Symmetry activates extrastriate visual cortex in human and nonhuman primates.
Humans often create and appreciate visual symmetry in their environment, and the underlying brain mechanisms have been a topic of increasing interest. Here, symmetric versus random dot stimuli produced robust functional MRI (fMRI) activity in higher-order regions of human visual cortex (especially areas V3A, V4, V7, and LO) but little activity elsewhere in brain. This fMRI response was found both with and without attention controls. Moreover, it was highly correlated with the psychophysical perception of symmetry. Similar symmetry responses were found by using line-based and dot stimuli and were found at a wide range of stimulus sizes and geometric configurations. Weaker symmetry responses were found in analogous regions of macaque visual cortex by using fMRI techniques with higher sensitivity. This evidence suggests that visual symmetry is specifically enhanced in the human brain, but that the underlying neural mechanisms may nevertheless be resolvable in nonhuman primates.


[Distribution, surface and protected area of palm-swamps in Costa Rica and Nicaragua].
In Central America, palm swamps are known collectively as yolillales. These wetlands are usually dominated by the raffia palm Raphia taedigera, but also by the royal palm Manicaria saccifera and -in lower extensions- by the American oil palm Elaeis oleifera. The yolillales tend to be poor in woody species and are characteristic of regions with high rainfall and extensive hydroperiods, so they remain flooded most of the year. The dominance of large raffia palm leaves in the canopy, allow these environments to be distinguishable in aerial photographs, which consequently has helped to map them along most of their distribution. However, while maps depicting yolillales are available, the extent of their surface area, perimeter and connectivity remains poorly understood. This is particularly true for yolillales in Costa Rica and Nicaragua, countries that share a good proportion of palm dominated swaps in the Rio San Juan Basin. In addition, it is not known the actual area of these environments that is under any category of protection according to the conservation systems of both countries. As a first step to catalog yolillal wetlands in Costa Rica and Nicaragua, this paper evaluates cartographic maps to delineate yolillales in the region. A subsample of yolillales mapped in this study were visited and we geo-referenced them and evaluate the extent and condition of the swamp. A total of 110 883.2ha are classified as yolillales in Nicaragua, equivalent to 22% of wetland surface area recorded for that country (excluding the Cocibolca and Xolothn Lakes). In Costa Rica, 53 931.3ha are covered by these palm dominated swamps, which represent 16.24% of the total surface area covered by wetlands. About 47% of the area covered by yolillales in Nicaragua is under some category of protection, the largest extensions protected by Cerro Silva, Laguna Tale Sulumas and Indio Maiz Nature Reserves. In Costa Rica, 55.5% of the area covered by yolillal is located within protected areas, mainly the Tortuguero National Park, Barra del Colorado Wildlife Refuge and the Sierpe-Thrraba National Wetland. Therefore, in both countries, about half the area covered by these wetlands is not protected by their systems of protection of wilderness areas.


Engineering equations for the filamentation collapse distance in lossy, turbulent, nonlinear media.
The propagation of high peak-power laser beams in real atmospheres has been an active research area for a couple of decades. Atmospheric turbulence and loss will induce decreases in the filamentation self-focusing collapse distance as the refractive index structure parameter and volume extinction coefficient, respectively, increase. This paper provides a validated analytical method for predicting the filamentation onset distance in lossy, turbulent, nonlinear media. It is based on a modification of Petrishchev's and Marburger theories. It postulates that the ratio of the peak power to critical power at range in turbulence is modified by a multiplicative, rather than additive, gain factor. Specifically, this new approach modifies the Petrishchev's turbulence equation to create the required multiplicative factor. This is necessary to create the shortened filamentation onset distance that occurs when a laser beam propagates through the cited nonlinear medium. This equation then is used with the Marburger distance and the Karr et al loss equations to yield the filamentation onset distance estimate in lossy, turbulent, nonlinear environment. Theory validation is done against two independent sets of computer simulation results. One comes from the NRL's HELCAP software and the other from MZA's Wave Train modeling software package. This paper also shows that once the zero-turbulence onset distance is set based on link loss, the addition of turbulence creates essentially the same PDFs at similar median distances for each loss case. This result had not been previously reported. This is the first quantitative comparison between closed form equations and computer simulation results characterizing filament generation in a lossy, turbulent, nonlinear medium.


Plumage microbiota covaries with the major histocompatibility complex in blue petrels.
To increase fitness, a wide range of vertebrates preferentially mate with partners that are dissimilar at the major histocompatibility complex (MHC) or that have high MHC diversity. Although MHC often can be assessed through olfactory cues, the mechanism by which MHC genes influence odour remains largely unclear. MHC class IIB molecules, which enable recognition and elimination of extracellular bacteria, have been suggested to influence odour indirectly by shaping odour-producing microbiota, i.e. bacterial communities. However, there is little evidence of the predicted covariation between an animal's MHC genotype and its bacterial communities in scent-producing body surfaces. Here, using high-throughput sequencing, we tested the covariation between MHC class IIB genotypes and feather microbiota in the blue petrel (Halobaena caerulea), a seabird with highly developed olfaction that has been suggested to rely on oduor cues during an MHC-based mate choice. First, we show that individuals with similar MHC class IIB profiles also have similar bacterial assemblages in their feathers. Then, we show that individuals with high MHC diversity have less diverse feather microbiota and also a reduced abundance of a bacterium of the genus Arsenophonus, a genus in which some species are symbionts of avian ectoparasites. Our results, showing that feather microbiota covary with MHC, are consistent with the hypothesis that individual MHC genotype may shape the semiochemical-producing microbiota in birds.


Elevated Acute Plasma miR-124-3p Level Relates to Evolution of Larger Cortical Lesion Area after Traumatic Brain Injury.
Mechanisms initiated by traumatic brain injury (TBI), leading to the development of progressive secondary injury are poorly understood. MicroRNAs (miRNAs) have a proposed role in orchestrating the post-injury aftermath as a single miRNA can control the expression of several genes. We hypothesized that the post-injury level of circulating brain-enriched miR-124-3p explains the extent of post-TBI cortical lesion. Three separate cohorts of adult male Sprague-Dawley rats (total n = 57) were injured with lateral fluid-percussion-induced TBI. The miR-124-3p levels were measured in whole blood and/or plasma in cohorts 1 and 2 before TBI as well as at 2 d, 7 d, 2 months or 3 months post-TBI. The third cohort (22/57) was imaged with T2-weighted magnetic resonance imaging (MRI) at 2 months post-TBI to quantify cortical lesion area and perilesional T2-enhancement volume. Our data shows that miR-124-3p levels were elevated at 2 d post-TBI in both blood (FC 4.63, p < 0.01) and plasma (FC 1.39, p < 0.05) as compared to controls. Receiver operating curve (ROC) analysis indicated that plasma miR-124-3p level of 34 copies/µl or higher differentiated TBI animals from controls [area under curve (AUC) 0.815, p < 0.05]. The data was validated in the third cohort (FC 1.68, p < 0.05). T2-weighted MRI revealed inter-animal differences in cortical lesion area. Linear regression analysis revealed that higher the plasma miR-124-3p level at 2 d post-TBI, larger the lesion area at chronic time point (R2 = 0.327, p < 0.01). Our findings indicate that the extent of lateral fluid-percussion injury-induced chronic cortical pathology associated with the acutely elevated plasma miR-124-3p level.


Evaluating the microbial diversity of soil samples: methodological innovations.
This manuscript is a review of the innovative methodologies that enable more precise evaluations of soil microbial diversity. Highlighting the molecular approach, which does not require the isolation of microorganisms and allows the inclusion of non-culturable genotypes in the analyses, the described methodologies revolutionised the environmental microbiology and opened gateways for an accurate understanding of the ecology and diversity of microorganisms. The application of techniques based on soil total DNA extraction, PCR amplification of genes or gene fragments, and sequence analysis revealed that the microbial universe is far more complex than ever imagined. Examples of applications of the molecular approach to study the diversity of soil diazotrophic bacteria are given.


Genome-wide association study identifies three novel genetic markers associated with elite endurance performance.
To investigate the association between multiple single-nucleotide polymorphisms (SNPs), aerobic performance and elite endurance athlete status in Russians. By using GWAS approach, we examined the association between 1,140,419 SNPs and relative maximal oxygen consumption rate ([Formula: see text]O2max) in 80 international-level Russian endurance athletes (46 males and 34 females). To validate obtained results, we further performed case-control studies by comparing the frequencies of the most significant SNPs (with P < 10(-5)-10(-8)) between 218 endurance athletes and opposite cohorts (192 Russian controls, 1367 European controls, and 230 Russian power athletes). Initially, six 'endurance alleles' were identified showing discrete associations with [Formula: see text]O2max both in males and females. Next, case-control studies resulted in remaining three SNPs (NFIA-AS2 rs1572312, TSHR rs7144481, RBFOX1 rs7191721) associated with endurance athlete status. The C allele of the most significant SNP, rs1572312, was associated with high values of [Formula: see text]O2max (males: P = 0.0051; females: P = 0.0005). Furthermore, the frequency of the rs1572312 C allele was significantly higher in elite endurance athletes (95.5%) in comparison with non-elite endurance athletes (89.8%, P = 0.0257), Russian (88.8%, P = 0.007) and European (90.6%, P = 0.0197) controls and power athletes (86.2%, P = 0.0005). The rs1572312 SNP is located on the nuclear factor I A antisense RNA 2 (NFIA-AS2) gene which is supposed to regulate the expression of the NFIA gene (encodes transcription factor involved in activation of erythropoiesis and repression of the granulopoiesis). Our data show that the NFIA-AS2 rs1572312, TSHR rs7144481 and RBFOX1 rs7191721 polymorphisms are associated with aerobic performance and elite endurance athlete status.


[Bladder dysfunctions in encephalomyelitis disseminata--drug and interventional therapeutic options].
Patients with disseminated encephalomyelitis have various urological presentations, ranging from pollakisuria to urge incontinence. After detailed evaluation (neuro-urological examination, urodynamic investigation) drug therapy and various interventional methods must be adapted to the individual manifestations. Patients with detrusor hyperreflexia are treated with oral anticholinergic agents (oxybutynin, trospium chloride, propiverine). Patients with urinary retention are recommended to be managed with clean intermittent (self)-catheterisation. The various interventional therapeutic options (bladder denervation, electrostimulation, local treatment with botulinum toxin) and the surgical therapy (sacral deafferentation and anterior root stimulation, bladder neck closure and cystostomy, sphincterotomy or augmentation cystoplasty) must be reserved for special cases.


