The case for OFSMOKE: how tobacco price regulation is needed to promote the health of markets, government revenue and the public.
Mainstream economic theory outlines four main causes of market failure and it is already well established that two of these (information failure and externalities) exist in a tobacco market. A third cause of market failure, market power, is also a serious problem in many tobacco markets. Market power--combined with unintended and often overlooked consequences of tobacco tax policies, notably that gradual increases in specific taxes may allow the industry to disguise significant price increases--has, at least in high income countries, given cigarette manufacturers considerable pricing power and profits. This paper examines ways this market failure could be addressed and proposes as a solution a system of price cap regulation wherein a cap is placed on the pre-tax cigarette manufacturers' price but not on the retail price that consumers face. Well established in the utilities industry, price cap regulation would set a maximum price that cigarette companies can charge for their product based on an assessment of the genuine costs each firm faces in its operations and an assumption about the efficiency savings it would be expected to make. Such a system would achieve three main benefits. First, it would address the problem of market failure and excess profits while simultaneously allowing current tobacco control policies, including tax and price increases, to expand--thus tax increases would remain a central tenet of tobacco control policies and retail prices could continue to increase. Second, it would increase government revenue by transferring the excess profits from the industry to the government purse. Third, it would bring numerous public health benefits. In addition to addressing market power, while simultaneously allowing tobacco control policies to expand, it could offer a means of preventing down-trading to cheaper products and controlling unwanted industry practices such as cigarette smuggling, price fixing and marketing to the young. The paper outlines in some detail how such a system might be developed in the UK, while briefly exploring how it could be applied elsewhere, including in markets with state monopolies.


Antimuscarinic antibodies in primary Sjögren's syndrome reversibly inhibit the mechanism of fluid secretion by human submandibular salivary acinar cells.
Sjögren's syndrome (SS) is an autoimmune condition affecting salivary glands, for which a clearly defined pathogenic autoantibody has yet to be identified. Autoantibodies that bind to the muscarinic M3 receptors (M3R), which regulate fluid secretion in salivary glands, have been proposed in this context. However, there are no previous data that directly show antisecretory activity. This study was undertaken to investigate and characterize the antisecretory activity of anti-M3R. Microfluorimetric Ca2+ imaging and patch clamp electrophysiologic techniques were used to measure the secretagogue-evoked increase in [Ca2+]i and consequent activation of Ca2+-dependent ion channels in individual mouse and human submandibular acinar cells. Together, these techniques form a sensitive bioassay that was used to determine whether IgG isolated from patients with primary SS and from control subjects has antisecretory activity. IgG (2 mg/ml) from patients with primary SS reduced the carbachol-evoked increase in [Ca2+]i in both mouse and human acinar cells by approximately 50%. IgG from control subjects had no effect on the Ca2+ signal. Furthermore, the inhibitory action of primary SS patient IgG on the Ca2+ signal was acutely reversible. We repeated our observations using rabbit serum containing antibodies raised against the second extracellular loop of M3R and found an identical pattern of acutely reversible inhibition. Anti-M3R-positive serum had no effect on Ca2+-dependent ion channel activation evoked by the direct intracellular infusion of inositol 1,4,5-triphosphate. These observations show for the first time that IgG from patients with primary SS contains autoantibodies capable of damaging saliva production and contributing to xerostomia. The unusual but not unprecedented acute reversibility of the effects of anti-M3 autoantibodies is the subject of further research.


Hypofractionated spinal stereotactic body radiation therapy for high-grade epidural disease.
To characterize the clinical outcomes when stereotactic body radiation therapy (SBRT) alone is used to treat high-grade epidural disease without prior surgical decompression, the authors conducted a retrospective cohort study of patients treated at the Memorial Sloan Kettering Cancer Center between 2014 and 2018. The authors report locoregional failure (LRF) for a cohort of 31 cases treated with hypofractionated SBRT alone for grade 2 epidural spinal cord compression (ESCC) with radioresistant primary cancer histology. High-grade epidural disease was defined as grade 2 ESCC, which is notable for radiographic deformation of the spinal cord by metastatic disease. Kaplan-Meier survival curves and cumulative incidence functions were generated to examine the survival and incidence experiences of the sample level with respect to overall survival, LRF, and subsequent requirement of vertebral same-level surgery (SLS) due to tumor progression or fracture. Associations with dosimetric analysis were also examined. Twenty-nine patients undergoing 31 episodes of hypofractionated SBRT alone for grade 2 ESCC between 2014 and 2018 were identified. The 1-year and 2-year cumulative incidences of LRF were 10.4% (95% CI 0-21.9) and 22.0% (95% CI 5.5-38.4), respectively. The median survival was 9.81 months (95% CI 8.12-18.54). The 1-year cumulative incidence of SLS was 6.8% (95% CI 0-16.0) and the 2-year incidence of SLS was 14.5% (95% CI 0.6-28.4). All patients who progressed to requiring surgery had index lesions at the thoracic apex (T5-7). In carefully selected patients, treatment of grade 2 ESCC disease with hypofractionated SBRT alone offers a 1-year cumulative incidence of LRF similar to that in low-grade ESCC and postseparation surgery adjuvant hypofractionated SBRT. Use of SBRT alone has a favorable safety profile and a low cumulative incidence of progressive disease requiring open surgical intervention (14.5%).


Adsorption and desorption properties of arsenate onto nano-sized iron-oxide-coated quartz.
This study was conducted to investigate the adsorption and desorption properties of arsenate [As(V)] on nano-sized iron-oxide-coated quartz (IOCQ) through batch experiments. The coating of nano-sized iron oxide on the quartz surface was performed using the heat treatment process which aimed to utilize the adsorption properties of the nano-sized iron oxide and the filtration properties of the quartz. Environmental SEM-EDAX and BET techniques were used to analyze the surface morphology, elemental composition, surface area and the porosity of the adsorbent. SEM-EDAX analyses confirmed that arsenate was adsorbed on the IOCQ surface. BET results showed that the IOCQ adsorbent had higher pore volumes and high specific surface areas compared with the pure quartz. The study revealed that the adsorption rate of As(V) ion was very rapid and reached the equilibrium within 5 min. This study also revealed that almost 100% of As(V) removal was achieved within 5 minutes of adsorption reaction from the initial solution containing 1,000 microg-As(V)/L. The Langmuir adsorption isotherm model suitably explained the sorption characteristics of As(V) onto IOCQ. This desorption study showed that the adsorbent could be reused after reacting with mild HCl solution but the concentration of acid eluant or pH has a great impact on the coated adsorbent surface. The results indicate that the nano-sized iron oxide-coated adsorbent is potentially suitable for removal of arsenate from drinking water.


A variable region 3 (V3) mutation determines a global neutralization phenotype and CD4-independent infectivity of a human immunodeficiency virus type 1 envelope associated with a broadly cross-reactive, primary virus-neutralizing antibody response.
The human serum human immunodeficiency virus type 1 (HIV-1)-neutralizing serum 2 (HNS2) neutralizes many primary isolates of different clades of HIV-1, and virus expressing envelope from the same donor, clone R2, is neutralized cross-reactively by HIV-immune human sera. The basis for this cross-reactivity was investigated. It was found that a rare mutation in the proximal limb of variable region 3 (V3), 313-4 PM, caused virus pseudotyped with the R2 envelope to be highly sensitive to neutralization by monoclonal antibodies (MAbs) directed against conformation-sensitive epitopes at the tip of the V3 loop, such as 19b, and moderately sensitive to MAbs against CD4 binding site (CD4bs) and CD4-induced (CD4i) epitopes, soluble CD4 (sCD4), and HNS2. In addition, introduction of this sequence by mutagenesis caused enhanced sensitivity to neutralization by 19b, anti-CD4i MAb, and HNS2 in three other primary HIV-1 envelopes and by anti-CD4bs MAb and sCD4 in one of the three. The 313-4 PM sequence also conferred increased infectivity for CD4(+) CCR5(+) cells and the ability to infect CCR5(+) cells upon all of these four and two of these four HIV-1 envelopes, respectively. Neutralization of R2 by HNS2 was substantially inhibited by the cyclized R2 V3 35-mer synthetic peptide. Similarly, the peptide also had some lesser efficacy in blocking neutralization of R2 by other sera or of neutralization of other primary viruses by HNS2. Together, these results indicate that the unusual V3 mutation in the R2 clone accounts for its uncommon neutralization sensitivity phenotype and its capacity to mediate CD4-independent infection, both of which could relate to immunogenicity and the neutralizing activity of HNS2. This is also the first primary HIV-1 isolate envelope glycoprotein found to be competent for CD4-independent infection.


Assessment of temperament and character profile with anxiety and depression in patients with acne.
Acne is the most common skin disease, affecting nearly 85% of the population as well as their lives. Acne can severely affect social and psychological functioning. Patients with acne may have anxiety, depression, decreased self-esteem, interpersonal difficulties, unemployment, social withdrawal, and even suicidal intent. The aim of this study was to evaluate the temperament and character inventory (TCI) of patients with acne and to compare the results with those of healthy controls. Case-control study. The study population consisted of 47 patients with acne, and 40 healthy control subjects. All participants were instructed to complete a self-administered 240-item TCI and the Hospital Anxiety and Depression Scale. In this study, the scores for the temperament properties Worry and pessimism (HA1) and Dependence (RD4) and the character properties Social acceptance (C1) and Integrated conscience (C5) were found to be higher in acne patients than in healthy controls (p<0.05). Compared to the controls, depression and anxiety scores were found to be markedly higher in the patients with acne. Acne type correlated positively with the Disorderliness (NS4) subscale of Novelty seeking (NS) and anxiety. Additionally, acne type correlated negatively with the Attachment (RD3) subscale of Reward Dependence (RD), with the Transpersonal identification (ST2) and Spiritual acceptance (ST3) subscales of Self-Trancendence (ST), and with the Compassion (C4) sub-scale of Cooperativeness (C). Studies in this area may lead to the development of specific and focused interventions for TCI in patients with acne vulgaris. We suggest that the evaluation and treatment of acne should also include psychosomatic approaches in clinical practice.


