Telomeric position effect--a third silencing mechanism in eukaryotes.
Eukaryotic chromosomes terminate in telomeres, complex nucleoprotein structures that are required for chromosome integrity that are implicated in cellular senescence and cancer. The chromatin at the telomere is unique with characteristics of both heterochromatin and euchromatin. The end of the chromosome is capped by a structure that protects the end and is required for maintaining proper chromosome length. Immediately proximal to the cap are the telomere associated satellite-like (TAS) sequences. Genes inserted into the TAS sequences are silenced indicating the chromatin environment is incompatible with transcription. This silencing phenomenon is called telomeric position effect (TPE). Two other silencing mechanisms have been identified in eukaryotes, suppressors position effect variegation [Su(var)s, greater than 30 members] and Polycomb group proteins (PcG, approximately 15 members). We tested a large number of each group for their ability to suppress TPE [Su(TPE)]. Our results showed that only three Su(var)s and only one PcG member are involved in TPE, suggesting silencing in the TAS sequences occurs via a novel silencing mechanism. Since, prior to this study, only five genes have been identified that are Su(TPE)s, we conducted a candidate screen for Su(TPE) in Drosophila by testing point mutations in, and deficiencies for, proteins involved in chromatin metabolism. Screening with point mutations identified seven new Su(TPE)s and the deficiencies identified 19 regions of the Drosophila genome that harbor suppressor mutations. Chromatin immunoprecipitation experiments on a subset of the new Su(TPE)s confirm they act directly on the gene inserted into the telomere. Since the Su(TPE)s do not overlap significantly with either PcGs or Su(var)s, and the candidates were selected because they are involved generally in chromatin metabolism and act at a wide variety of sites within the genome, we propose that the Su(TPE) represent a third, widely used, silencing mechanism in the eukaryotic genome.


Regulation of T-cell-receptor-stimulated bivalent-cation entry in Jurkat E6 cells: role of protein kinase C.
Stimulation of Jurkat E6 cells with anti-CD3 antibody results in a characteristic rise in [Ca2+]i which is due to both the release of Ca2+ from intracellular stores and the entry of external Ca2+. Individual components of the [Ca2+]i increase were investigated by measuring intracellular Ca2+ release in the absence of external Ca2+ and determining influx of bivalent cations by following the entry of Mn2+. The increase in [Ca2+]i induced by anti-CD3 antibody in the presence or absence of extracellular Ca2+ could be inhibited by the non-selective kinase inhibitor staurosporine, which also inhibits anti-CD3-stimulated phospholipase C activity. Staurosporine also inhibits the influx of bivalent cations induced by anti-CD3 antibody, but not that induced by depletion of intracellular Ca2+ stores using thapsigargin. The effect of staurosporine was compared with that of Ro 31-8425, a potent and selective inhibitor of protein kinase C (PKC). Ro 31-8425, at concentrations up to 10 microM, has no inhibitory effect on the anti-CD3 antibody-induced [Ca2+]i increase or phospholipase C activity. These studies are consistent with the concept that augmentation of [Ca2+]i by stimulated T-cell receptors requires activation of a kinase, probably a tyrosine kinase such as p56lck, ZAP-70 or p59fyn, and is independent of PKC. Phorbol esters inhibit the anti-CD3-stimulated [Ca2+]i increase and phospholipase C activity, showing that this can be negatively regulated by PKC. A small potentiation of the anti-CD3 antibody-induced [Ca2+]i rise in the presence of extracellular Ca2+ was detected in the presence of Ro 31-8425; this suggests that T-cell-receptor ligation can also limit the increase in [Ca2+]i via PKC activation.


An Association between Carpal Tunnel Syndrome and Migraine Headaches-National Health Interview Survey, 2010.
Migraine headaches have not historically been considered a compression neuropathy. Recent studies suggest that some migraines are successfully treated by targeted peripheral nerve decompression. Other compression neuropathies have previously been associated with one another. The goal of this study is to evaluate whether an association exists between migraines and carpal tunnel syndrome (CTS), the most common compression neuropathy. Data from 25,880 respondents of the cross-sectional 2010 National Health Interview Survey were used to calculate nationally representative prevalence estimates and 95% confidence intervals (95% CIs) of CTS and migraine headaches. Logistic regression was used to calculate adjusted odds ratios (aORs) and 95% CI for the degree of association between migraines and CTS after controlling for known demographic and health-related factors. CTS was associated with older age, female gender, obesity, diabetes, and smoking. CTS was less common in Hispanics and Asians. Migraine was associated with younger age, female gender, obesity, diabetes, and current smoking. Migraine was less common in Asians. Migraine prevalence was 34% in those with CTS compared with 16% in those without CTS (aOR, 2.60; 95% CI, 2.16-3.13). CTS prevalence in patients with migraine headache was 8% compared with 3% in those without migraine headache (aOR, 2.67; 95% CI, 2.22-3.22). This study is the first to demonstrate an association between CTS and migraine headache. Longitudinal and genetic studies with physician verification of migraine headaches and CTS are needed to further define this association.


Single-dose MGTA-145/plerixafor leads to efficient mobilization and in vivo transduction of HSCs with thalassemia correction in mice.
We have developed an in vivo hemopoietic stem cell (HSC) gene therapy approach without the need for myelosuppressive conditioning and autologous HSC transplantation. It involves HSC mobilization and IV injection of a helper-dependent adenovirus HDAd5/35++ vector system. The current mobilization regimen consists of granulocyte colony-stimulating factor (G-CSF) injections over a 4-day period, followed by the administration of plerixafor/AMD3100. We tested a simpler, 2-hour, G-CSF-free mobilization regimen using truncated GRO-β (MGTA-145; a CXCR2 agonist) and plerixafor in the context of in vivo HSC transduction in mice. The MGTA-145+plerixafor combination resulted in robust mobilization of HSCs. Importantly, compared with G-CSF+plerixafor, MGTA-145+plerixafor led to significantly less leukocytosis and no elevation of serum interleukin-6 levels and was thus likely to be less toxic. With both mobilization regimens, after in vivo selection with O6-benzylguanine (O6BG)/BCNU, stable GFP marking was achieved in >90% of peripheral blood mononuclear cells. Genome-wide analysis showed random, multiclonal vector integration. In vivo HSC transduction after mobilization with MGTA-145+plerixafor in a mouse model for thalassemia resulted in >95% human γ-globin+ erythrocytes at a level of 36% of mouse β-globin. Phenotypic analyses showed a complete correction of thalassemia. The γ-globin marking percentage and level were maintained in secondary recipients, further demonstrating that MGTA145+plerixafor mobilizes long-term repopulating HSCs. Our study indicates that brief exposure to MGTA-145+plerixafor may be advantageous as a mobilization regimen for in vivo HSC gene therapy applications across diseases, including thalassemia and sickle cell disease.


In vitro effects of several surface preparation methods on shear bond strength of orthodontic brackets to caries-like lesions of enamel.
The aim of this study was to evaluate the efficiency of several surface preparation methods for improving shear bond strength of brackets to demineralised enamel. in vitro study. Eighty premolars were selected and divided into 5 groups. Group 1 served as the control, while the remaining 4 groups were immersed in a demineralising solution (pH 4.8) for 12 weeks. In groups 1 (control) and 2 (demineralised/control) conventional acid etching was used. In group 3, a solution of 5% sodium hypochlorite (NaOCl) was applied on enamel surface for one minute after acid etching. The brackets in group 4 were bonded with Transbond Plus self-etching primer, and group 5 underwent treatment with a 2% sodium fluoride (NaF) gel, which was applied on the enamel surface for 4 minutes before etching. Shear bond strength (SBS) and adhesive remnant index (ARI) were determined in all groups, and surface morphology was examined under scanning electron microscope (SEM). The mean SBS of acid-etched demineralised enamel was significantly lower than that of acid-etched sound enamel (p<0.05). Treatment of caries-like lesions with 5% NaOCl or self-etching primer failed to improve the bond strength. After NaF treatment and acid etching of demineralised enamel, both type 1 and type 2 etching patterns were observed and the resulting SBS was comparable to that of sound enamel (p>0.05). The application of 2% NaF on enamel caries before bracket bonding is an effective way for enhancing the bond strength.


Management of high-energy acetabular fractures in the elderly individuals: a current review.
Acetabular fractures in the elderly individuals are increasing in prevalence. Although there is evidence in the literature that acetabular fractures in elderly patients sustained as a result of low-energy mechanisms can be well treated by nonoperative management, open reduction and internal fixation, or even acute arthroplasty, almost no literature exists that may appropriately guide the treatment of elderly acetabular fractures that occur as a result of high-energy mechanisms. In spite of this lack of evidence, specific principles for providing the best care in adult trauma patients may reasonably be adopted. These principles include aggressive resuscitation and medical optimization; surgical care that focuses on a patient's survival but does not sacrifice skeletal stability; and early mobilization. Best practices that guide the care of hip fracture patients, such as a team approach to care, the use of protocols to guide treatment, and the timing of surgery to occur as soon as is safely possible also should be employed to guide care in patients who have sustained acetabular fractures. Opportunity exists to better study these higher energy fractures and to, thereby, affect outcomes in patients who have sustained them.


Phylogenetic analysis of nitrite, nitric oxide, and nitrous oxide respiratory enzymes reveal a complex evolutionary history for denitrification.
Denitrification is a facultative respiratory pathway in which nitrite (NO2(-)), nitric oxide (NO), and nitrous oxide (N2O) are successively reduced to nitrogen gas (N(2)), effectively closing the nitrogen cycle. The ability to denitrify is widely dispersed among prokaryotes, and this polyphyletic distribution has raised the possibility of horizontal gene transfer (HGT) having a substantial role in the evolution of denitrification. Comparisons of 16S rRNA and denitrification gene phylogenies in recent studies support this possibility; however, these results remain speculative as they are based on visual comparisons of phylogenies from partial sequences. We reanalyzed publicly available nirS, nirK, norB, and nosZ partial sequences using Bayesian and maximum likelihood phylogenetic inference. Concomitant analysis of denitrification genes with 16S rRNA sequences from the same organisms showed substantial differences between the trees, which were supported by examining the posterior probability of monophyletic constraints at different taxonomic levels. Although these differences suggest HGT of denitrification genes, the presence of structural variants for nirK, norB, and nosZ makes it difficult to determine HGT from other evolutionary events. Additional analysis using phylogenetic networks and likelihood ratio tests of phylogenies based on full-length sequences retrieved from genomes also revealed significant differences in tree topologies among denitrification and 16S rRNA gene phylogenies, with the exception of the nosZ gene phylogeny within the data set of the nirK-harboring genomes. However, inspection of codon usage and G + C content plots from complete genomes gave no evidence for recent HGT. Instead, the close proximity of denitrification gene copies in the genomes of several denitrifying bacteria suggests duplication. Although HGT cannot be ruled out as a factor in the evolution of denitrification genes, our analysis suggests that other phenomena, such gene duplication/divergence and lineage sorting, may have differently influenced the evolution of each denitrification gene.


