Growth of Avena coleoptiles and pH drop of protoplast suspensions induced by chlorinated indoleacetic acids.
Several indoleacetic acids, substituted in the benzene ring, were compared in the Avena straight growth bioassay. 4-Chloroindoleacetic acid, a naturally occurring plant hormone, is one of the strongest hormones in this bioassay. With an optimum at 10(-6) mol l(-1), it is more active than indoleacetic acid, 2,4-dichlorphenoxyacetic acid and naphthaleneacetic acid. 5-Chloro- and 6-chloroindoleacetic acids are very strong auxins as well. Other derivatives tested have a lower activity. 5,7-Dichloro- and 5-hydroxyindoleacetic acids have very low auxin activity at 10(-4) mol l(-1) and may be anti-auxins. Some of the derivatives were compared for their effect on pH decline in stem protoplast suspensions of Helianthus annuus L. and Pisum sativum L. The change of pH occurs without a lag period or with only a very short one. Derivatives which are very active in the Avena straight growth assay cause a larger pH decline than indoleacetic acid, while inactive derivatives cause effectively no pH decline.


Expression of profibrotic mediators in small airways versus parenchyma after cigarette smoke exposure.
Cigarette smoke-induced lung disease presents a morphologic contradiction in that the small airways become fibrotic but the parenchyma becomes emphysematous over time. To examine the mechanisms behind these phenomena, we exposed mice to cigarette smoke for up to 6 months and isolated small airways from histologic sections by laser capture microdissection. We then removed residual airway tissue and vessels, and collected the remaining parenchymal tissue. Gene expression of 13 fibrogenic growth/signaling factors (particularly TGF-beta-related genes), matrix proteins, or enzymes involved in matrix production was examined by real-time RT-PCR. Combining present and previously published data from our laboratory, in the airways over the long term there was a sustained and marked increase in expression of almost all of these genes. By contrast, in the parenchyma, expression of most genes was elevated at 2 and 24 hours after initial exposure, and all were elevated at 1 month; but by 6 months, when emphysema was present, most genes (9/13) were either at control values or down-regulated below control. At 3 months, several genes that were considerably elevated at 1 month were back to control levels, suggesting that loss of the parenchymal response precedes the development of emphysema. We conclude that with smoke exposure the airways demonstrate an ongoing profibrotic/proelastogenic response and the parenchyma a generally anti-fibrotic/anti-elastogenic response, but one that develops only with long-term exposure to smoke. These observations support the idea that the parenchyma largely fails to repair smoke-induced matrix damage, but this phenomenon is a relatively late event.


Proteomics studies of childhood pilocytic astrocytoma.
Childhood pilocytic astrocytoma is the most frequent brain tumor affecting children. Proteomics analysis is currently considered a powerful tool for global evaluation of protein expression and has been widely applied in the field of cancer research. In the present study, a series of proteomics, genomics, and bioinformatics approaches were employed to identify, classify and characterize the proteome content of low-grade brain tumors as it appears in early childhood. Through bioinformatics database construction, protein profiles generated from pathological tissue samples were compared against profiles of normal brain tissues. Additionally, experiments of comparative genomic hybridization arrays were employed to monitor for genetic aberrations and sustain the interpretation and evaluation of the proteomic data. The current study confirms the dominance of MAPK pathway for the childhood pilocytic astrocytoma occurrence and novel findings regarding the ERK-2 expression are reported.


Evaluation of the temporally extrapolated absorbance method for dual-wavelength imaging through tissuelike scattering media.
An independent assessment is described of a dual-wavelength imaging technique, known as the temporally extrapolated absorbance method (TEAM), proposed by Yamada et al. [Opt. Eng. 32, 634-641 (1993)]. The technique involves recording the temporal distribution of light transmitted across a scattering medium at two carefully chosen wavelengths at which the scattering properties of the medium are assumed to be identical. The objective is to image internal structure that absorbs more strongly at one wavelength than it does at the other. A simple theoretical treatment of TEAM is presented that employs a perturbation model of photon transport. This indicates that despite the lack of a secure theoretical basis, the technique may provide a potentially effective ad hoc method of generating images of highly scattering media. The method was also evaluated experimentally by using, for the first time to our knowledge, a single object and two wavelengths. A single-projection, two-dimensional image was obtained of a solid phantom with optical properties representative of breast tissue. The results exhibited good agreement with the theoretical model, and a small embedded feature that absorbs 3.5 times as strongly as the surrounding medium at one wavelength was revealed successfully.


Development of a Novel, Genome Subtraction-Derived, SARS-CoV-2-Specific COVID-19-nsp2 Real-Time RT-PCR Assay and Its Evaluation Using Clinical Specimens.
The pandemic novel coronavirus infection, Coronavirus Disease 2019 (COVID-19), has affected at least 190 countries or territories, with 465,915 confirmed cases and 21,031 deaths. In a containment-based strategy, rapid, sensitive and specific testing is important in epidemiological control and clinical management. Using 96 SARS-CoV-2 and 104 non-SARS-CoV-2 coronavirus genomes and our in-house program, GolayMetaMiner, four specific regions longer than 50 nucleotides in the SARS-CoV-2 genome were identified. Primers were designed to target the longest and previously untargeted nsp2 region and optimized as a probe-free real-time reverse transcription-polymerase chain reaction (RT-PCR) assay. The new COVID-19-nsp2 assay had a limit of detection (LOD) of 1.8 TCID50/mL and did not amplify other human-pathogenic coronaviruses and respiratory viruses. Assay reproducibility in terms of cycle threshold (Cp) values was satisfactory, with the total imprecision (% CV) values well below 5%. Evaluation of the new assay using 59 clinical specimens from 14 confirmed cases showed 100% concordance with our previously developed COVID-19-RdRp/Hel reference assay. A rapid, sensitive, SARS-CoV-2-specific real-time RT-PCR assay, COVID-19-nsp2, was developed.


Phyllodes Tumor of Anogenital Mammary-like Glands with Diffuse Pseudoangiomatous Stromal Hyperplasia.
Anogenital mammary-like glands may give rise to various pathologic lesions identical to those known in mammary pathology. Tumor occurring in the anogenital region is extremely rare. The histogenetic origin of this tumor is controversial as it is being debated whether such lesions evolve from ectopic breast tissue and most recently, anogenital mammary-like gland. We report a 28-year-old girl who presented with a painless mass in the anogenital region, which was subsequently excised. Microscopic examination revealed morphologic pattern characteristic of benign phyllodes tumor with pseudoangiomatous stromal hyperplasia. We present this case to emphasize the importance of recognizing this uncommon lesion occurring at an extremely unusual site. We also discuss the histogenesis of phyllodes tumor and related lesions occurring in the anogenital region in light of the current literature along with a brief review of the previously reported cases of anogenital mammary-like glands.


[Differentiation of cells and organs from the point of view of the second law of thermodynamics and the "protein-machine" concept].
Differentiation of cells and organs arises on the basis of excessiveness at thermodynamically stable process of DNA synthesis as a thermodynamic system with a great relaxation time and alternative number for degrees of freedom. Entropy normalization for DNA is controlled by the exterior effects for DNA causing a thermodynamic unstable (quick) process of protein synthesis. While DNA is interacting with the medium, this process is stabilized not by a priori information which, probably, presupposes this in DNA, but by the ecologic recess inside the cell. The chain of reverse effect assumes transmission of DNA degrees of freedom of controlling effects not only from its neighboring environment, but both from the cell and the organism as a whole. A possibility of accidental occurrence in the natural selection is defined both by the above and the specification of the state equations for DNA which determines relative limitation of variants synthesized with its participation of key reaction groups in proteins. Evolution has no aim, but the principle of filling the ecologic recess creates an apparent expediency that does not differ from the presupposed one. The question--why are the state equations for DNA of this type--ultimately resolves itself into the question why the inner structure of a nucleus is of the kind it exists, i.e., at present it is beyond the possibility of scientific analysis. But with the existing equations of state the leading reason of differentiation for cells and organs is the second thermodynamics principle as tending to maximal chaos limited by the internal and external conditions.


Simple and complex nuclear loci created by newly transferred chloroplast DNA in tobacco.
Transfer of organelle DNA into the nuclear genome has been significant in eukaryotic evolution, because it appears to be the origin of many nuclear genes. Most studies on organelle DNA transfer have been restricted to evolutionary events but experimental systems recently became available to monitor the process in real time. We designed an experimental screen to detect plastid DNA (ptDNA) transfers to the nucleus in whole plants grown under natural conditions. The resultant genotypes facilitated investigation of the evolutionary mechanisms underlying ptDNA transfer and nuclear integration. Here we report the characterization of nuclear loci formed by integration of newly transferred ptDNA. Large, often multiple, fragments of ptDNA between 6.0 and 22.3 kb in size are incorporated into chromosomes at single Mendelian loci. The lack of chloroplast transcripts of comparable size to the ptDNA integrants suggests that DNA molecules are directly involved in the transfer process. Microhomology (2-5 bp) and rearrangements of ptDNA and nuclear DNA were frequently found near integration sites, suggesting that nonhomologous recombination plays a major role in integration. The mechanisms of ptDNA integration appear similar to those of biolistic transformation of plant cells, but no sequence preference was identified near junctions. This article provides substantial molecular analysis of real-time ptDNA transfer and integration that has resulted from natural processes with no involvement of cell injury, infection, and tissue culture. We highlight the impact of cytoplasmic organellar genome mobility on nuclear genome evolution.


Biochemical characterization of mapmodulin, a protein that binds microtubule-associated proteins.
Mapmodulin is a 31-kDa protein that stimulates the microtubule- and dynein-dependent localization of Golgi complexes in semi-intact Chinese hamster ovary cells. We have shown previously that it binds the microtubule binding domains of the microtubule-associated proteins, MAP2, MAP4, and tau. We also showed that mapmodulin is identical to a protein named PHAPI (Vaesen, M., Barnikol-Watanabe, S. , Götz, H., Awni, L.A., Cole, T., Zimmermann, B., Kratzin, H.D. and Hilschmann, N. (1994) Biol. Chem. Hoppe-Seyler 375, 113-126). We report here that mapmodulin is a phosphoprotein that is predominantly cytosolic but is also found peripherally associated with endoplasmic reticulum and Golgi membranes in mammalian cells. The protein occurs as a trimer in cytosol, and phosphorylation is required for its microtubule-associated protein-binding activity. Heat treatment of nonphosphorylated mapmodulin can render it competent for binding to microtubule-associated proteins, suggesting that phosphorylation induces a conformational change in mapmodulin. Finally, despite identity in polypeptide sequence with a protein reported to act as an inhibitor of protein phosphatase 2A, native mapmodulin was not able to inhibit protein phosphatase 2A in Chinese hamster ovary cell cytosol.


