were extracted including six genes in model 1 (CXCL1, CXCL3, CXCL8, CXCL11, NMU, and PPBP) and two genes and Metallothioneins (MTs) in model 2 (SLC26A3 and SLC30A10). Among them, CXCL8 was also related to prognosis. An eight-gene signature was proposed comprising AMH, WBSCR28, SFTA2, MYH2, POU4F1, SIX4, PGPEP1L, and PAX5. The study identified hub genes in CRC carcinogenesis and proposed an eight-gene signature with good reproducibility and robustness at the molecular level for CRC, which might provide directive significance for treatment selection and survival prediction.


Biflavonoids from Daphne feddei and their inhibitory activities against nitric oxide production.
Bioassay-directed fractionation led to the isolation of two new biflavonoids and 13 known biflavonoids from a sample of the dried stem barks of Daphne feddei. The structures of compounds 1 and 2 were elucidated as 2''-methoxy-daphnodorin C (1) and 2''-methoxy-2-epi-daphnodorin C (2) on the basis of detailed spectroscopic analysis and X-ray crystallography. All 15 biflavonoids were tested for inhibitory activities against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages. Compounds 1, 2, 8, 10, 14 and 15 showed varying degrees of inhibitory activities against the production of NO in tested concentration of 25, 50, 75 and 100 microg/ml.


Decreased injecting is associated with increased alcohol consumption among injecting drug users in northern Vietnam.
Reducing injecting frequency may reduce the risk of HIV infection and improve health outcomes among injection drug users (IDUs). However, the reduction of one risk behavior may be associated with an increase in other risk behaviors, including the use of other risk-associated substances. Our objective was to determine if an association exists between a reduction in injecting and level of alcohol use among IDU. We conducted a longitudinal analysis of data collected for a randomized controlled trial examining the efficacy of a peer education intervention in reducing HIV risk among IDU and their network members in Thai Nguyen, Vietnam. Our analysis included active male injectors (n = 629) who were study participants and attended both baseline and 3-month visits. Frequency of alcohol consumption was assessed as the number of alcoholic drinks in the past 30 days. Change in risk and outcome behaviors was calculated as the difference in frequencies of behaviors between baseline and 3-month follow-up visits. The outcome of interest was concurrent decreased drug injection and increased alcohol consumption. The mean difference between baseline and 3-month follow-up of alcohol consumption and injection frequency in the past 30 days was 19.03 drinks (93.68 SD) and 20.22 injections (35.66 SD), respectively. Participants who reported reduced injection frequency were almost three times as likely to report increased alcohol consumption (OR 2.8; 95% CI, 2.0, 4.0). The proportion that both decreased injecting and increased alcohol by any amount in the past 30 days was 35.6%. In multivariate analysis higher education was significantly associated with an increase in alcohol and decrease in injecting of any amount. Male IDU may be at risk for increasing alcohol consumption when they reduce injection frequency. Interventions with male IDU that encourage reduction of injection may need to review specific strategies to limit alcohol consumption.


Evaluation of mycosis fungoides management by total skin electron beam therapy with "translational technique".
The aim of this study was to evaluate the outcomes of total skin electron beam therapy (TSEBT) with "translational technique" in the management of mycosis fungoides (MF). Between January 1995 and October 2014, 51 patients with MF were treated using TSEBT with translational technique. The total dose was 2800-3600 cGy, de-livered in 7 to 20 fractions. Out of the total 51 patients, 22 (43.1%) had T2 (generalized patch/plaque) disease, 20 (39.3%) had T3 disease (tumor stage), and 9 (17.6%) had T4 (erythrodermic) disease. Radiation-related late skin injury parameters including atrophy, pigmentation changes, hair loss, telangiectasia and ulceration were assessed according to RTOG/EORTC Late Radiation Morbidity Scoring Schema after at least 3 months from TSEBT. Treatment response was categorized as complete remission (CR), partial remission (PR), or non-responding (NR) lesions. After TSEBT with translational technique, CR rate was 68.6% and PR rate 23.5%, while the NR rate was 7.9%. Overall, the rates of grade 1, grade 2, grade 3, and grade 4 toxicity were 17.6% )9 patients), 39.3% (20 patient), 35.3% (18 patients), and 7.8% (4 patients), respectively. At a median follow-up of 79 months (range 14-142), overall survival (OS) and disease-free survival (DFS) rates were 83% and 46%, respectively. For patients with MF refractory to topical chemotherapy and phototherapy, TSEBT with translational technique offers excellent local control (LC: CR+PR) and favorable OS rates along with substantial relief of symptoms.


Facile hyphenation of gas chromatography and a microcantilever array sensor for enhanced selectivity.
The very simple coupling of a standard, packed-column gas chromatograph with a microcantilever array (MCA) is demonstrated for enhanced selectivity and potential analyte identification in the analysis of volatile organic compounds (VOCs). The cantilevers in MCAs are differentially coated on one side with responsive phases (RPs) and produce bending responses of the cantilevers due to analyte-induced surface stresses. Generally, individual components are difficult to elucidate when introduced to MCA systems as mixtures, although pattern recognition techniques are helpful in identifying single components, binary mixtures, or composite responses of distinct mixtures (e.g., fragrances). In the present work, simple test VOC mixtures composed of acetone, ethanol, and trichloroethylene (TCE) in pentane and methanol and acetonitrile in pentane are first separated using a standard gas chromatograph and then introduced into a MCA flow cell. Significant amounts of response diversity to the analytes in the mixtures are demonstrated across the RP-coated cantilevers of the array. Principal component analysis is used to demonstrate that only three components of a four-component VOC mixture could be identified without mixture separation. Calibration studies are performed, demonstrating a good linear response over 2 orders of magnitude for each component in the primary study mixture. Studies of operational parameters including column temperature, column flow rate, and array cell temperature are conducted. Reproducibility studies of VOC peak areas and peak heights are also carried out showing RSDs of less than 4 and 3%, respectively, for intra-assay studies. Of practical significance is the facile manner by which the hyphenation of a mature separation technique and the burgeoning sensing approach is accomplished, and the potential to use pattern recognition techniques with MCAs as a new type of detector for chromatography with analyte-identifying capabilities.


