Surface acoustic wave devices for chemical sensing and microfluidics: A review and perspective.
Surface acoustic waves (SAWs), are electro-mechanical waves that form on the surface of piezoelectric crystals. Because they are easy to construct and operate, SAW devices have proven to be versatile and powerful platforms for either direct chemical sensing or for upstream microfluidic processing and sample preparation. This review summarizes recent advances in the development of SAW devices for chemical sensing and analysis. The use of SAW techniques for chemical detection in both gaseous and liquid media is discussed, as well as recent fabrication advances that are pointing the way for the next generation of SAW sensors. Similarly, applications and progress in using SAW devices as microfluidic platforms are covered, ranging from atomization and mixing to new approaches to lysing and cell adhesion studies. Finally, potential new directions and perspectives on the field as it moves forward are offered, with a specific focus on potential strategies for making SAW technologies for bioanalytical applications.


Clinical characterisation and long-term prognosis of women with Brugada syndrome.
Brugada syndrome (BS) in women is considered an infrequent condition with a more favourable prognosis than in men. Nevertheless, arrhythmic events and sudden cardiac death (SCD) also occur in this population. Long-term follow-up data of this group are sparse. The purpose of the present study was to investigate the clinical characteristics and long-term prognosis of women with BS. A consecutive cohort of 228 women presenting with spontaneous or drug-induced Brugada type I ECG at our institution were included and compared with 314 men with the same diagnosis. Mean age was 41.5±17.3 years. Clinical presentation was SCD in 6 (2.6%), syncope in 51 (22.4%) and the remaining 171 (75.0%) were asymptomatic. As compared with men, spontaneous type I ECG was less common (7.9% vs 23.2%, p<0.01) and less ventricular arrhythmias were induced during programmed electrical stimulation (5.5% vs 22.3%, p<0.01). An implantable cardioverter defibrillator (ICD) was implanted in 64 women (28.1%). During a mean follow-up of 73.2±56.2 months, seven patients developed arrhythmic events, constituting an event rate of 0.7% per year (as compared with 1.9% per year in men, p=0.02). Presentation as SCD or sinus node dysfunction (SND) was risk factor significantly associated with arrhythmic events (hazard risk (HR) 25.4 and 9.1). BS is common in women, representing 42% of patients in our database. Clinical presentation is less severe than men, with more asymptomatic status and less spontaneous type I ECG and prognosis is more favourable, with an event rate of 0.7% year. However, women with SCD or previous SND are at higher risk of arrhythmic events.


Bird hosts, blood parasites and their vectors--associations uncovered by molecular analyses of blackfly blood meals.
The level of host specificity of blood-sucking invertebrates may have both ecological and evolutionary implications for the parasites they are transmitting. We used blood meals from wild-caught blackflies for molecular identification of parasites and hosts to examine patterns of host specificity and how these may affect the transmission of avian blood parasites of the genus Leucocytozoon. We found that five different species of ornithophilic blackflies preferred different species of birds when taking their blood meals. Of the blackflies that contained avian blood meals, 62% were infected with Leucocytozoon parasites, consisting of 15 different parasite lineages. For the blackfly species, there was a significant association between the host width (measured as the genetic differentiation between the used hosts) and the genetic similarity of the parasites in their blood meals. The absence of similar parasite in blood meals from blackflies with different host preferences is interpreted as a result of the vector-host associations. The observed associations between blackfly species and host species are therefore likely to hinder parasites to be transmitted between different host-groups, resulting in ecologically driven associations between certain parasite lineages and hosts species.


Cycling in the Absence of Task-Related Feedback: Effects on Pacing and Performance.
To achieve personal goals in exercise task completion, exercisers have to regulate, distribute, and manage their effort. In endurance sports, it has become very commonplace for athletes to consult task-related feedback on external devices to do so. The aim of the present study was to explore the importance of the presence of this information by examining the influence of the absence of commonly available task-related feedback on effort distribution and performance in experienced endurance athletes. A 20-km cycling time trial was performed. Twenty Participants from a homogenous cyclist population were appointed to a group that did not receive any feedback (NoF), or a group that could consult task-related feedback (i.e., speed, heart rate, power output, cadence, elapsed time, and elapsed distance) continuously during their trial (FF). The distribution of power output (PO) differed between groups. Most evident is the spurt at the end of the trial of FF, which was not incorporated by NoF. Nevertheless, no between-group differences were found in performance time (FF: 28.86 ± 3.68 vs. NoF: 30.95 ± 2.77 min) and mean PO controlled by body mass (FF: 3.61 ± 0.60 vs. NoF: 3.43 ± 0.38 W/kg). Also, no differences in rating of perceived exertion scores were found. The current study provides a first indication that prior knowledge of task demands together with reliance on bodily and environmental information can be sufficient for experienced athletes to come to comparable time trial performances. This questions the necessity of the presence of in-race instantaneous task-related feedback via external devices for maximizing performance. Moreover, it seems that different pacing strategies emerge depending on sources of information available to experienced athletes.


Structural basis for catalysis by onconase.
Onconase (ONC) is a homolog of bovine pancreatic ribonuclease (RNase A) from the frog Rana pipiens. ONC displays antitumoral activity and is in advanced clinical trials for the treatment of cancer. Here, we report the first atomic structures of ONC-nucleic acid complexes: a T89N/E91A ONC-5'-AMP complex at 1.65 A resolution and a wild-type ONC-d(AUGA) complex at 1.90 A resolution. The latter structure and site-directed mutagenesis were used to reveal the atomic basis for substrate recognition and turnover by ONC. The residues in ONC that are proximal to the scissile phosphodiester bond (His10, Lys31, and His97) and uracil nucleobase (Thr35, Asp67, and Phe98) are conserved from RNase A and serve to generate a similar bell-shaped pH versus k(cat)/K(M) profile for RNA cleavage. Glu91 of ONC forms two hydrogen bonds with the guanine nucleobase in d(AUGA), and Thr89 is in close proximity to that nucleobase. Installing a neutral or cationic residue at position 91 or an asparagine residue at position 89 virtually eliminated the 10(2)-fold guanine:adenine preference of ONC. A variant that combined such substitutions, T89N/E91A ONC, actually preferred adenine over guanine. In contrast, installing an arginine residue at position 91 increased the guanine preference and afforded an ONC variant with the highest known k(cat)/K(M) value. These data indicate that ONC discriminates between guanine and adenine by using Coulombic interactions and a network of hydrogen bonds. The structure of the ONC-d(AUGA) complex was also used to probe other aspects of catalysis. For example, the T5R substitution, designed to create a favorable Coulombic interaction between ONC and a phosphoryl group in RNA, increased ribonucleolytic activity by twofold. No variant, however, was more toxic to human cancer cells than wild-type ONC. Together, these findings provide a cynosure for understanding catalysis of RNA cleavage in a system of high medicinal relevance.


Comparative analysis of the ability of the polymerase complexes of influenza viruses type A, B and C to assemble into functional RNPs that allow expression and replication of heterotypic model RNA templates in vivo.
Influenza viruses type A, B, and C are human pathogens that share common structural and functional features, yet they do not form natural reassortants. To determine to what extent type-specific interactions of the polymerase complex with template RNA contribute to this lack of genotypic mixing, we investigated whether homotypic or heterotypic polymerase complexes support the expression and replication of model type A, B, or C RNA templates in vivo. A plasmid-based expression system, as initially described by Pleschka et al. [(1996) J. Virol. 70, 4188-4192] for influenza A virus, was developed for influenza viruses B/Harbin/7/94 and C/Johannesburg/1/66. The type A core proteins expressed heterotypic model RNAs with similar efficiencies as the homotypic RNA. The influenza B virus model RNA was efficiently expressed by all three types of polymerase complexes. Although no functional polymerase complex could be reconstituted with heterotypic P protein subunits, when the influenza A virus P proteins were expressed together with heterotypic nucleoproteins, significant, albeit limited, expression of RNA templates of all influenza virus types was detected. Taken together, our results suggest that less strict type-specific interactions are involved for the polymerase complex of influenza A compared with influenza B or C viruses.


Using Online Survey Software to Enhance Rigor and Efficiency of Knowledge Synthesis Reviews.
With the explosion of scientific literature, information technologies, and the rise of evidence-based health care, methodologies for literature reviews continue to advance. Yet there remains a lack of clarity about techniques to rigorously and efficiently extract and synthesize data from primary sources. We developed a new method for data extraction and synthesis for completing rigorous, knowledge synthesis using freely available online survey software that results in a review-specific, online data extraction, and synthesis tool. The purpose of this paper is to delineate this method using our published integrative review as an exemplar. Although the purpose of online survey software is to obtain and analyze survey responses, these software programs allows for the efficient extraction and synthesize of disparate study features from primary sources. Importantly, use of the method has the potential to increase the rigor and efficiency of published reviews bringing the promise of advancing multiple areas of health science.


Mechanical bowel preparation in intestinal surgery: a meta-analysis and review of the literature.
Despite several meta-analyses and randomized controlled trials showing no benefit to patients, mechanical bowel preparation (MBP) remains the standard of practice for patients undergoing elective colorectal surgery. We performed a systematic review of the literature of trials that prospectively compared MBP with no MBP for patients undergoing elective colorectal resection. We searched MEDLINE, LILACS, and SCISEARCH, abstracts of pertinent scientific meetings and reference lists for each article found. Experts in the field were queried as to knowledge of additional reports. Outcomes abstracted were anastomotic leaks and wound infections. Meta-analysis was performed using Peto Odds ratio. Of 4,601 patients (13 trials), 2,304 received MBP (Group 1) and 2,297 did not (Group 2). Anastomotic leaks occurred in 97(4.2%) patients in Group 1 and in 81(3.5%) patients in Group 2 (Peto OR = 1.214, CI 95%:0.899-1.64, P = 0.206). Wound infections occurred in 227(9.9%) patients in Group 1 and in 201(8.8%) patients in Group 2 (Peto OR = 1.156, CI 95%:0.946-1.413, P = 0.155). This meta-analysis demonstrates that MBP provides no benefit to patients undergoing elective colorectal surgery, thus, supporting elimination of routine MBP in elective colorectal surgery. In conclusion, MBP is of no benefit to patients undergoing elective colorectal resection and need not be recommended to meet "standard of care."