Leuconostoc ficulneum sp. nov., a novel lactic acid bacterium isolated from a ripe fig, and reclassification of Lactobacillus fructosus as Leuconostoc fructosum comb. nov.
An isolate, designated strain FS-1T, was recovered from a ripe fig. Phylogenetic analysis of the 16S rRNA genes and DNA-DNA reassociation values showed that the organism represented a novel species of the genus Leuconostoc closely related to Lactobacillus fructosus. The novel isolate could be distinguished from the type strain of Lactobacillus fructosus by the fatty acid composition and several phenotypic and growth characteristics. In strain FS-1T, 18:1 delta9 (18:1omega9c) was present in relatively large amounts whilst, in Lactobacillus fructosus, this fatty acid was a minor component. Strain FS-1T and Lactobacillus fructosus produced acid in API 50CHL microtubes from glucose, fructose and mannitol within 48 h, whereas only strain FS-1T also fermented trehalose, gluconate, turanose and sucrose after 48 h. Other differences in acid production from carbohydrates also distinguished strain FS-1T from Lactobacillus fructosus. Both organisms were heterofermentative with fructose as a substrate and fermented glucose only in the presence of fructose, as determined by nuclear magnetic resonance studies. Strain FS-1T was catalase-positive. On the basis of the phylogenetic analysis, DNA-DNA reassociation values, physiological and biochemical characteristics and fatty acid composition, the name Leuconostoc ficulneum is proposed for the novel species represented by strain FS-1T, and it is proposed that Lactobacillus fructosus be reclassified in the genus Leuconostoc as Leuconostoc fructosum comb. nov.


Reduction of referral to assessment time for an older adults community mental health team.
Anecdotal evidence suggested that waiting times within the older adults community mental health team (OA CMHT) had been increasing over time. An assessment and evaluation was indicated to ensure best quality care was provided for patients. A comparison was made between waiting times in January to December 2011 compared with August 2013 to July 2014. In 2011 the mean number of days until initial assessment from the point of referral was 12 days for routine cases, and 3.6 days for urgent cases. The re-audit showed the number of days increased to 15.89 days for routine cases, and 9.81 days for urgent cases. Contributory factors were reviewed, and it was felt that to address this problem, a duty worker role was necessary. The role of the duty worker was divided into triaging and allocating work. The triaging process was to ensure all urgent cases were highlighted early and acted upon. The duty worker's role was also to gather sufficient information from the referrer, to reduce the risks of inadequate knowledge delaying assessment. In addition, the allocating process required the duty worker to designate a clinician in charge of the case upon receipt of referral. This ensured that clinicians were able to offer the earliest possible appointment slot for the initial assessment, and thus reduce waiting times. Following implementation, findings from September 2014 to February 2015 showed an improvement in average waiting times, as well as an improvement in the percentage of assessments reviewed within previously set standards. For routine reviews, the mean time until assessment was 10.68 days. For urgent reviews, the mean time until initial assessment was 6.8 days. However, it was noted that majority of urgent reviews were still not being reviewed in time. The outcomes of this study demonstrated an improvement of both waiting times, and percentage of patients being seen within set standards following a single intervention. In the current climate of cost efficiency savings, it is important for services to continue to find ways to streamline and improve upon current practices, to ensure the best outcome for patients.


Isolated cortical vein thrombosis after epidural anesthesia: report of three cases.
Cerebral venous thrombosis rarely develops after lumbar puncture and spinal anesthesia with accidental dural puncture, however, occurrence of isolated cortical vein thrombosis after epidural anesthesia is extremely rare. We report three cases who developed postural headache and isolated cortical vein thrombosis after epidural anesthesia. We postulate that intracranial hypotension is the cause of compensatory venous dilatation and resultant thrombosis.


Effects of neonatal methylmercury exposure on adrenergic receptor binding sites in peripheral tissues of the developing rat.
Neonatal exposure to methylmercury produces changes in patterns of tissue growth and function, in part, due to alterations in adrenergic neuronal input. To explore the mechanisms by which these changes come about, newborn rats were exposed to methylmercury (1 or 2.5 mg/kg per day) throughout the preweaning stage and the ontogeny of adrenergic receptor binding sites evaluated in liver, kidney, heart and lung, using [3H]prazosin (alpha 1-receptors), [3H]rauwolscine (alpha 2-receptors) and [125I]pindolol (beta-receptors). In the kidney, methylmercury caused decreases in beta- and alpha 1-receptor binding and increases in alpha 2-binding; previous work has shown that beta-receptor-mediated responses are generally enhanced in methylmercury-exposed pups, and the down-regulation of beta-receptor binding thus probably represents a compensatory action secondary to alterations in post-receptor coupling mechanisms. The effects of methylmercury on hepatic adrenergic receptors were different from those seen in the kidney, with substantial elevations in beta- and alpha 1-receptor binding apparent in the preweaning stage; this agrees also with the differences in effects of the mercurial on trophic reactivity and growth in the 2 tissues. Despite the fact that methylmercury causes activation of neonatal cardiac sympathetic nerves, beta-receptor binding sites in the heart were unaffected by methylmercury exposure; the failure to down-regulate cardiac postsynaptic receptors in the face of increased nerve activity again represents an anomaly of synaptic regulatory function. These results indicate that methylmercury alters adrenergic responsiveness, in part, through actions on the development of receptor binding sites, and further, that the organ-specificity and receptor subtype-selectivity are consistent with subsequent effects of the organomercurial on adrenergic participation in target organ growth; however, changes in receptor binding alone do not account for all of the effects of methylmercury on synaptic activity or trophic responses.


[Use of fibrin glue in pulmonary surgery].
The article deals with the experimental data on the use of the "Beriplast" (GFR) and phi K-1 (USSR) fibrin glue (FG) for providing hemostasis and hermetization of the resected surface of the lung. The results were evaluated during the operation by the method of pneumopressure and by means of morphological studies. The "Beriplast" FG was applied in the clinic for aerostasis in incomplete +hermetization of the sutured pulmonary wound in 11 patients. Complete +hermetization was produced in all cases. Complications linked with the use of FG were not encountered.


Colonic changes in patients with cirrhosis and in patients with extrahepatic portal vein obstruction.
Figures for the prevalence of anorectal varices and portal hypertensive colopathy have varied considerably in the available studies of patients with cirrhosis, and few studies have observed these changes in patients with extrahepatic portal vein obstruction (EHPVO). Our aim was to investigate the colonic changes, if any, in patients with EHPVO and to compare them with those seen in patients with cirrhosis of the liver. A total of 50 patients with cirrhosis and 35 patients with EHPVO, all of whom had a history of at least one episode of bleeding from esophageal varices, underwent both upper gastrointestinal endoscopy and colonoscopy. Anorectal varices were seen more commonly in patients with EHPVO than in patients with cirrhosis (63 % vs. 38 %, P < 0.03). Of the patients with anorectal varices, large anorectal varices were also more common in patients with EHPVO than in patients with cirrhosis (73 % vs. 32 %, P < 0.01). Colopathy was noted in 40 % of patients with EHPVO and in 62 % of patients with cirrhosis (P < 0.05). Of the patients with EHPVO, colopathy was noted in 27 % of patients who also had anorectal varices and in 61.5 % of patients without anorectal varices (P < 0.05). Similarly, patients with both cirrhosis and anorectal varices were found to have a lower prevalence of colopathy than cirrhotic patients without anorectal varices (42 % vs. 74 %, P < 0.03). Anorectal varices are more common in patients with EHPVO, while portal hypertensive colopathy is more common in patients with cirrhosis. Large anorectal varices are also more common in patients with EHPVO than in patients with cirrhosis and there is an inverse relationship between anorectal varices and colopathy in both cirrhotic patients and patients with EHPVO.


Nursing habits and dental decay in infants: "nursing bottle caries".
The decay-producing capabilities of certain foods can be influenced by eating habits. When a habit of frequent nocturnal bottle or breast feeding is maintained beyond a year of age, the potential for gross dental decay in very young children is established. Bovine milk, milk formulas and human breast milk have all been implicated in the condition of "nursing bottle caries," because of their lactose content. Additional sweeteners in the nursing bottle, the use of fruit juices or the use of honey-dipped pacifiers can also cause "nursing bottle caries." "Nursing bottle caries" can be prevented through a timely educational program to new parents. Prevention is particularly applicable in young children, since a healthy oral condition promotes good nutrition, a healthy state and normal growth. Both the American Dental Association and the American Society of Dentistry for Children have pamphlets explaining "nursing bottle caries," which are available for distribution to the public.


Segregation effects on the properties of (AuAg)₁₄₇.
AuAg nanoclusters are promising supported co-catalysts for photocatalytic hydrogen reduction. However, beyond the quantum regime (N > 100) little is known about how the electronic properties of these nanoparticles are affected by chemical ordering. We investigate the effects of chemical ordering on the properties of 147-atom cuboctahedral AuAg nanoclusters, using empirical potentials coupled with an atomic-swap basin-hopping search to optimise the elemental distribution, with the lowest energy arrangements then reminimised using Density Functional Theory (DFT). Force-field calculations show Au atoms preferentially occupy sub-surface positions in the bimetallic structures, which results in the formation of a pseudo-onion structure for Ag-rich compositions. At the DFT-level, however, an Ag core surrounded by an Au shell (Ag@Au) is energetically favoured, as electron density can be drawn more readily when Au atoms are positioned on the nanocluster surface, thus resulting in a partial negative charge. Core@shell configurations are analogous to structures that can be chemically synthesised, and further detailed electronic analysis is discussed in the context of nanocluster applications to co-catalysed photocatalysis.