Pros and cons of adjuvant interferon in the treatment of melanoma.
Should interferon alpha (IFN-alpha) be considered the standard of care for the adjuvant therapy of high-risk malignant melanoma? For 2003, it was estimated that 51,400 cases of invasive melanoma would be diagnosed. The risk of recurrence after surgery is reported to be approximately 60% for patients with thick primary lesions (T4N0M0, American Joint Committee on Cancer [AJCC] stage IIB) and 75% for patients with regional nodal metastases (T1-4N1M0, AJCC stage III). The observation that melanoma is susceptible to attack by the host's immune system has resulted in the testing of a remarkably broad spectrum of immunotherapies in the adjuvant setting. Many of these approaches failed to demonstrate a significant clinical impact, until the use of adjuvant IFN-alpha. Conflicting data from several large, randomized clinical trials resulted in a rapid rise and then decline in the use of IFN-alpha in the adjuvant setting. This roller coaster has left many clinicians still hesitant to strongly recommend it, and the use of adjuvant IFN-alpha in high-risk melanoma remains controversial. This manuscript reviews the leading arguments for and against its routine use and addresses questions regarding its role in the management of high-risk malignant melanoma.


The structure of cells during tobacco mosaic virus reproduction. Mesophyll cells containing virus crystals.
The submicroscopic organization of mesophyll cells from tobacco leaves systemically infected with tobacco mosaic virus (TMV) is described. After fixation with glutaraldehyde and osmium tetroxide the arrangement of the TMV particles within the crystalline inclusions is well preserved. Only the ribonucleic acid-containing core of the virus particles is visible in the micrographs. Besides the hexagonal virus crystals, several characteristic types of "inclusion bodies" are definable in the cytoplasm: The so-called fluid crystals seem to correspond to single layers of oriented TMV particles between a network of the endoplasmic reticulum and ribosomes. Unordered groups or well oriented masses of tubes with the diameter of the TMV capsid are found in certain areas of the cytoplasm. A complicated inclusion body is characterized by an extensively branched and folded part of the endoplasmic reticulum, containing in its folds long aggregates of flexible rods. Certain parts of the cytoplasm are filled with large, strongly electron-scattering globules, probably of lipid composition. These various cytoplasmic differentiations and the different forms of presumed virus material are discussed in relation to late stages of TMV reproduction and virus crystal formation.


Reduced or painful jaw movement after collision-related injuries: a population-based study.
The authors report the incidence of and factors associated with reduced and/or painful jaw movement after motor vehicle collisions that resulted in whiplash-associated disorders (WADs). All adults filing collision-related personal injury claims during an 18-month period in Saskatchewan, Canada, were evaluated via questionnaire to determine demographic characteristics, precollision health (including jaw pain), collision parameters and collision-related symptoms, including reduced and/or painful jaw movement and injury-related neck pain. The authors excluded patients who were hospitalized for more than two days and those who sustained injuries as a pedestrian, bicyclist or motorcyclist. In determining incidence rates, the authors also excluded those who had had jaw pain before the collision. The incidence of reduced and/or painful jaw movement was 14.9 percent (n = 1,158), and it was higher in subjects with WADs (15.8 percent) than in those without WADs (4.7 percent; relative risk = 3.36, 95 percent confidence interval, 2.36 to 4.78). Within the WAD injuries, multivariable logistic regression revealed that the onset of reduced and/or painful jaw movement was associated with female sex; age < 50 years; having hit one's head in the collision; and postinjury symptoms of difficulty swallowing, ringing in the ears, dizziness or unsteadiness, and more intense neck pain. Collision parameters, such as head position at the time of the crash and headrest use and type, were not associated with onset of jaw symptoms. Reduced or painful jaw movement was more common in people with WADs than in those with other collision-related injuries. Among those with WADs, reduced or painful jaw movement was more common in women and younger people. Reduced or painful jaw movement is an important aspect of WADs, and more studies are needed to determine how to best assess and treat this problem.


Analgesic and antacid properties of i.m. tramadol given before Caesarean section under general anaesthesia.
Intramuscular (i.m.) tramadol increases gastric pH during anaesthesia similar to famotidine. We investigated the antacid analgesic value of a single dose of i.m. tramadol given 1 h before elective Caesarean section performed under general anaesthesia. Sixty ASA I parturients undergoing elective Caesarean section were included in a randomized double-blind study. The patients were randomly allocated to receive i.m. tramadol 100 mg (n=30) or famotidine 20 mg (n=30) 1 h before general anaesthesia. At the beginning and the end of anaesthesia, patients receiving tramadol had a median gastric fluid pH of 6.4, which was not significantly different from those treated with famotidine (median 6.3). The infant well-being, as judged by Apgar score, cord blood gas analysis, and neurobehavioural assessment showed no significant difference between the two groups. Nalbuphine consumption in the first 24 h after operation was reduced by 35% in the tramadol group. Pain intensity score on sitting and sedation were significantly greater in famotidine group up to 24 h after surgery. There was no significant difference in incidence and severity of nausea and vomiting between the two groups. A single i.m. dose of tramadol is useful pre-treatment to minimize the risk of acid aspiration during operation, and in improving pain relief during 24 h after surgery.


Rearrangement of the chicken lambda light chain locus: a silencer/antisilencer regulation.
Chicken immunoglobulin lambda light chain rearrangement is regulated by different controlling elements. One negative control element, acting as a strong transcriptional silencer, is located in the V-J intervening sequence which is excised during the rearrangement process. Positive control elements include the V lambda promoter, the enhancer of transcription (3' of C lambda), and one (or two) putative antisilencer element(s) located on each side of the silencer. It is proposed that these antisilencer elements counteract transiently the silencer thus allowing rearrangement of one allele in chicken B cell progenitors. The implications of this regulation for mouse B cell development are discussed.


Differential transcriptional control of hematopoiesis in congenital and cyclic neutropenia patients harboring ELANE mutations.
Mutations in the ELANE gene, encoding the neutrophil elastase (NE) protein, are responsible for most CyN cases and approximately 25 % of CN cases. In CN and in CyN, a median of 2.8 % of CD34+ cells were early CD49f+ hematopoietic stem cells (eHSC) that did not express ELANE and thus escape from the unfolded protein response (UPR) caused by mutated NE. In CyN, the CD49f+ cells respond to G-CSF with a significant upregulation of the hematopoietic stem-cell-specific transcription factors, C/EBP/, MLL1, HOXA9, MEIS1, and HLF during the ascending arm of the cycle, resulting in the differentiation of myeloid cells to mature neutrophils at the cycle peak. However, NE protein released by neutrophils at the cycle's peak caused a negative feedback loop on granulopoiesis through the proteolytic digestion of G-CSF. In contrast, in CN patients, CD49f+ cells failed to express mRNA levels of HSC-specific transcription factors mentioned above. Rescue of C/EBP//expression in CN restored granulopoiesis.


