Mortality in relation to smoking: 50 years' observations on male British doctors.
To compare the hazards of cigarette smoking in men who formed their habits at different periods, and the extent of the reduction in risk when cigarette smoking is stopped at different ages. Prospective study that has continued from 1951 to 2001. United Kingdom. 34 439 male British doctors. Information about their smoking habits was obtained in 1951, and periodically thereafter; cause specific mortality was monitored for 50 years. Overall mortality by smoking habit, considering separately men born in different periods. The excess mortality associated with smoking chiefly involved vascular, neoplastic, and respiratory diseases that can be caused by smoking. Men born in 1900-1930 who smoked only cigarettes and continued smoking died on average about 10 years younger than lifelong non-smokers. Cessation at age 60, 50, 40, or 30 years gained, respectively, about 3, 6, 9, or 10 years of life expectancy. The excess mortality associated with cigarette smoking was less for men born in the 19th century and was greatest for men born in the 1920s. The cigarette smoker versus non-smoker probabilities of dying in middle age (35-69) were 42% nu 24% (a twofold death rate ratio) for those born in 1900-1909, but were 43% nu 15% (a threefold death rate ratio) for those born in the 1920s. At older ages, the cigarette smoker versus non-smoker probabilities of surviving from age 70 to 90 were 10% nu 12% at the death rates of the 1950s (that is, among men born around the 1870s) but were 7% nu 33% (again a threefold death rate ratio) at the death rates of the 1990s (that is, among men born around the 1910s). A substantial progressive decrease in the mortality rates among non-smokers over the past half century (due to prevention and improved treatment of disease) has been wholly outweighed, among cigarette smokers, by a progressive increase in the smoker nu non-smoker death rate ratio due to earlier and more intensive use of cigarettes. Among the men born around 1920, prolonged cigarette smoking from early adult life tripled age specific mortality rates, but cessation at age 50 halved the hazard, and cessation at age 30 avoided almost all of it.


Modulation of working memory function by motivation through loss-aversion.
Cognitive performance is affected by motivation. Few studies, however, have investigated the neural mechanisms of the influence of motivation through potential monetary punishment on working memory. We employed functional MRI during a delayed recognition task that manipulated top-down control demands with added monetary incentives to some trials in the form of potential losses of bonus money. Behavioral performance on the task was influenced by loss-threatening incentives in the form of faster and more accurate performance. As shown previously, we found enhancement of activity for relevant stimuli occurs throughout all task periods (e.g., stimulus encoding, maintenance, and response) in both prefrontal and visual association cortex. Further, these activation patterns were enhanced for trials with possible monetary loss relative to nonincentive trials. During the incentive cue, the amygdala and striatum showed significantly greater activation when money was at a possible loss on the trial. We also evaluated patterns of functional connectivity between regions responsive to monetary consequences and prefrontal areas responsive to the task. This analysis revealed greater delay period connectivity between and the left insula and prefrontal cortex with possible monetary loss relative to nonincentive trials. Overall, these results reveal that incentive motivation can modulate performance on working memory tasks through top-down signals via amplification of activity within prefrontal and visual association regions selective to processing the perceptual inputs of the stimuli to be remembered.


Generation of a stable, posttranslationally modified microtubule array is an early event in myogenic differentiation.
Microtubules (MTs) have been implicated to function in the change of cell shape and intracellular organization that occurs during myogenesis. However, the mechanism by which MTs are involved in these morphogenetic events is unclear. As a first step in elucidating the role of MTs in myogenesis, we have examined the accumulation and subcellular distribution of posttranslationally modified forms of tubulin in differentiating rat L6 muscle cells, using antibodies specific for tyrosinated (Tyr), detyrosinated (Glu), and acetylated (Ac) tubulin. Both Glu and Ac tubulin are components of stable MTs, whereas Tyr tubulin is the predominant constituent of dynamic MTs. In proliferating L6 myoblasts, as in other types of proliferating cells, the level of Glu tubulin was very low when compared with the level of Tyr tubulin. However, when we shifted proliferating L6 cells to differentiation media, we observed a rapid accumulation of Glu tubulin in cellular MTs. By immunofluorescence, the increase in Glu tubulin was first detected in MTs of prefusion myoblasts and was specifically localized to MTs that were associated with elongating portions of the cell. MTs in the multinucleated myotubes observed at later stages of differentiation maintained the elevated level of Glu tubulin that was observed in the prefusion myoblasts. When cells at early stages of differentiation (less than 1 d after switching the culture medium) were immunostained for Glu tubulin and the muscle-specific marker, muscle myosin, we found that the increase in Glu tubulin preceded the accumulation of muscle myosin. Thus, the elaboration of Glu MTs is one of the very early events in myogenesis. Ac tubulin also increased during L6 myogenesis; however, the increase in acetylation occurred later in myogenesis, after fusion had already occurred. Because detyrosination was temporally correlated with early events of myogenesis, we examined the mechanism responsible for the accumulation of Glu tubulin in the MTs of prefusion myoblasts. We found that an increase in the stability of L6 cell MTs occurred at the onset of differentiation, suggesting that the early increase in detyrosination that we observed is a manifestation of a decrease in MT dynamics in elongating myoblasts. We conclude that the establishment of an oriented array of microtubules heightened in its stability and its level of posttranslationally modified subunits may be involved in the subcellular remodeling that occurs during myogenesis.


The human antiporcine cellular repertoire. In vitro studies of acquired and innate cellular responsiveness.
Discordant xenogeneic transplantation offers a potentially unlimited source of donor organs from easily bred, nonendangered, physiologically compatible animals, but has been limited by the inevitable occurrence of hyperacute rejection (HAR). The potential existence of cell-mediated discordant graft rejection has remained obscured by HAR, and hence is incompletely understood. To define the cellular elements capable of recognition of and subsequent response against discordant tissue in a clinically applicable species combination, we have studied the in vitro interaction of human peripheral blood lymphocytes against 3 porcine B lymphoblastoid cell lines and 6 primary porcine endothelial cell populations. PBL from all individuals tested (n = 10) proliferated in response to culture for 72 hr in xenogeneic mixed lymphocyte culture (XMLC) with cell lines expressing porcine MHC (SLA) class II antigens, while endothelial cultures lacking SLA class II generally failed to evoke a response. The proliferative response to class II-positive cells was attenuated by addition of anti-SLA class II antibody but not by anti-SLA class I antibody. Two endothelial populations expressing class II stimulated an inhibitable proliferative response. The magnitude of the short-term proliferative xenogeneic response was similar to that evoked by fully mismatched allogeneic human B lymphoblastoid stimulators. Additionally, extended XMLC was performed with PBL from 3 individuals. All populations responded with continued proliferation when repeatedly stimulated by porcine cells. This was characterized not only by T cell growth, but by prominent NK cell growth as well. Elucidation of the TCR V beta chain usage patterns by semiquantitative PCR documented selection of TCR transcripts from gene family V beta 2 in each group, complemented by a heterogeneous mixture of other transcripts including V beta 17.1, 20.1, and 6.1, suggesting that direct human TCR binding of porcine cells occurs, and that it is likely to be an individualistic response complemented by a more homogeneous NK response. A 51Cr release assay was utilized to demonstrate that unprimed PBL could also lyse porcine target cells. This cytotoxic response was maintained despite the complete removal of T cells, suggesting that porcine-directed NK cell activity is present prior to the maturation of any T cell response. Cytolysis was also demonstrated in serum-free medium and thus was not mediated solely by antibody-dependent cellular cytotoxicity. Chinese hamster ovary cells transfected with the human T cell receptor accessory molecule CD4 were used to study the ability of this molecule to stabilize the interaction between the human TCR and SLA class II.(ABSTRACT TRUNCATED AT 400 WORDS)


Optimization and performance criteria of a Stokes polarimeter based on two variable retarders.
In this paper we present the analysis, optimization and implementation of several Stokes polarimeter configurations based on a set-up including two variable retarders. The polarimeter analysis is based on the Mueller-Stokes formalism, and as a consequence, it is suitable to deal with depolarized light. Complete Stokes polarimeters are optimized by minimizing the amplification of simulated errors into the final solution. Different indicators useful to achieve this aim, as the condition number or the equally weighted variance, are compared in this paper. Moreover, some of the optimized polarimeters are experimentally implemented and it is studied the influence of small deviations from the theoretical ones on the amplification of the Stokes component error. In addition, the benefit of using incomplete polarimeters, when detecting specific ranges of states of polarization, is discussed.