Identification and characterization of the genes encoding the core histones and histone variants of Neurospora crassa.
We have identified and characterized the complete complement of genes encoding the core histones of Neurospora crassa. In addition to the previously identified pair of genes that encode histones H3 and H4 (hH3 and hH4-1), we identified a second histone H4 gene (hH4-2), a divergently transcribed pair of genes that encode H2A and H2B (hH2A and hH2B), a homolog of the F/Z family of H2A variants (hH2Az), a homolog of the H3 variant CSE4 from Saccharomyces cerevisiae (hH3v), and a highly diverged H4 variant (hH4v) not described in other species. The hH4-1 and hH4-2 genes, which are 96% identical in their coding regions and encode identical proteins, were inactivated independently. Strains with inactivating mutations in either gene were phenotypically wild type, in terms of growth rates and fertility, but the double mutants were inviable. As expected, we were unable to isolate null alleles of hH2A, hH2B, or hH3. The genomic arrangement of the histone and histone variant genes was determined. hH2Az and the hH3-hH4-1 gene pair are on LG IIR, with hH2Az centromere-proximal to hH3-hH4-1 and hH3 centromere-proximal to hH4-1. hH3v and hH4-2 are on LG IIIR with hH3v centromere-proximal to hH4-2. hH4v is on LG IVR and the hH2A-hH2B pair is located immediately right of the LG VII centromere, with hH2A centromere-proximal to hH2B. Except for the centromere-distal gene in the pairs, all of the histone genes are transcribed toward the centromere. Phylogenetic analysis of the N. crassa histone genes places them in the Euascomycota lineage. In contrast to the general case in eukaryotes, histone genes in euascomycetes are few in number and contain introns. This may be a reflection of the evolution of the RIP (repeat-induced point mutation) and MIP (methylation induced premeiotically) processes that detect sizable duplications and silence associated genes.


On the relationship between clonidine hypotension and brain beta-endorphin in the spontaneously hypertensive rat: studies with alpha adrenergic and opiate blockers.
The relationship between the centrally mediated hypotensive and bradycardic effects of clonidine to central alpha-2 adrenergic receptor activation, brain beta-endorphin (BE) release and opiate receptor activation was studied in chloralose-anesthetized spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats, using a cerebroventricular perfusion system. Prior treatment of SHRs with i.v. naloxone (2 or 4 mg/kg) or i.c.v. yohimbine (10 or 20 micrograms/kg) reduced the hypotension and bradycardia induced by i.c.v. clonidine, but in Wistar-Kyoto rats naloxone had no similar blocking effects. Prazosin (20 micrograms/kg i.c.v.) reduced the clonidine bradycardia but not the hypotension in SHRs. Hypotension in the SHRs due to i.c.v. alpha-methylnorepinephrine (20 micrograms/kg) was reduced by both naloxone and yohimbine whereas alpha-methylnorepinephrine bradycardia was reduced by yohimbine but not by naloxone. Prior hypothalamic lesions in the SHRs reduced clonidine hypotension, but not bradycardia, and interfered with naloxone blockade of the residual clonidine hypotensive effect. Clonidine lowered immunoreactive BE levels in SHR hypothalamus, medulla and pituitary but did not change BE levels in the i.c.v. perfusate. The findings support the idea that in the SHRs, clonidine hypotension results from alpha-2 adrenergic stimulation of brain, causing BE release and central opiate receptor activation, and they suggest that the hypothalamus is involved in these interactions. Also, clonidine hypotension and bradycardia appear to involve different mechanisms in brain.


The effects of community pharmacy public health interventions on population health and health inequalities: a systematic review of reviews protocol.
Community pharmacies have great potential to deliver services aimed at promoting health and preventing disease, and are embedded within communities. In the light of a rapid increase in community pharmacy-delivered public health services and an accompanying increase in the evidence base, this systematic review of reviews will synthesise systematic reviews of public health community pharmacy interventions and assess their effects on public health and health inequalities. Systematic review methodology will be used to identify all systematic reviews that describe the health and health equity effects of community pharmacy public health interventions. Twenty databases will be searched using a pre-determined search strategy to evaluate community pharmacy-delivered public health interventions. Findings from the included reviews will be pooled, and a narrative synthesis executed to identify overarching patterns and results. Findings will support future decision-making around how community pharmacy public health services can be used alongside other strategies to promote health, prevent disease and reduce health inequalities. PROSPERO registration number: CRD42017056264 .


The dissonance mutant of courtship song in Drosophila melanogaster: isolation, behavior and cytogenetics.
The dissonance mutant of courtship song was induced by chemical mutagenesis. This X-chromosomal mutation causes the D. melanogaster male's acoustical output, resulting from his wing vibrations directed at a female, to include very long and loud tone "pulses." Yet, a given train of pulses starts out as normal, with the signals in all but the shortest singing bouts eventually becoming polycyclic and high-amplitude. The aberrant songs caused by diss (map position, 1-52; cytological interval, 14C1-2 to 14C4-5) were quantitatively compared to those produced by mutant cacophony males, whose pulses are much more uniformly polycyclic (due to a mutation mapping elsewhere on the X chromosome). Males or females expressing diss are normal in several "general" behaviors. Yet diss males not only sing abnormally, but they also exhibit longer-than-normal mating latencies in their courtship of females. These decrements seem to be associated, at least in part, with visually aberrant behavior of diss flies--measured with regard to male courtship per se, and also in tests of more general visual responses. Such defects were found when testing diss males or females, and the genetic etiology of the visual impairments were provisionally mapped to the same locus to which the song abnormality has been localized. Neurogenetic connections between the control of courtship singing behavior and visual system functions are discussed with respect to the new song mutation (diss) and the older one (cac)--which also turned out to be genetically related to a mutation that causes abnormalities of light-induced behavior and physiology.


The 1999 Eleanor Clarke Slagle Lecture. Defining lives: occupation as identity: an essay on competence, coherence, and the creation of meaning.
This article presents a view of occupation as the principal means through which people develop and express their personal identities. Based on a review of theory and research, it proposes that identity is instrumental to social life because it provides a context for deriving meaning from daily experiences and interpreting lives over time. The article proposes that identity also provides a framework for goal-setting and motivation. It is asserted that competence in the performance of tasks and occupations contributes to identity-shaping and that the realization of an acceptable identity contributes to coherence and well-being. Within this framework, it is postulated that performance limitations and disfigurement that sometimes result from illness or injury have identity implications that should be recognized by occupational therapy practitioners. By virtue of their expertise in daily living skills, occupational therapy practitioners are well positioned to help address the identity challenges of those whom they serve. In so doing, they make an important contribution to meaning and well-being.


Prevention of Aflatoxin B₁-Induced DNA Breaks by β-D-Glucan.
Aflatoxins are a group of naturally-occurring carcinogens that are known to contaminate different human and animal foodstuffs. Aflatoxin B1 (AFB1) is the most genotoxic hepatocarcinogenic compound of all of the aflatoxins. In this report, we explore the capacity of β-D-glucan (Glu) to reduce the DNA damage induced by AFB1 in mouse hepatocytes. For this purpose, we applied the comet assay to groups of animals that were first administered Glu in three doses (100, 400 and 700 mg/kg bw, respectively) and, 20 min later, 1.0 mg/kg of AFB1. Liver cells were obtained at 4, 10 and 16 h after the chemical administration and examined. The results showed no protection of the damage induced by AFB1 with the low dose of the polysaccharide, but they did reveal antigenotoxic activity exerted by the two high doses. In addition, we induced a co-crystallization between both compounds, determined their fusion points and analyzed the molecules by UV spectroscopy. The data suggested the formation of a supramolecular complex between AFB1 and β-D-glucan.


Changes in lung lipid during spontaneous labor in fetal sheep.
The goals of this study were 1) to examine changes in lung liquid formation and composition during spontaneous labor in fetal lambs and 2) to determine the importance of beta-adrenergic stimulation and transepithelial Na+ flux in removing liquid from the lung lumen near birth. We measured net production of lung liquid (Jv), lung liquid composition, and transpulmonary electrical potential difference (PD) before and during labor in fetal sheep with chronically implanted tracheal and vascular catheters. We determined Jv by measuring rate of change in lung liquid concentration of 125I-albumin, an impermeant tracer that was mixed in lung liquid at the start of each study. In 17 paired experiments, Jv decreased from 11 +/- 2 ml/h (Jv > 0 = secretion) before labor to -1 +/- 2 ml/h (Jv < 0 = absorption) during labor; in 5 paired experiments, PD changed from -7 +/- 1 mV (lumen negative) before labor to -12 +/- 1 mV during labor. To determine whether absorption of lung liquid during labor is the result of beta-adrenergic stimulation, we studied the effect of propranolol on Jv during labor. When propranolol (40 microM) was added to lung liquid during active labor, Jv decreased from -2 +/- 2 to -8 +/- 3 ml/h (n = 9). Thus, propranolol did not inhibit lung liquid absorption during labor. To determine whether transepithelial Na+ movement provides the driving force for lung liquid clearance during labor, we tested the effects of amiloride, an Na+ transport inhibitor, on Jv and PD.(ABSTRACT TRUNCATED AT 250 WORDS)


PCR detection and identification of bacterial contaminants in ocular samples from post-operative endophthalmitis.
Bacterial endophthalmitis is a sight-threatening complication of ocular surgery which requires urgent medical consideration including comprehensive diagnosis. Polymerase chain reaction (PCR) as a sensitive molecular method has been extensively used for detection of microbial species in clinical specimens. The aim of this study was to identify the causative organisms of endophthalmitis in our patient population using a procedure based on PCR. Vitreous samples from 32 patients with post-operative endophthalmitis were collected. Total vitreous DNA was extracted and then assessed by agarose gel electrophoresis. Bacterial 16S rRNA gene was amplified from genomic DNA using PCR with a pair of HAD2 universal primers. Library of PCR products from 16S rRNA, cloned into the pTZ57R/T vector. The ligated products were then transformed into E. coli DH5α strain and grown in the LB-ampicillin/X-Gal/IPTG plate. From the total of 32 vitreous samples, 18 specimens were positive, illustrating the presence of bacterial infection (56.4 %). Twelve species including Escherichia coli, Enterobacter cloacae, Bacillus subtilis, Neisseria gonorrhoeae, Streptococcus pneumoniae, Haemophilus influenzae, Chlamydia trachomatis, Staphylococcus aureus, Neisseria meningitides, Staphylococcus epidermidis, Pseudomonas aeruginosa and Bacillus cereus were identified using BLAST for known 16S rRNA sequences. Polymerase chain reaction (PCR) accompanied with cloning and sequencing approved to be sensitive and specific. The rapid molecular technique was useful in detection of 12 major microbial species, in infectious endophthalmitis.