A perioculomotor nitridergic population in the macaque and cat.
We determined the distribution of cells containing synthetic enzymes for the unconventional neurotransmitter, nitric oxide, with respect to the known populations within the oculomotor complex. The oculomotor complex was investigated in monkeys and cats by use of histochemistry to demonstrate nicotinamide adenine dinucleotide phosphate diaphorase positive (NADPHd(+)) cells and antibodies to localize neuronal nitric oxide synthase positive (NOS(+)) cells. In some cases, wheat germ agglutinin conjugated horseradish peroxidase (WGA-HRP) was injected into extraocular muscles to allow comparison of retrogradely labeled and NADPHd(+) cell distributions. The distribution of the NADPHd(+) and NOS(+) neurons did not coincide with that of preganglionic and extraocular motoneurons in the oculomotor complex. However, labeled perioculomotor neurons were observed. Specifically, in monkeys, they lay in an arc that extended from between the oculomotor nuclei into the supraoculomotor area (SOA). Comparison of WGA-HRP-labeled medial and superior rectus motoneurons with NADPHd staining confirmed that the distributions overlapped, but showed that the C- and S-group cells were not NADPHd(+). This suggested that NADPHd(+) cells are part of the centrally projecting Edinger-Westphal population (EWcp). Examination of the NADPHd(+) cell distribution in the cat showed that these cells were indeed found primarily within its well-defined EWcp. Based on their similar distributions, it appears that the peptidergic EWcp neurons, which project widely in the brain, also may be nitridergic. While the preganglionic and C- and S-group motoneuron populations do not use this nonsynaptic neurotransmitter, nitric oxide produced by surrounding NADPHd(+) cells may modulate the activity of these motoneurons.


Current Outcomes of Anti-VEGF Therapy in the Treatment of Macular Oedema Secondary to Branch Retinal Vein Occlusions: A Meta-Analysis.
The current body of evidence on the efficacy and safety of anti-VEGFs for macular oedema secondary to branch retinal vein occlusion (BRVO) is steadily growing as large clinical trials and observational studies are continually completed. The aim of this meta-analysis is to analyse anatomical and functional outcomes in response to anti-VEGF therapy using evidence generated from a pooled analysis of current clinical trials and observational studies. The current meta-analysis includes treatment of BRVO with aflibercept, bevacizumab and ranibizumab from randomised controlled trials and observational studies. Inclusion criteria included peer-reviewed publications with at least a 12-month follow-up period. On literature review using multiple electronic databases (PubMed, Embase and Cochrane), 22 studies met the inclusion criteria. Baseline patient characteristics, study design, sample size and 12- and 24-month change in best corrected visual acuity (BCVA) and central foveal thickness (CFT) as measured on optical coherence tomography imaging were pooled in a meta-analysis. Data were then stratified by study design and anti-VEGF therapy in subgroup analyses. A total of 1,236 eyes from 22 studies were included in this meta-analysis. Mean baseline BCVA ranged from 66 ETDRS letters (20/50 Snellen equivalent) to 35 letters (20/200 Snellen). Mean baseline CFT ranged from 406.0 to 681.0 µm. Anti-VEGF treatment demonstrated an overall mean improvement in BCVA at 12 months of 14 letters (95% CI 12.0 to 16.2, p < 0.001) and CFT reduction of 228 µm (95% CI -278.9 to -176.1, p < 0.001). The BCVA gains at 12 months were maintained to month 24 with a mean gain of 12.5 letters (95% CI 6.3 to 18.8, p < 0.001), as well as reduction of CFT of 238 µm (95% CI -336.0 to -140.2, p < 0.001). No cases of endophthalmitis or glaucoma were reported in any study. This meta-analysis confirms the comparable safety and efficacy of anti-VEGF therapies for patients with cystoid macular oedema secondary to BRVO. There is a need for randomised prospective comparative trials of anti-VEGF agents for BRVO.


Phenome-wide investigation of health outcomes associated with genetic predisposition to loneliness.
Humans are social animals that experience intense suffering when they perceive a lack of social connection. Modern societies are experiencing an epidemic of loneliness. Although the experience of loneliness is universally human, some people report experiencing greater loneliness than others. Loneliness is more strongly associated with mortality than obesity, emphasizing the need to understand the nature of the relationship between loneliness and health. Although it is intuitive that circumstantial factors such as marital status and age influence loneliness, there is also compelling evidence of a genetic predisposition toward loneliness. To better understand the genetic architecture of loneliness and its relationship with associated outcomes, we extended the genome-wide association study meta-analysis of loneliness to 511 280 subjects, and detect 19 significant genetic variants from 16 loci, including four novel loci, as well as 58 significantly associated genes. We investigated the genetic overlap with a wide range of physical and mental health traits by computing genetic correlations and by building loneliness polygenic scores in an independent sample of 18 498 individuals with EHR data to conduct a PheWAS with. A genetic predisposition toward loneliness was associated with cardiovascular, psychiatric, and metabolic disorders and triglycerides and high-density lipoproteins. Mendelian randomization analyses showed evidence of a causal, increasing, the effect of both BMI and body fat on loneliness. Our results provide a framework for future studies of the genetic basis of loneliness and its relationship to mental and physical health.


Optically pumped Floquet states of magnetization in ferromagnets.
Floquet states have been the subject of great research interest since Zel'dovich's pioneering work on the quasienergy of a quantum system influenced by a temporally periodic action. Nowadays, periodic modulation of the system Hamiltonian is achieved mostly by microwaves, leading to novel exciting phenomena in condensed matter physics. On the other hand, nonthermal optical control of magnetization at picosecond time scales is currently a highly appealing research topic for potential applications in magnetic data storage. Here we combine these two concepts to theoretically investigate Floquet states in the system of exchange-coupled spins in a ferromagnet. Periodic perturbation of the magnetization of an iron-garnet film by circularly polarized femtosecond laser pulses is shown to establish the magnetization dynamics behaving like Floquet states. An external magnetic field allows tuning of the Floquet states, leading to pronounced increase in the precession amplitude by one order of magnitude at the center of the Brillouin zone, i.e., when the precession frequency is a multiple of the laser pulse repetition rate. Floquet states might potentially allow for parametric generation of magnetic oscillations. The observed phenomena expand the capabilities of coherent ultrafast optical control of magnetization and pave the way for their application in quantum computation or data processing.


Effect of prosthetic design on center of pressure excursion in partial foot prostheses.
Investigations into the gait of persons with partial foot amputation (PFA) suggest that the effective foot length can be restored when the prosthesis incorporates a relatively stiff forefoot, restricts dorsiflexion, and includes a mechanism whereby forces caused by loading the toe lever can be comfortably distributed to the leg (e.g., an anterior tibial shell). The purpose of this investigation was to systematically alter these variables to understand which design elements are responsible for restoration of the effective foot length. By manipulating features of the prosthesis design in two persons with PFA, we demonstrated using three-dimensional motion analysis that the prosthesis must incorporate each of these design elements to restore the effective foot length. When these design elements were used in concert, the persons with PFA adopted a gait pattern more consistent with nondisabled persons. Further work is required on a larger cohort to ensure the observations are generalizable.


Structure learning in human sequential decision-making.
Studies of sequential decision-making in humans frequently find suboptimal performance relative to an ideal actor that has perfect knowledge of the model of how rewards and events are generated in the environment. Rather than being suboptimal, we argue that the learning problem humans face is more complex, in that it also involves learning the structure of reward generation in the environment. We formulate the problem of structure learning in sequential decision tasks using Bayesian reinforcement learning, and show that learning the generative model for rewards qualitatively changes the behavior of an optimal learning agent. To test whether people exhibit structure learning, we performed experiments involving a mixture of one-armed and two-armed bandit reward models, where structure learning produces many of the qualitative behaviors deemed suboptimal in previous studies. Our results demonstrate humans can perform structure learning in a near-optimal manner.


Comprehensive Intrinsic Disorder Analysis of 6108 Viral Proteomes: From the Extent of Intrinsic Disorder Penetrance to Functional Annotation of Disordered Viral Proteins.
Much of our understanding of proteins and proteomes comes from the traditional protein structure-function paradigm. However, in the last 2 decades, both computational and experimental studies have provided evidence that a large fraction of functional proteomes across different domains of life consists of intrinsically disordered proteins, thus triggering a quest to unravel and decipher protein intrinsic disorder. Unlike structured/ordered proteins, intrinsically disordered proteins/regions (IDPs/IDRs) do not possess a well-defined structure under physiological conditions and exist as highly dynamic conformational ensembles. In spite of this peculiarity, these proteins have crucial roles in cell signaling and regulation. To date, studies on the abundance and function of IDPs/IDRs in viruses are rather limited. To fill this gap, we carried out an extensive and thorough bioinformatics analysis of 283 000 proteins from 6108 reference viral proteomes. We analyzed protein intrinsic disorder from multiple perspectives, such as abundance of IDPs/IDRs across diverse virus types, their functional annotations, and subcellular localization in taxonomically divergent hosts. We show that the content of IDPs/IDRs in viral proteomes varies broadly as a function of virus genome types and taxonomically divergent hosts. We have combined the two most commonly used and accurate IDP predictors' results with charge-hydropathy (CH) versus cumulative distribution function (CDF) plots to categorize the viral proteins according to their IDR content and physicochemical properties. Mapping of gene ontology on the disorder content of viral proteins reveals that IDPs are primarily involved in key virus-host interactions and host antiviral immune response downregulation, which are reinforced by the post-translational modifications tied to disorder-enriched viral proteins. The present study offers detailed insights into the prevalence of the intrinsic disorder in viral proteomes and provides appealing targets for the design of novel therapeutics.


[Role of smell in the food-seeking activity of newborn puppies].
In 36 newborn puppies, positive responses to the mother hair smell appear immediately after birth which indicates emanation of a corresponding pheromone. Within 6 hrs after isolation from the mother, the preference for her smell is reduced and substituted with a response to hair smell of other females. Learning of the motor to the mother smell seems to occur yet in prenatal period. The inherent negative response to cat's smell does not depend on the duration of the puppy isolation from the mother. During first 3 days of life (the 1st period), learning of the food-seeking response to an artificial smell is possible (imprinting). Starting from the 4th-5th day of life, the ability to form a food-seeking response to smell disappears. In 11-12 day old puppies, a conditioning can be achieved by means of combining smell with feeding 5-6 times. The role of olfaction in the puppy food-seeking behaviour during ontogenesis, is discussed.