Adiponectin resistance exacerbates insulin resistance in insulin receptor transgenic/knockout mice.
Adiponectin increases insulin sensitivity and contributes to insulin's indirect effects on hepatic glucose production. To examine adiponectin's contribution to insulin action, we analyzed adiponectin levels and activation of AMP-activated protein kinase (AMPK) in insulin receptor transgenic/knockout mice (L1), a genetic model of resistance to insulin's indirect effects on hepatic glucose production. In euglycemic, insulin-resistant L1 mice, we detected hyperadiponectinemia with normal levels of adiponectin receptor-1 and -2. Moreover, adiponectin administration is unable to lower glucose levels or induce activation of AMPK, consistent with a state of adiponectin resistance. In a subset of hyperglycemic L1 mice, we observed decreased mRNA expression of AdipoR2 in liver and muscle, as well as decreased peroxisome proliferator-activated receptor (PPAR)alpha target gene expression in liver, raising the possibility that deterioration of adiponectin/AdipoR2 signaling via PPARalpha activation contributes to the progression from compensated insulin resistance to diabetes. In contrast, we failed to detect changes in other markers of the systemic or local inflammatory response. These data provide evidence for a mechanism of adiponectin resistance and corroborate the notion that adiponectin potentiates hepatic insulin sensitivity.


Amyloid-beta peptide binds with heme to form a peroxidase: relationship to the cytopathologies of Alzheimer's disease.
Amyloid-beta peptide (Abeta) is the toxic agent in Alzheimer's disease (AD), although the mechanism causing the neurodegeneration is not known. We previously proposed a mechanism in which excessive Abeta binds to regulatory heme, triggering functional heme deficiency (HD), causing the key cytopathologies of AD. We demonstrated that HD triggers the release of oxidants (e.g., H(2)O(2)) from mitochondria due to the loss of complex IV, which contains heme-a. Now we add more evidence that Abeta binding to regulatory heme in vivo is the mechanism by which Abeta causes HD. Heme binds to Abeta, thus preventing Abeta aggregation by forming an Abeta-heme complex in a cell-free system. We suggest that this complex depletes regulatory heme, which would explain the increase in heme synthesis and iron uptake we observe in human neuroblastoma cells. The Abeta-heme complex is shown to be a peroxidase, which catalyzes the oxidation of serotonin and 3,4-dihydroxyphenylalanine by H(2)O(2). Curcumin, which lowers oxidative damage in the brain in a mouse model for AD, inhibits this peroxidase. The binding of Abeta to heme supports a unifying mechanism by which excessive Abeta induces HD, causes oxidative damage to macromolecules, and depletes specific neurotransmitters. The relevance of the binding of regulatory heme with excessive Abeta for mitochondrial dysfunction and neurotoxicity and other cytopathologies of AD is discussed.


Disruption of Rho signal transduction upon cell detachment.
Serum-soluble factors play a dominant role in the activation of the small GTPase RhoA. Cell adhesion also modulates RhoA activity but the effect is modest in the absence of serum. Here, we show that cell adhesion is required for serum-stimulated Rho signal transduction leading to myosin light chain (MLC) phosphorylation. Characterization of Rho-kinase substrates revealed that diphosphorylation of MLC at Thr-18 and Ser-19 (ppMLC(T18/S19)) and phosphorylation of the myosin-binding subunit (MBS) of myosin phosphatase at Thr-853 (pMBS(T853)) were mostly Rho and Rho-kinase dependent in attached fibroblasts. MLC monophosphorylation at Ser-19 (pMLC(S19)) was partially dependent on Rho kinase, whereas phosphorylation of MBS at Thr-696 (pMBS(T696)) and phosphorylation of CPI-17 at Thr-38 (pCPI-17(T38)) were mostly Rho-kinase independent. Cell detachment caused a significant reduction in pMLC(S19) and a more dramatic decrease of ppMLC(T18/S19) without inhibiting RhoA. pMBS(T853), pMBS(T696) and pCPI-17(T38) were not significantly reduced, suggesting that myosin-phosphatase activity was little changed. Cells expressing active RhoA (RhoA(V14)) or Rho-kinase catalytic domain maintained elevated pMBS(T853) upon detachment but failed to support ppMLC(T18/S19), indicating that the ability of Rho kinase to phosphorylate MLC is impaired. Reattachment to immobilized fibronectin resulted in a gradual recovery of Rho-kinase-induced ppMLC(T18/S19) that is absent from the cells attached to poly-L-lysine. The convergence of signals from soluble factors and cell adhesion might therefore occur at the point of MLC phosphorylation, providing an effective mechanism for dynamic control of contractility during cell migration.


SIRT1 negatively regulates the activities, functions, and protein levels of hMOF and TIP60.
SIRT1 is a NAD(+)-dependent histone H4K16 deacetylase that controls several different normal physiologic and disease processes. Like most histone deacetylases, SIRT1 also deacetylates nonhistone proteins. Here, we show that two members of the MYST (MOZ, Ybf2/Sas3, Sas2, and TIP60) acetyltransferase family, hMOF and TIP60, are SIRT1 substrates. SIRT1 deacetylation of the enzymatic domains of hMOF and TIP60 inhibits their acetyltransferase activity and promotes ubiquitination-dependent degradation of these proteins. Importantly, immediately following DNA damage, the binding of SIRT1 to hMOF and TIP60 is transiently interrupted, with corresponding hMOF/TIP60 hyperacetylation. Lysine-to-arginine mutations in SIRT1-targeted lysines on hMOF and TIP60 repress DNA double-strand break repair and inhibit the ability of hMOF/TIP60 to induce apoptosis in response to DNA double-strand break. Together, these findings uncover novel pathways in which SIRT1 dynamically interacts with and regulates hMOF and TIP60 through deacetylation and provide additional mechanistic insights by which SIRT1 regulates DNA damage response.


Aspartame. Review of safety issues. Council on Scientific Affairs.
This report examines the safety issues related to the nutritive sweetener aspartame, including possible toxic effects of aspartame's component amino acids, aspartic acid and phenylalanine, and its major decomposition products, methanol and diketopiperazine, and the potential synergistic effect of aspartame and dietary carbohydrate on brain neurochemicals. Available evidence suggests that consumption of aspartame by normal humans is safe and is not associated with serious adverse health effects. Individuals who need to control their phenylalanine intake should handle aspartame like any other source of phenylalanine.


A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I).
The aim of this study was to compare the efficacy and tolerability of quetiapine and lithium monotherapy with that of placebo for a major depressive episode in bipolar disorder. 802 patients with DSM-IV-defined bipolar disorder (499 bipolar I, 303 bipolar II) were randomly allocated to quetiapine 300 mg/d (n = 265), quetiapine 600 mg/d (n = 268), lithium 600 to 1800 mg/d (n = 136), or placebo (n = 133) for 8 weeks. Primary endpoint was the change in Montgomery-Asberg Depression Rating Scale (MADRS) total score. The study was conducted from August 2005 to May 2007. Mean MADRS total score change from baseline at week 8 was -15.4 for quetiapine 300 mg/d, -16.1 for quetiapine 600 mg/d, -13.6 for lithium, and -11.8 for placebo (P < .001 for both quetiapine doses, P = .123 for lithium, vs placebo). Quetiapine 600 mg/d was significantly more effective than lithium in improving MADRS total score at week 8 (P = .013). Quetiapine-treated (both doses), but not lithium-treated, patients showed significant improvements (P < .05) in MADRS response and remission rates, Hamilton Depression Rating Scale (HDRS), Clinical Global Impressions-Bipolar-Severity of Illness and -Change, and Hamilton Anxiety Rating Scale (HARS) scores at week 8 versus placebo. Both quetiapine doses were more effective than lithium at week 8 on the HDRS and HARS. The most common adverse events were somnolence, dry mouth, and dizziness with quetiapine (both doses) and nausea with lithium. Quetiapine (300 or 600 mg/d) was more effective than placebo for the treatment of episodes of acute depression in bipolar disorder. Lithium did not significantly differ from placebo on the main measures of efficacy. Both treatments were generally well tolerated. clinicaltrials.gov Identifier: NCT00206141.