Diaryliodonium salts as hydrosilylation initiators for the surface functionalization of silicon nanomaterials and their collaborative effect as ring opening polymerization initiators.
Diaryliodonium salts were found to initiate hydrosilylation reactions on the surface of silicon nanosheets as well as silicon nanocrystals of different sizes. A variety of different functional substrates can be used to stabilize the surface of the photoluminescent materials. Additionally, the combination of hydride terminated silicon nanomaterials with diaryliodonium salts was found to initiate cationic ring opening polymerization, demonstrating the potential of silicon based nanomaterials as coinitiators and enabling a mild, straightforward reaction method.


Head to head comparison of [18F] AV-1451 and [18F] THK5351 for tau imaging in Alzheimer's disease and frontotemporal dementia.
Tau accumulation is a core pathologic change in various neurodegenerative diseases including Alzheimer's disease and frontotemporal lobar degeneration-tau. Recently, tau positron emission tomography tracers such as [18F] AV-1451 and [18F] THK5351 have been developed to detect tau deposition in vivo. In the present study, we performed a head to head comparison of these two tracers in Alzheimer's disease and frontotemporal dementia cases and aimed to investigate which tracers are better suited to image tau in these disorders. A cross-sectional study was conducted using a hospital-based sample at a tertiary referral center. We recruited eight participants (two Alzheimer's disease, four frontotemporal dementia and two normal controls) who underwent magnetic resonance image, amyloid positron emission tomography with [18F]-Florbetaben and tau positron emission tomography with both THK5351 and AV-1451. To measure regional AV1451 and THK5351 uptakes, we used the standardized uptake value ratios by dividing mean activity in target volume of interest by mean activity in the cerebellar hemispheric gray matter. Although THK5351 and AV-1451 uptakes were highly correlated, cortical uptake of AV-1451 was more striking in Alzheimer's disease, while cortical uptake of THK5351 was more prominent in frontotemporal dementia. THK5351 showed higher off-target binding than AV-1451 in the white matter, midbrain, thalamus, and basal ganglia. AV-1451 is more sensitive and specific to Alzheimer's disease type tau and shows lower off-target binding, while THK5351 may mirror non-specific neurodegeneration.


Improved visual function in IDDM patients with unchanged cumulative incidence of sight-threatening diabetic retinopathy.
To evaluate trends in visual acuity and the cumulative incidence of diabetic retinopathy in a clinic-based observational follow-up study. All patients visiting Hvidore Hospital in 1984 whose diagnosis of IDDM had been made before 41 years of age and between 1965 and 1979 (n = 356) were followed until 1994 or until their deaths. All patients were Caucasians and resided in Copenhagen. Patients were divided into three prevalence cohorts based on time of diabetes onset: group A, 1965-1969 (n = 113); group B, 1970-1974 (n = 130); and group C, 1975-1979 (n = 113). Fifteen years after diabetes onset, the visual acuity was significantly improved in patients with increasing calendar year of the disease onset. The median (interquartile range) visual acuity was 1.0 (0.8-1.0), 1.0(0.9-1.0), and 1.0 (1.0-1.0) in groups A, B, and C, respectively (P < 0.01 overall; P = 0.28 for group A vs. group B; and P < 0.01 for group A vs. group C) with 60, 66, and 93 having a visual acuity of 1.0 in groups A, B, and C, respectively. The cumulative incidence (+/-SEM), expressed as a percentage and calculated according to the life-table method, of proliferative retinopathy, maculopathy, and laser-treated retinopathy 15 years after onset of diabetes were, respectively, 13+/-3, 11+/-3, and 12+/-3 in group A; 16+/-3, 12+/-3, and 21+/-4 in group B; 11+/-3, 5+/-2, and 12+/-3 in group C, respectively (NS). The development of proliferative retinopathy was associated with the degree of retinopathy and albuminuria at baseline and the mean HbA1c during follow-up. The study revealed an improvement in visual acuity with increasing calendar year of diabetes onset but an unchanged cumulative incidence of diabetic retinopathy.


Increased EGFR mRNA Expression Levels in Non-Small Cell Lung Cancer.
In this study, we investigated the frequency of Epidermal growth factor receptor (EGFR) gene mutations, the level of EGFR mRNA and protein expressions in Turkish population for indicating substantial differences in the frequency of EGFR mutations, EGFR amplification and EGFR protein expression between populations and the effect of these parameters in response to EGFR tyrosine kinase inhibitors. The study included 34 patients with non-small cell lung cancers. The RNA and DNA were extracted from the normal and tumor side of the lung tissue removed by surgery. To investigate the most common mutations in the EGFR gene, exon 19 was sequenced and mutation specific PCR was performed for detecting the L858R mutation in exon 21. EGFR mRNA expression was measured by relative quantitative reverse transcription PCR. The EGFR protein levels were detected with immunohistochemistry methods from the sections of the patients' paraffin blocks. No EGFR mutation in exon 19 or L858R mutation in exon 21 were detected in the patients. Overexpression of EGFR gene mRNA was identified in 16 of 34 (%47) patients and overexpression of EGFR protein was detected in 15 of 34 (%44) patients. Statistical analysis was not significant for the correlation between sex, age, smoking, histopathology, pathological stage and overexpression of EGFR mRNA and protein. It was found that in Turkish population, EGFR mutation in exon 19 and L858R mutation were very rare, EGFR protein expression was similar and EGFR mRNA expression significantly increased compared to the literature. Markedly increased EGFR mRNA expression ratios in the absence of activating mutations showed that identifying the EGFR mRNA expression level for prediction of response to EGFR tyrosine kinase inhibitors might be significant in the Turkish population.


Modeling microbial metabolic trade-offs in a chemostat.
Microbes face intense competition in the natural world, and so need to wisely allocate their resources to multiple functions, in particular to metabolism. Understanding competition among metabolic strategies that are subject to trade-offs is therefore crucial for deeper insight into the competition, cooperation, and community assembly of microorganisms. In this work, we evaluate competing metabolic strategies within an ecological context by considering not only how the environment influences cell growth, but also how microbes shape their chemical environment. Utilizing chemostat-based resource-competition models, we exhibit a set of intuitive and general procedures for assessing metabolic strategies. Using this framework, we are able to relate and unify multiple metabolic models, and to demonstrate how the fitness landscape of strategies becomes intrinsically dynamic due to species-environment feedback. Such dynamic fitness landscapes produce rich behaviors, and prove to be crucial for ecological and evolutionarily stable coexistence in all the models we examined.


Antidotes in Poisoning.
Antidotes are agents that negate the effect of a poison or toxin. Antidotes mediate its effect either by preventing the absorption of the toxin, by binding and neutralizing the poison, antagonizing its end-organ effect, or by inhibition of conversion of the toxin to more toxic metabolites. Antidote administration may not only result in the reduction of free or active toxin level, but also in the mitigation of end-organ effects of the toxin by mechanisms that include competitive inhibition, receptor blockade or direct antagonism of the toxin. Reduction in free toxin level can be achieved by specific and non-specific agents that bind to the toxin. The most commonly used non-specific binding agent is activated charcoal. Specific binders include chelating agents, bioscavenger therapy and immunotherapy. In some situations, enhanced elimination can be achieved by urinary alkalization or hemadsorption. Competitive inhibition of enzymes (e.g. ethanol for methanol poisoning), enhancement of enzyme function (e.g. oximes for organophosphorus poisoning) and competitive receptor blockade (e.g. naloxone, flumazenil) are other mechanisms by which antidotes act. Drugs such as N-acetyl cysteine and sodium thiocyanate reduce the formation of toxic metabolites in paracetamol and cyanide poisoning respectively. Drugs such as atropine and magnesium are used to counteract the end-organ effects in organophosphorus poisoning. Vitamins such as vitamin K, folic acid and pyridoxine are used to antagonise the effects of warfarin, methotrexate and INH respectively in the setting of toxicity or overdose. This review provides an overview of the role of antidotes in poisoning. Chacko B, Peter JV. Antidotes in Poisoning. Indian J Crit Care Med 2019;23(Suppl 4):S241-S249.


Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression.
Most hypotheses of the therapeutic mechanism of action of antidepressant drugs have focused on the role of the monoamines. We examined the effect of catecholamine depletion on antidepressant-induced remission. The tyrosine hydroxylase inhibitor alpha-methylparatyrosine and the antihistamine diphenhydramine hydrochloride were administered, during separate test sessions, to depressed patients in remission maintained with either norepinephrine reuptake inhibitors (desipramine [n = 7] or mazindol [n = 2]) or serotonin reuptake inhibitors (fluoxetine hydrochloride [n = 9] or sertraline hydrochloride [n = 1]). Because of considerable sedation associated with alpha-methylparatyrosine testing, diphenhydramine was used as an active control rather than an inactive placebo. The effects of alpha-methylparatyrosine and diphenhydramine on depression, anxiety, and plasma catecholamine metabolites were assessed. alpha-Methylparatyrosine produced similar significant decreases in plasma 3-methoxy-4-hydroxyphenylethyleneglycol and homovanillic acid levels in the treatment groups. alpha-Methylparatyrosine produced a robust increase in depressive symptoms on the Hamilton Depression Rating Scale, including depressed mood, decreased concentration, anhedonia, loss of interest, and feelings of worthlessness, helplessness, and hopelessness, in the desipramine-mazindol but not in the fluoxetine-sertraline group. Diphenhydramine had no effects on mood in either treatment group. The therapeutic effects of norepinephrine reuptake inhibitors, but not serotonin reuptake inhibitors, are reversed by catecholamine depletion. Considered with previous reports that serotonin depletion produces depressive relapses in patients in remission maintained with serotonin reuptake inhibitors, but not norepinephrine reuptake inhibitors, these findings suggest that antidepressants may not work via a single monoamine-related mechanism.


