New bismuth-containing quadruple therapy in patients infected with Helicobacter pylori: A first Italian experience in clinical practice.
Rising antibiotic resistance requires the evaluation of new and effective therapies. To test the efficacy and safety of the new bismuth-containing quadruple therapy in patients infected with Helicobacter pylori. Consecutive H. pylori-positive dyspeptic patients were enrolled, either naïve or with previous failure treatment. Patients were treated with Pylera® (three-in-one capsules containing bismuth subcitrate potassium 140 mg, metronidazole 125 mg, and tetracycline 125 mg) three capsules q.i.d. plus omeprazole 20 mg or esomeprazole 40 mg b.i.d. for 10 days. Eradication was confirmed using an urea breath test (at least 30 days after the end of treatment). Efficacy was assessed by UBT and safety by means of treatment-emergent adverse events. One hundred and thirty-one patients were included in the study: 42% of patients were naïve, and 58%, with previous failure treatment. H. pylori eradication was achieved in 124 patients (94.7%, 95% confidence intervals (CIs) 89.3-97.8) in ITT population. In the PP population, the percentage was 97.6% (95%, CIs 93.3-99.2). No difference in eradication rate was found either between naïve and previously treated patients (92.7% vs 96.0%, P=.383), or smoking and nonsmoking ones, or in patients taking omeprazole or esomeprazole. Treatment-emergent adverse events occurred in 35 patients (26.7%, 95% CIs 19.9-34.9). They were mild in all cases except in four, who discontinued the study due to diarrhea (three patients) and diffuse urticarial rush (one patient). Pylera® achieved a remarkable eradication rate in clinical practice, irrespective if it was used as first treatment or as a rescue therapy. Treatment-emergent adverse events were uncommon generally mild.


Avoiding the ends: internal epitope tagging of proteins using transposon Tn7.
Peptide tags fused to proteins are used in a variety of applications, including as affinity tags for purification, epitope tags for immunodetection, or fluorescent protein tags for visualization. However, the peptide tags can disrupt the target protein function. When function is disrupted by fusing a peptide to either the N or C terminus of the protein of interest, identifying alternative ways to create functional tagged fusion proteins can be difficult. Here, we describe a method to introduce protein tags internal to the coding sequence of a target protein. The method employs in vitro Tn7-transposon mutagenesis of plasmids for random introduction of the tag, followed by subsequent Gateway cloning steps to isolate alleles with mutations in the coding sequence of the target gene. The Tn7-epitope cassette is designed such that essentially all of the transposon is removed through restriction enzyme digestion, leaving only the protein tag at diverse sites internal to the ORF. We describe the use of this system to generate a panel of internally epitope-tagged versions of the Saccharomyces cerevisiae GPI-linked membrane protein Dcw1 and the Candida glabrata transcriptional regulator Sir3. This internal protein tagging system is, in principle, adaptable to tag proteins in any organism for which Gateway-adapted expression vectors exist.


The antiulcer effect of Cibotium barometz leaves in rats with experimentally induced acute gastric ulcer.
Cibotium barometz is a pharmaceutical plant customarily used in traditional medicine in Malaysia for the treatment of different diseases, such as gastric ulcer. The gastroprotective effect of C. barometz leaves against ethanol-induced gastric hemorrhagic abrasions in Sprague Dawley rats has been evaluated in terms of medicinal properties. Seven groups of rats (normal control and ulcerated control groups, omeprazole 20 mg/kg, 62.5, 125, 250, and 500 mg/kg of C. barometz correspondingly) were used in antiulcer experiment and pretreated with 10% Tween 20. After 1 hour, the normal group was orally administered 10% Tween 20, whereas absolute alcohol was fed orally to ulcerated control, omeprazole, and experimental groups. Gastric's homogenate were assessed for endogenous enzymes activities. Stomachs were examined macroscopically and histologically. Grossly, the data demonstrated a significant decrease in the ulcer area of rats pretreated with plant extract in a dose-dependent manner with respect to the ulcerated group. Homogenates of the gastric tissue exhibited significantly increased endogenous enzymes activities in rats pretreated with C. barometz extract associated with the ulcerated control group. Histology of rats pretreated with C. barometz extract group using hematoxylin and eosin staining exhibited a moderate-to-mild disruption of the surface epithelium with reduction in submucosal edema and leucocyte infiltration in a dose-dependent manner. In addition, it showed heat shock protein70 protein up-expression and BCL2-associated X protein downexpression. These outcomes might be attributed to the gastroprotective and antioxidative effects of the plant.


The Effect of Misregistration Between CT-Attenuation and PET-Emission Images in 13N-Ammonia Myocardial PET/CT.
In 2-dimensional cardiac PET/CT, misregistration between the PET and CT images due to respiratory and cardiac motion causes tracer uptake to appear substantially reduced. The resolution and quality of the images have been considerably improved by the use of 3-dimensional (3D) PET acquisitions. In the current study, we investigated the impact that misregistration between PET and CT images has on myocardial (13)N-ammonia uptake in images reconstructed with 3D ordered-subset expectation maximization combined with time-of-flight and point-spread-function modeling. Eight healthy volunteers (7 men and 1 woman; mean age ± SD, 53 ± 19 y) underwent (13)N-ammonia cardiac PET/CT at rest. First, any misregistration between the PET and CT images was manually corrected to generate reference images. Then, the images were intentionally misregistered by shifting the PET images from the reference images by a degree of 1, 2, 3, 4, 5, 10, and 15 mm along both the x-axis (left) and the z-axis (cranial). For each degree of misregistration, the PET images were reconstructed using the CT-attenuation images. The left ventricular short-axis PET/CT images were divided into 4 segments: anterior wall, inferior wall, lateral wall, and septum. The erroneous decrease in myocardial uptake in basal, mid, and apical slices was visually graded using a 4-point scale (0 = none, 1 = mild, 2 = moderate, and 3 = severe). Wall-to-septum uptake ratios were evaluated for the anterior, inferior, and lateral walls in the basal, mid, and apical slices. A statistically significant reduction in myocardial (13)N-ammonia uptake in the anterior (P < 0.01) and lateral (P < 0.05) walls was observed when misregistration was 10 mm or more. The uptake ratios for the anterior, lateral, and inferior walls in the reference images were 1.00 ± 0.04, 0.96 ± 0.08, and 0.91 ± 0.03, respectively. The ratios for the anterior and lateral walls significantly decreased when misregistration exceeded 10 mm (anterior wall, 0.80 ± 0.06, P < 0.0001; lateral wall, 0.82 ± 0.07, P < 0.01), whereas the ratio for the inferior wall was relatively small at all 7 degrees of misregistration (0.86 ± 0.05 at 15-mm misregistration, P = 0.06). In PET/CT images reconstructed with 3D ordered-subset expectation maximization combined with time-of-flight and point-spread-function modeling, we found a statistically significant artifactual reduction in tracer uptake in heart regions overlapping lung when misregistration between PET and CT exceeded 10 mm.


Biochemical and biological studies of mouse APOBEC3.
Many murine leukemia viruses (MLVs) are partially resistant to restriction by mouse APOBEC3 (mA3) and essentially fully resistant to induction of G-to-A mutations by mA3. In contrast, Vif-deficient HIV-1 (ΔVif HIV-1) is profoundly restricted by mA3, and the restriction includes high levels of G-to-A mutation. Human APOBEC3G (hA3G), unlike mA3, is fully active against MLVs. We produced a glutathione S-transferase-mA3 fusion protein in insect cells and demonstrated that it possesses cytidine deaminase activity, as expected. This activity is localized within the N-terminal domain of this 2-domain protein; the C-terminal domain is enzymatically inactive but required for mA3 encapsidation into retrovirus particles. We found that a specific arginine residue and several aromatic residues, as well as the zinc-coordinating cysteines in the C-terminal domain, are necessary for mA3 packaging; a structural model of this domain suggests that these residues line a potential nucleic acid-binding interface. Mutation of a few potential phosphorylation sites in mA3 drastically reduces its antiviral activity by impairing either deaminase activity or its encapsidation. mA3 deaminates short single-stranded DNA oligonucleotides preferentially toward their 3' ends, whereas hA3G exhibits the opposite polarity. However, when packaged into infectious ΔVif HIV-1 virions, both mA3 and hA3G preferentially induce deaminations toward the 5' end of minus-strand viral DNA, presumably because of the sequence of events during reverse transcription in vivo. Despite the fact that mA3 in MLV particles does not induce detectable deaminations upon infection, its deaminase activity is easily detected in virus lysates. We still do not understand how MLV resists mA3-induced G-to-A mutation. One way that mammalian cells defend themselves against infection by retroviruses is with APOBEC3 proteins. These proteins convert cytidine bases to uridine bases in retroviral DNA. However, mouse APOBEC3 protein blocks infection by murine leukemia viruses without catalyzing this base change, and the mechanism of inhibition is not understood in this case. We have produced recombinant mouse APOBEC3 protein for the first time and characterized it here in a number of ways. Our mutational studies shed light on the mechanism by which mouse APOBEC3 protein is incorporated into retrovirus particles. While mouse APOBEC3 does not catalyze base changes in murine leukemia virus DNA, it can be recovered from these virus particles in enzymatically active form; it is still not clear why it fails to induce base changes when these viruses infect new cells.


Efficacy and safety of bevacizumab treatment for refractory brain edema: Case report.
This retrospective study investigated the efficacy and safety of bevacizumab treatment for refractory brain edema. Between March 2009 and December 2015, bevacizumab was used to treat 59 cases of brain metastatic patients with refractory brain edema. The median dose of bevacizumab was 4.68 mg/kg (range 2.8-6.52 mg/kg). The clinical-pathological data, the efficacy, and the side effects of bevacizumab were recorded. Magnetic resonance imaging (MRI) was performed before and after bevacizumab treatment. Tumor and edema volumes were measured separately. The clinical symptoms of 50 out of 59 cases (84.74%) improved the day after the bevacizumab treatment, and the edema volumes of 55 (93.22%) cases were reduced after the bevacizumab treatment. The average edema volume was significantly reduced after bevacizumab treatment from 125,583.43 ± 14,093.27 to 71,613.42 ± 9473.42 mm (Mann-Whitney rank test, P < .01), and the average edema index was significantly reduced from 25.66 ± 11.54 to 17.87 ± 6.87 (Mann-Whitney rank test, P < .01). One patient died from a hemorrhage due to a cancerous-ulcer of the maxillary sinus. The main complication observed was hypertension, which was observed in 11 cases (18.6%). The effective rate of bevacizumab for refractory brain edema is 84.74%. Hypertension was the main side effect of the bevacizumab treatment. Bevacizumab is an effective and relatively safe treatment for brain edema.