Fluid dynamics and epidemiology: Seasonality and transmission dynamics.
Epidemic models do not account for the effects of climate conditions on the transmission dynamics of viruses. This study presents the vital relationship between weather seasonality, airborne virus transmission, and pandemic outbreaks over a whole year. Using the data obtained from high-fidelity multi-phase, fluid dynamics simulations, we calculate the concentration rate of Coronavirus particles in contaminated saliva droplets and use it to derive a new Airborne Infection Rate (AIR) index. Combining the simplest form of an epidemiological model, the susceptible-infected-recovered, and the AIR index, we show through data evidence how weather seasonality induces two outbreaks per year, as it is observed with the COVID-19 pandemic worldwide. We present the results for the number of cases and transmission rates for three cities, New York, Paris, and Rio de Janeiro. The results suggest that two pandemic outbreaks per year are inevitable because they are directly linked to what we call weather seasonality. The pandemic outbreaks are associated with changes in temperature, relative humidity, and wind speed independently of the particular season. We propose that epidemiological models must incorporate climate effects through the AIR index.


Systematic review of host genomic biomarkers of invasive bacterial disease: Distinguishing bacterial from non-bacterial causes of acute febrile illness.
Infectious diseases play a significant role in the global burden of disease. The gold standard for the diagnosis of bacterial infection, bacterial culture, can lead to diagnostic delays and inappropriate antibiotic use. The advent of high- throughput technologies has led to the discovery of host-based genomic biomarkers of infection, capable of differentiating bacterial from other causes of infection, but few have achieved validation for use in a clinical setting. A systematic review was performed. PubMed/Ovid Medline, Ovid Embase and Scopus databases were searched for relevant studies from inception up to 30/03/2022 with forward and backward citation searching of key references. Studies assessing the diagnostic performance of human host genomic biomarkers of bacterial infection were included. Study selection and assessment of quality were conducted by two independent reviewers. A meta-analysis was undertaken using a diagnostic random-effects model. The review was registered with PROSPERO (ID: CRD42021208462). Seventy-two studies evaluating the performance of 116 biomarkers in 16,216 patients were included. Forty-six studies examined TB-specific biomarker performance and twenty-four studies assessed biomarker performance in a paediatric population. The results of pooled sensitivity, specificity, negative and positive likelihood ratio, and diagnostic odds ratio of genomic biomarkers of bacterial infection were 0.80 (95% CI 0.78 to 0.82), 0.86 (95% CI 0.84 to 0.88), 0.18 (95% CI 0.16 to 0.21), 5.5 (95% CI 4.9 to 6.3), 30.1 (95% CI 24 to 37), respectively. Significant between-study heterogeneity (I2 77%) was present. Host derived genomic biomarkers show significant potential for clinical use as diagnostic tests of bacterial infection however, further validation and attention to test platform is warranted before clinical implementation can be achieved. No funding received.


Opioids are responsible for neurochemical feminization of the brain in prenatally stressed male rats.
To study the role of opioids in early postnatal changes of the hypothalamic testosterone metabolism and catecholamine content underlying feminizing effect of prenatal stress on male sexual behavior in rats. 10 day-old male and female offspring from mothers given naltrexone prior to daily 1-hour restraint during the last gestational week were used in the study. Aromatase and 5 alpha-reductase activities, noradrenaline and dopamine contents in the brain preoptic area and medial basal hypothalamus were studied by thin layer chromatography, radiometric and spectrofluorimetric techniques. Sexual dimorphism of testosterone metabolism enzymes activity and catecholamine content in discrete brain regions of 10 day-old rat pups was found. Prenatal stress attenuated these gender-related differences. Naltrexone pre-treatment of stressed dams prevented modifying effect of prenatal stress on aromatase activity and noradrenaline content in the male preoptic area. The results of the study demonstrate preventive effect of naltrexone on stress-induced alterations of testosterone aromatization and noradrenaline concentration in the developing brain preoptic area associated with neuroendocrine control of the male sexual behavior in adult rats. These findings indicate that endogenic opioids mediate detrimental effect of prenatal stress on neurochemical determinants of the brain sexual differentiation that may underlie feminization of the male sexual behavior.


A 112 kb deletion in chromosome 19q13.42 leads to retinitis pigmentosa.
PURPOSE. This study sets out to identify novel mutations in PRPF31 in a cohort of autosomal dominant retinitis pigmentosa (adRP) patients with a history of nonpenetrance in the family. METHODS. Twenty-one patients with history of nonpenetrant autosomal dominant retinitis pigmentosa were selected; all underwent full ophthalmic examination. Multiplex ligation-dependent probe analysis (MLPA) was performed and, where a deletion was found, further family members were recruited. An individual suspected to harbor a large deletion was used as a positive control. Analysis of single nucleotide polymorphisms in the upstream region was used to determine the extent of the deletion, and the breakpoint was then characterized by PCR and sequencing. RESULTS. In one family, multiplex ligation-dependent probe analysis revealed a novel large deletion in 19q13.4 encompassing exons 1 to 13 of the PRPF31 gene. The mutation was characterized as a deletion of 112 kilobase (kb), encompassing over 90% of PRPF31 and five upstream genes: TFPT, OSCAR, NDUFA3, TARM-1, and VSTM-1. The breakpoint in the positive control family was also characterized. The mechanism of deletion in both families was Alu-mediated nonallelic homologous recombination. CONCLUSIONS. This study describes two large deletions, one in a previously reported family and one in a new family: the latter represents the largest deletion yet described on chromosome 19 and the first report of the involvement of VSTM-1. Remarkably, heterozygous deletion of this large region (encompassing six genes) produces little or no other clinical disease besides retinitis pigmentosa.


The role of root architecture in foraging behavior of entomopathogenic nematodes.
As obligate parasites, entomopathogenic nematodes (EPN) rely on insect hosts to complete their development. In insect pest management, EPN infectiousness has varied a lot. A better understanding of their host-finding behavior in the rhizosphere is therefore crucial to enhance EPN potential in biological control. As previously demonstrated, roots can be used as a pathway to insect hosts by EPN, but this interaction and its impact on EPN foraging remain poorly documented. Three artificial model-roots with different degrees of complexity and connectivity were designed to investigate the impact of root architecture on foraging behavior of the EPN Heterorhabditis megidis. Insect baits were placed at the bottom of each model-root that was subsequently buried in moist sand. After injection of the EPN, the number of EPN-infected baits as well as the number of mature nematodes inside each individual carcass was recorded. The influence of insect-induced root volatiles was also evaluated by spiking the baits with a synthetic version of a natural insect-induced root cue. The ecological relevance of the results was tested in soil with two maize genotypes each exhibiting broadly different root architectures. H. megidi performed better in presence of model-roots. Foraging performances of H. megidis declined with the increasing model-root complexity. Adding the synthetic root volatile dramatically changed this pattern and favored the EPN on the most complex model-roots. H. megidis also moved in the vicinity of maize roots to find the insect baits in soil, and natural root architecture also tended to shape H. megidis foraging behavior. This study adds to the scarce body of literature characterizing physical and chemical interactions between EPN and roots. The present data illustrate that root architecture not only modifies plant quality but also shapes upper trophic levels' ecology.


Alterations in 5-HT2A receptor binding in various brain regions among 6-hydroxydopamine-induced Parkinsonian rats.
The serotonergic system has close interactions with the dopaminergic system and is strongly implicated in the pathophysiological mechanisms and therapeutic paradigms of Parkinson's disease (PD). This study aims to investigate regional changes in 5-hydroxytryptamine (5-HT) 2A receptors in the rat brain 3 weeks after unilateral medial forebrain bundle lesion by 6-hydroxydopamine (6-OHDA). 5-HT 2A receptor distributions and alterations in the postmortem rat brain were detected by [(3)H]ketanserin-binding autoradiography. In the 6-OHDA-induced Parkinson's rat model, nigrostriatal dopaminergic neuron loss significantly mediated the decreased [(3)H]ketanserin binding, predominantly in the agranular insular cortex (17.3%, P = 0.03), cingulate cortex (18.2%, P < 0.001), prefrontal cortex (8%, P = 0.043), primary somatosensory cortex (17.7%, P = 0.002), and caudate putamen (14.5%, P = 0.02) compared to controls while a profound reduction of tyrosine hydroxylase (TH) immunostaining in the striatum was also observed. Alterations in [(3)H]ketanserin binding in the examined brain areas may represent the specific regions that mediate cognitive dysfunctions via the serotonin system. The downregulation of 5-HT(2A) receptor binding in this study also provides indirect evidence for plasticity in the serotonergic system in the rat brains. This study contributes to a better understanding of the critical roles of 5-HT(2A) receptors in treating neurodegenerative disorders and implicates 5-HT(2A) receptors as a novel therapeutic target in the treatment of PD.