[Sequential changes in the macrostructure and RNA-synthesizing activity of nucleolar and extranucleolar chromatin from rat liver cells during induction of DNA synthesis].
The dynamics of structural changes and RNA-polymerase activity in rat liver cell chromatin caused by drastic changes in the rates of protein synthesis was investigated. Inhibition of protein synthesis after a single injection of animals with cycloheximide (0.3 mg/100 g of body weight) increased the total condensibility of chromatin. Under these conditions, the stepwise activation of RNA-polymerases I and II correlated with decondensation of chromatin. By the 6-12th hour following cycloheximide injection, a chromatin fraction enriched with RNA-polymerase I and a RNA-polymerase II-rich fraction could be isolated from liver cell nuclei.


Comparative genomics of the major fungal agents of human and animal Sporotrichosis: Sporothrix schenckii and Sporothrix brasiliensis.
The fungal genus Sporothrix includes at least four human pathogenic species. One of these species, S. brasiliensis, is the causal agent of a major ongoing zoonotic outbreak of sporotrichosis in Brazil. Elsewhere, sapronoses are caused by S. schenckii and S. globosa. The major aims on this comparative genomic study are: 1) to explore the presence of virulence factors in S. schenckii and S. brasiliensis; 2) to compare S. brasiliensis, which is cat-transmitted and infects both humans and cats with S. schenckii, mainly a human pathogen; 3) to compare these two species to other human pathogens (Onygenales) with similar thermo-dimorphic behavior and to other plant-associated Sordariomycetes. The genomes of S. schenckii and S. brasiliensis were pyrosequenced to 17x and 20x coverage comprising a total of 32.3 Mb and 33.2 Mb, respectively. Pair-wise genome alignments revealed that the two species are highly syntenic showing 97.5% average sequence identity. Phylogenomic analysis reveals that both species diverged about 3.8-4.9 MYA suggesting a recent event of speciation. Transposable elements comprise respectively 0.34% and 0.62% of the S. schenckii and S. brasiliensis genomes and expansions of Gypsy-like elements was observed reflecting the accumulation of repetitive elements in the S. brasiliensis genome. Mitochondrial genomic comparisons showed the presence of group-I intron encoding homing endonucleases (HE's) exclusively in S. brasiliensis. Analysis of protein family expansions and contractions in the Sporothrix lineage revealed expansion of LysM domain-containing proteins, small GTPases, PKS type1 and leucin-rich proteins. In contrast, a lack of polysaccharide lyase genes that are associated with decay of plants was observed when compared to other Sordariomycetes and dimorphic fungal pathogens, suggesting evolutionary adaptations from a plant pathogenic or saprobic to an animal pathogenic life style. Comparative genomic data suggest a unique ecological shift in the Sporothrix lineage from plant-association to mammalian parasitism, which contributes to the understanding of how environmental interactions may shape fungal virulence. . Moreover, the striking differences found in comparison with other dimorphic fungi revealed that dimorphism in these close relatives of plant-associated Sordariomycetes is a case of convergent evolution, stressing the importance of this morphogenetic change in fungal pathogenesis.


Potential mechanisms for hypoalgesia induced by anti-nerve growth factor immunoglobulin are identified using autoimmune nerve growth factor deprivation.
Nerve growth factor (NGF) antagonism has long been proposed as a chronic pain treatment. In 2010, the FDA suspended clinical trials using tanezumab, a humanized monoclonal anti-NGF antibody, to treat osteoarthritis due to worsening joint damage in 16 patients. Increased physical activity in the absence of acute pain which normally prevents self-harm was purported as a potential cause. Such an adverse effect is consistent with an extension of tanezumab's primary mechanism of action by decreasing pain sensitivity below baseline levels. In animal inflammatory pain models, NGF antagonism decreases intraepidermal nerve fiber (IENF) density and attenuates increases in expression of nociception-related proteins, such as calcitonin gene-related peptide (CGRP) and substance P (SP). Little is known of the effects of NGF antagonism in noninflamed animals and the hypoalgesia that ensues. In the current study, we immunized rats with NGF or cytochrome C (cytC) and examined (1) nocifensive behaviors with thermal latencies, mechanical thresholds, the hot plate test, and the tail flick test, (2) IENF density, and (3) expression of CGRP, SP, voltage-gated sodium channel 1.8 (Nav1.8), and glutaminase in subpopulations of dorsal root ganglion (DRG) neurons separated by size and isolectin B4 (IB4) labeling. Rats with high anti-NGF titers had delayed responses on the hot plate test but no other behavioral abnormalities. Delayed hot plate responses correlated with lower IENF density. CGRP and SP expression was decreased principally in medium (400-800 μm(2)) and small neurons (<400 μm(2)), respectively, regardless of IB4 labeling. Expression of Nav1.8 was only decreased in small and medium IB4 negative neurons. NGF immunization appears to result in a more profound antagonism of NGF than tanezumab therapy, but we hypothesize that decreases in IENF density and nociception-related protein expression are potential mechanisms for tanezumab-induced hypoalgesia.


Undergraduate preparation for prescribing: the views of 2413 UK medical students and recent graduates.
To gather opinions from UK medical students and recent graduates about their undergraduate training to prescribe and their confidence about meeting the relevant competencies identified by the General Medical Council (GMC). We designed a web-based survey that was distributed to UK medical students and first year Foundation doctors (graduation years 2006-2008) via medical schools and postgraduate networks. Analysis was restricted to 2413 responses from students graduating in 2006-2008 from the 25 UK medical schools (mean 96.5 per school) with a complete undergraduate curriculum. Distinct courses and assessments in 'clinical pharmacology & therapeutics (or equivalent)' were identified by 17% and 13%, respectively, with mode of learning described most commonly as 'opportunistic learning during clinical attachments' (41%). Only 38% felt 'confident' about prescription writing and only a minority (35%) had filled in a hospital prescription chart more than three times during training. The majority (74%) felt that the amount of teaching in this area was 'too little' or 'far too little', and most tended to disagree or disagreed that their assessment 'thoroughly tested knowledge and skills' (56%). When asked if they were confident that they would be able to achieve the prescribing competencies set out by the GMC, 42% disagreed or tended to disagree, whereas only 29% agreed or tended to agree. Many respondents clearly perceived a lack of learning opportunities and assessment related to the safe and effective use of drugs and had little confidence that they would meet the competencies identified by the GMC. There is an urgent need to review undergraduate training in this area.


The kininogen gene family in obstructive uropathy.
Obstructive uropathy impairs nephron growth and function and is a major cause of end-stage renal disease in both adults and children. The major focus of this review article is to examine the evidence implicating a role for the kallikrein-kinin system in the pathophysiology of obstructive uropathy. Recent in vivo studies using specific kinin receptor antagonists and transgenic animals overexpressing or lacking various components of the kallikrein-kinin system have documented that kinins are involved in the regulation of renal function and blood pressure. Multiple roles have been proposed for kinins in obstructive uropathy. Renal kallikrein gene expression is suppressed in the kidney with chronic (>7 days) complete ureteral obstruction. In contrast, ureteral obstruction stimulates renin expression, creating a state of intrarenal angiotensin excess and kinin deficiency, which plays an important role in mediating the increased renal vascular resistance and decreased renal blood flow in the obstructed kidney. In addition to their hemodynamic effects, kallikrein and kinins influence tubular functions. For example, kallikrein influences urinary acidification in the distal nephron, suggesting that dysregulation of kallikrein expression may contribute to the acidification defect in the obstructed kidney. Also, kinins exert direct diuretic and natriuretic effects in the collecting duct and may be important in mediating the post-obstructive diuresis after the relief of urinary obstruction. The kinin substrate, kininogen, is a potent inhibitor of lysosomal cysteine proteases. Unlike kallikrein, kininogen synthesis is upregulated in the kidneys and liver of animals with urinary obstruction. By neutralizing cysteine proteases, kininogen may protect the tubular epithelium of obstructed nephrons from excessive apoptosis. The beneficial actions of kinins and kininogens on renal hemodynamics, tubular function, and cell survival suggest that strategies aimed at increasing intrarenal kinins, eg, ACE-kininase II inhibitors and kallikrein gene therapy, may represent a useful adjunct in the medical treatment of obstructive uropathy.


Using apoptosis for targeted cancer therapy by a new gonadotropin releasing hormone-DNA fragmentation factor 40 chimeric protein.
GnRH-based chimeric proteins have been shown to specifically target and kill adenocarcinomas both in vitro and in vivo. The purpose of this study is to construct a new GnRH-based chimeric protein for the treatment of adenocarcinomas in humans. In this study, we constructed and characterized a new chimeric protein, GnRH-DFF40, composed of a new human killing moiety: the apoptotic DNase-DFF40 (DNA fragmentation factor), known also as caspase-activated DNase (CAD). GnRH-DFF40 exhibits DNase activity in vitro. We found that this chimeric protein can target and kill adenocarcinoma cells. Such death occurs via apoptotic pathways, resulting in an increase in the sub-G(1) population, DNA fragmentation, terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL)-positive cells, and morphology typical of apoptotic cells. These apoptotic events involve the mitochondria because we found cytochrome c depletion and caspase-9 and caspase-3 activation. Preliminary in vivo results showed that treatment of colon adenocarcinoma xenografts in nude mice with the new chimeric protein caused a reduction in tumor weight. Because GnRH-DFF40 is a whole human-based chimeric protein when applied to humans, the nonspecific toxicity and immunogenicity seen with bacterial/plant-based chimeric proteins should be avoided. Thus, GnRH-DFF40 is a promising candidate for the treatment of adenocarcinomas in humans.