Spatially Correlated Time Series and Ecological Niche Analysis of Cutaneous Leishmaniasis in Afghanistan.
Leishmaniasis is the third most common vector-borne disease and a very important protozoan infection. Cutaneous leishmaniasis is one of the most common types of leishmaniasis infectious diseases with up to 1.2 million occurrences of new cases each year worldwide. A dynamic transmission multivariate time series model was applied to the data to account for overdispersion and evaluate the effects of three environmental layers as well as seasonality in the data. Furthermore, ecological niche modeling was used to study the geographically suitable conditions for cutaneous leishmaniasis using temperature, precipitation and altitude as environmental layers, together with the leishmaniasis presence data. A retrospective analysis of the cutaneous leishmaniasis spatial data in Afghanistan between 2003 and 2009 indicates a steady increase from 2003 to 2007, a small decrease in 2008, and then another increase in 2009. An upward trend and regularly repeating patterns of highs and lows were observed related to the months of the year, which suggests seasonality effect in the data. Two peaks were observed in the disease occurrence-January to March and September to December-which coincide with the cold period. Ecological niche modelling indicates that precipitation has the greatest contribution to the potential distribution of leishmaniasis.


An Evidence-Based Approach to the Management of Functional Dyspepsia Associated With Helicobacter pylori Infection.
Functional dyspepsia is defined as at least a 3-month history of dyspepsia without structural explanation for the symptoms, and it accounts for most cases of dyspepsia. We designed this study to investigate functional dyspepsia among a Chinese population in Taiwan. Data from the medical records of 1,143 adult patients who underwent transoral upper endoscopy for symptoms of dyspepsia in our hospital were retrospectively analyzed between January 2008 and December 2008. Exclusion criteria were structural gastrointestinal and hepatobiliary abnormalities, prior gastric surgery or history of chronic medication use. Patients were mainly in the third and fourth decades of life. More female patients were noted than male patients (ratio 2:1). The rate of Helicobacter pylori infection was 18.5%. The rate of response to therapeutic agents, including proton pump inhibitors, H2-receptor antagonists and prokinetic agents, ranged from 69% to 77% among all cases. Patients who underwent H. pylori eradication therapy (88.8%) had a significantly higher rate of symptom improvement than those without H. pylori infection (77.5%). Cases with functional dyspepsia have the characteristics of middle age, female predominance, a relatively lower H. pylori infection rate and a positive response to H. pylori eradication therapy.


Thalamocortical projections have a K+ channel that is phosphorylated and modulated by cAMP-dependent protein kinase.
The finding that some K+ channel mRNAs are restricted to certain populations of neurons in the CNS suggests that there are K+ channels tailored to certain neuronal circuits. One such example are the transcripts from the KV3.2 gene, the majority of which are expressed in thalamic relay neurons. To gain insights into the specific roles of KV3.2 subunits, site specific antibodies were raised to determine their localization in thalamic relay neurons. Immunohistochemical and focal lesioning studies demonstrate that KV3.2 proteins are localized to the terminal fields of thalamocortical projections. It is also shown that KV3.2 channels expressed in vitro are strongly inhibited through phosphorylation by cAMP-dependent protein kinase (PKA). Channels containing KV3.1 subunits, which otherwise exhibit nearly identical electrophysiological properties in heterologous expression systems but have a different and less restricted pattern of expression in the CNS, are not affected by PKA. Therefore, this modulation might be associated with the specific roles of KV3.2 subunits. Furthermore, we demonstrate that KV3.2 proteins can be phosphorylated in situ by intrinsic PKA. KV3.2 subunits display properties and have a localization consistent with a role in the regulation of the efficacy of the thalamocortical synapse, and could thereby participate in the neurotransmitter-mediated control of functional states of the thalamocortical system associated with global states of awareness.


Ab initio based polarizable force field parametrization.
Experimental and simulation studies of anion-water systems have pointed out the importance of molecular polarization for many phenomena ranging from hydrogen-bond dynamics to water interfaces structure. The study of such systems at molecular level is usually made with classical molecular dynamics simulations. Structural and dynamical features are deeply influenced by molecular and ionic polarizability, which parametrization in classical force field has been an object of long-standing efforts. Although when classical models are compared to ab initio calculations at condensed phase, it is found that the water dipole moments are underestimated by approximately 30%, while the anion shows an overpolarization at short distances. A model for chloride-water polarizable interaction is parametrized here, making use of Car-Parrinello simulations at condensed phase. The results hint to an innovative approach in polarizable force fields development, based on ab initio simulations, which do not suffer for the mentioned drawbacks. The method is general and can be applied to the modeling of different systems ranging from biomolecular to solid state simulations.


Revisiting Myosin Families Through Large-scale Sequence Searches Leads to the Discovery of New Myosins.
Myosins are actin-based motor proteins involved in many cellular movements. It is interesting to study the evolutionary patterns and the functional attributes of various types of myosins. Computational search algorithms were performed to identify putative myosin members by phylogenetic analysis, sequence motifs, and coexisting domains. This study is aimed at understanding the distribution and the likely biological functions of myosins encoded in various taxa and available eukaryotic genomes. We report here a phylogenetic analysis of around 4,064 myosin motor domains, built entirely from complete or near-complete myosin repertoires incorporating many unclassified, uncharacterized sequences and new myosin classes, with emphasis on myosins from Fungi, Haptophyta, and other Stramenopiles, Alveolates, and Rhizaria (SAR). The identification of large classes of myosins in Oomycetes, Cellular slime molds, Choanoflagellates, Pelagophytes, Eustigmatophyceae, Fonticula, Eucoccidiorida, and Apicomplexans with novel myosin motif variants that are conserved and thus presumably functional extends our knowledge of this important family of motor proteins. This work provides insights into the distribution and probable function of myosins including newly identified myosin classes.


Bone morphogenetic protein and Notch signalling crosstalk in poor-prognosis, mesenchymal-subtype colorectal cancer.
The functional role of bone morphogenetic protein (BMP) signalling in colorectal cancer (CRC) is poorly defined, with contradictory results in cancer cell line models reflecting the inherent difficulties of assessing a signalling pathway that is context-dependent and subject to genetic constraints. By assessing the transcriptional response of a diploid human colonic epithelial cell line to BMP ligand stimulation, we generated a prognostic BMP signalling signature, which was applied to multiple CRC datasets to investigate BMP heterogeneity across CRC molecular subtypes. We linked BMP and Notch signalling pathway activity and function in human colonic epithelial cells, and normal and neoplastic tissue. BMP induced Notch through a γ-secretase-independent interaction, regulated by the SMAD proteins. In homeostasis, BMP/Notch co-localization was restricted to cells at the top of the intestinal crypt, with more widespread interaction in some human CRC samples. BMP signalling was downregulated in the majority of CRCs, but was conserved specifically in mesenchymal-subtype tumours, where it interacts with Notch to induce an epithelial-mesenchymal transition (EMT) phenotype. In intestinal homeostasis, BMP-Notch pathway crosstalk is restricted to differentiating cells through stringent pathway segregation. Conserved BMP activity and loss of signalling stringency in mesenchymal-subtype tumours promotes a synergistic BMP-Notch interaction, and this correlates with poor patient prognosis. BMP signalling heterogeneity across CRC subtypes and cell lines can account for previous experimental contradictions. Crosstalk between the BMP and Notch pathways will render mesenchymal-subtype CRC insensitive to γ-secretase inhibition unless BMP activation is concomitantly addressed. © 2017 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Preemptive Tolerogenic Delivery of Donor Antigens for Permanent Allogeneic Islet Graft Protection.
We have previously developed a robust regimen for tolerance induction in murine models of islet cell transplantation using pre- and posttransplant infusions of donor splenocytes (SPs) treated with a chemical cross-linker ethylcarbodiimide (ECDI). However, the requirement for large numbers of fresh donor SPs for ECDI coupling impairs its clinical feasibility, and additionally, the compatibility of this tolerance regimen with commonly used immunosuppressive drugs is largely unknown. In the current study, we demonstrate that equivalent tolerance efficacy for islet cell transplantation can be successfully achieved not only with a significantly lower dose of ECDI-SPs than originally established but also with culture-expanded donor B-cells or with soluble donor antigens in the form of donor cell lysate, which is ECDI coupled to recipient SPs. We further demonstrate that tolerance induced by donor ECDI-SPs is dependent on a favorable apoptotic-to-necrotic cell ratio post-ECDI coupling and is not affected by a transient course of conventional immunosuppressive drugs including tacrolimus and mycophenolate mofetil. While splenic antigen-presenting cells of the recipient play an important role in mediating the tolerogenic effects of donor ECDI-SPs, splenectomized recipients can be readily tolerized and appear to employ liver Kupffer cells for uptaking and processing of the ECDI-SPs. We conclude that infusion of donor ECDI-SPs is a versatile tolerance strategy that has a high potential for adaptation to clinically feasible regimens for tolerance trials for human islet cell transplantation.


Transmembrane domain of surface-exposed outer membrane lipoprotein RcsF is threaded through the lumen of β-barrel proteins.
RcsF (regulator of capsule synthesis) is an outer membrane (OM) lipoprotein that functions to sense defects such as changes in LPS. However, LPS is found in the outer leaflet, and RcsF was thought to be tethered to the inner leaflet by its lipidated N terminus, raising the question of how it monitors LPS. We show that RcsF has a transmembrane topology with the lipidated N terminus on the cell surface and the C-terminal signaling domain in the periplasm. Strikingly, the short, unstructured, charged transmembrane domain is threaded through the lumen of β-barrel OM proteins where it is protected from the hydrophobic membrane interior. We present evidence that these unusual complexes, which contain one protein inside another, are formed by the Bam complex that assembles all β-barrel proteins in the OM. The ability of the Bam complex to expose lipoproteins at the cell surface underscores the mechanistic versatility of the β-barrel assembly machine.