Analysis of neural mechanisms accompanying different intensities of dynamic exercise.
The neural mechanisms accompanying dynamic exercise of different intensities were analyzed in dogs and human subjects by means of autoregressive spectral analysis of heart period and arterial pressure variabilities. In the animal experiments, 8 conscious dogs were examined after implanting a solid state pressure gauge in the left ventricle. Animals were examined at rest and during a treadmill run, at 4 km/h, and 0 degrees incline. The experiments were repeated after chronic alpha 1-adrenoreceptor blockade. During the treadmill run, heart rate and systolic left ventricular pressure increased significantly. Simultaneously, the low frequency (LF, 0.1 Hz) component of pulse interval and of systolic pressure variabilities, ie, markers, respectively, of sympathetic modulation of the SA node and of vasomotor activity, increased significantly (evaluated respectively, in normalized and absolute units). After chronic alpha 1-adrenoreceptor blockade, the increase in LF component of systolic pressure variability was prevented, while that observed in R-R interval variability was maintained. Human studies were carried out with either invasive or noninvasive techniques. In the former approach already described, performed in young hypertensive subjects, arterial pressure was recorded with a high fidelity technique. In the second approach applied to young champion swimmers, only the variability of the R-R interval was examined. In both studies, moderate levels of exercise were accompanied by an increase in the LF component of the spectrum: in the case of arterial pressure variability, this increase was detectable both in absolute and normalized units; vice versa, in the case of R-R variability, since physical exercise is accompanied by a marked abatement of the variance, normalized units had to be used in order to evaluate the shift of the sympathovagal balance in favor of sympathetic overactivity.


Role of Bcl-2 family members in caspase-independent apoptosis during Chlamydia infection.
Infection with an obligate intracellular bacterium, the Chlamydia trachomatis lymphogranuloma venereum (LGV/L2) strain or the guinea pig inclusion conjunctivitis serovar of Chlamydia psittaci, leads to apoptosis of host cells. The apoptosis is not affected by a broad-spectrum caspase inhibitor, and caspase-3 is not activated in infected cells, suggesting that apoptosis mediated by these two strains of Chlamydia is independent of known caspases. Overexpression of the proapoptotic Bcl-2 family member, Bax, was previously shown to induce caspase-independent apoptosis, and we find that Bax is activated and translocates from the cytosol to the mitochondria in C. psittaci-infected cells. C. psittaci-induced apoptosis is inhibited in host cells overexpressing Bax inhibitor-1 and is inhibited through overexpression of Bcl-2, which blocks both caspase-dependent and -independent apoptosis. As Bax and mitochondria are ideally located to sense stress-related metabolic changes emanating from the interior of an infected cell, it is likely that Bax-dependent apoptosis may also be observed in cells infected with other intracellular pathogens.


Cochlear implant outcome is not influenced by the choice of ear.
This study tested the hypothesis that patients with residual hearing in the nonimplanted ear had the same cochlear implant benefit whether the implanted ear had profound or severe hearing loss. A retrospective chart review of adult cochlear implant recipients with postlingual hearing loss. Patients were categorized according to the pure-tone average of the implanted and contralateral ears as (a) bilateral profound, (b) severe-profound, and (c) bilateral severe. The results of a test battery of spoken language measures were compared among patients belonging to these hearing categories at 6, 12, and 24 months after surgery, using a t-test and multivariate regression analyses. The presence of residual hearing in one or both ears was associated with significantly higher postoperative speech perception scores compared with participants with bilateral profound hearing loss. Among participants with similar amounts of residual hearing in the nonimplanted ear, however, there was no difference in speech recognition scores between those with profound and those with severe hearing loss in the implanted ear. Among participants with asymmetric hearing loss, there is no additional benefit to implanting the better-hearing ear that can be preserved for use with a hearing aid for better speech understanding in noise and sound localization. These results suggest that the additional benefit received by patients with residual hearing is mediated by trophic effects on crossed pathways in the central nervous system and is independent of the preoperative functional status of the implanted ear.


When are sexual difficulties distressing for women? The selective protective value of intimate relationships.
Recent studies have shown that sexual functioning and sexually related personal distress are weakly related in women, with only a minority of sexual difficulties resulting in significant levels of distress. However, there has been little systematic research to date on which factors moderate the relationship between sexual functioning and sexual distress. To assess the degree to which relational intimacy and attachment anxiety moderate the association between sexual functioning and sexual distress in college-age women. Two hundred women (mean age=20.25) completed surveys assessing sexual functioning, relational intimacy, attachment anxiety, and sexual distress. Participants completed the Sexual Satisfaction Scale for Women, the Female Sexual Function Index, the Dimensions of Relationship Quality Scale, and the Revised Experiences in Close Relationships Measure of Adult Romantic Attachment. Relational intimacy and attachment anxiety moderated the association between multiple aspects of sexual functioning and sexual distress. For lubrication and sexual pain, functioning was more strongly associated with distress in low-intimacy vs. high-intimacy relationships, but only for women with high levels of attachment anxiety. Results regarding desire were mixed and neither intimacy nor attachment anxiety interacted with subjective arousal or orgasm in predicting distress. Both relational intimacy and attachment anxiety are important moderators of the association between sexual functioning and subjective sexual distress in women. Theoretical and practical implications are discussed.


Reliability of plasma polar metabolite concentrations in a large-scale cohort study using capillary electrophoresis-mass spectrometry.
Cohort studies with metabolomics data are becoming more widespread, however, large-scale studies involving 10,000s of participants are still limited, especially in Asian populations. Therefore, we started the Tsuruoka Metabolomics Cohort Study enrolling 11,002 community-dwelling adults in Japan, and using capillary electrophoresis-mass spectrometry (CE-MS) and liquid chromatography-mass spectrometry. The CE-MS method is highly amenable to absolute quantification of polar metabolites, however, its reliability for large-scale measurement is unclear. The aim of this study is to examine reproducibility and validity of large-scale CE-MS measurements. In addition, the study presents absolute concentrations of polar metabolites in human plasma, which can be used in future as reference ranges in a Japanese population. Metabolomic profiling of 8,413 fasting plasma samples were completed using CE-MS, and 94 polar metabolites were structurally identified and quantified. Quality control (QC) samples were injected every ten samples and assessed throughout the analysis. Inter- and intra-batch coefficients of variation of QC and participant samples, and technical intraclass correlation coefficients were estimated. Passing-Bablok regression of plasma concentrations by CE-MS on serum concentrations by standard clinical chemistry assays was conducted for creatinine and uric acid. In QC samples, coefficient of variation was less than 20% for 64 metabolites, and less than 30% for 80 metabolites out of the 94 metabolites. Inter-batch coefficient of variation was less than 20% for 81 metabolites. Estimated technical intraclass correlation coefficient was above 0.75 for 67 metabolites. The slope of Passing-Bablok regression was estimated as 0.97 (95% confidence interval: 0.95, 0.98) for creatinine and 0.95 (0.92, 0.96) for uric acid. Compared to published data from other large cohort measurement platforms, reproducibility of metabolites common to the platforms was similar to or better than in the other studies. These results show that our CE-MS platform is suitable for conducting large-scale epidemiological studies.


Different circadian rest-active rhythms in Kleine-Levin syndrome: a prospective and case-control study.
Kleine-Levin syndrome (KLS) is a rare recurrent hypersomnia. Our study aimed at monitoring the movements of patients with KLS using actigraphy and evaluating their circadian rhythm. Twenty young patients with KLS and 14 age-matched controls were recruited. Each individual wore an actigraphy for more than 6 months to monitor at least two attacks. Controls kept wearing the device for at least 7 days. The activity counts were averaged in hourly basis and the day-to-night amplitude was quantified by the differences of the averaged activity counts during daytime and nighttime. The hourly activities of different days were aligned and averaged to construct the circadian profile. Parametric and nonparametric estimation of circadian rhythm was calculated. We applied detrended fluctuation analysis to evaluate the temporal correlations beneath the activity fluctuations at multiple time scales. Circadian rhythm in asymptomatic period showed no significant difference compared to the controls. During hypersomnia attack, the amplitude of the circadian rest-active rhythms drastically decreased and decreased interdaily stability (IS) was found, as well as significant decreased M10 and short-time fractal correlation (α1). Drastically decreased mean and standard deviation of activity were noted, compared to the pre-attack phase and recovery phase. α1 and M10 increased during the late attack phase, and overcompensated IS was noted in the recovery phase. This study confirmed that circadian rest-active rhythms was affected when KLS hypersomnia attack. Several parameters including M10, IS, and α1 may be physiological markers of KLS, which can help to predict the end of hypersomnia episodes.