Clinicopathological and Genetic Features of Supratentorial Cortical Ependymomas.
Supratentorial cortical ependymomas (CEs) are rare. These lesions, selectively occurring in the superficial cortex, have not been fully characterized. We analyzed the clinicopathological and genetic features of CEs. Eight patients with CEs from our institution and 84 other reported CE cases were included in the present study. We retrospectively reviewed their clinical characteristics, imaging findings, treatment methods, pathological features, molecular status, and clinical outcomes. The median age at diagnosis of our 8 patients was 7.5 years. The mean tumor diameter was 70 mm. All the tumors had a cystic appearance, and calcification was observed in 6. Gross total resection was achieved in 6 patients and subtotal resection in 2 patients. Of the 8 tumors, 7 were World Health Organization grade III and 1 was World Health Organization grade II. Six tumors were immunopositive for L1 cell adhesion molecule (L1CAM). We investigated the presence of C11orf95-RELA fusion in 5 patients, all of whom exhibited it. Postoperative radiotherapy was performed for all patients with grade III tumors, except for children aged <3 years. Although 4 patients developed recurrence, all were alive throughout the follow-up period. Compared with previously reported CEs, our patients were younger and had larger tumors; however, the clinical outcomes did not differ significantly. Although most CEs in our group were immunopositive for L1CAM and showed C11orf95-RELA fusion, which have been associated with a poor prognosis in supratentorial ependymomas, all our patients had good outcomes. Gross total resection and adjuvant radiotherapy contributed to the relatively favorable prognosis of CEs compared with other supratentorial ependymomas.


Improvement and optimization of standards for a preclinical animal test model of laser induced choroidal neovascularization.
As the murine model of laser-induced choroidal neovascularization (CNV) is becoming the most established and commonly utilized model worldwide for studying the pathogenesis of CNV and its response to treatment, specific operating standards are yet to be clarified. The purpose of this study is to compare the lesion size of CNV in mice with different ages, sex, durations of CNV process, and treated positions of laser spots, to make recommendations that may improve and optimize the quality of the model. C57/BL6 mice of different ages were treated with diode laser photocoagulation per eye and perfused with PBS containing fluorescein-labeled dextran at different time of observation. Choroid flat mounts, were then examined by fluorescence microscopy for the measurement of CNV area. Messenger-RNA expression levels of several angiogenic cytokines in eye cups of male and female C57BL/6 mice at 5-8 and 16-20 week-old were analyzed by real-time RT-PCR assay. The results showed significantly more CNV area in eyes of female mice compared to male mice with the expression level of several angiogenic cytokines elevated. 16-20-week-old female mice developed the biggest area of CNV. The mean area of CNV increased significantly at the 14th day after photocoagulation. Laser spots delivered 1PD away from the optic disc induced the biggest area of CNV compared to those 2PD or 3PD away. Interaction of NV was observed in laser spots delivered less than 1PD away from each other. The current results suggest that 16-20-week-old female C57BL/6 mice developed the most distinct CNV lesion size with laser spots delivered 1PD away from the optic disc. The best time to observe and analyze is the 14th day after photocoagulation.


Mechanism of inhibitory action of TMB-8 [8-(NN-diethylamino)octyl-3,4,5-trimethoxybenzoate] on aldosterone secretion in adrenal glomerulosa cells.
The mechanism of 8-(NN-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) action was evaluated in isolated adrenal glomerulosa cells. TMB-8 inhibits both angiotensin II- and K+-stimulated aldosterone secretion in a dose-dependent manner. The ID50 for angiotensin II- and K+-stimulated aldosterone secretion is 46 and 28 microM, respectively. In spite of the fact that 100 microM-TMB-8 inhibits angiotensin II-stimulated aldosterone secretion almost completely, TMB-8 (100 microM) does not inhibit angiotensin II-induced 45Ca2+ efflux from prelabelled cells nor does it affect inositol 1,4,5-trisphosphate-induced calcium release from non-mitochondrial pool(s) in saponin-permeabilized cells. TMB-8 has no inhibitory effect on A23187-induced aldosterone secretion, but 12-O-tetradecanoylphorbol 13-acetate-induced aldosterone secretion is completely abolished. TMB-8 effectively inhibits both angiotensin II- and K+-induced increases in calcium influx but has no effect on A23187-induced calcium influx. TMB-8 inhibits the activity of protein kinase C dose-dependently. These results indicate that TMB-8 inhibits aldosterone secretion without inhibiting mobilization of calcium from an intracellular pool. The inhibitory effect of TMB-8 is due largely to an inhibition of plasma membrane calcium influx, but this drug also inhibits the activity of protein kinase C directly.


Analysis of FK506-mediated protection in an organotypic model of spinal cord damage: heat shock protein 70 levels are modulated in microglial cells.
Functional loss after spinal cord injuries is originated by primary and secondary injury phases whose underlying mechanisms include massive release of excitatory amino acids to cytotoxic levels that contribute to neural death. Attenuation of this excitotoxicity is a key point for improving the functional outcome after injury. One of the drugs with potential neuroprotective actions is FK506, a molecule widely used as an immunosuppressant. FK506 may exert neuroprotection via inhibition of calcineurin by binding the FKBP12, or by binding other immunophilins such as FKBP52, leading to modulation of heat shock proteins (Hsp) 90 and 70. In the present study, we used an in vitro model of organotypic culture of rat spinal cord slices to assess whether FK506 is able to protect them against glutamate excitotoxicity. The results showed that FK506 promoted a significant protective effect on the spinal cord tissue at concentrations of 50 and 100 nM. Hsp70 induction was restricted to microglial cells in spinal cord slices treated with either glutamate or FK506. In contrast, the combination of both agents led to a transient reduction in Hsp70 levels in parallel to a marked reduction in IL-1beta precursor production by glial cells. The use of geldanamycin, which promotes persistent induction of Hsp70 in these cells as well as in motoneurons, did not produce tissue neuroprotection. These observations suggest that FK506 might protect spinal cord tissue by targeting on microglial cells and that transient downregulation of Hsp70 on these cells after excitotoxicity is a relevant mechanism of action of FK506.


Herpes simplex virus 2 meningitis: a retrospective cohort study.
Herpes simplex virus 2 is a leading cause of viral meningitis and the most commonly recognized infectious cause of benign, recurrent meningitis. We report a retrospective, observational cohort study of patients with herpes simplex virus type 2 (HSV-2) meningitis, confirmed by polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF). The terms "herpes simplex," "meningitis," or "encephalitis" were searched in the medical records system of the Mayo Clinic in Rochester, Minnesota (1995-2008). Patients were included if they had a clinical diagnosis of meningitis and HSV-2 detected by PCR in the CSF. There were 28 patients with 33 episodes identified (83 % female; mean age at presentation of meningitis 36 years, range 17-53; mean time to HSV2 detection from symptom onset 3 days, range 0-6; history of genital herpes 23 %). No patient took oral antiviral treatment at the time of presentation. Episodes were most likely to include headache (100 %), photophobia (47 %), self-reported fever (45 %), meningismus (44 %), and nausea and/or vomiting (29 %). CSF at the time of meningitis was notable for elevated protein (mean 156 g/dL, range 60-258) and white cell count (mean 504 cells/μL, range 86-1,860) with normal glucose (mean 54 mg/dL, range 32-80). Mollaret cells were never detected. Neuroimaging was most often normal (83 %) when performed, although some cases showed nonspecific (14 %) or meningeal changes (3 %). There was no consistent relationship to genital herpes. The duration of treatment with intravenous acyclovir ranged from 3 to 14 days for the first meningitic episode (daily dose range from 500 to 1,000 mg and total dose range from 500 mg q8h for 3 days to 800 mg q8h for 14 days). For subsequent episodes, the duration of treatment of intravenous acyclovir ranged from less than 1 to 14 days (total dose range from 1,390 mg for 1 day to 900 mg q8h for 10 days). The dose of valacyclovir ranged from 500 mg once daily to 500 mg four times daily. The median duration of valacyclovir treatment following the first episode was 10 days (range 3 to 14 days, n = 13). The median duration of valacyclovir treatment following a subsequent meningitic episode was 9 days (range 7 days to indefinite period, n = 9). No patient was reported to have seizures, neurological disability, or death in extended follow-up (mean follow-up 3.4 years). Recurrence of meningitic symptoms was not universal.


Paying for individual health insurance through tax-sheltered cafeteria plans.
When employees without group health insurance buy individual coverage, they do so using after-tax income--costing them from 20% to 50% more than others pay for equivalent coverage. Prior to the passage of the Patient Protection and Affordable Care Act (PPACA), several states promoted a potential solution that would allow employees to buy individual insurance through tax-sheltered payroll deduction. This technical but creative approach would allow insurers to combine what is known as "list-billing" with a Section 125 "cafeteria plan." However, these state-level reform attempts have failed to gain significant traction because state small-group reform laws and federal restrictions on medical underwriting cloud the legality of tax-sheltered list-billing. Several authorities have taken the position that insurance paid for through a cafeteria plan must meet the nondiscrimination requirements of the Health Insurance Portability and Accountability Act with respect to eligibility, premiums, and benefits. The recently enacted Patient Protection and Affordable Care Act addresses some of the legal uncertainty in this area, but much remains. For health reform to have its greatest effect, federal regulators must clarify whether individual health insurance can be purchased on a pre-tax basis through a cafeteria plan.


Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins.
Distinct modifications of histone amino termini, such as acetylation, phosphorylation and methylation, have been proposed to underlie a chromatin-based regulatory mechanism that modulates the accessibility of genetic information. In addition to histone modifications that facilitate gene activity, it is of similar importance to restrict inappropriate gene expression if cellular and developmental programmes are to proceed unperturbed. Here we show that mammalian methyltransferases that selectively methylate histone H3 on lysine 9 (Suv39h HMTases) generate a binding site for HP1 proteins--a family of heterochromatic adaptor molecules implicated in both gene silencing and supra-nucleosomal chromatin structure. High-affinity in vitro recognition of a methylated histone H3 peptide by HP1 requires a functional chromo domain; thus, the HP1 chromo domain is a specific interaction motif for the methyl epitope on lysine9 of histone H3. In vivo, heterochromatin association of HP1 proteins is lost in Suv39h double-null primary mouse fibroblasts but is restored after the re-introduction of a catalytically active SWUV39H1 HMTase. Our data define a molecular mechanism through which the SUV39H-HP1 methylation system can contribute to the propagation of heterochromatic subdomains in native chromatin.


