Urea and thiourea transport in Aspergillus nidulans.
Wild-type Aspergillus nidulans has an active transport system specific for urea which concentrates urea at least 50-fold relative to the extracellular concentration. It is substrate concentration dependent, with an apparent Km of 3 x 10-(5) M for urea. Competition studies and the properties of mutants indicate that thiourea is taken up by the same system as urea. Thiourea is toxic at 5mM to wild-type cells of Aspergillus nidulans. Mutants, designated ureA1 to ureA16, resistant to thiourea have been isolated, and transport assays and growth tests show that they are specifically impaired in urea transport. The mutant ureA1 has a higher Km value than the wild type for thiourea uptake. The ureA locus has been assigned to linkage group VIII. ureA1 is recessive for thiourea resistance while semidominant for the low uptake characteristic. The urea uptake system is under nitrogen regulation, with L-glutamine as the probable effector. The mutants, meaA8 and gdhA1, which are insensitive to ammonium control of many nitrogen-regulated metabolic systems, are also insensitive to ammonium control of urea uptake, but both are sensitive to L-glutamine regulation.


Inhibition of retinal neovascularization by a PEDF-derived nonapeptide in newborn mice subjected to oxygen-induced ischemic retinopathy.
Retinopathy of prematurity (ROP) is a growing cause of lifelong blindness and visual defects as improved neonatal care worldwide increases survival in very-low-birthweight preterm newborns. Advancing ROP is managed by laser surgery or a single intravitreal injection of anti-VEGF, typically at 33-36 weeks gestational age. While newer methods of scanning and telemedicine improve monitoring ROP, the above interventions are more difficult to deliver in developing countries. There is also concern as to laser-induced detachment and adverse developmental effects in newborns of anti-VEGF treatment, spurring a search for alternative means of mitigating ROP. Pigment epithelium-derived factor (PEDF), a potent angiogenesis inhibitor appears late in gestation, is undetected in 25-28 week vitreous, but present at full term. Its absence may contribute to ROP upon transition from high-to-ambient oxygen environment or with intermittent hypoxia. We recently described antiangiogenic PEDF-derived small peptides which inhibit choroidal neovascularization, and suggested that their target may be laminin receptor, 67LR. The latter has been implicated in oxygen-induced ischemic retinopathy (OIR). Here we examined the effect of a nonapeptide, PEDF 336, in a newborn mouse OIR model. Neovascularization was significantly decreased in a dose-responsive manner by single intravitreal (IVT) injections of 1.25-7.5 μg/eye (1.0-6.0 nmol/eye). By contrast, anti-mouse VEGFA164 was only effective at 25 ng/eye, with limited dose-response. Combination of anti-VEGFA164 with PEDF 336 gave only the poorer anti-VEGF response while abrogating the robust inhibition seen with peptide-alone, suggesting a need for VEGF in sensitizing the endothelium to the peptide. VEGF stimulated 67LR presentation on endothelial cells, which was decreased in the presence of PEDF 336. Mouse and rabbit eyes showed no histopathology or inflammation after IVT peptide injection. Thus, PEDF 336 is a potential ROP therapeutic, but is not expected to be beneficial in combination with anti-VEGF.


Assessing and Enhancing the Welfare of Animals with Equivocal and Reliable Cues.
The actions of human caretakers strongly influence animals living under human care. Here, we consider how intentional and unintentional signals provided by caretakers can inform our assessment of animals' well-being as well as help to support it. Our aim is to assist in further developing techniques to learn animals' affective state from their behavior and to provide simple suggestions for how animal caretakers' behavior can support animal welfare. We suggest that anticipatory behavior towards expected rewards is related to decision-making behavior as viewed through the cognitive bias lens. By considering the predictions of the theories associated with anticipatory behavior and cognitive bias, we propose to use specific cues to probe the cumulative affective state of animals. Additionally, our commentary draws on the logic of reward sensitivity and judgement bias theories to develop a framework that suggests how reliable and equivocal signals may influence animals' affective states. Application of this framework may be useful in supporting the welfare of animals in human care.


[Landmark of the internal carotid artery stenting, anterior interventricular branch of the left coronary artery and vertebral artery in a patient with multifocal atherosclerosis].
Presented herein is a clinical case report concerning a 59-year-old male patient suffering from multifocal atherosclerosis after endured repeat acute ischaemic attacks in various arterial basins of the brain. Analysing his case history revealed functional class II-IV angina of effort. Ultrasonographic and angiographic findings showed a haemodynamically significant plaque in the ostium of the left internal carotid artery, hypoplasia of the right vertebral artery, a haemodynamically meaningful narrowing of the left vertebral artery, subtotal stenosis of the anterior interventricular branch and pronounced alterations in the right vertebral artery. The first stage of surgery consisted in stenting of the left internal carotid artery and anterior interventricular branch, followed by the second stage consisting in the stenting of the left vertebral artery with an angiographically good outcome. The check-up CT of the brain and 24-hour ECG monitoring showed no negative dynamics. In July 2005, the patient was subjected to craniocerebral microarterial shunting on the right. No relapses of AIAs have so far been observed.


Endothelial endocytic pathways: gates for vascular drug delivery.
Vascular endothelium plays strategic roles in many drug delivery paradigms, both as an important therapeutic target itself and as a barrier for reaching tissues beyond the vascular wall. Diverse means are being developed to improve vascular drug delivery including stealth liposomes and polymer carriers. Affinity carriers including antibodies or peptides that specifically bind to endothelial surface determinants, either constitutive or pathological, enhance targeting of drugs to endothelial cells (EC) in diverse vascular areas. In many cases, binding to endothelial surface determinants facilitates internalization of the drug/carrier complex. There are several main endocytic pathways in EC, including clathrin- and caveoli-mediated endocytosis, phagocytosis and macropinocytosis (these two are less characteristic of generic EC) and the recently described Cell Adhesion Molecule (CAM)-mediated endocytosis. The latter may be of interest for intracellular drug delivery to EC involved in inflammation or thrombosis. The metabolism and effects of internalized drugs largely depend on the routes of intracellular trafficking, which may lead to degrading lysosomal compartments or other organelles, recycling to the plasma membrane or transcytosis to the basal surface of endothelium. The latter route, characteristic of caveoli-mediated endocytosis, may serve for trans-endothelial drug delivery. Paracellular trafficking, which can be enhanced under pathological conditions or by auxiliary agents, represents an alternative for transcytosis. Endothelial surface determinants involved in endocytosis, mechanisms of the latter and trafficking pathways, as well as specific characteristics of EC in different vascular areas, are discussed in detail in the context of modern paradigms of vascular drug delivery.


Embedding stakeholder preferences in setting priorities for health research: Using a discrete choice experiment to develop a multi-criteria tool for evaluating research proposals.
We determined weights for a multi-criteria tool for assessing the relative merits of clinical-trial research proposals, and investigated whether the weights vary across relevant stakeholder groups. A cross-sectional, adaptive discrete choice experiment using 1000minds online software was administered to consumers, researchers and funders affiliated with the Australian Clinical Trials Alliance (ACTA). We identified weights for four criteria-Appropriateness, Significance, Relevance, Feasibility-and their levels, representing their relative importance, so that research proposals can be scored between 0% (nil or very low merit) and 100% (very high merit). From 220 complete survey responses, the most important criterion was Appropriateness (adjusted for differences between stakeholder groups, mean weight 28.9%) and the least important was Feasibility (adjusted mean weight 19.5%). Consumers tended to weight Relevance more highly (2.7% points difference) and Feasibility less highly (3.1% points difference) than researchers. The research or grant writing experience of researchers or consumers was not associated with the weights. A multi-criteria tool for evaluating research proposals that reflects stakeholders' preferences was created. The tool can be used to assess the relative merits of clinical trial research proposals and rank them, to help identify the best proposals for funding.


Pharmacokinetics of intravenously administered liposomal all-trans-retinoic acid (ATRA) and orally administered ATRA in healthy volunteers.
To determine single-and multiple-dose pharmacokinetics of liposomal-all- trans -retinoic acid (Atragen) following intravenous and oral ATRA (Vesanoid) administration in healthy volunteers. This was a randomized, prospective, open-label, parallel pharmacokinetic study in which 29 subjects were given 90 mg/m (2) i.v. liposomal (L)-ATRA (16 subjects) every other day or 45 mg/m (2) oral ATRA (13 subjects) daily over 15 days. Pharmacokinetic parameters were assessed on days 1, 9, and 15. Twenty-two subjects (11 in each group) completed the study and were evaluated. Area under the plasma concentration-time curve [AUC(0, infinity)] and maximum plasma concentration (C(max) ) of ATRA did not decrease during the 15 days of L-ATRA treatment. However, the oral ATRA regimen resulted in a significant decrease in the AUC(0, infinity) and C(max) of 45.3% and 31.8%, respectively, on day 9 as compared with that to day 1 (p< 0.05). In addition, the mean AUC(0, infinity) was 13- and 22-fold greater for L-ATRA than for oral ATRA on days 1 and 9, respectively. Despite the significantly higher plasma concentrations after L-ATRA treatment, the side effects of each formulation were similar, except for dermal exfoliation, which was seen in 31% of the subjects after L-ATRA dosing, and abnormal liver function tests that were seen in 23% of the subjects after oral ATRA administration. These findings suggest that i.v. administration of L-ATRA maintains higher and stable plasma ATRA concentrations than oral ATRA in healthy subjects after repetitive administration. L-ATRA with a favorable pharmacokinetic profile may have potential advantages over oral ATRA and may be more efficacious in the treatment of acute promyelocytic leukemia or other retinoid-responsive cancers.


