The Effect of Head and Neck Radiotherapy on Blood Pressure and Orthostatic Hypotension in Patients With Head and Neck Tumors.
Radiotherapy (RT) plays a key role in the management of head and neck cancer (HNC), especially in locally advanced disease. Patients undergoing head and neck RT, especially elderly ones, are suffering from low and labile blood pressure (BP) during the treatment. They complain of weakness and fatigue and are prone to recurrent falls. The aim of this study was to characterize BP changes during RT period. Patients with HNC, receiving radiation to the neck, were recruited from Sheba medical center RT unit. Office BP, orthostatic measurements, 24-hour ambulatory BP monitoring, body weight, and metabolic parameters were measured at baseline after 30 days and after 90 days from beginning of therapy. Nineteen patients (17 males), 64 ± 12 years old were recruited. Nine hypertensive patients continued their antihypertensive treatment during the study. Office systolic BP and diastolic BP decreased significantly after 30 days (128 ± 4/80 ± 3 to 122 ± 3/74 ± 3 mm Hg; P < 0.05). Average 24-hour BP values after 30 days of RT decreased from 130 ± 3/76 ± 2 to 123 ± 3/71 ± 2 mm Hg; P < 0.05. A similar trend was observed for day and night BP levels. Decrease in office and ambulatory BP was sustained for several months after RT completion. No orthostasis was observed during the study period. Patient lost weight significantly during the study period. However, BP changes were independent of weight loss. There is a significant and sustained BP reduction after head and neck RT, without orthostatic changes. Clinicians should be aware of this phenomenon and consider treatment adaption accordingly.


Thymic uptake of gallium-67 citrate in a healthy 4 year old boy.
Gallium uptake in a mediastinal mass has been most often seen with lymphoma. A case is reported of thymic uptake in an otherwise healthy 4 1/2 year old boy who had recently had pneumonia. Serial films always showed an unchanging prominent though normal thymus and follow up gallium scans showed disappearance of thymic uptake. This and other similar cases indicate the need to consider a non-neoplastic thymus when gallium accumulation is noted in the anterior mediastinum of a child.


Effects of calcium antagonists and agonists on isolated human v. saphena magna used for coronary artery bypass grafting and guinea pig's papillary muscle.
The goal of this study was to investigate the movement of contraction-relaxation effects on isolated human blood vessel samples by the actions of amlodipine (CAS 88150-42-9), cerebrocrast (CAS 118790-71-9), diltiazem (CAS 42399-41-7), and a benzimidazole derivative. Additionally, their effects on isometric contraction force and the duration of the action potential (AP) were measured. The experiments were carried out on isolated human v. saphena magna samples and papillary muscles of adult guinea pigs. Isometric contraction and the AP were recorded using a force transducer and standard microelectrode technique. Phenylephrine (10(-4) M) caused contractions of vein rings to 928 +/- 76.5 mg. All the tested agents at a concentration of 10(-7)-10(-4) M significantly relaxed the smooth muscle in a dose-dependent manner. The weakest response was shown by amlodipine. Pre-treatment with 50 microM of amlodipine, diltiazem and benzimidazole for 30 min significantly increased the magnitude of the contraction induced by phenylephrine in concentration-dependent (10(-6)-10(-4) M) fashion but only in the benzimidazole group versus other tested agents and the control. The benzimidazole derivative caused augmentation of isometric contraction of the papillary muscles and negligible lengthening of AP duration; the other agents tested showed opposite effects. These results show that agents possessing positive or negative inotropic action significantly relaxed the isolated vein samples precontracted with phenylephrine. These responses point to a different mechanism of action underlying both calcium antagonist and agonist effects even though their action ultimately resulted in vasodilatation.


Mechanisms of Resistance in Multiple Myeloma.
Multiple myeloma (MM) is an incurable hematopoietic cancer that is characterized by malignant plasma cell infiltration of the bone marrow and/or extramedullary sites. Multi-modality approaches including "novel agents," traditional chemotherapy, and/or stem cell transplantation are used in MM therapy. Drug resistance, however, ultimately develops and the disease remains incurable for the vast majority of patients. In this chapter, we review both tumor cell-autonomous and non-autonomous (microenvironment-dependent) mechanisms of drug resistance. MM provides an attractive paradigm highlighting a number of current concepts and challenges in oncology. Firstly, identification of MM cancer stem cells and their unique drug resistance attributes may provide rational avenues towards MM eradication and cure. Secondly, the oligoclonal evolution of MM and alternation of "clonal tides" upon therapy challenge our current understanding of treatment responses. Thirdly, the success of MM "novel agents" provides exemplary evidence for the impact of therapies that target the immune and non-immune microenvironment. Fourthly, the rapid pace of drug approvals for MM creates an impetus for development of precision medicine strategies and biomarkers that promote efficacy and mitigate toxicity and cost. While routine cure of the disease remains the ultimate and yet unattainable prize, MM advances in the last 10-15 years have provided an astounding paradigm for the treatment of blood cancers in the modern era and have radically transformed patient outcomes.


Isoproterenol infusion increases level of consciousness during catheter ablation of atrial fibrillation.
The objective of this study was to determine the effects of isoproterenol infusion on level of consciousness during ablation using total intravenous anesthesia. Seven patients undergoing total intravenous anesthesia for atrial fibrillation ablation were monitored for level of consciousness using bispectral EEG levels (BIS). Isoproterenol infusion was performed after the ablation during anesthesia. BIS levels prior to, during, and post-isoproterenol infusion were recorded and correlated to isoproterenol infusion doses. In all patients, BIS levels significantly increased during isoproterenol infusion (median BIS prior to infusion, 46; during infusion, 64 (p < 0.02)). With a subsequent increase in anesthetic medication, BIS levels could again be reduced. Isoproterenol infusion alters consciousness level during total intravenous anesthesia for atrial fibrillation ablation. BIS monitoring is a novel way to modulate anesthesia during ablation to potentially optimize patient comfort and ablation success.


Monitoring clinical outcomes in aggressive B-cell lymphoma: From imaging studies to circulating tumor DNA.
Recent guidelines have de-emphasized the role of routine surveillance computed tomography (CT) scans for diffuse large B-cell lymphoma (DLBCL) patients who achieve a complete response to front-line therapy. This shift in practice recommendations was prompted by retrospective studies that failed to demonstrate clear clinical utility for surveillance CT in unselected DLBCL patients. Controversy remains, however, over the role of routine surveillance CT in the highest risk patients for treatment failure who would remain candidates for aggressive salvage therapies. Novel high-throughput sequencing methods can non-invasively monitor tumor-specific DNA in the blood and offers clear advantages designed to overcome fundamental limitations of CT scans. This review will discuss the current controversies surrounding monitoring clinical outcomes in aggressive B-cell lymphomas, with a specific emphasis on DLBCL. Fundamental limitations of imaging scans will be addressed and the potential of monitoring circulating tumor DNA as an adjunct or replacement for CT scans will be discussed.


Unbiased and efficient sampling of timeseries reveals redundancy of brain network and gradient structure.
Many studies in human neuroscience seek to understand the structure of brain networks and gradients. Few studies, however, have tested the redundancy between these outwardly distinct features. Here, we developed methods to directly enable such tests. We built on insights from linear algebra to develop methods for unbiased and efficient sampling of timeseries with network or gradient constraints. We used these methods to show considerable redundancy between popular definitions of network and gradient structure in functional MRI data. On the one hand, we found that network constraints largely accounted for the structure of three major gradients. On the other hand, we found that gradient constraints largely accounted for the structure of seven major networks. Our results imply that some networks and gradients may denote discrete and continuous representations of the same aspects of functional MRI data. We suggest that integrated explanations can reduce redundancy by avoiding the attribution of independent existence or function to these features.


Mortality for alcohol-related harm by country of birth in Scotland, 2000-2004: potential lessons for prevention.
Deaths caused by alcohol have increased in the UK, and Scotland in particular, but the change in the rates of alcohol-related deaths for migrants are uncertain, and could yield insights for the general population. Alcohol-related mortality in immigrants among Scotland's residents was assessed using 2001 census data and mortality data from 2000 to 2004. Mortality from direct alcohol-related causes accounted for nearly 1500 deaths per year in Scotland. Age-standardized mortality ratios were comparatively low for people born in Pakistan, other parts of the UK (largely England and Wales) and those from elsewhere in the world. Scotland's propensity to alcohol-related deaths is not shared by all its residents. Studying such variations in more depth could yield lessons for prevention.


Effect of oestrogen and progesterone on noradrenergic nerves and on nerves showing serotonin-like immunoreactivity in the basilar artery of the rabbit.
The effects of oestrogen and progesterone on noradrenergic nerves and nerves with serotonin (5-HT)-like immunoreactivity in the basilar artery were investigated in the rabbit using whole-mount stretch preparations. The noradrenergic nerves were demonstrated by glyoxylic acid fluorescence histochemistry and nerves with 5-HT-like immunoreactivity by indirect immunofluorescence techniques. Quantitative image analysis of fluorescent nerve fibres revealed that nerve density and varicosity diameter of nerves with 5-HT-like immunoreactivity were significantly (P less than 0.01 and P less than 0.05 respectively) reduced after 4-week administration of oestrogen and the intensity of fluorescence was also reduced. However, there were no significant changes after progesterone. Neither oestrogen nor progesterone had any effect on noradrenergic innervation. The findings are discussed in relation to higher incidence of migraine headaches in females taking oral contraceptives.


NDRG1 facilitates self-renewal of liver cancer stem cells by preventing EpCAM ubiquitination.
Portal vein tumour thrombus (PVTT) is the main pathway of HCC intrahepatic metastasis and is responsible for the poor prognosis of patients with HCC. However, the molecular mechanisms underlying PVTT vascular metastases have not been fully elucidated. NDRG1 expression was assessed by immunohistochemistry and immunoblotting in clinical specimens obtained from curative surgery. The functional relevance of NDRG1 was evaluated using sphere formation and animal models of tumorigenicity and metastasis. The relationship between NDRG1 and EpCAM was explored using molecular biological techniques. NDRG1 protein was upregulated in HCC samples compared to non-tumorous tissues. Furthermore, NDRG1 expression was enhanced in the PVTT samples. Our functional study showed that NDRG1 was required for the self-renewal of tumour-initiating/cancer stem cells (CSCs). In addition, NDRG1 knockdown inhibited the proliferation and migration of PVTT-1 cells in vitro and in vivo. NDRG1 was found to stabilise the functional tumour-initiating cell marker EpCAM through protein-protein interactions and inhibition of EpCAM ubiquitination. Our findings suggest that NDRG1 enhances CSCs expansion, PVTT formation and growth capability through the regulation of EpCAM stability. NDRG1 may be a promising target for the treatment of patients with HCC and PVTT.