Brain regulation of food intake and appetite: molecules and networks.
In the clinic, obesity and anorexia constitute prevalent problems whose manifestations are encountered in virtually every field of medicine. However, as the command centre for regulating food intake and energy metabolism is located in the brain, the basic neuroscientist sees in the same disorders malfunctions of a model network for how integration of diverse sensory inputs leads to a coordinated behavioural, endocrine and autonomic response. The two approaches are not mutually exclusive; rather, much can be gained by combining both perspectives to understand the pathophysiology of over- and underweight. The present review summarizes recent advances in this field including the characterization of peripheral metabolic signals to the brain such as leptin, insulin, peptide YY, ghrelin and lipid mediators as well as the vagus nerve; signalling of the metabolic sensors in the brainstem and hypothalamus via, e.g. neuropeptide Y and melanocortin peptides; integration and coordination of brain-mediated responses to nutritional challenges; the organization of food intake in simple model organisms; the mechanisms underlying food reward and processing of the sensory and metabolic properties of food in the cerebral cortex; and the development of the central metabolic system, as well as its pathological regulation in cancer and infections. Finally, recent findings on the genetics of human obesity are summarized, as well as the potential for novel treatments of body weight disorders.


Nerve growth factor-induced PKB/Akt activity is sustained by phosphoinositide 3-kinase dependent and independent signals in sympathetic neurons.
Phosphoinositide 3-kinase and its downstream effector kinase PKB/Akt have been suggested to have crucial roles in suppressing apoptosis in several classes of neurons. However, few studies have conducted a long-term investigation of either kinase activity, many studies relying instead on use of the phosphoinositide 3-kinase inhibitors wortmannin and LY294002. When we added LY294002 or wortmannin to sympathetic neurons, apoptosis in the presence of nerve growth factor (NGF) was very slow compared to that obtained by NGF deprivation. However, expression of a kinase-inactive mutant of PKB/Akt in the presence of NGF induced apoptosis in a significant proportion of the neurons. To understand this discrepancy, we investigated more closely the regulation of PKB/Akt activity by NGF. NGF stimulation induced a rapid increase in PKB/Akt activity which was sustained at approximately 6-fold up to 24 h. Phosphoinositide 3-kinase was also rapidly activated by NGF. However, concentrations of wortmannin which completely blocked phosphoinositide 3-kinase activity in the neurons inhibited no more than 50-70% of cellular PKB/Akt activity. Similarly, approximately 50% of maximal NGF-stimulated PKB/Akt activity remained elevated at concentrations of LY294002 which completely blocked neurite outgrowth, a process known to be phosphoinositide 3-kinase dependent. We suggest that a proportion of the sustained PKB/Akt activity induced by NGF is mediated by phosphoinositide 3-kinase-independent pathways. These results raise a cautionary note as to the usefulness of LY294002 or wortmannin as tools to dissect the role of PKB/Akt in neuronal survival.


Assessing the effects of cooperation bias and attrition in behavioral genetic research using data-weighting.
Because twins and adoptees are a rare resource, they are often studied repeatedly over a period of many years. Differential attrition, and in some studies initial cooperation bias, have the potential to lead to serious biases to estimates of genetic and environmental parameters. Since non-response is often influenced by multiple binary or categorical sociodemographic variables, maximum-likelihood methods are not easily adapted to adjust for such effects. In this brief note we illustrate the use of data-weighting to assess the likely effects of cooperation bias or attrition both on measures of mean or prevalence, and on twin pair correlations or concordances, using data from the Australian twin panel 1981 survey and alcohol challenge studies. Participants in the alcohol challenge study were on average younger, more socially nonconforming, heavier drinkers, more likely to be unmarried, and less likely to report their religion as Other Protestant. Reweighting the alcohol challenge sample to have the same distribution on these variables as the Australian twin panel 1981 survey respondents confirmed that individuals who would feel very intoxicated after a challenge dose of alcohol were underrepresented in the study. However, pairwise data-weighting indicated that this cooperation bias was leading to only a slight underestimation of the importance of genetic effects on subjective intoxication.


Thoracic Injury Risk Curves for Rib Deflections of the SID-IIs Build Level D.
Injury risk curves for SID-IIs thorax and abdomen rib deflections proposed for future NCAP side impact evaluations were developed from tests conducted with the SID-IIs FRG. Since the floating rib guide is known to reduce the magnitude of the peak rib deflections, injury risk curves developed from SID-IIs FRG data are not appropriate for use with SID-IIs build level D. PMHS injury data from three series of sled tests and one series of whole-body drop tests are paired with thoracic rib deflections from equivalent tests with SID-IIs build level D. Where possible, the rib deflections of SID-IIs build level D were scaled to adjust for differences in impact velocity between the PMHS and SID-IIs tests. Injury risk curves developed by the Mertz-Weber modified median rank method are presented and compared to risk curves developed by other parametric and non-parametric methods.


Urinary tract infection associated with conditions causing urinary tract obstruction and stasis, excluding urolithiasis and neuropathic bladder.
The aim of this study was to examine urinary tract infection (UTI) associated with conditions causing urinary tract obstruction and stasis, excluding urolithiasis and neuropathic bladder dysfunction. An electronic literature search was performed using the key words urinary tract infection (UTI), benign prostatic hyperplasia (BPH), hydronephrosis, obstruction, reflux, diverticulum, urethra, and stricture. In total, 520 abstracts were reviewed, 210 articles were studied in detail, and 36 were included as references. It is one of the axioms of Urological practice that urinary tract obstruction and stasis predispose to UTI. Experimental studies indicate that, whereas transurethral inoculates of bacteria are rapidly eliminated from the normal bladder, urethral obstruction leads to cystitis, pyelonephritis, and bacteremia. BPH is, next to urolithiasis, the most common cause of urinary tract obstruction predisposing to UTI. Urethral stricture remains a common cause of UTI in many parts of the world. Urinary stasis in diverticula of the urethra or bladder predisposes to UTI. Experimental studies have shown that, whereas the normal kidney is relatively resistant to infection by organisms injected intravenously, ureteric obstruction predisposes to pyelonephritis. It also causes renal dysfunction which impairs the excretion of antibiotics in the urine, making eradication of bacteria difficult. In patients with UTI and urinary tract obstruction, targeted antibiotic treatment according to urine culture should be complemented with urgent drainage (bladder catheterization, percutaneous nephrostomy or ureteric stenting) followed by definitive surgery to remove the cause of obstruction or stasis once infection is under control.


Effectiveness of conservative therapy and helmet therapy for positional cranial deformation.
The authors investigated the effectiveness of conservative (repositioning therapy with or without physical therapy) and helmet therapy, and identified factors associated with treatment failure. A total of 4378 patients evaluated for deformational plagiocephaly and/or deformational brachycephaly were assigned to conservative (repositioning therapy, n = 383; repositioning therapy plus physical therapy, n = 2998) or helmet therapy (n = 997). Patients were followed until complete correction (diagonal difference <5 mm and/or cranial ratio <0.85) or 18 months. Rates of correction were calculated, and independent risk factors for failure were identified by multivariate analysis. Complete correction was achieved in 77.1 percent of conservative treatment patients; 15.8 percent required transition to helmet therapy (n = 534), and 7.1 percent ultimately had incomplete correction. Risk factors for failure included poor compliance (relative risk, 2.40; p = 0.009), advanced age (relative risk, 1.20 to 2.08; p = 0.008), prolonged torticollis (relative risk, 1.12 to 1.74; p = 0.002), developmental delay (relative risk, 1.44; p = 0.042), and severity of the initial cranial ratio (relative risk, 1.41 to 1.64; p = 0.044) and diagonal difference (relative risk, 1.31 to 1.48; p = 0.027). Complete correction was achieved in 94.4 percent of patients treated with helmet therapy as first-line therapy and in 96.1 percent of infants who received helmets after failed conservative therapy (p = 0.375). Risk factors for helmet failure included poor compliance (relative risk, 2.42; p = 0.025) and advanced age (relative risk, 1.13 to 3.08; p = 0.011). Conservative therapy and helmet therapy are effective for positional cranial deformation. Treatment may be guided by patient-specific risk factors. In most infants, delaying helmet therapy for a trial of conservative treatment does not preclude complete correction. Therapeutic, III.


Katanin-p80 gene promoter characterization and regulation via Elk1.
Katanin is an ATPase family member protein that participates in microtubule severing. It has heterodimeric structure consisting of 60 kDa (katanin-p60) and 80 kDa (katanin-p80) subunits encoded by KATNA1 and KATNB1 genes, respectively. Katanin-p60 has the enzymatic activity for microtubule severing, whereas katanin-p80 consists of multiple domains with different functions such as targeting katanin-p60 to the centrosome, augmenting microtubule severing by katanin-p60, and even suppressing microtubule severing. Despite the various important functions of katanin-p80, its transcriptional regulation has not been studied yet. Elk1 transcription factor has been shown to interact with microtubules and regulate the transcription of another microtubule severing protein, spastin. In spite of katanin's importance, and structural and functional similarities to spastin, there is no study on the transcriptional regulation of katanin yet. In this study, we aimed to characterize KATNB1 promoter and analyze the effects of Elk1 on katanin-p80 expression. We identified a 518- bp TATA-less promoter including a critical CpG island and GC boxes as an optimal promoter, and sequential deletion of CpG island and the GC elements gradually decreased the KATNB1 promoter activity. In addition, we showed Elk1 binding on the KATNB1 promoter by EMSA. We found that Elk1 activated KATNB1 promoter, and increased both mRNA and protein levels of katanin-p80 in SH-SY5Y cells. On the other hand, KCl treatment increasing SUMOylation decreased KATNB1 promoter activity. Since microtubule severing is an important cellular mechanism of which malfunctions result in serious diseases such as spastic paraplegia, Alzheimer's disease and cell cycle related disorders, identification of KATNB1 transcriptional regulation is crucial in understanding the coordination of microtubule severing activity by different proteins in the cells.


Regulation of ciaXRH operon expression and identification of the CiaR regulon in Streptococcus mutans.
The ciaRH operon in Streptococcus mutans contains 3 contiguous genes, ciaXRH. Unlike the CiaRH system in other streptococci, only the ciaH-null mutant displays defective phenotypes, while the ciaR-null mutant behaves like the wild type. The objective of this study was to determine the mechanism of this unusual property. We demonstrate that the ciaH mutation caused a >20-fold increase in ciaR transcript synthesis. A ciaRH double deletion reversed the ciaH phenotype, suggesting that overexpressed ciaR might be responsible for the observed ciaH phenotypes. When ciaR was forced to be overexpressed by a transcriptional fusion to the ldh promoter in the wild-type background, the same ciaH phenotypes were restored, confirming the involvement of overexpressed ciaR in the ciaH phenotypes. The ciaH mutation and ciaR overexpression also caused transcriptional alterations in 100 genes, with 15 genes upregulated >5-fold. Bioinformatics analysis identified a putative CiaR regulon consisting of 8 genes/operons, including the ciaXRH operon itself, all of which were upregulated. In vitro footprinting on 4 of the 8 promoters revealed a protected region of 26 to 28 bp encompassing two direct repeats, NTTAAG-n5-WTTAAG, 10 bp upstream of the -10 region, indicating direct binding of the CiaR protein to these promoters. Taken together, we conclude that overexpressed CiaR, as a result of either ciaH deletion or forced expression from a constitutive promoter, is a mediator in the CiaH-regulated phenotypes.