Allelopathic bacteria and their impact on higher plants.
The impact of allelopathic, nonpathogenic bacteria on plant growth in natural and agricultural ecosystems is discussed. In some natural ecosystems, evidence supports the view that in the vicinity of some allelopathically active perennials (e.g., Adenostoma fasciculatum, California), in addition to allelochemicals leached from the shrub's canopy, accumulation of phytotoxic bacteria or other allelopathic microorganisms amplify retardation of annuals. In agricultural ecosystems allelopathic bacteria may evolve in areas where a single crop is grown successively, and the resulting yield decline cannot be restored by application of minerals. Transfer of soils from areas where crop suppression had been recorded into an unaffected area induced crop retardation without readily apparent symptoms of plant disease. Susceptibility of higher plants to deleterious rhizobacteria is often manifested in sandy or so-called skeletal soils. Evaluation of phytotoxic activity under controlled conditions, as well as ways to apply allelopathic bacteria in the field, is approached. The allelopathic effect may occur directly through the release of allelochemicals by a bacterium that affects susceptible plant(s) or indirectly through the suppression of an essential symbiont. The process is affected by nutritional and other environmental conditions, some may control bacterial density and the rate of production of allelochemicals. Allelopathic nonpathogenic bacteria include a wide range of genera and secrete a diverse group of plant growth-mediating allelochemicals. Although a limited number of plant growth-promoting bacterial allelochemicals have been identified, a considerable number of highly diversified growth-inhibiting allelochemicals have been isolated and characterized. Some species may produce more than one allelochemical; for example, three different phyotoxins, geldanamycin, nigericin, and hydanthocidin, were isolated from Streptomyces hygroscopicus. Efforts to introduce naturally produced allelochemicals as plant growth-regulating agents in agriculture have yielded two commercial herbicides, phosphinothricin, a product of Streptomyces viridochromogenes, and bialaphos from S. hygroscopicus. Many species of allelopathic bacteria that affect growth of higher plants are not plant specific, but some do exhibit specificity; for example, dicotyledonous plants were more susceptible to Pseudomonas putida than were monocotyledons. Differential susceptibility of higher plants to allelopathic bacteria was noted also in much lower taxonomical categories, at the subspecies level, in different cultivars of wheat, or of lettuce. Therefore, when test plants are employed to evaluate bacterial allelopathy, final evaluation must include those species that are assumed to be suppressed in nature. The release of allelochemicals from plant residues in plots of 'continuous crop cultivation' or from allelopathic living plants may induce the development of specific allelopathic bacteria. Both the rate by which a bacterium gains from its allelopathic activity through utilizing plant excretions, and the reasons for the developing of allelopathic bacteria in such habitats, are important goals for further research.


Stabilization of electro-optic modulator bias voltage drift using a lock-in amplifier and a proportional-integral-derivative controller in a distributed Brillouin sensor system.
In a distributed Brillouin sensor system, it is crucial to keep the pulse energy uniform for a constant signal-to-noise ratio. This means that the variable dc leakage (pulse base) for the electro-optic modulator (EOM) must be locked. We examine two different methods of locking the EOM bias voltage and look at the advantages and disadvantages of each locking method. It is found that the two locking methods, one based on a lock-in amplifier and the other using proportional-integral-derivative control, both have applications in which they excel at locking the pulse base.


Hierarchy of codon usage frequencies from codon-anticodon interaction in the crystal basis model.
Analyzing the codon usage frequencies of a specimen of 20 plants, for which the codon-anticodon pattern is known, we have remarked that the hierarchy of the usage frequencies present an almost "universal" behavior. Searching to explain this behavior, we assume that the codon usage probability results from the sum of two contributions: the first dominant term is an almost "universal" one and it depends on the codon-anticodon interaction; the second term is a local one, i.e. depends on the biological species. The codon-anticodon interaction is written as a spin-spin plus a z-spin term in the formalism of the crystal basis model. From general considerations, in particular from the choice of the signs and some constraints on the parameters defining the interaction, we are able to explain most of the observed data.


Production of Functionally Active and Immunogenic Non-Glycosylated Protective Antigen from Bacillus anthracis in Nicotiana benthamiana by Co-Expression with Peptide-N-Glycosidase F (PNGase F) of Flavobacterium meningosepticum.
Bacillus anthracis has long been considered a potential biological warfare agent, and therefore, there is a need for a safe, low-cost and highly efficient anthrax vaccine with demonstrated long-term stability for mass vaccination in case of an emergency. Many efforts have been made towards developing an anthrax vaccine based on recombinant protective antigen (rPA) of B. anthracis, a key component of the anthrax toxin, produced using different expression systems. Plants represent a promising recombinant protein production platform due to their relatively low cost, rapid scalability and favorable safety profile. Previous studies have shown that full-length rPA produced in Nicotiana benthamiana (pp-PA83) is immunogenic and can provide full protection against lethal spore challenge; however, further improvement in the potency and stability of the vaccine candidate is necessary. PA of B. anthracis is not a glycoprotein in its native host; however, this protein contains potential N-linked glycosylation sites, which can be aberrantly glycosylated during expression in eukaryotic systems including plants. This glycosylation could affect the availability of certain key epitopes either due to masking or misfolding of the protein. Therefore, a non-glycosylated form of pp-PA83 was engineered and produced in N. benthamiana using an in vivo deglycosylation approach based on co-expression of peptide-N-glycosidase F (PNGase F) from Flavobacterium meningosepticum. For comparison, versions of pp-PA83 containing point mutations in six potential N-glycosylation sites were also engineered and expressed in N. benthamiana. The in vivo deglycosylated pp-PA83 (pp-dPA83) was shown to have in vitro activity, in contrast to glycosylated pp-PA83, and to induce significantly higher levels of toxin-neutralizing antibody responses in mice compared with glycosylated pp-PA83, in vitro deglycosylated pp-PA83 or the mutated versions of pp-PA83. These results suggest that pp-dPA83 may offer advantages in terms of dose sparing and enhanced immunogenicity as a promising candidate for a safe, effective and low-cost subunit vaccine against anthrax.


Do Mid-term Outcomes of Lateral Ankle Stabilization Procedures Differ Between Military and Civilian Populations?
Ankle instability is common and previous studies have documented greater than 85% good-to-excellent outcomes based upon both patient-reported outcome measures and subjective evaluation of ability to return to previous activity levels after lateral ankle stabilization in the civilian population. However, patient-reported outcomes and performance may differ in the military population. The military oftentimes requires servicemembers to navigate uneven terrain and ladderwells, which can stress ankles differently than in their civilian counterparts. There has been limited evidence regarding patient outcomes after lateral ankle stabilization within a military population and its elucidation is important in optimizing outcomes for our servicemembers. Furthermore, the potential benefit of fibular periosteum augmentation with lateral ankle stabilization procedures in a military population has not been described. The results of using this extra tissue to reinforce the repair are important in determining whether its routine incorporation is indicated in the military. In an active-duty military population, we asked: (1) What proportion of patients who underwent lateral ankle stabilization using anatomic repair techniques with or without fibular periosteum augmentation achieved good-to-excellent outcomes based on the Foot and Ankle Disability Index (FADI) score at a minimum follow-up interval of 2 years? (2) Was the proportion of patients who achieved a good-to-excellent FADI score higher among those treated with fibular periosteum augmentation than those treated without? (3) Did the likelihood of achieving a good-to-excellent outcome after lateral ankle stabilization vary based on whether the procedure was performed by a fellowship-trained sports or foot and ankle orthopaedic surgeon versus a podiatrist? Between 2007 and 2017, 15 surgeons (six orthopaedic surgeons and nine podiatrists) performed 502 lateral ankle stabilizations. We excluded 4% (18 of 502) of patients because they were not active-duty at the time of surgery, and we excluded 12% (56 of 502) of lateral ankle stabilizations because they were performed as part of other potentially confounding foot or ankle procedures. We considered 60% (303 of 502) as lost to follow-up because the patients could not be contacted at least 2 years after surgery, they declined to participate, or they did not fully answer the questionnaires. This left 125 patients for analysis. Of those, 79% (99 of 125) had a procedure with fibular periosteum augmentation and 21% (26 of 125) had a procedure without augmentation. During the study period, five fellowship-trained orthopaedic foot and ankle surgeons and two podiatrists always used fibular periosteum augmentation. Orthopaedic surgeons performed 75% (94 of 125) of the procedures, and the other 25% (31 of 125) were performed by podiatrists. Whether a servicemember was treated by one specialty or the other was simply based upon whom they were referred to for care. Orthopaedic surgeons tended to perform procedures with augmentation (five with versus one without) and podiatrists tended to perform procedures without augmentation (two with versus seven without). To help account for this confounding factor, we performed separate analyses for procedures performed with versus without augmentation in addition to procedures performed by orthopaedic surgeons versus podiatrists. We retrospectively contacted each patient to obtain their self-reported overall result, FADI outcome score, and postoperative military capabilities. The minimum follow-up duration was 2 years; overall mean follow-up duration was 7 years. The fibular periosteum augmentation group mean follow-up was 7 ± 4 years and without augmentation was 6 ± 3 years. The orthopaedic surgeons group mean follow-up was 7 ± 3 years and the podiatrists group was 7 ± 3 years. We obtained postoperative FADI scores via phone interview along with data regarding the patients' postoperative military capabilities, but did not have preoperative FADI scores. Pooling both surgical treatments, 67% (84 of 125) of the patients reported good-to-excellent results and 33% (41 of 125) reported very poor-to-fair results. We found no difference in the proportion of patients treated with fibular periosteal augmentation who achieved a good or excellent score on the FADI than was observed among the patients treated without periosteal augmentation (68% [67 of 99] versus 65% [17 of 26]; odds ratio 1 [95% CI 0 to 2]; p = 0.81). The proportion of patients who achieved a good or excellent score on the FADI did not differ depending on whether the procedure was performed by an orthopaedic surgeon or a podiatric surgeon (66% [62 of 94] versus 71% [22 of 31]; OR 1 [95% CI 1 to 2]; p = 0.66). The patient-reported outcome scores after lateral ankle stabilization in our study of military servicemembers at a minimum of 2 years and a mean of 7 years were far lower than have been reported in studies on civilians. Indeed, our findings may represent a best-case scenario because more patients were lost to follow-up than were accounted for, and in general, surgical results among missing patients are poorer than among those who return for follow-up. Variability in the addition of fibular periosteum augmentation and whether an orthopaedic surgeon or podiatrist performed the procedure did not account for these findings. With one third of patients reporting very-poor-to-fair results after these reconstructions, and many patients lost to follow-up, we recommend surgeons counsel their servicemember patients accordingly before surgery. Specifically, that there is a one third chance they will need permanent restrictions or have to leave the military postoperatively; analogously, we believe that our findings may apply to similarly active patients outside the military, and we question whether these procedures may not be serving such patients as well as previously believed. Level III, therapeutic study.