Synthesis of some new anils: part 1. Reaction of 2-hydroxy-benzaldehyde and 2-hydroxynaphthaldehyde with 2-aminopyridene and 2-aminopyrazine.
New Schiff bases derived from 2-aminopyridene and 2-aminopyrazine have been synthesized. The UV-Visible spectra of the compounds have been investigated in acetonitrile and toluene. The compounds were in tautomeric equilibrium (enol-imine O- H...N, keto-amine O...H-N forms) in polar and nonpolar solvents. For some derivatives the keto-amine form was observed in both toluene and acetonitrile. 1H-NMR and IR results showed that all Schiff bases studied favor the enol-imine form over the keto form in a weakly polar solvent such as deuterochloroform.


The measurement of the cell cycle time in squamous epithelium using the metaphase arrest technique with vincristine.
In squamous epithelia with a single layer of germinative cells, the age distribution of cells in the cell cycle is shown to depend on the direction of the mitotic axis (i.e. a line joining the nuclei of daughter cells) relative to the plane of the basal layer. When axes are in the plane of the basal layer the age distribution is exponential; when cells divide at right angles to the plane of the basal layer, the age distribution is rectangular. When there is a ratio of vertical to horizontal axes, the age distribution is intermediate but can be calculated from knowledge of the proportion of axes in the plane of the layer. Squamous epithelia can be classified according to this arrangement of axes. When there are multiple layers of germinative cells, as in psoriasis, the age distribution is shown to be exponential to a good approximation, whatever the direction of the mitotic axes in the several layers. The importance of these observations is demonstrated by analysing metaphase arrest experiments with vincristine in the single layer of germinative cells in the mouse oesophagus, and in the several layers found in psoriatic epidermis. Choice of the wrong age distribution leads to an error of 6 h in the oesophagus and 23 h in psoriatic epidermis, when the mean cell cycle time is calculated. It is concluded that, in squamous epithelium, it is most important to know the age distribution before calculating the cell cycle time by methods involving measurement of the rate of entry of cells into mitosis or DNA synthesis.


[X-ray diagnosis of 128 cases of cerebral vascular malformations (AVM) with emphasis on analysis of cerebral angiogram].
128 cases of AVM studied by cerebroangiography were analysed. All were confirmed by operation and pathology. Based on the feeding arteries, draining veins and malformed vessels, the authors analysed the hemodynamics of AVM and divided them into six types. This classification will be of benefit to the surgeon. In this article the associated cerebral aneurysm and blood supply from meningeal arteries were also discussed. The CT findings of AVM as well as various diagnostic imaging methods used were described.


Increased risk of male cancer and identification of a potential prostate cancer cluster region in BRCA2.
The risk of cancer in men from BRCA1 and BRCA2 families is relevant to define to motivate genetic testing and optimize recommendations for surveillance. We assessed the risk of cancer in male mutation carriers and their first-degree relatives in 290 BRCA1 and BRCA2 families with comparison to matched controls with the aim to motivate genetic testing and optimize recommendations for surveillance. Mutation carriers in BRCA1 families were not at increased risk of cancer, whereas mutation carriers in BRCA2 families were at increased risk of male breast cancer and prostate cancer with cumulative risks of 12.5% and 18.8%, respectively. Breast cancer developed at a mean age of 59 years, typically as ER/PR positive ductal carcinomas. Prostate cancer developed at a mean age of 68 years, with Gleason scores ≥ 8 in 40% of the tumors. The hazard ratio for BRCA2-associated prostate cancer was 3.7 (p < 0.001) in mutation carriers and 3.1 (p = 0.001) in first-degree relatives. Of the 37 prostate cancers, 19 were linked to four BRCA2 mutations within a region defined by c.6373-c.6492. Individuals with mutations herein had a HR of 3.7 for prostate cancer compared to individuals with mutations outside of this region. Male mutation carriers and first-degree relatives in BRCA2 families are at an increased risk of breast cancer and prostate cancer with a potential prostate cancer cluster region within exon 11 of BRCA2.


Major histocompatibility complex antigens in normal, acanthotic and neoplastic ovine skin: an association been tumor invasiveness and low level MHC class I expression.
The distribution and density of ovine MHC class I and class II antigens in normal, acanthotic and malignantly transformed ovine skin was investigated using monoclonal antibodies and an immunoperoxidase technique. The subjects were sheep that had been exposed to high levels of sunlight for more than 6 years. The expression of MHC class II antigens in the plasma membrane of cells within the normal epidermis was restricted to basally located dendritic and mononuclear cells. Normal keratinocytes did not express MHC class II antigens. However, we observed low levels of intracellular MHC class II expression in both acanthotic and neoplastic keratinocytes. Expression of MHC class I antigens was variable in normal and acanthotic epithelium; it was usually present, but of low intensity in very early ovine squamous cell carcinoma and was increased in small, but morphologically typical, tumors. Tumors originating on the nose, which are more invasive than those on the ear, were found to express significantly less MHC class I (P < 0.05). Thus, an association between tumor invasiveness and low level expression of MHC class I was apparent. This may have diagnostic value and highlights a mechanism by which neoplastic cells may evade immune surveillance by T cells.


Patients Decision-Making Characteristics Affects Gynecomastia Treatment Satisfaction: A Multicenter Study Using the BODY-Q Chest Module.
Patient satisfaction is the most critical outcome in gynecomastia treatment. However, patient satisfaction may be affected by the patient's decision-making trait, such as exhaustively searching for the best outcome or being content with an outcome that satisfies a preconceived requirement. To assess whether patient's decision-making characteristic affect their satisfaction with gynecomastia treatment. This was a cross-sectional study including patients treated for gynecomastia between January 2009 and December 2019 at two tertiary hospitals in Denmark. Alive patients were sent the BODY-Q: Chest module, the SF-36 questionnaire, and the Maximizer/Satisficer decision-making survey. Patients were classified as Maximizers if they scored more than 40 points on the Maximizer/Satisficer survey. Percentage score differences (PDs) in quality of life scales were calculated between Maximizers and Satisficers. In total, 192 gynecomastia patients were included in this study and classified as Maximizers (n = 152) or Satisficers (n = 40). Maximizers were younger and more had gynecomastia following abuse of anabolic steroids than Satisficers (p < 0.05). With respect to bodily satisfaction, Maximizers showed significantly worse satisfaction with nipples (PDs: - 12.98%), psychological function (PDs: - 13.68%) and social function (PDs: - 8.77%, p < 0.05). In addition, Maximizers had significantly worse emotional role functioning (- 11.03%), vitality (PDs: - 11.72%) and mental health (PDs: - 10.00%, p < 0.05). Patients exhibiting maximizing-type decision-making characteristics have worse satisfaction with gynecomastia treatment and poorer psychosocial health. This information may facilitate patient counseling and alignment of treatment expectations. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


Diversity in Xanthophyll Cycle Pigments Content and Related Nonphotochemical Quenching (NPQ) Among Microalgae: Implications for Growth Strategy and Ecology.
Xanthophyll cycle-related nonphotochemical quenching (NPQ), which is present in most photoautotrophs, allows dissipation of excess light energy. Xanthophyll cycle-related NPQ depends principally on xanthophyll cycle pigments composition and their effective involvement in NPQ. Xanthophyll cycle-related NPQ is tightly controlled by environmental conditions in a species-/strain-specific manner. These features are especially relevant in microalgae living in a complex and highly variable environment. The goal of this study was to perform a comparative assessment of NPQ ecophysiologies across microalgal taxa in order to underline the specific involvement of NPQ in growth adaptations and strategies. We used both published results and data acquired in our laboratory to understand the relationships between growth conditions (irradiance, temperature, and nutrient availability), xanthophyll cycle composition, and xanthophyll cycle pigments quenching efficiency in microalgae from various taxa. We found that in diadinoxanthin-containing species, the xanthophyll cycle pigment pool is controlled by energy pressure in all species. At any given energy pressure, however, the diatoxanthin content is higher in diatoms than in other diadinoxanthin-containing species. XC pigments quenching efficiency is species-specific and decreases with acclimation to higher irradiances. We found a clear link between the natural light environment of species/ecotypes and quenching efficiency amplitude. The presence of diatoxanthin or zeaxanthin at steady state in all species examined at moderate and high irradiances suggests that cells maintain a light-harvesting capacity in excess to cope with potential decrease in light intensity.


The structured organization of Deinococcus radiodurans' cell envelope.
Surface layers (S-layers) are highly ordered coats of proteins localized on the cell surface of many bacterial species. In these structures, one or more proteins form elementary units that self-assemble into a crystalline monolayer tiling the entire cell surface. Here, the cell envelope of the radiation-resistant bacterium Deinococcus radiodurans was studied by cryo-electron microscopy, finding the crystalline regularity of the S-layer extended into the layers below (outer membrane, periplasm, and inner membrane). The cell envelope appears to be highly packed and resulting from a three-dimensional crystalline distribution of protein complexes organized in close continuity yet allowing a certain degree of free space. The presented results suggest how S-layers, at least in some species, are mesoscale assemblies behaving as structural and functional scaffolds essential for the entire cell envelope.


Stimulus dynamics increase the self-administration of compound visual and auditory stimuli.
Animals will acquire an operant task using sensory stimuli as a primary reinforcer. Many operant tasks use sensory stimuli as cues that are paired with other primary reinforcers. Recent studies have called attention to this potential confound, but there has not been a parametric assessment of the effect of stimulus variability on operant responding. We found that stimulus variability increased the amount of operant responding exhibited by mice, a phenomenon observed under both fixed- and progressive-ratio schedules.


Cytotoxic effects of acrylamide and its related compounds assessed by protein content, LDH activity and cumulative glucose consumption of neuron-rich cultures in a chemically defined medium.
Cytotoxicity of acrylamide on neuronal cells cultured in a chemically defined medium was studied with morphological alteration, protein content, LDH activity and cumulative glucose consumption as toxicity indicators. The cumulative glucose consumption was significantly reduced by exposure to acrylamide before the other indicators were affected, suggesting that it would be the most sensitive indicator in the present study and that inhibition of glucose utilization might be one of the mechanisms of acrylamide neurotoxicity. The cumulative glucose consumption was applied for assessing cytotoxicity of acrylamide and its related compounds in neuronal cultures. The ED50 values were 0.8, 5.8, 15.0 mM for acrylamide, N-isopropylacrylamide, and methacrylamide, respectively, which are neurotoxic in in vivo studies. N,N'-methylene-bis-acrylamide, which is not reported to be neurotoxic, however, showed the lowest ED50 value, 0.2 mM, indicating that it was most potently toxic to neuronal cells. The results suggest the necessity of a cautious approach to neurotoxicity assessment from culture studies.