Standards of Practice for Occupational Therapy.
This document defines minimum standards for the practice of occupational therapy. According to the Occupational Therapy Practice Framework: Domain and Process (4th ed.; OTPF-4), occupational therapy is defined as the therapeutic use of everyday life occupations with persons, groups, or populations (i.e., the client) for the purpose of enhancing or enabling participation. . . . Occupational therapy services are provided for habilitation, rehabilitation, and promotion of health and wellness for clients with disability- and non-disability-related needs. These services include acquisition and preservation of occupational identity for clients who have or are at risk for developing an illness, injury, disease, disorder, condition, impairment, disability, activity limitation, or participation restriction. (American Occupational Therapy Association [AOTA], 2020c, p. 1).


Dilated cardiomyopathy secondary to coarctation of the aorta was completely resolved after stent implantation.
Although rare in adults, coarctation of the aorta can present as an occult cause of cardiomyopathy. In this case report, we describe a 55-year-old man who presented to our clinic with new-onset symptoms of heart failure. Transthoracic echocardiography showed a dilated left ventricle with severely depressed systolic function. Cardiac catheterisation showed no critical coronary artery disease but a severe aortic coarctation just distal to the origin of the left subclavian artery, with a peak-to-peak systolic pressure gradient of 40 mmHg. We successfully implanted a balloon-expandable stent with good angiographic results. The procedure resulted in immediate clinical improvement. Six-months after stent implantation, the patient was free of symptoms and an echocardiographic examination showed completely normalised cardiac size and systolic function.


Site of Tagging Influences the Ochratoxin Recognition by Peptide NFO4: A Molecular Dynamics Study.
Molecular recognition by synthetic peptides is growing in importance in the design of biosensing elements used in the detection and monitoring of a wide variety of hapten bioanlaytes. Conferring specificity via bioimmobilization and subsequent recovery and purification of such sensing elements are aided by the use of affinity tags. However, the tag and its site of placement can potentially compromise the hapten recognition capabilities of the peptide, necessitating a detailed experimental characterization and optimization of the tagged molecular recognition entity. The objective of this study was to assess the impact of site-specific tags on a native peptide's fold and hapten recognition capabilities using an advanced molecular dynamics (MD) simulation approach involving bias-exchange metadynamics and Markov State Models. The in-solution binding preferences of affinity tagged NFO4 (VYMNRKYYKCCK) to chlorinated (OTA) and non-chlorinated (OTB) analogues of ochratoxin were evaluated by appending hexa-histidine tags (6× His-tag) to the peptide's N-terminus (NterNFO4) or C-terminus (CterNFO4), respectively. The untagged NFO4 (NFO4), previously shown to bind with high affinity and selectivity to OTA, served as the control. Results indicate that the addition of site-specific 6× His-tags altered the peptide's native fold and the ochratoxin binding mechanism, with the influence of site-specific affinity tags being most evident on the peptide's interaction with OTA. The tags at the N-terminus of NFO4 preserved the native fold and actively contributed to the nonbonded interactions with OTA. In contrast, the tags at the C-terminus of NFO4 altered the native fold and were agnostic in its nonbonded interactions with OTA. The tags also increased the penalty associated with solvating the peptide-OTA complex. Interestingly, the tags did not significantly influence the nonbonded interactions or the penalty associated with solvating the peptide-OTB complex. Overall, the combined contributions of nonbonded interaction and solvation penalty were responsible for the retention of the native hapten recognition capabilities in NterNFO4 and compromised native recognition capabilities in CterNFO4. Advanced MD approaches can thus provide structural and energetic insights critical to evaluate the impact of site-specific tags and may aid in the selection and optimization of the binding preferences of a specific biosensing element.


Fine scale measurements in Belgian coastal sediments reveal different mobilization mechanisms for cationic trace metals and oxyanions.
Belgian coastal sediment serves as an important sink for trace elements, yet a systematic study covering a wide range of elements including redox-sensitive metals (Fe, Mn, and Co), cationic trace metals (Cd, Pb, Ni, Cu, and Zn), oxyanions (P, V, As, and Mo), and sulfide has not been performed and the mechanisms controlling their mobilization were not investigated. Here, a passive sampling technique, Diffusive Gradients in Thin-films (DGT), was used in situ to obtain high resolution concentration profiles of these elements in the sediment porewater. Our results revealed two mobilization mechanisms of cationic trace metals and oxyanions in Belgian coastal sediments, both strongly linked to the cycling of Fe. Mobilization of Co, Pb, Ni, and Cu is controlled by electrogenic sulfur oxidation, acidification of the porewater and dissolution of FeS, while that of oxyanions (P, V, and As) is controlled by reductive dissolution of Fe oxyhydroxides. Constant cationic trace metal to Fe molar ratios were established in FeS, while the oxyanion to Fe ratios in Fe oxyhydroxides differ significantly between sampling stations, which is primarily caused by competing effects. We found no evidence that cationic trace metal mobilization was related to Fe oxyhydroxides, or oxyanion mobilization to FeS. This suggests that particulate organic matter forms the major pathway for cationic trace metal input in coastal sediments and that oxyanions will not be incorporated in FeS but form their own oxyanion-sulfide compound. These findings will contribute to a better understanding of the mobilization mechanisms of cationic trace metals and oxyanions in coastal sediments, and of their biogeochemical cycling in coastal ecosystems.


Effect of Roasting and Brewing on the Antioxidant and Antiproliferative Activities of Tartary Buckwheat.
We evaluated the effect of the roasting and brewing conditions of Tartary buckwheat (TB), which is widely used in infusion teas, on its antioxidant and antiproliferative activities in vitro. TB was roasted at 210 °C for 10 min and brewed at a high temperature for a short time (HTST; 85-90 °C, 3 min) or at room temperature for a long time (RTLT; 25-30 °C, 24 h). Roasted TB (RTB) tea brewed at RTLT had the highest total polyphenol content (TPC) and total flavonoid content (TFC) among the four TB teas for different roasting and brewing conditions. Moreover, RTB brewed at RTLT showed the greatest 2,2-diphenyl-1-picrylhydrazyl-, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid)-, and alkyl-scavenging activities. The TB tea brewed at RTLT had higher Fe2+-chelating activity than that brewed at HTST, irrespective of roasting. Moreover, RTB tea brewed at RTLT inhibited the proliferation of human pancreatic and breast cancer cells. Overall, RTB-RTLT displayed the largest effect on antioxidant and antiproliferative effects. Finally, rutin was found to possess the most pronounced effect on the antioxidant and antiproliferative activities of the TB teas. These results indicate that the antioxidant and antiproliferative activities of RTB are enhanced by RTLT brewing.


Repurposing Nimesulide, a Potent Inhibitor of the B0AT1 Subunit of the SARS-CoV-2 Receptor, as a Therapeutic Adjuvant of COVID-19.
The global pandemic caused by the SARS-CoV-2 infection is a health emergency that needs to be addressed immediately. The international scientific community, following World Health Organization (WHO) indications, launched different trials for testing drugs putatively able to block the SARS-CoV-2 infection or treat the COVID-19 disease symptoms. In parallel, studies devoted to a better understanding of SARS-CoV-2 biology are in the course for designing an effective vaccine. One of the human membrane proteins known to be docked by the virus is angiotensin-converting enzyme 2 (ACE2), proposed to be responsible for viral entry in target cells. Recently, the 3D structure of ACE2 has been obtained, showing its physical interaction with B0AT1 (SLC6A19), a plasma membrane transporter involved in the trafficking of amino acids in cells. The receptor targeted by SARS-CoV-2 is a supercomplex formed by a dimer of ACE2-B0AT1, in which ACE2 binds the viral protein and B0AT1 stabilizes the heterodimer. As a serendipity occurrence, nimesulide was shown to abolish the transport function of B0AT1. Here we suggest including nimesulide in the list of drugs to be tested for the identification of co-adjuvants in the treatment of COVID-19.


Yeast homologues of three BLOC-1 subunits highlight KxDL proteins as conserved interactors of BLOC-1.
Biogenesis of lysosome-related organelle complex-1 (BLOC-1) is one of the four multi-subunit complexes implicated in sorting cargo to lysosome-related organelles, as loss of function of any of these complexes causes Hermansky-Pudlak syndrome. Eight subunits of BLOC-1 interact with each other and with many other proteins. Identifying new interactors of BLOC-1 will increase understanding of its mechanism of action, and studies in model organisms are useful for finding such interactors. PSI-BLAST searches identify homologues in diverse model organisms, but there are significant gaps for BLOC-1, with none of its eight subunits found in Saccharomyces cerevisiae. Here we use more sensitive searches to identify distant homologues for three BLOC-1 subunits in S. cerevisiae: Blos1, snapin and cappuccino (cno). Published data on protein interactions show that in yeast these are likely to form a complex with three other proteins. One of these is the yeast homologue of the previously uncharacterized KxDL protein, which also interacts with Blos1 and cno in higher eukaryotes, suggesting that KxDL proteins are key interactors with BLOC-1.


High prevalence and diversity of Bartonella in small mammals from the biodiverse Western Ghats.
Bartonella species are recognized globally as emerging zoonotic pathogens. Small mammals such as rodents and shrews are implicated as major natural reservoirs for these microbial agents. Nevertheless, in several tropical countries, like India, the diversity of Bartonella in small mammals remain unexplored and limited information exists on the natural transmission cycles (reservoirs and vectors) of these bacteria. Using a multi-locus sequencing approach, we investigated the prevalence, haplotype diversity, and phylogenetic affinities of Bartonella in small mammals and their associated mites in a mixed-use landscape in the biodiverse Western Ghats in southern India. We sampled 141 individual small mammals belonging to eight species. Bartonella was detected in five of the eight species, including three previously unknown hosts. We observed high interspecies variability of Bartonella prevalence in the host community. However, the overall prevalence (52.5%) and haplotype diversity (0.9) was high for the individuals tested. Of the seven lineages of Bartonella identified in our samples, five lineages were phylogenetically related to putative zoonotic species-B. tribocorum, B. queenslandensis, and B. elizabethae. Haplotypes identified from mites were identical to those identified from their host species. This indicates that these Bartonella species may be zoonotic, but further work is necessary to confirm whether these are pathogenic and pose a threat to humans. Taken together, these results emphasize the presence of hitherto unexplored diversity of Bartonella in wild and synanthropic small mammals in mixed-use landscapes. The study also highlights the necessity to assess the risk of spillover to humans and other incidental hosts.