Distribution and persistence of Staphylococcus and Micrococcus species and other aerobic bacteria on human skin.
The districution of Staphylococcus and Micrococcus species and associated coryneform bacteria, Acinetobacter, Klebsiella, Enterobacter, Bacillus, and Streptomyces on skin was determined during October 1971 from samples collected on persons living in North Carolina and New Jersey. Persistence of these organisms on skin was estimated in temporal studies conducted during the period from June 1971 to June 1972 on persons living in North Carolina. Staphylococci and coryneforms were the most predominant and persistent bacteria isolated from the nares and axillae. Staphylococci, coryneforms, micrococci, and Bacillus were the most predominant and persistent bacteria isolated from the head, legs, and arms. Acinetobacters were most frequently isolated during the warmer months of the years. Staphylococcus aureus and S. epidermidis were the most predominant and persistent staphylococci isolated from the nares, whereas S. epidermidis and S. hominis were the most predominant and persistent staphylocicci isolated from the axillae, head, legs, and arms. S. capitis was often isolated from the head and arms and S. haemolyticus was often isolated from the head, legs, and arms. S. simulans, S. xylosus, S. cohnii, S. saprophyticus, S. warneri, and an unclassified coagulase-positive species were only occasionally isolated from skin. Micrococcus luteus was the most predominant and persistent Micrococcus isolated from skin and preferred regions of the head, legs, and arms. M. varians was the second most frequent Micrococcus isolated. M. lylae, M. sedentarius, M. roseus, M. kristinae, and M. nishinomiyaensis were only occasionally isolated from skin. M. lylae was most frequently isolated during the colder months of the years.


Screening Hepatotoxic Components in Euodia rutaecarpa by UHPLC-QTOF/MS Based on the Spectrum-Toxicity Relationship.
Euodia rutaecarpa is a common traditional Chinese medicine (TCM) in clinical practice, having the ability to suppress pain and cease coughing; however, with the increasing reports showing that it is toxic, particularly hepatotoxic, the concerns raised by what cause its toxicity is growing. In the current study, an analysis method based on the spectrum effect has been employed to screen the major hepatotoxic components in Euodia rutaecarpa so that the toxic material's basis would be elucidated. A fingerprinting method of the Euodia rutaecarpa extracts (which were petroleum ether, chloroform, ethyl acetate, n-butanol, and water) using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometer (UHPLC-QTOF/MS) has been developed. Orthogonal partial least squares (OPLS) was used to establish the spectrum-toxicity relationship with the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in mice serum as evaluation indices for liver injury. The UHPLC-MS fingerprint was established and the OPLS analytical results suggested that coniferin, 1-methyl-2-undecyl-4(1H)-quinolone, 1-methyl-2-[(6Z,9Z,12E)-pentadeca triene]-4(1H)-quinolone, evocarpine, 1-methyl-2-[(Z)-7-tridecenyl]-4(1H)-quinolone, dihydroevocarpine, and 1-methyl-2-tetradecy-4-(1H)-quinolone probably associated with the hepatotoxicity of Euodia rutaecarpa. This paper offered considerable methods and insight for the fundamental research of the toxic material basis of similar toxic TCMs.


[Stomatologic status of children 12 years old suffering from allergic pathology].
Stomatologic status of 77 children 12 year old suffering from allergic pathology was determined. Results of the study shown that in children with allergy there were high figures of dental caries experience (both frequency and intensity), of dentomaxillary anomalies, of systemic dental enamel hypoplasia, of different oral membrane diseases and of inflammatory changes in parodontal tissues. The conclusion was drown of the necessity of preventive programme development directed to reduction of stomatological morbidity in children with allergic pathology.


Oxidative phosphorylation at the fin de siècle.
Mitochondria produce most of the energy in animal cells by a process called oxidative phosphorylation. Electrons are passed along a series of respiratory enzyme complexes located in the inner mitochondrial membrane, and the energy released by this electron transfer is used to pump protons across the membrane. The resultant electrochemical gradient enables another complex, adenosine 5'-triphosphate (ATP) synthase, to synthesize the energy carrier ATP. Important new mechanistic insights into oxidative phosphorylation have emerged from recent three-dimensional structural analyses of ATP synthase and two of the respiratory enzyme complexes, cytochrome bc1 and cytochrome c oxidase. This work, and new enzymological studies of ATP synthase's unusual catalytic mechanism, are reviewed here.


The fine structure of the retinal epithelium in the scissortail (Rasbora trilineata) (Teleost).
The normal morphology of the retinal epithelium has been studied by transmission electron microscopy in the eye of a teleost; the scissortail (Rasbora trilineata). The retinal epithelium forms a single layer of cells joined laterally by cell junctions. Centrally in the retina these cells are columnar while moving peripherally they are cuboidal and eventually squamous in shape. Apical processes of these cells enclose photoreceptor inner and outer segments and reach almost to the external limiting membrane. Few basal infoldings are seen. In addition to the usual cell organelles seen in retinal epithelial cells, i. e., abundant smooth endoplasmic reticulum, numerous mitochondria and phagosomes, the central epithelial cells contain numerous lipid tapetal spheres and a few melanosomes. Peripherally the cells contain few or no tapetal spheres and more melanosomes. A population of wandering phagocytes within the epithelial layer is described. Bruch's membrane shows a three-layered composition rather than the usual pentalaminate structure seen in most vertebrates. The choriocapillaris endothelium facing Bruch's membrane is very thin but displays only a few fenestrae.


Alpha-2 agonist dissociative anesthetic combinations in fallow deer (Cervus dama).
Three anesthetic protocols, each using an alpha-2 agonist sedative in combination with a dissociative anesthetic, were evaluated in 17 captive fallow deer (Cervus dama). The alpha-2 agonist was given first in two of the three protocols: 1) detomidine (0.1-0.2 mg/kg i.m.) followed by tiletamine-zolazepam (3.0-6.3 mg/kg i.m.) and 2) xylazine (0.6-0.9 mg/kg i.m.) followed by tiletamine-zolazepam (4-5 mg/kg i.m.). In the third protocol, xylazine (1.0-6.2 mg/kg i.m.) and ketamine (2.5-5.1 mg/kg i.m.) were given simultaneously. Each of the sedative/anesthetic combinations produced acceptable immobilization in fallow deer and both provide an alternative to narcotic anesthesia.


Cerebral palsy and multiple births.
To compare the birthweight specific prevalence of cerebral palsy in singleton and multiple births. Registered births of babies with cerebral palsy born to mothers resident in the counties of Merseyside and Cheshire during the period 1982 to 1989 were ascertained. The crude prevalence of cerebral palsy was 2.3 per 1000 infant survivors in singletons, 12.6 in twins, and 44.8 in triplets. The prevalence of cerebral palsy rose with decreasing birthweight. The birthweight specific prevalence among those of low birthweight < 2500 g was not significantly different in singleton than in multiple births. Among infants weighing > or = 2500 g, there was a significantly higher risk in multiple than in singleton births. The higher crude cerebral palsy prevalence in multiple births is partly due to the lower birthweight distribution and partly due to the higher risk among normal birthweight infants. Multiple birth babies are at increased risk of cerebral palsy. There is also an increased risk of cerebral palsy within a twin pregnancy if the co-twin has died in utero.


Agrobacterium delivers VirE2 protein into host cells via clathrin-mediated endocytosis.
Agrobacterium tumefaciens can cause crown gall tumors on a wide range of host plants. As a natural genetic engineer, the bacterium can transfer both single-stranded DNA (ssDNA) [transferred DNA (T-DNA)] molecules and bacterial virulence proteins into various recipient cells. Among Agrobacterium-delivered proteins, VirE2 is an ssDNA binding protein that is involved in various steps of the transformation process. However, it is not clear how plant cells receive the T-DNA or protein molecules. Using a split-green fluorescent protein approach, we monitored the VirE2 delivery process inside plant cells in real time. We observed that A. tumefaciens delivered VirE2 from the bacterial lateral sides that were in close contact with plant membranes. VirE2 initially accumulated on plant cytoplasmic membranes at the entry points. VirE2-containing membranes were internalized through clathrin-mediated endocytosis to form endomembrane compartments. VirE2 colocalized with the early endosome marker SYP61 but not with the late endosome marker ARA6, suggesting that VirE2 escaped from early endosomes for subsequent trafficking inside the cells. Dual endocytic motifs at the carboxyl-terminal tail of VirE2 were involved in VirE2 internalization and could interact with the μ subunit of the plant clathrin-associated adaptor AP2 complex (AP2M). Both the VirE2 cargo motifs and AP2M were important for the transformation process. Because AP2-mediated endocytosis is well conserved, our data suggest that the A. tumefaciens pathogen hijacks conserved endocytic pathways to facilitate the delivery of virulence factors. This might be important for Agrobacterium to achieve both a wide host range and a high transformation efficiency.


Blood transfusion during acute myocardial infarction: association with mortality and variability across hospitals.
Blood transfusion is controversial for anemic patients with acute myocardial infarction (AMI), with some previous studies reporting increased risk of transfusion-associated mortality. The goal of this study was to examine variability in blood transfusions across hospitals and the relationship between blood transfusion and in-hospital mortality in a large, contemporary cohort of consecutive AMI patients. Among 34,937 AMI hospitalizations from 57 centers, patients receiving at least 1 packed red blood cell transfusion were compared with those who were not transfused. Using 45 disease severity, comorbidity, laboratory, and in-hospital treatment variables, we propensity matched patients who did and did not receive a packed red blood cell transfusion. A conditional logistic regression model was used to identify the association between transfusion and in-hospital mortality. A total of 1,778 patients (5.1%) had at least 1 transfusion. In unadjusted analyses, transfusion was associated with higher in-hospital mortality (odds ratio: 2.05 [95% confidence interval: 1.76 to 2.40]). The vast majority of patients (91.1%) with and without transfusion had nonoverlapping propensity scores, reflecting incomparable clinical profiles. Thus, they were excluded from the propensity-matched analyses. After propensity matching those with overlapping scores, blood transfusion was associated with a reduced risk of in-hospital death (odds ratio: 0.73 [95% confidence interval: 0.58 to 0.92]). The majority of patients undergoing blood transfusion in clinical practice cannot be matched with nontransfused patients due to their markedly different clinical profiles. Among comparable patients, blood transfusion was associated with a lower risk of in-hospital mortality. These findings suggest that previous observational reports of increased mortality with transfusion may have been influenced by selection bias, and they highlight the need for randomized trials to establish the role of transfusion during AMI.