Nursing needs of acutely ill older people.
Investigating older acutely ill hospitalized patients' nursing needs and quality of care is paramount, given the growing pressure on nurses to provide increasingly intensive levels of care to a growing older population while at the same time working with reduced staffing levels. The aims of this study were to determine: (1) important aspects of nursing care as perceived by older patients, their family member/carer who observed care during hospitalization, and nurses; (2) satisfaction levels of patients, family/carers and nurses on nursing care received; and (3) mismatches between nursing care priorities and satisfaction with nursing care. Two hundred and thirty-two acutely ill patients aged over 65 years, 99 carers/family members and 90 nurses completed the Caregiving Activities Survey, which measures importance of and satisfaction with various aspects of nursing care. Qualitative data, which qualified responses to survey items, were also obtained from participants. Patients, carers and nurses perceived that carrying out doctors' orders was the most important aspect of nursing care, followed by physical care, psychosocial care and discharge planning. Nurses and carers rated physical care, psychosocial care and discharge planning more highly than patients. Physical care was rated highly by patients in terms of importance, but rated moderately in terms of satisfaction. Carers' and patients' ratings of satisfaction with physical care were lower than nurses' ratings of opportunities to provide it. The importance of discharge planning was rated highly by nurses but all groups were only moderately satisfied with this aspect of care. The findings do not apply to acutely ill older patients with confusion, mental illness or more than early stage dementia. Patients, nurses and family/carers were generally in agreement about the relative importance of particular aspects of nursing care. Nurses may need to communicate more effectively with older patients and their family carers about the particular roles they will play during the patient's hospital episode, the expectations they have of patients in the process of healing and recovery, and the reasons for the actions they take in aiding this process. The findings are useful in making nurses more aware of the expectations and needs of older hospital patients and their carers. They provide evidence for developing both new models of nursing care for this patient group, and nursing education programmes.


Rabbit muscle glycogen-bound phosphoprotein phosphatases: substrate specificities and effects of inhibitor-1.
A phosphoprotein phosphatase which has an apparent molecular weight of 240,000 was partially purified (500-fold) from the glycogen-protein complex of rabbit skeletal muscle. The enzyme exhibited broad substrate specificity as it dephosphorylated phosphorylase, phosphohistones, glycogen synthase, phosphorylase kinase, regulatory subunit of cAMP-dependent protein kinase, and phosphatase inhibitor 1. The phosphatase showed high specificity towards dephosphorylation of the beta-subunit of phosphorylase kinase and site 2 of glycogen synthase. With the latter substrate, the presence of phosphate in sites 1a and 1b decreased the apparent Vmax, perhaps by inhibiting the dephosphorylation of site 2. The phosphorylated form of inhibitor 1 did not significantly inhibit this high-molecular-weight phosphatase. However, an inhibitor 1-sensitive phosphatase activity could be derived from this preparation by limited trypsinization. Furthermore, greater than 70% of the phosphatase activity in skeletal muscle extracts and in the glycogen-protein complex was insensitive to inhibitor 1. Limited trypsinization of each fraction obtained from the phosphatase purification increased the total activity (1.5- to 2-fold) and converted the enzyme into a form which was inhibited by inhibitor 1. The results suggest that inhibitor 1-sensitive phosphatase may be a proteolyzed enzyme.


Relative contribution of cytochromes P-450 and flavin-containing monoxygenases to the metabolism of albendazole by human liver microsomes.
Albendazole (ABZ; methyl 5-propylthio-1H-benzimidazol-2-yl carbamate) is a broad spectrum anthelmintic whose activity resides both in the parent compound and its sulphoxide metabolite (ABS). There are numerous reports of ABZ metabolism in animals but relatively few in humans. We have investigated the sulphoxidation of ABZ in human liver microsomes and recombinant systems. The specific enzymes involved in the sulphoxidation of ABZ were determined by a combination of approaches; inhibition with an antiserum directed against cytochrome P450 reductase, the effect of selective chemical inhibitors on ABZ sulphoxidation in human liver microsomes, the capability of expressed CYP and FMO to mediate the formation of ABS, regression analysis of the rate of metabolism of ABZ to ABS in human liver microsomes against selective P450 substrates and regression analysis of the rate of ABS sulphoxidation against CYP expression measured by Western blotting. Comparison of Vmax values obtained following heat inactivation (3min at 45 degrees C) of flavin monoxygenases (FMO), chemical inhibition of FMO with methimazole and addition of an antiserum directed against cytochrome P450 reductase indicate that FMO and CYP contribute approximately 30% and 70%, respectively, to ABS production in vitro. Comparison of CLint values suggests CYP is a major contributor in vivo. A significant reduction in ABZ sulphoxidation (n = 3) was seen with ketoconazole (CYP3 A4; 32-37%), ritonavir (CYP3 A4: 34-42%), methimazole (FMO: 28-49%) and thioacetamide (FMO; 32-35%). Additive inhibition with ketoconazole and methimazole was 69 +/- 8% (n = 3). ABS production in heat - treated microsomes (3 min at 45 degrees C) correlated significantly with testosterone 6beta-hydroxylation (CYP3A4; P < 0.05) and band intensities on Western blots probed with an antibody selective for 3A4 (P < 0.05). Recombinant human CYP3 A4, CYP1A2 and FMO3 produced ABS in greater quantities than control microsomes, with those expressing CYP3A4 producing threefold more ABS than those expressing CYP1A2. Kinetic studies showed the Km values obtained with both CYP3A4 and FMO3 were similar. We conclude that the production of ABS in human liver is mediated via both FMO and CYP, principally CYP3A4, with the CYP component being the major contributor.


Fate of phase I and phase II Coxiella burnetii in several macrophage-like tumor cell lines.
Several macrophage-like tumor cell lines of murine origin were exposed to phase I and phase II Coxiella burnetii, and the subsequent fate of the parasites was determined by electron and bright-field microscopy. Phase I C. burnetii proliferated within and established a persistent infection of P388D1, J774, and PU-5-IR cell lines but not of WEHI-3 and WEHI-274 cell lines. Phase II C. burnetii, however, entered into and persistently infected all five cell lines. The parasites proliferated within vacuoles. Macrophage cell lines persistently infected with phase I and phase II C. burnetii were maintained for over 200 and 100 days, respectively. Within P388D1 cells, the phase I C. burnetii converted, in part, to phase II; phase II organisms remained in the phase II state. The differential fate of the two rickettsial phases after exposure to the WEHI-3 and WEHI-274 cells may be attributable to surface differences such as lipopolysaccharide content.


Emergence of compulsive behavior and tantrums in children with Prader-Willi syndrome.
Many adults with Prader-Willi syndrome are affected by behaviors such as tantrums, skin-picking, and compulsions. The nature and extent of these problems suggest more attention be directed to their emergence in childhood. Our purpose was to investigate behavior problems in children with this syndrome and identify the age at which these behaviors emerge. Parents of children with Prader-Willi syndrome, Down syndrome, and those developing typically completed questionnaires. Children with Prader-Willi syndrome exhibited more compulsions, skin-picking, and tantrums than did the other groups. A discriminant analysis of behavior variables derived two statistically significant functions that were interpreted as developmental milestones and problematic behavior. These functions correctly predicted membership for 79% of grouped cases.


Hormonal contraception: recent advances and controversies.
This document will outline new delivery systems and contraceptive formulations, summarize recent advances in emergency contraception, and review the effects of hormonal contraception on cancer risks, cardiovascular disease, and bone.


The relationship between trophoblast differentiation and the production of bioactive hCG.
We previously showed that a significant number of failing pregnancies are associated with production of human chorionic gonadotropin (hCG) having relatively low bioactivity. The present study was designed to compare the secretion of intact, immunoreactive hCG to the secretion of bioactive hCG during trophoblast differentiation, and to test the hypothesis that the lower bioactive: immunoreactive hCG ratios in failing pregnancies are related to reduced or impaired trophoblast differentiation. Cytotrophoblast cells were isolated from term placentas and cultured under conditions that induced or did not induce syncytiotrophoblast formation. Culture media were collected at regular intervals up to 72 h and levels of immunoreactive and bioactive hCG were measured. The differentiation of cytotrophoblast cells to multinucleated syncytiotrophoblast was monitored by immunocytochemistry and electron microscopy. During the 72 h culture period, concentrations of immunoreactive and bioactive hCG increased in both differentiating and non-differentiating cells. However, the concentrations of immunoreactive and bioactive hCG were higher under culture conditions that promoted trophoblast differentiation. Furthermore, the ratio of bioactive hCG to immunoreactive hCG was higher in differentiating cultures. When differentiation was inhibited by dimethyl sulfoxide, the secretion of bioactive hCG was reduced and the bioactive: immunoreactive hCG ratio did not change. These findings are consistent with the idea that production of bioactive hCG accompanies syncytiotrophoblast formation.


Peripapillary and Macular Choroidal Vascularity Index in Eyes with Fuchs' Uveitis.
To investigate the choroidal vascularity alterations of macula and peripapillary area in eyes with unilateral Fuchs uveitis (FU). This study included 18 eyes with unilateral FU and 18 healthy fellow eyes. The choroidal vascularity index (CVI) was analyzed, and the results were compared between eyes with FU and healthy fellow eyes (control group). The mean subfoveal (s)CVI (%) value was significantly lower in the FU group as compared with the control group: 60.92 ± 2.63 vs. 64.01 ± 2.54, respectively (p = .001). The mean pCVI (%) values of superior and inferior quadrant were significantly lower in the Fuchs group as compared with the control group:58.87 ± 4.48 vs. 61.98 ± 3.32, respectively, in superior quadrant (p = .035); and 57.29 ± 6.65 vs. 61.44 ± 4.76, respectively, in inferior quadrant (p = .014). The chronic continuous inflammation in FU causes inflammation-mediated thinning in the vascular area of the subfoveal and peripapillary choroid. The changes in the peripapillary region are remarkable in terms of the further glaucoma risk of these eyes.