Rapid and robust spin state amplification.
Electron and nuclear spins have been employed in many of the early demonstrations of quantum technology. However, applications in real world quantum technology are limited by the difficulty of measuring single spins. Here we show that it is possible to rapidly and robustly amplify a spin state using a lattice of ancillary spins. The model we employ corresponds to an extremely simple experimental system: a homogenous Ising-coupled spin lattice in one, two, or three dimensions, driven by a continuous microwave field. We establish that the process can operate at finite temperature (imperfect initial polarization) and under the effects of various forms of decoherence.


Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS).
We describe a Chinese American family with a hereditary syndrome consisting of retinopathy, nephropathy, and stroke, affecting 11 members spanning three generations. Ophthalmologic evaluations revealed macular edema with capillary dropout and perifoveal microangiopathic telangiectases. Several members had renal abnormalities with proteinuria and hematuria. Initial manifestations were visual impairment and renal dysfunction; neurologic deficits occurred in the third or fourth decade of life. Symptoms included migraine-like headache, psychiatric disturbance, dysarthria, hemiparesis, and apraxia. Neuroimaging consistently demonstrated contrast-enhancing subcortical lesions with surrounding edema. Ultrastructural studies showed distinctive multilaminated vascular basement membranes in the brain and in other tissues, including the kidney, stomach, appendix, omentum, and skin. Genetic analysis ruled out linkage to the CADASIL locus on chromosome 19. Distinct from CADASIL, hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS) is an autosomal dominant multi-infarct syndrome with systemic involvement.


Development of a novel DNA aptamer ligand targeting to primary cultured tumor endothelial cells by a cell-based SELEX method.
The present study used a spontaneous cell-based SELEX method (Systemic Evolution of Ligands by EXponential Enrichment) to produce DNA aptamers that specifically bind to cell surface proteins or biomarkers produced by primary cultured mouse tumor endothelial cells (mTECs). In solid tumors, new blood vessels are formed through an angiogenesis process, and this plays a critical role in cancer development as well as metastasis. To combat angiogenesis, an appropriate diagnosis and a molecular-level understanding of the different cancer types are now a high priority. The novel DNA aptamer AraHH001, developed in this study, binds specifically to mTECs with high affinity in the nano-molar range, but does not bind to normal skin endothelial cells (skin-ECs). The selected DNA aptamer was also found to bind to cultured human tumor endothelial cells (hTECs), isolated from a clinical patient with a renal carcinoma. The aptamer AraHH001 showed significant anti-angiogenesis activity by inhibiting tube formation by mTECs on matrigel. Interestingly, a confocal laser scanning microscopy examination of in vitro cellular uptake revealed that AraHH001 was assimilated by mTECs, and became co-localized in acidic compartments, as detected by labeling with Lysotracker Red. Therefore, the development of a specific DNA aptamer that binds to mTECs, as reported here for the first time, holds great promise not only as a therapeutic aptamer but also as a targeted molecular probe that appears to play a major role in angiogenesis, and for the development of a targeted new drug delivery system.


Mindfulness-based cognitive therapy for individuals whose lives have been affected by cancer: a randomized controlled trial.
This study evaluated the effectiveness of mindfulness-based cognitive therapy (MBCT) for individuals with a diagnosis of cancer. Participants (N = 115) diagnosed with cancer, across site and stage, were randomly allocated to either the treatment or the wait-list condition. Treatment was conducted at 1 site, by a single therapist, and involved participation in 8 weekly 2-hr sessions that focused on mindfulness. Participants meditated for up to 1 hr daily and attended an additional full-day session during the course. Participants were assessed before treatment and 10 weeks later; this second assessment occurred immediately after completion of the program for the treatment condition. The treatment condition was also assessed at 3 months postintervention. All postinitial assessments were completed by assessors who were blind to treatment allocation. There were large and significant improvements in mindfulness (effect size [ES] = 0.55), depression (ES = 0.83), anxiety (ES = 0.59), and distress (ES = 0.53) as well as a trend for quality of life (ES = 0.30) for MBCT participants compared to those who had not received the training. The wait-list group was assessed before and after receiving the intervention and demonstrated similar change. These improvements represent clinically meaningful change and provide evidence for the provision of MBCT within oncology settings.


Temporary Diplopia After Gow-Gates Injection: Case Report and Review.
Complications associated with various local anesthetic techniques have been recorded in case reports and reviews. This current case reports a transient incident of blurred, double vision (diplopia) following a Gow-Gates mandibular block injection. There is descriptive discussion on possibilities associated with intra-arterial injection, intravenous injection, diffusion through tissue planes, and the autonomic nervous system pathway to lend credence suggesting the etiology of the complication. For practitioners, recognizing when a complication arises from anesthesia delivery and managing the patient in an appropriate manner is essential to an overall agreeable outcome.


Lightweight, highly compressible, noncrystalline cellulose capsules.
We demonstrate how to prepare extraordinarily deformable, gas-filled, spherical capsules from nonmodified cellulose. These capsules have a low nominal density, ranging from 7.6 to 14.2 kg/m(3), and can be deformed elastically to 70% deformation at 50% relative humidity. No compressive strain-at-break could be detected for these dry cellulose capsules, since they did not rupture even when compressed into a disk with pockets of highly compressed air. A quantitative constitutive model for the large deformation compression of these capsules is derived, including their high-frequency mechanical response and their low-frequency force relaxation, where the latter is governed by the gas barrier properties of the dry capsule. Mechanical testing corroborated these models with good accuracy. Force relaxation measurements at a constant compression rendered an estimate for the gas permeability of air through the capsule wall, calculated to 0.4 mL μm/m(2) days kPa at 50% relative humidity. These properties taken together open up a large application area for the capsules, and they could most likely be used for applications in compressible, lightweight materials and also constitute excellent model materials for adsorption and adhesion studies.


Brief reactive psychosis in naval aviation.
Five naval aviation personnel diagnosed with brief reactive psychosis (BRP) have appeared before the Special Board of Flight Surgeons (SBFS) at the Naval Aerospace Medical Institute (NAMI). These cases demonstrate the challenges in diagnosis and disposition that face the clinical aeromedical specialist in evaluating the aviator who develops psychiatric symptoms. We discuss the aeromedical factors that must be considered when contemplating returning aviators with psychiatric diagnoses to flying duties. Sudden behavioral changes in aviation personnel require a systematic assessment, thorough documentation, and continuing reevaluation. The differentiation between organic and functional etiologies may be difficult. Final disposition may require consultation with experienced physicians skilled in both aviation psychiatry and neurology.


The polypeptide composition of the mitochondrial NADH: ubiquinone reductase complex from several mammalian species.
The polypeptide composition of isolated mitochondrial NADH:ubiquinone reductase (NADH dehydrogenase) is very similar to that of material immunoprecipitated from detergent-solubilized bovine heart submitochondrial particles by antisera to the holoenzyme. The specificity of the antisera for dehydrogenase polypeptides was determined by immunoblotting, which showed that antisera reacting with only a few proteins were able to immunoprecipitate all others in parallel. The polypeptide compositions of rat, rabbit and human NADH dehydrogenase were determined by immunoprecipitation of the enzyme from solubilized submitochondrial particles and proved to be very similar to that of the bovine heart enzyme, particularly in the high-Mr region. Further homologies in these and other species were explored by immunoblotting with antisera to the holoenzyme and monospecific antisera raised against iron-sulphur-protein subunits of the enzyme.


Staphylococcus epidermidis agr quorum-sensing system: signal identification, cross talk, and importance in colonization.
Staphylococcus epidermidis is an opportunistic pathogen that is one of the leading causes of medical device infections. Global regulators like the agr quorum-sensing system in this pathogen have received a limited amount of attention, leaving important questions unanswered. There are three agr types in S. epidermidis strains, but only one of the autoinducing peptide (AIP) signals has been identified (AIP-I), and cross talk between agr systems has not been tested. We structurally characterized all three AIP types using mass spectrometry and discovered that the AIP-II and AIP-III signals are 12 residues in length, making them the largest staphylococcal AIPs identified to date. S. epidermidis agr reporter strains were developed for each system, and we determined that cross-inhibitory interactions occur between the agr type I and II systems and between the agr type I and III systems. In contrast, no cross talk was observed between the type II and III systems. To further understand the outputs of the S. epidermidis agr system, an RNAIII mutant was constructed, and microarray studies revealed that exoenzymes (Ecp protease and Geh lipase) and low-molecular-weight toxins were downregulated in the mutant. Follow-up analysis of Ecp confirmed the RNAIII is required to induce protease activity and that agr cross talk modulates Ecp activity in a manner that mirrors the agr reporter results. Finally, we demonstrated that the agr system enhances skin colonization by S. epidermidis using a porcine model. This work expands our knowledge of S. epidermidis agr system function and will aid future studies on cell-cell communication in this important opportunistic pathogen.


Unusual direct immunofluorescence (DIF) pattern in pemphigus herpetiformis- A case report.
Pemphigus herpetiformis (PH) is an autoimmune intraepithelial bullous skin disorder. A 61-year-old female presented with history of multiple pruritic erosions, ulcers all over body, and diffuse loss of hair over scalp. Oral and genital mucosas were uninvolved. Subcorneal separation with suprapapillary thinning of epidermis, neutrophilic spongiosis, and elongation of rete ridges were seen on histopathology. Direct immunofluorescence (DIF) revealed IgG deposits in intercellular zone in fish net like pattern and focal linear IgA deposits along basement zone. Indirect immunofluorescence (IIF) revealed antibodies to desmoglein1 (Dsg-1) positive. A final diagnosis of PH was given. The patient responded well to treatment with dapsone and steroids.


Perspective of placenta derived mesenchymal stem cells in acute liver failure.
Acute Liver failure (ALF) is a life-threatening disease and is determined by coagulopathy (with INR ≥ 1.5) and hepatic encephalopathy as a result of severe liver injury in patients without preexisting liver disease. Since there are problems with liver transplantation including lack of donors, use of immunosuppressive drugs, and high costs of this process, new therapeutic approaches alongside current treatments are needed. The placenta is a tissue that is normally discarded after childbirth. On the other hand, human placenta is a rich source of mesenchymal stem cells (MSCs), which is easily available, without moral problems, and its derived cells are less affected by age and environmental factors. Therefore, placenta-derived mesenchymal stem cells (PD-MSCs) can be considered as an allogeneic source for liver disease. Considering the studies on MSCs and their effects on various diseases, it can be stated that MSCs are among the most important agents to be used for novel future therapies of liver diseases. In this paper, we will investigate the effects of mesenchymal stem cells through migration and immigration to the site of injury, cell-to-cell contact, immunomodulatory effects, and secretory factors in ALF.