Comparison between the AA/EPA ratio in depressed and non depressed elderly females: omega-3 fatty acid supplementation correlates with improved symptoms but does not change immunological parameters.
Depression is one of the most frequently missed diagnoses in elderly people, with obvious negative effects on quality of life. Various studies have shown that long chain omega-3 polyunsaturated fatty acids (n-3 PUFA) may be useful in its management. Our objective was to evaluate whether a supplement containing n-3 PUFA improves depressive symptoms in depressed elderly patients, and whether the blood fatty acid pattern is correlated with these changes. The severity of depressive symptoms according to the Geriatric Depression Scale (GDS), blood fatty acid composition and erythrocyte phospholipids were analyzed in 46 depressed females aged 66-95y, diagnosed with depression according to DSMIV, within the context of a randomized, double-blind, placebo-controlled trial. 22 depressed females were included in the intervention group (2.5 g/day of n-3 PUFA for 8 weeks), and 24 in the placebo group. We also measured immunological parameters (CD2, CD3, CD4, CD8, CD16, CD19 and cytokines (IL-5, IL-15). The mean GDS score and AA/EPA ratio, in whole blood and RBC membrane phospholipids, were significantly lower after 2 months supplementation with n-3 PUFA. A significant correlation between the amelioration of GDS and the AA/EPA ratio with some immunological parameters, such as CD2, CD19, CD4, CD16 and the ratio CD4/CD8, was also found. Nevertheless, omega-3 supplementation did not significantly improve the studied immunological functions. n-3 PUFA supplementation ameliorates symptoms in elderly depression. The n-3 PUFA status may be monitored by means of the determination of whole blood AA/EPA ratio.


The dynamics of benzene on Cu(111): a combined helium spin echo and dispersion-corrected DFT study into the diffusion of physisorbed aromatics on metal surfaces.
We use helium spin-echo spectroscopy (HeSE) to investigate the dynamics of the diffusion of benzene adsorbed on Cu(111). The results of these measurements show that benzene moves on the surface through an activated jump-diffusion process between the adsorption sites on a Bravais lattice. Density Functional Theory (DFT) calculations with van der Waals (vdW) corrections help us understand that the molecule diffuses by jumping through non-degenerate hollow sites. The results of the calculations shed light on the nature of the binding interaction between this prototypical aromatic molecule and the metallic surface. The highly accurate HeSE experimental data provide a quantitatively stringent benchmark for the vdW correction schemes applied to the DFT calculations and we compare the performances of several dispersion interaction schemes.


Phosphodiesterase-5 activity exerts a coronary vasoconstrictor influence in awake swine that is mediated in part via an increase in endothelin production.
Nitric oxide (NO)-induced coronary vasodilation is mediated through production of cyclic guanosine monophosphate (cGMP) and through inhibition of the endothelin-1 (ET) system. We previously demonstrated that phosphodiesterase-5 (PDE5)-mediated cGMP breakdown and ET each exert a vasoconstrictor influence on coronary resistance vessels. However, little is known about the integrated control of coronary resistance vessel tone by these two vasoconstrictor mechanisms. In the present study, we investigated the contribution of PDE5 and ET to the regulation of coronary resistance vessel tone in swine both in vivo, at rest and during graded treadmill exercise, and in vitro. ETA/ETB receptor blockade with tezosentan (3 mg/kg iv) and PDE5 inhibition with EMD360527 (300 μg·min(-1)·kg(-1) iv) each produced coronary vasodilation at rest and during exercise as well as in preconstricted isolated coronary small arteries. In contrast, tezosentan failed to produce further coronary vasodilation in the presence of EMD360527, both in vivo and in vitro. Importantly, EMD360527 (3 μM) and cGMP analog 8-Br-cGMP (100 μM) had no significant effects on ET-induced contractions of isolated porcine coronary small arteries, suggesting unperturbed ET receptor responsiveness. In contrast, PDE5 inhibition and cGMP blunted the contractions produced by the ET precursor Big ET, but only in vessels with intact endothelium, suggesting that PDE5 inhibition limited ET production in the endothelium of small coronary arteries. In conclusion, PDE5 activity exerts a vasoconstrictor influence on coronary resistance vessels that is mediated, in part, via an increase in endothelial ET production.


Age-related trends (1986-1993) in the use of thrombolytic agents in patients with acute myocardial infarction. The Worcester Heart Attack Study.
To examine age-related differences and temporal trends in the use of thrombolytic therapy in a community-wide study of patients hospitalized with acute myocardial infarction (AMI) between 1986 and 1993. All hospitals in the Worcester, Mass, metropolitan area (1990 census population, 4370000) were included. A total of 3824 patients with validated AMI categorized according to age comprised the study sample: younger than 55 years (n = 577), 55 to 64 years (n = 758), 65 to 74 years (n = 1143), and 75 years or older (n = 1346). Use of thrombolytic therapy increased during the period under study in all patients hospitalized with AMI (9% in 1986; 26% in 1993). In 1986, the majority of treated patients received streptokinase; while increases over time in the use of tissue-type plasminogen activator were noted, streptokinase remained the thrombolytic agent of choice in 1993. Marked age-related trends in the use of thrombolytic therapy were observed, with the most striking increases in the use of thrombolytic therapy over time seen in those aged 65 years or older. Between 1986 and 1993 the relative increases in the use of thrombolytic therapy were observed in the following age groups: younger than 55 years (106%), 55 to 64 years (85%), 65 to 74 years (694%), and 75 years or older (571%). Despite these encouraging trends in the use of thrombolytic therapy in older patients, after controlling for a variety of potential confounding variables elderly patients were significantly less likely to receive thrombolytic therapy during hospitalization for AMI. Compared with patients aged 75 years or older, patients younger than 55 years were 6.4 times (95% confidence interval [CI], 4.8-8.5), patients aged 55 to 64 years were 4.9 times (95% CI, 3.8-6.4), and patients aged 65 to 74 years were 3.0 times (95% CI, 2.3-3.9) significantly more likely to receive thrombolytic therapy. These differences were in part related to the proportion of patients with myocardial infarction satisfying eligibility criteria for the receipt of thrombolytic therapy; patients aged 75 years or older were significantly less likely to meet these criteria (19%) than were those younger than 55 years (49%), those aged 55 to 64 years (38%), and those aged 65 to 74 years (28%). The present results show that while there have been substantial increases over time in the use of thrombolytic therapy in patients with AMI, most particularly in older individuals, the elderly remain appreciably less likely to receive these agents during hospitalization for AMI. These differences may be due to the smaller percentage of elderly patients satisfying criteria for the use of these agents compared with younger patients with coronary heart disease, as well as to a reluctance by physicians to use these agents in older patients. Continued monitoring of these trends remains important for examining changes in physicians' practice patterns regarding the use of thrombolytic therapy in this vulnerable population.


Heart rate variability is related to impaired haemorheology in older women with type 2 diabetes.
Impaired heart rate variability (HRV)and haemorheology are independently associated with cardiovascular disease and diabetic complications. The aim of the present study was to investigate the relationships between parameters of HRV,and red blood cell (RBC) aggregation and deformability, in older women with type 2 diabetes. Twenty women (age 69 ± 2 yr) with uncomplicated type 2 diabetes and twenty controls (age 69 ± 3 yr) participated in the study. Beat-to-beat cardiac (RR) intervals over 5 min were analysed for HRV parameters in the time and frequency domains. Blood was sampled for RBC deformability, as well as RBC aggregation in two suspending mediums: haematocrit adjusted plasma and 3% dextran 70. RBC aggregation was increased and HRV was impaired for those with type 2 diabetes when compared with control. RBC aggregation was negatively related to low frequency power of HRV, and was positively related to high frequency power of HRV, for subjects with type 2 diabetes. RBC deformability was positively related to HRV only for those with type 2 diabetes. Impaired haemorheology is associated with reduced HRV in older women with type 2 diabetes, suggesting changes in the microcirculation may result in impaired modulation of cardiac cycles.


Inhibiting calpain 1 and 2 in cyclin G associated kinase-knockout mice mitigates podocyte injury.
Evidence for reduced expression of cyclin G associated kinase (GAK) in glomeruli of patients with chronic kidney disease was observed in the Nephroseq human database, and GAK was found to be associated with the decline in kidney function. To examine the role of GAK, a protein that functions to uncoat clathrin during endocytosis, we generated podocyte-specific Gak-knockout mice (Gak-KO), which developed progressive proteinuria and kidney failure with global glomerulosclerosis. We isolated glomeruli from the mice carrying the mutation to perform messenger RNA profiling and unearthed evidence for dysregulated podocyte calpain protease activity as an important contributor to progressive podocyte damage. Treatment with calpain inhibitor III specifically inhibited calpain-1/-2 activities, mitigated the degree of proteinuria and glomerulosclerosis, and led to a striking increase in survival in the Gak-KO mice. Podocyte-specific deletion of Capns1, essential for calpain-1 and calpain-2 activities, also improved proteinuria and glomerulosclerosis in Gak-KO mice. Increased podocyte calpain activity-mediated proteolysis of IκBα resulted in increased NF-κB p65-induced expression of growth arrest and DNA-damage-inducible 45 beta in the Gak-KO mice. Our results suggest that loss of podocyte-associated Gak induces glomerular injury secondary to calcium dysregulation and aberrant calpain activation, which when inhibited, can provide a protective role.


Age-specific Serum Prostate Specific Antigen Ranges Among Apparently Healthy Nigerian Men Without Clinical Evidence of Prostate Cancer.
Serum prostate specific antigen (PSA) levels increase with age and varies among different races and communities. The study was aimed at defining the age-specific reference ranges of serum PSA in our environment. We evaluated the relationship between age and serum PSA levels and the age-specific reference ranges of serum PSA among civil servants in Lagos, who underwent routine medical checkups. Criteria for inclusion were men who have no lower urinary tract symptoms, normal digital rectal examination and serum PSA ≤ 20 ng/ml. SPSS Statistic 21 was used for data evaluation and the mean, median, 95(th) percentile PSA levels were estimated. Pearson's correlation was used to examine the relationship, and P < 0.05 was considered significant. 4032 men met the criteria for inclusion in the evaluation. The mean age was 51.6 (range 40-70) years, and there was a strong correlation between serum PSA levels and age (r = 0.097, P < 0.001). PSA ranges of 0-2.5, >2.5-4.0, >4.0-10, and >10 ng/ml were found in 3218 (80%), 481 (12%), 284 (7%), and 52 (1%) men, respectively. The mean, median and the 95(th) percentile PSA for the overall group were 1.84, 1.33, and 5.2 ng/ml respectively. However the 95(th) percentile PSA levels for men aged 40-49, 50-59, and 60-70 years were 4.78, 5.47, and 8.93 ng/ml respectively. The age-specific PSA levels among Nigerian men for each age group is higher than what was described for men in the Western world. These reference ranges of serum PSA should be considered for men aged ≥40 years in our environment.