Conservation overstretch and long-term decline of wildlife and tourism in the Central African savannas.
When in 2010 the world's governments pledged to increase protected area coverage to 17% of the world's land surface, several Central African countries had already set aside 25% of their northern savannas for conservation. To evaluate the effectiveness of this commitment, we analyzed the results of 68 multispecies surveys conducted in the seven main savanna national parks in Central Africa (1960-2017). We also assembled information on potential drivers of large herbivore population trends (rainfall and number of rangers) and on tourist numbers and revenues. In six out of the seven parks, wild large herbivore populations declined dramatically over time, livestock numbers increased severalfold, and tourism, the pillar under a once thriving local wildlife industry, collapsed. Zakouma National Park (Chad) stood out because its large herbivore populations increased, an increase that was positively correlated with rainfall and number of rangers (a proxy for management inputs). With increasing insecurity and declining revenues, governments find themselves confronted with too few resources to protect vast areas. To deal with this conversation overstretch, we propose to extend the repeatedly promoted solutions--scaled up funding, enhanced management--with a strategic retreat, focusing scarce resources on smaller areas to save wildlife in the Central African savannas.


Validation of a multivariate prediction rule for history of periodontitis in a separate population.
Validation of a previously derived prediction rule for periodontitis in an external population sample. Age, smoking and self-reported tooth mobility were used in logistic models to predict moderate and severe periodontitis as diagnosed from panoramic radiographs of 246 patients attending private practices in Germany. Coefficients derived from these models were used to predict periodontitis in a representative population-based sample of 3297 residents of the region of Pomerania, Germany. In the full derivation sample, the predictive power of the logistic model as measured by the c-statistic was 0.82 and 0.84 for moderate and severe periodontitis, respectively. In the validation set, these models yielded c-statistics of 0.82 for both moderate and severe periodontitis. Lower c-statistics were obtained among subjects aged 40 years and older in the derivation set (c=0.74 and 0.77), and the performance was poorer in the validation set with c-statistics of 0.69 and 0.72, respectively. A prediction rule based on age, smoking and self-reported tooth mobility can yield a moderately useful external validity. Validity may be dependent on specific population characteristics, and derivation of a prediction rule based on a clinical subsample of the target population with a larger set of predictors may provide better results in an application.


Bio-orthogonal labeling as a tool to visualize and identify newly synthesized proteins in Caenorhabditis elegans.
In this protocol we describe the incorporation of bio-orthogonal amino acids as a versatile method for visualizing and identifying de novo-synthesized proteins in the roundworm Caenorhabditis elegans. This protocol contains directions on implementing three complementary types of analysis: 'click chemistry' followed by western blotting, click chemistry followed by immunofluorescence, and isobaric tags for relative and absolute quantification (iTRAQ) quantitative mass spectrometry. The detailed instructions provided herein enable researchers to investigate the de novo proteome, an analysis that is complicated by the fact that protein molecules are chemically identical to each other, regardless of the timing of their synthesis. Our protocol circumvents this limitation by identifying de novo-synthesized proteins via the incorporation of the chemically modifiable azidohomoalanine instead of the natural amino acid methionine in the nascent protein, followed by facilitating the visualization of the resulting labeled proteins in situ. It will therefore be an ideal tool for studying de novo protein synthesis in physiological and pathological processes including learning and memory. The protocol requires 10 d for worm growth, liquid culture and synchronization; 1-2 d for bio-orthogonal labeling; and, with regard to analysis, 3-4 d for western blotting, 5-6 d for immunofluorescence or ~3 weeks for mass spectrometry.


Using AI to Improve Radiologist Performance in Detection of Abnormalities on Chest Radiographs.
Background Chest radiography remains the most common radiologic examination, and interpretation of its results can be difficult. Purpose To explore the potential benefit of artificial intelligence (AI) assistance in the detection of thoracic abnormalities on chest radiographs by evaluating the performance of radiologists with different levels of expertise, with and without AI assistance. Materials and Methods Patients who underwent both chest radiography and thoracic CT within 72 hours between January 2010 and December 2020 in a French public hospital were screened retrospectively. Radiographs were randomly included until reaching 500 radiographs, with about 50% of radiographs having abnormal findings. A senior thoracic radiologist annotated the radiographs for five abnormalities (pneumothorax, pleural effusion, consolidation, mediastinal and hilar mass, lung nodule) based on the corresponding CT results (ground truth). A total of 12 readers (four thoracic radiologists, four general radiologists, four radiology residents) read half the radiographs without AI and half the radiographs with AI (ChestView; Gleamer). Changes in sensitivity and specificity were measured using paired t tests. Results The study included 500 patients (mean age, 54 years ± 19 [SD]; 261 female, 239 male), with 522 abnormalities visible on 241 radiographs. On average, for all readers, AI use resulted in an absolute increase in sensitivity of 26% (95% CI: 20, 32), 14% (95% CI: 11, 17), 12% (95% CI: 10, 14), 8.5% (95% CI: 6, 11), and 5.9% (95% CI: 4, 8) for pneumothorax, consolidation, nodule, pleural effusion, and mediastinal and hilar mass, respectively (P < .001). Specificity increased with AI assistance (3.9% [95% CI: 3.2, 4.6], 3.7% [95% CI: 3, 4.4], 2.9% [95% CI: 2.3, 3.5], and 2.1% [95% CI: 1.6, 2.6] for pleural effusion, mediastinal and hilar mass, consolidation, and nodule, respectively), except in the diagnosis of pneumothorax (-0.2%; 95% CI: -0.36, -0.04; P = .01). The mean reading time was 81 seconds without AI versus 56 seconds with AI (31% decrease, P < .001). Conclusion AI-assisted chest radiography interpretation resulted in absolute increases in sensitivity for all radiologists of various levels of expertise and reduced the reading times; specificity increased with AI, except in the diagnosis of pneumothorax. © RSNA, 2023 Supplemental material is available for this article.


Energizing compassion: using music and community focus to stimulate compassion drive and sense of connectedness.
The last 20 years have seen considerable research on the nature and biopsychosocial impacts of compassion training on self and others. This training is usually focused on calming and slowing the mind and body and on individual imagery practices and mantras. This study explored the effects of three variations: 1. The impact of using energizing music to generate activation and "drive" for compassion; 2. To focus on imagining "breathing in and breathing out a white light or mist of compassion" to bring compassion to the world; and 3. While listening to energizing music, participants were guided to imagining connecting to the compassion (Sangha) community, imagining oneself as linking with others as part of communities seeking to help the world. From approximately 1,600 members of the Compassionate Mind discussion list, participants were invited to take part in a new energizing focused self-practice study. The study involved listening to recorded guidance on the evolutionary model of compassion and the need to address the potentially harmful side of our nature. This was followed by a 4 1/2-min tonglen-informed guided practice of breathing in and breathing out compassion accompanied by energizing music. Forty-three participants completed several self-report scales measuring compassion orientation, wellbeing, social safeness, and positive affect before and following 2 weeks of practice. Participant experiences were recorded from 6 open explorative questions. Self-report measures taken before and following 2 weeks of practice revealed significant increases in self-compassion, compassion to others, openness to compassion from others, activated positive affect, safe positive affect, social safeness, and wellbeing, with the largest effect size relating to compassion for the self (d = -0.76). In addition, qualitative data revealed that the participants had experienced the practice as energizing, inspiring, and felt socially connected and that it had significant impacts on other aspects of their lives. Some participants noted that engaging with suffering also stimulated sadness. This study found that pairing energizing music with breathing practices and specific compassion visualizations, focusing on the desire to bring compassion to the world and be part of a compassionate community, was well-accepted and had a range of significant positive impacts. This study indicates the potential value of exploring energizing in comparison to the more standard soothing and settling practices as ways of stimulating the biopsychosocial processes of compassion.


Separation of two thyrotropin binding components from porcine thyroid tissue by affinity chromatography: characterization of high and low affinity sites.
Two distinct thyrotropin (TSH) binding species have been separated from solubilized porcine thyroid membranes. Membranes was solubilized with 1% Triton X-100, and the supernatant was recovered by centrifugation at 105,000 X g. Scatchard analysis of thyrotropin binding to solubilized membranes (SM) yielded a nonlinear plot with Kd values for the high and low affinity components similar to those of intact membranes. Chromatography of the SM preparation on concanavalin A-Sepharose 4B resulted in the retention of 10-20% of the binding activity. Upon elution of the column, a peak of binding material (5-7% of total activity) was eluted at 0.3 M alpha-methyl-D-mannoside. This concanavalin A (Con A) bound fraction exhibited a linear Scatchard plot with a Kd value similar to that of the high affinity component of the SM. The protein fraction that did not bind to Con A (Con A unbound) also exhibited a linear Scatchard plot, but with affinity similar to that of the low affinity component of SM. Discontinuous sucrose density gradient ultracentrifugation revealed the presence of two major binding peaks in the solubilized membrane preparation. The slowly sedimenting peak corresponded to that seen in the Con A bound fraction, whereas the rapidly sedimenting peak corresponded to that of the Con A unbound fraction. Sepharose 6B chromatography indicated that in the case of the Con A unbound fraction, a single peak of specific binding activity was eluted in the void volume, and in the case of the Con A bound fraction, one major peak with an approximate Stokes radius of 67 A and several other minor peaks were eluted. These results demonstrate the physical separation of two distinct TSH binding species from thyroid membranes and provide further support for the model of multiple classes of binding sites.


Effects of CPAP on nitrate and norepinephrine levels in severe and mild-moderate sleep apnea.
Reduced plasma nitrate (NO(x)) levels and increased urinary norepinephrine (U-NE) levels have been described in severe obstructive sleep apnea (OSA), and are reverted by continuous positive airway pressure (CPAP). The effect of CPAP on these biomarkers in mild-moderate OSA is not well understood. The aim of this study was to compare NO(x) and U-NE levels and blood pressure (BP) between male patients with mild-moderate and severe OSA and determine the impact of 1 month of CPAP therapy on these parameters. We undertook a prospective study of 67 consecutive OSA patients (36 mild-moderate, 31 severe). Measurements of plasma NO(x) at 11 pm, 4 am and 7 am, 24-h U-NE and ambulatory BP were obtained at baseline and after 1 month of CPAP. At baseline, NO(x) levels showed a significant decrease during the night in both groups (p < 0.001). U-NE level and BP were significantly higher in the severe OSA group. After 1 month of CPAP, there was a significant increase in NO(x) levels and a reduction in U-NE level and BP only in patients with severe OSA. One month of CPAP results in significant improvements in NO(x) levels, 24-h U-NE level and BP in patients with severe OSA, but not in patients with mild-moderate OSA. ClinicalTrials.gov: NCT01769807.