Fabrication of highly porous, functional cellulose-based microspheres for potential enzyme carriers.
Here, we present highly porous, cellulose-based microspheres using (2,2,6,6-tetramethylpiperidine-1-oxyl) TEMPO-oxidized cellulose fibers (TOCFs) as starting materials. The TOCFs were first dissolved in a NaOH/urea solvent and transformed into microspheres via an emulsification method. The carboxyl groups on the surface of TOCFs were successfully carried on the cellulose-based microspheres, which provides them numerous reacting or binding sites, allowing them to be easily functionalized or immobilized with biomolecules for multi-functional applications. Furthermore, the introduction of magnetic nanoparticles awards these microspheres magnetic properties, allowing them to be attracted by a magnetic field. As a proof of concept, we demonstrate the application of using these carboxylate cellulose-based microspheres for enzyme immobilization. The cellulose-based microspheres can successfully create stable covalent bonds with enzymes after the activation of carboxyl groups. The enhanced pH tolerance, thermal stability, convenient recovery, and reusability position the emulsified microspheres as promising carriers for enzyme immobilization.


Quantitative aspects of RNA silencing in metazoans.
Small regulatory RNAs (microRNAs, siRNAs, and piRNAs) exhibit several unique features that clearly distinguish them from other known gene regulators. Their genomic organization, mode of action, and proposed biological functions raise specific questions. In this review, we focus on the quantitative aspect of small regulatory RNA biology. The original nature of these small RNAs accelerated the development of novel detection techniques and improved statistical methods and promoted new concepts that may unexpectedly generalize to other gene regulators. Quantification of natural phenomena is at the core of scientific practice, and the unique challenges raised by small regulatory RNAs have prompted many creative innovations by the scientific community.


Transgenesis and active immunization mediated reduction of sperm associated antigen 11A mRNA and protein levels affect fecundity in the rat.
Spermatozoa acquire motility and fertilizing ability during their transit through the epididymis. A wide variety of proteins secreted into the epididymal lumen are added on to the sperm surface to allow morphological and molecular changes involved in sperm maturation. Proteins of the Sperm Associated Antigen 11 (SPAG11) family are known to be localized on the sperm surface. The rat SPAG11A protein was implicated in sperm maturation during epididymal transit in vitro. However, systematic analyses on the significance of SPAG11A in fertility and sperm function is not yet reported in vivo. In this study, using testicular electroporation, we generated transgenic rats that express shRNA to ablate endogenous Spag11a mRNA. Genotyping revealed the integration of the plasmid that expresses shRNA against Spag11a mRNA. Significant decrease in the mRNA levels of Spag11a and its encoded protein was observed in the caput epididymis of transgenic rats. We also generated an active immunization rat model to ablate endogenous SPAG11A protein by administering recombinant SPAG11A protein. Immunized rats had a high antibody titer in the serum and the tissue fluids of caput, cauda and testis. In both these model systems, the litter size and sperm count was significantly reduced. However, spermatozoa obtained from the transgenic or immunized rats underwent capacitation and acrosome reaction and the associated calcium release. Results of this study indicate the role of SPAG11A in fecundity and sperm production and not in sperm function, especially capacitation and acrosome reaction.


Determination of optimal water solubility of capsaicin for its usage as a non-toxic antifoulant.
Capsaicin, a non-toxic natural product antifoulant, is an attractive alternative to the currently used toxic metal-based antifoulants for protecting the submerged surfaces. The problem associated with conducting capsaicin experiments is its limited aqueous solubility. A procedure was developed to obtain the maximum capsaicin concentration in water. Capsaicin was first dissolved in one of the three organic solvents, methanol, ethanol, and acetone. The organic solvent was replaced by gradually adding distilled water and evaporating the organic solvent. The best solvent for obtaining highest concentration of capsaicin in water was ethanol. A maximum capsaicin in water 6400 ppm was achieved by using 16 mg capsaicin dissolved in 0.8 ml ethanol followed with the addition of 2.5 ml distilled water in 0.2 ml increments and then slow evaporation of the solvent. The concentration obtained using our approach is well above the threshold concentration of capsaicin in deterring the marine organism attachments.


The aggregate effect of dopamine genes on dependence symptoms among cocaine users: cross-validation of a candidate system scoring approach.
Genome-wide studies of psychiatric conditions frequently fail to explain a substantial proportion of variance, and replication of individual SNP effects is rare. We demonstrate a selective scoring approach, in which variants from several genes known to directly affect the dopamine system are considered concurrently to explain individual differences in cocaine dependence symptoms. 273 SNPs from eight dopamine-related genes were tested for association with cocaine dependence symptoms in an initial training sample. We identified a four-SNP score that accounted for 0.55% of the variance in a separate testing sample (p = 0.037). These findings suggest that (1) limiting investigated SNPs to those located in genes of theoretical importance improves the chances of identifying replicable effects by reducing statistical penalties for multiple testing, and (2) considering top-associated SNPs in the aggregate can reveal replicable effects that are too small to be identified at the level of individual SNPs.


Gamma oscillations in the pedunculopontine nucleus are regulated by F-actin: neuroepigenetic implications.
The pedunculopontine nucleus (PPN) is part of the reticular activating system (RAS) in charge of arousal and rapid eye movement sleep. The presence of high-frequency membrane oscillations in the gamma-band range in the PPN has been extensively demonstrated both in vivo and in vitro. Our group previously described histone deacetylation (HDAC) inhibition in vitro induced protein changes in F-actin cytoskeleton and intracellular Ca2+ concentration regulation proteins in the PPN. Here, we present evidence that supports the presence of a fine balance between HDAC function and calcium calmodulin kinase II-F-actin interactions in the PPN. We modified F-actin polymerization in vitro by using jasplakinolide (1 μM, a promoter of F-actin stabilization), or latrunculin-B (1 μM, an inhibitor of actin polymerization). Our results showed that shifting the balance in either direction significantly reduced PPN gamma oscillation as well as voltage-dependent calcium currents.


Psychological interventions for delayed ejaculation/orgasm.
Of all the male sexual dysfunctions, delayed ejaculation (DE) is the least understood, least common and least studied. This paper aims to review and integrate the diverse psychological theories and proposed psychological interventions for DE. Clinicians will then be able to more clearly discern the relevant psychological/interpersonal issues of the patient/couple and implement systematically based effective interventions. After reviewing the literature, it is clear that no one theory accounts for all the varied presentations of DE, and no theory by itself has strong empirical support. However, awareness of the diverse points of view helps clinicians conduct better assessments and broaden their understanding of the patient's ejaculatory dysfunction. Similarly, no one psychological intervention works for all patients, nor will unsystematic random selection of interventions. This paper stresses on the need to clearly identify the source of the dysfunction and select treatments based upon the precipitating and maintaining factors. Much work remains to be done with regard to our understanding and treatment of DE. Specifically, we need to craft an evidence-based definition, assess the true prevalence of the dysfunction, demonstrate the efficacy of psychological interventions and design validated outcome measures.


"Me First, Others Later" A focused ethnography of ongoing cultural features of waiting in an Iranian emergency department.
Waiting is an inevitable experience in all emergency departments (EDs). This waiting time may negatively influence the patients and their relatives' satisfaction, healthcare professionals' (HCPs) performance, and the quality of care provided. This study aims to explore, gain understanding of and describe what it is like to wait in an Iranian emergency department (ED) with particular focus on cultural features. A focused ethnographic approach based on Spradley's (1980) developmental research sequence was conducted in the ED of a tertiary academic medical center in northwest Iran over a 9-month study period from July 2017 to March 2018. Participant observation, ethnographic interviews and examination of related documents and artefacts were used to collect data. All the data were recorded in either field notes or verbatim transcripts and were analysed using Spradley's ethnographic data analysis method concurrently. The overarching theme of "Me first, others later" emerged. Within this overarching theme there were seven sub-themes as follows: human-related factors, system-related factors, patients and their relatives' beliefs and behaviors, HCPs' beliefs and behaviors, consequences for patients and their relatives, consequences for HCPs, and consequences for ED environment and care process. The mentality 'me first, others later' as the main cultural barrier to emergency care, strenuously undermined our positive practice environment. An accountable patient/relative support liaison, a clearly-delineated process of ED care delivery, guidelines for providing culturally competent ED care, and public awareness programs are needed to address the concerns and conflicts which establish a mutual trust and rapport.


Multicentric glioma presenting with hemorrhage.
We report a case of multicentric malignant astrocytoma occurring simultaneously in both cerebrum and cerebellum, presenting with hemorrhage into the cerebellar tumor. Hemorrhage into a cerebellar glioma in an adult is very rare. None of the cases of multicentric glioma described in the literature presented with intratumoral hemorrhage. This combination in our patient has prompted us to report this case and to reaffirm the need to consider the diagnosis of malignant glioma in patients with multiple intracranial tumors.


Same day service: A genetic testing station model to improve germline genetic testing in patients with ovarian cancer.
Genetic testing for ovarian cancer (OC) patients is essential to consideration of PARP inhibitor therapy. To improve access, we piloted a Genetic Testing Station (GTS) allowing patients to have a same-day genetic testing visit facilitated by Genetic Counselor Assistants (GCAs) under the supervision of Genetic Counselors (GCs). The GTS was implemented December 2018 and operated through February 2020. Gynecologic Oncologists offered ovarian cancer patients a same-day GTS visit with a GCA. The patient received education via videos designed by GCs and then provided consent, a brief family history, and a sample for a standardized 133-gene panel. Results were provided by a GC. Patients were retrospectively identified by querying the medical record for OC patients seen 12 months prior to and 18 months after GTS implementation. A total of 482 patients pre-GTS were compared to 625 patients post-GTS. Genetic testing increased from 68.5% to 75.4% (p = 0.012) after implementation, primarily in patients with epithelial histologies (80% vs 89% in pre-GTS vs post-GTS, p = 0.005). Time from referral for genetic testing to obtaining results was evaluated in the post-GTS cohort, comparing patients who had traditional counseling to those who utilized the GTS. Time to obtaining results was 21 days in the GTS group (95% CI [10, 34]) compared to 56 days (95% CI [41,76]) in the traditional genetic counseling group. The GTS reduces barriers to care and facilitates discussion of precision treatment within a timely fashion while optimizing GC clinic time. Access improvement remains integral to improving uptake of genetic testing.