Population vulnerability to storm surge flooding in coastal Virginia, USA.
This study aims to assess the vulnerability of populations to storm surge flooding in 12 coastal localities of Virginia, USA. Population vulnerability is assessed by way of 3 physical factors (elevation, slope, and storm surge category), 3 built-up components (road availability, access to hospitals, and access to shelters), and 3 household conditions (storm preparedness, financial constraints to recovering from severe weather events, and health fragility). Fuzzy analysis is used to generate maps illustrating variation in several types of population vulnerability across the region. When considering physical factors and household conditions, the most vulnerable neighborhoods to sea level rise and storm surge flooding are largely found in urban areas. However, when considering access to critical infrastructure, we find rural residents to be more vulnerable than nonrural residents. These detailed assessments can inform both local and state governments in catastrophic planning. In addition, the methodology may be generalized to assess vulnerability in other coastal corridors and communities. The originality is highlighted by evaluating socioeconomic conditions at refined scale, incorporating a broader range of human perceptions and predispositions, and employing a geoinformatics approach combining physical, built-up, and socioeconomic conditions for population vulnerability assessment. Integr Environ Assess Manag 2016;12:500-509. © 2015 SETAC.


Chest CT features associated with the clinical characteristics of patients with COVID-19 pneumonia.
Coronavirus disease 2019 (COVID-19) has rapidly swept across the world. This study aimed to explore the relationship between the chest CT findings and clinical characteristics of COVID-19 patients. Patients with COVID-19 confirmed by next-generation sequencing or RT-PCR who had undergone more than 4 serial chest CT procedures were retrospectively enrolled. This study included 361 patients - 192 men and 169 women. On initial chest CT, more lesions were identified as multiple bilateral lungs lesions and localised in the peripheral lung. The predominant patterns of abnormality were ground-glass opacities (GGO) (28.5%), consolidation (13.0%), nodule (23.0%), fibrous stripes (5.3%) and mixed (30.2%). Severe cases were more common in patients with a mixed pattern (21.1%) and less common in patients with nodules (2.4%). During follow-up CT, the mediumtotal severity score (TSS) in patients with nodules and fibrous strips was significantly lower than that in patients with mixed patterns in all three stages (p < .01). Chest CT plays an important role in diagnosing COVID-19. The CT features may vary by age. Different CT features are not only associated with clinical manifestation but also patient prognosis. Key messages The initial chest CT findings of COVID-19 could help us monitor and predict the outcome. Nodules were more common in non severe cases and had a favorable prognosis. The mixed pattern was more common in severe cases and usually had a relatively poor outcome.


Neurosteroid regulation of GABAA receptor single-channel kinetic properties of mouse spinal cord neurons in culture.
1. Single-channel kinetics of steroid enhancement of single gamma-aminobutyric acidA (GABA) receptor currents obtained from somata of mouse spinal cord neurones in culture were investigated using the excised outside-out patch-clamp recording technique. GABA (2 microM) and GABA (2 microM) plus androsterone (5 alpha-androstan-3 alpha-ol-17-one, AND, 10 nM-10 microM) or pregnanolone (5 beta-pregnan-3 alpha-ol-20-one, PRE, 100 nM-10 microM) applied by pressure ejection from micropipettes evoked inward currents when patches were voltage clamped at -75 mV in symmetrical chloride solutions. Averaged GABA receptor currents were increased in the presence of the steroids. 2. GABA receptor currents were recorded with at least two conductance levels, a predominant or main-conductance level of about 28 pS (which contributed 96% of the current evoked) and a minor or sub-conductance level of about 20 pS. The current amplitudes of the two conductance levels were unchanged by the steroids. The gating (opening and closing) kinetics of both of the conductance levels were analysed. Findings for the main-conductance level are summarized below. 3. Both steroids increased the average GABA receptor channel open duration. Consistent with the increased GABA receptor channel average open duration, the steroids shifted frequency histograms of GABA receptor channel open durations to longer durations. Three exponential functions were required to fit best the frequency histograms of GABA open durations, consistent with at least three kinetic open states of the main-conductance level. Time constants obtained from the GABA receptor channel open-duration frequency histograms were unchanged in the presence of the steroids. The basis for the increased average GABA receptor channel open durations by the steroids was due to an increased relative proportion of the two longer open-duration time constants. The GABA receptor channel average open durations were increased by AND and PRE in a concentration-dependent manner by shifting the proportion of openings to the longer open time constants. At a concentration of 10 microM, the prolongation of the average open duration was decreased, suggesting that the GABA receptor channel was blocked by these steroids. 4. GABA receptor channel opening frequency was increased and average channel-closed duration was decreased by AND or PRE. Consistent with this, areas of the frequency histograms of channel closed durations were shifted to shorter durations. Closed frequency distributions were fitted best with five to six exponential functions, suggesting that the channel had multiple kinetic closed states. The three briefest time constants were not greatly altered by the steroids.(ABSTRACT TRUNCATED AT 400 WORDS)


Testing the evolution process of prostate-specific antigen in early stage prostate cancer: what is the proper underlying model?
This paper empirically tests a model of stochastic evolutions of prostate-specific antigen (PSA), a trigger for intervention in an early stage prostate cancer surveillance program. It conducts hypothesis testing of the Geometric Browning Motion model based on its attributes of independent increments and linearity of the variance in the increment length versus a wide range of stochastic and deterministic alternatives. These alternatives include the currently accepted deterministic growth model. The paper reports strong empirical evidence in favour of the Geometric Browning Motion model. A model that best describes PSA evolution is a prerequisite to the establishment of decision-making criteria for abandoning active surveillance (i.e. a strategy that involves close monitoring) in early stage prostate cancer. Thus, establishing empirically the type of PSA process is a first step toward the identification of more accurate triggers for abandoning active surveillance and starting treatment while the chances of curing the disease are still high.


Electromagnetic fields and cancer: the cost of doing nothing.
Everyone is exposed to electromagnetic fields (EMFs) from electricity (extremely low frequency, ELF), communication frequencies, and wireless devices (radiofrequency, RF). Concern of health hazards from EMFs has increased as the use of cell phones and other wireless devices has grown in all segments of society, especially among children. While there has been strong evidence for an association between leukemia and residential or occupational exposure to ELF EMFs for many years, the standards in existence are not sufficiently stringent to protect from an increased risk of cancer. For RF EMFs, standards are set at levels designed to avoid tissue heating, in spite of convincing evidence of adverse biological effects at intensities too low to cause significant heating. Recent studies demonstrate elevations in rates of brain cancer and acoustic neuroma only on the side of the head where individuals used their cell phone. Individuals who begin exposure at younger ages are more vulnerable. These data indicate that the existing standards for radiofrequency exposure are not adequate. While there are many unanswered questions, the cost of doing nothing will result in an increasing number of people, many of them young, developing cancer.


A mouse gene related to Distal-less shows a restricted expression in the developing forebrain.
Many genes known to be involved in embryogenesis and morphogenesis of the fruitfly Drosophila melanogaster encode proteins with a highly conserved region of 60 amino acids called the homeodomain. Mammalian counterparts for most of these genes have been identified, including those homologous to the Drosophila homeotic genes or to genes such as evenskipped, engrailed or caudal. We have isolated a murine homeobox gene that encodes a homeodomain similar to that encoded by the Drosophila Distalless (Dll) gene. Dll has a crucial role in Drosophila limb morphogenesis, partially specifying pattern along the proximo-distal axis of the limb. The murine counterpart is expressed in a restricted region of the developing brain, within the diencephalon and the adjacent telencephalic regions.