Major bleeding events in Jordanian patients undergoing percutaneous coronary intervention (PCI): Incidence, associated factors, impact on prognosis, and predictability of the CRUSADE bleeding risk score. Results from the First Jordanian PCR (PCR1).
Determine the incidence of major bleeding events, their risk factors, and their impact on prognosis in Jordanian patients undergoing percutaneous coronary intervention (PCI). Evaluate the ability of the CRUSADE bleeding risk score (BRS) to predict major bleeding. Major bleeding events were defined according to the CRUSADE classification and their incidence was evaluated from hospital admission to one year of follow up. The CRUSADE bleeding risk score was calculated for each patient during the index admission. Incidence of major bleeding events was evaluated in each of the bleeding score quintiles. JoPCR1 is a prospective, observational, multicenter registry of consecutive patients who underwent PCI at 12 tertiary care centers in Jordan. A case report form was used to record data prospectively at hospital admission, at discharge, and at 1 and 12 months of follow-up. The study included 2426 consecutive patients who underwent PCI. During the index hospitalization, major and minor bleeding events occurred in 0.95% and 2.6% of patients, respectively. Multivariate analysis showed that only two variables were significantly associated with major bleeding: female gender (OR=3.7; 95% CI 1.6, 8.5; p=0.002) and past history of cardiovascular disease (OR=2.6; 95% CI 1.1, 5.9; p=0.026). Patients who had in-hospital major bleeding events had higher cardiac mortality during index hospitalization (13.0% vs. 0.7%, p<0.005) and at one year of follow up (13.0% vs. 1.8%, p<0.005) compared to those who had no such events. Receiver operating characteristic curve analysis showed that the CRUSADE BRS has a high ability to predict major bleeding. Major bleeding events were uncommon in this ME registry of a contemporary cohort of patients undergoing PCI but were associated with a higher mortality rate compared with those who did not have major bleeding events. CRUSADE BRS was highly predictive of the incidence of major bleeding events.


Association of blood pressure and aortic distensibility with P wave indices and PR interval: the multi-ethnic study of atherosclerosis (MESA).
Hypertension is an established risk factor for atrial fibrillation. Understanding the association of blood pressure (BP) levels and aortic distensibility with P wave indices (PWIs) and PR interval, intermediate phenotypes of atrial fibrillation, could provide insights into underlying mechanisms. This analysis included 3180 men and women aged 45-84years participating in the Multi-Ethnic Study of Atherosclerosis, a community-based cohort in the United States. Aortic distensibility was evaluated in 2243 of these individuals using cardiac magnetic resonance imaging. PWIs and PR interval were automatically measured in standard 12-lead ECGs. Sitting BP and other cardiovascular risk factors were assessed using standardized protocols. Left ventricular mass was measured by magnetic resonance imaging. Higher systolic BP, and diastolic BPs and greater pulse pressure were associated with a significantly greater P wave terminal force. These associations, however, were markedly attenuated or disappeared after adjustment for left ventricular mass. Systolic BP, diastolic BP, and pulse pressure were not strongly associated with PR interval or maximum P wave duration. Reduced aortic distensibility was associated with a longer PR interval but not with PWIs: compared with individuals in the top quartile of aortic distensibility, participants in the lowest quartile had on average a 3.7-ms longer PR interval (95% CI: 0.7, 6.7, p=0.02), after multivariable adjustment. In this large community-based sample, associations of BP and aortic distensibility with PWIs and PR interval differed. These results suggest that processes linking hypertension with the electrical substrate of atrial fibrillation, as characterized by these intermediate phenotypes, are diverse.


Vitreous fluorophotometer data analysis by deconvolution.
The measurement process in fluorophotometry inherently involves a loss of information due to the finite sampling volume of the instrument. Mathematically, the effect is expressed as a convolution of the actual fluorescein distribution with the spread function of the instrument. Scattering by the ocular media can increase the spread function over that due to the instrument alone. A method is proposed for deconvolution of vitreous fluorophotometry data. Simulation studies and analyses of patient data demonstrate recovery of information with this method, including enhancement of retinal peaks and resolution of detail in the posterior vitreous which was not apparent from the original scans.


Beta-cell crosstalk: a further dimension in the stimulus-secretion coupling of glucose-induced insulin release.
Pancreatic beta-cells are connected by gap junction channels made of a connexin protein, referred to as Cx36. Through these channels, beta-cells are coupled to each other, i.e. exchange cytoplasmic ions and small metabolites. Previous experiments have indicated that these exchanges are important for coordinating the function of individual cells within pancreatic islets, particularly with regard to glucose-induced insulin secretion. Advances in molecular biology, genetics and mouse transgenic approaches allow now for a direct experimental testing of this mechanism in vitro as well as in vivo. Recent experiments in rodent and culture models suggest that connexin-dependent cell-to-cell crosstalk is a significant player in the multifactorial regulation of insulin secretion and, possibly, of other beta-cell functions, such as growth. Elucidating the still obscure mechanism whereby connexin signalling exerts this influence will provide insights on the contribution of direct cell-to-cell interactions in the physiological regulation of beta-cell life. The presence of Cx36 within human pancreatic islets, raises the further challenge to determine whether a dysfunction of connexin signaling may contribute to the pathophysiology of beta-cell dysfunctions in type I and/or type II diabetes. Efforts to understand the functions of beta-cell connexins are also a prerequisite for the engineering of surrogate cells and their proper tridimensional packaging, which are instrumental for the future implementation of a replacement cell therapy in diabetic patients.


Are epidurals worthwhile in vascular surgery?
Patients undergoing major vascular surgery are at increased risk for postoperative complications due to the high incidence of comorbidities in this population.Epidural anaesthesia provides potential benefits but its effect on morbidity and mortality is unclear. Existing studies fail to demonstrate improved clinical outcome and reduced mortality for epidural anaesthesia or combined epidural/general techniques compared with general anaesthesia. Postoperative epidural analgesia provides better pain relief and reduces the duration of postoperative mechanical ventilation. Optimization of perioperative care rather than the anaesthetic technique may have potential benefit in improving postoperative outcome.


Serotonin alters the subcellular distribution of a Ca2+/calmodulin-binding protein in neurons of Aplysia.
We purified and radioiodinated calmodulin from Aplysia nervous tissue. Using blot analysis, we detected 14 calmodulin-binding proteins in extracts of the abdominal ganglion after gel electrophoresis in NaDodSO4. All 14 components are present in extracts from each of the major central Aplysia ganglia, but their relative proportions differed characteristically from one ganglion to another. When neural components are extracted with nonionic detergents in 2 M glycerol, we obtain a cytoplasmic and a membrane-cytoskeleton fraction. Of the 14 calmodulin-binding proteins, 2 are cytoplasmic, 10 are loosely associated, and 2 remain bound to the membrane-cytoskeleton complex. Treatment of isolated ganglia with serotonin, which has been shown to increase the content of cAMP within neurons, or with dibutyryl cAMP causes the partial dissociation of one of the loosely associated proteins, which has an apparent Mr of 55,000. In extracts prepared in the presence of glycerol and cAMP, this component also is dissociated from the membrane-cytoskeleton complex, but only if ATP is also present. These results suggest that a cAMP-dependent protein phosphorylation controls the subcellular distribution of the Mr 55,000 calmodulin-binding protein, whose state of phosphorylation itself, however, does not appear to be increased by cAMP.


Misclassification of exposure: coffee as a surrogate for caffeine intake.
This study was conducted to assess the effect of exposure misclassification when coffee is used as a surrogate measure of caffeine exposure. Subjects were randomly selected from the telephone directories of four regional municipalities in southern Ontario, CANADA: Data on daily caffeine intake from foods, beverages, and medications were collected from June to November 1995 through self-administered, mailed questionnaires from 481 men and women aged 30-75 years. Although coffee was the main source of caffeine, cross-tabulations of exposure to coffee by total caffeine intake showed that assessment of coffee alone severely underestimated caffeine intake by at least one exposure level. A hypothetical 10-fold increase in risk was completely obscured when only coffee was used to estimate total caffeine intake. The results of this study suggest that measuring coffee instead of caffeine intake may contribute to a lack of positive findings in studies of coffee as a risk factor for disease occurrence, if in fact caffeine is the exposure of interest. On the other hand, measurement of coffee, tea, and cola soft drink intake in the present study appeared to approximate caffeine intake sufficiently and not affect risk estimates adversely.


Social isolation, loneliness, and inflammation: A multi-cohort investigation in early and mid-adulthood.
Social isolation and loneliness have been associated with poor health and increased risk for mortality, and inflammation might explain this link. We used data from the Danish TRIAGE Study of acutely admitted medical patients (N = 6,144, mean age 60 years), and from two population-representative birth cohorts: the New Zealand Dunedin Longitudinal Study (N = 881, age 45) and the UK Environmental Risk (E-Risk) Longitudinal Twin Study (N = 1448, age 18), to investigate associations of social isolation with three markers of systemic inflammation: C-reactive protein (CRP), interleukin-6 (IL-6), and a newer inflammation marker, soluble urokinase plasminogen activator receptor (suPAR), which is thought to index systemic chronic inflammation. In the TRIAGE Study, socially isolated patients (those living alone) had significantly higher median levels of suPAR (but not CRP or IL-6) compared with patients not living by themselves. Social isolation prospectively measured in childhood was longitudinally associated with higher CRP, IL-6, and suPAR levels in adulthood (at age 45 in the Dunedin Study and age 18 in the E-Risk Study), but only suPAR remained associated after controlling for covariates. Dunedin Study participants who reported loneliness at age 38 or age 45 had elevated suPAR at age 45. In contrast, E-Risk Study participants reporting loneliness at age 18 did not show any elevated markers of inflammation. In conclusion, social isolation was robustly associated with increased inflammation in adulthood, both in medical patients and in the general population. It was associated in particular with systemic chronic inflammation, evident from the consistently stronger associations with suPAR than other inflammation biomarkers.


Change of Heart: The Underexplored Role of Plaque Hemorrhage in the Evaluation of Stroke of Undetermined Etiology.
In the evaluation of embolic strokes of undetermined source, great emphasis is often placed on cardiovascular disease, namely on atrial fibrillation. Other pathophysiologic mechanisms, however, may also be involved. Carotid artery intraplaque hemorrhage (IPH)-the presence of blood components within an atheromatous plaque-has become increasingly recognized as a possible etiologic mechanism in some cryptogenic strokes. IPH is a marker of plaque instability and is associated with ipsilateral neurologic ischemic events, even in nonstenotic carotid plaques. As recognition of carotid IPH as an etiology of embolic strokes has grown, so too has the complexity with which such patients are evaluated and treated, particularly because overlaps exist in the risk factors for atrial fibrillation and IPH. In this article, we review what is currently known about carotid IPH and how this clinical entity should be approached in the context of the evaluation of embolic strokes of undetermined source.