The development and evaluation of alternative communication strategies to facilitate interactions with Somali refugees in primary care: a preliminary study.
The work reported in this paper forms part of a larger project to develop and evaluate alternative forms of communication to facilitate cross-cultural consultations in primary care. As a case study and proof-of-concept, work was conducted with Somali refugees who tend to experience significant communication difficulties in primary care consultations. The alternative communication methods developed in this study originate from the field of Augmentative and Alternative Communication (AAC). These methods may include non-verbal communication or aided communication using a mix of pictographic symbols, bilingual text and digitised (recorded) or synthetic speech. These can be delivered on a range of paper-based or computer-based devices. A paper-based and computer-based method was developed to assess whether a group of literate and illiterate Somalis were able to answer a set of questions using these tools. The purpose of this preliminary study was to assess whether either of these communication methods were suitable for further evaluation in primary care consultations. Twenty Somalis were presented with three communication tools and were asked a set of general questions in Somali which they had to answer using each tool: (1) a paper-based communication book containing symbols and bilingual text labels; (2) a laptop PC with mouse pad containing the same symbols, text labels and augmented with digitised Somali speech; (3) a tablet PC with touch screen containing the same software and digitised Somali speech. These two computer-based delivery platforms were compared for ease of use among a participant group who are likely to have little computing experience. Each task was timed and scored for level of correctness; feedback was gained from Somalis and experimenters' observations were noted. Participants clearly found the computerised devices with Somali speech output easier to use and more acceptable than the simpler paper-based device.


Multiple Family Group Service Model for Children With Disruptive Behavior Disorders: Child Outcomes at Post-Treatment.
The purpose of this study was to determine the benefits of a multiple family group (MFG) service delivery model compared with services as usual (SAU) in improving the functioning of youth with oppositional defiant/conduct disorder in families residing in socioeconomically disadvantaged communities. Participants included 320 youth aged 7 to 11 and their families who were referred to participating outpatient clinics. Participants were assigned to the MFG or the SAU condition, with parent report of child oppositional behavior, social competence, and level of youth impairment as primary outcomes at post-treatment. Family engagement to MFG was measured by attendance to each group session. Caregivers of youth in the MFG service delivery model condition reported significant improvement in youth oppositional behavior and social competence compared with youth in the SAU condition. Impairment improved over time for both groups with no difference between treatment conditions. The MFG led to greater percentage of youth with clinically significant improvements in oppositional behavior. Attendance to the MFG was high, given the high-risk nature of the study population. The MFG service delivery model offers an efficient and engaging format to implement evidence-based approaches to improving functioning of youth with oppositional defiant and/or conduct disorder in families from socioeconomically disadvantaged communities.


Spontaneous prolonged contractions during antenatal fetal heart rate monitoring.
Uterine contractions of more than 2 minutes' duration occurred spontaneously in 1.4% of 6,399 antenatal fetal heart rate (FHR) recordings. All recordings were made in the Department of Obstetrics and Gynaecology at Tygerberg Hospital. The patients with spontaneous prolonged contractions (SPC) were compared with a randomly selected control group. Patients who had an SPC during antenatal FHR recording were not at a higher risk of abruptio placentae, preterm labour or unexpected intra-uterine death. Of the infants born to the mothers in the study group, 65.5% were male. There were more primigravidas in the study group, which may have been responsible for the longer duration of the second stage of labour in this group. When primigravidas only were examined no difference between the two groups could be found except for a larger placental mass in the study group. It is uncertain why primigravidas were more likely to develop SPCs as observed during antenatal FHR monitoring.


Shaping of Signal Transmission at the Photoreceptor Synapse by EAAT2 Glutamate Transporters.
Photoreceptor ribbon synapses tonically release glutamate. To ensure efficient signal transmission and prevent glutamate toxicity, a highly efficient glutamate removal system provided by members of the SLC1 gene family is required. By using a combination of biophysical and in vivo studies, we elucidate the role of excitatory amino acid transporter 2 (EAAT2) proteins in synaptic glutamate homeostasis at the zebrafish photoreceptor synapse. The main glutamate sink is provided by the glial EAAT2a, reflected by reduced electroretinographic responses in EAAT2a-depleted larvae. EAAT2b is located on the tips of cone pedicles and contributes little to glutamate reuptake. However, this transporter displays both a large chloride conductance and leak current, being important in stabilizing the cone resting potential. This work demonstrates not only how proteins originating from the same gene family can complement each other's expression profiles and biophysical properties, but also how presynaptic and glial transporters are coordinated to ensure efficient synaptic transmission at glutamatergic synapses of the central nervous system.


Cardiac function and hemodynamics in Kenyan children with severe malaria.
Mortality from severe malaria remains unacceptably high in sub-Saharan Africa. Several markers of cardiovascular compromise and metabolic acidosis correlate with mortality. The role of cardiac dysfunction in the pathogenesis of severe childhood malaria remains unknown. We examined 30 children admitted with severe malaria by using portable echocardiography to assess their cardiac function and hemodynamic status on admission (day 0), day 1, and discharge. We compared hemodynamic parameters in two study groups: children presenting with metabolic acidosis (base deficit >8) and children without acidosis. High-dependency unit, Kilifi District Hospital, Kenya. Acidotic patients received fluid resuscitation with either dextran 70 or starch at admission. Several markers of hemodynamic compromise were noted on admission, including severe tachycardia, low stroke volume index, and high inferior vena cava collapsibility index, which improved with subsequent readings. Overall, cardiac function assessed by ejection fraction (63.1% +/- 5.2% vs. 71.9% +/- 2.8%; p < .001) and left myocardial performance index (0.32 +/- 0.16 vs. 0.25 +/- 0.08; p = .03) was mildly abnormal on admission compared with discharge. Acidotic patients had worse hemodynamic indicators, with a significantly higher inferior vena cava collapsibility index on day 0 than nonacidotic patients (52.1 +/- 21 .9 vs. 37.7 +/- 15.4; p = .03), plus lower stroke volume index and worse cardiac function with higher left myocardial performance index (0.38 +/- 0.18 vs. 0.26 +/- 0.11; p = .05). Stroke volume index increased after first fluid bolus in 80% of children. Children with severe malaria and metabolic acidosis have evidence of hypovolemia and evidence of cardiac dysfunction.


The effects of ACL injury on knee proprioception: a meta-analysis.
It is suggested the anterior cruciate ligament (ACL) plays a significant role in knee proprioception, however, the effect of ACL injury on knee proprioception is unclear. Studies utilising the two most common measurement techniques, joint position sense and threshold to detect passive motion, have provided evidence both for and against a proprioceptive deficient following ACL injury. The objective of the study was to undertake a meta-analysis investigating the effects of ACL injury, treated conservatively or by reconstruction, on proprioception of the knee, measured using joint position sense and/or threshold to detect passive movement techniques. Seven databases were searched from their inception to September 2013 using the subject headings 'anterior cruciate ligament, proprioception, postural sway, joint position sense, balance, equilibrium or posture' to identify relevant studies. PRISMA guidelines were followed as much as possible. Studies that investigated the effect of ACL injury on either knee joint kinaesthesia or position sense were included in this review. Two reviewers independently extracted data using a standardised assessment form. Comparisons were made using a fixed effect model with an inverse variance method using Review Manager Software (V5.1). Patients with ACL injury have poorer proprioception than people without such injuries (SMD=0.35°; P=0.001 and SMD=0.38°; P=0.03) when measured using joint position sense and threshold to detect passive motion techniques respectively. Patients had poorer proprioception in the injured than uninjured leg (SMD=0.52°; P<0.001) and the proprioception of people whose ACL was repaired was better than those whose ligament was left unrepaired (SMD=-0.62°; P<0.001). Heterogeneity of measurement techniques and lack of psychometric details. ACL injuries may cause knee proprioception deficits compared to uninjured knees and control groups. Although differences were statistically significant, the clinical significance of findings can be questioned. Clinical practitioners using joint position sense or threshold to detect passive motion techniques need to consider the reliability and validity of data provided.


Comparing two methods of clinical measurement: a personal history.
Despite the fundamental importance of measurement in medicine, studies which compare methods of clinical measurement are often analysed inappropriately and may thus come to incorrect conclusions. We explain the problems with the main methods used, notably correlation and regression, and describe the limits of agreement approach which we have proposed. We consider why incorrect methods are so widely used and describe our own experience in bringing this issue to the attention of medical researchers.


Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression.
The LRRK2 mutation G2019S is the most common genetic cause of Parkinson's disease (PD). To better understand the link between mutant LRRK2 and PD pathology, we derived induced pluripotent stem cells from PD patients harboring LRRK2 G2019S and then specifically corrected the mutant LRRK2 allele. We demonstrate that gene correction resulted in phenotypic rescue in differentiated neurons and uncovered expression changes associated with LRRK2 G2019S. We found that LRRK2 G2019S induced dysregulation of CPNE8, MAP7, UHRF2, ANXA1, and CADPS2. Knockdown experiments demonstrated that four of these genes contribute to dopaminergic neurodegeneration. LRRK2 G2019S induced increased extracellular-signal-regulated kinase 1/2 (ERK) phosphorylation. Transcriptional dysregulation of CADPS2, CPNE8, and UHRF2 was dependent on ERK activity. We show that multiple PD-associated phenotypes were ameliorated by inhibition of ERK. Therefore, our results provide mechanistic insight into the pathogenesis induced by mutant LRRK2 and pointers for the development of potential new therapeutics.