Analysis of RNA-Seq datasets reveals enrichment of tissue-specific splice variants for nuclear envelope proteins.
Laminopathies yield tissue-specific pathologies, yet arise from mutation of ubiquitously-expressed genes. A little investigated hypothesis to explain this is that the mutated proteins or their partners have tissue-specific splice variants. To test this, we analyzed RNA-Seq datasets, finding novel isoforms or isoform tissue-specificity for: Lap2, linked to cardiomyopathy; Nesprin 2, linked to Emery-Dreifuss muscular dystrophy and Lmo7, that regulates the Emery-Dreifuss muscular dystrophy linked emerin gene. Interestingly, the muscle-specific Lmo7 exon is rich in serine phosphorylation motifs, suggesting regulatory function. Muscle-specific splice variants in non-nuclear envelope proteins linked to other muscular dystrophies were also found. Nucleoporins tissue-specific variants were found for Nup54, Nup133, Nup153 and Nup358/RanBP2. RT-PCR confirmed novel Lmo7 and RanBP2 variants and specific knockdown of the Lmo7 variantreduced myogenic index. Nuclear envelope proteins were enriched for tissue-specific splice variants compared to the rest of the genome, suggesting that splice variants contribute to its tissue-specific functions.


A multicenter study in Malaysia to determine the efficacy and safety of a generic atorvastatin.
A multicenter study was conducted to assess the efficacy of a generic form of Atorvastatin (Ranbaxy's Storvas) in the treatment of Primary Hypercholesterolemia. One hundred and nineteen patients were given 10 mg of Storvas for four weeks and increased to 20 mg if target LDL-Cholesterol was not achieved. LDL-Cholesterol was reduced by 36.6% at four weeks and 37.5% at eight weeks from baseline. Total cholesterol and triglycerides were significantly reduced. There were no drug-related serious adverse events. We conclude that the generic atorvastatin is safe and effective in the treatment of primary hypercholesterolaemia and the results are comparable to published data on innovator atorvastatin.


Structure-function relationships in H+-secreting epithelia.
Stimulation or inhibition of H+ secretion has been associated with characteristic ultrastructural changes in various epithelial cells, including the parietal cell of the gastric mucosa, the carbonic anhydrase (CA)-rich cell of the turtle urinary bladder, and the intercalated (I) cell of the mammalian collecting duct. An electroneutral potassium-activated H+-ATPase is responsible for H+ secretion in the stomach, whereas acidification in the turtle bladder and the mammalian collecting duct is mediated by an electrogenic H+-translocating ATPase. Despite these differences, the parietal cell, the CA-rich cell, and the I cell have several morphological features in common. They are rich in mitochondria, contain numerous tubulovesicular membrane structures in the apical region of the cell, and possess a variable number of microprojections on the luminal surface. After stimulation of H+ secretion there is a significant increase in the surface area of the apical membrane concomitant with a decrease in the tubulovesicular membrane compartment in these cells, as revealed by morphometric analysis. These findings suggest that membrane (possibly containing an H+ pump) is being transferred from the tubulovesicular compartment to the apical plasma membrane on stimulation of H+ secretion. A hypothesis of membrane recycling is proposed to account for the observed morphological changes.


Enhanced photoproduct repair: its role in the DNA damage-resistance phenotype of human malignant melanoma cells.
A fundamental issue in understanding melanoma is to seek the basis for the cellular resistance to DNA damaging agents, which is manifested in vivo as pronounced tumor resistance to therapeutic agents. The published consensus on melanoma has been that exaggerated postreplication recovery (PRR), rather than excision repair, underlies the unusual damage-resistance phenotype. We examined the resistance to the model DNA damaging agent, UV-C, of subclones derived from a human metastatic melanoma cell line. The clones essentially fall into two groups: one with normal and the other with enhanced resistance. We exploited this range to investigate the interrelationships between replication, transcription, and repair of DNA after UV irradiation. Subclones resistant to UV killing were indeed found to possess enhanced rates of PRR and were coresistant to cisplatin. However, we now report an overall elevation of photoproduct repair in both melanoma groups compared to nonmelanoma controls and conclude that this accounts for the resistant melanoma phenotype, including that of enhanced PRR. Repair enhancement may explain chemoresistance, while loss of efficiency of certain functions, such as PRR, due to the intrinsic genetic lability of tumor cells, may generate the class of melanoma subclones exhibiting only normal resistance.


The Effect of Co-Verbal Remote Touch on Electrodermal Activity and Emotional Response in Dyadic Discourse.
This article explores the affective impact of remote touch when used in conjunction with video telecon. Committed couples were recruited to engage in semi-structured discussions after they watched a video clip that contained emotionally charged moments. They used paired touch input and output devices to send upper-arm squeezes to each other in real-time. Users were not told how to use the devices and were free to define the purpose of their use. We examined how remote touch was used and its impact on skin conductance and affective response. We observed 65 different touch intents, which were classified into broader categories. We employed a series of analyses within a framework of behavioral and experiential timescales. Our findings revealed that remote touches created a change in the overall psychological affective experience and skin conductance response. Only remote touches that were judged to be affective elicited significant changes in EDA measurements. Our study demonstrates the affective power of remote touch in video telecommunication, and that off-the-shelf wearable EDA sensing devices can detect such affective impacts. Our findings pave the way for new species of technologies with real-time feedback support for a range of communicative and special needs such as isolation, stress, and anxiety.


Promiscuous mating in the harem-roosting fruit bat, Cynopterus sphinx.
Observations on mating behaviours and strategies guide our understanding of mating systems and variance in reproductive success. However, the presence of cryptic strategies often results in situations where social mating system is not reflective of genetic mating system. We present such a study of the genetic mating system of a harem-forming bat Cynopterus sphinx where harems may not be true indicators of male reproductive success. This temporal study using data from six seasons on paternity reveals that social harem assemblages do not play a role in the mating system, and variance in male reproductive success is lower than expected assuming polygynous mating. Further, simulations reveal that the genetic mating system is statistically indistinguishable from promiscuity. Our results are in contrast to an earlier study that demonstrated high variance in male reproductive success. Although an outcome of behavioural mating patterns, standardized variance in male reproductive success (I(m)) affects the opportunity for sexual selection. To gain a better understanding of the evolutionary implications of promiscuity for mammals in general, we compared our estimates of I(m) and total opportunity for sexual selection (I(m) /I(f), where I(f) is standardized variance in female reproductive success) with those of other known promiscuous species. We observed a broad range of I(m) /I(f) values across known promiscuous species, indicating our poor understanding of the evolutionary implications of promiscuous mating.


Unsustainability of a measles immunisation campaign--rise in measles incidence within 2 years of the campaign.
The 1990 national mass measles immunisation campaign resulted in a marked reduction in measles incidence in Natal/KwaZulu in the first 6 months after the campaign. Data from the measles ward admissions book at Clairwood Hospital were collated for the period 1 January 1989 to 31 May 1992 to assess the sustainability of the effects of the campaign. For the first 12 months after the campaign, measles admissions were consistently low. Thereafter, the number increased steadily, rising sharply to above pre-campaign levels 21 months after the campaign. The age distribution of measles patients indicated that the initial fall in the 10-12-month age group had been reversed in the second year after the campaign, suggesting that the high vaccination coverage achieved for this age group during the campaign had not been maintained. Measles admissions to Clairwood Hospital indicate that the effect of the measles immunisation campaign has not been sustained and that urgent action is required to avert a possible epidemic.


LRRK2 and Rab GTPases.
Leucine-rich repeat kinase 2 (LRRK2) is mutated in familial Parkinson's disease, and pathogenic mutations activate the kinase activity. A tour de force screen by Mann and Alessi and co-workers identified a subset of Rab GTPases as bona fide LRRK2 substrates. Rab GTPases are master regulators of membrane trafficking and this short review will summarize what we know about the connection between LRRK2 and this family of regulatory proteins. While, in most cases, Rab GTPase phosphorylation is predicted to interfere with Rab protein function, the discovery of proteins that show preferential binding to phosphorylated Rabs suggests that more complex interactions may also contribute to mutant LRRK2-mediated pathology.


Parasagittal Approach of Epidural Steroid Injection as a Treatment for Chronic Low Back Pain: A Systematic Review and Meta-Analysis.
Background: Epidural steroid injection (ESI) has proven benefits in controlling chronic low back pain and can be performed via the midline interlaminar (MIL) or transforaminal (TF) approach. A modified interlaminar approach, the parasagittal interlaminar (PIL), has surfaced as a more reliable, safe, and suitable approach to minimize complications related to MIL and TF. Objective: To conduct a systematic review and meta-analysis to assess and compare the effectiveness and safety of PIL with both MIL and TF approaches in adult patients with a history of chronic low back pain. Methods: A literature search was conducted using major electronic databases, such as PubMed, EMBASE, and Cochrane. Selected studies included patients with unilateral radicular symptoms, secondary to lumbar intervertebral disc hernias or degenerative lumbar disc disease, that, additionally, received ESIs via PIL or either MIL or TF under fluoroscopic guidance. Randomized and observational studies with pain relief score and/or functional disability assessment and at least a 2-week follow-up were included. Results: The search led to the initial identification of 174 studies. Following the screening, eight studies were included in the qualitative analysis and seven randomized controlled trials (RCTs) were included in the statistical analysis. PIL showed statistically significantly more pain relief and functional improvement than MIL at 1-, 3-, and 6-month post-procedure. Compared to TF, PIL showed statistically significantly more pain relief at 3- and 6-month after the procedure. Additionally, PIL showed benefits in terms of lower mean fluoroscopy time, less radiation exposure, zero adverse events in all the included studies, no cases of intravascular spread compared with the TF approach, and a higher anterior epidural spread (AES) of PIL compared with TF. Conclusions: Our systematic review and meta-analysis suggest that the PIL approach is an effective and safe alternative to the MIL and TF approaches in patients presenting with chronic low back pain when epidural injections are indicated, demonstrating a higher level of pain relief and a stronger improvement in functionality post-procedure.