[Health Impact Assessment: assessing the effectiveness of policies in population health].
Health Impact Assessment is a comprehensive methodology proposed by the World Health Organization to determine the impact on health of projects, policies and strategies that are no originally specifically health-related but that could have on effect on health. This work aims to review the methodological approaches to Health Impact Assessment, and determine its value in Public Health. Health Impact Assessment is a multidisciplinary process that combines both qualitative and quantitative evidence in a decision-making frame. It is based on a model of health that includes the economic, political, social, psychological, and environmental determinants of health. If interventions with a real impact on the population s health require a comprehensive and structural approach, with Public Health measures taken at political level, those responsible for implementing such measures have to engage in the decision-making process and in the assessment of its effectiveness. To conduct Health Impact Assessment it is necessary to facilitate the integration of the existing data in order to perform the initial diagnosis and be able to investigate the late effects of the policy measures implemented. This way it will be possible to systematically monitor the effects on health of the actions which derive from Health Impact Assessment, thus maximizing potential positive effects on health and preventing the potential adverse effects.


How, when, and why do inter-organisational collaborations in healthcare work? A realist evaluation.
Inter-organisational collaborations (IOCs) in healthcare have been viewed as an effective approach to performance improvement. However, there remain gaps in our understanding of what helps IOCs function, as well as how and why contextual elements affect their implementation. A realist review of evidence drawing on 86 sources has sought to elicit and refine context-mechanism-outcome configurations (CMOCs) to understand and refine these phenomena, yet further understanding can be gained from interviewing those involved in developing IOCs. We used a realist evaluation methodology, adopting prior realist synthesis findings as a theoretical framework that we sought to refine. We drew on 32 interviews taking place between January 2020 and May 2021 with 29 stakeholders comprising IOC case studies, service users, as well as regulatory perspectives in England. Using a retroductive analysis approach, we aimed to test CMOCs against these data to explore whether previously identified mechanisms, CMOCs, and causal links between them were affirmed, refuted, or revised, and refine our explanations of how and why interorganisational collaborations are successful. Most of our prior CMOCs and their underlying mechanisms were supported in the interview findings with a diverse range of evidence. Leadership behaviours, including showing vulnerability and persuasiveness, acted to shape the core mechanisms of collaborative functioning. These included our prior mechanisms of trust, faith, and confidence, which were largely ratified with minor refinements. Action statements were formulated, translating theoretical findings into practical guidance. As the fifth stage in a larger project, our refined theory provides a comprehensive understanding of the causal chain leading to effective collaborative inter-organisational relationships. These findings and recommendations can support implementation of IOCs in the UK and elsewhere. Future research should translate these findings into further practical guidance for implementers, researchers, and policymakers.


Adaptation and response of Bifidobacterium animalis subsp. lactis to bile: a proteomic and physiological approach.
Bile salts are natural detergents that facilitate the digestion and absorption of the hydrophobic components of the diet. However, their amphiphilic nature makes them very inhibitory for bacteria and strongly influences bacterial survival in the gastrointestinal tract. Adaptation to and tolerance of bile stress is therefore crucial for the persistence of bacteria in the human colonic niche. Bifidobacterium animalis subsp. lactis, a probiotic bacterium with documented health benefits, is applied largely in fermented dairy products. In this study, the effect of bile salts on proteomes of B. animalis subsp. lactis IPLA 4549 and its bile-resistant derivative B. animalis subsp. lactis 4549dOx was analyzed, leading to the identification of proteins which may represent the targets of bile salt response and adaptation in B. animalis subsp. lactis. The comparison of the wild-type and the bile-resistant strain responses allowed us to hypothesize about the resistance mechanisms acquired by the derivative resistant strain and about the bile salt response in B. animalis subsp. lactis. In addition, significant differences in the levels of metabolic end products of the bifid shunt and in the redox status of the cells were also detected, which correlate with some differences observed between the proteomes. These results indicate that adaptation and response to bile in B. animalis subsp. lactis involve several physiological mechanisms that are jointly dedicated to reduce the deleterious impact of bile on the cell's physiology.


Parry-Romberg syndrome: findings in advanced magnetic resonance imaging sequences - case report.
Parry-Romberg syndrome is a rare disease characterized by progressive hemifacial atrophy associated with other systemic changes, including neurological symptoms. Currently, there are few studies exploring the utilization of advanced magnetic resonance sequences in the investigation of this disease. The authors report the case of a 45-year-old patient and describe the findings at structural magnetic resonance imaging and at advanced sequences, correlating them with pathophysiological data.


Apoptosis and the thymic microenvironment in murine lupus.
The thymus of New Zealand black (NZB) mice undergoes premature involution. In addition, cultured thymic epithelial cells from NZB mice undergo accelerated preprogrammed degeneration. NZB mice also have distinctive and well-defined abnormalities of thymic architecture involving stromal cells, defined by staining with monoclonal antibodies specific for the thymic microenvironment. We took advantage of these findings, as well as our large panel of monoclonal antibodies which recognize thymic stroma, to study the induction of apoptosis in the thymus of murine lupus and including changes of epithelial architecture. We studied NZB, MRL/lpr, BXSB/Yaa, C3H/gld mice and BALB/c and C57BL/6 as control mice. Apoptosis was studied both at basal levels and following induction with either dexamethasone or lipopolysaccharide (LPS). The apoptotic cells were primarily found in the thymic cortex, and the frequency of apoptosis in murine lupus was less than 20% of controls. Moreover, all strains of murine lupus had severe abnormalities of the cortical network. These changes were not accentuated by dexamethasone treatment in cultured thymocytes. However, the thymus in murine lupus was less susceptible to LPS-induced apoptosis than control mice. Finally we note that the number of thymic nurse cells (TNC) was lowest in NZB mice. Our findings demonstrate significant abnormalities in the induction of apoptosis and the formation of TNC-like epithelial cells in SLE mice, and suggest that the abnormalities of the thymic microenvironment have an important role in the pathogenesis of murine lupus.


Chemotherapy in cancer patients undergoing haemodialysis: a nationwide study in Japan.
Cancer is a major cause of death in patients undergoing haemodialysis. However, information about the actual clinical practice of chemotherapy for patients with cancer undergoing haemodialysis is lacking. We conducted a nationwide survey using questionnaires on the clinical practice of chemotherapy for such patients. The nationwide survey included patients undergoing haemodialysis who were subsequently diagnosed with cancer in 20 hospitals in Japan from January 2010 to December 2012. We reviewed their clinical data, including cancer at the following primary sites: kidney, colorectum, stomach, lung, liver, bladder, pancreas and breast. The questionnaires consisted of the following subjects: (1) patient characteristics; (2) regimen, dosage and timing of chemotherapy; and (3) clinical outcome. Overall, 675 patients were registered and assessed for main primary cancer site involvement. Of 507 patients with primary site involvement, 74 patients (15%) received chemotherapy (44 as palliative chemotherapy and 30 as perioperative chemotherapy). The most commonly used cytotoxic drugs were fluoropyrimidine (15 patients), platinum (8 patients) and taxane (8 patients), and the dosage and timing of these drugs differed between institutions; however, the dosage of molecular targeted drugs (24 patients) and hormone therapy drugs (15 patients) was consistent. The median survival time of patients receiving palliative chemotherapy was 13.0 months (0.1-60.3 months). Three patients (6.8%) died from treatment-related causes and nine patients (20%) died of causes other than cancer. Of the 30 patients who received perioperative chemotherapy, 6 (20%) died of causes other than cancer within 3 years after the initiation of chemotherapy. Among the haemodialysis patients with cancer who received chemotherapy, the rates of mortality from causes other than cancer might be high for both palliative and perioperative chemotherapy. Indications for the use of chemotherapy in patients undergoing haemodialysis should be considered carefully.


[The development of hearing sensitivity in altricial birds: the absolute thresholds of the generation of evoked potentials].
Thresholds of field L auditory evoked potentials EP were studied in 1.5-9-day-old nestlings of pied flycatcher in response to pure tone signals of different frequencies. According to the tendencies of age dynamics of auditory EP thresholds (2-9 days of life) all hearing range was divided into three separate channels: low-frequency (0.3-1.0 kHz), intermediate-(1.5-4.0 kHz) and high-frequency (5.0-8.0 kHz) ones. The widening of the hearing range in its high-frequency part was demonstrated on days 4-5 of life. The development of auditory sensitivity was shown to continue within all three channels in postembryonic period (days 2-9 post-hatching), each of the channels being characterized by its own age dynamics of auditory EP thresholds. Reproduction of tape-recorded species song during days 1-3 post-hatching resulted in significant decrease of auditory EP thresholds.


Modulation of Gut Microbiota by Lonicera caerulea L. Berry Polyphenols in a Mouse Model of Fatty Liver Induced by High Fat Diet.
Polyphenols from the Lonicera caerulea L. berry have shown protective effects on experimental non-alcoholic fatty liver disease (NAFLD) in our previous studies. As endotoxins from gut bacteria are considered to be the major trigger of inflammation in NAFLD, this study aims to clarify the regulatory effects of L. caerulea L. berry polyphenols (LCBP) on gut microbiota in a high fat diet (HFD)-induced mouse model. C57BL/6N mice were fed with a normal diet, HFD, or HFD containing 0.5⁻1% of LCBP for 45 days. The results revealed that supplementation with LCBP decreased significantly the levels of IL-2, IL-6, MCP-1, and TNF-α in serum, as well as endotoxin levels in both serum and liver in HFD-fed mice. Fecal microbiota characterization by high throughput 16S rRNA gene sequencing revealed that a HFD increased the Firmicutes/Bacteroidetes ratio, and LCBP reduced this ratio by increasing the relative abundance of Bacteroides, Parabacteroides, and another two undefined bacterial genera belonging to the order of Bacteroidales and family of Rikenellaceae, and also by decreasing the relative abundance of six bacterial genera belonging to the phylum Firmicutes, including Staphylococcus, Lactobacillus, Ruminococcus, and Oscillospira. These data demonstrated that LCBP potentially attenuated inflammation in NAFLD through modulation of gut microbiota, especially the ratio of Firmicutes to Bacteroidetes.


Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B.
The sphingolipid ceramide negatively regulates insulin action by inhibiting Akt/protein kinase B (PKB), a serine/threonine kinase that is a central regulator of glucose uptake and anabolic metabolism. Despite considerable attention, the molecular mechanism accounting for this action of ceramide has remained both elusive and controversial. Herein we utilized deletion constructs encoding two different functional domains of Akt/PKB to identify which region of the enzyme conferred responsiveness to ceramide. Surprisingly the findings obtained with these separate domains reveal that ceramide blocks insulin stimulation of Akt/PKB by two independent mechanisms. First, using the isolated pleckstrin homology domain, we found that ceramide specifically blocks the translocation of Akt/PKB, but not its upstream activator phosphoinositide-dependent kinase-1, to the plasma membrane. Second, using a construct lacking this pleckstrin homology domain, which does not require translocation for activation, we found that ceramide stimulates the dephosphorylation of Akt/PKB by protein phosphatase 2A. Collectively these findings identify at least two independent mechanisms by which excessive ceramide accumulation in peripheral tissues could contribute to the development of insulin resistance. Moreover the results obtained provide a unifying theory to account for the numerous dissenting reports investigating the actions of ceramide toward Akt/PKB.


Perioperative Factors Associated With Chronic Opioid Use After Spine Surgery.
Retrospective case control. The purpose of the current study is to determine risk factors associated with chronic opioid use after spine surgery. In our single institution retrospective study, 1,299 patients undergoing elective spine surgery at a tertiary academic medical center between January 2010 and August 2017 were enrolled into a prospectively collected registry. Patients were dichotomized based on renewal of, or active opioid prescription at 3-mo and 12-mo postoperatively. The primary outcome measures were risk factors for opioid renewal 3-months and 12-months postoperatively. These primarily included demographic characteristics, operative variables, and in-hospital opioid consumption via morphine milligram equivalence (MME). At the 3-month and 12-month periods, we analyzed the aforementioned covariates with multivariate followed by bivariate regression analyses. Multivariate and bivariate analyses revealed that script renewal at 3 months was associated with black race (P = 0.001), preoperative narcotic (P < 0.001) or anxiety/depression medication use (P = 0.002), and intraoperative long lumbar (P < 0.001) or thoracic spine surgery (P < 0.001). Lower patient income was also a risk factor for script renewal (P = 0.01). Script renewal at 12 months was associated with younger age (P = 0.006), preoperative narcotics use (P = 0.001), and ≥4 levels of lumbar fusion (P < 0.001). Renewals at 3-mo and 12-mo had no association with MME given during the hospital stay or with the usage of PCA (P > 0.05). The current study describes multiple patient-level factors associated with chronic opioid use. Notably, no metric of perioperative opioid utilization was directly associated with chronic opioid use after multivariate analysis.


Antifungal interventions for the primary prevention of cryptococcal disease in adults with HIV.
Cryptococcal disease is an opportunistic infection that causes significant morbidity and mortality in adults with HIV. Primary prophylaxis with antifungal interventions may decrease cryptococcal disease incidence and associated mortality. To assess the efficacy of antifungal interventions for the primary prevention of cryptococcal disease in adults with HIV. We searched the following databases: MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), ClinicalTrials.gov, Database of Abstracts of Reviews of Effectiveness (DARE), Latin American and Caribbean Literature on the Health Sciences (LILACS), and the Cochrane Controlled Trials Register (CCTR). We reviewed abstracts from the following relevant conferences: International AIDS Conference, International AIDS Society Conference on HIV Pathogenesis and Treatment, and Conference on Retroviruses and Opportunistic Infections. We searched reference lists for all primary and other pertinent articles identified. We attempted to contact experts in the field, particularly primary authors of included studies, to better ensure completeness of included studies. We also approached pharmaceutical companies for any available and relevant unpublished data. The time period searched was from 1980 to August 2004. We placed no language restrictions on the search. Key words used include: meningitis, cryptococcal, cryptococcus, cryptococcosis, acquired immunodeficiency syndrome, human immunodeficiency virus, prophylaxis, chemoprevention, antifungal agents, and the Cochrane screen for randomized controlled trials. Randomized controlled trials using antifungal interventions for the primary prevention of cryptococcal disease in adults with HIV were selected. Two reviewers independently assessed trial eligibility and quality. Trial authors, experts, and pharmaceutical companies were contacted for additional and/or missing information. Data were abstracted by two reviewers. Data were pooled, where appropriate, to yield summary estimates. Five studies (N=1316) were identified. All study patients had CD4 cell counts <300 cells/microl, and the majority of patients had CD4 cell counts <150 cells/microl. When all five studies are analyzed as a single group (N=1316), the incidence of cryptococcal disease was decreased in those taking primary prophylaxis (RR 0.21, 95% CI 0.09, 0.46) compared to those taking placebo. However, there was no significant difference in overall mortality observed (RR 1.01, 95% CI 0.71, 1.44). When the three studies using itraconazole as the intervention were analyzed together (N=798), the incidence of cryptococcal disease was decreased in those taking itraconazole for primary prophylaxis (RR 0.12, 95% CI 0.03, 0.51) compared to those taking placebo; however, there was no significant difference in overall mortality (RR 1.12, 95% CI 0.70, 1.80). When the two studies using fluconazole as the intervention were analyzed together (N=518), the incidence of cryptococcal disease was decreased in those taking fluconazole for primary prophylaxis (RR 0.25, 95% CI 0.07, 0.87) compared to those taking placebo; however, there was no significant difference in overall mortality (RR 0.59, 95% CI 0.14, 2.62). Antifungal primary prophylaxis with either itraconazole or fluconazole is effective in reducing the incidence of cryptococcal disease in adults with advanced HIV disease. However, neither of these interventions has a clear effect on overall mortality. Further research is needed to better understand these interventions and the populations in which they may be most effective.


Impact of CD200-Fc on dendritic cells in lupus-prone NZB/WF1 mice.
Abnormal expression of CD200/CD200R1 may contribute to the immunologic abnormalities in patients with systemic lupus erythematosus (SLE). This study aimed to assess the function of CD200/CD200R1and impact of CD200-Fc on dendritic cells in lupus-prone NZB/WF1 mice. Female NZB/WF1 mice were treated with CD200-Fc or control for 4 weeks. Plasma samples were collected to measure autoantibody levels. The expression levels of CD200/CD200R1 in peripheral blood mononuclear cells (PBMCs) and splenocytes were examined. The percentage of CD200/CD200R1-positive cells in splenocytes from NZB/WF1 mice was lower than that of C57BL/6 mice (p < 0.05). The plasma level of anti-dsDNA was significantly higher in NZB/WF1 mice than C57BL/6 mice (p < 0.001). However, the anti-dsDNA levels decreased (p = 0.047) after CD200-Fc treatment. Finally, CD200-Fc reduced the levels of IL-6 (p = 0.017) and IL-10 (p = 0.03) in the dendritic cell culture supernatant. This study suggests that the immunosuppressive CD200/CD200R1 signaling pathway might be involved in the immunopathology of NZB/WF1 mice; the present results merit further exploration of agents that can modulate the CD200/CD200FR1 pathway as a therapy for human lupus.


[Role of the priority national health project in implementing HIV epidemic control strategy in the Russian Federation].
According to the data of the UN AIDS control program, the estimated number of persons living with HIV infection worldwide is close to 36 million. There is only one way to reduce HIV infection treatment and care costs; this is to develop large-scale HIV prevention programs. The geography of the HIV infection epidemic is inhomogeneous; about 70% of the absolute number of all notified HIV cases are concentrated in 15 subjects of Russia; bulk of them are industrially developed high-income areas. The laboratory base of AIDS prevention and control centers has been drastically renewed; about 400 units of up-to-date laboratory equipment have been purchased. The problem of preventing the prevalence of HIV infection is being primarily solved within the framework of the priority national project. The programs to prevent HIV infection among particularly vulnerable population groups have been elaborated with regard to the realities and specific features of development of the epidemic of HIV infection.


Increased respiratory burst in myeloperoxidase-deficient monocytes.
Studies of the respiratory burst in myeloperoxidase (MPO) deficient monocytes were undertaken to assess the physiologic consequence of the absence of MPO in these cells. As previously demonstrated with neutrophils, MPO-deficient monocytes had a greater initial rate, duration, and total superoxide production in response to phagocytosis of zymosan than did normal monocytes. Introduction of purified eosinophil peroxidase (EPO) into the phagosome by binding the enzyme to the surface of the zymosan particles changed the hypermetabolic characteristics of superoxide production in MPO-deficient cells to more closely resemble normal cells, but had no effect on superoxide generation by the normal monocytes. Further, inactivation of the bound EPO before ingestion restored the supranormal respiratory burst by the MPO-deficient cells. Iodination by MPO-deficient monocytes was significantly depressed as compared to normal monocytes following the ingestion of zymosan (1.9 versus 10.1 nmole I-/10(7) monocytes/30 min; p less than 0.01). In contrast, iodination was markedly augmented in MPO-deficient cells compared to normal cells after ingestion of zymosan coated with EPO (208 versus 70 nmole I-/10(7) monocytes/30 min; p less than 0.005), presumably reflecting the greater amounts of hydrogen peroxide formed by MPO-deficient cells. There were no differences in the levels of endogenous scavengers of reactive oxygen products (catalase, superoxide dismutase, glutathione peroxidase and reductase, and total glutathione) in MPO-deficient and normal monocytes that would account for the enhanced respiratory burst of MPO-deficient cells. These findings support a role for peroxidase in the termination of the respiratory burst of monocytes.


Selective replacement of organosilicon units in the cluster [(PhSi)4S6] with coinage metal complex fragments.
Adamantane-type organo-group 14 chalcogenide clusters were shown to possess extreme non-linear optical properties. Reactivity studies of corresponding organosilicon sulfide clusters towards copper and silver complexes indicate a replacement of exactly one of the organosilicon groups with a metal complex fragment to form [(Et3PAg)3(PhSi)3S6] (1) and [Na2(thf)2.33][(Me3PCu)(PhSi)3S6] (2)-in striking contrast to reactions of organotin chalcogenide clusters, which are more significantly and less systematically re-organized. The silicon compounds are thus more suited for controlled modifications of their geometric and electronic structures.