Difficulty processing temporary syntactic ambiguities in Lewy body spectrum disorder.
While grammatical aspects of language are preserved, executive deficits are prominent in Lewy body spectrum disorder (LBSD), including Parkinson's disease (PD), Parkinson's dementia (PDD) and dementia with Lewy bodies (DLB). We examined executive control during sentence processing in LBSD by assessing temporary structural ambiguities. Using an on-line word detection procedure, patients heard sentences with a syntactic structure that has high-compatibility or low-compatibility with the main verb's statistically preferred syntactic structure, and half of the sentences were lengthened strategically between the onset of the ambiguity and its resolution. We found selectively slowed processing of lengthened ambiguous sentences in the PDD/DLB subgroup. This correlated with impairments on measures of executive control. Regression analyses related the working memory deficit during ambiguous sentence processing to significant cortical thinning in frontal and parietal regions. These findings emphasize the role of prefrontal disease in the executive limitations that interfere with processing ambiguous sentences in LBSD.


Experimental and theoretical investigations of Dy(III) complex with 2,2'-bipyridine ligand: DNA and BSA interactions and antimicrobial activity study.
In this study, the interactions of a novel metal complex [Dy(bpy)2Cl3.OH2] (bpy is 2,2'-bipyridine) with fish salmon DNA (FS-DNA) and bovine serum albumin (BSA) were investigated by experimental and theoretical methods. All results suggested significant binding between the Dy(III) complex with FS-DNA and BSA. The binding constants (Kb), Stern-Volmer quenching constants (KSV) of Dy(III)-complex with FS-DNA and BSA at various temperatures as well as thermodynamic parameters using Van't Hoff equation were obtained. The experimental results from absorption, ionic strength, iodide ion quenching, ethidium bromide (EtBr) quenching studies and positive ΔH˚ and ΔS˚ suggested that hydrophobic groove-binding mode played a predominant role in the binding of Dy(III)-complex with FS-DNA. Indeed, the molecular docking results for DNA-binding were in agreement with experimental data. Besides, the results found from experimental and molecular modeling indicated that the Dy(III)-complex bound to BSA via Van der Waals interactions. Moreover, the results of competitive tests by phenylbutazone, ibuprofen, and hemin (as a site-I, site-II and site-III markers, respectively) considered that the site-III of BSA is the most possible binding site for Dy(III)-complex. In addition, Dy(III) complex was concurrently screened for its antimicrobial activities. The presented data provide a promising platform for the development of novel metal complexes that target nucleic acids and proteins with antimicrobial activity.Communicated by Ramaswamy H. Sarma.


Fatty acid supply and organ phospholipid turnover in two canine shock models.
Serum free fatty acid (FFA) flux is decreased in shock. The question arose whether the limited availability of FFA would result in a fuel deficit in organs containing no stored lipid and also in the slower turnover of organ phospholipids. The fasting dog's lung, stomach, heart, and liver contained little or no triglyceride, while skeletal muscle, diaphragm, and occasionally intestine had large lipid stores. The replacement rate of lipid fuels and the turnover rate of the fatty acyl moieties of phospholipids were determined by radioactive tracer methods in several organs of dogs in shock due to controlled cardiac tamponade or hemorrhage and their respective controls. In the normotensive controls one-third of the FFA available was directly oxidized; the rest was temporarily incorporated into phospholipids and triglycerides. This incorporation represents replacement of lipid fuels in the organs. Both shock models caused a similar decrease in the total FFA flux and a similar pattern of redistribution among organs. Organs other than heart, lung, and diaphragm replenished their lipid stores slowly in shock. This could cause a fuel deficit in liver and stomach, neither of which have large triglyceride stores. FFA incorporation into phospholipids was slower than esterification into triglycerides in all organs except diaphragm and skeletal muscle both in shock and in normotension. The rate of phospholipid turnover decreased significantly in shock in liver, intestine, and stomach, but increased in heart and lung. Thus liver and stomach are the organs most likely to be affected by the decreased availability of FFA in shock.


Tumor Size and Oncological Outcomes in Patients with Early Cervical Cancer Treated by Fertility Preservation Surgery: A Multicenter Retrospective Cohort Study.
Background: The aim of this study was to analyze the impact of tumor size > 2 cm on oncological outcomes of fertility-sparing surgery (FSS) in early cervical cancer in a Spanish cohort. Methods: A multicenter, retrospective cohort study of early cervical cancer (stage IA1 with lymphovascular space invasion -IB1 (FIGO 2009)) patients with gestational desire who underwent FSS at 12 tertiary departments of gynecology oncology between 01/2005 and 01/2019 throughout Spain. Results: A total of 111 patients were included, 82 (73.9%) with tumors < 2 cm and 29 (26.1%) with tumors 2−4 cm. Patients' characteristics were balanced except from lymphovascular space invasion. All were intraoperative lymph node-negative. Median follow-up was 55.7 and 30.7 months, respectively. Eleven recurrences were diagnosed (9.9%), five (6.0%) and six (21.4%) (p < 0.05). The 3-year progression-free survival (PFS) was 95.7% (95%CI 87.3−98.6) and 76.9% (95% CI 55.2−89.0) (p = 0.011). Only tumor size (<2 cm vs. 2−4 cm) was found to be significant for recurrence. After adjusting for the rest of the variables, tumor size 2−4 cm showed a Hazard Ratio of 5.99 (CI 95% 1.01−35.41, p = 0.036). Conclusions: Tumor size ≥ 2 cm is the most important negative prognostic factor in this multicenter cohort of patients with early cervical cancer and gestational desire who underwent FSS in Spain.


Two-dimensional trajectory analysis of the diatom Navicula sp. using a micro chamber.
We describe a trajectory analysis of diatom cell locomotion by combining a micro chamber and two-dimensional position coordinate analysis. By shutting cells in a micro chamber, continuous microscopic observation of Navicula sp. cells was possible. The trajectory of each cell was visualized once every second by using position coordinate analysis although time resolution of previous papers were range of minutes. Our data revealed frequent change of movement direction. Furthermore, the correlation between the distances moved, the velocity, and the acceleration of the cells was discussed in detail.


Relationship between presarcopenia and event occurrence in patients with primary hepatocellular carcinoma.
Presarcopenia is a prognostic factor in patients with hepatocellular carcinoma (HCC). The Japan integrated staging (JIS) score is a prognostic method that combines the Child-Turcotte-Pugh classification and the tumor-node-metastasis (TNM) staging for HCC. We investigated the relationship between presarcopenia, the JIS score, and prognosis in patients with primary HCC. This retrospective study included 153 patients with primary HCC who were hospitalized from October 2011 to March 2018 at Municipal Hospital of Kofu. The skeletal muscle mass was measured using simplified psoas muscle mass index (PMI) based on CT imaging, and PMI using the volume analyzer SYNAPSE VINCENT ver3.0. We diagnosed presarcopenia based on the cut off value according to the assessment criteria for sarcopenia in liver disease defined by the Japan Society of Hepatology. Forty-three patients (28%) were diagnosed with presarcopenia. The median event-free survival was significantly worse in patients with presarcopenia than those without presarcopenia (P = 0.016). In multivariate analysis, presence of presarcopenia, JIS score ≥3, alpha-fetoprotein ≥200 ng/ml, and prothrombin induced by vitamin K absence-II ≥ 200 mAU/ml were significant prognostic factors. Among the patients with JIS scores ≥3, there was no difference in the event occurrence rate with presence of presarcopenia (P = 0.96). Among the patients with JIS scores ≤2, the median event-free-survival was significantly shorter in those with presarcopenia than those without presarcopenia (P = 0.045). Presarcopenia was an independent prognostic factor in patients with primary HCC. In patients with JIS scores ≤2, the median event-free survival was significantly shorter in those with presarcopenia compared to those without presarcopenia. In the patients with JIS scores ≥3, there was no difference in the event occurrence rates in those with and without presarcopenia.


Effective small interfering RNAs targeting matrix and nucleocapsid protein gene inhibit influenza A virus replication in cells and mice.
RNA interference (RNAi) is a powerful tool to silence gene expression. Small interfering RNA (siRNA)-induced RNA degradation has been recently used as an antivirus agent to inhibit specific virus replication. Here, we showed that several siRNAs specific for conserved regions of influenza virus matrix (M2) and nucleocapsid protein (NP) genes could effectively inhibit expression of the corresponding viral protein. We also evaluated the antiviral potential of these siRNAs targeting M2 and NP of H5N1 avian influenza virus (AIV), which are essential to viral replication. We investigated the inhibitory effect of M2-specific siRNAs and NP-specific siRNAs on influenza A virus (H5N1, H1N1 and H9N2) replication in Madin-Darby canine kidney (MDCK) cells and BALB/c mice. The results showed that treatment with these siRNAs could specifically inhibit influenza A virus replication in MDCK cells (0.51-1.63 TCID(50) reduction in virus titers), and delivery of pS-M48 and pS-NP1383 significantly reduced lung virus titers in the infected mice (16-50-fold reduction in lung virus titers) and partially protected the mice from lethal influenza virus challenge (a survival rate of 4/8 for H1N1 virus-infected mice and 2/8 for H5N1 virus infected mice). Moreover, the treatment of pS-M48 and pS-NP1383 could suppress replication of different subtypes of influenza A viruses, including a H5N1 highly pathogenic avian isolate strain. The results provided a basis for further development of siRNA for prophylaxis and therapy of influenza virus infection in humans and animals.


Seaweeds as potential therapeutic interventions for the metabolic syndrome.
Seaweeds are a characteristic part of the traditional diet in countries such as Japan and Korea; these countries also have a lower prevalence of metabolic syndrome than countries such as the USA and Australia. This suggests that seaweeds may contain compounds that reduce the characteristic signs of obesity, diabetes, hypertension, fatty liver and inflammation in the metabolic syndrome. Potentially bioactive compounds from seaweeds include polysaccharides, peptides, pigments, minerals and omega-3 fatty acids. This review emphasises current research on these compounds in isolated cells, animal models and patients. Key problems for future research include chemical characterisation of the bioactive principles, defining pharmacological responses in all aspects of the metabolic syndrome, determining if a therapeutic dose has been administered, and defining oral bioavailability of the active ingredients.