Cytotoxicity and chemical composition of women's personal PM2.5 exposures from rural China.
Personal exposure PM samples aid in determining the sources and chemical composition of real-world exposures, particularly in settings with household air pollution. However, their use in toxicological research is limited, despite uncertainty regarding health effects in these settings and evidence of differential toxicity among PM2.5 sources and components. This study used women's PM2.5 exposure samples collected using personal exposure monitoring in rural villages in three Chinese provinces (Beijing, Shanxi, and Sichuan) during summer and winter. Water-soluble organic carbon, ions, elements, and organic tracers (e.g. levoglucosan and polycyclic aromatic hydrocarbons [PAHs]) were quantified in water and organic PM2.5 extracts. Human lung epithelial cells (A549) were exposed to the extracts. Cell death, reactive oxygen species (ROS), and gene expression were measured. Biomass burning contributions were higher in Sichuan samples than in Beijing or Shanxi. Some PM characteristics (total PAHs and coal combustion source contributions) and biological effects of organic extract exposures (cell death, ROS, and cytokine gene expression) shared a common trend of higher levels and effects in winter than in summer for Shanxi and Beijing but no seasonal differences in Sichuan. Modulation of phase I/AhR-related genes (cyp1a1 and cyp1b1) and phase II/oxidative stress-related genes (HO-1, SOD1/2, NQO-1, and catalase) was either low or insignificant, without clear trends between samples. No significant cell death or ROS production was observed for water extract treatments among all sites and seasons, even at possible higher concentrations tested. These results support organic components, particularly PAHs, as essential drivers of biological effects, which is consistent with some other evidence from ambient PM2.5.


A comparison of organochlorine pesticide residues in maternal adipose tissue, maternal blood, cord blood, and human milk from mother/infant pairs.
A total of 41 samples of maternal blood, milk, subcutaneous fat and umbilical cord blood were collected from mothers giving birth by Caesarean operation at Kenyatta National Hospital in Nairobi in 1986. The samples were analyzed for organochlorine contaminants. The main contaminants found in all the samples were p,p'-DDT (100%), p,p'-DDE (100%), o,p'-DDT (59%), dieldrin (27%), transnonachlor (15%), beta-HCH (12%) and lindane (2%) of all the samples analyzed. Polychlorobiphenyl (PCB) residues were not detected in any of the samples. The mean levels (mg/kg fat) of sum of DDT were 5.9 in subcutaneous fat, 4.8 in mothers milk, 2.7 in maternal serum and 1.9 in umbilical cord serum. There was a significant correlation between the levels of sum DDT in subcutaneous fat and milk fat (r = 0.963), subcutaneous fat and maternal serum fat (r = 0.843), and maternal serum fat and maternal milk fat (r = 0.868), indicating the coherence of DDT in the body. Hexachlorocyclohexane (beta-HCH) was found in subcutaneous fat and milk fat with the mean levels of 0.03 and 0.26 mg/kg fat, respectively. Dieldrin detected in mothers milk and subcutaneous fat could not be quantified.


Effects of p,p'-DDE on male reproductive organs in peripubertal Wistar rats following a single intraperitoneal injection.
The effects of p,p'-DDE on male reproductive organs were investigated in detail in peripubertal Wistar rats following a single intraperitoneal injection. 220 mg/kg of p,p'-DDE (1/4 of LD50) were injected once into prepubertal and postpubertal Wistar rats and its effects were observed until 20 weeks of age. Weights of the body and reproductive organs in p,p'-DDE-injected rats were similar to those in control rats, who were injected with corn oil only. Sperm profile parameters such as spermatid number within the testis, sperm number within the epididymis, sperm motility and its morphology were not different between the prepubertal or postpubertal p,p'-DDE-exposed group and the control group. Like-wise, the histopathological examination at stage VII of the seminiferous epithelium cycle, when the germ cells are sensitive to testosterone, was similar in all three groups during the observation period. Serum levels of testosterone also showed no significant changes by exposure to p,p'-DDE under the conditions of this study. From these results, the antiandrogenic or estrogenic activity attributed to p,p'-DDE was not confirmed in male reproductive organs and no impairment of sperm profile was observed. This study confirmed that the reproductive functions of matured animals are scarcely affected by p,p'-DDE exposure during the peripubertal period and revealed that they might be relatively resistant to exogenous endocrine-disrupting chemicals. p,p'-DDE may threaten the hormonal equilibrium required for normal gonadal development during the organogenesis period, at an earlier stage of life. Further studies are necessary to fully reveal all the effects of p,p'-DDE on male reproductive organs and sperm profile.


Hospital standardized mortality ratios: sensitivity analyses on the impact of coding.
Hospital standardized mortality ratios (HSMRs) are derived from administrative databases and cover 80 percent of in-hospital deaths with adjustment for available case mix variables. They have been criticized for being sensitive to issues such as clinical coding but on the basis of limited quantitative evidence. In a set of sensitivity analyses, we compared regular HSMRs with HSMRs resulting from a variety of changes, such as a patient-based measure, not adjusting for comorbidity, not adjusting for palliative care, excluding unplanned zero-day stays ending in live discharge, and using more or fewer diagnoses. Overall, regular and variant HSMRs were highly correlated (ρ>0.8), but differences of up to 10 points were common. Two hospitals were particularly affected when palliative care was excluded from the risk models. Excluding unplanned stays ending in same-day live discharge had the least impact despite their high frequency. The largest impacts were seen when capturing postdischarge deaths and using just five high-mortality diagnosis groups. HSMRs in most hospitals changed by only small amounts from the various adjustment methods tried here, though small-to-medium changes were not uncommon. However, the position relative to funnel plot control limits could move in a significant minority even with modest changes in the HSMR.


Somatostatin receptor subtype 2-mediated scintigraphy and localization using (99m)Tc-HYNIC-Tyr(3)-octreotide in human hepatocellular carcinoma-bearing nude mice.
To investigate the uptake of (99m)Tc-HYNIC-Tyr(3)-octreotide ((99m)Tc-HYNIC-TOC) in human hepatocellular carcinoma (HCC), which can provide the localizable diagnosis in hepatic carcinoma. The expression of somatostatin receptor 2 (SSTR2) messenger RNA (mRNA) in human HCC cell line HepG(2) was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). Uptake of (99m)Tc-HYNIC-TOC was evaluated in the human HCC implanted into BALB/c nude mice. ANMIS2000 nuclear medicine analysis system was used to calculate the ratio of (99m)Tc uptake between tumor tissue and vital organs. We demonstrated the expression of SSTR2 mRNA in human HCC cell line HepG(2) by RT-PCR. The size of the RT-PCR products was 364 bp detected by sequence analysis of the human SSTR2 mRNA. Scintigraphy proved that (99m)Tc-HYNIC-TOC was uptaken in the tumor tissue, liver and kidney of the tumor-bearing mice. Based on expression of the SSTR2 mRNA in human HCC, (99m)Tc-HYNIC-TOC can markedly bind with and be uptaken by human HCC tissues as compared with normal liver tissue. The significant retention of radionuclide in kidney and bladder is probably related to non-specific peptide uptake in the tubulus cells of kidney and possibly due to excretion by kidney. Our results show that localizable diagnosis and targeting radiotherapy with radionuclide-labeled somatostatin analog for HCC are of great value to be further studied.


Optical and electron spin resonance studies of xenon-nitrogen-helium condensates containing nitrogen and oxygen atoms.
We present the first observations of excimer XeO* molecules in molecular nitrogen films surrounding xenon cores of nanoclusters. Multishell nanoclusters form upon the fast cooling of a helium jet containing small admixtures of nitrogen and xenon by cold helium vapor (T = 1.5 K). Such nanoclusters injected into superfluid helium aggregate into porous impurity-helium condensates. Passage of helium gas with admixtures through a radio frequency discharge allows the storage of high densities of radicals stabilized in impurity-helium condensates. Intense recombination of the radicals occurs during destruction of such condensates and generates excited species observable because of optical emission. Rich spectra of xenon-oxygen complexes have been detected upon destruction of xenon-nitrogen-helium condensates. A xenon environment quenches metastable N((2)D) atoms but has a much weaker effect on the luminescence of N((2)P) atoms. Electron spin resonance spectra of N((4)S) atoms trapped in xenon-nitrogen-helium condensates have been studied. High local concentrations of nitrogen atoms (up to 10(21) cm(-3)) stabilized in xenon-nitrogen nanoclusters have been revealed.


Rhodotorula septicemia: report of a case.
With the increased use of central venous catheters in cancer patients, there has been an increase in the recovery of environmental and skin organisms from blood cultures. A red yeast, Rhodotorula, an infrequent cause of infection in humans, was isolated from a patient with acute myeloblastic leukemia undergoing bone marrow transplant while he received parenteral nutritional fluids by an indwelling catheter. The patient was clinically ill, as manifested by fever and chills. The patient was treated with amphotericin B and the catheter was removed. He survived the fungemic episode with no recurrence of fungal infection.


Validation of the psychometric properties of the Malay advance care planning questionnaire.
There is a growing interest among the developing countries on advance care planning (ACP) due to the reported benefits of planning ahead in the developed countries. Validated instruments in various languages have been developed to facilitate study on the views of public prior to its implementation. However, instrument to explore the views on ACP in Malay has not been developed and validated yet, even though Malay is spoken extensively by approximately 220 million people in the Malay Archipelago. There is also a need for instrument in Malay language to facilitate the assessment of knowledge, attitude and practice (KAP) of Malaysians regarding ACP. Therefore, the aim of this study was to validate the psychometric properties of the Malay Advance Care Planning Questionnaire (ACPQ-M). The ACPQ was translated according to international guidelines. This validation study was conducted from January to June 2018. Participants who were ≥ 21 years old, and able to understand Malay were recruited from an urban primary care clinic and a tertiary education institution in Malaysia. A researcher administered the ACPQ-M to participants via a face-to-face interview at baseline and 2 weeks later. Each interview took approximately 10-20 min. A total of 222/232 participants agreed to participate (response rate = 96.0%). Exploratory factor analysis and confirmatory factor analysis found that the ACPQ-M was a 4-factor model. The Cronbach's α values for the four domains ranged from 0.674-0.947. Only 157/222 participants completed the test-retest (response rate = 71%). At test-retest, quadratic weighted kappa values for all domains ranged from 0.340-0.674, except for two domains which ranged from - 0.200-0.467. The ACPQ-M was found to be a 4-factor model, and a valid and reliable instrument to assess the KAP regarding ACP. This instrument can contribute to profound understanding of the KAP of Malaysians regarding ACP, and assist policy makers in determining the readiness for legislation of ACP in Malaysia.