In pursuit of small molecule chemistry for calcium-permeable non-selective TRPC channels -- mirage or pot of gold?
The primary purpose of this review is to address the progress towards small molecule modulators of human Transient Receptor Potential Canonical proteins (TRPC1, TRPC3, TRPC4, TRPC5, TRPC6 and TRPC7). These proteins generate channels for calcium and sodium ion entry. They are relevant to many mammalian cell types including acinar gland cells, adipocytes, astrocytes, cardiac myocytes, cochlea hair cells, endothelial cells, epithelial cells, fibroblasts, hepatocytes, keratinocytes, leukocytes, mast cells, mesangial cells, neurones, osteoblasts, osteoclasts, platelets, podocytes, smooth muscle cells, skeletal muscle and tumour cells. There are broad-ranging positive roles of the channels in cell adhesion, migration, proliferation, survival and turning, vascular permeability, hypertrophy, wound-healing, hypo-adiponectinaemia, angiogenesis, neointimal hyperplasia, oedema, thrombosis, muscle endurance, lung hyper-responsiveness, glomerular filtration, gastrointestinal motility, pancreatitis, seizure, innate fear, motor coordination, saliva secretion, mast cell degranulation, cancer cell drug resistance, survival after myocardial infarction, efferocytosis, hypo-matrix metalloproteinase, vasoconstriction and vasodilatation. Known small molecule stimulators of the channels include hyperforin, genistein and rosiglitazone, but there is more progress with inhibitors, some of which have promising potency and selectivity. The inhibitors include 2-aminoethoxydiphenyl borate, 2-aminoquinolines, 2-aminothiazoles, fatty acids, isothiourea derivatives, naphthalene sulfonamides, N-phenylanthranilic acids, phenylethylimidazoles, piperazine/piperidine analogues, polyphenols, pyrazoles and steroids. A few of these agents are starting to be useful as tools for determining the physiological and pathophysiological functions of TRPC channels. We suggest that the pursuit of small molecule modulators for TRPC channels is important but that it requires substantial additional effort and investment before we can reap the rewards of highly potent and selective pharmacological modulators.


Oral antioxidants and cardiovascular health in the exercise-trained and untrained elderly: a radically different outcome.
Both antioxidant supplementation and exercise training have been identified as interventions which may reduce oxidative stress and thus improve cardiovascular health, but the interaction of these interventions on arterial BP (blood pressure) and vascular function has not been studied in older humans. Thus in six older (71+/-2 years) mildly hypertensive men, arterial BP was evaluated non-invasively at rest and during small muscle mass (knee-extensor) exercise with and without a pharmacological dose of oral antioxidants (vitamins C and E, and alpha-lipoic acid). The efficacy of the antioxidant intervention to decrease the plasma free radical concentration was verified via EPR (electron paramagnetic resonance) spectroscopy, while changes in endothelial function in response to exercise training and antioxidant administration were evaluated via FMD (flow-mediated vasodilation). Subjects were re-evaluated after a 6-week aerobic exercise training programme. Prior to training, acute antioxidant administration did not change resting arterial BP or FMD. Six weeks of knee-extensor exercise training reduced systolic BP (from 150+/-8 mmHg at pre-training to 138+/-3 mmHg at post-training) and diastolic BP (from 91+/-5 mmHg at pre-training to 79+/-3 mmHg at post-training), and improved FMD (1.5+/-1 to 4.9+/-1% for pre- and post-training respectively). However, antioxidant administration after exercise training negated these improvements, returning subjects to a hypertensive state and blunting training-induced improvements in FMD. In conclusion, the paradoxical effects of these interventions suggest a need for caution when exercise and acute antioxidant supplementation are combined in elderly mildly hypertensive individuals.


Complex cellular composition of solitary fibrous tumor of the prostate.
Solitary fibrous tumors (SFTs) of the prostate are a rare type of spindle cell neoplasm that can demonstrate either a benign or malignant phenotype. SFTs represent a clinical challenge along with other spindle cell lesions of the prostate in terms of both diagnosis and treatment. The present study shows, for the first time, that SFTs of the prostate and other organs can comprise a mixed population of fibroblast, myofibroblast, and smooth muscle cell types. The highly proliferative component demonstrated a fibroblastic phenotype that readily underwent myofibroblast differentiation on exposure to profibrotic stimuli. Consistent with other recent studies, the prostatic SFTs demonstrated NAB2-STAT6 gene fusions that were also present in the fibroblast, myofibroblast, and smooth muscle cell types of the SFT. The results of these studies suggest that benign and malignant prostatic tumors of mesenchymal origin may be distinguished at the molecular and cellular levels, and that delineation of such defining characteristics may help elucidate the etiology and prognosis of such tumors.


An experimental method for measuring force on the spinal facet joint: description and application of the method.
A technique is described for measuring load magnitude and resultant load contact location in the facet joint in response to applied loads and moments, and the technique applied to the canine lumbar spine motion segment. Due to the cantilever beam geometry of the cranial articular process, facet joint loads result in surface strains on the lateral aspect of the cranial articular process. Strains were quantified by four strain gages cemented to the bony surface of the process. Strain measured at any one gage depended on the loading site on the articular surface of the caudal facet and on the magnitude of the facet load. Determination of facet loads during in vitro motion segment testing required calibration of the strains to known loads of various magnitudes applied to multiple sites on the caudal facet. The technique is described in detail, including placement of the strain gages. There is good repeatability of strains to applied facet loads and the strains appear independent of load distribution area. Error in the technique depends on the location of the applied facet loads, but is only significant in nonphysiologic locations. The technique was validated by two independent methods in axial torsion. Application of the technique to five in vitro canine L2-3 motion segments testing resulted in facet loads (in newtons, N) of 74+ / -23 N (mean + / -STD) in 2 newton-meter, Nm, extension, to unloaded in flexion. Lateral bending resulted in loads in the right facet of 40+ / -32 N for 1 Nm right lateral bending and 54+ / -29 N for 1 Nm left lateral bending. 4 Nm Torsion with and without 100 N axial compression resulted in facet loads of 92+ / -27 N and 69+ / -19 N, respectively. The technique is applicable to dynamic and in vivo studies.


Cathelicidin CATH-B1 Inhibits Pseudorabies Virus Infection via Direct Interaction and TLR4/JNK/IRF3-Mediated Interferon Activation.
Pseudorabies virus (PRV), the causative pathogen of Aujeszky's disease, is one of the most important pathogens threatening the global pig industry. Although vaccination has been used to prevent PRV infection, the virus cannot be eliminated in pigs. Thus, novel antiviral agents as complementary to vaccination are urgently needed. Cathelicidins (CATHs) are host defense peptides that play an important role in the host immune response against microbial infections. In the study, we found that the chemical synthesized chicken cathelicidin B1 (CATH-B1) could inhibit PRV regardless of whether CATH-B1 was added pre-, co-, or post-PRV infection in vitro and in vivo. Furthermore, coincubation of CATH-B1 with PRV directly inactivated virus infection by disrupting the virion structure of PRV and mainly inhibited virus binding and entry. Importantly, pretreatment of CATH-B1 markedly strengthened the host antiviral immunity, as indicated by the increased expression of basal interferon-β (IFN-β) and several IFN-stimulated genes (ISGs). Subsequently, we investigated the signaling pathway responsible for CATH-B1-induced IFN-β production. Our results showed that CATH-B1 induced phosphorylation of interferon regulatory transcription factor 3 (IRF3) and further led to production of IFN-β and reduction of PRV infection. Mechanistic studies revealed that the activation of Toll-like receptor 4 (TLR4), endosome acidification, and the following c-Jun N-terminal kinase (JNK) was responsible for CATH-B1-induced IRF3/IFN-β pathway activation. Collectively, CATH-B1 could markedly inhibit PRV infection via inhibiting virus binding and entry, direct inactivation, and regulating host antiviral response, which provided an important theoretical basis for the development of antimicrobial peptide drugs against PRV infection. IMPORTANCE Although the antiviral activity of cathelicidins could be explained by direct interfering with the viral infection and regulating host antiviral response, the specific mechanism of cathelicidins regulating host antiviral response and interfering with pseudorabies virus (PRV) infection remains elusive. In this study, we investigated the multiple roles of cathelicidin CATH-B1 against PRV infection. Our study showed that CATH-B1 could suppress the binding and entry stages of PRV infection and direct disrupt PRV virions. Remarkably, CATH-B1 significantly increased basal interferon-β (IFN-β) and IFN-stimulated gene (ISG) expression levels. Furthermore, TLR4/c-Jun N-terminal kinase (JNK) signaling was activated and involved in IRF3/IFN-β activation in response to CATH-B1. In conclusion, we elucidate the mechanisms by which the cathelicidin peptide direct inactivates PRV infection and regulates host antiviral IFN-β signaling.


Evidence for ACE2-utilizing coronaviruses (CoVs) related to severe acute respiratory syndrome CoV in bats.
In 2002, severe acute respiratory syndrome (SARS)-coronavirus (CoV) appeared as a novel human virus with high similarity to bat coronaviruses. However, while SARS-CoV uses the human angiotensin-converting enzyme 2 (ACE2) receptor for cellular entry, no coronavirus isolated from bats appears to use ACE2. Here we show that signatures of recurrent positive selection in the bat ACE2 gene map almost perfectly to known SARS-CoV interaction surfaces. Our data indicate that ACE2 utilization preceded the emergence of SARS-CoV-like viruses from bats.


Runx1 Deficiency Protects Against Adverse Cardiac Remodeling After Myocardial Infarction.
Myocardial infarction (MI) is a leading cause of heart failure and death worldwide. Preservation of contractile function and protection against adverse changes in ventricular architecture (cardiac remodeling) are key factors to limiting progression of this condition to heart failure. Consequently, new therapeutic targets are urgently required to achieve this aim. Expression of the Runx1 transcription factor is increased in adult cardiomyocytes after MI; however, the functional role of Runx1 in the heart is unknown. To address this question, we have generated a novel tamoxifen-inducible cardiomyocyte-specific Runx1-deficient mouse. Mice were subjected to MI by means of coronary artery ligation. Cardiac remodeling and contractile function were assessed extensively at the whole-heart, cardiomyocyte, and molecular levels. Runx1-deficient mice were protected against adverse cardiac remodeling after MI, maintaining ventricular wall thickness and contractile function. Furthermore, these mice lacked eccentric hypertrophy, and their cardiomyocytes exhibited markedly improved calcium handling. At the mechanistic level, these effects were achieved through increased phosphorylation of phospholamban by protein kinase A and relief of sarco/endoplasmic reticulum Ca2+-ATPase inhibition. Enhanced sarco/endoplasmic reticulum Ca2+-ATPase activity in Runx1-deficient mice increased sarcoplasmic reticulum calcium content and sarcoplasmic reticulum-mediated calcium release, preserving cardiomyocyte contraction after MI. Our data identified Runx1 as a novel therapeutic target with translational potential to counteract the effects of adverse cardiac remodeling, thereby improving survival and quality of life among patients with MI.