Adeno-associated virus-vectored erythropoietin gene therapy for anemia in cats with chronic kidney disease.
A treatment of chronic kidney disease (CKD)-associated anemia in cats is needed. SB-001 is an adeno-associated virus-vectored (AAV)-based gene therapeutic agent that is administered intramuscularly, causing the expression of feline erythropoietin. We hypothesized that SB-001 injection would lead to a sustained increase in PCV in cats with CKD-associated anemia. Twenty-three cats with International Renal Interest Society (IRIS) Stage 2 to 4 CKD-associated anemia were enrolled at 4 veterinary clinics. In a prospective clinical trial, cats were treated with 1 of 3 regimens of SB-001 (Lo 1.2 × 109 genome copies [GCs] on Day 0; Lo ± Hi [supplemental 2nd dose of 3.65 × 109 GC on Day 42]; Hi 3.65 × 109 GC IM on Day 0) and followed for 70 days. A response to SB-001 at any time between Day 28 and Day 70 was seen in 86% (95% confidence interval 65, 97%) of all cats. There was a significant (P < .003) increase in PCV from Day 0 to Day 28 (mean increase 6 ± 6 percentage points [pp]; n = 21), Day 42 (8 ± 9 pp; n = 21), Day 56 (10 ± 11 pp; n = 17), and Day 70 (13 ± 14 pp, n = 14). Twelve cats were hypertensive at baseline, 4 of which developed encephalopathy during the study. An additional 6 cats became hypertensive during the study. Results of this study suggest that SB-001 therapy represents a suitable single injection treatment that can address nonregenerative anemia in cats with CKD. It was generally well tolerated; however, hypertension and encephalopathy developed in some cats as previously described in association with erythropoiesis-stimulating agent therapy.


Clinical effectiveness of beta-lactams versus fluoroquinolones as empirical therapy in patients with diabetes mellitus hospitalized for urinary tract infections: A retrospective cohort study.
Diabetic patients are at risk of severe urinary tract infections (UTIs). Due to the emerging resistance rates to fluoroquinolones and β-lactams, we aimed to evaluate the effectiveness of β-lactams versus fluoroquinolones as empirical therapy for diabetic patients hospitalized for UTIs. A retrospective cohort study was conducted in a medical center in Taiwan between 2016 and 2018. Patients with type 2 diabetes, aged ≥20 and hospitalized for UTIs were enrolled. Patients with UTI diagnosis within one year before the admission, co-infections at the admission, or ≥2 pathogens in the urine cultures were excluded. The primary outcome was empiric treatment failure. 298 patients were followed for at least 30 days after the admission. Escherichia coli (61.07%) was the most common pathogen. The resistance rates of the pathogens to levofloxacin were 28.52% and 34.22% according to the historical Clinical and Laboratory Standards Institute (CLSI) breakpoints and the updated 2019 CLSI breakpoints, respectively. The resistance rates of ceftazidime and cefepime were 21.81% and 11.41%, respectively. Empirical β-lactams were associated with less treatment failure compared to fluoroquinolones (adjusted OR = 0.32, 95% CI = 0.17-0.60). Beta-lactams were associated with less treatment failure than fluoroquinolones when appropriatness was determined by the pre-2019 CLSI breakpoints but not the 2019 CLSI breakpoints. In diabetic patients hospitalized for UTIs, β-lactams were associated with less empiric treatment failure compared to fluoroquinolones when the resistance rate to fluoroquinolone is higher than β-lactams. The updated 2019 CLSI breakpoint for fluoroquinolone was better than pre-2019 CLSI breakpoints to correlate with treatment outcomes for hospitalized UTIs in diabetic patients.


Detection of CD4(+)- and CD8(+)-T-cell responses to human papillomavirus type 1 antigens expressed at various stages of the virus life cycle by using an enzyme-linked immunospot assay of gamma interferon release.
Human papillomavirus (HPV) antigens are expressed in epithelial cells at different stages of differentiation, and this may affect how they are handled by the immune system. We assessed the relative immunogenicities of four different HPV type 1 proteins: E6 and E7, which are made early in basal or parabasal cells; E4, which is made suprabasally in differentiating cells; and L1, a late protein which appears in the highly differentiated upper spinous layers. Pools of 15-mer peptides covering the primary sequences of all four proteins were used to screen 15 normal donors in enzyme-linked immunospot assays of gamma interferon release for both CD4(+)- and CD8(+)-T-cell reactivities. CD8(+)-T-cell responses were detected to the L1 protein in 7 of the 15 samples examined. No responses to E6, E7, or E4 were detected. CD4(+)-T-cell reactivities were again detected in 7 of the 15 donors. A broader spectrum of responses to E6 (three of seven), E4 (six of seven), and L1 (three of seven) was apparent, but there was no reactivity to E7. The predominant CD4(+) response was to E4. Reactivities were seen in some cases to corresponding regions on other common HPV types but were probably due to a multiple infection rather than to a cross-reaction. Antibodies to HPV1 virus-like particles were detected in 12 of the 15 (80%) donors, but antibody status did not correlate with T-cell reactivity. The differences in the relative immunogenicities of the four proteins revealed in this study are discussed in relation to how they may be processed and presented to the immune system by differentiating epithelial cells.


Efficient CO2 Removal for Ultra-Pure CO Production by Two Hybrid Ultramicroporous Materials.
Removal of CO2 from CO gas mixtures is a necessary but challenging step during production of ultra-pure CO as processed from either steam reforming of hydrocarbons or CO2 reduction. Herein, two hybrid ultramicroporous materials (HUMs), SIFSIX-3-Ni and TIFSIX-2-Cu-i, which are known to exhibit strong affinity for CO2 , were examined with respect to their performance for this separation. The single-gas CO sorption isotherms of these HUMs were measured for the first time and are indicative of weak affinity for CO and benchmark CO2 /CO selectivity (>4000 for SIFSIX-3-Ni). This prompted us to conduct dynamic breakthrough experiments and compare performance with other porous materials. Ultra-pure CO (99.99 %) was thereby obtained from CO gas mixtures containing both trace (1 %) and bulk (50 %) levels of CO2 in a one-step physisorption-based separation process.