Bicyclol for chronic hepatitis C.
Bicyclol is a novel synthetic 'anti-hepatitis' drug, used in China for chronic hepatitis C. Until now, systematic reviews on bicyclol therapy have not been performed. To study the benefits and harms of bicyclol for patients with chronic hepatitis C. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (July 2005), the Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 2, 2005), MEDLINE (1994 to July 2005), EMBASE (1994 to July 2005), Science Citation Index Expanded (1994 to July 2005), The Chinese Biomedical Database (1994 to August 2005), Chinese Journals Full-article Database (1994 to August 2005), VIP Chinese Science and Technique Journals Database (1994 to August 2005), and China National Infrastructure (CNKI) (1994 to August 2005). We also contacted manufacturers and researchers in the field. Randomised clinical trials on bicyclol versus no intervention, placebo, or other interventions in patients with chronic hepatitis C were included, irrespective of blinding, publication status, or language. The primary outcome measures were total and liver-related mortality and liver-related morbidity (eg, cirrhosis and carcinoma). Secondary outcome measures were viral response and liver histology. The search identified one randomised clinical trial comparing bicyclol with placebo for 39 patients with chronic hepatitis C. The follow-up was three months. In the trial, there was no evidence that bicyclol was superior to placebo for clearance of HCV RNA (RR 3.80, 95% CI 0.47 to 31.0) and anti-HCV antibodies, but bicyclol was associated with statistically significant decrease in alanine aminotransferase activity at 12-th week after treatment (WMD -69 IU/L, 95% CI -115 to -24). Only one randomised clinical trial has examined bicyclol for patients with chronic hepatitis C. This small, short-term trial found no evidence to support or refute its use. Large, randomised, double-blind clinical trials with long-term follow-up are needed to examine the possible benefits and harms associated with bicyclol. Bicyclol can only be recommended for use in randomised trials.


Photophysical and biological investigation of phenol substituted rhenium tetrazolato complexes.
The synthesis, structural and photophysical characterisation of four tricarbonyl rhenium(i) complexes bound to 1,10-phenanthroline and a tetrazolato ancillary ligand are reported. The complexes are differentiated by the nature (hydroxy or methoxy) and position (meta or para) of the substituent attached to the phenyl ring in conjugation to the tetrazole ring. The complexes exhibit phosphorescence emission from triplet charge transfer excited states, with the maxima around 600 nm, excited state lifetime decays in the 200-300 ns range, and quantum yield values of 4-6% in degassed acetonitrile solutions. The nature and position of the substituent does not significantly affect the photophysical properties, which remain unchanged even after deprotonation of the hydroxide group on the phenol ring. The interpretation of the photophysical data was further validated by resonance Raman spectroscopy and time-dependent density functional theory calculations. All the complexes are internalised within cells, albeit to variable degrees. As highlighted by a combination of flow cytometry and confocal microscopy, the species display diffuse cytoplasmic localisation except for the complex with the hydroxy functional group at the para position, which reveals lower accumulation in cells and more pronounced punctate staining. Overall, the complexes displayed low levels of cytotoxicity.


A novel approach to analyze lysosomal dysfunctions through subcellular proteomics and lipidomics: the case of NPC1 deficiency.
Superparamagnetic iron oxide nanoparticles (SPIONs) have mainly been used as cellular carriers for genes and therapeutic products, while their use in subcellular organelle isolation remains underexploited. We engineered SPIONs targeting distinct subcellular compartments. Dimercaptosuccinic acid-coated SPIONs are internalized and accumulate in late endosomes/lysosomes, while aminolipid-SPIONs reside at the plasma membrane. These features allowed us to establish standardized magnetic isolation procedures for these membrane compartments with a yield and purity permitting proteomic and lipidomic profiling. We validated our approach by comparing the biomolecular compositions of lysosomes and plasma membranes isolated from wild-type and Niemann-Pick disease type C1 (NPC1) deficient cells. While the accumulation of cholesterol and glycosphingolipids is seen as a primary hallmark of NPC1 deficiency, our lipidomics analysis revealed the buildup of several species of glycerophospholipids and other storage lipids in selectively late endosomes/lysosomes of NPC1-KO cells. While the plasma membrane proteome remained largely invariable, we observed pronounced alterations in several proteins linked to autophagy and lysosomal catabolism reflecting vesicular transport obstruction and defective lysosomal turnover resulting from NPC1 deficiency. Thus the use of SPIONs provides a major advancement in fingerprinting subcellular compartments, with an increased potential to identify disease-related alterations in their biomolecular compositions.


Identifying patients with undetected renal tract cancer in primary care: an independent and external validation of QCancer® (Renal) prediction model.
To evaluate the performance of QCancer® (Renal) for predicting the absolute risk of renal tract cancer in a large independent UK cohort of patients from general practice records. Open cohort study to validate QCancer® (Renal) prediction model. Record from 365 practices from United Kingdom contributing to The Health Improvement Network (THIN) database. 2.1 million patients registered with a general practice surgery between 01 January 2000 and 30 June 2008, aged 30-84 years (3.7 million person years) with 2283 renal tract cancer cases. Renal tract cancer was defined as incident diagnosis of renal tract cancer during the 2 years after study entry. Model discrimination was measured using the receiver operating characteristics derived area under the curve. Calibration plots examined the relationship between predicted and observed probabilities of undetected renal tract cancer. The results from this independent and external validation of QCancer® (Renal) demonstrated good performance data on a large cohort of general practice patients. QCancer® (Renal) had very good discrimination with areas under the ROC curve of 0.92 and 0.95 for women and men respectively. QCancer® (Renal) was well calibrated across all tenths of risk and over all age ranges with predicted risks closely matching observed risks. QCancer® (Renal) explained 74.4% and 74.2% of the variation in men and women respectively. A limitation of our study is the recording of symptoms might be less complete, as patients with mild symptoms may not visit their general practitioner or not report mild symptoms. QCancer® (Renal) are useful tools to help in identifying undetected cases of undiagnosed renal tract cancer in primary care in the UK.


[Facioscapulohumeral muscular dystrophy: Report of seven patients].
Facioscapulohumeral muscular dystrophy is the third most common muscular dystrophy with an estimated prevalence of 1 per 20.000 and a normal life expectancy in the majority of patients. However, approximately 15% of patients become wheelchair bound in the course of their life. It is a hereditary autosomal dominant disease with high (95%) penetrance by the age of 20, but with variable degree of phenotypic expression even in the same family group. Symptoms frequently start in the second decade of life, with facial and scapular weakness. To report the clinical features of seven patients with the disease, seen at a public hospital. Analysis of seven patients with genetic study seen in a public Hospital in Santiago. The age of patients fluctuated from 18 to 61 years and four were females. The mean age at onset of symptoms was 29 years and four had a family history of the disease. The usual presenting complaint was arm or shoulder asymmetric weakness. Four patients had bone pain. Facial involvement was present in four. A genetic study was done in five patients, the other two patients were relatives, confirming the contraction or lower number of repetitions in D4Z4 region. After 12 years of follow up only 2 patients older than 60 years cannot work and one female patients is in a semi dependent state at the age of 30. The clinical workup in the diagnosis and the timely indication of genetic studies are highlighted, to avoid unnecessary and invasive procedures. The variability in the phenotypic expression in a similar genetic defect is discussed and the genetic or epigenetic mechanisms of this muscular dystrophy are described.


Identification of Potentially Preventable Traumatic Injury Among Military Working Dogs Deployed During the Global War on Terror.
Prevention of deployment-related injury is critical for readiness of US military working dogs (MWDs). This study evaluated deployment-related injuries to determine if they were potentially preventable and identify possible abatement strategies. Data were collected on 195 MWD injury events that occurred between 11 September 2001 and 31 December 2018. Injuries were reviewed by a panel of veterinarians and categorized into groups based on panel consensus. The panel also established which interventions could have been effective for mitigating injuries. Multipurpose canine (MPC) and conventional MWD injury event characteristics were compared to identify meaningful differences. Of the 195 injuries, 101 (52%) were classified as preventable or potentially preventable. Most (72%) of the potentially preventable injuries occurred in conventional MWDs, with penetrating injuries (64%) being the most common type of trauma. For the preventable/potentially preventable injuries, the most common preventative intervention identified was handler training (53%) followed by protective equipment (46%). There were differences between MPCs and conventional MWDs for injury prevention category, type of trauma, mechanism of injury, and preventative intervention (all p < .001). The application of a preventable review process to MWD populations may be beneficial in identifying potentially preventable injuries and preventative intervention strategies.


Regulation of geminin by neuropeptide Y in vascular smooth muscle cell proliferation : A current review.
Geminin, a key regulator of DNA replication licensing in the cell cycle, plays an essential role in determining the fate of cells via suppression of cell proliferation and cellular differentiation. Neuropeptide Y (NPY) intensifies the proliferation of vascular smooth muscle cells (VSMCs) directly by binding with Y1 receptors. In vitro experiments have shown that stimulation of NPY on VSMCs via regulation of geminin is a double-edged sword. Given that the proliferation and the phenotypic transformation of VSMCs increase the risk for progression of atherosclerosis, we focus on the role of geminin interference in determining the fate of VSMCs. Furthermore, we discuss the therapeutic potential of peripheral neurotransmitter interference, thus pointing toward future research directions in the treatment of atherosclerosis.


Relaxation of risk-sensitive behaviour of prey following disease-induced decline of an apex predator, the Tasmanian devil.
Apex predators structure ecosystems through lethal and non-lethal interactions with prey, and their global decline is causing loss of ecological function. Behavioural changes of prey are some of the most rapid responses to predator decline and may act as an early indicator of cascading effects. The Tasmanian devil (Sarcophilus harrisii), an apex predator, is undergoing progressive and extensive population decline, of more than 90% in long-diseased areas, caused by a novel disease. Time since local disease outbreak correlates with devil population declines and thus predation risk. We used hair traps and giving-up densities (GUDs) in food patches to test whether a major prey species of devils, the arboreal common brushtail possum (Trichosurus vulpecula), is responsive to the changing risk of predation when they forage on the ground. Possums spend more time on the ground, discover food patches faster and forage more to a lower GUD with increasing years since disease outbreak and greater devil population decline. Loss of top-down effects of devils with respect to predation risk was evident at 90% devil population decline, with possum behaviour indistinguishable from a devil-free island. Alternative predators may help to maintain risk-sensitive anti-predator behaviours in possums while devil populations remain low.