Granulocyte-macrophage colony-stimulating factor is a key mediator in experimental osteoarthritis pain and disease development.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to be important in the development of inflammatory models of rheumatoid arthritis and there is encouraging data that its blockade may have clinical relevance in patients with rheumatoid arthritis. The aims of the current study were to determine whether GM-CSF may also be important for disease and pain development in a model of osteoarthritis. The role of GM-CSF was investigated using the collagenase-induced instability model of osteoarthritis. We studied both GM-CSF-/- mice and wild-type (C57BL/6) mice treated prophylactically or therapeutically with a monoclonal antibody to GM-CSF. Disease development (both early and late) was evaluated by histology and knee pain development was measured by assessment of weight distribution. In the absence of GM-CSF, there was less synovitis and matrix metalloproteinase-mediated neoepitope expression at week 2 post disease induction, and less cartilage damage at week 6. GM-CSF was absolutely required for pain development. Therapeutic neutralization of GM-CSF not only abolished the pain within 3 days but also led to significantly reduced cartilage damage. GM-CSF is key to the development of experimental osteoarthritis and its associated pain. Importantly, GM-CSF neutralization by a therapeutic monoclonal antibody-based protocol rapidly and completely abolished existing arthritic pain and suppressed the degree of arthritis development. Our results suggest that it would be worth exploring the importance of GM-CSF for pain and disease in other osteoarthritis models and perhaps clinically for this form of arthritis.


Effect of NF-kappaB, survivin, Bcl-2 and Caspase3 on apoptosis of gastric cancer cells induced by tumor necrosis factor related apoptosis inducing ligand.
To study the effect of NF-kappaB, survivin, Bcl-2 and Caspase3 on tumor necrosis factors related apoptosis inducing ligand (TRAIL) induced apoptosis of gastric cancer cells. Gastric cancer cells of SGC-7901, MKN28, MKN45 and AGS lines were cultured in PRMI-1640 medium and the apoptosis rates of the cells of 4 lines were observed after treatment of tumor necrosis factors related apoptosis inducing ligand (TRAIL) with a flow cytometer. The expression of NF-kappaB, survivin, Bcl-2 and Caspase3 in gastric cancer cells of 4 lines was analyzed with Western blot. After the gastric cancer cells were exposed to TRAIL 300 ng/ml for 24 hours, the apoptosis rate was 36.05%, 20.27%, 16.50% and 11.80% in MKN28, MKN45, AGS and SGC-7901cells respectively. Western blot revealed that the expressions of NF-kappaB and survivin were lower in MKN28 cells than in MKN45, AGS and SGC-7901 cells. In contrast, the expression of Caspase3 was higher in MKN28 cells than in MKN45, AGS and SGC-7901 cells. There is a selectivity of TRAIL potency to induce apoptosis in gastric cancer cells of different cell lines. The anticancer potency of TRAIL is associated with the decreased expression of NF-kappaB and survivin and increased expression of Caspase3 of gastric cancer cells.


Reduced risk of pancreatic cancer associated with asthma and nasal allergies.
Studies indicate an inverse association between ductal adenocarcinoma of the pancreas (PDAC) and nasal allergies. However, controversial findings are reported for the association with asthma. Understanding PDAC risk factors will help us to implement appropriate strategies to prevent, treat and diagnose this cancer. This study assessed and characterised the association between PDAC and asthma and corroborated existing reports regarding the association between allergies and PDAC risk. Information about asthma and allergies was collated from 1297 PDAC cases and 1024 controls included in the PanGenEU case-control study. Associations between PDAC and atopic diseases were studied using multilevel logistic regression analysis. Meta-analyses of association studies on these diseases and PDAC risk were performed applying random-effects model. Asthma was associated with lower risk of PDAC (OR 0.64, 95% CI 0.47 to 0.88), particularly long-standing asthma (>=17 years, OR 0.39, 95% CI 0.24 to 0.65). Meta-analysis of 10 case-control studies sustained our results (metaOR 0.73, 95% CI 0.59 to 0.89). Nasal allergies and related symptoms were associated with lower risk of PDAC (OR 0.66, 95% CI 0.52 to 0.83 and OR 0.59, 95% CI 0.46 to 0.77, respectively). These results were supported by a meta-analysis of nasal allergy studies (metaOR 0.6, 95% CI 0.5 to 0.72). Skin allergies were not associated with PDAC risk. This study shows a consistent inverse association between PDAC and asthma and nasal allergies, supporting the notion that atopic diseases are associated with reduced cancer risk. These results point to the involvement of immune and/or inflammatory factors that may either foster or restrain pancreas carcinogenesis warranting further research to understand the molecular mechanisms driving this association.


Synergistic effect of band convergence and carrier transport on enhancing the thermoelectric performance of Ga doped Cu2Te at medium temperatures.
Recent advances in high performance thermoelectric materials have garnered unprecedented attention owing to their capability of direct transformation of heat energy to useful electricity. Copper Telluride (Cu2Te), a member of the chalcogenide family has emerged as a state-of-the-art thermoelectric material with low thermal conductivity and high thermoelectric (TE) performance, however, this material exhibits exceptional transport properties only at very high temperatures. In this study, we have investigated the synergistic effects of Ga doping on the TE performance by first principles calculations along with experimental validations. The DFT (Density Functional Theory) calculations predicted that Ga doping, within considerable limits enhanced the electrical conductivity and Seebeck coefficients in Cu2Te. This proof of concept was validated by experimental synthesis of Ga doped Cu2Te by simple direct annealing for shorter durations of 48 hours at 1120 ºC (~1/4th) than in previous work and subsequent thermoelectric characterization. The enhanced electrical conductivity, thermopower, and moderate thermal conductivities led to the optimized TE performance in 3 atomic % Ga doping (Cu1.97Ga0.03Te), exhibiting a ZT value of 0.46 at 600 K, almost three times that of pristine Cu2Te in this temperature range. This comprehensive study provides the platform for developing new low-cost and energy efficient TE materials with enhanced ZT performance in medium temperature applications.


Successful treatment of herpes labialis with topical acyclovir.
A double blind, placebo controlled trial of 5% acyclovir cream, applied topically five times a day for five days, was carried out in 49 patients with recurrent herpes labialis. These patients had a total of 74 episodes, 34 of which were treated with the 5% acyclovir cream and 40 with matching placebo. First episodes and all episodes treated with acyclovir cream had significantly shorter times to formation of ulcer or crust and to complete healing (p less than 0.05 for all variables). The duration of all symptoms and proportion of patients developing itching was also reduced by acyclovir cream in first episodes, though the difference was not significant. When the patient started treatment early in the course of a first episode acyclovir cream significantly reduced the percentage of lesions progressing beyond the papular stage (p less than 0.05). Acyclovir cream is well tolerated and effective for the treatment of recurrent herpes labialis.


The role of the Hes1 crosstalk hub in Notch-Wnt interactions of the intestinal crypt.
The Notch pathway plays a vital role in determining whether cells in the intestinal epithelium adopt a secretory or an absorptive phenotype. Cell fate specification is coordinated via Notch's interaction with the canonical Wnt pathway. Here, we propose a new mathematical model of the Notch and Wnt pathways, in which the Hes1 promoter acts as a hub for pathway crosstalk. Computational simulations of the model can assist in understanding how healthy intestinal tissue is maintained, and predict the likely consequences of biochemical knockouts upon cell fate selection processes. Chemical reaction network theory (CRNT) is a powerful, generalised framework which assesses the capacity of our model for monostability or multistability, by analysing properties of the underlying network structure without recourse to specific parameter values or functional forms for reaction rates. CRNT highlights the role of β-catenin in stabilising the Notch pathway and damping oscillations, demonstrating that Wnt-mediated actions on the Hes1 promoter can induce dynamic transitions in the Notch system, from multistability to monostability. Time-dependent model simulations of cell pairs reveal the stabilising influence of Wnt upon the Notch pathway, in which β-catenin- and Dsh-mediated action on the Hes1 promoter are key in shaping the subcellular dynamics. Where Notch-mediated transcription of Hes1 dominates, there is Notch oscillation and maintenance of fate flexibility; Wnt-mediated transcription of Hes1 favours bistability akin to cell fate selection. Cells could therefore regulate the proportion of Wnt- and Notch-mediated control of the Hes1 promoter to coordinate the timing of cell fate selection as they migrate through the intestinal epithelium and are subject to reduced Wnt stimuli. Furthermore, mutant cells characterised by hyperstimulation of the Wnt pathway may, through coupling with Notch, invert cell fate in neighbouring healthy cells, enabling an aberrant cell to maintain its neighbours in mitotically active states.


Historical shifts in Brazilian P. falciparum population structure and drug resistance alleles.
Previous work suggests that Brazilian Plasmodium falciparum has limited genetic diversity and a history of bottlenecks, multiple reintroductions due to human migration, and clonal expansions. We hypothesized that Brazilian P. falciparum would exhibit clonal structure. We examined isolates collected across two decades from Amapá, Rondônia, and Pará state (n = 190). By examining more microsatellites markers on more chromosomes than previous studies, we hoped to define the extent of low diversity, linkage disequilibrium, bottlenecks, population structure, and parasite migration within Brazil. We used retrospective genotyping of samples from the 1980s and 1990s to explore the population genetics of SP resistant dhfr and dhps alleles. We tested an existing hypothesis that the triple mutant dhfr mutations 50R/51I/108N and 51I/108N/164L developed in southern Amazon from a single origin of common or similar parasites. We found that Brazilian P. falciparum had limited genetic diversity and isolation by distance was rejected, which suggests it underwent bottlenecks followed by migration between sites. Unlike Peru, there appeared to be gene flow across the Brazilian Amazon basin. We were unable to divide parasite populations by clonal lineages and pairwise FST were common. Most parasite diversity was found within sites in the Brazilian Amazon, according to AMOVA. Our results challenge the hypothesis that triple mutant alleles arose from a single lineage in the Southern Amazon. SP resistance, at both the double and triple mutant stages, developed twice and potentially in different regions of the Brazilian Amazon. We would have required samples from before the 1980s to describe how SP resistance spread across the basin or describe the complex internal migration of Brazilian parasites after the colonization efforts of past decades. The Brazilian Amazon basin may have sufficient internal migration for drug resistance reported in any particular region to rapidly spread to other parts of basin under similar drug pressure.