Crebanine ameliorates ischemia-reperfusion brain damage by inhibiting oxidative stress and neuroinflammation mediated by NADPH oxidase 2 in microglia.
The urgent challenge for ischemic stroke treatment is the lack of effective neuroprotectants that target multiple pathological processes. Crebanine, an isoquinoline-like alkaloid with superior pharmacological activities, presents itself as a promising candidate for neuroprotection. However, its effects and mechanisms on ischemic stroke remain unknown. The effects of crebanine on brain damage following ischemic stroke were evaluated using the middle cerebral artery occlusion and reperfusion (MCAO/R) model. Mechanism of action was investigated using both MCAO/R rats and lipopolysaccharide (LPS)-activated BV-2 cells. We initially demonstrated that crebanine effectively ameliorated the neurological deficits in MCAO/R rats, while also reducing brain edema and infarction. Treatment with crebanine resulted in the up-regulation of NeuN+ fluorescence density and down-regulation of FJB+ cell count, and mitigated synaptic damage. Crebanine attenuated the hyperactivation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) by downregulating NADP+ and NADPH levels, suppressing gp91phox and p47phox expressions, and reducing p47phox membrane translocation in Iba-1+ cells. Additionally, crebanine reduced the quantity of Iba-1+ cells and protein expression. Correlation analysis has demonstrated that the inhibition of NOX2 activation in microglia is beneficial for mitigating I/R brain injuries. Moreover, crebanine exhibited significant antioxidant properties by down-regulating the expression of superoxide anion and intracellular reactive oxygen species in vivo and in vitro, and reducing lipid and DNA peroxidation. Crebanine exerted anti-inflammatory effect, as evidenced by the reduction in the expressions of nitric oxide, interleukin 1β, tumor necrosis factor α, interleukin 6, and inducible nitric oxide synthase. The effect of crebanine was achieved through the suppression of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPK) signaling pathway. This is supported by evidence showing reduced NF-κB p65 promoter activity and nucleus translocation, as well as suppressed IκBα phosphorylation and degradation. Additionally, it inhibited the phosphorylation of ERK, JNK, and p38 MAPKs. Importantly, the anti-oxidative stress and neuroinflammation effects of crebanine were further enhanced after silencing gp91phox and p47phox. Crebanine alleviated the brain damages of MCAO/R rats by inhibiting oxidative stress and neuroinflammation mediated by NOX2 in microglia, implying crebanine might be a potential natural drug for the treatment of cerebral ischemia.


Co-cultivation of keratinocyte-human mesenchymal stem cell (hMSC) on sericin loaded electrospun nanofibrous composite scaffold (cationic gelatin/hyaluronan/chondroitin sulfate) stimulates epithelial differentiation in hMSCs: In vitro study.
Fortifying the scaffold with bioactive molecules and glycosaminoglycans (GAGs), is an efficient way to design new generation tissue engineered biomaterials. In this study, we evaluated the synergistic effect of electrospun nanofibrous composite scaffold (cationic gelatin/hyaluronan/chondroitin sulfate) loaded with sericin and, contact co-culture of human mesenchymal stem cells (hMSCs)-keratinocytes on hMSCs' differentiation towards epithelial lineage. Cationic gelatin is prepared with one step novel synthesis process by grafting quaternary ammonium salts to the backbone of gelatin. Release kinetics studies showed that Fickian diffusion is the major release mechanism for both GAGs and sericin/gelatin. In vitro biocompatibility of the electrospun scaffold was evaluated in terms of LDH and DNA quantification assay on human foreskin fibroblast, human keratinocyte and hMSC. Significant proliferation (∼ 4-6 fold) was detected after culturing all three cell on the electrospun scaffold containing sericin. After 5 days of contact co-culture, results revealed that electrospun scaffold containing sericin promote epithelial differentiation of hMSC in terms of several protein markers (keratin 14, ΔNp63α and Pan-cytokeratin) and gene expression of some dermal proteins (keratin 14, ΔNp63α). Findings of this study will foster the progress of current skin tissue engineering scaffolds by understanding the skin regeneration and wound healing process.


Immunoglobulin kappa deleting element rearrangements are candidate targets for minimal residual disease evaluation in mantle cell lymphoma.
Minimal residual disease (MRD) assessment is of high clinical relevance in patients with mantle cell lymphoma (MCL). In mature B-cell malignancies, the presence of somatic hypermutations (SHM) in Variable-Diversity-Joining Heavy chain (VDJH) rearrangements leads to frequent mismatches between primers, probes, and the target, thus impairing tumor cells quantification. Alternative targets, such as immunoglobulin kappa-deleting-element (IGK-Kde) rearrangements, might be suitable for MRD detection. We aimed at evaluating the applicability of IGK-Kde rearrangements for MRD quantification in MCL patients by real-time quantitative polymerase chain reaction (RQ-PCR)/digital-droplet-PCR (ddPCR). IGK screening was performed on bone marrow samples from two cohorts: the first from Turin (22 patients enrolled in the FIL-MCL0208 trial, NCT02354313) and the second from Rome (15 patients). IGK-Kde rearrangements were found in 76% (28/37) of cases, representing the sole molecular marker in 73% (8/11) of IGH-BCL1/IGH negative cases. MRD RQ-PCR monitoring was possible in 57% (16/28) of cases, showing a 100% concordance with the conventional targets. However, the frequent background amplification affected the sensitivity of the assay, that was lower in MCL compared to acute lymphoblastic leukemia and in line with multiple myeloma published results. ddPCR had a good concordance with RQ-PCR and it might help to identify false positive/negative results. From a clinical perspective, we suggest that IGK-Kde can be a candidate target for MRD monitoring and deserves a validation of its predictive value in prospective MCL series.


Targeting the Mevalonate Pathway in Cancer.
The mevalonate synthesis inhibitors, statins, are mainstay therapeutics for cholesterol management and cardiovascular health. Thirty years of research have uncovered supportive roles for the mevalonate pathway in numerous cellular processes that support oncogenesis, most recently macropinocytosis. Central to the diverse mechanisms of statin sensitivity is an acquired dependence on one mevalonate pathway output, protein geranylgeranylation. New chemical prenylation probes and the discovery of a novel geranylgeranyl transferase hold promise to deepen our understanding of statin mechanisms of action. Further, insights into statin selection and the counterproductive role of dietary geranylgeraniol highlight how we should assess statins in the clinic. Lastly, rational combination strategies preview how statins will enter the oncology toolbox.


Self-reported course of olfactory impairment determines outcome for successful surgical intervention in nasal polyps with anosmia.
Olfactory impairment is one of important symptoms of Chronic rhinosinusitis with nasal polyps (CRSwNP). However, the relationship between course of olfactory impairment and postoperative symptom improvement was still unclear. The aim of this study was to assess the relationship between the self-reported course of olfactory loss and the degree of improvement in olfaction to determine the timing for successful surgical intervention in improving olfaction in patients with CRSwNP. A total of 86 CRSwNP patients with loss of smell and undergoing functional endoscopic sinus surgery (FESS) were recruited consecutively. The self-reported course of smell lose before treatment was recorded. Olfactory function was recorded before and after FESS using T&T Olfactometry. Fifty-seven patients demonstrated recovery of olfaction and 29 patients no-recovery. The average recovery time of smell loss in the study was 2.6 weeks. The course of smell loss showed moderate accuracy as a marker for determining the timing for successful FESS; with up to 4.5 years of self-reported smell loss being the cut-off point for recovery of smell following FESS. This study suggests that FESS in CRSwNP patients with self-reported significant olfactory impairment for less than 4.5 years may lead to improvement in olfaction. FESS in CRSwNP patients with self-reported significant olfactory impairment persisting for less than 4.5 years may lead to considerable improvement in olfaction in these patients.


Importance of genetic study in elderly patients with transthyretin cardiac amyloidosis.
Cardiac transthyretin amyloidosis (CA-ATTR) is a prevalent disease with age. Genetic study is recommended, even in eldest patients. We aim to analyze the prevalence of hereditary transthyretin amyloidosis (ATTRv) in elderly patients (≥75years) with CA-ATTR and its implications. Retrospective observational study of the cohort of elderly patients with CA-ATTR diagnosed according to the international recommended protocol. We analyze the results of sequencing TTR gene, the differential characteristics and their clinical implications. Between 2016 and 2022, 130 elderly patients (89% cohort) were diagnosed with CA-ATTR (85% male). In 8 of the 123 patients with a genetic study, a pathogenic variant in TTR was identified (6.5%), initiating specific treatment in 4 subjects (50%). The family study identified another case and 6 asymptomatic carriers. There were no significant differences between baseline characteristics or in clinical events. The prevalence of ATTRv in elderly patients with CA-ATTR was 6.5% without observing differential characteristics that allow guiding a selective indication of genetic analysis.


Fetal heart rate monitoring during caesarean section.
The fetal heart rate was monitored during 30 deliveries by Caesarean section. General anaesthesia, but not epidural analgesia, caused a loss of beat-to-beat variation, but appeared to have no other adverse effects on fetal heart rate. The loss of beat-to-beat variation occurred after intravenous thiopentone and was most marked when atropine was used as premedication.


Microbial distributions in the conjunctiva and lacrimal sacs of patients with chronic dacryocystitis in a tertiary hospital.
The aim was to clarify the distributions of bacteria in the conjunctival sac and lacrimal sac in patients with chronic dacryocystitis. In total, 297 (322 eyes) chronic dacryocystitis patients who underwent nasal endoscopic dacryocystorhinostomy (EN-DCR) were included. Conjunctival sac secretions from the affected eye were collected preoperatively, and lacrimal sac retention fluid from the affected side in the same patient was collected intraoperatively. Bacterial culture and drug sensitivity testing were performed to determine bacterial distributions. In total, 127 bacterial isolates (49 species) were detected in 123 eyes in the conjunctival group, with a positivity rate of 38.2% (123/322); 85 bacterial isolates (30 species) were detected in 85 eyes in the lacrimal sac group, with a positivity rate of 26.4% (85/322). The positivity rates were significantly different (P = 0.001) between two groups. The gram-negative bacilli proportion in the lacrimal sac group (36/85, 42.4%) was significantly higher than that in the conjunctival sac group (37/127, 29.2%) ( P = 0.047). Positive conjunctival sac secretion culture (123/322) was significantly associated with increased ocular secretion (281/322, 87.3%) (P = 0.002). Among the culture-positive bacteria in the conjunctival sac group and the lacrimal sac group, 30/127, 23.6% and 43/127, 26.7% and 21/85, 24.7% and 20/85, 23.5% were resistant to levofloxacin and tobramycin, respectively. This study illustrated differences in bacterial distributions between conjunctival sac secretions and retained lacrimal sac fluid in chronic dacryocystitis patients, with a higher proportion of gram-negative bacilli in lacrimal sac secretions. The ocular surface flora in chronic dacryocystitis patients is partially resistant to levofloxacin and tobramycin, which need to be considered by ophthalmologists.


Clinical outcomes in cystic fibrosis patients with Trichosporon respiratory infection.
Relationships between clinical outcomes and novel respiratory pathogens such as Trichosporon are not well understood. Respiratory cultures from CF patients were screened for novel pathogens Trichosporon and Chryseobacterium as well as other pathogens over 28months. Relationships between microbiologic and clinical data were assessed using univariate and multivariate methods. Of 4934 respiratory cultures from 474 CF patients, 37 cultures from 10 patients were Trichosporon positive. Patients with positive Trichosproron cultures had a greater decline in FEV1 over time (-3.9%/year vs. -1.3%/year, p<0.05), whereas Chryseobacterium did not influence lung function. These findings were confirmed in multivariate analyses that included age, gender, and other common pathogens as confounders. Treatment of Trichosporon infected patients was associated with improved lung function. Trichosporon can be recovered from a small but clinically meaningful fraction of CF patients. The presence of Trichosporon, but not Chryseobacterium, is associated with greater declines in lung function.