Gut Dysbiosis in Animals Due to Environmental Chemical Exposures.
The gut microbiome consists of over 103-104 microorganism inhabitants that together possess 150 times more genes that the human genome and thus should be considered an "organ" in of itself. Such communities of bacteria are in dynamic flux and susceptible to changes in host environment and body condition. In turn, gut microbiome disturbances can affect health status of the host. Gut dysbiosis might result in obesity, diabetes, gastrointestinal, immunological, and neurobehavioral disorders. Such host diseases can originate due to shifts in microbiota favoring more pathogenic species that produce various virulence factors, such as lipopolysaccharide. Bacterial virulence factors and metabolites may be transmitted to distal target sites, including the brain. Other potential mechanisms by which gut dysbiosis can affect the host include bacterial-produced metabolites, production of hormones and factors that mimic those produced by the host, and epimutations. All animals, including humans, are exposed daily to various environmental chemicals that can influence the gut microbiome. Exposure to such chemicals might lead to downstream systemic effects that occur secondary to gut microbiome disturbances. Increasing reports have shown that environmental chemical exposures can target both host and the resident gut microbiome. In this review, we will first consider the current knowledge of how endocrine disrupting chemicals (EDCs), heavy metals, air pollution, and nanoparticles can influence the gut microbiome. The second part of the review will consider how potential environmental chemical-induced gut microbiome changes might subsequently induce pathophysiological responses in the host, although definitive evidence for such effects is still lacking. By understanding how these chemicals result in gut dysbiosis, it may open up new remediation strategies in animals, including humans, exposed to such chemicals.


Selective activation of Dopamine D3 receptors and norepinephrine transporter blockade enhances sustained attention.
Catecholamine transmitters dopamine (DA) and norepinephrine (NE) regulate prefrontal cortical (PFC) circuit activity and PFC-mediated executive functions. Accordingly, pharmacological agents that influence catecholamine neurotransmission exert prominent effects on cognition. Many such agents are used clinically to treat attention disorders. For example, methylphenidate blocks DA and NE reuptake and is the leading choice for attention deficit hyperactivity disorder (ADHD) treatment. Recently, we have designed SK609 - a selective small molecule agonist of the DA D3 receptor (D3R). In this study, we further characterized SK609's ability to selectively inhibit the reuptake of NE by NE transporters (NET). Our results indicate SK609 selectively inhibits NET with a Ki value of ∼500 nM and behaves as a NET substrate. Systemic dosing of SK609 (4 mg/kg; i.p.) in naïve rats produced a 300% and 160% increase in NE and DA, respectively, in the PFC as measured by microdialysis. Based on these neurochemical results, SK609 was tested in a PFC-dependent, visually-guided sustained attention task in rats. SK609 improved performance in a dose-dependent manner with a classical inverted-U dose response function with a peak effect at 4 mg/kg. SK609's peak effect was blocked by a pre-treatment with either the D2/D3R antagonist raclopride (0.05 mg/kg; i.p) or the alpha-1 adrenergic receptor antagonist prazosin (0.25 mg/kg; i.p), confirming a role for both DA and NE in promoting sustained attention. Additionally, SK609 improved sustained attention more prominently among low-performing animals. Doses of SK609 (2, 4, and 8 mg/kg) associated with cognitive enhancement did not produce an increase in spontaneous locomotor activity, suggesting a lack of side effects mediated by DA transporter (DAT) activity. These results demonstrate that the novel catecholaminergic modulator SK609 has the potential to treat sustained attention deficits without affecting DAT activity, distinguishing it from amphetamines and methylphenidate.


Nanotechnology in cancer therapy.
Cancer is one of the major causes of mortality worldwide and advanced techniques for therapy are urgently needed. The development of novel nanomaterials and nanocarriers has allowed a major drive to improve drug delivery in cancer. The major aim of most nanocarrier applications has been to protect the drug from rapid degradation after systemic delivery and allowing it to reach tumor site at therapeutic concentrations, meanwhile avoiding drug delivery to normal sites as much as possible to reduce adverse effects. These nanocarriers are formulated to deliver drugs either by passive targeting, taking advantage of leaky tumor vasculature or by active targeting using ligands that increase tumoral uptake potentially resulting in enhanced antitumor efficacy, thus achieving a net improvement in therapeutic index. The rational design of nanoparticles plays a critical role since structural and physical characteristics, such as size, charge, shape, and surface characteristics determine the biodistribution, pharmacokinetics, internalization and safety of the drugs. In this review, we focus on several novel and improved strategies in nanocarrier design for cancer therapy.


Compression behaviour of anhydrous and hydrate forms of sodium naproxen.
The aim of the present work was to investigate the technological properties and the compression behaviour of the anhydrous and hydrate solid forms of sodium naproxen. Among the hydrates, the following forms were studied: the monohydrate (MSN), obtained by dehydrating a dihydrated form (DSN) in each turn obtained by exposing the anhydrous form at 55% RH; a dihydrated form (CSN) obtained by crystallizing sodium naproxen from water, the tetrahydrated form (TSN) obtained by exposing the anhydrous form at 75% RH. The physico-chemical (crystalline form and water content), the micromeritic (crystal morphology and particle size) and the mechanical properties (Carr's index, apparent particle density, compression behaviour, elastic recovery and strength of compact) were evaluated. We made every effort to reduce differences in crystal habit, particle size and distribution, and amount of absorbed water among the samples, so that the only factors affecting their technological behaviour would be the degree of hydration and the crystalline structure. This study demonstrates a correlation between the compression behaviour and the water molecules present in the crystalline structures. The sites where water molecules are accommodated in the crystalline structure behave like weak points where the crystalline lattice yields under compression. The crystal deformability is proportional to the number of water molecules in these sites; the higher the water content, the higher the deformability, because the densification behaviour changes from a predominantly elastic deformation to a plastic behaviour. The deformability is responsible for a higher densification tendency that favours larger interparticle bonding areas that may explain the better tabletability of TSN and CSN.


[The age at which the grade of Special Child Dependent's Allowance Act can be judged in the case of deaf children].
The spread of neonatal hearing screening has made the identification of hearing loss in early childhood possible, and most of the children with hearing loss are diagnosed and provided with early intervention within several months after their birth. However, they have to wait to receive the Special Child Dependent's Allowance until their hearing levels are evaluated with audiometers. Under the Special Child Dependent's Allowance Act now in force, a delay of several years occurs for those children before they can receive the allowance after diagnosis. We retrospectively reviewed hearing test results of children who had not reacted at 90dBnHL bilaterally in ABR within 12 months after birth, and examined when those results were certain enough to determine their allowance eligibility. We found that the eligibility in children with hearing loss alone could be determined at 1 year of age; as for children who had other disorders, since it was mostly difficult to test them with an audiometer, the diagnosis of hearing loss must always be made carefully but it was also possible to determine the eligibility for the allowance at 1 year of age.


Fesoterodine for the treatment of urinary incontinence and overactive bladder.
Overactive bladder (OAB) is a highly prevalent condition, affecting males and females. The prevalence increases with age. Behavioral therapy and antimuscarinic therapy remain the first-line therapies for management of OAB. Despite improvements in symptoms, persistence with antimuscarinic therapy has remained low. Multiple factors including patient expectations, adverse effects and cost may affect persistence. Fesoterodine is one of the newest antimuscarinic agent approved for the management of OAB. It is unique in that it shares the same active metabolite as tolterodine, 5-hydoxymethyltolterodine (5-HMT); however, this conversion is established via ubiquitous esterases and not via the cytochrome P450 system, thus providing a faster and more efficient conversion to 5-HMT. Fesoterodine is available in 2 doses, 4 mg and 8 mg. Clinical trials have established a dose response relationship in efficacy parameters as well as improvements in quality of life. As with all antimuscarinics, dry mouth and constipation are the more common side effects. A combination of medical therapy and behavioral therapy improves the overall outcome in management of OAB. Dose flexibility may help improve efficacy outcomes and patient education on the management of common adverse effects may improve tolerability with these agents.


The Endometrioma Treatment Paradigm when Fertility Is Desired: A Systematic Review.
To establish an endometrioma treatment paradigm (decision tree) in the treatment of an ovarian endometrioma through the review of current literature. A thorough literature search, including PubMed, Google Scholar, and the Cochrane Library, was performed from April 2020 to July 2020. The review was completed by using the following keywords: METHODS OF STUDY SELECTION: Articles published in English that addressed the endometrioma in regard to the following were included: (1) diagnosis, (2) treatment of pain on the basis of size and/or surgical intervention, (3) treatment of fertility on the basis of size and/or surgical intervention, (4) surgical technique, (5) in vitro fertilization success on the basis of size and/or surgical intervention, (6) risk of rupture at the time of egg retrieval, (7) impact on the antimüllerian hormone and antral follicle count postsurgery, and (8) impact on implantation. Fifty-six articles were included in this systematic review. While conducting this literature review, several themes were noted. In general, the literature on the ovarian endometrioma seems to be homogeneous in regard to imaging the endometrioma, excision rather than desiccation for an endometrioma ≥3-cm causing pain and/or infertility, minimal use of bipolar energy at the time of ovarian surgery, and risk of severe infection secondary to inadvertent rupture of cysts during egg retrieval. Conversely, studies on the ovarian endometrioma are much more heterogeneous in terms of surgery and assisted reproductive technology, that is, whether surgery should be performed. Certainly, an endometrioma ≥5-cm should be excised before assisted reproductive technology. Moreover, it seems that the antral follicle count and implantation may be enhanced with surgery. By completing an extensive literature review, an easy-to-use algorithm for the diagnosis, evaluation, and treatment of endometriomas was developed to help clinicians in their treatment of patients with endometriosis in the short and long terms.


Clinical Practice Settings Associated with GPs Who Take on Patients with Mental Disorders.
In light of current reforms to reinforce primary mental healthcare and service integration, this paper assesses general practitioners' (GPs') management of patients with mental disorders (PMD) and its associated practice settings and clinical characteristics. The study is based on a survey of 398 Quebec GPs. Results showed that GPs who receive patients with moderate and transient mental disorders (PMD-M) usually follow them on a continuous basis; conversely, only a quarter of GPs who see patients with severe and persistent mental disorders (PMD-S) provide follow-up. With the exception of walk-in clinics, all clinical settings are associated with GPs who take on PMD-M. No setting was found to be significantly associated with GPs taking on PMD-S. Competency, skills and confidence seem to be core factors in decisions to take on PMD. Group practice models (CLSCs, network clinics) and shared-care initiatives should be encouraged to manage more complex PMD cases.