Adipose Tissue in Cardiovascular Disease: From Basic Science to Clinical Translation.
The perception of adipose tissue as a metabolically quiescent tissue, primarily responsible for lipid storage and energy balance (with some endocrine, thermogenic, and insulation functions), has changed. It is now accepted that adipose tissue is a crucial regulator of metabolic health, maintaining bidirectional communication with other organs including the cardiovascular system. Additionally, adipose tissue depots are functionally and morphologically heterogeneous, acting not only as sources of bioactive molecules that regulate the physiological functioning of the vasculature and myocardium but also as biosensors of the paracrine and endocrine signals arising from these tissues. In this way, adipose tissue undergoes phenotypic switching in response to vascular and/or myocardial signals (proinflammatory, profibrotic, prolipolytic), a process that novel imaging technologies are able to visualize and quantify with implications for clinical prognosis. Furthermore, a range of therapeutic modalities have emerged targeting adipose tissue metabolism and altering its secretome, potentially benefiting those at risk of cardiovascular disease. Expected final online publication date for the Annual Review of Physiology, Volume 86 is February 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.


Diagnostic radiology in fundoplication according to Nissen.
Radiological examination of oesophagus and stomach after fundoplication with hiatoplasty for hiatal hernia reveals unmistakable evidence of this intervention, and this indicates a good result. After relapse of the hiatal hernia, with or without reflux, the fundoplication is no longer recognizable, apart from a distinct demarcation of the oesophageogastric junction in some cases. The criteria for evaluation in the case of relapse are the same as those for preoperative evaluation.


Distinct craniofacial syndrome of lagophthalmia and bilateral cleft lip and palate.
We report on several individuals with bilateral cleft lip and palate, lagophthalmia, megaloblepharon, distichiasis, and ectropion of the lower eyelids, representing in total a distinct craniofacial syndrome. Eight cases (3 from 1 family) in ages ranging from 1-45 years were identified over a 7-year period in the Cleft Palate and Craniofacial Clinic at our center. All cases (3 male, 5 female) presented with bilateral cleft lip and palate and lagophthalmia. Birth weight, growth, and development were normal in all cases, except for one who probably has familial small stature. Five of the 8 cases have distichiasis, and 5 have ectropion in varying degrees; dental findings consisted of hypodontia in 5 and delayed dentition in 1 patient. Hypoplastic nails and clinodactyly were confined to 3 members of 1 family. Clinical evidence in these cases and a review of the literature regarding distichiasis and lagophthalmia, either alone or in combination with ectropion, suggest that this craniofacial syndrome is most likely an autosomal-dominant trait. The 5 non-familial cases probably represent new mutations.


Estimating cardiovascular disease incidence from prevalence: a spreadsheet based model.
Disease incidence and prevalence are both core indicators of population health. Incidence is generally not as readily accessible as prevalence. Cohort studies and electronic health record systems are two major way to estimate disease incidence. The former is time-consuming and expensive; the latter is not available in most developing countries. Alternatively, mathematical models could be used to estimate disease incidence from prevalence. We proposed and validated a method to estimate the age-standardized incidence of cardiovascular disease (CVD), with prevalence data from successive surveys and mortality data from empirical studies. Hallett's method designed for estimating HIV infections in Africa was modified to estimate the incidence of myocardial infarction (MI) in the U.S. population and incidence of heart disease in the Canadian population. Model-derived estimates were in close agreement with observed incidence from cohort studies and population surveillance systems. This method correctly captured the trend in incidence given sufficient waves of cross-sectional surveys. The estimated MI declining rate in the U.S. population was in accordance with the literature. This method was superior to closed cohort, in terms of the estimating trend of population cardiovascular disease incidence. It is possible to estimate CVD incidence accurately at the population level from cross-sectional prevalence data. This method has the potential to be used for age- and sex- specific incidence estimates, or to be expanded to other chronic conditions.


Antiinflammatory effect of peripheral nerve blocks after knee surgery: clinical and biologic evaluation.
Nerve blocks provide analgesia after surgery. The authors tested whether nerve blocks have antiinflammatory effects. Patients had combined sciatic (single-shot) and continuous femoral block (48 h) (block group) or morphine patient-controlled analgesia after total knee arthroplasty. Pain at rest and upon movement was monitored at 1 (D1), 4 (D4), and 7 days (D7) and 1 (M1) and 3 months (M3) after surgery. Knee inflammation was evaluated (skin temperature, knee circumference) before surgery and at D1, D4, D7, M1, and M3. Plasma cytokine concentrations (interleukin [IL]-6, IL-1beta, tumor necrosis factor [TNF], IL-10, soluble receptor 1 of TNF [sTNF-R1]) were measured before surgery and at 4 h, D1, D4, and D7 after surgery. Capsule and synovial membrane cytokines were measured (IL-6, TNF, IL-1, IL-10). Knee flexion was evaluated before surgery and at D1, D4, D7, M1, and M3. Morphine use and recovery time to autonomy were monitored. Pain at rest and upon movement was lower in the block group than in patient-controlled analgesia patients between D1 and D7 (analysis of variance, P < 0.005). Knee flexion was improved in the block group for D1 to M1 (analysis of variance, P < 0.0001). Block group patients recovered nonassisted mobilization (t test, P = 0.04) and toilet use (t test, P = 0.03) more rapidly. Knee circumference and skin temperature were lower in the block group between D1 and D7 (analysis of variance, P < 0.05). Synovial membrane IL-1 (P < 0.05) and IL-10 (P < 0.01) increased, and plasma IL-6 and sTNF-R1 peaked at 24 h, with no difference between groups. Nerve blocks inhibited clinical inflammation after total knee arthroplasty, with no change in tissue and plasma cytokine concentrations.


Multimodal bioinformatic analyses of the neurodegenerative disease-associated TECPR2 gene reveal its diverse roles.
Loss of tectonin β-propeller repeat-containing 2 (TECPR2) function has been implicated in an array of neurodegenerative disorders, yet its physiological function remains largely unknown. Understanding TECPR2 function is essential for developing much needed precision therapeutics for TECPR2-related diseases. We leveraged considerable amounts of functional data to obtain a comprehensive perspective of the role of TECPR2 in health and disease. We integrated expression patterns, population variation, phylogenetic profiling, protein-protein interactions and regulatory network data for a minimally biased multimodal functional analysis. Genes and proteins linked to TECPR2 via multiple lines of evidence were subject to functional enrichment analyses to identify molecular mechanisms involving TECPR2. TECPR2 was found to be part of a tight neurodevelopmental gene expression programme that includes KIF1A, ATXN1, TOM1L2 and FA2H, all implicated in neurological diseases. Functional enrichment analyses of TECPR2-related genes converged on a role in late autophagy and ribosomal processes. Large-scale population variation data demonstrated that this role is non-redundant. TECPR2 might serve as an indicator for the energy balance between protein synthesis and autophagy, and a marker for diseases associated with their imbalance, such as Alzheimer's disease and Huntington's disease. Specifically, we speculate that TECPR2 plays an important role as a proteostasis regulator during synaptogenesis, highlighting its importance in developing neurons. By advancing our understanding of TECPR2 function, this work provides an essential stepping stone towards the development of precision diagnostics and targeted treatment options for TECPR2-related disorders.


Role of associating liver partition and portal vein ligation for staged hepatectomy in colorectal liver metastases: a review.
Colorectal cancer is the third most common cancer in the Western world. Approximately half of patients will develop liver metastases, which is the most common cause of death. The only potentially curative treatment is surgical resection. However, many patients retain a to small future liver remnant (FLR) to allow for resection directly. There are therefore strategies to decrease the tumor with neoadjuvant chemotherapy and to increase the FLR. An accepted strategy to increase the FLR is portal vein occlusion (PVO). A concern with this strategy is that a large proportion of patients will never be operated because of progression during the interval between PVO and resection. ALPPS (associating liver partition and portal vein ligation for staged hepatectomy) is a new procedure with a high resection rate. A concern with this approach is the rather high frequency of complications and high mortality, compared to PVO. In this review, it is shown that with ALPPS the resection rate was 97.1% for CRLM and the mortality rate for all diagnoses was 9.6%. The mortality rate was likely lower for patients with CRLM, but some data were lacking in the reports. Due to the novelty of ALPPS, the indications and technique are not yet established but there are arguments for ALPPS in the context of CRLM and a small FLR.


Outcomes of patients after aborted radical cystectomy for intraoperative findings of metastatic disease.
To assess the clinical outcome of patients with bladder cancer who underwent attempted radical cystectomy (RC) with curative intent, but whose procedures were aborted due to intraoperative findings of metastatic disease, as the presence of metastatic disease at RC is associated with a poor prognosis and there are no data on the optimum management strategy in this situation. In all, 248 consecutive patients with bladder cancer had attempted RC at one academic institution between 1994 and 2003. We retrospectively reviewed the records of 35 patients who had an aborted RC due to intraoperative findings of metastatic disease. The pathological characteristics, time to recurrence, overall survival, disease-specific survival, and suitability for adjuvant or salvage therapies were examined. Of the 35 patients who had an aborted RC for metastatic disease, 21 (60%) died from the disease within the study period (median time to cancer-specific death 26.4 months), 11 (31%) are alive with evidence of persistent disease or progression, and three (9%) are alive with no evidence of recurrence or progression. Seven patients had a salvage RC after successful adjuvant treatment, of whom three died from recurrent disease (at a mean of 46.5 months after initial exploration, 31.9 months after salvage RC), one is alive with bladder cancer recurrence to the rectum 10 months after salvage cystectomy, and three have no evidence of disease progression at a mean of 10 months after salvage RC. The prognosis of patients who undergo an aborted attempt at curative RC due to intraoperative findings of metastatic disease is poor. Although a few patients might subsequently have salvage RC, many of these patients still have poor outcomes even if adjuvant treatments are used. When metastatic disease is discovered at RC, completing the cystectomy should be considered, although further studies are needed to show a clinical benefit.