Disparities in Cardiovascular Care and Outcomes for Women From Racial/Ethnic Minority Backgrounds.
Racial, ethnic, and gender disparities in cardiovascular care are well-documented. This review aims to highlight the disparities and impact on a group particularly vulnerable to disparities, women from racial/ethnic minority backgrounds. Women from racial/ethnic minority backgrounds remain underrepresented in major cardiovascular trials, limiting the generalizability of cardiovascular research to this population. Certain cardiovascular risk factors are more prevalent in women from racial/ethnic minority backgrounds, including traditional risk factors such as hypertension, obesity, and diabetes. Female-specific risk factors including gestational diabetes and preeclampsia as well as non-traditional psychosocial risk factors like depressive and anxiety disorders, increased child care, and familial and home care responsibility have been shown to increase risk for cardiovascular disease events in women more so than in men, and disproportionately affect women from racial/ethnic minority backgrounds. Despite this, minimal interventions to address differential risk have been proposed. Furthermore, disparities in treatment and outcomes that disadvantage minority women persist. The limited improvement in outcomes over time, especially among non-Hispanic Black women, is an area that requires further research and active interventions. Understanding the lack of representation in cardiovascular trials, differential cardiovascular risk, and disparities in treatment and outcomes among women from racial/ethnic minority backgrounds highlights opportunities for improving cardiovascular care among this particularly vulnerable population.


Receptor-mediated antigen delivery into macrophages. Complexing antigen to alpha 2-macroglobulin enhances presentation to T cells.
Macrophages secrete alpha 2-macroglobulin (alpha 2M), a protein that may facilitate early Ag handling. alpha 2M is able to entrap and form covalent linkages with diverse proteins during a transient proteinase-activated state. The resulting complexes are rapidly endocytosed after binding to high affinity receptors. Such a system could be capable of efficiently delivering a multitude of proteins to macrophages. We have used T hybridoma clones that respond only to hen egg lysozyme, in a MHC-restricted manner, to probe the effect of complex formation on Ag uptake and processing by murine macrophages. Radiolabeled lysozyme was internalized more rapidly and to a greater extent when bound to alpha 2M than when unbound. Macrophages pulsed with lysozyme-alpha 2M-elastase complexes required 200 to 250 times less Ag than those pulsed with free lysozyme to achieve effective presentation to T cells. Adding equimolar amounts of alpha 2M-elastase complexes, or of alpha 2M-methylamine, to free lysozyme had no effect on basal lysozyme presentation. Receptor-recognized forms of alpha 2M, but not lysozyme or BSA, competed effectively for both uptake and presentation of lysozyme-alpha 2M-elastase complexes. These results indicate that proteinase-activated alpha 2M can enhance Ag processing by carrying Ag into macrophages through a receptor-mediated process.


Atg8 and Ire1 in combination regulate the autophagy-related endoplasmic reticulum stress response in Candida albicans.
The unfolded protein response (UPR) is an important pathway to prevent endoplasmic reticulum (ER) stress in eukaryotic cells. In Saccharomyces cerevisiae, Ire1 is a key regulatory factor required for HAC1 gene splicing for further production of functional Hac1 and activation of UPR gene expression. Autophagy is another mechanism involved in the attenuation of ER stress by ER-phagy, and Atg8 is a core protein in autophagy. Both autophagy and UPR are critical for ER stress response, but whether they act individually or in combination in Candida albicans is unknown. In this study, we explored the interaction between Ire1 and the autophagy protein Atg8 for the ER stress response by constructing the atg8Δ/Δire1Δ/Δ double mutant in the pathogenic fungus C. albicans. Compared to the single mutants atg8Δ/Δ or ire1Δ/Δ, atg8Δ/Δire1Δ/Δ exhibited much higher sensitivity to various ER stress-inducing agents and more severe attenuation of UPR gene expression under ER stress. Further investigations showed that the double mutant had a defect in ER-phagy, which was associated with attenuated vacuolar fusion under ER stress. This study revealed that Ire1 and Atg8 in combination function in the activation of the UPR and ER-phagy to maintain ER homeostasis under ER stress in C. albicans.


Evaluation of toxicity of Cercospora piaropi in a mycoherbicide formulation by using bacterial bioluminescence and the Ames mutagenicity tests.
An evaluation of the potential hazards associated with mutagenicity and acute toxicity of a mycoherbicide formulation based on the fungal pathogen Cercospora piaropi was performed. Neither the mycoherbicide nor any of its components were mutagenic to Salmonella typhimurium TA98 and TA100 with or without metabolic activation. Both the C. piaropi and the mycoherbicide formulation were shown to be moderately toxic with a bacterial bioluminescence assay. No acute toxicity was found in water samples taken from tanks after treatment of water hyacinth with the mycoherbicide.


Reliability of frozen section examination in identifying poor prognostic indicators in stage I endometrial adenocarcinoma.
Management of Stage I adenocarcinoma of the uterus includes hysterectomy, bilateral salpingo-oophorectomy, and selective paraaortic and pelvic lymphadenectomy. Postoperative radiation therapy (RT) is selectively employed in patients with histologically defined poor prognostic indicators. We attempted to identify these poor prognostic indicators by frozen section (FS) at primary surgery in 55 patients with Stage I endometrial adenocarcinoma; we found an excellent correlation between the results obtained on gross examination of the uterus with selected FS and the results after extensive sampling and microscopic examination of permanent section (PS). The depth of myometrial invasion was accurately predicted in 96.5%, and histologic grade in 94.5% of these patients. Sixty-six percent of patients with occult invasion of the cervix on PS were identified on FS. Using the above criteria, we identified by FS all patients (15/55) who required adjuvant RT obviating the need for pelvic lymph node dissection. On the basis of our preliminary data, we recommend the use of careful gross examination and selective FS to identify patients requiring selective pelvic and paraaortic lymphadenectomy and adjuvant therapy, thereby eliminating the need for staging lymph node dissection with its associated morbidity and complications.


Effect of low-intensity 50-Hz magnetic fields on kindling acquisition and fully kindled seizures in rats.
The possibility that chronic exposure to power-line frequency (50 Hz) magnetic fields (MFs) might affect the acquisition or characteristics of focal and generalized seizures in amygdala kindled rats was studied. Acute, short-lasting 50-Hz MF exposure of fully kindled rats at either 1 or 100 microT had no effect on afterdischarge threshold (ADT) or seizure parameters recorded at ADT. In the chronic experiments, rats with electrodes implanted in the basolateral amygdala were exposed to a 50-Hz, 100-microT (1 Gauss) MF or to a sham field condition before and after onset of daily electrical stimulations over the whole period of kindling development. The focal seizure threshold (ADT) was determined before and after kindling development in MF exposed and sham exposed rats. Pre-kindling ADT was significantly increased by MF exposure. Exposed rats needed about the same number of stimulations to kindle than sham exposed rats, but the cumulative afterdischarge duration to reach criterion (i.e., a stage 5 seizure) was significantly reduced in MF exposed animals. Post-kindling ADT was similar in the two groups, but MF exposed rats showed a significantly higher threshold for generalized seizures. The data indicate that chronic exposure of rats to a 50-Hz, 100-microT MF exerts weak inhibitory effects on some seizure parameters of the kindling model.


Nitrogen-doped carbonized polymer dots activated by alkalinity of arginine for multicolor multi-platform sensor.
Among carbon-based materials, carbon dots (CDs) are popular because of their stable optical properties and good biocompatibility. Their fluorescence properties often are tailored by size, surface modification, or heteroatom doping with multiple precursors. In this paper, the alkalinity of Arginine (Arg) acts as an activator to promote carbonation and increase luminescence efficiency. Meanwhile, Arg acts as a tetrahedron and plays another three roles in preparing amino-modified nitrogen-doped carbonized polymer dots (SA-NCPDs), in which Arg serves as carbon source, nitrogen-doped nitrogen source, and surface modifier. The NCPDs based only on arginine display narrow full width at half maximum (FWHM) of 54 nm. The SA-NCPDs present dual emission distribution in the UV and visible blue regions, respectively. The SA-NCPDs present multicolor emission, especially crimson emission in water under 77 K in different solvents. Besides, SA-NCPDs in different solvents and the prepared polyvinyl alcohol (PVA) composite film have different phosphorescence and long afterglow at 77 K. The excellent biocompatibility and stability of the SA-NCPDs imply it is a potential material in biomedicine. In addition, a multiplatform multicolor ratiometric sensor and visualized colorimetric sensor with high selectivity were constructed successfully for detecting Cu2+, H2O2, and OPD based on self-absorption.


Cell kinetics of hypoxic cells in a murine tumour in vivo: flow cytometric determination of the radiation-induced blockage of cell cycle progression.
Cells from the small cell population of viable cells in the large necrotic centre of murine M8013 tumours were investigated with respect to their cell kinetics. Flow cytometry (FCM) of this part of subcutaneously transplanted tumours revealed the presence of tumour cells with G1, S and G2 + M phase DNA-contents. These severely hypoxic cells could have stopped cell cycle progression due to the nutritional deprivation, irrespective of their position within the cell cycle. Labelling methods, used to disclose the cell kinetics of this cell population, are hampered by the absence of a transport system in these large necrotic areas. Therefore, FCM was used to monitor radiation-induced changes in the cell cycle distribution. From this investigation it was concluded that hypoxic cells in the necrotic centre of the M8013 tumour progress through the cell cycle. As well as a cell population with a cell cycle time (Tc) of approximately 84 hr, a subpopulation with a Tc of approximately 21 hr occurred.


What is the Relevance of Gastric Microbiota Beyond H. pylori?
The role of Helicobacter pylori as key factor in gastric inflammation and the development of (pre-)cancerous lesions is undisputable. As an open system, the human upper gastrointestinal tract harbors a complex bacterial community which is highly impacted by the absence or presence of H. pylori. The interaction between other bacteria and H. pylori might impact on gastric carcinogenesis. Several studies demonstrated differences in the composition of the gastric bacterial community in different stages of gastritis and between samples from tumor and adjacent tissue. In addition, animal studies demonstrated an increased and accelerated development of precancerous lesions in mice colonized with intestinal flora and H. pylori compared with mice mono-infected with H. pylori. Other bacteria beyond H. pylori enter the focus in research on gastric carcinogenesis. However, we are still far from a thorough understanding of the pathophysiology of host-microbiota interaction and its impact on the development of malignant and precancerous changes.