Heart rate variability during hemodialysis and following renal transplantation.
Previous studies have shown awareness of uremic dysfunction in end-stage renal disease (ESRD) patients. Dysautonomia in ESRD patients may be reversible after renal transplantation. We used a power spectral analysis (PSA) of heart rate variability (HRV) to assess alterations of autonomic activity in 14 controls and 14 nondiabetic hemodialysis ESRD patients who had undergone renal transplantation. Compared with matched control subjects, the power frequency determinations of low frequency (LF; 3.42 ln(ms(2)) vs 6.38 ln(ms(2)); P < .05 high frequency (HF; 2.29 ln(ms(2)) vs 5.27 ln(ms(2)); P < .05)), and total power (TP; 5.39 ln(ms(2)) vs 7.53 ln(ms(2)); P < .05) were significantly suppressed in ESRD patients undergoing hemodialysis. ESRD patients showed significantly improved HRV after renal transplantation. After renal transplantation, there was no significant difference in the TP (6.82 ln(ms(2)) vs 7.53 ln(ms(2)); P = .15) component between measurements in both patient subgroups. We further divided the ESRD patients into 2 groups based on their pretransplantation HRV, observing alterations in HRV after renal transplantation. Patients with significantly improved HRV were those with more suppressed HRV before transplantation (HF <3 In(ms(2)). Autonomic dysfunction in ESRD patients was not irreversible even if severe, and recovery was observed as early as 6 months after transplantation.


Antiviral effect of guanidine.
It has been found that soluble guanidine salts show an antiviral effect on poliovirus and on some other enteroviruses. The activity was first detected in a cell culture screening system when the guanidine salt of hydroxyaminomethylene malononitrile inhibited the cytopathic effect of poliovirus in cell cultures. The studies were extended to various in vivo experiments in which the suggestive therapeutic activity of guanidine salts was again observed in monkeys infected with poliovirus. While these drugs cannot be considered for use in human disease because of severe toxicity, it is significant that potential antiviral compounds detected by the cell culture test show in vivo activity and point to the validity of such direct chemotherapeutic trials.


Assessment and Treatment of the Anorexia of Aging: A Systematic Review.
(1) Background: Appetite loss in older people, the 'Anorexia of Aging' (AA), is common, associated with under-nutrition, sarcopenia, and frailty and yet receives little attention. This review had two aims: describe interventions for AA and their effectiveness, and identify the methods of appetite assessment. (2) Methods: Study inclusion: participants aged ≥65, intervention for AA, and appetite assessment, any design, and comparator. Exclusion: studies on specific health cohorts. Searches in four databases with hand searching of references and citing works. Two researchers independently assessed eligibility and quality. (3) Results: Authors screened 8729 titles, 46 full texts. Eighteen articles were included describing nine intervention types: education (n = 1), exercise (n = 1), flavor enhancement (n = 2), increased meal variety (n = 1), mealtime assistance (n = 1), fortified food (n = 1), oral nutritional supplement (ONS) (n = 8), amino acids (n = 1), and medication (n = 2). Three studies evaluated combinations: education + exercise, ONS + exercise, and ONS + medication. Five intervention types exhibited favorable effects on appetite but in single datasets or not replicated. Appetite was assessed predominantly by Likert (n = 9), or visual analogue scales (n = 7). (4) Conclusions: A variety of interventions and methods of appetite assessments were used. There was a lack of clarity about whether AA or undernutrition was the intervention target. AA is important for future research but needs standardized assessment so that effectiveness of a range of interventions can be fully explored.


Consistent Pulmonary Drug Delivery with Whole Lung Deposition Using the Aerosphere Inhaler: A Review of the Evidence.
Metered dose inhalers (MDIs) are one of the most common device types for delivering inhaled therapies. However, there are several technical challenges in development and drug delivery of these medications. In particular, suspension-based MDIs are susceptible to suspension heterogeneity, in vitro drug-drug interactions, and patient handling errors, which may all affect drug delivery. To overcome these challenges, new formulation approaches are required. The AerosphereTM inhaler, formulated using co-suspension delivery technology, combines drug crystals with porous phospholipid particles to create stable, homogenous suspensions that dissolve once they reach the airways. Two combination therapies using this technology have been developed for the treatment of COPD: glycopyrrolate/formoterol fumarate (GFF MDI; dual combination) and budesonide/glycopyrrolate/formoterol fumarate (BGF MDI; triple combination). Here, we review the evidence with a focus on studies assessing dose delivery, lung deposition, and effects on airway geometry. In vitro assessments have demonstrated that the Aerosphere inhaler provides consistent dose delivery, even in the presence of simulated patient handling errors. Combination therapies delivered with this technology also show a consistent fine particle fraction (FPF) and an optimal particle size distribution for delivery to the central and peripheral airways even when multiple drugs are delivered via the same inhaler. Studies using gamma scintigraphy and functional respiratory imaging have demonstrated that GFF MDI is effectively deposited in the central and peripheral airways, and provides clinically meaningful benefits on airway volume and resistance throughout the lung. Overall, studies suggest that the Aerosphere inhaler, formulated using co-suspension delivery technology, may offer advantages over traditional formulations, including consistent delivery of multiple components across patient handling conditions, optimal particle size and FPF, and effective delivery to the central and peripheral airways. Future studies may provide additional evidence to further characterize the clinical benefits of these technical improvements in MDI drug delivery.


Nonmammalian sources of eicosanoids.
Despite the considerable effort expended in the exploration of alternative, large-scale sources of eicosanoids, the first-discovered nonmammalian source--the gorgonian Plexaura homomalla--remains by far the most impressive. The evolutionary reasons for the huge concentrations of prostaglandins in this coral and the origin of the dependence of C-15 configuration on geographical location still constitute fascinating areas for speculation and research. Although the coral provided an extremely valuable interim source of prostaglandins between the eras of biosynthesis and total chemical synthesis, the best of the many synthetic routes now available offer the advantages of versatility and unlimited scale-up potential, and are economically competitive as well. Partial synthesis from various readily available iridoid glycoside intermediates still appears to be an attractive alternative for the preparation of selected eicosanoids. The discovery of unusual eicosanoids such as hybridalactone and the clavulones demonstrates that the oxidative metabolism of C20 unsaturated fatty acids may be considerably more complex than yet realized. The discovery of additional structurally novel, biologically significant eicosanoids from both animal and plant sources can be predicted with virtual certainty. Given the low levels of C20 unsaturated fatty acids in most plants, it is not surprising that the levels of oxidized eicosanoids (e.g., prostaglandins) observed to date in plants have also been very low. The levels were sufficient, however, to dispel the long-popular notion that prostaglandins existed only in the animal kingdom. Plants such as the mosses and ferns mentioned earlier (3,55), which contain unusually large amounts of arachidonic acid, seem to be particularly promising species in which to search for additional novel eicosanoids. In addition to new structures, further information regarding the physiological role of eicosanoids in plants will undoubtedly be forthcoming.


Understanding rib fracture patterns: incomplete and buckle fractures.
Reconstructing traumatic thoracic events, especially when soft tissues are absent, requires an advanced understanding of ribcage fracture patterns. The morphology and orientation of ribs complicate the fracture pattern, as a single blow often causes multiple fractures at various locations. Furthermore, fracture types observed in ribs are not explained easily by current bone biomechanic literature. Using evidential skeletal material archived at the Regional Forensic Center, Memphis, the ribs of 43 blunt force trauma cases were analyzed. A total of 195 incomplete fractures and 63 buckle fractures were noted. Incomplete fractures, previously thought to be common in children but rare in adults, were found among individuals ranging in age from 21-76 years. A buckle fracture, failure resulting from compressive instability, has been undefined previously in bone trauma literature but was repeatedly observed in this sample. This study elucidates recognizable rib fracture patterns while emphasizing gross bone examination for force and mechanical factors.


Single-cell detection of DMSO promoted HL-60 differentiation toward granulocyte based on DC-iDEP for medicine screening.
The most common form of leukemia in adults is acute leukemia. Drug differentiation control is an extremely critical treatment for acute leukemia. Unfortunately, current techniques detecting differentiation control experience long time and complex steps of verification hindering the pace of medicine discovery: flow cytometry and RT-PCR are highly accurate and efficient at a cost of inconvenient fluorescent labeling or a high risk of contamination; conventional staining leads to cell death unavailable for further pharmacological tests. There is a great interest in developing simple, fast, and non-invasive techniques to screen medicine. DC-iDEP is an emerging label-free identification technique taking advantage of the whole cell native biophysical property for sorting cell populations. Here, HL-60 cell line has been used as a model to study the differentiation process toward granulocytes and medicine efficacy. The results showed that DEP succeeded in detecting the DMSO promoted HL-60 differentiation degree by the weighted average characterization factor. This factor is related to the single cell biophysical property, which accumulates to generate differences in each population with distinct constitutions. Furthermore, cichoric acid was investigated to be capable of promoting DMSO-induced differentiation efficiently. Using the change induced by cichoric acid, the HL-60 medicine screening application has been first attempted based on DEP. A rapid, label-free medicine screening method has been established to monitor HL-60 differentiation toward granulocyte and has great potential for medicine screening.


Membrane-bound progesterone receptor expression in human aortic endothelial cells.
Observational studies demonstrate that estradiol and progesterone affect vasoreactivity. In animal studies, progesterone treatment causes immediate relaxation of precontracted arteries with inhibition of calcium influx in vascular endothelial and smooth muscle cells, suggesting a non-genomic mechanism of action. In this study we investigated the presence of novel membrane-bound progesterone receptors in human aortic endothelial cells and correlated the expression with cell-cycle stage. Western blotting analysis with an antibody directed to the hormone-binding domain of the classic progesterone receptors shows predominant bands at 100 and 60 kD, whereas analysis with an antibody to the DNA-binding region shows only the 100-kD band. In contrast, classic nuclear progesterone receptors B and A are identified at 116 and 94 kD in similarly processed T47D cells. Both novel bands localize to the membrane fraction after differential centrifugation. Plasma membrane-bound progesterone receptor was further shown with immunofluorescent antibody and ligand-binding studies in a small percentage of human aortic endothelial cells. Fluorescent activated cell sorting demonstrated that approximately 8% of the human aortic endothelial cells expressed a plasma membrane progesterone receptor and that a greater percentage of the expressing cells were in the G2/M-phase of the cell cycle. Treatment with progesterone conjugated to BSA did not show any significant cell-cycle changes. Plasma membrane-bound progesterone receptor in vascular endothelial cells may regulate the non-genomic actions of progesterone, and expression of the receptor appears to vary with cell cycle stage.