Precise correlation of macroscopic mechanical properties and microscopic structures of animal silks-using Antheraea pernyi silkworm silk as an example.
Animal silks, as one type of high performance natural material, display a unique combination of modulus, tensile strength, and extensibility that gives rise to a greater toughness than any other natural or synthetic fibers. Many previous researchers have already suggested that such excellent comprehensive mechanical properties should be closely related to their special molecular structures. In this paper, we provide more direct evidence to such an assumption by using Antheraea pernyi silkworm silk (tussah silk) as an example with synchrotron radiation FTIR microspectroscopy as a major characterization tool. Being a silkworm silk, A. pernyi silk has the same function as other silkworm silks (like common Bombyx mori silk), but on the other hand, its amino acid residue sequence is similar to that of spider dragline silk. Thus, A. pernyi silk can be a bridge between silkworm silk and spider silk that is worth investigating. Hence, in this research we designed different forcibly reeled A. pernyi silk samples by controlling the reeling rate, and subsequently tested their mechanical properties and then correlated them with their molecular structures and orientation degrees. Results show that the Young's modulus and breaking stress of forcibly reeled A. pernyi silks increased with the reeling rate, whereas the breaking strain was reduced. In the meantime, structure characterization revealed that the β-sheet content and molecular chain orientation in A. pernyi silk all increased significantly with an increase in reeling rate. In addition, the mechanical performance of A. pernyi silk can be altered from close to that of spider dragline silk to that of B. mori silkworm silk, with just a change of the reeling rate. All these phenomena clearly indicate that structural changes in A. pernyi silks contrived and controlled by reeling rate have a great effect upon their final mechanical properties. These observations further confirm that the mechanical properties of animal silks are able to be tuned by structure control during harvest time. Furthermore, the results obtained in this study may provide useful guidance when designing and producing high performance regenerated silk fibers for different applications.


Early and mid-term results of drug-eluting stent implantation in unprotected left main.
The safety and efficacy of percutaneous coronary intervention in unprotected left main (ULM) coronary arteries are still a matter of debate. All consecutive patients who had a sirolimus-eluting stent (Cypher, Cordis, Johnson and Johnson Co) or a paclitaxel-eluting stent (Taxus, Boston Scientific) electively implanted in de novo lesions on unprotected left main were analyzed. Patients treated with a drug-eluting stent (DES) were compared with the historical group of consecutive patients treated with bare metal stent (BMS). Eighty-five patients were treated with DES; 64 had BMS implantation. Patients treated with DES had lower ejection fractions (51.1+/-11% versus 57.4+/-13%, P=0.002) and were more often diabetics (21.2% versus 10.9%, P=0.12) with more frequent distal left main involvement (81.2% versus 57.8%, P=0.003). Furthermore, in the DES group, smaller vessels (3.33+/-0.6 versus 3.7+/-0.7 mm, respectively; P=0.0001) with more lesions (2.94+/-1.6 versus 2.25+/-1.3, P=0.004) and vessels (2.03+/-0.69 versus 1.8+/-0.72, P=0.05) were treated with longer stents (24.3+/-12 versus 15.8+/-8.6 mm, P=0.0001). Despite the higher-risk patients and lesion profiles in the DES group, the incidence of major cardiac events at a 6-month clinical follow-up was lower in the DES than in the BMS group (20.0% versus 35.9%, respectively; P=0.039). Moreover, cardiac deaths occurred in 3 DES patients (3.5%), as compared with 6 (9.3%) in the BMS group (P=0.17). In this early experience with DES in unprotected left main, this procedure appears safe with favorable and improved clinical results as compared with historical control subjects with a BMS. A randomized study comparing surgery appears justified at present.


[Clinical criteria of removable denture quality].
Clinical examination of 412 different constructions of removable dentures used in 273 patients (104 men, 169 women) aged from 31 to 69 years was carried out. The influence of such construction on soft and periodontal tissues was also studied. The result of the study was the prosthodontic assessment, including preliminary stage of prosthetic treatment. Clinical criteria of removable denture quality are proposed.


Somatostatin receptor in human hepatocellular carcinomas: biological, patient and tumor characteristics.
The evidence on the efficacy of somatostatin analogues in the treatment of hepatocellular carcinoma (HCC) in humans is conflicting. A variety of human tumors demonstrate somatostatin receptors. All subtypes bind human somatostatin with high affinity, while somatostatin analogues bind with high affinity to somatostatin receptor subtype 2 (sst2). We investigated the sst2 expression in HCC and examined whether HCCs expressing sst2 are a distinct subgroup. Forty-five human HCCs were tested for sst2 expression and biological alterations. The proliferative capacity was determined with Ki67 immunostaining and the DNA ploidy status was measured by fluorescent in situ hybridization with a chromosome 1-specific repetitive DNA probe. Expression of tumor suppressor genes (p16, p53 and Rb1) was measured by immunohistochemistry. sst2 expression was detected in 30 tumors (67%). No correlation existed between sst2 expression and the immunoprofiles of the tumor suppressor genes, aneuploidy, proliferation, age, gender, alpha-fetoprotein levels, tumor size, tumor grade and underlying liver disease. In 67% of the patients with HCC, sst2 could be detected in the tumor. No clinical, pathological or biological characteristics were specific for sst2-positive tumors.


Sodium arsenite inhibited genomic estrogen signaling but induced pERα (Ser118) via MAPK pathway in breast cancer cells.
Arsenic (As) is considered a major environmental health threat worldwide due to its widespread contamination in drinking water. Recent studies reported that arsenic is a potential xenoestrogen as it interfered with the action of estrogen (E2) and estrogen receptor (ER) signaling. The present study investigated the effects of sodium arsenite (NaAsO2 ) on estrogen signaling in human breast cancer cells. The results demonstrated that NaAsO2 dose-dependently increased viability of hormone-dependent breast cancer MCF-7 and T47D cells expressing both ERα and ERβ but not hormone-independent MDA-MB-231 cells expressing ERβ. These suggested ERα contribution to NaAsO2 -stimulated breast cancer cells growth. NaAsO2 induced down-regulation of ERα but up-regulation of ERβ protein expressions in T47D cells. Moreover, NaAsO2 dose-dependently inhibited E2-induced ER transcriptional activity as it decreased E2-mediated ERE-luciferase transcription activation and PgR mRNA transcription but increased pS2 mRNA transcription. However, NaAsO2 induced both rapid and sustained activation of ERK1/2 and increased in phosphorylation of ERα at serine 118 residue, c-fos and c-myc protein expressions. These results indicated that NaAsO2 interferes the genomic estrogen-signaling pathway but induces activation of a rapid nongenomic signal transduction through ERK1/2 pathway which may contribute to its proliferative effect on hormone-dependent breast cancer cells. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1133-1146, 2016.


[Cinematographic functional diagnosis of swallowing after plastic reconstruction of large tumor defects of the mouth cavity and pharynx].
Reestablishing good swallowing function after resection and reconstruction of head and neck tumors is very important for our patients' well-being. Today many different surgical concepts for reconstruction after tumor surgery are in common use. It is necessary to establish a good diagnostic procedure for postoperative assessment of the swallowing function. High-speed cineradiography at a minimum of 50 frames per second is well established for evaluating swallowing problems in head and neck patients. Thirty-six patients divided into three groups were examined using high speed cineradiography after surgical treatment of pharyngeal and oral cavity cancer. Group 1 (n = 12) included patients with a subtotal or total tongue resection and reconstruction with infrahyoid myofascial flap and jejunal flap; Group II (n = 8), patients with total resection of the oropharynx soft palate and velum and reconstruction with a free radial forearm flap; Group III (n = 15), patients with total laryngopharyngektomy and reconstruction with jejunal flap and siphon and with or without repair of the digastric muscle. Group I: All patients with tongue reconstruction were able to swallow normally from the oral cavity into the pharynx. All patients had normal bolus propulsion because of a good tongue volume and tongue motility. There was only one case of aspiration after total glossectomy with the larynx left in place. All patients could swallow with the head and neck in a normal position. Group II: All patients with reconstruction of the soft palate and velum were able to initiate proper bolus propulsion without nasal regurgitation or rhinolalia aperta. Only one patients suffered from chronic aspiration after hemiresection of the oropharynx and hypopharynx. Group III: All patients with pharynx reconstruction had no problems with bolus transfer through the reconstructed pharynx. Aspiration into the reconstructed pharynx was a major problem for those patients without repair of the digastric muscle (5/8 = 63%). Better results were observed in the patients who underwent repair of the digastric muscle. There was only one case (13%) of aspiration. By using high-speed cineradiography it is possible to make a detailed description of the swallowing function after extensive surgical treatment of pharyngeal and oral cavity cancer. We think that high-speed cineradiography is a very sensitive diagnostic procedure capable of detecting all functional aspects of swallowing. High-speed cineradiography should be one of the standard diagnostic studies performed surgery of the oral cavity and pharynx.


[Case report: simultaneous bilateral testicular tumors with different cell types].
A 29-year-old man was admitted to our hospital due to bilateral testicular tumors. The bilateral testicular tumors were palpated and visualized by ultrasound and magnetic resonance imaging (right 8 cm, left 6 cm in diameter). Bilateral high orchiectomies were performed after frozen storage of the sperm. Pathological examination revealed seminoma and immature teratoma in the right testis and seminoma in the left testis. Three months later, computed tomography (CT) showed multiple metastatic lung nodules. In addition, positron emission tomography (PET)-CT examination revealed peri-caval lymph node metastasis together with the lung metastases. Lung metastases disappeared, but the lymph node metastasis reduced and remained after 3 courses of combination chemotherapy with bleomycin, etoposide and cisplatin. PET-CT examination revealed that no uptake of FDG was seen in the lung and lymph nodes. Retroperitoneal lymph node dissection was performed. No viable tumor cells were histologically present in the excited lymph nodes. The postoperative course was good and uneventful at 10 months under androgen replacement therapy without disease recurrences.


A nursing screening program for diabetes in northern New Mexico.
This paper presents the results of a community screening program conducted by nurses in northern New Mexico. Seven hundred and ninety-nine persons were screened for diabetes following American Diabetes Association guidelines. Screening procedures included having participants complete a questionnaire and testing them for capillary blood glucose levels. Initial results found a 5.7% positive screening rate. A large proportion of those who tested positive (80%) were unavailable for follow-up procedures.