Efficiency of excision of 8-oxo-guanine within DNA clustered damage by XRS5 nuclear extracts and purified human OGG1 protein.
A major DNA lesion is the strongly mutagenic 8-oxo-7,8-dihydroguanine (8-oxoG) base, formed by oxidative attack at guanine and which leads to a high level of G.C-->T.A transversions. Clustered DNA damages are formed in DNA following exposure to ionizing radiation or radiomimetic anticancer agents and are thought to be biologically severe. The presence of 8-oxoG within clustered DNA damage may present a challenge to the repair machinery of the cell, if the OGG1 DNA glycosylase/AP lyase protein, present in eukaryotic cells, does not efficiently excise its substrate, 8-oxoG. In this study, specific oligonucleotide constructs containing an 8-oxoG located in several positions opposite to another damage (5,6-dihydrothymine (DHT), uracil, 8-oxoG, AP site, or various types of single strand breaks) were used to determine the relative efficiency of purified human OGG1 and mammalian XRS5 nuclear extracts to excise 8-oxoG from clustered damages. A base damage (DHT, uracil, and 8-oxoG) on the opposite strand has little or no influence on the rate of excision of 8-oxoG whereas the presence of either an AP site or various types of single strand breaks has a strong inhibitory effect on the formation of a SSB due to the excision of 8-oxoG by both hOGG1 and the nuclear extract. The binding of hOGG1 to 8-oxoG is not significantly affected by the presence of a neighboring lesion.


Time to listen: a review of methods to solicit patient reports of adverse events.
Patients have been shown to report accurate observations of medical errors and adverse events. Various methods of introducing patient reporting into patient safety systems have been published with little consensus among researchers on the most effective method. Terminology for use in patient safety reporting has yet to be standardised. Two databases, PubMed and MEDLINE, were searched for literature on patient reporting of medical errors and adverse events. Comparisons were performed to identify the optimal method for eliciting patient initiated events. Seventeen journal publications were reviewed by patient population, type of healthcare setting, contact method, reporting method, duration, terminology and reported response rate. Few patient reporting studies have been published, and those identified in this review covered a wide range of methods in diverse settings. Definitive comparisons and conclusions are not possible. Patient reporting has been shown to be reliable. Higher incident rates were observed when open-ended questions were used and when respondents were asked about personal experiences in hospital and primary care. Future patient reporting systems will need a balance of closed-ended questions for cause analysis and classification, and open-ended narratives to allow for patient's limited understanding of terminology. Establishing the method of reporting that is most efficient in collecting reliable reports and standardising terminology for patient use should be the focus of future research.


Vascular Changes in Intermediate Age-Related Macular Degeneration Quantified Using Optical Coherence Tomography Angiography.
To examine changes in retinal vasculature and ganglion cell layer (GCL) thickness in intermediate age-related macular degeneration (AMD) using optical coherence tomography angiography (OCTA). Zeiss Cirrus Angioplex OCTA 6 × 6 mm scans and a macula 512 × 128 cube scans of the central retina were taken of 63 eyes with intermediate AMD and 51 control eyes. For OCTA scans, the superficial and deep capillary plexus were automatically segmented and vascular density quantified as total number of pixels contributing to the blood flow signal detectable by OCTA. Images were then skeletonized and vessel length, diameter index, morphology, and branching complexity determined. Foveal avascular zone (FAZ) characteristics and GCL thickness were extracted from in-built Angioplex software. Vascular density was significantly reduced in the superficial capillary plexus of AMD eyes compared with normal eyes, particularly in the superior quadrant (42.4% ± 1.6% vs. 43.2% ± 1.4%; P < 0.05). A nonsignificant reduction was also seen in the deep capillary plexus (P = 0.06). Total vessel length and average vessel diameter were all significantly decreased in AMD eyes suggesting density changes were related to decreased vessel number and caliber. Vascular complexity and number of branch points was significantly decreased in the deep capillary plexus (P < 0.05) suggesting loss or significantly reduced flow of vessels. Average GCL thickness was also significantly reduced in the AMD eyes (P < 0.05). No significant changes in FAZ parameters were observed in AMD eyes. This study suggests intermediate AMD affects both the quantity and morphology of inner retinal vasculature and may be associated with changes in inner retinal structure. This work builds upon the notion that AMD pathogenesis may extends beyond the outer retina. Better understanding of retinal vascular changes in AMD can provide insights in the development of treatment and prevention protocols for these diseases.


Prognosis and disability of stroke patients after 5 years in Akita, Japan.
The system of registering stroke patients was begun in 1963 in Ikawa Town, Akita Prefecture, Japan. The town is located in the northeastern part of the country and in 1975 had a population of 6,427. From 1975 to 1981, 109 patients who suffered their first stroke were registered and were monitored for 5 years. The average annual incidence rates of stroke were 2.8 and 2.0 per 1,000 population in males and females, respectively. Mean age at stroke onset was 63.3 and 71.4 years in males and females, respectively (p less than 0.01). According to the clinical classification of stroke, 76 patients suffered cerebral infarction, 21 cerebral bleeding, and six subarachnoid hemorrhage; six strokes were unclassified. The survival rates were compared by sex, age, and clinical stroke type using Cox's proportional hazards model. The survival rate of female stroke patients was lower than that of males, but not significantly so. The survival rate of stroke patients greater than or equal to 65 years old was significantly lower (p less than 0.01) than that of younger patients. Moreover, the survival rate of patients with cerebral bleeding was significantly lower (p less than 0.01) than that of patients with cerebral infarction. In the analysis of self-care among the survivors, performance of the activities of daily living in older patients indicated significantly less independence (p less than 0.01) in younger patients. Follow-up of new stroke cases showed that age and clinical stroke type were significantly associated with survival and that age was also related to disability of the survivors.


Emotion brain alterations in anorexia nervosa: a candidate biological marker and implications for treatment.
Identification of the biological markers of anorexia nervosa (AN) is crucial for the development of new treatments. We aimed to determine whether AN is associated with disturbances in the nonconscious neural processing of innate signals of emotion and whether these disturbances persist after weight gain. In a retest design, 28 adolescent females with AN were tested at first ad not mission to hospital and again after they had gained weight. Matched healthy control participants were tested at the same times. We assessed emotion-elicited event-related potentials (ERPs) during overt and covert presentation of emotion expressions, scores on an emotion-identification behavioural task, and symptom measures. We performed between and within group analyses. Individuals with AN had a marked alteration in ERPs relative to healthy controls. Irrespective of the form of stimulus, early and late ERP componotnents were significantly reduced in AN patients at baseline (when underweight) and on retest (after weight gain), especially in the temporo-occipital regions, suggesting a persistent disruption of the early automatic appraisal of salient emotional signals. This study could have been improved with a longer standardized retest interval. There is likely a core, generic disturbance in AN in the early "automatic" neural processing of emotion irrespective of weight or nutritional status. New innovative emotion-based psychologic or pharmacologic treatments targeting these nonconscious processes may prove beneficial.


Post-assembly processing of [2]rotaxanes.
The concept of using [2]rotaxanes that carry one or more surrogate stoppers which can subsequently be converted chemically into other structural units, resulting in the formation of new interlocked molecular compounds, is introduced and exemplified. Starting from simple NH2(+)-centered/crown-ether-based [2]rotaxanes, containing either one or two benzylic triphenylphosphonium stoppers, the well-known Wittig reaction has been employed to make, 1) other [2]rotaxanes, 2) higher order rotaxanes, 3) branched rotaxanes, and 4) molecular shuttles--all isolated as pure compounds, following catalytic hydrogenations of their carbon-carbon double bonds, obtained when aromatic aldehydes react with the ylides produced when the benzylic triphenylphosphonium derivatives are treated with strong base. The two starting [2]rotaxanes were characterized fully in solution and also in the solid state by X-ray crystallography. The new interlocked molecular compounds that result from carrying out post-assembly Wittig reactions on two [2]rotaxanes were characterized by (dynamic) 1H NMR spectroscopy. In the case of a molecular shuttle in which the crown ether component is dibenzo[24]-crown-8 (DB24C8), shuttling is slow on the 1H NMR timescale, even at high temperatures. However, when DB24C8 is replaced by benzometaphenylene[25]-crown-8 as the ring component in the molecular shuttle, the frequency of the shuttling is observed to be around 100 Hz in [D4]methanol at 63 degrees C.


Muscular Pre-activation Can Boost the Maximal Explosive Eccentric Adaptive Force.
The improvement of power is an objective in training of athletes. In order to detect effective methods of exercise, basic research is required regarding the mechanisms of muscular activity. The purpose of this study is to investigate whether or not a muscular pre-activation prior to an external impulse-like force impact has an effect on the maximal explosive eccentric Adaptive Force (xpAFeccmax). This power capability combines different probable power enhancing mechanisms. To measure the xpAFeccmax an innovative pneumatic device was used. During measuring, the subject tries to hold an isometric position as long as possible. In the moment in which the subjects' maximal isometric holding strength is exceeded, it merges into eccentric muscle action. This process is very close to motions in sports, where an adaptation of the neuromuscular system is required, e.g., force impacts caused by uneven surfaces during skiing. For investigating the effect of pre-activation on the xpAFeccmax of the quadriceps femoris muscle, n = 20 subjects had to pass three different pre-activation levels in a randomized order (level 1: 0.4 bar, level 2: 0.8 bar, level 3: 1.2 bar). After adjusting the standardized pre-pressure by pushing against the interface, an impulse-like load impacted on the distal tibia of the subject. During this, the xpAFeccmax was detected. The maximal voluntary isometric contraction (MVIC) was also measured. The torque values of the xpAFeccmax were compared with regard to the pre-activation levels. The results show a significant positive relation between the pre-activation of the quadriceps femoris muscle and the xpAFeccmax (male: p = 0.000, η2= 0.683; female: p = 0.000, η2= 0.907). The average percentage increase of torque amounted +28.15 ± 25.4% between MVIC and xpAFeccmax with pre-pressure level 1, +12.09 ± 7.9% for the xpAFeccmax comparing pre-pressure levels 1 vs. 2 and +2.98 ± 4.2% comparing levels 2 and 3. A higher but not maximal muscular activation prior to a fast impacting eccentric load seems to produce an immediate increase of force outcome. Different possible physiological explanatory approaches and the use as a potential training method are discussed.