The THAP-zinc finger protein THAP1 regulates endothelial cell proliferation through modulation of pRB/E2F cell-cycle target genes.
We recently cloned a novel human nuclear factor (designated THAP1) from postcapillary venule endothelial cells (ECs) that contains a DNA-binding THAP domain, shared with zebrafish E2F6 and several Caenorhabditis elegans proteins interacting genetically with retinoblastoma gene product (pRB). Here, we show that THAP1 is a physiologic regulator of EC proliferation and cell-cycle progression, 2 essential processes for angiogenesis. Retroviral-mediated gene transfer of THAP1 into primary human ECs inhibited proliferation, and large-scale expression profiling with microarrays revealed that THAP1-mediated growth inhibition is due to coordinated repression of pRB/E2F cell-cycle target genes. Silencing of endogenous THAP1 through RNA interference similarly inhibited EC proliferation and G1/S cell-cycle progression, and resulted in down-regulation of several pRB/E2F cell-cycle target genes, including RRM1, a gene required for S-phase DNA synthesis. Chromatin immunoprecipitation assays in proliferating ECs showed that endogenous THAP1 associates in vivo with a consensus THAP1-binding site found in the RRM1 promoter, indicating that RRM1 is a direct transcriptional target of THAP1. The similar phenotypes observed after THAP1 overexpression and silencing suggest that an optimal range of THAP1 expression is essential for EC proliferation. Together, these data provide the first links in mammals among THAP proteins, cell proliferation, and pRB/E2F cell-cycle pathways.


Comparison of three small-area mortality metrics according to urbanity in Korea: the standardized mortality ratio, comparative mortality figure, and life expectancy.
This study aimed to compare three small-area level mortality metrics according to urbanity in Korea: the standardized mortality ratio (SMR), comparative mortality figure (CMF), and life expectancy (LE) by urbanity. We utilized the National Health Information Database to obtain annual small-area level age-specific numbers of population and deaths in Korea between 2013 and 2017. First, differences in the SMR by urbanity were examined, assuming the same age-specific mortality rates in all small areas. Second, we explored the differences in ranking obtained using the three metrics (SMR, CMF, and LE). Third, the ratio of CMF to SMR by population was analyzed according to urbanity. We found that the age-specific population distributions in urbanized areas were similar, but rural areas had a relatively old population structure. The age-specific mortality ratio also differed by urbanity. Assuming the same rate of age-specific mortality across all small areas, we found that comparable median values in all areas. However, areas with a high SMR showed a strong predominance of metropolitan areas. The ranking by SMR differed markedly from the rankings by CMF and LE, especially in areas of high mortality, while the latter two metrics did not differ notably. The ratio of CMF to SMR showed larger variations in small areas in rural areas, particularly in those with small populations, than in metropolitan and urban areas. In a comparison of multiple SMRs, bias could exist if the study areas have large differences in population structure. The use of CMF or LE should be considered for comparisons if it is possible to acquire age-specific mortality data for each small area.


A patent review of the therapeutic potential of isoflavones (2012-2016).
Isoflavones are well-studied natural products isolated from natural sources with interesting chemodiversity and possess a wide variety of biological effects. Moreover, chemical modifications based on the isoflavone scaffold, has generated synthetic chemodiversity to enhance the bioactivities of isoflavones. Areas covered: The current review summarizes the discovery of new chemotherapeutic agents possessing the isoflavone skeleton. This review incorporates patents filed between 2012 and 2016 mostly related to anticancer, antidiabetic, antimicrobial, anti-HIV, anti-gastric ulcer, anti-gastritis, antiparasitic and some other biological effects demonstrated by isoflavone analogs. Expert opinion: The number of interesting patents published during the five year period (2012-2016) on the therapeutic potential of isoflavones indicated the importance of this molecule. Natural isoflavones possess potent anticancer, anti-HIV and antidiabetic activities and chemical analogs of natural isoflavones increase the abovementioned biological effects. Additionally isoflavones have only been tested for a limited number of biological activities and thus future research should focus on additional biological activities viz., anti-inflammatory, antimalarial, and anti-leishmanial effects. However, the absence of SAR studies and in vivo data restricted the rational design of more potent isoflavone analogs and we believe that in order to get lead compounds, there needs to be a greater focus on SAR and in vivo studies.


Mutated forms of the [2Fe-2S] ferredoxin from Clostridium pasteurianum with noncysteinyl ligands to the iron-sulfur cluster.
The [2Fe-2S] ferredoxin from Clostridium pasteurianum is unique among ferredoxins, both by its sequence and by the distribution of its cysteine residues (in positions 11, 14, 24, 56, 60). Thus, no homologous sequences are available to infer, by comparison, the identity of the ligands of the iron-sulfur cluster. Therefore, in order to obtain information on the latter point, a combination of site-directed mutagenesis and UV-vis, EPR, and resonance Raman spectroscopy has been implemented. All of the cysteine residues have individually been replaced by serine and two of them by alanine. Cysteine 14 could be replaced by either serine or alanine without any modification of the spectroscopic properties of the protein and was therefore dismissed as a ligand of the [2Fe-2S] cluster. The C56S, and C60S-mutated proteins were both found to display UV-vis, EPR, and resonance Raman spectra consistent with serine-coordinated [2Fe-2S] clusters. The C11S-mutated protein was considerably less stable than the wild type ferredoxin. This observation, together with the hypsochromic shifts of UV-visible absorption features upon cysteine 11-->serine mutation, suggested cysteine 11 to be a ligand of the [2Fe-2S] cluster. Cysteine 24 could be replaced by either serine or alanine without decreasing the stability of the protein and without dramatically changing its spectroscopic properties. Thus, either cysteine 24 is not a ligand of the [2Fe-2S] cluster or it is replaced by another ligand in the C24A mutated protein. A [2Fe-2S] cluster was also assembled in the C14A/C24A doubly mutated protein, i.e., in a polypeptide chain containing only three cysteine residues.2+ off