Associations of circulating immunomarkers with the efficacy of immunotherapy for primary hepatic carcinoma.
Peripheral blood immunomarkers are associated with prognosis in patients with solid tumors receiving chemotherapy or immunotherapy. In this study, the associations of circulating neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR), as well as their dynamic changes were investigated in relation to the efficacy of immunotherapy in patients with primary liver cancer. Comparisons were made between NLR, MLR, and PLR among individuals exhibiting disease control (defined as the best response of partial response [PR] or stable disease [SD]) and those with progressive disease (PD). Additionally, disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) were compared between individuals with different NLR, MLR, and PLR levels before initiating palliative immunotherapy. Furthermore, comparisons were made between patients with different alterations in the ratios at the second cycle of immunotherapy compared to baseline. These analyses were performed using univariate and multivariate approaches. A total of 119 Chinese patients with liver cancer who underwent immunotherapy were included in this study, which focused on hepatocellular carcinoma (HCC). In cases with HCC (n = 104), the cutoffs of NLR, MLR, and PLR to differentiate treatment responders from nonresponders were 3.38, 0.28, and 227.18, respectively. Patients with the best response of PR or SD had significantly lower NLR and MLR. Patients with NLR <3.38 and those with MLR <0.28 significantly had longer OS and PFS than their counterparts, and those with PLR <227.18 had significantly longer PFS, both in overall patients and in various patient subgroups. Lower NLR, MLR, or PLR was associated with earlier BCLC stage, fewer metastatic sites, less frequent extrahepatic metastasis, or better performance status. For individuals who had an unfavorable baseline NLR ≥3.38, MLR ≥0.28, or a favorable baseline PLR <227.18 prior to first immunotherapy, a decrease in NLR, MLR, or PLR at Cycle 2 of immunotherapy was significantly associated with a higher DCR. Among patients with HCC who received immunotherapy, lower NLR, and MLR at baseline in overall patients were significantly associated with better disease control and more favorable survival outcomes (both OS and PFS), and lower PLR was significantly associated with longer PFS. The findings of this research may offer useful hints foranoptimized selection of patients with liver cancer who may benefit more from immunotherapy.


Can physicians be replaced with gynecological teaching women to train medical students in their first pelvic examination? A pilot study from Northern Sweden.
The main objective was to gain a deeper understanding of how medical students perceive and experience learning from gynecological teaching women (GTW) instead of physicians in their first pelvic examination. A second aim was to describe how the women experience their roles as GTW. Data were collected from individual interviews with 24 medical students from a medical school in Sweden and with 5 GTW. Discourse analysis was performed to acquire a deeper understanding of the informants' experiences and to understand social interactions. Five themes revealed in the medical students' experiences: "Hoping that anxiety will be replaced with security," "Meeting as equals creates a sense of calm," "Succeeding creates a sense of security for the future," "Wanting but not having the opportunity to learn more," and "Feeling relieved and grateful." One theme revealed in the GTW experiences: "Hoping to relate in a trustworthy way." To replace physicians with GTW may facilitate the learning process and may also help medical students improve their communicative skills. Using GTW will hopefully further improve students' basic medical examination techniques and physician-patient relationships. Since GTW seems to increase self-confidence and skills of medical students performing their first pelvic examination we recommend that the use of GTW is considered in the training of medical students.


Vitamin D, cardiovascular disease, and survival in dialysis patients.
Dialysis patients have an increased burden of cardiovascular disease, with >70% of patients dying from a cardiovascular event. Several recent retrospective cohort studies have shown an association of treatment with calcitriol or its analogs and improved survival. The similar findings of these studies increase the validity of the observations, but these studies are subject to biases inherent in this type of study design. In particular, the nonrandom choice to treat, lack of information on concomitant medications, and differences in characteristics of patients who are treated compared with those not treated can lead to significant bias. Thus, prospective studies are needed. Two, small, uncontrolled, prospective studies showed improvement in left ventricular hypertrophy in dialysis patients treated with alpha-calcidiol or calcitriol, and there is abundant animal and in vitro studies showing biological plausibility. Thus, given the available evidence, it seems prudent to advise that most dialysis patients receive some form of vitamin D while we await results of a prospective interventional trial. The unknown is what type and how much to give, and whether this approach is safe, especially in patients with low levels of PTH.


Multiple imputation of covariates by fully conditional specification: Accommodating the substantive model.
Missing covariate data commonly occur in epidemiological and clinical research, and are often dealt with using multiple imputation. Imputation of partially observed covariates is complicated if the substantive model is non-linear (e.g. Cox proportional hazards model), or contains non-linear (e.g. squared) or interaction terms, and standard software implementations of multiple imputation may impute covariates from models that are incompatible with such substantive models. We show how imputation by fully conditional specification, a popular approach for performing multiple imputation, can be modified so that covariates are imputed from models which are compatible with the substantive model. We investigate through simulation the performance of this proposal, and compare it with existing approaches. Simulation results suggest our proposal gives consistent estimates for a range of common substantive models, including models which contain non-linear covariate effects or interactions, provided data are missing at random and the assumed imputation models are correctly specified and mutually compatible. Stata software implementing the approach is freely available.


Oxidative stress in vivax malaria.
Malaria is still a leading cause of morbidity and mortality. The increase in lipid peroxidation reported in malaria infection and antioxidant status may be a useful marker of oxidative stress during malaria infection. The aim of this study was to investigate the role of antioxidant enzymes against toxic reactive oxygen species in patients infected with Plasmodium vivax and healthy controls. Malondialdehyde levels, superoxide dismutase, and glutathione peroxidase activities were determined in 91 P. vivax patients and compared with 52 controls. Malondialdehyde levels, superoxide dismutase, and glutathione peroxidase activities were 8.07±2.29 nM/ml, 2.69±0.33 U/ml, and 49.6±3.2 U/g Hb in the patient group and 2.72±0.50 nM/ml, 3.71±0.47 U/ml, and 62.3±4.3 U/g Hb in the control group, respectively. Malondialdehyde levels were found statistically significant in patients with vivax malaria higher than in healthy controls (P<0.001). On the other hand, superoxide dismutase and glutathione peroxidase activities were found to be significantly lower in vivax malaria patients than in controls (P<0.05). There was an increase in oxidative stress in vivax malaria. The results suggested that antioxidant defense mechanisms may play an important role in the pathogenesis of P. vivax.


Resveratrol ameliorates 2,4-dinitrofluorobenzene-induced atopic dermatitis-like lesions through effects on the epithelium.
Background. Resveratrol is a natural polyphenol that exhibits anti-inflammatory effects. The aim of this study was to investigate the effects of resveratrol treatment on epithelium-derived cytokines and epithelial apoptosis in a murine model of atopic dermatitis-like lesions. Material and Methods. Atopic dermatitis-like lesions were induced in BALB/c mice by repeated application of 2,4-dinitrofluorobenzene to shaved dorsal skin. Twenty-one BALB/c mice were divided into three groups: group I (control), group II (vehicle control), and group III (resveratrol). Systemic resveratrol (30 mg/kg/day) was administered repeatedly during the 6th week of the experiment. After the mice had been sacrificed, skin tissues were examined histologically for epithelial thickness. Epithelial apoptosis (caspase-3) and epithelium-derived cytokines [interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP)] were evaluated immunohistochemically. Results. Epithelial thickness and the numbers of IL-25, IL-33, TSLP and caspase-3-positive cells were significantly higher in group II compared to group I mice. There was significant improvement in epithelial thickness in group III compared with group II mice (p < 0.05). The numbers of IL-25, IL-33, and TSLP-positive cells in the epithelium were lower in group III than in group II mice (p < 0.05). The number of caspase-3-positive cells, as an indicator of apoptosis, in the epithelium was significantly lower in group III than in group II mice (p < 0.05). Conclusion. Treatment with resveratrol was effective at ameliorating histological changes and inflammation by acting on epithelium-derived cytokines and epithelial apoptosis.


Non-Invasive Physiological Indicators of Heat Stress in Cattle.
Cattle are susceptible to heat stress, especially those kept on high levels of nutrition for the purpose of maximising growth rates, which leads to a significant heat increment in their bodies. Consequences include compromised health and productivity and mortalities during extreme events, as well as serious economic loss. Some measures of heat stress, such as plasma cortisol and temperature in the rectum, vagina, or rumen, are invasive and therefore unlikely to be used on farms. These may cause additional stress to the animal due to handling, and that stress in itself can confound the measure. Consequently, it is desirable to find non-invasive alternatives. Panting score (PS), cortisol metabolites in faeces, milk, or hair, and the infrared temperature of external body surfaces are all potentially useful. Respiratory indicators are difficult and time consuming to record accurately, and cortisol metabolites are expensive and technically difficult to analyse. Infrared temperature appears to offer the best solution but requires further research to determine the thresholds that define when corrective actions are required to ensure optimal health and productivity. Research in this area has the potential to ultimately improve the welfare and profitability of cattle farming.


Alemtuzumab: a review of efficacy and risks in the treatment of relapsing remitting multiple sclerosis.
Alemtuzumab is a selective humanized monoclonal antibody directed against the CD52 antigen, and has been found to be a powerful treatment for relapsing remitting multiple sclerosis. Alemtuzumab demonstrated high efficacy in several clinical studies. The risk of relapse and sustained accumulation of disability showed significant reduction in the Phase II CAMMS223 and the Phase III clinical trials CARE MS I and CARE MS II. The data presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis confirmed these results. After completion of a 1-year treatment cycle, alemtuzumab showed a sustained effect. Although the efficacy of alemtuzumab has been widely proven, several severe adverse effects have been reported with its use. Infusion-associated reactions, increased risk of infections, and secondary autoimmunity have been associated with alemtuzumab. Autoimmune disease - mainly of the thyroid - has been reported. Immune thrombocytopenic purpura and autoimmune nephropathies have been observed less frequently. These adverse effects, given the short period of alemtuzumab marketing for relapsing remitting multiple sclerosis, require strict monitoring.


Sleep Spindles and Fragmented Sleep as Prodromal Markers in a Preclinical Model of LRRK2-G2019S Parkinson's Disease.
Sleep disturbances co-occur with and precede the onset of motor symptoms in Parkinson's disease (PD). We evaluated sleep fragmentation and thalamocortical sleep spindles in mice expressing the p.G2019S mutation of the leucine-rich repeat kinase 2 (LRRK2) gene, one of the most common genetic forms of PD. Thalamocortical sleep spindles are oscillatory events that occur during slow-wave sleep that are involved in memory consolidation. We acquired data from electrocorticography, sleep behavioral measures, and a rotarod-based motor enrichment task in 28 LRRK2-G2019S knock-in mice and 27 wild-type controls (8-10 month-old males). Sleep was more fragmented in LRRK2-G2019S mice; sleep bouts were shorter and more numerous, even though total sleep time was similar to controls. LRRK2-G2019S animals expressed more sleep spindles, and individual spindles were longer in duration than in controls. We then chronically administered the LRRK2-inhibitor MLi-2 in-diet to n = 12 LRRK2-G2019S and n = 15 wild-type mice for a within-subject analysis of the effects of kinase inhibition on sleep behavior and physiology. Treatment with MLi-2 did not impact these measures. The data indicate that the LRRK2-G2019S mutation could lead to reduced sleep quality and altered sleep spindle physiology. This suggests that sleep spindles in LRRK2-G2019S animals could serve as biomarkers for underlying alterations in sleep networks resulting from the LRRK2-G2019S mutation, and further evaluation in human LRRK2-G2019S carriers is therefore warranted.