Modelled impact of insecticide-contaminated dung on the abundance and distribution of dung fauna.
Deterministic models assessed the effects that contaminated dung from insecticide-treated cattle had on populations of three hypothetical species of dung fauna that dispersed randomly and could double their numbers every 1-28 weeks at low density. Insecticide was allowed to kill 2-98 % of adults and prevent 16-100% of breeding in pats produced immediately after cattle treatment, with toxicity declining to < 1% in pats produced 2-23 days later. Treatment intervals were 10-40 days. The modelled impact of insecticide was affected little by approximately four-fold variations in: length and density dependence of the attractive life span of pats, frequency of pat occupation by immature adults, distribution of pat toxicity during treatment interval, and changes in dispersal rates due to age and population density. Of greater importance were variations in: pat toxicity, treatment interval, frequency of pat occupation by breeding adults, density dependence of recruitment and death, natural adversity and mortality in dormancy, general rate of dispersal, and the size and shape of the area with treated cattle. Overall, it seemed that wide variations in the impact of contamination will occur in the field, but in many situations the risk to dung fauna can be substantial, especially for slow breeding beetles, and muscoids contacting insecticide on cattle. Risk extends outside the treated areas, for a distance equal to several daily displacements of the insects. Untreated refuges for species survival should be compact blocks at least 25 daily displacements wide.


Autofluorescence and diffuse reflectance spectroscopy of oral epithelial tissue using a depth-sensitive fiber-optic probe.
Optical spectroscopy can provide useful diagnostic information about the morphological and biochemical changes related to the progression of precancer in epithelial tissue. As precancerous lesions develop, the optical properties of both the superficial epithelium and underlying stroma are altered; measuring spectral data as a function of depth has the potential to improve diagnostic performance. We describe a clinical spectroscopy system with a depth-sensitive, ball lens coupled fiber-optic probe for noninvasive in vivo measurement of oral autofluorescence and diffuse reflectance spectra. We report results of spectroscopic measurements from oral sites in normal volunteers and in patients with neoplastic lesions of the oral mucosa; results indicate that the addition of depth selectivity can enhance the detection of optical changes associated with precancer.


Hepatoprotective effect of methanolic Tanacetum parthenium extract on CCl4-induced liver damage in rats.
The purpose of this study was to investigate the effects of Tanacetum Parthenium Extract (TPE) on Lipid peroxidation, antioxidant enzymes, biochemical factors, and liver enzymes in the rats damaged by Carbon Tetrachloride (CCl4). 54 male Wistar rats were divided into 9 groups each consisting of 6 rats. Two of the groups were control groups (normal and damage control groups), 4 of them were exposure groups which were respectively administered with 40, 80, and 120 mg/kg of TPE and silymarin for 14 days before being damaged by CCl4, and the other 3 groups were post-treatment groups which received 80 and 120 mg/kg of TPE and silymarin 2, 6, 24, and 48 h after being injected with CCl4. At the end of the study, biochemical factors, serum liver enzymes, malondialdehyde level, antioxidant enzymes, and liver morphology were assayed. Pre- and post-treatment with TPE could significantly decrease ALT, AST, ALP, TG, LDL, TC, and glucose levels and increase HDL, and albumin levels and catalase, SOD, and GPx activities compared to the CCl4-damaged control group. The results of this study are indicative of the antioxidant activity of TPE, its potential hepatoprotective effects, and its probable therapeutic properties for laboratory animals damaged by CCl4.


Anaerobic biodegradation of aliphatic polyesters: poly(3-hydroxybutyrate-co-3-hydroxyoctanoate) and poly(epsilon-caprolactone).
Poly(3-hydroxybutyrate-co-3-hydroxyoctanoate), PHBO, represents a class of PHA copolymers that contain both short-chain-length and medium-chain-length repeat units. Radiolabeled and cold PHBO, containing 90 mol % 3-hydroxybutyrate and 10 mol % 3-hydroxyoctanoate were chemically synthesized using a new difunctional alkoxyzinc initiator. (14)C-PHBO was incubated with samples of anaerobic digester sludge, septage, freshwater sediment, and marine sediment under conditions resembling those in situ. In addition, it was incubated in laboratory-scale landfill reactors. (14)C-PCL (poly-epsilon-caprolactone) was incubated with anaerobic digester sludge and in landfill reactors. Biodegradation was determined by measuring generation of (14)CO(2) and (14)CH(4) resulting from mineralization of the radiolabeled polymers. PHBO was extensively mineralized in digester sludge, septage sediments, and the landfill reactors, with half-lives less than 30 days. PCL was not significantly mineralized in digester sludge over 122 days. In the landfill reactors, PCL mineralization was slow and was preceded by a long lag period (>200 days), suggesting that PCL mineralization is limited by its rate of hydrolysis. The results indicate that PHBO is practically biodegradable in the major anaerobic habitats that it may enter. In contrast, anaerobic biodegradation of PCL is less ubiquitous and much slower.


An ontological foundation for ocular phenotypes and rare eye diseases.
The optical accessibility of the eye and technological advances in ophthalmic diagnostics have put ophthalmology at the forefront of data-driven medicine. The focus of this study is rare eye disorders, a group of conditions whose clinical heterogeneity and geographic dispersion make data-driven, evidence-based practice particularly challenging. Inter-institutional collaboration and information sharing is crucial but the lack of standardised terminology poses an important barrier. Ontologies are computational tools that include sets of vocabulary terms arranged in hierarchical structures. They can be used to provide robust terminology standards and to enhance data interoperability. Here, we discuss the development of the ophthalmology-related component of two well-established biomedical ontologies, the Human Phenotype Ontology (HPO; includes signs, symptoms and investigation findings) and the Orphanet Rare Disease Ontology (ORDO; includes rare disease nomenclature/nosology). A variety of approaches were used including automated matching to existing resources and extensive manual curation. To achieve the latter, a study group including clinicians, patient representatives and ontology developers from 17 countries was formed. A broad range of terms was discussed and validated during a dedicated workshop attended by 60 members of the group. A comprehensive, structured and well-defined set of terms has been agreed on including 1106 terms relating to ocular phenotypes (HPO) and 1202 terms relating to rare eye disease nomenclature (ORDO). These terms and their relevant annotations can be accessed in http://www.human-phenotype-ontology.org/ and http://www.orpha.net/ ; comments, corrections, suggestions and requests for new terms can be made through these websites. This is an ongoing, community-driven endeavour and both HPO and ORDO are regularly updated. To our knowledge, this is the first effort of such scale to provide terminology standards for the rare eye disease community. We hope that this work will not only improve coding and standardise information exchange in clinical care and research, but also it will catalyse the transition to an evidence-based precision ophthalmology paradigm.


Periodontal ligament cells are chemotactic to fibroblast collagenase.
Periodontal ligament (PDL) cell motility and the passage of PDL cells along a root surface are important components of tissue remodeling during periodontal regeneration. Proteolytic enzymes, including fibroblast collagenase, have been demonstrated to play an important role in tissue remodeling. Previous studies have shown that PDL cells chemotactically respond to a variety of matrix and growth factors. We therefore studied the effects of type I collagen fragments and fibroblast collagenase on PDL cell migration, since PDL cells have been shown to adhere preferentially to partially demineralized root surfaces with exposed type I collagen. Gingival epithelial cells were used as a control cell population. We report that PDL cells but not gingival epithelial cells preferentially migrate in a dose-dependent manner to both fibroblast collagenase and to type I collagen degradation products. Epithelial cell migration to fibroblast collagenase and type I collagen fragments was observed. Antibody to type I collagen inhibited the type I collagen fragment-mediated migration. Collagenase pre-treatment of PDL cells enhanced PDL cell migration to type I collagen fragments. In other assays, enzyme inhibitors were shown to decrease the collagenase-mediated PDL cell motility. Epithelial cells were shown to migrate preferentially to 92-kDa type IV collagenase and type IV collagen degradation products. Antibody to type IV collagen inhibited type IV collagen-induced epithelial cell migration. Taken together, these data suggest a role for collagenase in the fine control of PDL cell migration in tissue remodeling during periodontal regeneration.


High AST/ALT ratio may indicate advanced alcoholic liver disease rather than heavy drinking.
To assess the place of AST/ALT ratio (the ratio of serum aspartate aminotransferase to serum alanine aminotransferase) as a diagnostic marker in medical populations. Laboratory tests were viewed retrospectively in three groups of patients: 313 patients with alcohol dependence, consecutively admitted to an alcohol and drug treatment unit for treatment of withdrawal (W) symptoms, 78 patients with alcohol abuse or dependence consecutively admitted to surgical or medical wards with various primary somatic (S) diagnoses (e.g. respiratory, gastrointestinal and metabolic), and 48 consecutive patients with alcohol abuse or dependence admitted to surgical or medical wards for treatment of alcohol-related liver cirrhosis and its complications (C). Comparison between groups was made of the pattern of patients' AST/ALT ratios using, for Groups S and C, laboratory data from patients' first admission for their condition. There was a significant rise in the AST/ALT ratio from the W to the S patients, and from the S to the C patients. In the W group, the ratio was < or = 1.0 in 64% of the patients, and only exceptionally > or = 2. In the C group, 69% had a ratio > or = 2, and 8% a ratio < or = 1.0. The mean ratio was midway in the S group. In the C group, there was a progressive decline in aspartate (AST/ALT) ratios after admission. Most patients with high alcohol consumption but without severe liver disease do not have an AST/ALT ratio above 1. High AST/ALT ratio suggests advanced alcoholic liver disease.