Prognosis of Mucosal, Uveal, Acral, Nonacral Cutaneous, and Unknown Primary Melanoma From the Time of First Metastasis.
Subtypes of melanoma, such as mucosal, uveal, and acral, are believed to result in worse prognoses than nonacral cutaneous melanoma. After a diagnosis of distant metastatic disease, however, the overall survival of patients with mucosal, uveal, acral, nonacral cutaneous, and unknown primary melanoma has not been directly compared. We conducted a single-center, retrospective analysis of 3,454 patients with melanoma diagnosed with distant metastases from 2000 to 2013, identified from a prospectively maintained database. We examined melanoma subtype, date of diagnosis of distant metastases, age at diagnosis of metastasis, gender, and site of melanoma metastases. Of the 3,454 patients (237 with mucosal, 286 with uveal, 2,292 with nonacral cutaneous, 105 with acral cutaneous, and 534 with unknown primary melanoma), 2,594 died. The median follow-up was 46.1 months. The median overall survival for those with mucosal, uveal, acral, nonacral cutaneous, and unknown primary melanoma was 9.1, 13.4, 11.4, 11.7, and 10.4 months, respectively. Patients with uveal melanoma, cutaneous melanoma (acral and nonacral), and unknown primary melanoma had similar survival, but patients with mucosal melanoma had worse survival. Patients diagnosed with metastatic melanoma in 2006-2010 and 2011-2013 had better overall survival than patients diagnosed in 2000-2005. In a multivariate model, patients with mucosal melanoma had inferior overall survival compared with patients with the other four subtypes. Additional research and advocacy are needed for patients with mucosal melanoma because of their shorter overall survival in the metastatic setting. Despite distinct tumor biology, the survival was similar for those with metastatic uveal melanoma, acral, nonacral cutaneous, and unknown primary melanoma. Uveal, acral, and mucosal melanoma are assumed to result in a worse prognosis than nonacral cutaneous melanoma or unknown primary melanoma. No studies, however, have been conducted assessing the overall survival of patients with these melanoma subtypes starting at the time of distant metastatic disease. The present study found that patients with uveal, acral, nonacral cutaneous, and unknown primary melanoma have similar overall survival after distant metastases have been diagnosed. These findings provide information for oncologists to reconsider previously held assumptions and appropriately counsel patients. Patients with mucosal melanoma have worse overall survival and are thus a group in need of specific research and advocacy.


Fast and slow voltage-dependent dynamics of magnesium block in the NMDA receptor: the asymmetric trapping block model.
The NMDA receptor (NMDAR) produces a long-lasting component of the glutamatergic EPSC in mammalian central neurons. The current through NMDARs is voltage dependent as a result of block by extracellular magnesium, which has recently been shown to give rise to a complex time dependence, with fast and slow components of responses to changes in membrane potential. Here, we studied the dynamics of block and unblock by measuring voltage step responses in conjunction with fast perfusion of agonist in nucleated patches isolated from rat cortical pyramidal neurons. We found that slow unblock shows a progressive onset during synaptic-like responses to brief pulses of agonist. Repolarizing briefly from +40 to -70 mV revealed that slow unblock is reestablished with a time constant of approximately 5 msec at room temperature. Also, the time course of deactivation, in response to a pulse of agonist, slows twofold over the potential range -30 to +40 mV. An asymmetric "trapping block" model in which the voltage-independent closing rate constant of the blocked channel is approximately three times that of the unblocked channel accounts quantitatively for all of these phenomena and for responses to action potential waveform clamp. This model allows much more accurate prediction of NMDAR current in physiological conditions of magnesium concentration and changing membrane potential than previously possible. It suggests a positive allosteric link between occupation of the NMDAR pore by magnesium and closure of the permeation gate.


Immunophenotyping of leukaemias by flow cytometry and APAAP: a two-year comparative analysis in hospital practice.
Using a panel of monoclonal antibodies for the immunophenotyping of haematological malignancies, we have made a direct comparison of the usefulness of indirect immunofluorescence using flow cytometry (IFC) alongside the alkaline phosphatase-anti-alkaline phosphatase (APAAP) immunoenzyme method. Analysis of 400 consecutive patient samples (blood and bone marrow) over a 2-year period, resulted in unequivocal phenotyping agreement by both methods in 98 per cent of cases. The positive results accounting for 2 per cent discordance were obtained by the APAAP method. The value of the technique in the clinical management of patients with leukaemia is documented together with guidelines for clinical laboratories.


[Outcomes of video-assisted thoracic lung resections and pneumonectomies in patients with pulmonary tuberculosis].
The paper pools some experience with 6 videothoracoscopic and 505 video-assisted thoracoscopic (VATS) resections of the lung and 105 VATS pneumonectomies. The bulk of the operations [451 (73.2%)] was made for pulmonary tuberculosis in patients aged 7 to 77 years. 81% operations by separately treating root elements, including all pneumonectomies and major lung resections, were performed. A new SOMI-80 suturing apparatus designed for mini-invasive surgery was employed to suture lung tissue in most cases. Intraoperative and postoperative complications occurred in 5 and 8 cases, respectively. The efficiency of operations for tuberculosis was 98.6%.


Effect of dutasteride on the risk of prostate cancer.
We conducted a study to determine whether dutasteride reduces the risk of incident prostate cancer, as detected on biopsy, among men who are at increased risk for the disease. In this 4-year, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, we compared dutasteride, at a dose of 0.5 mg daily, with placebo. Men were eligible for inclusion in the study if they were 50 to 75 years of age, had a prostate-specific antigen (PSA) level of 2.5 to 10.0 ng per milliliter, and had had one negative prostate biopsy (6 to 12 cores) within 6 months before enrollment. Subjects underwent a 10-core transrectal ultrasound-guided biopsy at 2 and 4 years. Among 6729 men who underwent a biopsy or prostate surgery, cancer was detected in 659 of the 3305 men in the dutasteride group, as compared with 858 of the 3424 men in the placebo group, representing a relative risk reduction with dutasteride of 22.8% (95% confidence interval, 15.2 to 29.8) over the 4-year study period (P<0.001). Overall, in years 1 through 4, among the 6706 men who underwent a needle biopsy, there were 220 tumors with a Gleason score of 7 to 10 among 3299 men in the dutasteride group and 233 among 3407 men in the placebo group (P=0.81). During years 3 and 4, there were 12 tumors with a Gleason score of 8 to 10 in the dutasteride group, as compared with only 1 in the placebo group (P=0.003). Dutasteride therapy, as compared with placebo, resulted in a reduction in the rate of acute urinary retention (1.6% vs. 6.7%, a 77.3% relative reduction). The incidence of adverse events was similar to that in studies of dutasteride therapy for benign prostatic hyperplasia, except that in our study, as compared with previous studies, the relative incidence of the composite category of cardiac failure was higher in the dutasteride group than in the placebo group (0.7% [30 men] vs. 0.4% [16 men], P=0.03). Over the course of the 4-year study period, dutasteride reduced the risk of incident prostate cancer detected on biopsy and improved the outcomes related to benign prostatic hyperplasia. (ClinicalTrials.gov number, NCT00056407.)