Prevalence of Antibiotic-Resistant Pathogens in Culture-Proven Sepsis and Outcomes Associated With Inadequate and Broad-Spectrum Empiric Antibiotic Use.
Broad-spectrum antibiotics are recommended for all patients with suspected sepsis to minimize the risk of undertreatment. However, little is known regarding the net prevalence of antibiotic-resistant pathogens across all patients with community-onset sepsis or the outcomes associated with unnecessarily broad empiric treatment. To elucidate the epidemiology of antibiotic-resistant pathogens and the outcomes associated with both undertreatment and overtreatment in patients with culture-positive community-onset sepsis. This cohort study included 17 430 adults admitted to 104 US hospitals between January 2009 and December 2015 with sepsis and positive clinical cultures within 2 days of admission. Data analysis took place from January 2018 to December 2019. Inadequate empiric antibiotic therapy (ie, ≥1 pathogen nonsusceptible to all antibiotics administered on the first or second day of treatment) and unnecessarily broad empiric therapy (ie, active against methicillin-resistant Staphylococcus aureus [MRSA]; vancomycin-resistant Enterococcus [VRE]; ceftriaxone-resistant gram-negative [CTX-RO] organisms, including Pseudomonas aeruginosa; or extended-spectrum β-lactamase [ESBL] gram-negative organisms when none of these were isolated). Prevalence and empiric treatment rates for antibiotic-resistant organisms and associations of inadequate and unnecessarily broad empiric therapy with in-hospital mortality were assessed, adjusting for baseline characteristics and severity of illness. Of 17 430 patients with culture-positive community-onset sepsis (median [interquartile range] age, 69 [57-81] years; 9737 [55.9%] women), 2865 (16.4%) died in the hospital. The most common culture-positive sites were urine (9077 [52.1%]), blood (6968 [40.0%]), and the respiratory tract (2912 [16.7%]). The most common pathogens were Escherichia coli (5873 [33.7%]), S aureus (3706 [21.3%]), and Streptococcus species (2361 [13.5%]). Among 15 183 cases in which all antibiotic-pathogen susceptibility combinations could be calculated, most (12 398 [81.6%]) received adequate empiric antibiotics. Empiric therapy targeted resistant organisms in 11 683 of 17 430 cases (67.0%; primarily vancomycin and anti-Pseudomonal β-lactams), but resistant organisms were uncommon (MRSA, 2045 [11.7%]; CTX-RO, 2278 [13.1%]; VRE, 360 [2.1%]; ESBLs, 133 [0.8%]). The net prevalence for at least 1 resistant gram-positive organism (ie, MRSA or VRE) was 13.6% (2376 patients), and for at least 1 resistant gram-negative organism (ie, CTX-RO, ESBL, or CRE), it was 13.2% (2297 patients). Both inadequate and unnecessarily broad empiric antibiotics were associated with higher mortality after detailed risk adjustment (inadequate empiric antibiotics: odds ratio, 1.19; 95% CI, 1.03-1.37; P = .02; unnecessarily broad empiric antibiotics: odds ratio, 1.22; 95% CI, 1.06-1.40; P = .007). In this study, most patients with community-onset sepsis did not have resistant pathogens, yet broad-spectrum antibiotics were frequently administered. Both inadequate and unnecessarily broad empiric antibiotics were associated with higher mortality. These findings underscore the need for better tests to rapidly identify patients with resistant pathogens and for more judicious use of broad-spectrum antibiotics for empiric sepsis treatment.


A previously unrecognized promoter of LMO2 forms part of a transcriptional regulatory circuit mediating LMO2 expression in a subset of T-acute lymphoblastic leukaemia patients.
The T-cell oncogene Lim-only 2 (LMO2) critically influences both normal and malignant haematopoiesis. LMO2 is not normally expressed in T cells, yet ectopic expression is seen in the majority of T-acute lymphoblastic leukaemia (T-ALL) patients with specific translocations involving LMO2 in only a subset of these patients. Ectopic lmo2 expression in thymocytes of transgenic mice causes T-ALL, and retroviral vector integration into the LMO2 locus was implicated in the development of clonal T-cell disease in patients undergoing gene therapy. Using array-based chromatin immunoprecipitation, we now demonstrate that in contrast to B-acute lymphoblastic leukaemia, human T-ALL samples largely use promoter elements with little influence from distal enhancers. Active LMO2 promoter elements in T-ALL included a previously unrecognized third promoter, which we demonstrate to be active in cell lines, primary T-ALL patients and transgenic mice. The ETS factors ERG and FLI1 previously implicated in lmo2-dependent mouse models of T-ALL bind to the novel LMO2 promoter in human T-ALL samples, while in return LMO2 binds to blood stem/progenitor enhancers in the FLI1 and ERG gene loci. Moreover, LMO2, ERG and FLI1 all regulate the +1 enhancer of HHEX/PRH, which was recently implicated as a key mediator of early progenitor expansion in LMO2-driven T-ALL. Our data therefore suggest that a self-sustaining triad of LMO2/ERG/FLI1 stabilizes the expression of important mediators of the leukaemic phenotype such as HHEX/PRH.


Periprocedural management of rivaroxaban-treated patients.
The increasing and widespread use of direct oral anticoagulants (DOACs) demands guidelines and experts' consensus for their rational and safe use, especially in certain situations for which there is no evidence-based consensus, such as the periprocedural setting. Rivaroxaban is an oral factor Xa inhibitor approved for stroke prevention in atrial fibrillation (AF) and for treatment and prevention of venous thromboembolism (VTE) in major orthopedic surgery. This article is addressed to all the clinicians involved in the periprocedural approach of patients treated with rivaroxaban, with the aim to give practical recommendations to improve patients' management during and after surgery. This article is based on a consensus of specialists involved in anticoagulant treatment and in periprocedural setting, including experts in thrombosis, cardiologists, internists, clinical pathologists and anesthesiologists. The authors performed a review of the literature and expressed statements based on the results of the review as well as on personal experience. Rivaroxaban is a safe and effective drug that simplifies management of anticoagulation also in patients undergoing invasive procedures. However, periprocedural management could be challenging and physicians must carefully balance the risk of bleeding and the risk of thrombosis.


Hemodialysis clearance of glyphosate following a life-threatening ingestion of glyphosate-surfactant herbicide.
Ingestion of glyphosate-surfactant herbicides (GlySH) can result in acute kidney injury, electrolyte abnormalities, acidosis, cardiovascular collapse, and death. In severe toxicity, the use of hemodialysis is reported, but largely unsupported by kinetic analysis. We report the dialysis clearance of glyphosate following a suicidal ingestion of a glyphosate-containing herbicide. A 62-year-old man was brought to the emergency department (ED) 8.5 h after drinking a bottle of commercial herbicide containing a 41% solution of glyphosate isopropylamine, in polyoxyethyleneamine (POEA) surfactant and water. He was bradycardic and obtunded with respiratory depression necessitating intubation and mechanical ventilation. Initial laboratory results were significant for the following: pH, 7.11; PCO2, 64 mmHg; PO2, 48 mmHg; potassium, 7.8 mEq/L; Cr 3.3, mg/dL; bicarbonate, 22 mEq/L; anion gap, 18 mEq/L; and lactate, 7.5 mmol/L. Acidosis and hyperkalemia persisted despite ventilation and fluid resuscitation. The patient underwent hemodialysis 16 h post ingestion, after which he demonstrated resolution of acidosis and hyperkalemia, and improvement in clinical status. Serum glyphosate concentrations were drawn prior to, during, and after hemodialysis. The extraction ratio and hemodialysis clearance were calculated to be 91.8% and 97.5 mL/min, respectively. We demonstrate the successful clearance of glyphosate using hemodialysis, with corresponding clinical improvement in a patient with several poor prognostic factors (advanced age, large volume ingested, and impaired consciousness). The effects of hemodialysis on the surfactant compound are unknown. Hemodialysis can be considered when severe acidosis and acute kidney injury complicate ingestion of glyphosate-containing products.


Molecular beam epitaxy.
Molecular beam epitaxy is an ultrahigh vacuum technique for growing very thin epitaxial layers of semiconductor crystals. Because it is inherently a slow growth process, extreme dimensional control over both major compositional variations and impurity incorporation can be achieved. The result is that it has been possible, with one combination of lattice-matched semiconductors, GaAs and Alx-Gal-xAs, to demonstrate a large variety of novel single-crystal structures. These results have important implications for fundamental studies of the physics of thin-layered structures and for the development of new semiconductor electronic and optoelectronic devices.


Characterization of 164 patients with NRAS mutated non-small cell lung cancer (NSCLC).
NRAS mutations are observed in less than 1% of non-small cell lung cancer (NSCLC). Clinical data regarding this rare subset of lung cancer are scarce and response to systemic treatment such as chemotherapy or immune checkpoint inhibitors (ICI) has never been reported. All consecutive patients with an NRAS mutated NSCLC, diagnosed between August 2014 and November 2020 in 14 French centers, were included. Clinical and molecular data were collected and reviewed from medical records. Out of the 164 included patients, 106 (64.6%) were men, 150 (91.5%) were current or former smokers, and 104 (63.4%) had stage IV NSCLC at diagnosis. The median age was 62 years, and the most frequent histology was adenocarcinoma (81.7%). NRAS activating mutations were mostly found in codon 61 (70%), while codon 12 and 13 alterations were observed in 16.5% and 4.9% of patients, respectively. Programmed death ligand-1 expression level <1%/1-49%/≥50% were respectively found in 30.8%/27.1%/42.1% of tumors. With a median follow-up of 12.5 months, median overall survival (OS) of stage IV patients was 15.3 months (95% CI 9.9-27.6). No significant difference in OS was found according to the type of mutation (codon 61 vs. other), HR = 1.12 (95% CI 0.65-1.95). Among stage IV patients treated with platinum-based doublet (n = 66), ICI (n = 48), or combination of both (n = 10), objective response rate, and median progression free survival were respectively 45% and 5.8 months, 35% and 6.9 months, 70% and 8.6 months. NRAS mutated NSCLC are characterized by a high frequency of smoking history and codon 61 mutations. Further studies are needed to confirm the encouraging outcome of immunotherapy in combination with chemotherapy.