Subtle Microwave-Induced Overheating Effects in an Industrial Demethylation Reaction and Their Direct Use in the Development of an Innovative Microwave Reactor.
A systematic study of the conventional and microwave (MW) kinetics of an industrially relevant demethylation reaction is presented. In using industrially relevant reaction conditions the dominant influence of the solvent on the MW energy dissipation is avoided. Below the boiling point, the effect of MWs on the activation energy Ea and k0 is found nonexistent. Interestingly, under reflux conditions, the microwave-heated (MWH) reaction displays very pronounced zero-order kinetics, displaying a much higher reaction rate than observed for the conventionally thermal-heated (CTH) reaction. This is related to a different gas product (methyl bromide, MeBr) removal mechanism, changing from classic nucleation into gaseous bubbles to a facilitated removal through escaping gases/vapors. Additionally, the use of MWs compensates better for the strong heat losses in this reaction, associated with the boiling of HBr/water and the loss of MeBr, than under CTH. Through modeling, MWH was shown to occur inhomogeneously around gas/liquid interfaces, resulting in localized overheating in the very near vicinity of the bubbles, overall increasing the average heating rate in the bubble vicinity vis-à-vis the bulk of the liquid. Based on these observations and findings, a novel continuous reactor concept is proposed in which the escaping MeBr and the generated HBr/water vapors are the main driving forces for circulation. This reactor concept is generic in that it offers a viable and low cost option for the use of very strong acids and the managed removal/quenching of gaseous byproducts.


Preparation of insoluble collagen from human cartilage.
A simple technique is described for the removal of proteoglycans from human cartilage by sequential treatments with H(2)O(2) followed by trypsin digestion. The resultant fibres contain no uronic acids and have the amino acid composition of highly purified collagen.


The Relationship Between Pain, and Freezing of Gait and Falls in Parkinson's Disease.
To investigate the relationship between pain, freezing of gait (FOG) and falls in Parkinson's Disease (PD). The study included 110 PD patients. The Unified PD Rating Scale (UPDRS) and Hoehn and Yahr Scale were used to evaluate disease severity. The patients self-reported occurrence of FOG and falls, and the FOG Questionnaire was administered to evaluate the severity of FOG. A visual analog scale (VAS) was used to measure the severity of pain and pain localization was self-reported by the patients. Fifty-eight of the patients had FOG and 43 experienced falls. Among the patients, 42 had no pain, whereas 35 had lower extremity pain. Higher UPDRS motor and FOG scores, and advanced-stage disease were noted in significantly more of the patients with FOG and falls. VAS scores were not affected by the presence of FOG or falls. There was a positive correlation between the severity of FOG and VAS score in the male patients (r=0.308; p=0.010). More patients with falls had lower extremity pain than those without falls (r=0.308; p=0.010). Patients with FOG and falls had more severe motor findings. Pain is correlated with both FOG and falls. Further investigations should be done to understand the mechanism of this relationship to prevent the motor complications in advanced PD.


Radioisotopic renal function studies in essential hypertension.
Renal and intrarenal distribution of flow together with an index of cardiac output is measurable using a single injection of 123I-o-iodohippurate. The argument is presented that in the treatment of essential hypertension one should avoid using drugs that reduce renal blood flow, a property of chronic therapy with most beta-blockers or diuretics. Reduction of renal blood flow is a stimulus to salt retention and renin release which tend to maintain hypertension. Drugs which increase renal blood flow, thereby augmenting the renal loss of salt and decreasing renin release, tend to reduce hypertension in the long term.


Epstein-Barr Virus-Encoded Products Promote Circulating Tumor Cell Generation: A Novel Mechanism of Nasopharyngeal Carcinoma Metastasis.
Epstein-Barr virus (EBV) is a specific tumorigenic factor in the pathogenesis of nasopharyngeal carcinoma (NPC). Viral products encoded by EBV (LMP1, LMP2A, EBNA1, and miRNAs) have been shown to promote NPC metastasis. EBV-encoded oncoproteins and miRNAs have been shown to induce epithelial-mesenchymal transition (EMT) indirectly by inducing EMT transcription factors (EMT-TFs). These EBV-encoded products also promote the expression of EMT-TFs through post-transcriptional regulation. EMT contributes to generation of circulating tumor cells (CTCs) in epithelial cancers. CTCs exhibit stem cell characteristics, including increased invasiveness, enhanced cell intravasation, and improved cell survival in the peripheral system. EBV may contribute NPC metastasis through promoting generation of CTCs. Furthermore, CTC karyotypes are associated with NPC staging, therapeutic sensitivity, and resistance. We summarized studies showing that EBV-encoded virus-proteins and miRNAs promote generation of NPC CTCs, and highlighted the associated mechanism. This synthesis indicated that EBV mediates NPC metastasis through generation of CTCs.


Identifying Personal Risk Factors for Falls in the Workplace.
Falls can occur in any occupational setting. Occupational health professionals may focus on creating a safe work environment and training programs to prevent falls. However, an important aspect of safety management is identifying at-risk employees. The purpose of this article is to identify personal risk factors and offer interventions to prevent falls in the workplace.


Pharmacokinetics and variation in the clearance of oxycodone and hydrocotarnine in patients with cancer pain.
Compound injections of oxycodone and hydrocotarnine are currently used as one of the treatment options for some cases with cancer pain. However, there have been no reports examining the factors that influence oxycodone and hydrocotarnine clearance, so detailed examination is necessary. As for hydrocotarnine, there have been no reports examining the pharmacokinetics. Therefore in this study, we determined the pharmacokinetics of oxycodone and hydrocotarnine in patients with cancer pain. The study was conducted on 19 patients, in whom pain control was attempted by using the compound injections of oxycodone and hydrocotarnine. We used HPLC-electrochemical detector (ECD) to determine oxycodone and hydrocotarnine serum concentrations, and used the nonlinear least-squares method (MULTI) for calculation of the pharmacokinetic parameters. Furthermore, we examined the factors that influence the clearance of oxycodone and hydrocotarnine by multiple regression analysis (step wise method). The pharmacokinetic parameters were as follows: Oxycodone; V(d)=226.7+/-105.5 l (mean+/-S.D.), CL=37.9+/-25.1 l/h, t(1/2)=4.1+/-1.9 h. Hydrocotarnine; V(d)=276.8+/-237.2 l, CL=95.1+/-64.3 l/h, t(1/2)=2.0+/-0.7 h. The clearance of oxycodone represented by a regression formula was significantly correlated to the age, the presence or absence of within 7 d on the death or liver metastasis, or of the heart failure of the patients. The clearance of hydrocotarnine represented by a regression formula was significantly correlated to the presence or absence of within 7 d on the death or liver metastasis, or of the heart failure of the patients. The clearance also indicated that oxycodone concentration in the blood was likely to be higher in patients having these factors. Oxycodone/hydrocotarnine compound injections should be used with caution and dose reduction may be necessary in such populations.


Dynorphin / kappa-opioid receptor regulation of excitation-inhibition balance toggles afferent control of prefrontal cortical circuits in a pathway-specific manner.
The medial prefrontal cortex (mPFC) controls behavior via connections with limbic excitatory afferents that engage various inhibitory motifs to shape mPFC circuit function. The dynorphin (Dyn) / kappa-opioid receptor (KOR) system is highly enriched in the mPFC, and its dysregulation is implicated in neuropsychiatric disorders. However, it is unclear how the Dyn / KOR system modulates excitatory and inhibitory circuits that are integral for mPFC information processing and behavioral control. Here, we provide a circuit-based framework wherein mPFC Dyn / KOR signaling regulates excitation-inhibition balance by toggling which afferents drive mPFC neurons. Dyn / KOR regulation of afferent inputs is pathway-specific. Dyn acting on presynaptic KORs inhibits glutamate release from afferent inputs to the mPFC, including the basolateral amygdala (BLA), paraventricular nucleus of the thalamus, and contralateral cortex. The majority of excitatory synapses to mPFC neurons, including those from the ventral hippocampus (VH), do not express presynaptic KOR, rendering them insensitive to Dyn / KOR modulation. Dyn / KOR signaling also suppresses afferent-driven recruitment of specific inhibitory sub-networks, providing a basis for Dyn to disinhibit mPFC circuits. Specifically, Dyn / KOR signaling preferentially suppresses SST interneuron- relative to PV interneuron-mediated inhibition. Selective KOR action on afferents or within mPFC microcircuits gates how distinct limbic inputs drive spiking in mPFC neurons. Presynaptic Dyn / KOR signaling decreases KOR-positive input-driven (e.g. BLA) spiking of mPFC neurons. In contrast, KOR-negative input recruitment of mPFC neurons is enhanced by Dyn / KOR signaling via suppression of mPFC inhibitory microcircuits. Thus, by acting on distinct circuit elements, Dyn / KOR signaling shifts KOR-positive and negative afferent control of mPFC circuits, providing mechanistic insights into the role of neuropeptides in shaping mPFC function. Together, these findings highlight the utility of targeting the mPFC Dyn / KOR system as a means to treat neuropsychiatric disorders characterized by dysregulation in mPFC integration of long-range afferents with local inhibitory microcircuits.


Perceived risk of infection and smoking behavior change during COVID-19 in Ohio.
The recent COVID-19 pandemic may catalyze smoking behavior modification. The purpose of the study was to examine factors associated with reducing smoking exposure during the COVID-19 outbreak. Cross-sectional design using the Health Belief Model to develop an online survey distributed throughout Ohio early during the outbreak. 810 adults in Ohio (77.9% non-smokers, 22.1% current smokers). Sociodemographic factors, smoking and behavior changes since the COVID-19 outbreak, and perceived risk of infection were collected. Logistic regression analyses were conducted to determine factors associated with indoor smoking bans and factors associated with desire to quit smoking since the outbreak. For the overall sample, the odds of indoor smoking bans were significantly associated with never smoked, college education, single-family residence, not living with smokers, and perceived importance of avoiding public places. For smokers, the desire to quit smoking since the COVID-19 outbreak was associated with diabetes and perceived risk of severe infection. Identified factors inform residential smoking exposure reduction through indoor smoking bans. Having an increased perceived risk of severe infection among smokers may motivate cessation. Public health nurses can provide accurate and accessible resources for smoking cessation during the COVID-19 pandemic to promote healthy lifestyle modification.