A conserved HH-Gli1-Mycn network regulates heart regeneration from newt to human.
The mammalian heart has a limited regenerative capacity and typically progresses to heart failure following injury. Here, we defined a hedgehog (HH)-Gli1-Mycn network for cardiomyocyte proliferation and heart regeneration from amphibians to mammals. Using a genome-wide screen, we verified that HH signaling was essential for heart regeneration in the injured newt. Next, pharmacological and genetic loss- and gain-of-function of HH signaling demonstrated the essential requirement for HH signaling in the neonatal, adolescent, and adult mouse heart regeneration, and in the proliferation of hiPSC-derived cardiomyocytes. Fate-mapping and molecular biological studies revealed that HH signaling, via a HH-Gli1-Mycn network, contributed to heart regeneration by inducing proliferation of pre-existing cardiomyocytes and not by de novo cardiomyogenesis. Further, Mycn mRNA transfection experiments recapitulated the effects of HH signaling and promoted adult cardiomyocyte proliferation. These studies defined an evolutionarily conserved function of HH signaling that may serve as a platform for human regenerative therapies.


Study of electronic and magnetic properties and related x-ray absorption spectroscopy of ultrathin Co films on BaTiO3.
We present a first-principles study of electronic and magnetic properties of thin Co films on a BaTiO3(0 0 1) single crystal. The crystalline structure of 1-3 monolayer thick Co films was determined and served as input for calculations of the electronic and magnetic properties of the films. The estimation of exchange constants indicates that the Co films are ferromagnetic with a high critical temperature, which depends on the film thickness and the interface geometry. In addition, we calculated x-ray absorption spectra, related magnetic circular dichroism (XMCD) and linear dichroism (XLD) of the Co L 2, 3 edges as a function of Co film thickness and ferroelectric polarization of BaTiO3. We found characteristic features, which depend strongly on the magnetic properties and the structure of the film. While there is only a weak dependence of XMCD spectra on the ferroelectric polarization, the XLD of the films is much more sensitive to the polarization switching, which could possibly be observed experimentally.


Positive correlation between vitamin D receptor gene TaqI variant and gastric cancer predisposition in a sample of Iranian population.
Gastric cancer is the second cause of cancer-related mortality and the fourth most common cancers worldwide. Owing to the immune modulatory effect of vitamin D in the body, the role of vitamin D receptor gene in vitamin D regulation receives a great deal of research interest. The aim of the current study was to highlight the association between two variants of TaqI and FokI in the vitamin D receptor gene and gastric cancer predisposition in a sample of South Khorasan population. The present investigation consisted of 69 patients affected with gastric cancer and 100 healthy individuals. The genomic DNA was extracted by salting out the protocol from peripheral venous blood. Genotyping of TaqI and FokI variants were performed by PCR-RFLP method. Our findings manifested that TC genotype of TaqI polymorphism was statistically significant between the case and the control groups (p = 0.002). Moreover, the frequency of TC + CC genotypes was statistically significant between the two groups (p = 0.009). Furthermore, we could not find any meaningful association between FokI variant and the participant groups. The present results declared that, in our population, TC genotype of TaqI polymorphism has an association with gastric cancer susceptibility. In addition, more investigation with greater sample sizes is needed to confirm our results.


Systemic approaches to biodegradation.
Biodegradation, the ability of microorganisms to remove complex chemicals from the environment, is a multifaceted process in which many biotic and abiotic factors are implicated. The recent accumulation of knowledge about the biochemistry and genetics of the biodegradation process, and its categorization and formalization in structured databases, has recently opened the door to systems biology approaches, where the interactions of the involved parts are the main subject of study, and the system is analysed as a whole. The global analysis of the biodegradation metabolic network is beginning to produce knowledge about its structure, behaviour and evolution, such as its free-scale structure or its intrinsic robustness. Moreover, these approaches are also developing into useful tools such as predictors for compounds' degradability or the assisted design of artificial pathways. However, it is the environmental application of high-throughput technologies from the genomics, metagenomics, proteomics and metabolomics that harbours the most promising opportunities to understand the biodegradation process, and at the same time poses tremendous challenges from the data management and data mining point of view.


[Evaluation of the carcinogenic effect of ceramic fibers in experiments on rats and mice].
The carcinogenic effect of Kaowoll raw and thermally used ceramic fibres was assessed in experiments on rats and mice. The fibers were applied intraperitoneally in doses by 25 and 5 mg, and the animals were observed over their life-span. It was found that Kaowoll fibers were carcinogenic and that high temperature did not change these properties.


A self-determination multiple risk intervention trial to improve smokers' health.
Little is known about how interventions motivate individuals to change multiple health risk behaviors. Self-determination theory (SDT) proposes that patient autonomy is an essential factor for motivating change. An SDT-based intervention to enhance autonomous motivation for tobacco abstinence and improving cholesterol was tested. The Smokers' Health Study is a randomized multiple risk behavior change intervention trial. Smokers were recruited to a tobacco treatment center. A total of 1.006 adult smokers were recruited between 1999 and 2002 from physician offices and by newspaper advertisements. A 6-month clinical intervention (4 contacts) to facilitate internalization of autonomy and perceived competence for tobacco abstinence and reduced percent calories from fat was compared with community care. Clinicians elicited patient perspectives and life strivings, provided absolute coronary artery disease risk estimates,enumerated effective treatment options, supported patient initiatives,minimized clinician control, assessed motivation for change, and developed a plan for change. Twelve-month prolonged tobacco abstinence, and change in percent calories from fat and low-density lipoprotein-cholesterol (LDL-C) from baseline to 18 months. RESULTS- Intention to treat analyses revealed that the intervention significantly increased 12-month prolonged tobacco abstinence (6.2% vs 2.4%; odds ratio [OR]=2.7, P=.01, number needed to treat [NNT] =26), and reduced LDL-C (-8.9 vs -4.1 mg/dL; P=.05). There was no effect on percent calories from fat. An intervention focused on supporting smokers'autonomy was effective in increasing prolonged tobacco abstinence and lowering LDL-C. Clinical interventions for behavior change may be improved by increasing patient autonomy and perceived competence.