Factors Associated With Severe COVID-19 Infection Among Persons of Different Ages Living in a Defined Midwestern US Population.
To identify risk factors associated with severe COVID-19 infection in a defined Midwestern US population overall and within different age groups. We used the Rochester Epidemiology Project research infrastructure to identify persons residing in a defined 27-county Midwestern region who had positive results on polymerase chain reaction tests for COVID-19 between March 1, 2020, and September 30, 2020 (N=9928). Age, sex, race, ethnicity, body mass index, smoking status, and 44 chronic disease categories were considered as possible risk factors for severe infection. Severe infection was defined as hospitalization or death caused by COVID-19. Associations between risk factors and severe infection were estimated using Cox proportional hazard models overall and within 3 age groups (0 to 44, 45 to 64, and 65+ years). Overall, 474 (4.8%) persons developed severe COVID-19 infection. Older age, male sex, non-White race, Hispanic ethnicity, obesity, and a higher number of chronic conditions were associated with increased risk of severe infection. After adjustment, 36 chronic disease categories were significantly associated with severe infection. The risk of severe infection varied significantly across age groups. In particular, persons 0 to 44 years of age with cancer, chronic neurologic disorders, hematologic disorders, ischemic heart disease, and other endocrine disorders had a greater than 3-fold increased risk of severe infection compared with persons of the same age without those conditions. Associations were attenuated in older age groups. Older persons are more likely to experience severe infections; however, severe cases occur in younger persons as well. Our data provide insight regarding younger persons at especially high risk of severe COVID-19 infection.


Factors related to survival in hepatocellular carcinoma in the geographic area of Sabadell (Catalonia, Spain).
hepatocellular carcinoma (HCC) is a very frequent tumor. Screening for the disease is effective, but the prognostic factors are difficult to evaluate. 1. To determine epidemiological data and the clinical course of HCC in our setting. 2. To compare patient survival according to whether screening is performed or not. 3. To evaluate survival prognostic factors. data on the epidemiology and clinical course of patients diagnosed with HCC were collected on a prospective basis (January 2004-December 2006). Two groups were considered according to whether screening had been performed (group A) or not (group B). a total of 110 patients were diagnosed with HCC (70% males). The most common etiology of cirrhosis was hepatitis C (56.1%), and 69% presented mild liver failure (Child-Pugh grade A). The median follow-up was 1.8 years. Fifty-one percent had been subjected to screening. The diagnosis of HCC was established by imaging techniques in 48.2% of the cases, and by histological criteria in 51.8%. The median tumor size was 23 mm in group A and 28 mm in group B (p = 0.005). Treatment with curative intent was provided in 72% of the cases in group A and in 48% in group B (p = 0.011). The median overall survival was 1.99 years -2.67 years in group A and 1.75 years in group B (p = 0.05). The multivariate analysis of overall survival showed the type of treatment (OR = 2.82 95%CI: 1.3-6.12, p = 0.009) and liver function (OR = 1.71 95%CI: 1.1-2.68, p = 0.020) to be independent predictors of survival. screening allows the diagnosis of smaller lesions and a higher percentage of curative treatments. The degree of liver function and the provision of curative treatment are independent predictors of survival.


A high-throughput, quantitative cell-based screen for efficient tailoring of RNA device activity.
Recent advances have demonstrated the use of RNA-based control devices to program sophisticated cellular functions; however, the efficiency with which these devices can be quantitatively tailored has limited their broader implementation in cellular networks. Here, we developed a high-efficiency, high-throughput and quantitative two-color fluorescence-activated cell sorting-based screening strategy to support the rapid generation of ribozyme-based control devices with user-specified regulatory activities. The high-efficiency of this screening strategy enabled the isolation of a single functional sequence from a library of over 10(6) variants within two sorting cycles. We demonstrated the versatility of our approach by screening large libraries generated from randomizing individual components within the ribozyme device platform to efficiently isolate new device sequences that exhibit increased in vitro cleavage rates up to 10.5-fold and increased in vivo activation ratios up to 2-fold. We also identified a titratable window within which in vitro cleavage rates and in vivo gene-regulatory activities are correlated, supporting the importance of optimizing RNA device activity directly in the cellular environment. Our two-color fluorescence-activated cell sorting-based screen provides a generalizable strategy for quantitatively tailoring genetic control elements for broader integration within biological networks.


Cytokinin oxidase/dehydrogenase genes in barley and wheat: cloning and heterologous expression.
The cloning of two novel genes that encode cytokinin oxidase/dehydrogenase (CKX) in barley is described in this work. Transformation of both genes into Arabidopsis and tobacco showed that at least one of the genes codes for a functional enzyme, as its expression caused a cytokinin-deficient phenotype in the heterologous host plants. Additional cloning of two gene fragments, and an in silico search in the public expressed sequence tag clone databases, revealed the presence of at least 13 more members of the CKX gene family in barley and wheat. The expression of three selected barley genes was analyzed by RT-PCR and found to be organ-specific with peak expression in mature kernels. One barley CKX (HvCKX2) was characterized in detail after heterologous expression in tobacco. Interestingly, this enzyme shows a pH optimum at 4.5 and a preference for cytokinin ribosides as substrates, which may indicate its vacuolar targeting. Different substrate specificities, and the pH profiles of cytokinin-degrading enzymes extracted from different barley tissues, are also presented.


Virtual Reality during Intrathecal Pump Refills in Children: A Case Series.
Virtual reality has proven to be an effective approach to decrease pain in acute settings, both in adults and children. The aim of this study is to evaluate whether virtual reality (VR) could reduce pain during an intrathecal pump refill procedure in children receiving intrathecal drug delivery, compared to a standard refill procedure. This is a three-arm crossover randomized controlled trial, evaluating the effect of VR on pain in children with cerebral palsy undergoing an intrathecal pump refill compared to a standard refill and a refill with distraction (watching a video). Pain was evaluated using the Wong-Baker Faces Scale. Secondary outcomes were procedural pain, fear, state anxiety, the incidence of adverse events and satisfaction. Six children participated in this study, whereby all children underwent the three conditions. Five children indicated an equal of lower pain score during VR, compared to a standard refill. This finding of an equal or lower pain intensity score for the VR condition compared to the control condition was also revealed by the ratings of the parents, physician and the researcher. The influence of VR on anxiety and fear seem to be in line with the influence of watching a video. In terms of satisfaction, all children and parents agreed with the statement that they would like to use VR again for a next refill. Due to the lack of adverse events, the high degree of satisfaction of children with VR and the decreased pain levels after a refill with VR, physicians may aim to explore the implementation of VR during intrathecal pump refill procedures in children in a daily clinical routine care setting.


Placenta passage of the thyroid hormone analog DITPA to male wild-type and Mct8-deficient mice.
Monocarboxylate transporter 8 (MCT8) deficiency causes severe X-linked intellectual and neuropsychological impairment associated with abnormal thyroid function tests (TFTs) producing thyroid hormone (TH) deprivation in brain and excess in peripheral tissues. The TH analog diiodothyropropionic acid (DITPA) corrected the TFTs abnormalities and hypermetabolism of MCT8-deficient children but did not improve the neurological phenotype. The latter result was attributed to the late initiation of treatment. Therefore, we gave DITPA to pregnant mice carrying Mct8-deficient embryos to determine whether DITPA, when given prenatally, crosses the placenta and affects the serum TFTs and cerebral cortex of embryos. After depletion of the endogenous TH, Mct8-heterozygous pregnant dams carrying both wild-type (Wt) and Mct8-deficient (Mct8KO) male embryos were given DITPA. Effects were compared with those treated with levothyroxine (L-T4). With DITPA treatment, serum DITPA concentration was not different in the two genotypes, which produced equal effect on serum TSH levels in both groups of pups. In contrast, with L-T4 treatment, TSH did not normalize in Mct8KO pups whereas it did in the Wt littermates and dams despite higher concentration of serum T4. Finally, both treatments similarly modulated the expression of the TH-dependent genes Shh, Klf9, and Aldh1a3 in brain. Thus, the ability of DITPA to cross the placenta, its thyromimetic action on the expression of TH-dependent genes in brain, and its better accessibility to the pituitary than L-T4, as assessed by serum TSH, make DITPA a candidate for the prenatal treatment of MCT8 deficiency.


Expectation-Driven Text Extraction from Medical Ultrasound Images.
In this study an expectation-driven approach is proposed to extract data stored as pixel structures in medical ultrasound images. Prior knowledge about certain properties like the position of the text and its background and foreground grayscale values is utilized. Several open source Java libraries are used to pre-process the image and extract the textual information. The results are presented in an Excel table together with the outcome of several consistency checks. After manually correcting potential errors, the outcome is automatically stored in the main database. The proposed system yielded excellent results, reaching an accuracy of 99.94% and reducing the necessary human effort to a minimum.


Prognostic factors influencing cisplatin-induced emesis. Definition and validation of a predictive logistic model.
Data obtained from 209 patients who entered different prospective randomized antiemetic trials were analyzed to establish the prognostic value of some variables on the control of cisplatin-induced emesis. The antiemetic regimens evaluated included the following: metoclopramide (M) at 1, 2, and 4 mg/kg total dose and a combination of M (4 mg/kg) with dexamethasone (D) (40 mg). Vomiting lasting more than 1 hour (no protection [NP]) was the endpoint selected for the analysis. A logistic model carried out, first on the 110 subjects receiving the M + D regimen and then on the whole sample, selected sex (P = 0.0001), Eastern Cooperative Oncology Group performance status (PS) (P = 0.006), and age (P = 0.01) among the six factors considered. Since the prognostic value of these variables is mostly related to their interaction, three major risk classes were identified. The corresponding NP rates were 26.3%, 42.4%, and 70.8% for the low-risk, intermediate-risk, and high-risk groups, respectively (P = 0.000002). Except for the lowest M level, the observed NP rates were significantly associated to the risk classes, whereas the antiemetic regimen influenced the antiemetic outcome only in the low-risk class. Regardless of the regimen employed, certain patient characteristics, such as sex, PS, and age, significantly affect cisplatin-related emesis and should be carefully considered in planning further studies.