Autologous hematopoietic stem cell transplantation for autoimmune diseases: an observational study on 12 years' experience from the European Group for Blood and Marrow Transplantation Working Party on Autoimmune Diseases.
Autologous hematopoietic stem cell transplantation has been used since 1996 for the treatment of severe autoimmune diseases refractory to approved therapies. We evaluated the long-term outcomes of these transplants and aimed to identify potential prognostic factors. In this observational study we analyzed all first autologous hematopoietic stem cell transplants for autoimmune diseases reported to the European Group for Blood and Marrow Transplantation (EBMT) registry between 1996-2007. The primary end-points for analysis were overall survival, progression-free survival and transplant-related mortality at 100 days. Nine hundred patients with autoimmune diseases (64% female; median age, 35 years) who underwent a first autologous hematopoietic stem cell transplant were included. The main diseases were multiple sclerosis (n=345), systemic sclerosis (n=175), systemic lupus erythematosus (n=85), rheumatoid arthritis (n=89), juvenile arthritis (n=65), and hematologic immune cytopenia (n=37). Among all patients, the 5-year survival was 85% and the progression-free survival 43%, although the rates varied widely according to the type of autoimmune disease. By multivariate analysis, the 100-day transplant-related mortality was associated with the transplant centers' experience (P=0.003) and type of autoimmune disease (P=0.03). No significant influence of transplant technique was identified. Age less than 35 years (P=0.004), transplantation after 2000 (P=0.0015) and diagnosis (P=0.0007) were associated with progression-free survival. This largest cohort studied worldwide shows that autologous hematopoietic stem cell transplantation can induce sustained remissions for more than 5 years in patients with severe autoimmune diseases refractory to conventional therapy. The type of autoimmune disease, rather than transplant technique, was the most relevant determinant of outcome. Results improved with time and were associated with the transplant centers' experience. These data support ongoing and planned phase III trials to evaluate the place of autologous hematopoietic stem cell transplantation in the treatment strategy for severe autoimmune diseases.


The literature landscape on peace-sustainability nexus: A scientometric analysis.
Academics, policymakers, and practitioners have long considered peace and sustainability to be fundamentally linked. However, despite the increased attention paid toward the intersection of peace and sustainability, there is still limited knowledge on the nature of their linkages. To advance the current understanding on the peace-sustainability nexus and inform an integrated research agenda, this paper employs a scientometric analysis of literature to identify publication trends, thematic clusters, and knowledge gaps. Analyzing the publications according to the types of peace, the pillars of positive peace, the dimensions of sustainability, and the SDGs further reveals weak engagement among academic disciplines and across the SDGs. The results of this analysis emphasize the need for future research to focus on underexamined subjects, geographic regions, and sectors to bolster the linkages between peace and sustainability.


Severe drug induced acute hepatitis associated with use of St John's wort (Hypericum perforatum) during treatment with pegylated interferon α.
A 61-year-old woman with chronic hepatitis C received peginterferon α 180 μg/week, and obtained undetectable qualitative hepatitis C virus (HCV) RNA (lower limit of detection 50 IU/ml) after 8 weeks of treatment. Shortly thereafter aminotransferase values greatly increased (>20 × upper limit of normal) and did not decline after treatment suspension. The patient admitted taking St John's wort (Hypericum perforatum) for depressed mood, recommended by a friend, during the preceding 6 weeks. Liver function tests continued to worsen and international normalised ratio (INR) prolongation developed; the patient was hospitalised. Test for antinuclear antibody was positive (1:320) and treatment with methylprednisolone was started; bilirubin and aminotransferase levels slowly declined, though a new flare occurred when steroids were tapered. After 6 months of prednisone treatment, the liver function tests returned to baseline levels. The combination of peginterferon α and St John's wort resulted in a severe acute hepatitis in this patient. Patients should be advised of this potential toxic effect of this herbal remedy.


Use of Donor Human Milk and Maternal Breastfeeding Rates: A Systematic Review.
The number of human milk banks is growing worldwide. The introduction of donor human milk (DHM) to neonatal units has been advocated as a strategy to promote maternal breastfeeding. However, concern has been raised that the introduction of DHM may actually lead to a decrease in maternal breastfeeding. To address this question, we conducted a systematic literature review of studies that assessed maternal breastfeeding rates before and after the introduction of DHM. We searched 7 electronic databases, carried out citation tracking, and contacted experts in the field. Where data for breastfeeding rates before and after the introduction of DHM were directly comparable, a relative risk was calculated. Our search identified 286 studies, of which 10 met the inclusion criteria. Definitions of patient populations and study outcomes varied, limiting meaningful comparison. Where possible, relative risks (RR) were calculated on aggregated data. The introduction of DHM had a significant positive impact on any breastfeeding on discharge (RR, 1.19; 95% confidence interval [CI], 1.06-1.35;P= .005) but none on exclusive maternal breastfeeding on discharge (RR, 1.12; 95% CI, 0.91-1.40;P= .27) or on exclusive administration of own mother's milk (OMM) days 1 to 28 of life (RR, 1.08; 95% CI, 0.78-1.49; P= .65). A single-center study demonstrated a significant decrease in the percentage of feeds that were OMM after the introduction of DHM. In conclusion, the available data demonstrate some evidence of positive and negative effects on measures of maternal breastfeeding when DHM is introduced to a neonatal unit.


Is the association of airborne particles with daily deaths confounded by gaseous air pollutants? An approach to control by matching.
Although particulate air pollution has been associated with increased numbers of daily deaths in dozens of cities around the world, issues still remain about the association. Some have questioned the complex modeling used to control for season in Poisson regression or the role of gaseous air pollutants as potential confounders of the association. I examined the association between deaths and particulate matter with an aerodynamic diameter less than or equal to 10 microm (PM10) using a case-crossover design. In this approach, the pollution on the day of each death is contrasted with the pollution level on control days when the subject did not die. Season and gaseous air pollutants were controlled by matching. Control days were chosen within the same month of the same year to control for season, and matched on either sulfur dioxide (SO2; within 1 ppb), nitrogen dioxide (within 1 ppb), maximum ozone (within 2 ppb), or carbon monoxide (within 0.03 ppm). The analysis was conducted in 14 U.S. cities that have daily PM10 monitoring. After matching, there were about 400,000 deaths in each analysis. Results were combined across cities using a maximum likelihood method. PM10 was a significant predictor of mortality when controlling for gaseous air pollutants, with effect sizes ranging from a 0.45% increase per 10 microg/m3 increment of PM10 [95% confidence interval (CI), 0.12-0.79%] when matched on maximum hourly ozone levels, to a 0.81% increase per 10 microg/m3 increment of PM10 (95% CI, 0.47-1.16%) when matched on 24-hr average SO2.


Magnetic composite BiOCl-SrFe12O19: a novel p-n type heterojunction with enhanced photocatalytic activity.
The magnetic composite BiOCl-SrFe12O19, a novel p-n type heterojunction was synthesized by hydrolysis with a medium temperature sintering method. The microstructure and magnetic properties of the prepared material were characterized by FTIR, XRD, SEM, TEM, HRTEM, SAED, and VSM. The results showed the [001] facet of BiOCl with high photocatalytic activity was exposed in the BiOCl-SrFe12O19. The heterostructured BiOCl-SrFe12O19 had better magnetic properties, contributing to its reuse and improvement in photocatalysis. Moreover, the composite was blessed with excellent photocatalytic activity and stability. In the BiOCl-SrFe12O19 system, SrFe12O19 not only inhibited the growth of BiOCl along the [001] direction to enhance the exposure of the [001] wafer, but also acted as a sensitizer absorbing light irradiation. The magnetic field generated from SrFe12O19 made BiOCl, under light irradiation, produce more photo-induced electrons and holes and simultaneously hampered their recombination. For the first time we propose the possible mechanism of how to enhance photocatalytic activity by a magnetic field effect originating from the magnetic photocatalyst itself.


Performing a knee arthroscopy among patients with degenerative knee disease: one-third is potentially low value care.
The purpose of this study was to assess in which proportion of patients with degenerative knee disease aged 50+ in whom a knee arthroscopy is performed, no valid surgical indication is reported in medical records, and to explore possible explanatory factors. A retrospective study was conducted using administrative data from January to December 2016 in 13 orthopedic centers in the Netherlands. Medical records were selected from a random sample of 538 patients aged 50+ with degenerative knee disease in whom arthroscopy was performed, and reviewed on reported indications for the performed knee arthroscopy. Valid surgical indications were predefined based on clinical national guidelines and expert opinion (e.g., truly locked knee). A knee arthroscopy without a reported valid indication was considered potentially low value care. Multivariate logistic regression analysis was performed to assess whether age, diagnosis ("Arthrosis" versus "Meniscal lesion"), and type of care trajectory (initial or follow-up) were associated with performing a potentially low value knee arthroscopy. Of 26,991 patients with degenerative knee disease, 2556 (9.5%) underwent an arthroscopy in one of the participating orthopedic centers. Of 538 patients in whom an arthroscopy was performed, 65.1% had a valid indication reported in the medical record and 34.9% without a reported valid indication. From the patients without a valid indication, a joint patient-provider decision or patient request was reported as the main reason. Neither age [OR 1.013 (95% CI 0.984-1.043)], diagnosis [OR 0.998 (95% CI 0.886-1.124)] or type of care trajectory [OR 0.989 (95% CI 0.948-1.032)] were significantly associated with performing a potentially low value knee arthroscopy. In a random sample of knee arthroscopies performed in 13 orthopedic centers in 2016, 65% had valid indications reported in the medical records but 35% were performed without a reported valid indication and, therefore, potentially low value care. Patient and/or surgeons preference may play a large role in the decision to perform an arthroscopy without a valid indication. Therefore, interventions should be developed to increase adherence to clinical guidelines by surgeons that target invalid indications for a knee arthroscopy to improve care. IV.