Simultaneous spatiotemporal tracking and oxygen sensing of transient implants in vivo using hot-spot MRI and machine learning.
A varying oxygen environment is known to affect cellular function in disease as well as activity of various therapeutics. For transient structures, whether they are unconstrained therapeutic transplants, migrating cells during tumor metastasis, or cell populations induced by an immunological response, the role of oxygen in their fate and function is known to be pivotal albeit not well understood in vivo. To address such a challenge in the case of generation of a bioartificial pancreas, we have combined fluorine magnetic resonance imaging and unsupervised machine learning to monitor over time the spatial arrangement and the oxygen content of implants encapsulating pancreatic islets that are unconstrained in the intraperitoneal (IP) space of healthy and diabetic mice. Statistically significant trends in the postimplantation temporal dependence of oxygen content between aggregates of 0.5-mm or 1.5-mm alginate microcapsules were identified in vivo by looking at their dispersity as well as arrangement in clusters of different size and estimating oxygen content on a pixel-by-pixel basis from thousands of 2D images. Ultimately, we found that this dependence is stronger for decreased implant capsule size consistent with their tendency to also induce a larger immunological response. Beyond the bioartificial pancreas, this work provides a framework for the simultaneous spatiotemporal tracking and oxygen sensing of other cell populations and biomaterials that change over time to better understand and improve therapeutic design across diverse applications such as cellular transplant therapy, treatments preventing metastatic formation, and modulators for improving immunologic response, for all of which oxygen is a major mechanistic component.


Decreased protein C activation in patients with fulminant hepatic failure.
Abnormalities of the blood coagulation system have an influence on outcome in patients with fulminant hepatic failure (FHF). The protein C (PC) pathway is one of the main modulators of the blood coagulation system. The role of the PC pathway in FHF is not clear. In the present study, we evaluated endothelial cell injury and the grade of activated protein C (APC) generation in FHF patients. The effect of APC on the expression of tumor necrosis factor (TNF)-alpha and monocyte chemoattractant protein (MCP)-1 from LI90 stellate cells was also evaluated. This study comprised 5 patients with FHF, 6 with acute hepatitis (AH), 12 with chronic hepatitis (CH) and 20 healthy subjects. The plasma concentrations of thrombin-antithrombin complex and thrombomodulin were significantly increased in FHF patients compared with those in AH patients and healthy subjects. The circulating levels of activated protein C-protein C inhibitor (APC-PCI) complex and the APC-PCI/PC ratio were significantly decreased in patients with FHF compared to healthy controls. APC significantly inhibited in vitro the expression of TNFalpha and MCP-1 from LI90 stellate cells. This study demonstrated enhanced endothelial cell injury in association with decreased PC activation and hypercoagulability in FHF.


Osteocyte death and hip fracture.
The viability of osteocytes can be demonstrated in sawn decalcified sections of bone by their lactate dehydrogenase activity. In the cancellous bone of the femoral head, the proportion of lacunae containing viable osteocytes decreased from 88 +/- 7% (mean +/- SD) at 10-29 years to 58 +/- 12% (P < 0.001) by 70-89 years. Viability in the second lumbar vertebra was 88 +/- 3% in subjects aged 25-90 years and did not decrease with age. Mean osteocyte viability in the femoral head of 21 hip fracture patients aged 72-94 years was 58 +/- 21%, similar to controls of a similar age, though there was greater variation and, in five patients, osteocyte viability was less than 25%. In hip fracture patients, microfracture callus incidence correlated positively with osteocyte viability, with little or no fracture callus observed if the bone viability was low. Ultimate compressive strength did not correlate with osteocyte viability. In the femoral head there is gradual, age-related reduction in osteocyte viability that can be more pronounced in hip fracture. Osteocyte death may affect bone quality by impairing repair of fatigue damage.


Effects of the order of running and cycling of similar intensity and duration on pulmonary diffusing capacity in triathletes.
To study the pathophysiological mechanisms involved in the decrease of post-triathlon diffusing capacity (DLco), blood rheologic properties (blood viscosity: eta(b); changes in plasma volume: deltaPV) and atrial natriuretic factor (ANF) were assessed in ten triathletes during cycle-run (CR) and run-cycle (RC) trials at a metabolic intensity of 75% of maximal oxygen consumption ( VO(2max)). The DLco was measured before and 10 min after trials. ANF and deltaPV were measured at rest, after the cycle and run of CR and RC trials, and at the end of and 10 min after exercise. RC led to a greater deltaDLco decrease, a lower ANF concentration and a lower deltaPV than did CR, whereas for both CR and RC eta(b) was increased throughout exercise and 10 min after. In addition, after CR the deltaDLco decrease was inversely correlated ( r=-0.764; P<0.01) with deltaPV. The association of decreased plasma volume, increased eta(b), and lower ANF concentrations after RC suggested that lower blood pulmonary volume may have caused the greater decrease in Dlco as compared with CR. The inverse correlation between deltaPV and deltaDLco reinforces the hypothesis that fluid shifts limit the post-exercise DLco decrease after the CR succession in triathletes. Lastly, cycling in the crouched position might increase intra-thoracic pressure, decrease thorax volume due to the forearm position on the handlebars, and weaken peripheral muscular pump efficacy, all of which would limit venous return to the heart, and thus result in low pulmonary blood volume. Compared with cycling, running appeared to induce the opposite effects.


Exposure to human-associated fecal indicators and self-reported illness among swimmers at recreational beaches: a cohort study.
Fecal indicator bacteria used to assess illness risks in recreational waters (e.g., Escherichia coli, Enterococci) cannot discriminate among pollution sources. To address this limitation, human-associated Bacteroides markers have been proposed, but the risk of illness associated with the presence of these markers in recreational waters is unclear. Our objective was to estimate associations between human-associated Bacteroides markers in water and self-reported illness among swimmers at 6 U.S. beaches spanning 2003-2007. We used data from a prospectively-enrolled cohort of 12,060 swimmers surveyed about beach activities and water exposure on the day of their beach visit. Ten to twelve days later, participants reported gastroinestinal, diarrheal, and respiratory illnesses experienced since the visit. Daily water samples were analyzed for the presence of human-associated Bacteroides genetic markers: HF183, BsteriF1, BuniF2, HumM2. We used model-based standardization to estimate risk differences (RD) and 95% confidence intervals (CI). We assessed whether the presence of Bacteroides markers were modifiers of the association between general Enterococcus and illness among swimmers using interaction contrast. Overall we observed inconsistent associations between the presence of Bacteroides markers and illness. There was a pattern of increased risks of gastrointestinal (RD = 1.9%; 95% CI: 0.1%, 3.7%), diarrheal (RD = 1.3%; 95% CI: -0.2%, 2.7%), and respiratory illnesses (RD = 1.1%; 95% CI: -0.2%, 2.5%) associated with BsteriF1. There was no evidence that Bacteroides markers acted as modifiers of Enterococcus and illness. Patterns were similar when stratified by water matrix. Quantitative measures of fecal pollution using Bacteroides, rather than presence-absence indicators, may be necessary to accurately assess human risk specific to the presence of human fecal pollution.


Between-day reliability of a method for non-invasive estimation of muscle composition.
Tensiomyography is a method for valid and non-invasive estimation of skeletal muscle fibre type composition. The validity of selected temporal tensiomyographic measures has been well established recently; there is, however, no evidence regarding the method's between-day reliability. Therefore it is the aim of this paper to establish the between-day repeatability of tensiomyographic measures in three skeletal muscles. For three consecutive days, 10 healthy male volunteers (mean±SD: age 24.6 ± 3.0 years; height 177.9 ± 3.9 cm; weight 72.4 ± 5.2 kg) were examined in a supine position. Four temporal measures (delay, contraction, sustain, and half-relaxation time) and maximal amplitude were extracted from the displacement-time tensiomyogram. A reliability analysis was performed with calculations of bias, random error, coefficient of variation (CV), standard error of measurement, and intra-class correlation coefficient (ICC) with a 95% confidence interval. An analysis of ICC demonstrated excellent agreement (ICC were over 0.94 in 14 out of 15 tested parameters). However, lower CV was observed in half-relaxation time, presumably because of the specifics of the parameter definition itself. These data indicate that for the three muscles tested, tensiomyographic measurements were reproducible across consecutive test days. Furthermore, we indicated the most possible origin of the lowest reliability detected in half-relaxation time.


A non-contacting intraoperative electron cone apparatus.
Aluminum tubes, 20 cm long, of various diameter and face angle have been used to collimate electron beams for intraoperative radiotherapy. The tubes placed in a body cavity are clamped to the treatment couch. A thin rod is fixed coaxially to a disc which is placed on the entrance face of the tube. A stepwise procedure involving couch translation, rotation, and gantry rotation is used to align the central axis of the beam with the axis of the cone. Further collimation is provided by an aperture mounted in an assembly which slides into the standard accessory holder of the machine and is separated by a 10 cm air gap from the tube in the patient. Careful adjustment of this aperture diameter results in a relatively uniform dose across the treated area. The use of 3 mm wall thickness aluminum tube provides for minimal leakage outside of the cone. A camera has been mounted to a plate that also mounts in the standard accessory holder and is used to document the area treated.


Burns from buried electric cables.
Twenty-six patients who sustained significant burn injuries as a result of striking underground electric cables are reviewed. This study sets out to highlight why such injuries occur and to recommend preventive measures to those digging in the London area. There were three deaths in this series.


Echocardiography in valvular vegetations.
Echocardiography represents the only noninvasive technic available for detecting vegetations. In fact, the technic is more sensitive in indentifying these lesions than even angiography. The invasive examination is only capable of detecting very large valvular vegetations. Although echocardiography frequently discloses no abnormalities in patients with clinically suspected or proved bacterial endocarditis, the presence of vegetations can be very helpful in the management of these patients. In addition to identifying vegetations echocardiography can be of great assistance in demonstrating disruption of the affected valve and in identifying that valve which might require surgical replacement.