Effects of Hexane on Protein Profile, Solubility and Foaming Properties of Defatted Proteins Extracted from Tenebrio molitor Larvae.
Inclusion of edible insects in human diets is increasingly promoted as a sustainable source of proteins with high nutritional value. While consumer acceptability remains the main challenge to their integration into Western food culture, the use of edible insects as meal and protein concentrate could decrease neophobia. The defatting of edible insects, mostly done with hexane, is the first step in producing protein ingredients. However, its impact on protein profiles and techno-functionality is still unclear. Consequently, this study compares the protein profiles of hexane-defatted and non-hexane-defatted yellow mealworm (Tenebrio molitor) meals and protein extracts, and evaluates the impact of hexane on protein solubility and foaming properties. Results showed that profiles for major proteins were similar between hexane-defatted and non-defatted samples, however some specific content differences (e.g., hexamerin 2) were observed and characterized using proteomic tools. Protein solubility was markedly lower for T. molitor meals compared to protein extracts. A large increase in the foaming capacity was observed for defatted fractions, whereas foam stability decreased similarly in all fractions. Consequently, although the hexane-defatting step was largely studied to produce edible insect protein ingredients, it is necessary to precisely understand its impact on their techno-functional properties for the development of food formulations.


A new yeti crab phylogeny: Vent origins with indications of regional extinction in the East Pacific.
The recent discovery of two new species of kiwaid squat lobsters on hydrothermal vents in the Pacific Ocean and in the Pacific sector of the Southern Ocean has prompted a re-analysis of Kiwaid biogeographical history. Using a larger alignment with more fossil calibrated nodes than previously, we consider the precise relationship between Kiwaidae, Chirostylidae and Eumunididae within Chirostyloidea (Decapoda: Anomura) to be still unresolved at present. Additionally, the placement of both new species within a new "Bristly" clade along with the seep-associated Kiwa puravida is most parsimoniously interpreted as supporting a vent origin for the family, rather than a seep-to-vent progression. Fossil-calibrated divergence analysis indicates an origin for the clade around the Eocene-Oligocene boundary in the eastern Pacific ~33-38 Ma, coincident with a lowering of bottom temperatures and increased ventilation in the Pacific deep sea. Likewise, the mid-Miocene (~10-16 Ma) rapid radiation of the new Bristly clade also coincides with a similar cooling event in the tropical East Pacific. The distribution, diversity, tree topology and divergence timing of Kiwaidae in the East Pacific is most consistent with a pattern of extinctions, recolonisations and radiations along fast-spreading ridges in this region and may have been punctuated by large-scale fluctuations in deep-water ventilation and temperature during the Cenozoic; further affecting the viability of Kiwaidae populations along portions of mid-ocean ridge.


Reduction and augmentation mammoplasty.
Women seek reduction mammoplasty for alleviation of their symptoms of mammary hypertrophy, which may include upper back and neck pain, strain, or muscle spasm. Many of these women also desire an improvement in their appearance. Augmentation mammoplasty is sought by women for enlargement of the breasts and to attain a well-proportioned figure. Women who have experienced postpartum involution of the breasts request augmentation mammoplasty to regain the size and shape of their breasts prior to pregnancy. The historical background of these procedures, preoperative evaluation, and technical considerations are presented.


Minimal invasive transforaminal lumbar interbody fusion versus open transforaminal lumbar interbody fusion.
The aim of the present prospective study is to evaluate whether the touted advantages of minimal invasive-transforaminal lumbar interbody fusion (MI-TLIF) translate into superior, equal, or inferior outcomes as compared to open-transforaminal lumbar interbody fusion (O-TLIF). This is the first study from the Indian subcontinent prospectively comparing the outcomes of MI-TLIF and O-TLIF. All consecutive cases of open and MI-TLIF were prospectively followed up. Single-level TLIF procedures for spondylolytic and degenerative conditions (degenerative spondylolisthesis, central disc herniations) operated between January 2011 and January 2013 were included. The pre and postoperative Oswestry Disability Index (ODI) and visual analog scale (VAS) for back pain and leg pain, length of hospital stay, operative time, radiation exposure, quantitative C-reactive protein (QCRP), and blood loss were compared between the two groups. The parameters were statistically analyzed (using IBM® SPSS® Statistics version 17). 129 patients underwent TLIF procedure during the study period of which, 71 patients (46 MI-TLIF and 25 O-TLIF) fulfilled the inclusion criteria. Of these, a further 10 patients were excluded on account of insufficient data and/or no followup. The mean followup was 36.5 months (range 18-54 months). The duration of hospital stay (O-TLIF 5.84 days + 2.249, MI-TLIF 4.11 days + 1.8, P < 0.05) was shorter in MI-TLIF cases. There was less blood loss (open 358.8 ml, MI 111.81 ml, P < 0.05) in MI-TLIF cases. The operative time (O-TLIF 2.96 h + 0.57, MI-TLIF 3.40 h + 0.54, P < 0.05) was longer in MI group. On an average, 57.77 fluoroscopic exposures were required in MI-TLIF which was significantly higher than in O-TLIF (8.2). There was no statistically significant difference in the improvement in ODI and VAS scores in MI-TLIF and O-TLIF groups. The change in QCRP values preoperative and postoperative was significantly lower (P < 0.000) in MI-TLIF group than in O-TLIF group, indicating lesser tissue trauma. The results in MI TLIF are comparable with O-TLIF in terms of outcomes. The advantages of MI-TLIF are lesser blood loss, shorter hospital stay, lesser tissue trauma, and early mobilization. The challenges of MI-TLIF lie in the steep learning curve and significant radiation exposure. The ultimate success of TLIF lies in the execution of the procedure, and in this respect the ability to achieve similar results using a minimally invasive technique makes MI-TLIF an attractive alternative.


Postoperative Purulent Chondritis of Thyroid Cartilage in a Diabetic Patient: A Case Report.
Purulent chondritis of the thyroid cartilage is a rare affliction that is not frequently observed in patients undergoing laryngeal surgery. The formation of abscesses between the inner and outer perichondria can cause constriction of the laryngeal lumen, leading to hoarseness and difficulty breathing. This report details the case of a middle-aged diabetic woman who experienced swelling in the tissue of her laryngeal cavity and destruction of her thyroid cartilage plate after undergoing laryngectomy. The pathological examination revealed evidence of inflammation, and the patient was ultimately diagnosed with purulent chondritis of the thyroid cartilage.


Genomewide scan for adaptive differentiation along altitudinal gradient in the Andrew's toad Bufo andrewsi.
Recent studies of humans, dogs and rodents have started to discover the genetic underpinnings of high altitude adaptations, yet amphibians have received little attention in this respect. To identify possible signatures of adaptation to altitude, we performed a genome scan of 15 557 single nucleotide polymorphisms (SNPs) obtained with restriction site-associated DNA sequencing of pooled samples from 11 populations of Andrew's toad (Bufo andrewsi) from the edge of the Tibetan Plateau, spanning an altitudinal gradient from 1690 to 2768 m.a.s.l. We discovered significant geographic differentiation among all sites, with an average FST = 0.023 across all SNPs. Apart from clear patterns of isolation by distance, we discovered numerous outlier SNPs showing strong associations with variation in altitude (1394 SNPs), average annual temperature (1859 SNPs) or both (1051 SNPs). Levels and patterns of genetic differentiation in these SNPs were consistent with the hypothesis that they have been subject to directional selection and reflect adaptation to altitudinal variation among the study sites. Genes with footprints of selection were significantly enriched in binding and metabolic processes. Several genes potentially related to high altitude adaptation were identified, although the identity and functional significance of most genomic targets of selection remain unknown. In general, the results provide genomic support for results of earlier common garden and low coverage genetic studies that have uncovered substantial adaptive differentiation along altitudinal and latitudinal gradients in amphibians.


Improved oral delivery of N-(4-hydroxyphenyl)retinamide with a novel LYM-X-SORB organized lipid complex.
Fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)] is a cytotoxic retinoid that suffers from a wide interpatient variation in bioavailability when delivered orally in a corn oil capsule. The poor bioavailability of the capsule formulation may have limited responses in clinical trials, and the large capsules are not suitable for young children. To support the hypothesis that a novel organized lipid matrix, LYM-X-SORB, can increase the oral bioavailability of fenretinide, fenretinide in LYM-X-SORB matrix and in a powderized LYM-X-SORB formulation was delivered to mice. Fenretinide was delivered orally to mice as the contents of the corn oil capsule, in LYM-X-SORB matrix (4-HPR/LYM-X-SORB matrix) or in a LYM-X-SORB matrix powderized with sugar and flour (4-HPR/LYM-X-SORB oral powder). Levels of 4-HPR, and its principal metabolite, N-(4-methoxyphenyl)retinamide, were assayed in plasma and tissues. In a dose-responsive manner, from 120 to 360 mg/kg/d, delivery to mice of 4-HPR in LYM-X-SORB matrix, or as 4-HPR/LYM-X-SORB oral powder, increased 4-HPR plasma levels up to 4-fold (P<0.01) and increased tissue levels up to 7-fold (P<0.01) compared with similar doses of 4-HPR delivered using capsule contents. Metabolite [N-(4-methoxyphenyl)retinamide] levels mirrored 4-HPR levels. Two human neuroblastoma murine xenograft models showed increased survival (P<0.03), when treated with 4-HPR/LYM-X-SORB oral powder, confirming the bioactivity of the formulation. 4-HPR/LYM-X-SORB oral powder is a novel, oral drug delivery formulation, suitable for pediatric use, which warrants further development for the delivery of fenretinide in the treatment of cancer. A phase I clinical trial in pediatric neuroblastoma is in progress.


Cholesterol depletion disorganizes oocyte membrane rafts altering mouse fertilization.
Drastic membrane reorganization occurs when mammalian sperm binds to and fuses with the oocyte membrane. Two oocyte protein families are essential for fertilization, tetraspanins and glycosylphosphatidylinositol-anchored proteins. The firsts are associated to tetraspanin-enriched microdomains and the seconds to lipid rafts. Here we report membrane raft involvement in mouse fertilization assessed by cholesterol modulation using methyl-β-cyclodextrin. Cholesterol removal induced: (1) a decrease of the fertilization rate and index; and (2) a delay in the extrusion of the second polar body. Cholesterol repletion recovered the fertilization ability of cholesterol-depleted oocytes, indicating reversibility of these effects. In vivo time-lapse analyses using fluorescent cholesterol permitted to identify the time-point at which the probe is mainly located at the plasma membrane enabling the estimation of the extent of the cholesterol depletion. We confirmed that the mouse oocyte is rich in rafts according to the presence of the raft marker lipid, ganglioside GM1 on the membrane of living oocytes and we identified the coexistence of two types of microdomains, planar rafts and caveolae-like structures, by terms of two differential rafts markers, flotillin-2 and caveolin-1, respectively. Moreover, this is the first report that shows characteristic caveolae-like invaginations in the mouse oocyte identified by electron microscopy. Raft disruption by cholesterol depletion disturbed the subcellular localization of the signal molecule c-Src and the inhibition of Src kinase proteins prevented second polar body extrusion, consistent with a role of Src-related kinases in fertilization via signaling complexes. Our data highlight the functional importance of intact membrane rafts for mouse fertilization and its dependence on cholesterol.