Proteomic analysis of Fasciola hepatica excretory-secretory products.
This paper describes a global investigation of the components of Fasciola hepatica excretory-secretory (ES) products by a proteomic approach. Despite the absence of a F. hepatica genome sequencing project we have shown that it was possible to identify 29 of the 60 prominent proteins found using two-dimensional gel electrophoresis. As well as cathepsin L proteases, a number of enzymes implicated in parasite protection from the host immune system were also found to be present in relatively large abundance. These included superoxide dismutase, thioredoxin peroxidase, glutathione S-transferases and fatty acid binding proteins, all of which may play a part in the detoxification of reactive oxygen intermediates. Interestingly, ovine superoxide dismutase was the only protein from the host identified on the gel. We suggest that the relative abundance and protective nature of the components of the ES products of this organism play an important role in its survival within the host. The precise identification, to individual NCBI database entries, of a number of glutathione S-transferases and cathepsin Ls from F. hepatica, by peptide mass fingerprinting, was hampered by multi-database submissions of the two protein superfamilies from this organism.


Conventional (MG-BR46 Conquista) and transgenic (BRS Valiosa RR) soybeans have no mutagenic effects and may protect against induced-DNA damage in vivo.
In the present study, we evaluated the pesticide and metal concentrations as well as the antimutagenic and mutagenic properties of commercial soybeans (Glycine max). Male Swiss mice were fed diets containing 1%, 10%, or 20% (w/w) transgenic soybeans (BRS Valiosa RR) or parental isogenic conventional soybeans (MG-BR46 Conquista). Cyclophosphamide (50 mg kg⁻¹ b.w.) was added in a single dose 24 h before euthanasia as an induction agent. There was no difference in the composition (ash, total fat, protein, moisture, and carbohydrates) of the diets containing the same soybean concentration. The results show that the commercially available Brazilian soybeans tested are free of organochlorine, organophosphate, and carbamate pesticides and contain acceptable heavy metal concentrations. Both cyclophosphamide and soybean treatments were not sufficient to cause detectable oxidative damage on liver by the levels of malondialdehyde and protein carbonyl. The transgenic soybeans are also nonmutagenic and have protective effects against DNA damage similar to those of conventional soybeans but to a lesser percentage (64%-101% for conventional and 23%-33% for transgenic diets).


Study of the α-conformation of the conjugated polymer poly(9,9-dioctylfluorene) in dilute solution.
In this work, the α-conformation (individual locally separated chain) of the conjugated polymer poly(9,9-dioctylfluorene) (PFO) in dilute solution is studied by the following three points: the Mark-Houwink exponent a, the fractal dimension D, and the form factor R(g)/R(h). From the result of a, the α-conformation of PFO is considered to have a semirigid chain conformation in dilute solution. We establish the mathematical relationship between the Mark-Houwink exponent a and the fractal dimension D in dilute solution. To prove the rationality of this mathematical relationship, the classic polymer polystyrene (PS) is used for comparison. According to the result of D, it can be known that the α-conformation of PFO has a relatively loose and extended chain conformation. Moreover, we use light scattering to get the form factor R(g)/R(h) of the PFO solution in which the α-conformation and β-conformation coexist. It is found that R(g)/R(h) increases with the proportion of α-conformation, which indicates that the α-conformation of PFO has a loose and extended chain conformation, and this result agrees well with the conclusions drawn from a and D. On the basis of the fact that the β-conformation (ordered conformation) and α-conformation of PFO can transform into each other in solution, this work is significant for the control of the β-conformation and will have a potential meaning to increase the charge carrier mobility and efficiency from the PFO solution to films.


Ascending aorta replacement with concomitant coronary and peripheral artery bypass grafting.
Atherosclerosis of the aorta is a well-known risk factor for peri-operative complications in patients undergoing cardiac surgery. Coronary and peripheral artery bypass procedures can be challenging when the native aorta is not amenable to bypass grafting due to severe calcification. We describe the successful management of a patient who underwent ascending aorta replacement with concomitant three-vessel coronary artery bypass, bilateral aorto-axillary bypass and left axillary-to-carotid bypass.


Evolutionary divergence of phytochrome protein function in Zea mays PIF3 signaling.
Two maize phytochrome-interacting factor (PIF) basic helix-loop-helix (bHLH) family members, ZmPIF3.1 and ZmPIF3.2, were identified, cloned and expressed in vitro to investigate light-signaling interactions. A phylogenetic analysis of sequences of the maize bHLH transcription factor gene family revealed the extent of the PIF family, and a total of seven predicted PIF-encoding genes were identified from genes encoding bHLH family VIIa/b proteins in the maize genome. To investigate the role of maize PIFs in phytochrome signaling, full-length cDNAs for phytochromes PhyA2, PhyB1, PhyB2 and PhyC1 from maize were cloned and expressed in vitro as chromophorylated holophytochromes. We showed that ZmPIF3.1 and ZmPIF3.2 interact specifically with the Pfr form of maize holophytochrome B1 (ZmphyB1), showing no detectable affinity for the Pr form. Maize holophytochrome B2 (ZmphyB2) showed no detectable binding affinity for PIFs in either Pr or Pfr forms, but phyB Pfr from Arabidopsis interacted with ZmPIF3.1 similarly to ZmphyB1 Pfr. We conclude that subfunctionalization at the protein-protein interaction level has altered the role of phyB2 relative to that of phyB1 in maize. Since the phyB2 mutant shows photomorphogenic defects, we conclude that maize phyB2 is an active photoreceptor, without the binding of PIF3 seen in other phyB family proteins.