The long noncoding RNA HIF1A-AS2 facilitates cisplatin resistance in bladder cancer.
Chemotherapy drug resistance frequently happens in more than 50% of bladder cancer patients and is the major obstacle for the bladder cancer therapy. Recent studies have shown that long noncoding RNA (lncRNA) is involved in the development of chemoresistance. In this study, we reported hypoxia inducible factor 1α-antisense RNA 2 (HIF1A-AS2), as a subtype-specific hypoxia inducible lncRNA, is upregulated in bladder cancer cells and tissue after cisplatin (Cis) treatment. The induction of HIF1A-AS2 in bladder cancer cells rendered resistance to Cis-induced apoptosis. Silencing HIF1A-AS2 in Cis-resistant bladder cancer cells was re-sensitized to Cis-induced apoptosis. Mechanically, we found that HIF1A-AS2 suppressed the transcription activity of p53 family proteins by promoting the expression of high-mobility group A1 (HMGA1). The induction of HMGA1 physically interacts with p53, p63, and p73, and therefore constrains their transcriptional activity on Bax. Knockdown of HIF1A-AS2 or HMGA1 rescued the expression of Bax, which therefore enhanced the killing effect of Cis. Furthermore, we also found that the expression of HIF1A-AS2 was higher in the human bladder tumor tissues after Cis treatment, and was positive correlated to the expression of HIF1α and HMGA1. This study suggests that upregulated HIF1A-AS2 hampers the p53 family proteins dependent apoptotic pathway to promote Cis resistance in bladder cancer. Our data suggested that HIF1A-AS2 plays oncogenic roles and can be used as a therapeutic target for treating human bladder cancer.


Assessment of clinical practice in intensive care: a review of the literature.
Nursing is a practice-based discipline, with clinical practice forming the heart of any programme of study. The major goal of all programmes should be on facilitating students to develop the skills necessary for competent and compassionate practice. Assessment of clinical competence is a fundamental aspect of programme development and as such deserves attention during the curriculum design process. The literature on assessment of students in clinical practice suggests that the tools used have evolved through various stages, ranging from the use of simple check list and rating scale to the development of competence assessment tools. Each stage has been fraught with difficulties and has taxed nurse educators, clinical assessors and students alike. The literature also indicates that there is a limited range of research available on clinical assessment tools, especially with an intensive care context. In part one of this two-part paper, the literature on assessment of clinical practice is explored, with specific emphasis on the assessment of competence with the Intensive Care environment. Part two of the paper reports on the findings of a study on students perceptions on a clinical competence assessment tool, used in an Intensive Care environment.


Ber-EP4 enhances the differential diagnostic accuracy of cytokeratin 7 in pagetoid cutaneous neoplasms.
While cytokeratin 7 is a reliable marker for most cases of Paget's disease, it is not 100% sensitive. Moreover, cases of cytokeratin 7-positive pagetoid squamous cell carcinoma in situ are reported in the literature. The monoclonal antibody Ber-EP4 is diagnostically highly reliable in the differentiation between basal cell carcinoma and cutaneous squamous cell carcinoma. Here we report its application in the differential diagnosis of cutaneous pagetoid neoplasms. Biopsy samples from 21 cases of extramammary Paget's disease, 12 pagetoid squamous cell carcinomas in situ and 10 pagetoid melanomas in situ of the superficial spreading type were examined immunohistochemically with Ber-EP4, 34betaE12 and HMB-45. Ber-EP4 selectively labeled all cases of extramammary Paget's disease but none of the other pagetoid neoplasms. The majority of cases (18 = 85.7%) displayed strong and three (14.3%) showed moderate immunoreactivity. Ber-EP4 reliably differentiates extramammary Paget's disease from pagetoid squamous cell carcinoma in situ and pagetoid melanoma in situ. The antibody should be included along with a panel of other markers when evaluating for pagetoid cutaneous neoplasms in order to avoid a possible misdiagnosis of pagetoid squamous cell carcinoma in situ.


Variation in EGF-induced EGF receptor downregulation in human hepatoma-derived cell lines expressing different amounts of EGF receptor.
The effect of epidermal growth factor (EGF) receptor overexpression on ligand-induced EGF receptor downregulation was examined using a hepatoma-derived cell line, PLC/PRF/5, which expresses normal amounts of the EGF receptor, and a subline, NPLC/PRF/5, which expresses 10-fold more receptors at its cell surface. PLC/PRF/5 cells efficiently downregulated surface receptor levels upon exposure to saturating and subsaturating concentrations of EGF; the rate of receptor downregulation corresponded to that of ligand-receptor internalization. Upon internalization, EGF receptors were degraded and receptor biosynthesis remained at basal levels. EGF surface receptor remained downregulated for as long as cells were exposed to EGF. By contrast, surface EGF receptor abundance in NPLC/PRF/5 cells decreased by only 5-15% after 1-4 h incubation with subsaturating doses of EGF and actually increased by 67% within 20 h. Exposure of these cells to saturating concentrations of EGF induced modest decreases in surface receptor abundance during the initial 12 h incubation, followed by a progressive decline to 30% of initial values by 24 h. Relative ligand-receptor internalization rates in NPLC/PRF/5 cells were lower than those in PLC/PRF/5, although their surface receptor population was even higher than that predicted by the decreased internalization rates. EGF receptor degradation in NPLC/PRF/5 cells was also inhibited; exposure to saturating levels of EGF for more than 16 h was necessary before significant degradation occurred. Receptor protein and mRNA biosynthesis in NPLC/PRF/5 were stimulated by 8 h exposure to EGF but when saturating concentrations of EGF were present for 16 h, receptor biosynthesis was inhibited. EGF receptor overexpression circumvents the downregulatory effect of EGF by decreasing the rate of receptor internalization, inhibiting degradation of the internalized receptor pool, and stimulating EGF receptor biosynthesis. Conversely, receptor downregulation becomes pronounced at late times when receptor degradation is high and biosynthesis is inhibited.


Phylogeny and antigenic relationships of three cervid herpesviruses.
Elk herpesvirus (ElkHV) from North American elk (wapiti, Cervus elaphus nelsoni) is a recently identified alphaherpesvirus related to bovine herpesvirus-1 (BHV-1). In this study, we determined its relationship with European cervid herpesviruses: cervid herpesvirus-1 (CerHV-1) from red deer and rangiferine herpesvirus (RanHV) from reindeer. For phylogenetic analysis, genes for the gC and gD proteins of these viruses were sequenced. These genes demonstrated an extremely high GC content (76-79%). Genetically, ElkHV was found to be closely related to CerHV-1 and both viruses are more closely related to BHV-1 than to RanHV. Antigenically, the same relationships were found. ElkHV shares common neutralizing epitopes with both CerHV-1 and RanHV. A total of 10 epitopes were defined on the gB, gC and gD proteins of these viruses, including a shared neutralizing epitope on gD. The results indicate that ElkHV and CerHV-1 have diverged from a common ancestor virus. Cervid herpesviruses may be useful in determination of evolutionary rates of change for alphaherpesvirus genes.


Retention of OsNMD3 in the cytoplasm disturbs protein synthesis efficiency and affects plant development in rice.
The ribosome is the basic machinery for translation, and biogenesis of ribosomes involves many coordinated events. However, knowledge about ribosomal dynamics in higher plants is very limited. This study chose a highly conserved trans-factor, the 60S ribosomal subunit nuclear export adaptor NMD3, to characterize the mechanism of ribosome biogenesis in the monocot plant Oryza sativa (rice). O. sativa NMD3 (OsNMD3) shares all the common motifs and shuttles between the nucleus and cytoplasm via CRM1/XPO1. A dominant negative form of OsNMD3 with a truncated nuclear localization sequence (OsNMD3(ΔNLS)) was retained in the cytoplasm, consequently interfering with the release of OsNMD3 from pre-60S particles and disturbing the assembly of ribosome subunits. Analyses of the transactivation activity and cellulose biosynthesis level revealed low protein synthesis efficiency in the transgenic plants compared with the wild-type plants. Pharmaceutical treatments demonstrated structural alterations in ribosomes in the transgenic plants. Moreover, global expression profiles of the wild-type and transgenic plants were investigated using the Illumina RNA sequencing approach. These expression profiles suggested that overexpression of OsNMD3(ΔNLS) affected ribosome biogenesis and certain basic pathways, leading to pleiotropic abnormalities in plant growth. Taken together, these results strongly suggest that OsNMD3 is important for ribosome assembly and the maintenance of normal protein synthesis efficiency.


Control for delayed bilateral teleoperation of a quadrotor.
This paper proposes a cascade control scheme for delayed bilateral teleoperation of a quadcopter. The strategy transforms a 6D real quadcopter to an easy-to-teleoperate 3D virtual quadcopter. The scheme is formed by a P+d plus PID controller for each dof. The analysis based on Lyapunov theory gets as result the way to set the control parameters depending on the magnitude of the asymmetric time delays (forward and backward delays). This technic aims to reach stability, simplicity and good performance in practice. Besides, experimental tests about delayed bilateral teleoperation of a quadcopter including the proposed control scheme are shown in order to evaluate the system performance.


Relationship of Barthel Index and its Short Form with the Modified Rankin Scale in acute stroke patients.
Modified Rankin Scale and Barthel Index are the most common scales for assessing stroke outcomes in clinical practice and trials. Concordance between the Barthel Index scores and the modified Rankin Scale grades is important to define favorable outcome in clinical practice and stroke trials consistently. The purpose of this study was to examine the relationship between the scores of Barthel Index and 3-item Barthel Index Short Form with the modified Rankin Scale grades of acute stroke patients. Barthel Index, Barthel Index Short Form scores and modified Rankin Scale grades of 516 stroke patients were obtained from a follow-up study of the Longshi Scale in China. A study showed that the assignment of modified Rankin Scale grades to stroke patients was prone to misclassification. Therefore, the recorded modified Rankin Scale grades were compared with the Barthel Index scores of each patient to produce the adjusted modified Rankin Scale grades. Receiver operating characteristics curve analyses were performed to determine the optimal cutoff scores, respective sensitivities and specificities of Barthel Index and Barthel Index Short Form with the corresponding adjusted modified Rankin Scale grades ≤1, ≤2 and ≤3. About 44% of the recorded modified Rankin Scale grades of patients required adjustment. The optimal cutoff scores were ≥100 (sensitivity 100%; specificity 95.3%), ≥100 (sensitivity 98.1%; specificity 100%) and ≥75 (sensitivity 93.8%; specificity, 91.9%) for the Barthel Index and ≥40 (sensitivity 100%; specificity 78.9%), ≥40 (sensitivity 98.1%; specificity 82.8%), and ≥35 (sensitivity 99.3%; specificity, 91.6%) for the Barthel Index Short Form corresponding to the adjusted modified Rankin Scale grade ≤1, ≤2, and ≤3 respectively. The areas under the receiver operating characteristic curves were nearly all above 0.9. The optimal cutoff scores of Barthel Index and Barthel Index Short Form corresponding to the modified Rankin Scale grades ≤1, ≤2 and ≤3 were recommended to be ≥100 and ≥40, ≥100 and ≥40, and ≥75 and ≥35 respectively for determining the favorable and unfavorable outcome of stroke patients within three months of onset in clinical practice and trials.