Nature of the Excitatory Sarcoplasmic Reticular Junction.
The appositional regions between the surface membrane and sarcoplasmic reticulum in insects, decapod crustaceans, and barnacles are largely diadic and show a four-layered structure which is roughly circular in surface view. Each consists of the 56-angstrom double-membrane of the in-termediary (here called excitatory) element, and the 75-A double-membrane of the cisternal element of the reticulum, separated by a space of about 100 A. A sheet of electron-dense material is found between the two elements, giving the superficial appearance of an additional membrane. The orbits of thin filaments around the thick filaments adjacent to both excitatory and reticular elements are incomplete on the contact side. Regularly spaced bridges connect the thick filaments with both the excitatory elements and cisternal elements and hold the diads in place during stretch and contraction.


A higher frequency of physical activity is associated with reduced rates of SARS-CoV-2 infection.
Physical activity (PA) is associated with health benefits. Previous studies have shown that regular PA decreases the incidence of viral respiratory tract infections, but data on severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection are unavailable. The objective of this study is to examine the association between PA frequency and SARS-CoV-2 infection. A population-based cross-sectional study was conducted on data from 1 February 2020 to 31 December 2020, using the registry of Leumit Health Services (LHS), a national health maintenance organisation in Israel. All LHS patients aged 18 to 80 years who underwent at least one RT-PCR test for SARS-CoV-2 during the study period were included. We examined the association between PA frequency (hours per week) and being tested positive for SARS-CoV-2. Of 113,075 subjects tested for SARS-CoV-2 by RT-PCR (mean age 41.6 years, 54.4% female), 17,465 (15%) were positive. In the SARS-CoV-2-negative group, significantly more subjects were engaged with PA than in the SARS-CoV-2-positive group [crude odds ratio (OR) for any PA 0.75 (95% confidence interval (CI) 0.72-0.77)]. After adjusting for possible confounders, PA frequency had a significant negative association with the likelihood of being SARS-CoV-2 positive (adjusted OR 0.67, 95% CI 0.64-0.68). Moreover, as the frequency of PA increased, the ORs of being SARS-CoV-2-positive decreased (occasional PA: OR 0.71, 95% CI 0.67-0.74; PA 1-3 times/week: OR 0.62, 95% CI 0.58-0.65 and PA > 3 times/week: OR 0.54, 95% CI 0.49 - 0.59). Our large population-based study in patients undergoing SARS-CoV-2 RT-PCR testing showed that a higher frequency of PA is associated with a lower rate of positive test results.


Enhanced hydrogen photogeneration by bulk g-C3N4 through a simple and efficient oxidation route.
The search for new environment-friendly visible-light absorbing catalysts is an urgent task. g-C3N4 has excellent photocatalytic properties and the possibility of developing cost-effective routes to make this material a viable alternative to the currently used catalysts is required. In this work, we show that a simple chemical oxidation process of g-C3N4 with nitric acid allowed significantly enhancing the hydrogen photogeneration from aqueous triethanolamine, under simulated solar light. An 8-fold improvement of the H2 production, with respect to the pristine sample, was achieved by properly controlling the physical-chemical parameters of the oxidation process, reaching a value of about 4000 μmol g-1 h-1, which is one of the highest hydrogen production rates for bulk g-C3N4. Such high levels of photocatalytic activity result from the combination of improved surface area and changes in the electronic structure induced by the oxidation process.


Modeling logistic performance in quantitative microbial risk assessment.
In quantitative microbial risk assessment (QMRA), food safety in the food chain is modeled and simulated. In general, prevalences, concentrations, and numbers of microorganisms in media are investigated in the different steps from farm to fork. The underlying rates and conditions (such as storage times, temperatures, gas conditions, and their distributions) are determined. However, the logistic chain with its queues (storages, shelves) and mechanisms for ordering products is usually not taken into account. As a consequence, storage times-mutually dependent in successive steps in the chain-cannot be described adequately. This may have a great impact on the tails of risk distributions. Because food safety risks are generally very small, it is crucial to model the tails of (underlying) distributions as accurately as possible. Logistic performance can be modeled by describing the underlying planning and scheduling mechanisms in discrete-event modeling. This is common practice in operations research, specifically in supply chain management. In this article, we present the application of discrete-event modeling in the context of a QMRA for Listeria monocytogenes in fresh-cut iceberg lettuce. We show the potential value of discrete-event modeling in QMRA by calculating logistic interventions (modifications in the logistic chain) and determining their significance with respect to food safety.


Polycyclic aromatic hydrocarbons in the work atmosphere. I. Determination in an aluminum reduction plant.
The content of polycyclic aromatic hydrocarbons (PAH) in a Søderberg prebaked aluminum reduction plant and an anode plant was studied. Both stationary and personal sampling were used, and the samples were analyzed by glass capillary gas chromatography. In many samples more than 30 PAH and heterocyclic compounds were identified. Comparison of the results from the different plants revealed that the atmospheric PAH content was significantly higher in the Søderberg plant than in the others. However, the relative distribution of PAH components (PAH profile) was relatively constant in the prebaked and the anode baking plant, and different in the Søderberg plant. As a consequence of the variation in the pollution level among the different job categories, personal sampling showed a broader range of PAH concentrations than the stationary method.


[Autoimmune limbic encephalitis: importance of early diagnosis and treatment].
Autoimmune limbic encephalitis is a rare disorder, characterised by the subacute onset of seizures, short-term memory loss, and psychiatric and behavioural symptoms. Initially, it was recognised as a paraneoplastic disorder, but recently a subgroup of patients without systemic cancer was identified. This type of limbic encephalitis is associated with voltage-gated potassium channel (VGKC) or N-methyl-D-aspartate receptor (NMDAR) antibodies. We describe a 69-year-old man with anti-VGKC limbic encephalitis suffering from generalised tonic-clonic seizures, severe insomnia, increasing memory deficits, visual hallucinations and depression. We also describe a 22-year-old woman, suffering from complex partial seizures and dysphasia, and displaying inappropriate behaviour. She was diagnosed with anti-NMDAR limbic encephalitis. Both showed marked improvement after starting prednisone and intravenous immunoglobulin therapy. These case descriptions emphasise the importance of timely recognition of autoimmune limbic encephalitis in order to rule out malignancy and to quickly initiate treatment. This potentially life-threatening disease responds well to immunomodulatory therapy.


[Tumors of the small intestine].
Peculiarities of the clinical picture, diagnosis and surgical treatment of the small intestine tumors are considered in the paper, as well as immediate and late results of the treatment. The results of the treatment of 14 cases of the small intestine tumors are summed up (6 benign neoplasms and 8 malignant ones). The authors have come to the conclusion that in the most of cases tumors of the small intestine remain symptom-free for a long time; not infrequently they are complicated with intestinal ileus, perforation of the tumor and peritonitis. Resection of the portion of the intestine with tumors and of a segment of the mesentery with the removal of the enlarged regional lymph nodes provides an only radical method of the treatment. An original scheme of the small intestine tumors localization is set forth in the paper.


Flowers in flour: avalanches in cohesive granular matter.
We report on the intermittent dynamics of the free surface of a cohesive granular material during a silo discharge. In absence of cohesion, one observes the formation and the growth of a conical crater whose angle is well defined and constant in time. When the cohesion is involved the free surface exhibits a complex dynamics and the crater, resulting from a series of individual avalanches, is no longer axisymmetric. However, in spite of the intermittent behavior of the free surface, the flow rate is observed to remain constant throughout the discharge.


Advanced Maillard reaction end products are associated with Alzheimer disease pathology.
During aging long-lived proteins accumulate specific post-translational modifications. One family of modifications, termed Maillard reaction products, are initiated by the condensation between amino groups of proteins and reducing sugars. Protein modification by the Maillard reaction is associated with crosslink formation, decreased protein solubility, and increased protease resistance. Here, we present evidence that the characteristic pathological structures associated with Alzheimer disease contain modifications typical of advanced Maillard reaction end products. Specifically, antibodies against two Maillard end products, pyrraline and pentosidine, immunocytochemically label neurofibrillary tangles and senile plaques in brain tissue from patients with Alzheimer disease. In contrast, little or no staining is observed in apparently healthy neurons of the same brain. The Maillard-reaction-related modifications described herein could account for the biochemical and insolubility properties of the lesions of Alzheimer disease through the formation of protein crosslinks.


DNA sequence of the adenovirus type 41 hexon gene and predicted structure of the protein.
The gene for the major capsid protein (hexon) of human adenovirus type 41 (Ad41) has been isolated and the complete DNA sequence determined. Comparison of the predicted amino acid sequence with hexons from human Ad2 and Ad5 and bovine adenovirus type 3 reveals regions of high homology at the N and C termini separated by a central region of low homology. Fitting of the Ad41 hexon sequence to the known three-dimensional structure of the Ad2 hexon demonstrates that both hexons have a common architecture. Regions of the hexon which in the trimer constitute the pseudohexagonal base are highly conserved, with the major amino acid changes concentrated in the domains forming the triangular towers which represent the surface of the capsid. Changes in the Ad41 towers therefore permit the virus to present a unique surface to the environment while conservation of residues in the base maintains the integrity of hexon-hexon contacts. A striking difference is the absence in the Ad41 sequence of 32 amino acids which are present in the Ad2 sequence. In Ad2 this region is highly charged and may be responsible for pH-induced conformational changes within the virus capsid. The DNA sequence in the region surrounding the Ad41 hexon gene was also determined and revealed an open reading frame which appeared to code for the homologue of the Ad2-coded endoprotease. Comparison of the predicted amino acid sequences of the Ad41 and Ad2 proteins revealed a high degree of homology suggesting that this protein may have an important role in the infectious cycle of the virus.