Treatment with verapamil for restoration of sinus rhythm in atrial fibrillation with rapid ventricular response: A case report.
Atrial fibrillation (AF) is a common arrhythmia disease that can cause thromboembolic disease and/or heart failure, resulting in increased mortality. Propafenone, amiodarone, and flecainide are recommended for converting AF to sinus rhythm. Beta blockers, verapamil, diltiazem, and digoxin are recommended for controlling AF with fast ventricular rate (VR). In this case report, we found that verapamil successfully converted AF into sinus rhythm. A 92-year-old woman presented with fast VR AF with a history of coronary heart disease, hypertension, and diabetes. Verapamil can successfully convert AF into sinus rhythm. The patient was treated with amiodarone or propafenone, yet still had AF. After stopping amiodarone and propafenone, the patient was given verapamil to control the VR, and following 9 days of treatment the patient switched to sinus rhythm. When verapamil treatment was stopped, the patient experienced AF recurrence. Upon receiving verapamil again, the AF again converted into sinus rhythm. For the treatment of AF, nondihydropyridine calcium antagonists can be tried in the absence of antiarrhythmic drugs.


The effects of minodronate and activated vitamin D on bone mineral density and muscle mass in postmenopausal women with osteoporosis.
Osteoporosis and sarcopenia are said to be similar disorders. However, few reports have described the effects of anti-osteoporosis drugs on muscle mass in clinical practice. We selected 150 postmenopausal women with osteoporosis treated by minodronate (osteoporosis medication [OM] group) and 50 postmenopausal women without osteoporosis who did not receive treatment (no osteoporosis [NO] group). The OM group was further divided into two treatment subgroups: a combination of monthly minodronate and daily activated vitamin D vs. monthly minodronate alone. We measured lumbar spine and femoral neck bone mineral density (BMD) with dual-energy X-ray absorptiometry and muscle mass of the upper limbs, lower limbs, and trunk with bioelectrical impedance analysis at baseline and after 6 months. The OM and NO groups contained 130 and 37 patients, respectively (mean age: 73.9 ± 8.3 and 74.1 ± 10.0 years, respectively). In the OM group, lumbar spine BMD significantly increased after 6 months, while lower limb muscle mass significantly decreased. In the NO group, lumbar spine BMD and lower limb muscle mass did not significantly change after 6 months. In the OM group, BMD of the lumbar spine significantly increased but the lower limb muscle mass significantly decreased after 6 months relative to the NO group. In the combination therapy subgroup of the OM group muscle mass decreased significantly less than in the minodronate-alone subgroup. In postmenopausal women with osteoporosis, minodronate can increase BMD but cannot increase muscle mass. However, simultaneous use of activated vitamin D can suppress muscle mass decrease. The combination of activated vitamin D and minodronate may be useful for treating osteoporosis in postmenopausal women.


Sustained efficacy of adjuvant immunotherapy with cytokine-induced killer cells for hepatocellular carcinoma: an extended 5-year follow-up.
Our earlier multicenter randomized controlled trial showed that adjuvant immunotherapy with cytokine-induced killer (CIK) cells resulted in longer recurrence-free survival (RFS) and overall survival (OS) as well in patients who received curative treatment for hepatocellular carcinoma (HCC). In the present study, we determined if the efficacy of CIK cell therapy continued after end of repeated CIK cell injections. We performed a follow-up study of our preceding trial. We included 226 patients: 114 patients in the immunotherapy group (injection of 6.4 × 109 CIK cells, 16 times during 60 weeks) and 112 patients in the control group (no treatment) after potentially curative treatment for HCC. In total, 162 patients (89 of the immunotherapy group and 73 of controls) underwent an extended follow-up for 60 months after randomization of the last patient. The primary endpoint was RFS, and secondary endpoints included OS. During follow-up time of median 68.5 months (interquartile range 45.0-82.2 months), the immunotherapy group continued to show a significantly lower risk of recurrence or death [hazard ratio (HR) 0.67; 95% confidence interval (CI) 0.48-0.94; P = 0.009 by one-sided log-rank test]. At 5 years, RFS rate was 44.8% in the immunotherapy group and 33.1% in the control group. The risk of all-cause death was also lower in the immunotherapy group compared to the control group (HR 0.33; 95% CI 0.15-0.76; P = 0.006). In patients who received curative treatment for HCC, the significant improvement in RFS and OS as a result of adjuvant CIK cell immunotherapy lasted over 5 years without boosting.


Single-cell proteomic and transcriptomic analysis of macrophage heterogeneity using SCoPE2.
Macrophages are innate immune cells with diverse functional and molecular phenotypes. This diversity is largely unexplored at the level of single-cell proteomes because of the limitations of quantitative single-cell protein analysis. To overcome this limitation, we develop SCoPE2, which substantially increases quantitative accuracy and throughput while lowering cost and hands-on time by introducing automated and miniaturized sample preparation. These advances enable us to analyze the emergence of cellular heterogeneity as homogeneous monocytes differentiate into macrophage-like cells in the absence of polarizing cytokines. SCoPE2 quantifies over 3042 proteins in 1490 single monocytes and macrophages in 10 days of instrument time, and the quantified proteins allow us to discern single cells by cell type. Furthermore, the data uncover a continuous gradient of proteome states for the macrophages, suggesting that macrophage heterogeneity may emerge in the absence of polarizing cytokines. Parallel measurements of transcripts by 10× Genomics suggest that our measurements sample 20-fold more protein copies than RNA copies per gene, and thus, SCoPE2 supports quantification with improved count statistics. This allowed exploring regulatory interactions, such as interactions between the tumor suppressor p53, its transcript, and the transcripts of genes regulated by p53. Even in a homogeneous environment, macrophage proteomes are heterogeneous. This heterogeneity correlates to the inflammatory axis of classically and alternatively activated macrophages. Our methodology lays the foundation for automated and quantitative single-cell analysis of proteins by mass spectrometry and demonstrates the potential for inferring transcriptional and post-transcriptional regulation from variability across single cells.


Application of a myoelectric elbow flexion assist orthosis in adult traumatic brachial plexus injury: patient perspectives.
Individuals with brachial plexus injuries (BPIs) can be prescribed assistive devices, including myoelectric elbow orthoses (MEOs), for rehabilitation or functional use after failed treatment for elbow flexion restoration. Although recent case studies indicate potential for clinical improvements after using an MEO after BPI, the patients' perspectives on such use are still unknown. To explore patient perspectives on the use of an MEO after surgical treatment for a traumatic BPI. Qualitative using both a focus group and semistructured interviews. Patients with BPI that used an MEO were recruited. Five patients participated in an in-person focus group, whereas three patients participated in individual phone interviews. Themes that emerged from the focus group were compared against those that emerged from the personal interviews. Feedback was grouped into three themes: device usage, hardware performance, and device design. Within each theme, positive elements, areas for improvement, and additional considerations emerged. Patients indicated a positive attitude toward using an MEO as a rehabilitation tool. They desired a streamlined, stronger device to support them and assist during activities of daily living. For patients with BPI, a well-designed MEO that meets their needs could assist with rehabilitation and increase independence in daily activities. Continued patient engagement in the evaluation and development of both medical devices and treatment plans offers the best opportunity for improved outcomes that are important to the patient.


Mouse models for infectious diseases caused by Staphylococcus aureus.
Staphylococcus aureus - a commensal of the human skin, nares and gastrointestinal tract - is also a leading cause of bacterial skin and soft tissue infection (SSTIs), bacteremia, sepsis, peritonitis, pneumonia and endocarditis. Antibiotic-resistant strains, designated MRSA (methicillin-resistant S. aureus), are common and represent a therapeutic challenge. Current research and development efforts seek to address the challenge of MRSA infections through vaccines and immune therapeutics. Mice have been used as experimental models for S. aureus SSTI, bacteremia, sepsis, peritonitis and endocarditis. This work led to the identification of key virulence factors, candidate vaccine antigens or immune-therapeutics that still require human clinical testing to establish efficacy. Past failures of human clinical trials raised skepticism whether the mouse is an appropriate model for S. aureus disease in humans. S. aureus causes chronic-persistent infections that, even with antibiotic or surgical intervention, reoccur in humans and in mice. Determinants of S. aureus evasion from human innate and adaptive immune responses have been identified, however only some of these are relevant in mice. Future research must integrate these insights and refine the experimental mouse models for specific S. aureus diseases to accurately predict the failure or success for candidate vaccines and immune-therapeutics.


Current treatment options: impact of cytogenetics on the course of myelodysplasia.
The heterogeneity of myelodysplastic syndromes (MDS) has driven the search for unifying biologic and clinical features that would stratify patients into distinct prognostic and therapeutic subgroups. Cytogenetics has been shown to impact the course of myelodysplasia. Despite the presence of non-random cytogenetic abnormalities in approximately 50% of MDS patients, it is significant that only a proportion of metaphases may contain the abnormality. Clonality studies however show that the karyotypically normal metaphases are still part of the MDS clone. This would suggest that the chromosomal abnormality may not be the initiating lesion in MDS, and that the gross karyotypic changes represent clonal evolution in a genetically unstable population. Yet, as will be described below, specific cytogenetic abnormalities are associated with clinically and biologically distinct forms of the disease, most notable in the response of del(5q) patients to lenalidomide. One possible explanation for the appearance of non-random mutational events could relate to the interaction of MDS cells with their microenvironment. Whatever the initiating lesion in the MDS stem cell, the end result is a clonal expansion where the marrow becomes populated by the monoclonal progeny of this cell. Interaction of these cells with a microenvironment which has been shown to be rich in pro-apoptotic cytokines such as tumor necrosis factor alpha (TNFa), leads to increased genetic instability. Hypoxia mediated decrease in DNA repair enzymes could further accelerate mutational events culminating in accumulation of multiple chromosomal abnormalities. Some of these chromosomal changes are associated with increased sensitivity to specific drugs. Lenalidomide has shown a high degree of efficacy in MDS patients with del(5q), although the target for the drug is unknown since a small but significant subset of MDS patients without del(5q) abnormality also respond to the drug. In contrast, the molecular target for imatinib mesylate is known; mutations in tyrosine kinase receptor family of genes found in patients with t(5;12) and del(4q12) make these individuals sensitive to the drug. Patients with isolated trisomy 8 have an immune component to the disease phenotype which can be targeted by cyclosporine and or anti-thymocyte globulin (ATG), especially in the presence of a PNH (paroxysmal nocturnal hemoglobinurea) clone. In the absence of these specific cytogenetic abnormalities described above, the two FDA approved hypomethylating agents 5 azacytidine and decitabine should be considered as therapeutic alternatives.