Technical note: Quantifying and characterizing behavior in dairy calves using the IceTag automatic recording device.
The objectives of the current study were 1) to validate the IceTag (http://www.icerobotics.com) automatic recording device for measuring lying, standing, and moving behavior in dairy calves, and 2) to improve the information yield from this device by applying a filtering procedure allowing for the detection of lying versus upright. The IceTag device provides measures of intensity (I) of lying, standing, and activity measured as percent lying, percent standing, and percent active, but does not directly measure lying, standing, and moving behavior because body movements occurring while lying (e.g., shifts in lying position) and while upright (e.g., grooming) are recorded as activity. Therefore, the following 3-step procedure was applied. First, thresholds for I were determined by choosing the cutoff that maximized the sum of sensitivity (Se) and specificity (Sp). Second, a lying period criterion (LPC) was established empirically, and IceTag data were filtered according to the LPC, providing information on the posture of the animal as lying versus being upright. Third, a new threshold of I was estimated for moving activity conditional on the animal being upright. IceTag recordings from 9 calves were compared with video recordings during a 12-h period and analyzed using 2 x 2 contingency tables. Data from the first 4 calves were used to determine an LPC, whereas the remaining 5 calves served for validation of the procedure. An optimal LPC was found by modeling the deviance between IceTag and video recordings as a function of the LPC and choosing the LPC threshold that minimized the deviance. The IceTag device was found to accurately measure the high-prevalence behaviors (lying and standing; Se+Sp >1.90) and less accurately measure the low-prevalence behavior (moving; Se+Sp = 1.39). Application of the 3-step procedure using an optimal LPC estimate of 24.8 s resulted in an improved description of calf behavior, yielding a valid representation of the number and duration of lying and upright periods (Se+Sp = 2.00) within a precision of 0 to 49 s (95% confidence interval). In group-housed dairy calves, valid measures of the number and duration of lying and upright periods may be obtained from the IceTag device when applying the presented filtering procedure to the data. Measures regarding locomotion, on the other hand, should be used with caution.


Understanding collaboration between nurses and physicians as knowledge at work.
Collaboration between nurses and physicians is linked to positive outcomes for patients, especially in the intensive care unit. However, effective collaboration poses challenges because of traditional barriers such as sex and class differences, hierarchical organizational structures in health-care, and physicians' belief that they are the final arbiter of clinical decisions. To further analyze the results of an investigation on how intensive care unit culture, expressed through everyday practices, affected the care of patients who became confused. A model of the types of knowledge (case, patient, and person) used in clinical work was used to analyze the breakdown in collaboration detected in the original study. Breakdown of collaboration occurred because of the types of knowledge used by physicians and nurses. Certain types of knowledge were privileged even when not applicable to the clinical problem, whereas other types were dismissed even when applicable. Viewing collaboration through the conceptual lens of knowledge use reveals new insights. Collaboration broke down in the specific context of caring for patients with confusion because the use of case knowledge, rather than patient knowledge, was prominent in the intensive care unit culture.


Photoinduction of spontaneous surface relief gratings on Azo DR1 glass.
Surface relief gratings were spontaneously photoinduced from a collimated Nd:YAG laser beam at 532 nm on thin films of a disperse red 1 functionalized glass-forming compound. Pattern formation was studied by measuring the diffraction intensity of a He-Ne laser probe beam at 633 nm and by atomic force microscopy (AFM). The dependence of pattern formation on both irradiation time and intensity was studied. The gratings could be erased both optically and thermally. The orientation of the gratings is influenced by the polarization of the writing beam, and it is accompanied by strong diffraction of the incident light into the sample plane, thereby providing a way to couple and trap the light into the substrate. Interestingly, photobleaching upon prolonged irradiation yields transparent gratings, and the process is partially reversible upon thermal erasure.


Evaluation of 99mTc-hexamethylpropyleneamine oxime cerebral blood flow mapping after acute focal ischemia in rats.
Although the blood flow tracer hexamethylpropyleneamine oxime is now widely used for cerebral blood flow mapping using single-photon emission computed tomography, its uptake into acutely ischemic brain has not been well studied. We performed a double-label autoradiographic study in which 99mTc-hexamethylpropyleneamine oxime uptake was compared with [14C]iodoantipyrine-derived cerebral blood flow 0.5, 24, and 72 hours after middle cerebral artery occlusion in 11 rats. We noted excellent correspondence between iodoantipyrine and hexamethylpropyleneamine oxime autoradiograms at all times with both simultaneous tracer injection and 30-minute separation of tracer injections. When the ischemic and hyperemic areas were measured from the same brain section using the two different tracers, hexamethylpropyleneamine oxime underestimated the iodoantipyrine-derived areas by less than 1% (95% confidence interval -2.9% to 2.3%). The maximum discrepancy (-19%) was seen at high flows. When the two tracers were injected separately, the uptake of hexamethylpropyleneamine oxime was not linear compared with iodoantipyrine-derived cerebral blood flow, but the relation became linear after the Lassen correction factor was applied. Hexamethylpropyleneamine oxime uptake thus accurately represents cerebral blood flow 0.5-72 hours after acute cerebral ischemia.


Degenerate photon echoes: simultaneous storage of multiple optical data.
It is shown that simultaneous and spatially overlapping multiple photon echoes can occur following application of a single optical pulse followed by multiple pairs of counterpropagating pulses in various directions-degenerate photon echoes. This scheme has been experimentally verified in Pr(3+):LaF(3) for the doubly degenerate case. In the small-pulse-area regime, the two echoes are observed to be independent with no cross talk between them. From the viewpoint of transient optical memory, this enables us to store multiple independent optical data in one sample spot and to retrieve any one of them, thereby multiplying the memory capacity of the crystal.


Correlation microscope.
We have constructed a correlation microscope based on the Mirau interferometer configuration using a thin silicon nitride film beam splitter, and we have developed a method to extract the amplitude and phase information of the reflected signal from a sample located at the microscope object plane. An imaging theory for the interference microscope has been derived, which predicts accurately both the transverse response at a sharp edge and the range response to a perfect plane reflector.


Time for an Adolescent Health Surveillance System in Saudi Arabia: Findings From "Jeeluna".
With the increasing burden of noncommunicable disease, adolescence is viewed as an opportune time to prevent the onset of certain behaviors and promote healthy states. Although adolescents comprise a considerable portion of Saudi Arabia's population, they have received insufficient attention and indicators of their health status, as a first step in a prevention cycle are unavailable. This study was carried out with the aim of identifying the health risk behaviors and health status of adolescents in Saudi Arabia. This cross-sectional, school-based study was carried out in all 13 regions of Saudi Arabia. Through multistage, cluster, random sampling, intermediate, and secondary school students were invited to participate. Data were collected by means of a self-administered questionnaire addressing health risk behaviors and health status, clinical anthropometric measurements, and laboratory investigations. A total of 12,575 adolescents participated. Various health risk behaviors, including dietary and sedentary behaviors, lack of safety measures, tobacco use, bullying, and violence were highly prevalent. Twenty-eight percent of adolescents reported having a chronic health condition, 14.3% reported having symptoms suggestive of depression, 30.0% were overweight/obese, and 95.6% were vitamin D deficient. Behaviors and conditions known to persist into adulthood and result in morbidity and premature mortality are prevalent among adolescents in Saudi Arabia. Preventive measures and local health policies are urgently needed and can impact adolescents and future adults. Establishing adolescent health surveillance is necessary to monitor trends and impacts of such measures.


Global REACH 2018: High Blood Viscosity and Hemoglobin Concentration Contribute to Reduced Flow-Mediated Dilation in High-Altitude Excessive Erythrocytosis
Excessive erythrocytosis (EE; hemoglobin concentration [Hb] ≥21 g/dL in adult males) is associated with increased cardiovascular risk in highlander Andeans. We sought to quantify shear stress and assess endothelial function via flow-mediated dilation (FMD) in male Andeans with and without EE. We hypothesized that FMD would be impaired in Andeans with EE after accounting for shear stress and that FMD would improve after isovolemic hemodilution. Brachial artery shear stress and FMD were assessed in 23 male Andeans without EE (age: 40±15 years [mean±SD]; Hb<21 g/dL) and 19 male Andeans with EE (age: 43±14 years; Hb≥21 g/dL) in Cerro de Pasco, Peru (4330 m). Shear stress was quantified from Duplex ultrasound measures of shear rate and blood viscosity. In a subset of participants (n=8), FMD was performed before and after isovolemic hemodilution with blood volume replaced by an equal volume of human serum albumin. Blood viscosity and Hb were 48% and 23% higher (both P<0.001) and FMD was 28% lower after adjusting for the shear stress stimulus ( P=0.013) in Andeans with EE compared to those without. FMD was inversely correlated with blood viscosity ( r2=0.303; P<0.001) and Hb ( r2=0.230; P=0.001). Isovolemic hemodilution decreased blood viscosity by 30±10% and Hb by 14±5% (both P<0.001) and improved shear stress stimulus-adjusted FMD from 2.7±1.9% to 4.3±1.9% ( P=0.022). Hyperviscosity, high Hb, or both, actively contribute to acutely reversible impairments in FMD in EE, suggesting that this plays a pathogenic role in the increased cardiovascular risk.


Reconceptualizing drug use prevention processes.
The field of drug use prevention has been advanced through a convergence of theories of human behavior, a more enhanced understanding of the factors that have been found to be associated with the onset of drug use, and more sophisticated research methodologies impacting not only study design and measurement but also data analysis. For these reasons, there is a need for a reconceptualization of the intent and function of prevention in order to refine intervention development and implementation. This review will focus primarily on drug use prevention but the implications are clear for other prevention outcome behaviors. The concepts included in this paper are stimulated by recent advances in understanding neurobiological development and revised understanding of the interaction between individual vulnerability and environmental influences. It also draws on the concept of socialization and the role of socialization and socializing agents in any society.


WPA guidance on mental health and mental health care in migrants.
The purpose of this guidance is to review currently available evidence on mental health problems in migrants and to present advice to clinicians and policy makers on how to provide migrants with appropriate and accessible mental health services. The three phases of the process of migration and the relevant implications for mental health are outlined, as well as the specific problems of groups such as women, children and adolescents, the elderly, refugees and asylum seekers, and lesbian, gay, bisexual and transgender individuals. The concepts of cultural bereavement, cultural identity and cultural congruity are discussed. The epidemiology of mental disorders in migrants is described. A series of recommendations to policy makers, service providers and clinicians aimed to improve mental health care in migrants are provided, covering the special needs of migrants concerning pharmacotherapies and psychotherapies.