Sleep is more sensitive to high doses of caffeine in the middle years of life.
During the middle years of life, sleep becomes more fragile and its sensitivity to psychostimulants may increase. This study evaluated the effects of 200 mg and 400 mg of caffeine on sleep in young and middle-aged adults. The sleep of 22 young (23.5 ± 1.9 years) and 24 middle-aged (51.7 ± 11.5 years) adults was recorded using polysomnography in two conditions (placebo and caffeine) in a double-blind cross-over design. Compared to placebo, caffeine increased sleep latency, shortened total sleep duration and reduced sleep efficiency. At the higher dose, these effects were more pronounced in middle-aged than in young adults. Furthermore, the higher dose of caffeine increased absolute stage 1 sleep in young adults, whereas it decreased absolute stage 2 sleep in middle-aged adults. Caffeine also induced dose-dependent increases in relative stage 1 sleep and reductions in absolute and relative slow wave sleep and absolute rapid eye movement sleep in both age groups. There was no dose- or age-related modulation of the effects of caffeine on quantified electroencephalographic measures. These results indicate that, compared to young adults, middle-aged adults are generally more sensitive to the effects of a high dose of caffeine on sleep quantity and quality.


The Operational Development and Empirical Testing of the Terrorist Radicalization Assessment Protocol (TRAP-18).
The Terrorist Radicalization Assessment Protocol (TRAP-18) is a structured professional judgment instrument for threat assessment of the individual terrorist. It is a rationally derived theoretical model comprising eight proximal warning behaviors and 10 distal characteristics. Empirical research on the TRAP-18 is reviewed, including both nomothetic and idiographic studies of individual terrorists in both the United States and Europe. Mean interrater reliability is 0.895 (Cohen's kappa), ranging from 0.69 to 1.0. Evidence of criterion validity has been demonstrated, including usefulness of the instrument across various extremist ideologies (jihadism, ethnic nationalism, and single-issue), and its ability to discriminate between thwarted and successful attackers. The instrument appears to advance the domain recommendations of Monahan (2012, 2016) for the risk assessment of the individual terrorist. The TRAP-18 is further discussed as a threat assessment instrument for mental health clinicians. The limitations of the current research provide direction for further studies to assess its reliability and construct, discriminant, and predictive validity.


Brain development is impaired in c-fos -/- mice.
c-Fos is a proto-oncogene involved in diverse cellular functions. Its deregulation has been associated to abnormal development and oncogenic progression. c-fos-/- mice are viable but present a reduction in their body weight and brain size. We examined the importance of c-Fos during neocortex development at 13.5, 14.5 and 16.5 days of gestation. At E14.5, neocortex thickness, apoptosis, mitosis and expression of markers along the different stages of Neural Stem Progenitor Cells (NSPCs) differentiation in c-fos-/- and wild-type mice were analyzed. A ~15% reduction in the neocortex thickness of c-fos-/- embryos was observed which correlates with a decrease in the number of differentiated cells and an increase in apoptosis at the ventricular zone. No difference in mitosis rate was observed, although the mitotic angle was predominantly vertical in c-fos-/- embryos, suggesting a reduced trend of NSPCs to differentiate. At E13.5, changes in differentiation markers start to be apparent and are still clearly observed at E16.5. A tendency of more AP-1/DNA complexes present in nuclear extracts of cerebral cortex from c-fos-/- embryos with no differences in the lipid synthesis activity was found. These results suggest that c-Fos is involved in the normal development of NSPCs by means of its AP-1 activity.


Diffractive optics development using a modified stack-and-draw technique.
We present a novel method for the development of diffractive optical elements (DOEs). Unlike standard surface relief DOEs, the phase shift is introduced through a refractive index variation achieved by using different types of glass. For the fabrication of DOEs we use a modified stack-and-draw technique, originally developed for the fabrication of photonic crystal fibers, resulting in a completely flat element that is easy to integrate with other optical components. A proof-of-concept demonstration of the method is presented-a two-dimensional binary optical phase grating in the form of a square chessboard with a pixel size of 5 μm. Two types of glass are used: low refractive index silicate glass NC21 and high refractive index lead-silicate glass F2. The measured diffraction characteristics of the fabricated component are presented and it is shown numerically and experimentally that such a DOE can be used as a fiber interconnector that couples light from a small-core fiber into the several cores of a multicore fiber.


Epigenetic activation of SOX11 in lymphoid neoplasms by histone modifications.
Recent studies have shown aberrant expression of SOX11 in various types of aggressive B-cell neoplasms. To elucidate the molecular mechanisms leading to such deregulation, we performed a comprehensive SOX11 gene expression and epigenetic study in stem cells, normal hematopoietic cells and different lymphoid neoplasms. We observed that SOX11 expression is associated with unmethylated DNA and presence of activating histone marks (H3K9/14Ac and H3K4me3) in embryonic stem cells and some aggressive B-cell neoplasms. In contrast, adult stem cells, normal hematopoietic cells and other lymphoid neoplasms do not express SOX11. Such repression was associated with silencing histone marks H3K9me2 and H3K27me3. The SOX11 promoter of non-malignant cells was consistently unmethylated whereas lymphoid neoplasms with silenced SOX11 tended to acquire DNA hypermethylation. SOX11 silencing in cell lines was reversed by the histone deacetylase inhibitor SAHA but not by the DNA methyltransferase inhibitor AZA. These data indicate that, although DNA hypermethylation of SOX11 is frequent in lymphoid neoplasms, it seems to be functionally inert, as SOX11 is already silenced in the hematopoietic system. In contrast, the pathogenic role of SOX11 is associated with its de novo expression in some aggressive lymphoid malignancies, which is mediated by a shift from inactivating to activating histone modifications.


Comparing the profile of respiratory fungal pathogens amongst immunocompetent and immunocompromised hosts, their susceptibility pattern and correlation of various opportunistic respiratory fungal infections and their progression in relation to the CD4+T-cell counts.
Invasive fungal infections are increasingly common in the nosocomial setting. The patients were divided into two groups immunocompetent and immunocompromised that is, patients with significant neutropenia <500 neutrophils/μl for longer than 10 days. microscopy, culture, identification of isolates were done and some specilised tests on serum and BAL for antigen detection were performed. Majority of the patients were young adult males in this study. A higher prevalence of 26.7% was seen in immunocompromised patients. Amongst yeasts, Candida albicans was the predominant species followed by the National AIDS Control that is, Candida glabrata, Candida dubliniensis, Candida parapsilosis and Candida tropicalis in the same order. Amongst moulds, Aspergillus fumigatus was the most common species followed by Aspergillus flavus and Aspergillus niger. Mucor and Penicillium marneffei were seen in a lower prevalence. By Broth microdilution method, isolates of Candida spp. were most sensitive to caspofungin, amphotericin B, ketoconazole and fluconazole in the same order. Isolates of Aspergillus spp. were most sensitive to caspofungin, amphotericin B and itraconazole in the same order. By disc diffusion method, resistance to fluconazole was observed in 6.9% isolates of C. albicans. 50% of C. dubliniensis and 20% of C. glabrata showed resistance to fluconazole. A total mortality of 27.7% was observed during this study. This was distributed as 24.1%, 26.7%, 50%, 50%, 100% and 0% among by patients of candidiasis, aspergillosis, cryptococcosis, pneumocystosis, mucormycosis and penicilliosis. Fifteen per cent were lost to follow-up. Patterns of invasive fungal infections are changing in many ways. In the midst of these evolving trends, IFI of the respiratory tractcontinue to remain important causes of morbidity and mortality. Diagnostic tools can be adequately used only if the treating physician is aware of the propensity of patients to acquire a fungal infection. Thus, continuous awareness and education is crucial for successful management of patients. Judicious use of antifungal medications as prophylactic measures must be employed, particularly in the critically ill and patients of HIV.