Oligomerization of herpes simplex virus glycoprotein B.
Glycoprotein B (gB) specified by herpes simplex virus can be extracted from virions or infected cells in the form of detergent-stable, heat-dissociable oligomers. The composition of the oligomers and requirements for their formation were investigated. Evidence is presented that the faster-migrating forms of the oligomers are homodimers of gB. Dimerization was shown to occur within minutes of polypeptide synthesis and did not depend on glycosylation, the expression of other viral proteins, or virion morphogenesis. The multiple, electrophoretically distinct forms of gB dimers differ in extent or rate of N-linked oligosaccharide processing and also have other differences that influence electrophoretic mobility.


Elucidating the process of activation of methyl-coenzyme M reductase.
Methyl-coenzyme M reductase (MCR) catalyzes the reversible reduction of methyl-coenzyme M (CH3-S-CoM) and coenzyme B (HS-CoB) to methane and heterodisulfide CoM-S-S-CoB (HDS). MCR contains the hydroporphinoid nickel complex coenzyme F430 in its active site, and the Ni center has to be in its Ni(I) valence state for the enzyme to be active. Until now, no in vitro method that fully converted the inactive MCRsilent-Ni(II) form to the active MCRred1-Ni(I) form has been described. With the potential use of recombinant MCR in the production of biofuels and the need to better understand this enzyme and its activation process, we studied its activation under nonturnover conditions and achieved full MCR activation in the presence of dithiothreitol and protein components A2, an ATP carrier, and A3a. It was found that the presence of HDS promotes the inactivation of MCRred1, which makes it essential that the activation process is isolated from the methane formation assay, which tends to result in minimal activation rates. Component A3a is a multienzyme complex that includes the mcrC gene product, an Fe-protein homolog, an iron-sulfur flavoprotein, and protein components involved in electron bifurcation. A hypothetical model for the cellular activation process of MCR is presented.


Characterization of a sodium pump-induced hyperpolarization in isolated human atrium.
Specimens of right atrial appendage from 106 patients were incubated in cold Tyrode solution, and transmembrane resting potentials (Em) were recorded during rewarming at selected temperatures. Rewarming caused a transient hyperpolarization to develop. The hyperpolarization had a temperature threshold between 17 and 22 degrees C and was inhibited by acetylstrophanthidin. Acetylcholine (ACh) induced a depolarization during early rewarming in 7, 10, 20, and 40 mM K+, indicating that Em hyperpolarized to a potential negative to the equilibrium potential for K+. ACh had no effect after some decline of Em, and hyperpolarization was induced by ACh when Em had reached steady state. The relationship between [K+] in the bulk phase of the superfusate [( K]b) and the "reversal potentials" for the ACh effect was log linear and had a slope of 61.7 mV per tenfold change in [K]b. The relationship between [K]b and hyperpolarization was studied in the presence of 0.5 mM Ba2+. The apparent [K]b resulting in half-maximal pump-induced hyperpolarization was 1.3 mM. The data indicate that human atrium can pump Na+ electrogenically and that the characteristics of the Na+ pump-induced hyperpolarization resemble those described for cardiac tissue from several other mammalian species.


Brominating oxidants generated by human eosinophils.
Eosinophils are white blood cells that in humans are found in association with helminthic infections and various inflammatory disease processes. These cells contain a unique lysosomal peroxidase that oxidizes halides to generate highly reactive and toxic hypohalous acids. Although chloride is found in vivo at concentrations at least 1000-fold greater than those of other halides, human eosinophils did not preferentially oxidize chloride under physiologic conditions. Instead, eosinophils used bromide, a halide with a hitherto unknown function in humans, to generate a halogenating oxidant with characteristics similar, if not identical, to those of hypobromous acid. These results indicate that physiological concentrations of bromide arm human eosinophils with the ability to generate and release an unusual oxidant capable of destroying a wide range of prokaryotic and eukaryotic targets.


Anti-beta(2)-glycoprotein I autoantibody expression as a potential biomarker for strokes in patients with anti-phospholipid syndrome.
Anti-phospholipid syndrome (APS) is an autoimmune disease. Cerebral ischemia associated with APS occurs at a younger age than typical atherothrombotic cerebrovascular disease, is often recurrent, and is associated with high positive IgG anti-phospholipid (GPL) unit levels. This study sought to determine the frequency rates of anti-cardiolipin (aCL) dependent on the presence of beta(2)-GPI, anti-beta(2)-glycoprotein I (abeta(2)-GPI), and anti-phosphatidyl serine (aPS) IgG autoantibodies among stroke patients, and thus demonstrate the importance of testing for abeta(2)-GPI autoantibodies. For these study, stroke patients and control subjects recruited from Mosul, Erbil, and Dohuk provinces in Northeren Iraq between March 2004 and March 2005 were evaluated. All cases were under 50 years-of-age and had no recognizable risk factors. Using ELISA to evaluate the presence of IgG isotype of aCL, abeta(2)-GPI, and aPS autoantibodies in their blood, the results indicated that the frequency of abeta(2)-GPI was 14/50 (28%), aCL was 11/50 (22%), and aPS was 9/50 (18%) among stroke patients. In contrast, aCL was detected in 2/30 (6.7%) of control subjects; each of the other anti-phospholipid antibodies (APLA) was never observed. Of all the abeta(2)-GPI(+) cases, the incidence of stroke patients having the combined profile of abeta(2)-GPI + aCL was 11/14 (78.6%) and of abeta(2)-GPI + aPS was 9/14 (64.3%). Only 2/14 (14.3%) of these abeta(2)-GPI(+) patients also expressed aCL in the absence of aPS. The frequency of patients expressing all three markers was only 9/14 (64.3 %). In none of the APS/stroke patients were aCL or aPS expressed in the absence of the abeta(2)-GPI. Conversely, abeta(2)-GPI as a sole marker was seen in 3/14 (21.4%) of these patients (i.e., in absence of either other marker). It can be concluded from these studies that the among the three major forms of APLA examined, the presence of abeta(2)-GPI IgG autoantibodies appeared to correlate best with stroke in patients who were concurrently suffering APS.


Epinephrine plasma thresholds for lipolytic effects in man: measurements of fatty acid transport with [l-13C]palmitic acid.
To determine the plasma epinephrine thresholds for its lipolytic effect, 60-min epinephrine infusions at nominal rates of 0.1, 0.5, 1.0, 2.5, and 5.0 micrograms/min were performed in each of four normal young adult men while they also received a simultaneous infusion of [1-13C]palmitic acid to estimate inflow transport of plasma free fatty acids. These 20 infusions resulted in steady-state plasma epinephrine concentrations ranging from 12 to 870 pg/ml. Plasma epinephrine thresholds for changes in blood glucose, lactate, and beta-hydroxybutyrate were in the 150--200-pg/ml range reported by us previously (Clutter, W. E., D. M. Bier, S. D. Shah, and P. E. Cryer. 1980. J. Clin. Invest. 66: 94--101.). Increments in plasma glycerol and free fatty acids and in the inflow and outflow transport of palmitate, however, occurred at lower plasma epinephrine thresholds in the range of 75 to 125 pg/ml. Palmitate clearance was unaffected at any steady-state epinephrine level produced. These data indicate that (a) the lipolytic effects of epinephrine occur at plasma levels approximately threefold basal values and (b) lipolysis is more sensitive than glycogenolysis to increments in plasma epinephrine.


A growth factor from neuronal cell lines stimulates myelin protein synthesis in mammalian brain.
Oligodendroglia growth factor (OGF) is a 16-kDa soluble protein produced by neuronal cell lines. This factor, when incubated with brain glia in culture, selectively stimulates growth of oligodendroglia, the myelin-producing cells of the CNS. OGF infused into the cerebral cortex of the adult rat accelerates the production of myelin proteins as shown by increased specific activity of the myelin enzyme 2',3'-cyclic nucleotide 3'-phosphohydrolase (2',3'-CNPase), by stimulated synthesis of myelin basic protein, and by elevations in levels of myelin proteolipid protein RNA. The ability of OGF to induce myelin protein production in vivo suggests that neuron-secreted growth factors help to regulate myelin formation within the CNS.


[LEGAL CONSIDERATIONS FOR NURSES. THE PRINCIPLE OF AUTONOMY AND THE REJECTION OF THERAPY WITH BLOOD: JEHOVAH'S WITNESSES].
Although it seems that the issue of law and bioethics has been much debated today, still raising doubts and conflicts among the nursing staff on what their regulation must relationship between law and bioethics, or that we should know about informed consent and advance directive, if the Jehovah's Witnesses can refuse the treatments, and how these decisions affect the person and how it relates to the principle of autonomy, which are covered by a legal framework that gives greater freedom and autonomy to the patient's decision. The Jehovah's Witnesses are a Christian community descended from a group of scholars, who base their beliefs on a particular interpretation of the Bible and that, in Spain, like other denominations, are registered in the Registry of Religious Entities of the Directorate General of Religious Affairs of the Ministry of Justice. Therefore, this paper intends to analyze through a literature review the ethical and legal concepts within the existing legal framework, and how the decisions made by people, even still risking their life, must be accepted andprotected by a legalremedy, without prejudice to the exceptions provided by law.


Fit of zirconia fixed partial denture: a systematic review.
The aim of this study is to review all the published literature investigating the accuracy of fit of zirconia fixed partial dentures (FPD). A comprehensive electronic search was performed through PubMed (MEDLINE) using Boolean operators to combine the following key words: 'zirconia,''margin,''FPD,''internal,''fit,''gap,''fitting surface,''bridge' and 'fixed prosthesis.' The search was limited to articles written in English, published up to January 2010. In addition, a manual search was also conducted through articles and reference lists retrieved from the electronic search and peer-reviewed journals. A total of 115 articles were retrieved and only 15 met the specified inclusion criteria for the review. Twelve of these articles were in vitro and three of them were in vivo. The selected articles had assessed marginal and/or internal fit of zirconia FPDs against the effect of various parameters that were computer-aided design and computer-aided manufacturing (CAD/CAM) and CAM systems, post-sintered and pre-sintered milling, framework configuration, span length, veneer application and ageing. CAD/CAM, post-sintered milling, straight configuration and shorter span frameworks provided superior results than CAM, pre-sintered milling, curved configuration and longer span frameworks. Veneering zirconia frameworks caused deterioration in fit, while ageing of zirconia had no implications on the fit. Further studies are needed to determine the clinical significance of the differences in the accuracy reported in this review.