Spray-dried albumin microspheres for the intra-articular delivery of dexamethasone.
This work deals with the preparation of corticosteroid-loaded albumin microspheres designed for intra-articular administration. Dexamethasone was chosen as the model drug and bovine serum albumin was used as the biodegradable, natural polymer. Albumin microspheres were produced by spray drying, a 'one-step' technique seldom used in the preparation of microparticulate drug delivery systems with particle sizes < 10 microns. The effects of both polymer/drug ratio used in the formulations and the different heat-stabilization conditions were evaluated on morphology, size, solubility characteristics, drug loading and 'in vitro' drug release of the microparticles.


Outcome after resection for invasive intraductal papillary mucinous neoplasia is similar to conventional pancreatic ductal adenocarcinoma.
Resections for intraductal papillary mucinous neoplasm (IPMN) have increased last decades. Overall survival (OS) for conventional pancreatic ductal adenocarcinoma (PDAC) is well known but OS for invasive IPMN (inv-IPMN) is not as conclusive. This study aims to elucidate potential differences in clinicopathology and OS between these tumor types and to investigate if the raised number of resections have affected outcome. Consecutive patients ≥18 years of age resected for inv-IPMN and PDAC at Karolinska University Hospital between 2009 and 2018 were included. Clinicopathological variables were analyzed in multivariable regression models. Outcome was assessed calculating two-year OS, estimating OS using the Kaplan-Meier model and comparing survival functions with log-rank test. 513 patients were included, 122 with inv-IPMN and 391 with PDAC. During the study period both the proportion resected inv-IPMN and two-year OS, irrespective of tumor type, increased (2.5%-45%; p < 0.001 and 44%-57%; p = 0.005 respectively). In Kaplan-Meier survival analysis inv-IPMN had more favorable median OS (mOS) compared to PDAC (33.6 months vs 19.3 months, p = 0.001). However, in multivariable Cox Regression analysis, tumor type was not a predictor for death, but so were resection period, tumor subtype and N-stage (all p < 0.001). In this large single center observational cohort study, inv-IPMN seemed to have favorable survival outcome compared to PDAC, but after adjusting for predictors for death this benefit vanished. The combination of a pronounced increase in resected inv-IPMN and a concurrent hazard abatement for death within 2 years during the study period proved to be a principal factor.


Adverse Childhood Environment: Relationship With Sexual Risk Behaviors and Marital Status in a Large American Sample.
A substantial theoretical and empirical literature suggests that stressful events in childhood influence the timing and patterning of subsequent sexual and reproductive behaviors. Stressful childhood environments have been predicted to produce a life history strategy in which adults are oriented more toward short-term mating behaviors and less toward behaviors consistent with longevity. This article tests the hypothesis that adverse childhood environment will predict adult outcomes in two areas: risky sexual behavior (engagement in sexual risk behavior or having taken an HIV test) and marital status (currently married vs. never married, divorced, or a member of an unmarried couple). Data come from the Behavioral Risk Factor Surveillance System. The sample contains 17,530 men and 23,978 women aged 18-54 years living in 13 U.S. states plus the District of Columbia. Adverse childhood environment is assessed through 11 retrospective measures of childhood environment, including having grown up with someone who was depressed or mentally ill, who was an alcoholic, who used or abused drugs, or who served time in prison; whether one's parents divorced in childhood; and two scales measuring childhood exposure to violence and to sexual trauma. The results indicate that adverse childhood environment is associated with increased likelihood of engaging in sexual risk behaviors or taking an HIV test, and increased likelihood of being in an unmarried couple or divorced/separated, for both men and women. The predictions are supported by the data, lending further support to the hypothesis that childhood environments influence adult reproductive strategy.


Tick bite anaphylaxis in Australia.
Tick bite anaphylaxis has rarely been reported. It may follow the bite of any of the different tick life cycle forms, is related to the release of salivary juices, and may range from mild itch to severe wheeze or shock. Data obtained suggest that it is more common and potentially life threatening than tick paralysis, which is more widely reported. Emergency physicians should recognise this possibility following a tick bite and be prepared to give treatment such as adrenaline rapidly. Patients should be referred to an allergist after recovery.


Maternal-fetal transport of immunoglobulin G and its subclasses during the third trimester of human pregnancy.
We determined the maternal-fetal transport of immunoglobulin G (IgG) during the third trimester of human pregnancy. The concentration of IgG and its subclasses (IgG1-4) was determined in sera of blood samples from 38 pregnancies collected at the time of delivery from a peripheral maternal vein (MV) and from the placental umbilical artery (UA) and vein (UV). Gestational age varied between 28 and 42 weeks (WG). Whereas placental weight showed a significant correlation with gestational age, the maternal level of IgG and the ratio of its subclasses did not vary with gestational age. At 28-33 WG (n = 15) the mean values in the UA (5.91 +/- 1.53 g/l) and UV (6.41 +/- 1.57 g/l) for total IgG concentration were lower than in the MV (10.74 +/- 2.55 g/l). At the end of gestation (37-42 WG, n = 12), IgG in both UA (11.21 +/- 1.95 g/l) and UV (12.26 +/- 2.06 g/l) exceeded the maternal concentration (9.69 +/- 1.84 g/l). In addition to the significant positive correlation between IgG concentration in the fetal circulation (UV + UA) and gestational age (28-42 WG), an increase in the positive difference between UV and UA at the end of pregnancy indicates that there is a substantial rise in placental IgG transport capacity. All four subclasses IgG1-4 were detectable in the umbilical circulation (28-42 WG). Whereas IgG3 and IgG4 in UA and UV had a similar concentration as in MV and remained unchanged, IgG2 increased with gestation from 0.67/0.74 g/l (UA/UV, 28-33 WG) to 1.29/1.58 g/l (UA/UV, 37-42 WG), but nevertheless remained lower than the level found in the MV (2.65 +/- 1.12 g/l). The main increase in IgG concentration, however, was due to the substantial rise in the transport of IgG1, which increased from 4.37 +/- 1.24 (UA) and 4.94 +/- 1.52 g/l (UV) at 28-33 WG to 8.94 +/- 1.66 (UA) and 10.89 +/- 1.96 g/l (UV) at the end of gestation, which was even higher than the overall IgG concentration in MV.