Venetoclax and hypomethylating agents in acute myeloid leukemia: Mayo Clinic series on 86 patients.
Venetoclax and hypomethylating agent (HMA) combination therapy is FDA-approved for elderly or unfit acute myeloid leukemia (AML) patients unable to withstand intensive chemotherapy. The primary objective of the current study was to impart our institutional experience with the above regimen, outlining response, survival outcomes, and its determinants amongst 86 treatment- naïve and relapsed/refractory AML patients. A total of 44 treatment-naïve AML patients, median age 73.5 years, enriched with secondary, therapy related and ELN adverse risk disease (n = 27) were studied. The CR/CRi rates of 50% (22 of 44 patients) were superior to 23% in a matched AML cohort treated with HMA alone (P = .005). Response rates were similar with TP53, FLT3, NPM1 and IDH mutations (P = .31). Moreover, CEPBA mutations (P = .03) and neutropenia (P = .05) emerged as predictors of complete response. Survivalwas prolonged in patients achieving CR/CRi (17 vs 3 months without CR/CRi, P < .001; conversely adverse ELN risk portended inferior survival. Amongst 42 relapsed/refractory AML patients, half received ≥2 prior therapies excluding transplant, and 15 (35.7%) had received HMA. A group of 14 patients (33.3%) attained CR/CRi; age > 65 years, AML with myelodysplasia, JAK2, DNMT3A, and BCOR mutations predicted complete response. Survival distinctions were based on CR/CRi (median survival 15 vs 3 months with/without CR/CRi; P < .001), and TP53 mutation status (P = .04). In summary, we corroborate existing reports demonstrating superior response and prolonged survival with venetoclax and HMA in treatment -naïve and relapsed/refractory AML patients regardless of genotype. Additionally, we identify unique predictors of response to therapy which require validation.


Prescription of oxycodone versus codeine after childbirth and risk of persistent opioid use: a population-based cohort study.
Oxycodone is increasingly prescribed for postpartum analgesia in lieu of codeine owing to concerns regarding the neonatal safety of codeine during lactation. We examined whether initiation of oxycodone after delivery was associated with an increased risk of persistent opioid use relative to initiation of codeine. We conducted a population-based cohort study of people who filled a prescription for either codeine or oxycodone within 7 days of discharge from hospital after delivery between Sept. 1, 2012, and June 30, 2020. The primary outcome was persistent opioid use, defined as 1 or more additional prescriptions for an opioid within 90 days of the first postpartum prescription and 1 or more additional prescriptions in the 91 to 365 days thereafter. We used inverse probability of treatment weighting to assess the risk of persistent postpartum opioid use, comparing people who initiated oxycodone with those who initiated codeine. Over the 8-year study period, we identified 70 607 people who filled an opioid prescription within 7 days of discharge from hospital: 21 308 (30.2%) received codeine and 49 299 (69.8%) oxycodone. Compared with people who filled a prescription for codeine, receipt of oxycodone was not associated with persistent opioid use (relative risk [RR] 1.04, 95% confidence interval [CI] 0.91-1.20). We found an association between a prescription for oxycodone and persistent use after vaginal delivery (RR 1.63, 95% CI 1.31-2.03), but not after cesarean delivery (RR 0.85, 95% CI 0.73-1.00). Initiation of oxycodone (v. codeine) was not associated with an increased risk of persistent opioid use, except after vaginal delivery.


Identification of a Leu-lle internalization motif within the cytoplasmic domain of the leukaemia inhibitory factor receptor.
Leukaemia inhibitory factor (LIF) signals via a heterodimeric receptor complex comprised of the LIF receptor (LIFR) and the interleukin (IL)-6 signal transducer gp130. Upon binding to its cognate receptor LIF is internalized. In this study, we show that the LIFR is endocytosed independently of gp130. By using a heterochimaeric receptor system we identified a dileucine-based internalization motif within the cytoplasmic domain of the LIFR. Our findings suggest that a heterodimeric LIFR/gp130 complex and homodimeric gp130/gp130 complex are endocytosed via distinct internalization signals.


Prostate stem cell antigen is an endogenous lynx1-like prototoxin that antagonizes alpha7-containing nicotinic receptors and prevents programmed cell death of parasympathetic neurons.
Vertebrate alpha-bungarotoxin-like molecules of the Ly-6 superfamily have been implicated as balancers of activity and survival in the adult nervous system. To determine whether a member of this family could be involved in the development of the avian ciliary ganglion, we identified 6 Gallus genes by their homology in structure to mouse lynx1 and lynx2. One of these genes, an ortholog of prostate stem cell antigen (psca), is barely detectable at embryonic day (E) 8, before neuronal cell loss in the ciliary ganglion, but increases >100-fold as the number of neurons begins to decline between E9 and E14. PSCA is highly expressed in chicken and mouse telencephalon and peripheral ganglia and correlates with expression of alpha7-containing nicotinic acetylcholine receptors (alpha7-nAChRs). Misexpressing PSCA before cell death in the ciliary ganglion blocks alpha7-nAChR activation by nicotine and rescues the choroid subpopulation from dying. Thus, PSCA, a molecule previously identified as a marker of prostate cancer, is a member of the Ly-6 neurotoxin-like family in the nervous system, and is likely to play a role as a modulator of alpha7 signaling-induced cell death during development.


Depressive symptoms carry an increased risk for suicidal ideation and behavior in bipolar disorder without any additional contribution of mixed symptoms.
To determine whether the risk of suicidal ideation or behavior during mixed states exceeds that attributable to the depressive components of these states alone in bipolar disorder. We utilized real-world, longitudinal clinical data collected on 290 patients with bipolar disorders (bipolar I, bipolar II, and bipolar not otherwise specified (NOS)) from the National Network of Depression Centers (NNDC) Clinical Care Registry (CCR) seen for 891 visits over a mean of 27.5 weeks. Depressive symptoms were measured with the Patient Health Questionnaire-9 (PHQ-9), manic symptoms with the Altman Self-Rating Mania (ASRM), and suicidal ideation and behavior with the Columbia-Suicide Severity Rating Scale (C-SSRS), obtained as part of the routine, measurement-based care provided across the NNDC. The relations between depressive symptoms, manic symptoms, and the interaction thereof (mixed symptoms) on coinciding suicidal ideation and behavior were modeled in generalized linear mixed models. Depressive symptoms, as measured by the PHQ-9, were strongly associated with suicidal ideation and behavior (p < 0.0001), while there was no significant association with manic symptoms as measured by the ASRM or the interaction between depressive and manic symptoms. Similar results were observed when the outcome was restricted to suicidal behavior and when mood was modeled categorically. There was evidence of a gender by ASRM interaction (p = 0.011) and risk of suicidal ideation or behavior was significant for women, but not men with manic symptoms. Diagnoses were based on clinician assessment and not structured interview. Mood assessments were self-reported rather than clinician-administered. Suicidal ideation was more frequently observed than suicidal behavior (23/272 visits where outcome positive). Depression represents the primary mood state accounting for suicide risk in bipolar disorder. Co-occurring symptoms of mania (mixed symptoms) do not appear to convey an elevated risk for suicidal ideation or behavior beyond that explained by the depressive symptoms alone.


A machine learning-based framework for diagnosis of COVID-19 from chest X-ray images.
Corona virus disease (COVID-19) acknowledged as a pandemic by the WHO and mankind all over the world is vulnerable to this virus. Alternative tools are needed that can help in diagnosis of the coronavirus. Researchers of this article investigated the potential of machine learning methods for automatic diagnosis of corona virus with high accuracy from X-ray images. Two most commonly used classifiers were selected: logistic regression (LR) and convolutional neural networks (CNN). The main reason was to make the system fast and efficient. Moreover, a dimensionality reduction approach was also investigated based on principal component analysis (PCA) to further speed up the learning process and improve the classification accuracy by selecting the highly discriminate features. The deep learning-based methods demand large amount of training samples compared to conventional approaches, yet adequate amount of labelled training samples was not available for COVID-19 X-ray images. Therefore, data augmentation technique using generative adversarial network (GAN) was employed to further increase the training samples and reduce the overfitting problem. We used the online available dataset and incorporated GAN to have 500 X-ray images in total for this study. Both CNN and LR showed encouraging results for COVID-19 patient identification. The LR and CNN models showed 95.2-97.6% overall accuracy without PCA and 97.6-100% with PCA for positive cases identification, respectively.


Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis.
The genetic architectures of common, complex diseases are largely uncharacterized. We modeled the genetic architecture underlying genome-wide association study (GWAS) data for rheumatoid arthritis and developed a new method using polygenic risk-score analyses to infer the total liability-scale variance explained by associated GWAS SNPs. Using this method, we estimated that, together, thousands of SNPs from rheumatoid arthritis GWAS explain an additional 20% of disease risk (excluding known associated loci). We further tested this method on datasets for three additional diseases and obtained comparable estimates for celiac disease (43% excluding the major histocompatibility complex), myocardial infarction and coronary artery disease (48%) and type 2 diabetes (49%). Our results are consistent with simulated genetic models in which hundreds of associated loci harbor common causal variants and a smaller number of loci harbor multiple rare causal variants. These analyses suggest that GWAS will continue to be highly productive for the discovery of additional susceptibility loci for common diseases.


Epidermal growth factor downregulates the expression of SH-PTP2.
Protein phosphorylation/dephosphorylation on tyrosine residues are regulated by tyrosine kinases/phosphatases. The tyrosine phosphatase SH-PTP2 (PTP1D, PTP2C) interacts physically through its SH2 domain with phosphorylated epidermal growth factor receptor (EGFR). In KB cells, an oral epidermoid carcinoma, high epidermal growth factor (EGF) concentrations (10-9, 10-8 and 10-7 M) downregulate its receptor for the duration of the incubation with EGF. Thus, it was hypothesized that in KB cells, SH-PTP2 expression would also be downregulated by high EGF concentrations. This hypothesis was investigated by incubating the KB cells with increasing concentrations of EGF (0, 10-11, 10-10, 10-9, 10-8, 10-7 M) and by evaluating the expression of SH-PTP2 protein under these conditions. This study showed that EGF 10-7 and 10-8 M significantly decreased SH-PTP2 protein expression compared to controls. EGF 10-10 and 10-11 M did not change the expression of SH-PTP2 protein. We conclude that high EGF concentrations downregulate the expression of SH-PTP2 protein.