[Analysis of risk factors for hypertension in Colima, Mexico].
To evaluate the possible association that age, sex, excess weight, family history of hypertension, alcoholism, and sedentary lifestyle have with hypertension in the adult population of the city of Colima, Mexico. This was a population-based analytic cross-sectional study. A structured survey was used with 280 adults older than 30 years of age who were living in the city of Colima in 2001 and 2002. The variables studied were sex, age, weight, height, family history of hypertension, engaging in physical exercise, smoking, and consuming alcohol. Blood pressure (BP) was measured with the auscultatory method. Borderline or doubtful measurements were checked again four or five days later. Hypertension was defined as systolic BP > or = 140 mm Hg and diastolic blood pressure > or = 90 mm Hg, or as the person being under antihypertensive treatment. The odds ratios (ORs) of the variables studied were calculated, along with their 95% confidence intervals (95% CIs). The association between the variables and hypertension was estimated through logistic regression, and their interaction through the coefficient of the interaction products. The overall prevalence of hypertension was 28.6%. The prevalence was higher in men than in women (42.1% vs. 19.2%; OR = 3.04, 95% CI: 1.8 to 5.2) and in people older than 49 years than in people 30 to 49 years old (36.8% vs. 21.9%; OR = 2.07, 95% CI: 1.22 to 3.50). A family history of hypertension and excess weight were associated with hypertension, while physical exercise had a protective effect (OR = 0.45; 95% CI: 0.23 to 0.86). There was interaction between hypertension and age > or = 50 years, a family history of hypertension, overweight, and physical exercise, especially among women. The prevalence of hypertension in Colima is very similar to that for Mexico as a whole. The strong association that hypertension had with male gender, regardless of the other variables, emphasizes the need for promoting prevention campaigns that focus more on men.


Organ donation after death in Ontario: a population-based cohort study.
Shortfalls in deceased organ donation lead to shortages of solid organs available for transplantation. We assessed rates of deceased organ donation and compared hospitals that had clinical services for transplant recipients (transplant hospitals) to those that did not (general hospitals). We conducted a population-based cohort analysis involving patients who died from traumatic brain injury, subarachnoid hemorrhage, intracerebral hemorrhage or other catastrophic neurologic conditions in Ontario, Canada, between Apr. 1, 1994, and Mar. 31, 2011. We distinguished between acute care hospitals with and without transplant services. The primary outcome was actual organ donation determined through the physician database for organ procurement procedures. Overall, 87,129 patients died from catastrophic neurologic conditions during the study period, of whom 1930 became actual donors. Our primary analysis excluded patients from small hospitals, reducing the total to 79,746 patients, of whom 1898 became actual donors. Patients who died in transplant hospitals had a distribution of demographic characteristics similar to that of patients who died in other large general hospitals. Transplant hospitals had an actual donor rate per 100 deaths that was about 4 times the donor rate at large general hospitals (5.0 v. 1.4, p < 0.001). The relative reduction in donations at general hospitals was accentuated among older patients, persisted among patients who were the most eligible candidates and amounted to about 121 fewer actual donors per year (adjusted odds ratio 0.58, 95% confidence interval 0.36-0.92). Hospital volumes were only weakly correlated with actual organ donation rates. Optimizing organ donation requires greater attention to large general hospitals. These hospitals account for most of the potential donors and missed opportunities for deceased organ donation.


Family participation in care to the critically ill: opinions of families and staff.
Allowing family members to participate in the care of patients in intensive care units (ICUs) may improve the quality of their experience. No previous study has investigated opinions about family participation in ICUs. Prospective multicenter survey in 78 ICUs (1,184 beds) in France involving 2,754 ICU caregivers and 544 family members of 357 consecutive patients. We determined opinions and experience about family participation in care; comprehension (of diagnosis, prognosis, and treatment) and satisfaction (Critical Care Family Needs Inventory) scores to assess the effectiveness of information to families and the Hospital Anxiety and Depression score for family members. Among caregivers 88.2% felt that participation in care should be offered to families. Only 33.4% of family members wanted to participate in care. Independent predictors of this desire fell into three groups: patient-related (SAPS II at ICU admission, OR 0.984); ICU stay length, OR 1.021), family-related (family member age, OR 0.97/year); family not of European descent, OR 0.294); previous ICU experience in the family, OR 1.59), and those related to emotional burden and effectiveness of information provided to family members (symptoms of depression in family members, OR 1.58); more time wanted for information, OR 1.06). Most ICU caregivers are willing to invite family members to participate in patient care, but most family members would decline.


Polymer Electrolyte Membrane Electrolyzers Utilizing Non-precious Mo-based Hydrogen Evolution Catalysts.
The development of low-cost hydrogen evolution reaction (HER) catalysts that can be readily integrated into electrolyzers is critical if H2 from renewable electricity-powered electrolysis is to compete cost effectively with steam reforming. Herein, we report three distinct earth-abundant Mo-based catalysts, namely those based on MoSx , [Mo3 S13 ](2-) nanoclusters, and sulfur-doped Mo phosphide (MoP|S), loaded onto carbon supports. The catalysts were synthesized through facile impregnation-sulfidization routes specifically designed for catalyst-device compatibility. Fundamental electrochemical studies demonstrate the excellent HER activity and stability of the Mo-sulfide based catalysts in an acidic environment, and the resulting polymer electrolyte membrane (PEM) electrolyzers that integrate these catalysts exhibit high efficiency and durability. This work is an important step towards the goal of replacing Pt with earth-abundant catalysts for the HER in commercial PEM electrolyzers.


Internal transcribed spacer rRNA gene sequencing analysis of fungal diversity in Kansas City indoor environments.
Compared to traditional methods of fungal exposure assessment, molecular methods have provided new insight into the richness of fungal communities present in both indoor and outdoor environments. In this study, we describe the diversity of fungi in the homes of asthmatic children located in Kansas City. Fungal diversity was determined by sequencing the internal transcribed spacer (ITS) regions of ribosomal RNA derived from fungi collected in air and dust samples from 31 homes participating in the Kansas City Safe and Healthy Homes Program (KCSHHP). Sequencing results were then compared to data obtained using viable and non-viable fungal exposure assessment methods. ITS clone libraries were predominantly derived from the phylum Ascomycota in both air (68%) and dust (92%) samples and followed by the Basidiomycota and Zygomycota. The majority of Ascomycota clones belonged to four orders including the Pleosporales, Eurotiales, Capnodiales, and Dothideales. ITS sequencing revealed the presence of a number of rarely documented fungal species placed in the Pleosporales. Several species placed in the Basidiomycota were detected in ITS clone libraries but not by viable or non-viable methods. The prevalence of organizational taxonomic units (OTUs) was significantly higher in air than in dust samples (p < 0.0001); however, no differences between OTUs in air samples collected in the subjects' room and basement were observed. These sequencing results demonstrate a much broader diversity of Ascomycota and Basidiomycota communities in KCSHHP indoor environments than previously estimated using traditional methods of assessment.


Inositol 1,3,4,6-tetrakisphosphate mobilizes calcium in Xenopus oocytes with high potency.
Injection of Ins(1,3,4,6)P4 into Xenopus oocytes evoked Ca2(+)-dependent membrane currents with a potency 5-10 times less than Ins(1,4,5)P3, whereas Ins(1,3,4)P3 and Ins(1,3,4,5,6)P5 were almost ineffective. Responses to Ins(1,3,4,6)P4 arose through liberation of intracellular Ca2+ and through entry of extracellular Ca2+. These results, together with the observation that Ins(1,3,4,6)P4 facilitated responses to Ins(1,4,5)P3, suggests that both of these compounds may act on the same intracellular receptors.


Perchlorate in human milk samples from the maternal-infant research on environmental chemicals study (MIREC).
Perchlorate is a low molecular weight highly soluble anion. It occurs naturally in the environment, primarily near potash deposits and in arid regions. The determination of perchlorate in human milk is of interest in vulnerable populations such as infants and pregnant women. In this study, a sensitive and selective isotope dilution ion chromatography/tandem mass spectrometry (ID IC-MS/MS) method was developed and validated for the determination of perchlorate in human milk samples collected from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study. The limit of detection (LOD) was 0.27 µg·kg-1 for human milk. A total of 439 human milk samples were analysed with measurable levels of perchlorate in most of the milk samples, and the mean value was 7.62 ± 32.7 µg·kg-1. This project provided important information related to perchlorate levels in human milk collected across Canada and the extent to which pregnant women and their infants may be exposed to perchlorate. A dietary exposure assessment was also conducted in infants based on the measured values in human milk. The mean perchlorate probable daily intakes (PDIs) for infants consuming human milk were 0.31 ± 0.07 μg/kg bw/day for infants under 1 year and 0.17 ± 0.10 μg/kg bw/day for infants between 1 and 3 years old. None of the estimates exceeded the FAO/WHO provisional maximum tolerable daily intake (PMTDI) of 10 μg/kg bw/day.


Numerical simulation of a TLD pulsed laser-heating scheme for determination of shallow dose and deep dose in low-LET radiation fields.
A new method is described to determine the depth-dose distribution in low-LET radiation fields using a thick thermoluminescent dosimeter (TLD) with a pulsed laser-heating scheme to obtain TL glow output. The computational simulation entails heat conduction and glow curve production processes. An iterative algorithm is used to obtain the dose distribution in the detector. The simulation results indicate that the method can predict the shallow and deep dose in various radiation fields with relative errors less than 20%.


Major depressive disorder during pregnancy and emotional attachment to the fetus.
While there is good evidence that depression negatively impacts mother-to-infant emotional attachment in the postpartum period, the impact of depression in pregnancy on maternal emotions and cognitions about the fetus (often termed "maternal-fetal attachment" or MFA) is unclear. This study compared MFA scores from women meeting clinical criteria for Major Depressive Disorder (MDD) with scores from nondepressed women. Participants were 161 women enrolled at 23-36 weeks gestation, of whom 65 met criteria for MDD via the Structured Clinical Interview for the DSM-IV-TR during their second and/or third trimesters. Cranley's Maternal Fetal Attachment Scale was administered at 26 and 36 weeks gestation. Generalized linear modeling was used to assess the effect of MDD, anxiety, and antidepressant use on MFA. MDD was negatively related to MFA (LR) = 4.58, df = 1, p < 0.04). Neither anxiety (LR = 0.22, p < 0.64), nor antidepressant use (LR = 0.20, df = 1, p < 0.66) were related to MFA. Depression severity was negatively related to MFAS scores (B = -0.005, SE = .002, p < 0.0012) when including the interaction of MDD group and HRSD scores in the model. This study is the first to demonstrate that clinically defined MDD during pregnancy negatively impacts MFA, suggesting that the basis for poor mother-to-infant attachment in postpartum MDD may have roots in pregnancy.