Can a renal nurse assess fluid status using ultrasound on the inferior vena cava? A cross-sectional interrater study.
Ultrasound of the inferior vena cava (IVC-US) has been used to estimate intravascular volume status and fluid removal during a hemodialysis session. Usually, renal nurses rely on other, imprecise methods to determine ultrafiltration. To date, no study has examined whether renal nurses can reliably perform ultrasound for volume assessment and for potential prevention of intradialytic hypotension. This pilot study aimed to determine if a renal nurse could master the skill of performing and correctly interpreting Point of Care Ultrasound on patients receiving hemodialysis. After receiving theoretical training and performing 100 training scans, a renal nurse performed 60 ultrasound scans on 10 patients. These were categorized by the nurse into hypovolemic, euvolemic, or hypervolemic through measurement of the maximal diameter and degree of collapse of the IVC. Scans were subsequently assessed for adequacy and quality by two sonologists, who were blinded to each other's and the nurse's results. The interrater reliability of 60 scans was good, with intraclass correlation 0.79 (95% confidence interval (CI) =0.63-0.87) and with a good interrater agreement for the following estimation of intravascular volume (Cohen's weighted Kappa κw = 0.62), when comparing the nurse to an expert sonographer. A renal nurse can reliably perform ultrasound of the IVC in hemodialysis patients, obtaining high quality scans for volume assessment of hemodialysis patients. This novel approach could be more routinely applied by other renal nurses to obtain objective measures of patient volume status in the dialysis setting.


Making meaning of financial scarcity in old age.
The purpose of this paper is twofold: first, we explore how older people (aged 69 to 85 years) living on the edge of relative poverty experience their everyday lives, and second, we investigate how they cope with their financial situation. We examine these aspects through 16 life story interviews to understand which paths these older people believe have led them to where they are today. First, we show how the older people highlight events or decisions in their life that mainly have an individual origin placing the responsibility of their current financial situation on themselves. We argue that these accounts reflect a change in the discourse on poverty; a transformation from poverty as collective destiny to poverty as the result of individual failure. Second, we show how these older people's control strategies vary across their life spans. In earlier phases of their lives, these older people attempted actively to improve their financial situation; however, in their old age, they focus more on adapting to and accepting the situation because their advanced age makes it difficult for them to use active coping strategies to overcome financial scarcity. Third, we argue that the imprints the interviewees received growing up in financial scarcity during the Second World War and the postwar years may have instilled them with silence and modesty, thus they are likely to adjust stoically.


Introduction to the special issue: Substance use and the adolescent brain: Developmental impacts, interventions, and longitudinal outcomes.
Adolescent substance abuse is a major public health problem, particularly given the negative brain and behavioral consequences that often occur during and following acute intoxication. Negative outcomes appear to be especially pronounced when substance use is initiated in the early adolescent years, perhaps due to neural adaptations that increase risk for substance use disorders into adulthood. Recent models to explain these epidemiological trends have focused on brain-based vulnerabilities to use as well as neurodevelopmental aberrations associated with initiation of use in substance naïve samples or through the description of case-control differences between heavy users and controls. Within this research, adolescent alcohol and marijuana users have shown relative decreases in regional gray matter volumes, substance-specific alterations in white matter volumes, deviations in microstructural integrity in white matter tracts that regulate communication between subcortical areas and higher level regulatory control regions, and deficits in functional connectivity. How these brain anomalies map onto other types of youth risk behavior and later vulnerabilities represent major questions for continued research. This special issue addresses these compelling and timely questions by introducing new methodologies, empirical relationships, and perspectives from major leaders in this field.


Potential contributing factors to noncompliance with dietary sodium restriction in patients with heart failure.
Although sodium restriction is considered essential in the management of patients with chronic heart failure (CHF), there are no data available regarding patients awareness of and ability to comply with the sodium restriction guideline. Between May 1999 and August 2000, 50 patients referred to the Parkland Memorial Hospital CHF clinic were assessed by a registered dietitian for (1) awareness of the sodium restriction guideline, (2) ability to read the sodium content from a Nutrition Facts label, and (3) ability to sort 12 food containers, all bearing a Nutrition Facts label, into high- and low-sodium groups. A global measure of dietary sodium knowledge was calculated ("sodium knowledge score," range 0-10). These tests were repeated after the patient completed one or more educational sessions (mean 2.8 +/- 1.5) with the dietitian. The proportion of patients aware of the sodium restriction guideline was 14% at baseline and 42% at follow-up (P <.01). The proportion of patients able to read the sodium content from the Nutrition Facts label was 58% at baseline and 92% at follow-up (P <.01). The sodium knowledge score was 3.8 +/- 3.4 at baseline and 5.8 +/- 3.2 at follow-up (P <.01). The proportion of subjects who achieved a perfect sodium knowledge score of 10 was 8% at baseline and 26% at follow-up (P <.05). The number of food containers sorted accurately was 10.6 +/- 1.5 at baseline and 11.3 +/- 1.1 at follow-up, P =.09. On referral to a specialty CHF clinic, many patients had severe deficiencies in their knowledge base regarding dietary sodium intake that would preclude compliance with the sodium restriction guideline. Directed education focusing on sodium intake corrected many of these deficiencies.


Influence of intron length on alternative splicing of CD44.
Although the splicing of transcripts from most eukaryotic genes occurs in a constitutive fashion, some genes can undergo a process of alternative splicing. This is a genetically economical process which allows a single gene to give rise to several protein isoforms by the inclusion or exclusion of sequences into or from the mature mRNA. CD44 provides a unique example; more than 1,000 possible isoforms can be produced by the inclusion or exclusion of a central tandem array of 10 alternatively spliced exons. Certain alternatively spliced exons have been ascribed specific functions; however, independent regulation of the inclusion or skipping of each of these exons would clearly demand an extremely complex regulatory network. Such a network would involve the interaction of many exon-specific trans-acting factors with the pre-mRNA. Therefore, to assess whether the exons are indeed independently regulated, we have examined the alternative exon content of a large number of individual CD44 cDNA isoforms. This analysis shows that the downstream alternatively spliced exons are favored over those lying upstream and that alternative exons are often included in blocks rather than singly. Using a novel in vivo alternative splicing assay, we show that intron length has a major influence upon the alternative splicing of CD44. We propose a kinetic model in which short introns may overcome the poor recognition of alternatively spliced exons. These observations suggest that for CD44, intron length has been exploited in the evolution of the genomic structure to enable tissue-specific patterns of splicing to be maintained.


Prevalence of Disaccharidase Deficiency in Adults With Unexplained Gastrointestinal Symptoms.
Disaccharidase assay is used for assessing carbohydrate intolerance in children, but its usefulness in adults is not known. The aim of this study is to assess the prevalence of disaccharidase deficiency in patients with unexplained gastrointestinal symptoms. A retrospective review of adults with chronic (> 1 year) abdominal symptoms and negative imaging and endoscopy/colonoscopy and who completed bowel symptom questionnaire and duodenal biopsy for lactase, maltase, sucrase, and palatinase was performed. A subset also underwent 25 g lactose breath test (LBT). One hundred twenty patients (females = 83) were evaluated, of whom 48 also underwent LBT. Fifty-six (46.7%) patients had enzyme deficiency; 44 (36.7%) had single (either lactase or maltase), 1 had 3 enzyme deficiencies, 11 (9.2 %) had all 4 disaccharidase enzyme (pan-disaccharidase) deficiency, and 64 (53.0%) had normal enzyme levels. Baseline prevalence and severity of 11 gastrointestinal symptoms were similar between normal and single enzyme deficiency groups. The sensitivity and specificity of LBT was 78.3% and 72.0%, respectively and overall agreement with lactase deficiency was 75.0%. Isolated disaccharidase deficiency occurs in adults, usually lactase and rarely maltase, and pan-disaccharidase deficiency is rare. Baseline symptoms or its severity did not predict enzyme deficiency.


MELAS syndrome with mitochondrial tRNA(Leu(UUR)) gene mutation in a Chinese family.
The clinical features of a patient in a Chinese family with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome) are reported. The study revealed that hearing and visual impairments and miscarriages may be early clinical presentations in MELAS. A heteroplasmic A to G transition in the tRNA(Leu(UUR)) gene was noted at the nucleotide pair 3243 in the mitochondrial DNA of muscle, blood, and hair follicles of the proband and his maternal relatives. Quantitative analysis of the mutated mitochondrial DNA revealed variable proportions in different tissues and subjects of maternal lineage in the family. Muscle tissue contained a higher proportion of the mutant mitochondria than other tissues examined. The function of the reproductive system of the proband seems to be impaired. In one clinically healthy sibling, the 3243rd point mutation was found in sperm mitochondrial DNA, although sperm motility was not affected. It seems that biochemical defects in mitochondrial respiration and oxidative phosphorylation are tissue specific expressions of the 3243rd point mutation in the mitochondrial DNA of the affected target tissues.


Switchgrass for bioethanol and other value-added applications: a review.
Switchgrass is a promising feedstock for value-added applications due to its high productivity, potentially low requirements for agricultural inputs and positive environmental impacts. The objective of this paper is to review published research on the conversion of switchgrass into bioethanol and other value-added products. Environmental benefits associated with switchgrass include the potential for carbon sequestration, nutrient recovery from runoff, soil remediation and provision of habitats for grassland birds. Pretreatment of switchgrass is required to improve the yields of fermentable sugars. Based on the type of pretreatment, glucose yields range from 70% to 90% and xylose yields range from 70% to 100% after hydrolysis. Following pretreatment and hydrolysis, ethanol yields range from 72% to 92% of the theoretical maximum. Other value-added uses of switchgrass include gasification, bio-oil production, newsprint production and fiber reinforcement in thermoplastic composites. Future prospects for research include increased biomass yields, optimization of feedstock composition for bioenergy applications, and efficient pentose fermentation to improve ethanol yields.