Factors affecting occlusion pressure and ischemic preconditioning.
To determine the effect of limb selection (upper/lower), cuff width (small (6 cm)/medium (13 cm) upper; medium/large (18 cm) lower) and anthropometry on arterial occlusion pressure (AOP) in ischemic preconditioning (IPC). Twenty athletes (10 females and 10 males) had surface anthropometry and dual x-ray absorptiometry (DXA) assessments before using Doppler ultrasound to confirm AOP for each limb. Subsequently, 5 min of occlusion occurred, with near-infrared spectroscopy (NIRS) measuring muscle oxygenation changes. Resultant AOP was compared between sexes, limbs and cuff sizes using linear regression models. Mean AOP was higher in the lower limbs than the upper limbs (161 ± 18 vs. 133 ± 12 mm Hg; p < .001), and with smaller cuffs in upper (161 ± 16 vs. 133 ± 12 mm Hg; p < .001), but not lower limbs (161 ± 16 vs. 170 ± 26 mm Hg; p = .222). Sex and resting systolic blood pressure (SBP) accounted for 77% (small cuff) to 83% (medium cuff) of variance in AOP for upper limbs, and 61% (medium cuff) to 63% (large cuff) in lower limbs. Including anthropometry accounted for 82% (small cuff) to 89% (medium cuff) and 78% (medium cuff) to 79% (large cuff) of variance for upper and lower limbs, respectively. Adding DXA variables improved the explained variance up to 83% (small cuff) to 91% (medium cuff) and 79% (medium cuff) to 87% (large cuff) for upper and lower limbs, respectively. NIRS data showed significantly greater tissue oxygenation changes in upper versus lower limbs. The AOP in athletes is dependent on limb occluded, sex, SBP, limb and cuff size, and body composition.


Shaping Workflows in Digital and Remote Diabetes Care During the COVID-19 Pandemic via Service Design: Prospective, Longitudinal, Open-label Feasibility Trial.
The COVID-19 pandemic poses new challenges to health care providers and the delivery of continuous care. Although many diabetes technologies, such as insulin pumps and continuous glucose monitors, have been established, the data from these devices are rarely assessed. Furthermore, telemedicine has not been sufficiently integrated into clinical workflows. We sought to remotely support children with type 1 diabetes and their caregivers, enhance the clinical outcomes and quality of life of children with diabetes, increase multiple stakeholders' engagement with digital care via a participatory approach, evaluate the feasibility of using an interoperable open-source platform in a university hospital setting, and analyze the success factors and barriers of transitioning from conventional care to digital care. Service design methods were used to adapt clinical workflows. Remote consultations were performed on a monthly and on-demand basis. Diabetes device data were uploaded from patients' homes to an open-source platform. Clinical and patient-reported outcomes were assessed before, during, and after the COVID-19 lockdown period in Germany. A total of 28 children with type 1 diabetes and their caregivers enrolled in this study and completed 6 months of remote visits. Of these 28 participants, 16 (57%) also opted to attend at least one of their regular visits remotely. After 3 months of remote visits, participants' time in range (P=.001) and time in hyperglycemia (P=.004) significantly improved, and their time in hypoglycemia did not increase. These improvements were maintained during the COVID-19 lockdown period (ie, between months 3 and 6 of this study). Participants' psychosocial health improved after 6 months. Remote consultations and commonly shared data access can improve the clinical outcomes and quality of life of children with type 1 diabetes, even during challenging circumstances. A service design approach helped with the delivery of comprehensive and holistic solutions that accounted for the needs of multiple stakeholders. Our findings can inform the future integration of digital tools into clinical care during and beyond the pandemic. German Clinical Trials Register DRKS00016170; https://tinyurl.com/skz4wdk5.


Propofol Use in Pediatric Patients With Food Allergy and Eosinophilic Esophagitis.
Propofol is a safe, well-tolerated anesthetic that is labeled as contraindicated in patients with egg or soy allergy. This contraindication has become increasingly problematic given the rising incidence of food allergy and eosinophilic esophagitis (EoE). To address this issue, we studied practice patterns of propofol use for esophagogastroduodenoscopies in children with EoE and food allergies at our institution. A retrospective observational study of 1365 esophagogastroduodenoscopies from January 2013 to June 2014 was performed. Data were analyzed using Student t tests, chi square tests, Fisher exact tests, and multivariable logistic regression. We found that propofol was used significantly less in patients with egg or soy allergy, and in patients with EoE, even after adjusting for the presence of food allergy. There was no difference in complication rates relative to propofol use. Propofol was used safely in pediatric patients with EoE and food allergy in this limited single-center review.


A perturbation-based balance training program for older adults: study protocol for a randomised controlled trial.
Previous research investigating exercise as a means of falls prevention in older adults has shown mixed results. Lack of specificity of the intervention may be an important factor contributing to negative results. Change-in-support (CIS) balance reactions, which involve very rapid stepping or grasping movements of the limbs, play a critical role in preventing falls; hence, a training program that improves ability to execute effective CIS reactions could potentially have a profound effect in reducing risk of falling. This paper describes: 1) the development of a perturbation-based balance training program that targets specific previously-reported age-related impairments in CIS reactions, and 2) a study protocol to evaluate the efficacy of this new training program. The training program involves use of unpredictable, multi-directional moving-platform perturbations to evoke stepping and grasping reactions. Perturbation magnitude is gradually increased over the course of the 6-week program, and concurrent cognitive and movement tasks are included during later sessions. The program was developed in accordance with well-established principles of motor learning, such as individualisation, specificity, overload, adaptation-progression and variability. Specific goals are to reduce the frequency of multiple-step responses, reduce the frequency of collisions between the stepping foot and stance leg, and increase the speed of grasping reactions. A randomised control trial will be performed to evaluate the efficacy of the training program. A total of 30 community-dwelling older adults (age 64-80) with a recent history of instability or falling will be assigned to either the perturbation-based training or a control group (flexibility/relaxation training), using a stratified randomisation that controls for gender, age and baseline stepping/grasping performance. CIS reactions will be tested immediately before and after the six weeks of training, using platform perturbations as well as a distinctly different method of perturbation (waist pulls) in order to evaluate the generalisability of the training effects. This study will determine whether perturbation-based balance training can help to reverse specific age-related impairments in balance-recovery reactions. These results will help to guide the development of more effective falls prevention programs, which may ultimately lead to reduced health-care costs and enhanced mobility, independence and quality of life.


Coelomycetous Fungi in the Clinical Setting: Morphological Convergence and Cryptic Diversity.
Human infections by coelomycetous fungi are becoming more frequent and range from superficial to systemic dissemination. Traumatic implantation of contaminated plant material is the most common cause. The typical morphological feature of these fungi is the production of asexual spores (conidia) within fruiting bodies called conidiomata. This study aimed to determine the distribution of the coelomycetes in clinical samples by a phenotypic and molecular study of a large set of isolates received from a U.S. reference mycological institution and by obtaining the in vitro antifungal susceptibility pattern of nine antifungals against a selected group of isolates. A total of 230 isolates were identified by sequencing the D1 and D2 domains of the large subunit (LSU) nuclear ribosomal RNA (nrRNA) gene and by morphological characterization. Eleven orders of the phylum Ascomycota were identified: Pleosporales (the largest group; 66.1%), Botryosphaeriales (19.57%), Glomerellales (4.35%), Diaporthales (3.48%), Xylariales (2.17%), Hysteriales and Valsariales (0.87%), and Capnodiales, Helotiales, Hypocreales and Magnaporthales (0.43% each). The most prevalent species were Neoscytalidium dimidiatum, Paraconiothyrium spp., Phoma herbarum, Didymella heteroderae, and Epicoccum sorghinum The most common anatomical site of isolation was superficial tissue (66.5%), followed by the respiratory tract (17.4%). Most of the isolates tested were susceptible to the majority of antifungals, and only flucytosine showed poor antifungal activity.


Classification of ocular allergy.
The purpose of this article is to summarize the clinical presentations associated with the classification of ocular allergy. This article also serves to summarize recent findings of pathophysiological mechanisms associated with ocular allergy and to highlight recently improved diagnostic methods for ocular allergic inflammation. The term allergic conjunctivitis may not sufficiently describe all forms of allergic eye disease, thus a new classification system is desirable, preferably derived from the varied pathophysiological mechanisms operating in the different forms of ocular allergy. Recent published material has further characterized the roles that inflammatory and structural cells have in ocular allergic inflammation. Improved diagnostic methods have also been developed to assess the underlying causes of ocular allergy. The underlying immune responses of ocular allergies are complex, indicating the critical need to understand the pathophysiology behind these diseases. Extensive research over the past several years has provided valuable insight into understanding the pathophysiology associated with the different forms of allergic conjunctivitis. Further clarification of the mechanisms associated with different forms of ocular allergy is essential for improved methods of classification, diagnosis, and treatment.


Paris vs. Prague: A "Suspicion of Fraud": Ernst Mach Argues over Photographs and Epistemological Prerequisites.
Argument In spring 1888, an anonymous critic raised severe doubts about Ernst Mach's and Peter Salcher's studies, published one year before, on the processes in the air caused by very rapid projectiles. Paraphrasing the experiments for the French popular science magazine La Nature, the critic insinuated that the photographs upon which Mach and Salcher's argument were ostensibly based must have been of such low quality that they did not allow any well-founded conclusion. The critic did not deny the phenomena Mach and Salcher had presented in their article; he denied that the photographs taken in the course of the experiments could permit any observation of the phenomena. I take the resulting quarrel as a window into the actors' ideas on the requirements of "good observations" and the role of technical devices in this case. In particular I enquire how the various arguments relate to Lorraine Daston's and Peter Galison's framing of photography as an emblem of "mechanical objectivity." We will see that in the case under debate, actors considered naked-eye observation, observation by telescope and photography mainly with regard to the challenges of the particular research object.


Effects of amoxicillin treatment on the salivary microbiota in children with acute otitis media.
Amoxicillin is a first-line antibiotic treatment for acute otitis media in children and one of the most commonly used antibiotics for human bacterial infections. We investigated changes in salivary bacterial communities among children treated with amoxicillin for acute otitis media (n = 18), using a culture-independent approach based on pyrosequencing of the V3 region of the bacterial 16S rRNA gene. The control group consisted of children with acute otitis media who were not given antibiotics (n = 15). One species-level phylotype assigned to the genus Streptococcus was identified across all (n = 99) saliva samples. Two additional species-level phylotypes from the genera Gemella and Granulicatella were shared by all (n = 45) samples of control subjects. Amoxicillin treatment resulted in reduced species richness and diversity, and a significant shift in the relative abundance of 35 taxa at different ranks from phylum to species-level phylotype. At the phylum level, prevalence of TM7 and Actinobacteria decreased at the end of treatment, whereas Proteobacteria had a higher relative abundance post-treatment. Multivariate analysis showed that samples from the same control subject taken over time intervals tended to cluster together. Among antibiotic-treated subjects, samples taken before and at the end of amoxicillin treatment formed two relatively well-separated clusters both of which greatly overlapped with samples taken about 3 weeks post-treatment. Our results point to a substantial but incomplete recovery of the salivary bacterial community from the antibiotic about 3 weeks after the end of treatment.