Posttraumatic growth in exposure therapy for PTSD.
This study aims to increase our understanding of trauma positive outcomes by (a) exploring associations between posttraumatic growth and posttraumatic stress disorder (PTSD), and (b) investigating posttraumatic growth course and its impact on exposure treatment. In 80 mixed trauma PTSD patients, growth was negatively related to PTSD symptoms, especially emotional numbing. Sixty-five PTSD patients also completed Prolonged Exposure therapy with pretreatment and posttreatment assessments. Posttraumatic growth-New Possibilities and Personal Strength-increased during exposure therapy, and these increases were associated to decreases of PTSD symptoms. Pretreatment posttraumatic growth, more specifically the Appreciation of Life subscale, predicted better treatment outcome after controlling for pretreatment PTSD. The results indicate that posttraumatic growth may be a valuable new concept in trauma therapy.


Crystal structure of 12-lipoxygenase catalytic-domain-inhibitor complex identifies a substrate-binding channel for catalysis.
Lipoxygenases are critical enzymes in the biosynthesis of families of bioactive lipids including compounds with important roles in the initiation and resolution of inflammation and in associated diseases such as diabetes, cardiovascular disease, and cancer. Crystals diffracting to high resolution (1.9 Å) were obtained for a complex between the catalytic domain of leukocyte 12-lipoxygenase and the isoform-specific inhibitor, 4-(2-oxapentadeca-4-yne)phenylpropanoic acid (OPP). In the three-dimensional structure of the complex, the inhibitor occupied a new U-shaped channel open at one end to the surface of the protein and extending past the redox-active iron site that is essential for catalysis. In models, the channel accommodated arachidonic acid, defining the binding site for the substrate of the catalyzed reaction. There was a void adjacent to the OPP binding site connecting to the surface of the enzyme and providing a plausible access channel for the other substrate, oxygen.


Folate receptor–targeted single-photon emission computed tomography/computed tomography to detect activated macrophages in atherosclerosis: can it distinguish vulnerable from stable atherosclerotic plaques?
The need for noninvasive imaging to distinguish stable from vulnerable atherosclerotic plaques is evident. Activated macrophages play a role in atherosclerosis and express folate receptor folate receptor β (FR-β). The feasibility of folate targeting to detect atherosclerosis was demonstrated in human and mouse plaques, and it was suggested that molecular imaging of FR-β through folate conjugates might be a specific marker for plaque vulnerability. However, these studies did not allow differentiation between stable and vulnerable atherosclerotic plaques. We investigated the feasibility of a folate-based radiopharmaceutical (111)In-EC0800) with high-resolution animal single-photon emission computed tomography/computed tomography (SPECT/CT) to differentiate between stable and vulnerable atherosclerotic plaques in apolipoprotein E(−/−) mice in which we can induce plaques with the characteristics of stable and vulnerable plaques by placing a flow-modifying cast around the common carotid artery. Both plaques showed (111)In-EC0800 uptake, with higher uptake in the vulnerable plaque. However, the vulnerable plaque was larger than the stable plaque. Therefore, we determined tracer uptake per plaque volume and demonstrated higher accumulation of (111)In-EC0800 in the stable plaque normalized to plaque volume. Our data show that (111)In-EC0800 is not a clear-cut marker for the detection of vulnerable plaques but detects both stable and vulnerable atherosclerotic plaques in a mouse model of atherosclerosis.


The epithelial-mesenchymal transition (EMT) and colorectal cancer progression.
During embryonic development, epithelial cells must escape the structural constraints imposed by tissue architecture and adopt a phenotype more amenable to cell movement, a process known as the epithelial-mesenchymal transition (EMT). The progression of carcinomas to invasive and metastatic disease may also involve localized occurrences of EMT. However, data that support the actual occurrence of EMT in specific carcinomas and the relevance of this process to the progression of these tumors had been scant. This review highlights recent studies that substantiate the importance of the EMT to colorectal carcinoma. Specifically, a novel model for studying the EMT of colorectal carcinoma has been used to gain insight into the nature of the EMT itself and to identify molecular events that contribute to disease progression. Although loss of E-cadherin function is a primal event for the EMT, the expression of specific integrins such as alpha(v)beta6 as a consequence of the EMT enables invasive cells to interact with interstitial matrices and to sustain activation of TGF-beta. Of note, alpha(v)beta6 expression in tumors is a marker of cells that have undergone an EMT and it is prognostic for tumors that will progress more rapidly to terminal disease. The EMT also induces autocrine signaling involving VEGF and Flt-1 that enable invasive cells to become 'self-sufficient' for survival. Thus, the EMT appears to be an integral component of colorectal cancer progression and its analysis can yield novel targets for prognosis and therapy.


Sds3 (suppressor of defective silencing 3) is an integral component of the yeast Sin3[middle dot]Rpd3 histone deacetylase complex and is required for histone deacetylase activity.
SDS3 (suppressor of defective silencing 3) was originally identified in a screen for mutations that cause increased silencing of a crippled HMR silencer in a rap1 mutant background. In addition, sds3 mutants have phenotypes very similar to those seen in sin3 and rpd3 mutants, suggesting that it functions in the same genetic pathway. In this manuscript we demonstrate that Sds3p is an integral subunit of a previously identified high molecular weight Rpd3p.Sin3p containing yeast histone deacetylase complex. By analyzing an sds3Delta strain we show that, in the absence of Sds3p, Sin3p can be chromatographically separated from Rpd3p, indicating that Sds3p promotes the integrity of the complex. Moreover, the remaining Rpd3p complex in the sds3Delta strain had little or no histone deacetylase activity. Thus, Sds3p plays important roles in the integrity and catalytic activity of the Rpd3p.Sin3p complex.


Pedicle screw placement in the thoracic spine: a comparison of image-guided and manual techniques in cadavers.
A cadaveric study comparing image guidance technology to fluoroscopic guidance as a means of pedicle screw placement in the thoracic spine, using a unique starting point for screw placement. To assess accuracy of thoracic pedicle screw placement using image guidance versus fluoroscopic guidance for screw insertion. While use of pedicle screws in the thoracic spine has been increasing, its adoption has been slower than for the lumbar spine, reflecting concern regarding possible vascular or spinal cord injury due to screw malplacement. Given these risks, efforts to improve the accuracy of thoracic pedicle screw placement remain appropriate. Stereotactic guidance has been applied in other aspects of spinal surgery to improve the accuracy of instrumentation placement. Pedicle screws were placed in the thoracic spines of eight cadavers, using either a stereotactic guidance or a manual, fluoroscopically guided technique. A slightly more superior and lateral starting point from prior descriptions was used. Each cadaver was instrumented with pedicle screws in the upper thoracic (T1-T2), middle thoracic (T4-T7), and lower thoracic (T9-T10) regions. In the upper and middle thoracic regions, screws with a 4.0-mm shank diameter were used while in the lower thoracic region a shank diameter of 4.5 mm was used. Postinstrumentation CT scans, followed by anatomic dissections, were used to evaluate screw exit rates and orientation relative to the pedicle axis. Exit rates for the two techniques and the effect of vertebral level on exit rate were compared using a chi analysis. The effect of pedicle diameter was tested using a Pearson correlation coefficient. No significant differences in the overall exit rates or orientation were found between the two techniques. There were significant differences in exit rates between the middle (47%), compared with the upper (9%) and lower (16%) thoracic regions, respectively (P < 0.001). A significant correlation between pedicle diameter and exit rate was also found (P < 0.0001). Our study showed no significant differences in the overall exit rates between the two techniques. Image guidance may increase confidence of surgeons with limited experience in thoracic pedicle screw placement. Successful placement of screws within the pedicle varies with the anatomic diameter of the pedicle itself. Concerns regarding accuracy of screw placement should be greatest in the middle thoracic vertebrae (T4-T7), where pedicle diameters are smallest and proximity of the great vessels is nearest.


Maturation of the tyrosine kinase c-src as a kinase and as a substrate depends on the molecular chaperone Hsp90.
Although Hsp90 displays general chaperone activity in vitro, few substrates of the chaperone have been identified in vivo, and the characteristics that render these substrates dependent on Hsp90 remain elusive. To investigate this issue, we exploited a paradoxical observation: several unrelated oncogenic viral tyrosine kinases, including v-src, attain their native conformation after association with Hsp90, yet their nearly identical cellular homologs interact only weakly with the chaperone. It has been controversial whether Hsp90 is vital for normal maturation of the cellular kinases or is simply binding a misfolded subfraction of the proteins. By modulating Hsp90 levels in Saccharomyces cerevisiae, we determined that Hsp90 is indeed necessary for the maturation of c-src (the normal homolog of v-src). c-src maturation is, however, less sensitive to Hsp90 perturbations than is v-src maturation. Dependence of the two proteins on Hsp90 does not correspond to their relative efficiency in reaching their final destination (the plasma membrane); we observed that in yeast, unlike in vertebrate cells, neither c-src nor v-src concentrate in the membrane. Expression of different v/c-src chimeras in cells carrying wild-type or temperature-sensitive Hsp90 alleles revealed that the difference between the proteins instead arises from multiple, naturally occurring mutations in the C-terminal region of v-src.


Associations between sleep habits and mental health status and suicidality in a longitudinal survey of monozygotic twin adolescents.
Several epidemiological studies have indicated that there is a relationship between sleep habits, such as sleep duration, bedtime and bedtime regularity, and mental health status, including depression and anxiety in adolescents. However, it is still to be clarified whether the relationship is direct cause-and-effect or mediated by the influence of genetic and other traits, i.e. quasi-correlation. To examine this issue, we conducted a twin study using a total of 314 data for monozygotic twins from a longitudinal survey of sleep habits and mental health status conducted in a unified junior and senior high school (grades 7-12), located in Tokyo, Japan. Three-level hierarchical linear model analysis showed that both bedtime and sleep duration had significant associations with the Japanese version of the 12-item General Health Questionnaire (GHQ-12) score, suicidal thoughts and the experience of self-harm behaviours when genetic factors and shared environmental factors, which were completely shared between co-twins, were controlled for. These associations were statistically significant even after controlling for bedtime regularity, which was also associated significantly with the GHQ-12 score. These suggest that the associations between sleep habits and mental health status were still statistically significant after controlling for the influence of genetic and shared environmental factors of twins, and that there may be a direct cause-and-effect in the relationship in adolescents. Thus, late bedtime and short sleep duration could predict subsequent development of depression and anxiety, including suicidal or self-injury risk. This suggests that poor mental health status in adolescents might be improved by health education and intervention concerning sleep and lifestyle habits.