[Molecular biological focus on stem cell research].
Stem cells are defined by their capacity to reproduce themselves and to differentiate into many other cell types. Differentiation requires external signals and involves activation of a small number of genes. Which source of stems cell will eventually be used in the clinic has not yet been determined. Embryonic stem cells have unlimited in vitro division capacity and can differentiate to all cell types, but there may be a problem with genomic instability. Stem cells from cord blood and adult tissue seem to have limited in vitro division and differentiation potential, but stable genomes.


Waist Circumference, Body Mass Index, and ESRD in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study.
The association between waist circumference and end-stage renal disease (ESRD) remains poorly explored. Longitudinal population-based cohort. Participants in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study (n=30,239) with information for body mass index (BMI), waist circumference, spot urine albumin-creatinine ratio (ACR), and estimated glomerular filtration rate (eGFR; n=26,960). Elevated waist circumference or BMI. Incident cases of ESRD were identified through linkage of REGARDS participants with the US Renal Data System. Mean baseline age was 64.8 years, 45.8% were men, and 40.3% were black. Overall, 297 (1.1%) individuals developed ESRD during a median of 6.3 years. After adjustment for all covariates including waist circumference, no significant association was noted between BMI categories and ESRD incidence compared to BMI of 18.5 to 24.9 kg/m2 (referent). Higher waist circumference categories showed significantly increased hazard rates of ESRD, with waist circumference ≥ 108 cm in women and ≥122 cm in men (highest category) showing a 3.97-fold higher hazard rate (95% CI, 2.10-6.86) for ESRD compared to waist circumference < 80 cm in women and <94 cm in men (referent) after adjusting for demographic factors and BMI. However, no significant association was noted between any waist circumference category and ESRD incidence after adjustment for obesity-associated comorbid conditions and baseline ACR and eGFR. Short follow-up period (6.3 years) to assess ESRD risk among adults with eGFRs>60 mL/min/1.73 m2. In this cohort of older adults, obesity as measured by waist circumference is associated with higher ESRD risk even with adjustment for BMI, whereas obesity as measured by BMI is not associated with higher ESRD risk after adjustment for waist circumference. However, no significant association is noted between increased waist circumference and ESRD risk after adjustment for obesity-related comorbid conditions, eGFR, and ACR.


Mapping drug physico-chemical features to pathway activity reveals molecular networks linked to toxicity outcome.
The identification of predictive biomarkers is at the core of modern toxicology. So far, a number of approaches have been proposed. These rely on statistical inference of toxicity response from either compound features (i.e., QSAR), in vitro cell based assays or molecular profiling of target tissues (i.e., expression profiling). Although these approaches have already shown the potential of predictive toxicology, we still do not have a systematic approach to model the interaction between chemical features, molecular networks and toxicity outcome. Here, we describe a computational strategy designed to address this important need. Its application to a model of renal tubular degeneration has revealed a link between physico-chemical features and signalling components controlling cell communication pathways, which in turn are differentially modulated in response to toxic chemicals. Overall, our findings are consistent with the existence of a general toxicity mechanism operating in synergy with more specific single-target based mode of actions (MOAs) and provide a general framework for the development of an integrative approach to predictive toxicology.


Nonocclusive mesenteric ischaemia: think about it.
Nonocclusive mesenteric ischaemia (NOMI) is an acute mesenteric circulatory disorder that is not caused by an organic occlusion of blood vessels. It could involve all the abdominal parenchymas and viscera and the whole gastrointestinal tract (from the oesophagus to the rectum), insomuch that the involvement of the entire colon should be considered a distinctive tract in diagnosing this condition in respect of the occlusive forms of ischaemia. The aim of this article is to review the role of imaging in the diagnosis of NOMI and in particular its CT appearances. Recognition of the characteristic CT appearances and the variations associated with a reperfusion event may help in the accurate interpretation of CT in the diagnosis and management of NOMI.


Mechanical response properties of nociceptors innervating feline hairy skin.
1. The responses of feline cutaneous nociceptors were examined in vivo by systematically manipulating the intensive and spatial dimensions of mechanical stimulation. A computer-controlled motor was used to apply prescribed forces (5-90 g) to a nociceptor's receptive field, with flat-tipped, cylindrical probes of various sizes (contact areas: 0.1-5.0 mm2). The stimulating device and protocols were similar to those previously used to evaluate human perception, thus allowing for comparisons of the two data sets. 2. With a ramp-and-hold stimulus of controlled force, most nociceptors showed a slowly adapting (SA) response throughout the stimulus. In this way, nociceptors resembled low-threshold SA mechanoreceptors. However, in contrast to SA mechanoreceptors, nociceptors failed to exhibit an onset burst of activity associated with the stimulus ramp. Nineteen percent (6 of 31) of the nociceptors often showed the opposite trend during the stimulus, e.g., a gradually increasing firing rate. Most of these nociceptors (5 of 6) had particularly high mechanical thresholds. 3. With 30 stimuli repeated at short intervals (6-8 s), response rates tended to decrease across trials. This phenomenon was most evident with more intense stimuli. When two series of stimuli were separated by 4-5 min, there was no apparent trend of reduced responsiveness between series. 4. Overall, nociceptors responded in an orderly way to variations in force and probe size. For a given probe size, larger forces produced greater responses; for a given force, smaller probes produced greater responses. The relationship between probe size and force was best described as an even tradeoff between force and a linear dimension of the probe (i.e., probe perimeter), rather than the area of the probe. Thus a given pressure (force/area) did not evoke the same response from nociceptors as probe size was varied. 5. There were two significant differences in the mechanical responsiveness between A fiber and C fiber nociceptors. First, for a given set of stimuli, A fiber nociceptors exhibited a greater response rate than the C fiber nociceptors. Second, the A fiber nociceptors exhibited a greater differential response related to probe size than the C fiber nociceptors. On the basis of these two features, the A fiber nociceptors' response profiles showed a closer parallel with previously reported human pain thresholds than the C fiber nociceptors did. 6. When the nociceptors were subdivided as to their mechanical threshold, those with lower thresholds [mechanically sensitive afferents (MSAs)] showed a response saturation with the more intense stimuli. On average, the stimulus levels at which saturation occurred were close to human pain threshold. Those nociceptors with higher thresholds [mechanically insensitive afferents (MIAs)] did not show such saturation. Thus only the MIAs appeared to have the capacity to unambiguously encode mechanical stimulus intensities above pain threshold. The MSAs, on the other hand, exhibited their greatest dynamic response range near the threshold for nonpainful sharpness. Thus the group of afferents commonly defined as nociceptors exhibit a heterogeneity of mechanical response properties, which may serve functionally different roles for perception.


The tissue-based triad: a process approach to augmentation mastopexy.
Among the most exigent operations in plastic surgery is the combination of augmentation and mastopexy. The surgical challenge is related to oppositional forces that complicate the operative predictability. The purpose of this study was to investigate use of the tissue-based triad process approach in patients undergoing augmentation mastopexy. Measured components of the approach include skin stretch, nipple to inframammary fold distance on maximal stretch, and vertical excess. Patients were selected for the study if they had been treated with one- or two-stage augmentation mastopexy, or mastopexy alone. Data gathered included preoperative measurements, operative details, complications, and outcomes including reoperation rate. A total of 176 consecutive patients were identified as meeting study inclusion criteria. Mean follow-up was 1.5 years. Seventy-one of 176 patients underwent mastopexy alone. Of the 176 patients included, 105 were treated with augmentation mastopexy. Ninety-one of 105 augmentation mastopexy operations were performed in one stage. The average amount of vertical excess was 5 cm. Nine patients exhibited delayed wound healing, while six (6.5 percent) required reoperations for scar revision (n=1), delayed wound healing requiring revision (n=2), hematoma (n=1), seroma (n=1), and soft-tissue stretch (n=1). Fourteen of 105 patients were treated in two stages. Average vertical excess was 7.5 cm. Use of the tissue-based triad process approach provided objectivity in determining which patients should undergo one- versus two-stage augmentation mastopexy. Use of this approach helps guide surgical decision making and is associated with lower reoperation rates. Therapeutic, IV.


Alzheimer's disease: making the diagnosis.
Alzheimer's disease accounts for about 60 percent of dementia cases. Misdiagnosis of the treatable dementias can have devastating results. Pseudodementia accompanying major depression and chronic cognitive dysfunction due to psychoactive drugs are among the most commonly missed diagnoses. Although cortical atrophy is regularly found on computed tomographic scans in Alzheimer's disease, it is not necessarily diagnostic. A relatively distinct onset of cognitive impairment is not characteristic of Alzheimer's disease.


Fluorescence and Ultrafast Fluorescence Unveil the Formation, Folding Molecularity, and Excitation Dynamics of Homo-Oligomeric and Human Telomeric i-Motifs at Acidic and Neutral pH.
i-Motifs are tetraplex DNAs known to be stable at acidic pH. The structure of i-motifs is important in DNA nanotechnology; i-motif-forming sequences with consecutive cytosine (C) molecules are abundant throughout the human genome. There is, however, little information on the structure of C-rich DNAs under physiologically relevant neutral conditions. The electron dynamics of i-motifs, crucial to both biology and materials applications, also remains largely unexplored. In this work, we report a combined femtosecond and nanosecond broadband time-resolved fluorescence (TRF) and steady-state fluorescence investigation on homo-oligomer dC20 , a human telomeric sequence (HTS) 5'-dC3 (TA2 C3 )3 , and its analogue performed with different excitation at both acidic and neutral pH. Our study provides direct observation of intrinsic fluorescence and the first full probe of the real-time dynamics of the intrinsic fluorescence from i-motifs formed from varied sequences and pH conditions. The results obtained demonstrate concrete evidence for the existence at neutral pH of i-motifs from both dC20 and the HTS. It also identifies that, under neutral conditions, the i-motif from dC20 adopting the bimolecular folding structure is significantly more stable than the HTS i-motif featuring the unimolecular topology. Our femtosecond and nanosecond TRF study unveils excitation dynamics distinctive of the interdigitated architecture of i-motifs with the excited states involved exhibiting deactivation over a remarkably broad timescale through multiple channels involving proton-coupled electron transfer lasting tens of picoseconds, as signified by the solvent kinetic isotope effect, and structure-dependent charge recombination in the hundreds of picoseconds to tens of nanoseconds time regime.