Mesenchymal stem cells generate a CD4+CD25+Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells.
Mesenchymal stem cells (MSCs) are adult, multipotent, stem cells with immunomodulatory properties. The mechanisms involved in the capacity of MSCs to inhibit the proliferation of proinflammatory T lymphocytes, which appear responsible for causing autoimmune disease, have yet to be fully elucidated. One of the underlying mechanisms studied recently is the ability of MSCs to generate T regulatory (Treg) cells in vitro and in vivo from activated peripheral blood mononuclear cells (PBMC), T-CD4+ and also T-CD8(+) cells. In the present work we investigated the capacity of MSCs to generate Treg cells using T-CD4(+) cells induced to differentiate toward the proinflammatory Th1 and Th17 lineages. MSCs were obtained from mouse bone marrow and characterized according to their surface antigen expression and their multilineage differentiation potential. CD4(+) T cells isolated from mouse spleens were induced to differentiate into Th1 or Th17 cells and co-cultured with MSCs added at day 0, 2 or 4 of the differentiation processes. After six days, CD25, Foxp3, IL-17 and IFN-γ expression was assessed by flow cytometry and helios and neuropilin 1 mRNA levels were assessed by RT-qPCR. For the functional assays, the 'conditioned' subpopulation generated in the presence of MSCs was cultured with concanavalin A-activated CD4(+) T cells labeled with carboxyfluorescein succinimidyl ester. Finally, we used the encephalomyelitis autoimmune diseases (EAE) mouse model, in which mice were injected with MSCs at day 18 and 30 after immunization. At day 50, the mice were euthanized and draining lymph nodes were extracted for Th1, Th17 and Treg detection by flow cytometry. MSCs were able to suppress the proliferation, activation and differentiation of CD4(+) T cells induced to differentiate into Th1 and Th17 cells. This substantial suppressive effect was associated with an increase of the percentage of functional induced CD4(+)CD25(+)Foxp3(+) regulatory T cells and IL-10 secretion. However, using mature Th1 or Th17 cells our results demonstrated that while MSCs suppress the proliferation and phenotype of mature Th1 and Th17 cells they did not generate Treg cells. Finally, we showed that the beneficial effect observed following MSC injection in an EAE mouse model was associated with the suppression of Th17 cells and an increase in the percentage of CD4(+)CD25(+)Foxp3(+) T lymphocytes when administrated at early stages of the disease. This study demonstrated that MSCs contribute to the generation of an immunosuppressive environment via the inhibition of proinflammatory T cells and the induction of T cells with a regulatory phenotype. Together, these results might have important clinical implications for inflammatory and autoimmune diseases.


A meta-analysis of HLA peptidome composition in different hematological entities: entity-specific dividing lines and "pan-leukemia" antigens.
Hematological malignancies (HM) are highly amenable targets for immunotherapeutic intervention and may be effectively treated by antigen-specific T-cell based treatment. Recent studies demonstrate that physiologically occurring anti-cancer T-cell responses in certain HM entities target broadly presented non-mutated epitopes. HLA ligands are thus implied as prime targets for broadly applicable and antigen-specific off-the-shelf compounds. With the aim of assessing the presence of common targets shared among different HM which may enable addressing a larger patient collective we conducted a meta-analysis of 83 mass spectrometry-based HLA peptidome datasets (comprising 40,361 unique peptide identifications) across four major HM (19 AML, 16 CML, 35 CLL, and 13 MM/MCL samples) and investigated similarities and differences within the HLA presented antigenic landscape. We found the cancer HLA peptidome datasets to cluster specifically along entity and lineage lines, suggesting that the immunopeptidome directly reflects the differences in the underlying (tumor-)biology. In line with these findings, we only detected a small set of entity-spanning antigens, which were predominantly characterized by low presentation frequencies within the different patient cohorts. These findings suggest that design of T-cell immunotherapies for the treatment of HM should ideally be conducted in an entity-specific fashion.


Stenting and glycoprotein IIb/IIIa inhibition in patients with acute myocardial infarction undergoing percutaneous coronary intervention: findings from the global registry of acute coronary events (GRACE).
Stenting and GP IIb/IIIa inhibition are promising adjunctive therapies in PCI. The Global Registry of Acute Coronary Events (GRACE) is a registry of unselected patients with acute coronary syndromes, allowing for the study of treatments in a real-world environment. Data from GRACE patients with AMI who underwent PCI were analyzed. After adjusting for demographics, baseline characteristics, and previous medications, treatment with GP IIb/IIIa inhibitors and a stent and treatment with a stent alone were significant predictors of survival at 6 months. Stents were used in 90.9% of patients. GP IIb/IIIa inhibitors were used in 59.7%; in most cases they were started after the beginning of the procedure. The in-hospital death rate (7.6%) was highest in patients undergoing urgent PCI. Mortality at 6 months following PCI was 14.4% among patients who received neither GP IIb/IIIa inhibitors nor a stent, compared to patients who received both GP IIb/IIIa inhibitors and a stent (7.3%), GP IIb/IIIa inhibitors alone (12.8%), or a stent alone (6.7%).


Investigations of the marine flora and fauna of the Fiji Islands.
Over the past 30 years, approximately 140 papers have been published on marine natural products chemistry and related research from the Fiji Islands. These came about from studies starting in the early 1980s by the research groups of Crews at the University of California Santa Cruz, Ireland at the University of Utah, Gerwick from the Scripps Institution of Oceanography, the University of California at San Diego and the more recent groups of Hay at the Georgia Institute of Technology (GIT) and Jaspars from the University of Aberdeen. This review covers both known and novel marine-derived natural products and their biological activities. The marine organisms reviewed include invertebrates, plants and microorganisms, highlighting the vast structural diversity of compounds isolated from these organisms. Increasingly during this period, natural products chemists at the University of the South Pacific have been partners in this research, leading in 2006 to the development of a Centre for Drug Discovery and Conservation (CDDC).


Effect of Workload on Job Stress of Ghanaian OPD Nurses: The Role of Coworker Support.
Although the concept of workload is important to nursing practice, only a few nursing researchers have focused on the issue of workload within the nursing context. Knowledge of how the dynamics of workload affects the job stress of nurses working in a specific unit or department in a hospital setting, and the influence of coworker support on this relationship, still remains limited. This study, therefore examined the effect of workload on job stress of Ghanaian outpatient department nurses and the moderating effect of coworker support on this relationship. A cross-sectional survey design was used, and questionnaire was used to collect data from a sample of 216 outpatient department nurses from four major hospitals in Ghana. The data collected measured workload, job stress, and coworker support using National Aeronautics and Space Administration (NASA) Task Load Index, job stress scale, and coworker support scale, respectively. Data were analysed using descriptive statistics, correlation, and hierarchical regression. High levels of workload were associated with high levels of job stress of the nurses. Also, higher levels of workload were related to higher levels of job stress for nurses who received high levels of coworker support, but this was not the case for those who received low levels of coworker support (reserve buffering effect). The finding reiterates the adverse effect of workloads on employees' health, and the reverse buffering effect implies that supporting a colleague at work should be conveyed in a positive manner devoid of negative appraisal.


Use of hair dyes by patients with breast cancer: a case-control study.
The recent finding that many permanent and semipermanent hair dyes are strongly mutagenic in a laboratory test, together with the fact that single female hair-dressers had higher than expected death rates from breast-cancer in 1959-63, prompted a study into the use of hair dyes by patients with breast cancer and by matched controls. There was no difference between the patients and their controls in their use of hair dyes. There were also no significant differences between the two groups when the analysis was confinedto women who had used dyes over four years and over nine years before diagnosis. The only significant findings were a higher proportion of past or present smokers among women aged over 50 who used hair dyes and an association between hair dyes use and age at first pregnancy. Further epidemiological studies are clearly needed in view of the mutagenicity found in the Ames test, and the fact th & several human carcinogens are also mutagenic according to this test.


Towards accurate, contiguous and complete alignment-based polyploid phasing algorithms.
Phasing, and in particular polyploid phasing, have been challenging problems held back by the limited read length of high-throughput short read sequencing methods which can't overcome the distance between heterozygous sites and labor high cost of alternative methods such as the physical separation of chromosomes for example. Recently developed single molecule long-read sequencing methods provide much longer reads which overcome this previous limitation. Here we review the alignment-based methods of polyploid phasing that rely on four main strategies: population inference methods, which leverage the genetic information of several individuals to phase a sample; objective function minimization methods, which minimize a function such as the Minimum Error Correction (MEC); graph partitioning methods, which represent the read data as a graph and split it into k haplotype subgraphs; cluster building methods, which iteratively grow clusters of similar reads into a final set of clusters that represent the haplotypes. We discuss the advantages and limitations of these methods and the metrics used to assess their performance, proposing that accuracy and contiguity are the most meaningful metrics. Finally, we propose the field of alignment-based polyploid phasing would greatly benefit from the use of a well-designed benchmarking dataset with appropriate evaluation metrics. We consider that there are still significant improvements which can be achieved to obtain more accurate and contiguous polyploid phasing results which reflect the complexity of polyploid genome architectures.


Dissecting abdominal aortic aneurysm in Ang II-infused mice: suprarenal branch ruptures and apparent luminal dilatation.
In this work, we provide novel insight into the morphology of dissecting abdominal aortic aneurysms in angiotensin II-infused mice. We demonstrate why they exhibit a large variation in shape and, unlike their human counterparts, are located suprarenally rather than infrarenally. We combined synchrotron-based, ultra-high resolution ex vivo imaging (phase contrast X-Ray tomographic microscopy) with in vivo imaging (high-frequency ultrasound and contrast-enhanced micro-CT) and image-guided histology. In all mice, we observed a tear in the tunica media of the abdominal aorta near the ostium of the celiac artery. Independently we found that, unlike the gradual luminal expansion typical for human aneurysms, the outer diameter increase of angiotensin II-induced dissecting aneurysms in mice was related to one or several intramural haematomas. These were caused by ruptures of the tunica media near the ostium of small suprarenal side branches, which had never been detected by the established small animal imaging techniques. The tear near the celiac artery led to apparent luminal dilatation, while the intramural haematoma led to a dissection of the tunica adventitia on the left suprarenal side of the aorta. The number of ruptured branches was higher in those aneurysms that extended into the thoracic aorta, which explained the observed variability in aneurysm shape. Our results are the first to describe apparent luminal dilatation, suprarenal branch ruptures, and intramural haematoma formation in dissecting abdominal aortic aneurysms in mice. Moreover, we validate and demonstrate the vast potential of phase contrast X-ray tomographic microscopy in cardiovascular small animal applications.