Achromatopsia-Visual Cortex Stability and Plasticity in the Absence of Functional Cones.
Achromatopsia is a rare inherited disorder rendering retinal cone photoreceptors nonfunctional. As a consequence, the sizable foveal representation in the visual cortex is congenitally deprived of visual input, which prompts a fundamental question: is the cortical representation of the central visual field in patients with achromatopsia remapped to take up processing of paracentral inputs? Such remapping might interfere with gene therapeutic treatments aimed at restoring cone function. We conducted a multicenter study to explore the nature and plasticity of vision in the absence of functional cones in a cohort of 17 individuals affected by autosomal recessive achromatopsia and confirmed biallelic disease-causing CNGA3 or CNGB3 mutations. Specifically, we tested the hypothesis of foveal remapping in human achromatopsia. For this purpose, we applied two independent functional magnetic resonance imaging (fMRI)-based mapping approaches, i.e. conventional phase-encoded eccentricity and population receptive field mapping, to separate data sets. Both fMRI approaches produced the same result in the group comparison of achromatopsia versus healthy controls: sizable remapping of the representation of the central visual field in the primary visual cortex was not apparent. Remapping of the cortical representation of the central visual field is not a general feature in achromatopsia. It is concluded that plasticity of the human primary visual cortex is less pronounced than previously assumed. A pretherapeutic imaging workup is proposed to optimize interventions.


The mitochondrial compartment.
Mitochondria are vital organelles that perform a variety of fundamental functions ranging from the synthesis of ATP through to being intimately involved in programmed cell death. Comprised of at least six compartments: outer membrane, inner boundary membrane, intermembrane space, cristal membranes, intracristal space, and matrix, mitochondria have a complex, dynamic internal structure. This internal dynamism is reflected in the pleomorphy and motility of mitochondria. Mitochondria contain their own DNA (mtDNA), encoding a small number of vital genes, but this role as a genetic vault is not compatible with the role of mitochondria in bioenergetics since electron transport results in the generation of reactive oxygen species (ROS) that induce lesions in the mtDNA. It is hypothesized that ROS shape the morphological organization of the higher plant cell mitochondrial population into a discontinuous whole, and that ROS are a selective pressure affecting the organization of the mitochondrial genome. This review describes how inter- and intra-mitochondrial compartmentalization underpins the biology of this complex organelle.


Modules or Mean-Fields?
The segregation of neural processing into distinct streams has been interpreted by some as evidence in favour of a modular view of brain function. This implies a set of specialised 'modules', each of which performs a specific kind of computation in isolation of other brain systems, before sharing the result of this operation with other modules. In light of a modern understanding of stochastic non-equilibrium systems, like the brain, a simpler and more parsimonious explanation presents itself. Formulating the evolution of a non-equilibrium steady state system in terms of its density dynamics reveals that such systems appear on average to perform a gradient ascent on their steady state density. If this steady state implies a sufficiently sparse conditional independency structure, this endorses a mean-field dynamical formulation. This decomposes the density over all states in a system into the product of marginal probabilities for those states. This factorisation lends the system a modular appearance, in the sense that we can interpret the dynamics of each factor independently. However, the argument here is that it is factorisation, as opposed to modularisation, that gives rise to the functional anatomy of the brain or, indeed, any sentient system. In the following, we briefly overview mean-field theory and its applications to stochastic dynamical systems. We then unpack the consequences of this factorisation through simple numerical simulations and highlight the implications for neuronal message passing and the computational architecture of sentience.


Genetic and physiological analysis of the major OxyR-regulated katA from Xanthomonas campestris pv. phaseoli.
katA encodes the major catalase that accounts for 90 % of the total catalase activity present in Xanthomonas campestris pv. phaseoli. katA is located upstream of an ORF designated ankA encoding a cytoplasmic membrane protein homologous to eukaryotic ankyrin. Transcriptional analysis of katA and ankA identified two katA transcripts: a major monocistronic katA transcript and a minor bicistronic katA-ankA transcript. KatA expression was induced in the presence of various oxidants including H2O2, organic hydroperoxides and the superoxide-generating agent menadione, in an OxyR-dependent manner. Analysis of the katA promoter region showed a putative OxyR binding site located upstream of an Escherichia coli-like sigma70 -35 region that is likely to be responsible for transcription activation in response to oxidant treatment. Gel mobility shift experiments confirmed that purified OxyR specifically binds to the katA promoter. A katA mutant was highly sensitive to H2O2 during both the exponential and stationary phases of growth. This phenotype could be complemented by functional katA, confirming the essential role of the gene in protecting X. campestris from H2O2 toxicity. Unexpectedly, inactivation of ankA also significantly reduced resistance to H2O2 and the phenotype could be complemented by plasmid-borne expression of ankA. Physiological analyses showed that katA plays an important role in, but is not solely responsible for, both the adaptive and menadione-induced cross-protective responses to H2O2 killing in X. campestris.


Uranium facilitated transport by water-dispersible colloids in field and soil columns.
The transport of uranium through a sandy podzolic soil has been investigated in the field and in column experiments. Field monitoring, numerous years after surface contamination by depleted uranium deposits, revealed a 20 cm deep uranium migration in soil. Uranium retention in soil is controlled by the <50 microm mixed humic and clayey coatings in the first 40 cm i.e. in the E horizon. Column experiments of uranium transport under various conditions were run using isotopic spiking. After 100 pore volumes elution, 60% of the total input uranium is retained in the first 2 cm of the column. Retardation factor of uranium on E horizon material ranges from 1300 (column) to 3000 (batch). In parallel to this slow uranium migration, we experimentally observed a fast elution related to humic colloids of about 1-5% of the total-uranium input, transferred at the mean porewater velocity through the soil column. In order to understand the effect of rain events, ionic strength of the input solution was sharply changed. Humic colloids are retarded when ionic strength increases, while a major mobilization of humic colloids and colloid-borne uranium occurs as ionic strength decreases. Isotopic spiking shows that both (238)U initially present in the soil column and (233)U brought by input solution are desorbed. The mobilization process observed experimentally after a drop of ionic strength may account for a rapid uranium migration in the field after a rainfall event, and for the significant uranium concentrations found in deep soil horizons and in groundwater, 1 km downstream from the pollution source.


New Perianal Sepsis Risk Score Predicts Outcome of Elderly Patients with Perianal Abscesses.
Antibiotic therapy following surgical perianal abscess drainage is debated, but may be necessary for high-risk patients. Frailty has been shown to increase the risk of unfavorable outcomes in elderly surgical patients. This study aims to identify high-risk patients by retrospectively analyzing a single-center cohort and using a pretherapeutic score to predict the need for postoperative antibiotics and extended nursing care following perianal abscess drainage surgery. The perianal sepsis risk score was developed through univariable and multivariable analysis. Internal validation was assessed using the area under receiver-operating characteristic curve. Elderly, especially frail patients exhibited more severe perianal disease, higher frequency of antibiotic therapy, longer hospitalization, poorer clinical outcomes. Multivariable analysis revealed that scores in the 5-item modified frailty index, severity of local infection, and preoperative laboratory markers of infection independently predicted the need for prolonged hospitalization and anti-infective therapy after abscess drainage surgery. These factors were combined into the perianal sepsis risk score, which demonstrated better predictive accuracy for prolonged hospitalization and antibiotic therapy compared with chronological age or frailty status alone. Geriatric assessments are becoming increasingly important in clinical practice. The perianal sepsis risk score identifies high-risk patients before surgery, enabling early initiation of antibiotic therapy and allocation of additional nursing resources.


Burden of Heart Failure Signs and Symptoms, Prognosis, and Response to Therapy: The PARAGON-HF Trial.
This study investigated the prognostic importance of heart failure (HF) signs and symptoms in patients with heart failure and preserved ejection fraction (HFpEF), and the effect of sacubitril/valsartan on HF signs and symptoms. In patients with HFpEF, worsening of HF symptoms, as a marker of cardiac decompensation, is frequently the reason for hospitalization. In this heterogenous disease entity, the prognostic value of HF signs and symptoms with regard to cardiovascular (CV) outcomes is poorly defined. The authors examined the association between baseline HF signs and symptoms (rest dyspnea, exertional dyspnea, paroxysmal nocturnal dyspnea, orthopnea, fatigue, edema, jugular venous distension, rales, and third heart sound) as well as burden of these HF signs and symptoms (classified as ≤2 and ≥3 HF signs and symptoms) and the primary composite of total HF hospitalizations and CV death, its components, and all-cause death in 4,725 patients enrolled in PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in HFpEF) with available signs and symptoms at randomization. Response to sacubitril/valsartan on the basis of the presence of signs and symptoms was evaluated. Effects of sacubitril/valsartan on signs and symptoms over time were assessed using binary repeated-measures logistic regression. Patients with high (≥3) burden of HF signs and symptoms (n = 1,772 [38%]) were more commonly women, had slightly lower left ventricular ejection fractions, higher body mass index, and more advanced New York Heart Association functional class compared with patients with low (≤2) burden (n = 2,953 [62%]) (p < 0.001 for all). Levels of N-terminal pro-B-type natriuretic peptide did not differ significantly between groups (p = 0.14). Greater burden of signs and symptoms was associated with higher risk for total HF hospitalizations and CV death (rate ratio [RR]: 1.50; 95% confidence interval [CI]: 1.30 to 1.74) and all-cause death (RR: 1.41; 95% CI: 1.21 to 1.65). Among individual signs and symptoms, orthopnea (RR: 1.29; 95% CI: 1.04 to 1.61) and rales (RR: 1.52; 95% CI: 1.10 to 2.10) were most predictive of the primary endpoint. Treatment response to sacubitril/valsartan was not significantly modified by burden of HF signs and symptoms (p for interaction = 0.08), though patients with orthopnea appeared to derive greater benefit from sacubitril/valsartan (RR: 0.67; 95% CI: 0.49 to 0.90) than those without orthopnea (RR: 0.97; 95% CI: 0.82 to 1.14; p for interaction = 0.04). Compared with valsartan, sacubitril/valsartan did not significantly decrease overall burden of HF signs and symptoms over time (odds ratio: 0.84; 95% CI: 0.67 to 1.07) but did reduce exertional dyspnea (odds ratio: 0.76; 95% CI: 0.63 to 0.93). High burden of HF signs and symptoms, particularly the presence of orthopnea and rales, portends a higher risk for adverse CV events in patients with HF with preserved ejection fraction. Sacubitril/valsartan did not significantly decrease the burden of HF signs and symptoms over time but did reduce exertional dyspnea relative to valsartan. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).