Spontaneous chylothorax in a 2-year-old child.
A previously well 2-year-old girl presented with acute respiratory distress. After multiple investigations she was diagnosed with spontaneous chylothorax, attributed to strenuous vomiting. To our knowledge, this is the second reported case of spontaneous chylothorax occurring after the neonatal period.


Variation in Practice Patterns for Listing Patients for Renal Transplantation in the United Kingdom: A National Survey.
Despite the availability of guidelines for the evaluation of candidates for renal transplantation, variation in access to transplantation exists. This national survey investigates whether center variation exists in the assessment of patients for renal transplantation in the United Kingdom. An online survey, informed by qualitative interviews, was distributed to all UK renal centers. This survey examined center approaches to chronic kidney disease service provision, transplant recipient assessment, education provision, and waitlisting decision making processes. Center reevaluation policies for patients already listed and priorities for future development were also examined. All 71 renal centers responded. Of these, 83% reviewed predialysis patients in a low clearance clinic. In 26% of the centers, transplantation was not discussed as a treatment option with all patients. Fourteen centers reported having a dedicated transplant assessment clinic, whereas 28% did not have a formal assessment protocol. Age was an exclusion criterion for listing in 3 centers, all of which had a cutoff at 75 years. Eighty-three percent of the centers excluded patients with a high body mass index. Cardiac investigations were risk-stratified in 90% of centers. Surgical involvement varied with 11% of centers listing patients without formal surgical review. There was no formal protocol in place to reevaluate listed patients in 62% of centers. There is wide variation in UK practice patterns for listing patients for renal transplantation, though its impact on access to transplantation is unclear. The extent to which center-specific and patient-specific factors affect access to transplantation requires further analysis in a prospective cohort of patients.


Acupuncture Resolves Persistent Pain and Neuroinflammation in a Mouse Model of Chronic Overlapping Pain Conditions.
Patients with chronic overlapping pain conditions have decreased levels of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. Consistent with clinical syndromes, we previously demonstrated that COMT inhibition in rodents produces persistent pain and heightened immune responses. Here, we sought to determine the efficacy of manual acupuncture in resolving persistent pain and neuroinflammation in the classic inbred C57BL/6 strain and the rapid-wound healing MRL/MpJ strain. Mice received subcutaneous osmotic minipumps to deliver the COMT inhibitor OR486 or vehicle for 13 days. On day 7 after pump implantation, acupuncture was performed at the Zusanli (ST36) point or a non-acupoint for 6 consecutive days. Behavioral responses to mechanical stimuli were measured throughout the experiment. Immunohistochemical analysis of spinal phosphorylated p38 mitogen-activated protein kinase, a marker of inflammation, and glial fibrillary acidic protein, a marker of astrogliosis, was performed on day 13. Results demonstrated that ST36, but not sham, acupuncture resolved mechanical hypersensitivity and reduced OR486-dependent increases in phosphorylated p38 and glial fibrillary acidic protein in both strains. The magnitude of the analgesic response was greater in MRL/MpJ mice. These findings indicate acupuncture as an effective treatment for persistent pain linked to abnormalities in catecholamine signaling and, furthermore, that analgesic efficacy may be influenced by genetic differences. PERSPECTIVE: Chronic overlapping pain conditions remain ineffectively managed by conventional pharmacotherapies. Here, we demonstrate that acupuncture alleviates persistent pain and neuroinflammation linked to heightened catecholaminergic tone. Mice with superior healing capacity exhibit greater analgesic efficacy. Findings indicate acupuncture as an effective treatment for chronic overlapping pain conditions and provide insight into treatment response variability.


Interweaving in/on the Air: A Scripted Synthesis of Indigenous and Settler Knowledges for Environmental Protection in Resource Development.
The ever-rising threat of environmental catastrophe and the continuing displacement, dishonor, and attempted erasure of Indigenous Peoples and their traditional lands are linked by capitalism's externalizing the costs of conquest, whether ecological or human. This work investigates efforts to address these intertwined issues of social, economic, and environmental justice through interweaving Indigenous and settler ways of knowing in resource-development projects in Canada. In seeking to dramatize the need for further informed and engaged public dialogue on how to redress the twin menaces of extractivism and colonization, this arts-based research unfolds as a script for a semi-satirical radio play or podcast. Here, our researcher seeks to explain research findings and advance environmental protection and decolonization on a radio talk show, only to be confronted by a skeptical host and a battery of opinionated guests reflecting real-world challenges to those two emancipatory goals. We close with a brief methodological reflection.


The Association Between Longevity-Associated FOXO3 Allele and Heart Disease in Septuagenarians and Octogenarians: The SONIC Study.
The G allele of FOXO3 gene (single-nucleotide polymorphism; rs2802292) is strongly associated with human longevity. However, knowledge of the effect of FOXO3 in older populations, men or women, with heart disease is limited. This cross-sectional study in Japan included 1836 older adults in the 70- and 80-year-old groups. DNA samples isolated from buffy coat samples of peripheral blood were used to genotype FOXO3 (rs2802292). Self-reports were used to obtain heart disease data according to physician diagnosis. Multiple logistic regression was used to test the association by adjusting for the traditional risk factor of heart disease. The prevalence of heart disease in women FOXO3 G-allele carriers was higher than noncarriers (16.7% vs 11.6%, p = .022). The prevalence of coronary heart disease was lower for FOXO3 G carriers in the 70-year-old group for both sexes (men: 9.3% vs 4.3%, p = .042 and women: 10% vs 9%, p = .079, respectively). The G allele was negatively associated with heart disease after adjusting for diabetes, hypertension, dyslipidemia, and smoking in men (odds ratio [OR] = 0.70, 95% confidence intervals [CIs], 0.49-0.99, p = .046), although the association was weaker after full adjustment. In contrast, women carriers of the FOXO3 G allele showed a positive association with heart disease after total adjustment (OR = 1.49, 95% CI, 1.00-2.21, p = .049). In conclusion, the longevity-associated G allele of FOXO3 was observed to have contrasting associations with heart disease prevalence according to sex in older Japanese. To further confirm this association, a longitudinal study and a large sample size will be required.


Large-scale plurimodal networks common to listening to, producing and reading word lists: an fMRI study combining task-induced activation and intrinsic connectivity in 144 right-handers.
We aimed at identifying plurimodal large-scale networks for producing, listening to and reading word lists based on the combined analyses of task-induced activation and resting-state intrinsic connectivity in 144 healthy right-handers. In the first step, we identified the regions in each hemisphere showing joint activation and joint asymmetry during the three tasks. In the left hemisphere, 14 homotopic regions of interest (hROIs) located in the left Rolandic sulcus, precentral gyrus, cingulate gyrus, cuneus and inferior supramarginal gyrus (SMG) met this criterion, and 7 hROIs located in the right hemisphere were located in the preSMA, medial superior frontal gyrus, precuneus and superior temporal sulcus (STS). In a second step, we calculated the BOLD temporal correlations across these 21 hROIs at rest and conducted a hierarchical clustering analysis to unravel their network organization. Two networks were identified, including the WORD-LIST_CORE network that aggregated 14 motor, premotor and phonemic areas in the left hemisphere plus the right STS that corresponded to the posterior human voice area (pHVA). The present results revealed that word-list processing is based on left articulatory and storage areas supporting the action-perception cycle common not only to production and listening but also to reading. The inclusion of the right pHVA acting as a prosodic integrative area highlights the importance of prosody in the three modalities and reveals an intertwining across hemispheres between prosodic (pHVA) and phonemic (left SMG) processing. These results are consistent with the motor theory of speech postulating that articulatory gestures are the central motor units on which word perception, production, and reading develop and act together.


Impact of Electric Stimulation on Residual Hearing.
Candidacy criteria for cochlear implantation are expanding to include patients with substantial low-to-mid frequency hearing sensitivity. Postoperative hearing preservation has been achieved in cochlear implant recipients, though with variable outcomes. Previous investigations on postoperative hearing preservation outcomes have evaluated intraoperative procedures. There has been limited review as to whether electric stimulation influences hearing preservation. The purpose of this analysis was to evaluate whether charge levels associated with electric stimulation influence postoperative hearing preservation within the first year of listening experience. Retrospective analysis of unaided residual hearing and charge levels. Twenty-eight cochlear implant recipients with postoperative residual hearing in the operative ear and at least 12 mo of listening experience with electric-acoustic stimulation (EAS). Assessment intervals included initial cochlear implant activation, initial EAS activation, and 3-, 6-, and 12-mo postinitial EAS activation. A masked low-frequency bone-conduction (BC) pure-tone average (PTA) was calculated for all participants at each assessment interval. Charge levels for each electrode were determined using the most comfortable loudness level and pulse width values. Charge levels associated with different regions of the electrode array were compared to the change in the low-frequency BC PTA between two consecutive intervals. Charge levels had little to no association with the postoperative change in low-frequency BC PTA within the first year of listening experience. Electric charge levels do not appear to be reliably related to the subsequent loss of residual low-frequency hearing in the implanted ear within the first year of EAS listening experience.


[Mastitis in sheep in the Netherlands].
Little is known of udder health in sheep in the Netherlands. The present study represents an effort to gain some insight into this matter. For this purpose, test samples were taken during the period from March 6, 1981 to April 17, 1981, on sixteen commercial farms in the province of Gelderland, on which there were a total number of 936 nursing ewes; this was done again during the period from June 22, 1981 to June 25, 1981, final sampling being done during April 1982, though this was confined to animals showing poor udder health in the year before. Cell counts were made by an adjusted method using the Coulter Counter. The cell counts recorded were higher than those reported in the literature. Of the samples examined, from 20 to 25 per cent contained more than 2,000,000 cells per ml. Cell counts were high during the early period of lactation, subsequently diminished and then increased again about the time of weaning. Moreover, cell counts increased with age and possibly, though not significantly so, with the number of suckling lambs. Bacteriological examination shortly after lambing was positive in 7.3 per cent of the ewes and 4.1 per cent of samples of udder halves.