Redox regulation of diaphragm proteolysis during mechanical ventilation.
Prevention of oxidative stress via antioxidants attenuates diaphragm myofiber atrophy associated with mechanical ventilation (MV). However, the specific redox-sensitive mechanisms responsible for this remain unknown. We tested the hypothesis that regulation of skeletal muscle proteolytic activity is a critical site of redox action during MV. Sprague-Dawley rats were assigned to five experimental groups: 1) control, 2) 6 h of MV, 3) 6 h of MV with infusion of the antioxidant Trolox, 4) 18 h of MV, and 5) 18 h of MV with Trolox. Trolox did not attenuate MV-induced increases in diaphragmatic levels of ubiquitin-protein conjugation, polyubiquitin mRNA, and gene expression of proteasomal subunits (20S proteasome alpha-subunit 7, 14-kDa E2, and proteasome-activating complex PA28). However, Trolox reduced both chymotrypsin-like and peptidylglutamyl peptide hydrolyzing (PGPH)-like 20S proteasome activities in the diaphragm after 18 h of MV. In addition, Trolox rescued diaphragm myofilament protein concentration (mug/mg muscle) and the percentage of easily releasable myofilament protein independent of alterations in ribosomal capacity for protein synthesis. In summary, these data are consistent with the notion that the protective effect of antioxidants on the diaphragm during MV is due, at least in part, to decreasing myofilament protein substrate availability to the proteasome.


Ursolic and Oleanolic Acids Induce Mitophagy in A549 Human Lung Cancer Cells.
Ursolic and oleanolic acids are natural isomeric triterpenes known for their anticancer activity. Here, we investigated the effect of triterpenes on the viability of A549 human lung cancer cells and the role of autophagy in their activity. The induction of autophagy, the mitochondrial changes and signaling pathway stimulated by triterpenes were systematically explored by confocal microscopy and western blotting. Ursolic and oleanolic acids induce autophagy in A549 cells. Ursolic acid activates AKT/mTOR pathways and oleanolic acid triggers a pathway independent on AKT. Both acids promote many mitochondrial changes, suggesting that mitochondria are targets of autophagy in a process known as mitophagy. The PINK1/Parkin axis is a pathway usually associated with mitophagy, however, the mitophagy induced by ursolic or oleanolic acid is just dependent on PINK1. Moreover, both acids induce an ROS production. The blockage of autophagy with wortmannin is responsible for a decrease of mitochondrial membrane potential (Δψ) and cell death. The wortmannin treatment causes an over-increase of p62 and Nrf2 proteins promote a detoxifying effect to rescue cells from the death conducted by ROS. In conclusion, the mitophagy and p62 protein play an important function as a survival mechanism in A549 cells and could be target to therapeutic control.


Plasma membrane Ca2+-ATPase isoform 2a is the PMCA of hair bundles.
Mechanoelectrical transduction channels of hair cells allow for the entry of appreciable amounts of Ca(2+), which regulates adaptation and triggers the mechanical activity of hair bundles. Most Ca(2+) that enters transduction channels is extruded by the plasma membrane Ca(2+)-ATPase (PMCA), a Ca(2+) pump that is highly concentrated in hair bundles and may be essential for normal hair cell function. Because PMCA isozymes and splice forms are regulated differentially and have distinct biochemical properties, we determined the identity of hair bundle PMCA in frog and rat hair cells. By screening a bullfrog saccular cDNA library, we identified abundant PMCA1b and PMCA2a clones as well as rare PMCA2b and PMCA2c clones. Using immunocytochemistry and immunoprecipitation experiments, we showed in bullfrog sacculus that PMCA1b is the major isozyme of hair cell and supporting cell basolateral membranes and that PMCA2a is the only PMCA present in hair bundles. This complete segregation of PMCA1 and PMCA2 isozymes holds for rat auditory and vestibular hair cells; PMCA2a is the only PMCA isoform in hair bundles of outer hair cells and vestibular hair cells and is the predominant PMCA of hair bundles of inner hair cells. Our data suggest that hair cells control plasma membrane Ca(2+)-pumping activity by targeting specific PMCA isozymes to distinct subcellular locations. Because PMCA2a is the only Ca(2+) pump present at appreciable levels in hair bundles, the biochemical properties of this pump must account fully for the physiological features of transmembrane Ca(2+) pumping in bundles.


Cultivating multiple aspects of attention through mindfulness meditation accounts for psychological well-being through decreased rumination.
In the last few decades, mindfulness meditation has gained prominence as an adjunctive psychotherapeutic technique. In fact, a vast literature of controlled studies has found that mindfulness meditation is related to improved mental health across a variety of disorders. Elucidating the components involved in mindfulness meditation's positive impact on psychological well-being is an important step in more precisely identifying the populations that would most benefit from its therapeutic utilization. Yet, a consensus regarding the particular underlying mechanisms that contribute to these outcomes is very much limited. There are many reasons for this, including the inconsistent operationalization and use of mindfulness meditation across research investigations. Despite the elusive mechanisms, many studies seem to indicate that cultivating different aspects of attention is a feasible, consistent, and parsimonious starting point bridging mindfulness practice and psychological well-being. Attention in itself is a complex construct. It comprises different networks, including alerting, orienting, and executive attention, and is also explained in terms of the way it is regulated. This paper supports a previously suggested idea that cultivating all aspects of attention through mindfulness meditation leads to greater psychological well-being through decreased ruminative processes. Ruminative processes are decreased by engaging in both focused and receptive attention, which foster the ability to distract and decenter.


Positive versus negative signaling of LET-23: regulation through the adaptor protein, SEM-5.
Worby and Margolis highlight advances in our understanding of signaling from growth factor receptors using the worm Caenorhabditis elegans as a model organism. ARK-1, a cytoplasmic tyrosine kinase, appears to be a negative regulator of multiple pathways in C. elegans. The authors discuss several models for how this negative regulation may occur. The adaptor protein (Grb2 in mammals or SEM-5 in C. elegans) may serve as a regulated scaffold for the binding of other signaling proteins that include both positive (Ras) and negative (ACK) regulators. Thus, Grb2 may function in a cellular decision point for transducing the incoming signals.


Host behaviour and physiology underpin individual variation in avian influenza virus infection in migratory Bewick's swans.
Individual variation in infection modulates both the dynamics of pathogens and their impact on host populations. It is therefore crucial to identify differential patterns of infection and understand the mechanisms responsible. Yet our understanding of infection heterogeneity in wildlife is limited, even for important zoonotic host-pathogen systems, owing to the intractability of host status prior to infection. Using novel applications of stable isotope ecology and eco-immunology, we distinguish antecedent behavioural and physiological traits associated with avian influenza virus (AIV) infection in free-living Bewick's swans (Cygnus columbianus bewickii). Swans infected with AIV exhibited higher serum δ13C (-25.3±0.4) than their non-infected counterparts (-26.3±0.2). Thus, individuals preferentially foraging in aquatic rather than terrestrial habitats experienced a higher risk of infection, suggesting that the abiotic requirements of AIV give rise to heterogeneity in pathogen exposure. Juveniles were more likely to be infected (30.8% compared with 11.3% for adults), shed approximately 15-fold higher quantity of virus and exhibited a lower specific immune response than adults. Together, these results demonstrate the potential for heterogeneity in infection to have a profound influence on the dynamics of pathogens, with concomitant impacts on host habitat selection and fitness.


Effects of fermented soymilk with Lactobacillus casei Shirota on skin condition and the gut microbiota: a randomised clinical pilot trial.
Several clinical studies have shown that isoflavones and Lactobacillus casei Shirota (LcS) have beneficial effects on skin condition and the gut microbiota, respectively. Thus, we investigated the effects of consecutive intake of fermented soymilk (FSM) with LcS on skin condition and the gut microbiota, as well as isoflavone bioavailability, in a randomised, double-blind, placebo-controlled trial as a pilot study. Sixty healthy premenopausal Japanese women received FSM containing a moderate level of isoflavone aglycones and a probiotic LcS, or soymilk (SM) containing neither of them, twice a day for 8 weeks. Skin condition was assessed by a subjective questionnaire for face and morphological analysis of the stratum corneum on the inner forearm. Faecal microbiota and urinary isoflavone were analysed by 16S rRNA gene amplicon sequencing and high-performance liquid chromatography tandem mass spectrometry, respectively. Both the FSM and SM groups had improved skin condition as assessed from scores of overall satisfaction, dryness, moisture, elasticity, coarseness, pigmentation and/or stratum corneum morphology, as well as significantly increased levels of urinary isoflavones during the intake period compared with the pre-intake period, although there were no significant differences between the two groups. There was a significant positive correlation between urinary isoflavone levels and skin questionnaire scores. In contrast, the relative abundance levels of Lactobacillaceae significantly increased and those of Bifidobacteriaceae tended to increase during the intake period compared with the pre-intake period. For the after-intake period they only decreased significantly in the FSM group. The levels of Enterobacteriaceae and Porphyromonadaceae significantly decreased during the intake period in the FSM group. These findings suggest that daily intake of FSM, as well as SM, provides health benefits that improve skin condition via increased levels of isoflavone absorption in the body, and that only FSM beneficially modifies the gut microbiota in premenopausal healthy women.


Factors associated with radiographic progression in patients with rheumatoid arthritis who were treated with methotrexate.
To identify factors associated with radiographic progression at 52 weeks in patients with rheumatoid arthritis (RA) after 12 weeks of methotrexate (MTX) therapy. The study population consisted of patients from the MTX arm of the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO). Logistic regression analysis was used to identify clinical and laboratory assessments performed at Week 12 of MTX therapy that might be associated with Week 52 radiographic outcome (modified total Sharp score). Classification and regression tree (CART) modeling of the Week 12 assessments was used to determine the subgroups of patients with the best and worst radiographic outcomes. A total of 169 patients were analyzed: 116 patients in the best radiographic outcome group and 53 patients in the worst radiographic outcome group. Logistic regression analysis showed that Week 12 C-reactive protein (CRP) level, erythrocyte sedimentation rate, tender joint count, swollen joint count (SJC), and Health Assessment Questionnaire scores were significantly associated with radiographic progression at Week 52 (p < 0.05 for each assessment). CART modeling showed that patients with Week 12 CRP > 0.67 mg/dl and SJC > 1 and patients with Week 12 CRP ≤ 0.67 mg/dl and SJC > 10 were likely to show the worst radiographic progression at Week 52. The CART model had a sensitivity of 85%, specificity of 60%, and overall classification accuracy of 68%. In patients with RA, measures of CRP and SJC after 12 weeks of MTX therapy emerged as the factors most associated with radiographic progression at Week 52.