Oral perception of liquid volume changes with age.
Bolus volume has been widely studied, and research has demonstrated a variety of physiological impacts on swallowing and swallowing disorders. Oral perception of bolus volume has not, to our knowledge, been investigated in association with normal ageing processes. Research suggests many sensory changes with age, some within the oral cavity, and changes in swallowing function with age have been defined. The role of perception in oropharyngeal deglutition with age requires further investigation. The purpose of this study was to establish the psychophysical relationship between liquid volume and oral perception and examine changes with age. Healthy young and older adults were prospectively assessed using a magnitude estimation task differentiating five volumes of water delivered randomly to the oral cavity. Results suggest a fourfold increase in liquid volume is required by older participants to perceive an approximate twofold increase in the perception of volume compared with younger healthy adults. Sensory receptors in the oral cavity provide a feedback loop that modulates the swallowing motor response so that it is optimal for the size and consistency of the bolus. Changes in perception of bolus volume with age are consistent with other perceptual changes and may provide valuable information regarding sensorineural rehabilitation strategies in the future.


The effect of a basic home stimulation programme on the development of young children infected with HIV.
The human immunodeficiency virus (HIV) potentially causes a significant encephalopathy and resultant developmental delay in infected children. The aim of this study was to determine whether a home-based intervention programme could have an impact on the neurodevelopmental status of children infected with HIV. A longitudinal, randomized, controlled trial was conducted. A total of 122 children aged less than 2 years 6 months were assigned to either a comparison or an experimental group. Children in the experimental group were given a home stimulation programme that was updated every 3 months. The home programme included activities to promote motor, cognitive, and speech and language development. Children in the comparison group received no developmental intervention. Children were assessed by a blinded assessor at baseline, 6 months, and 12 months using the Bayley Scales of Infant Development, 2nd edition. The children in this study came from poor socioeconomic backgrounds and their nutritional status was suboptimal. The experimental group included 60 children (30 males, 30 females) with a mean age of 18 months (SD 8.1 mo). The comparison group included 62 children (32 males, 30 females) with a mean age 19 months (SD 8.2 mo). Cognitive and motor development were severely affected at baseline, with 52% of the children having severe cognitive delay and 72% having severe motor delay at baseline. Children in the experimental group showed significantly greater improvement in cognitive (p=0.010) and motor (p=0.020) development over time than children in the comparison group. A home stimulation programme taught to the caregiver can significantly improve cognitive and motor development in young children infected with HIV.


The effects of hyperoxic and hypercarbic gases on tumour blood flow.
Carbogen (95% O2 and 5% CO2) has been used in preference to 100% oxygen (O2) as a radiosensitizer, because it is believed that CO2 blocks O2-induced vasoconstriction. However, recent work suggests that both normal and tumour arterioles of dorsal flap window chambers exhibit the opposite: no vasoconstriction vs constriction for O2 vs carbogen breathing respectively. We hypothesized that CO2 content might cause vasoconstriction and investigated the effects of three O2-CO2 breathing mixtures on tumour arteriolar diameter (TAD) and blood flow (TBF). Fischer 344 rats with R3230Ac tumours transplanted into window chambers breathed either 1%, 5%, or 10% CO2 + O2. Intravital microscopy and laser Doppler flowmetry were used to measure TAD and TBF respectively. Animals breathing 1% CO2 had increased mean arterial pressure (MAP), no change in heart rate (HR), transient reduction in TAD and no change in TBF. Rats breathing 5% CO2 (carbogen) had transiently increased MAP, decreased HR, reduced TAD and a sustained 25% TBF decrease. Animals exposed to 10% CO2 experienced a transient decrease in MAP, no HR change, reduced TAD and a 30-40% transient TBF decrease. The effects on MAP, HR, TAD and TBF were not CO2 dose-dependent, suggesting that complex physiologic mechanisms are involved. Nevertheless, when > or = 5% CO2 was breathed, there was clear vasoconstriction and TBF reduction in this model. This suggests that the effects of hypercarbic gases on TBF are site-dependent and that use of carbogen as a radiosensitizer may be counterproductive in certain situations.


O-GlcNAcylation prevents aggregation of the Polycomb group repressor polyhomeotic.
The glycosyltransferase Ogt adds O-linked N-Acetylglucosamine (O-GlcNAc) moieties to nuclear and cytosolic proteins. Drosophila embryos lacking Ogt protein arrest development with a remarkably specific Polycomb phenotype, arising from the failure to repress Polycomb target genes. The Polycomb protein Polyhomeotic (Ph), an Ogt substrate, forms large aggregates in the absence of O-GlcNAcylation both in vivo and in vitro. O-GlcNAcylation of a serine/threonine (S/T) stretch in Ph is critical to prevent nonproductive aggregation of both Drosophila and human Ph via their C-terminal sterile alpha motif (SAM) domains in vitro. Full Ph repressor activity in vivo requires both the SAM domain and O-GlcNAcylation of the S/T stretch. We demonstrate that Ph mutants lacking the S/T stretch reproduce the phenotype of ogt mutants, suggesting that the S/T stretch in Ph is the key Ogt substrate in Drosophila. We propose that O-GlcNAcylation is needed for Ph to form functional, ordered assemblies via its SAM domain.


Estimating the frequency of indolent breast cancer in screening trials.
Cancer screening can detect cancer that would not have been detected in a patient's lifetime without screening. Standard methods for analyzing screening data do not explicitly account for the possibility that a fraction of tumors may remain latent indefinitely. We extend these methods by representing cancers as a mixture of those that progress to symptoms (progressive) and those that remain latent (indolent). Given sensitivity of the screening test, we derive likelihood expressions to simultaneously estimate (1) the rate of onset of preclinical cancer, (2) the average preclinical duration of progressive cancers, and (3) the fraction of preclinical cancers that are indolent. Simulations demonstrate satisfactory performance of the estimation approach to identify model parameters subject to precise specifications of input parameters and adequate numbers of interval cancers. In application to four breast cancer screening trials, the estimated indolent fraction among preclinical cancers varies between 2% and 35% when assuming 80% test sensitivity and varying specifications for the earliest time that participants could plausibly have developed cancer. We conclude that standard methods for analyzing screening data can be extended to allow some indolent cancers, but accurate estimation depends on correctly specifying key inputs that may be difficult to determine precisely in practice.


Subungual melanoma with osteocartilaginous differentiation.
Osteocartilaginous metaplasia is known to occur rarely in melanomas, particularly in subungual melanomas. We present a case of a calcified subungual soft tissue tumour in which biopsy of the lesion showed malignant round and spindle-shaped tumour cells, many of which were associated with the formation of cartilage and osteoid-like material. Subsequent resection showed clear histological evidence of a subungual melanoma. Tumour cells expressed S100, melan-A and neurone-specific enolase but were negative for HMB45. Diagnostic radiological and histological features and the nature of the osteocartilaginous differentiation within this lesion is discussed.


Soy protein products: processing and use.
Soy protein products are mainly used as ingredients in formulated foods and seldom are seen by the public. They consist of four broad categories. (1) Most soy proteins are derived from "white flakes," made by dehulling, flaking and defatting soybeans by hexane extraction. These may then be milled into defatted flours or grits containing approximately 50-54% protein; extracted with ethanol or acidic waters to remove flavor compounds and flatulence sugars, producing soy protein concentrates containing 65-70% protein; or processed into soy protein isolates containing 90+% protein by alkali extraction of the protein, removal of fiber by centrifugation and reprecipitation and drying of the protein. (2) Full-fat products are made in enzyme-active and in toasted forms. (3) Various dried soyfoods, including soy milk and tofu, are produced. (4) Mixtures of soy proteins with cereals, dried milk or egg fractions, gelatin, stabilizers and emulsifiers are offered for specific baking, whipping, breading and batter applications. Texturized products, resembling meat chunks or bacon chips, are made by extrusion of flours and concentrates or spinning of isolates. Soy protein ingredients are used in compounded foods for their functional properties, including water and fat absorption, emulsification, aeration (whipping) and heat setting and for increasing total protein content and improving the essential amino acids profile.


Behavior and daily activity patterns of specialist and generalist predators of the hemlock woolly adelgid, Adelges tsugae.
The behavior and daily activity patterns of two specialist predators, Laricobius nigrinus Fender (Coleoptera: Derodontidae) and Sasajiscymnus tsugae, Sasaji and McClure (Coleoptera: Coccinellidae), and a generalist predator, Harmonia axyridis Pallas (Coleoptera: Coccinellidae), of hemlock woolly adelgid, Adelges tsugae (Hemiptera: Adelgidae), were examined using digital video recording in the laboratory. The two specialists are part of a biological control program for A. tsugae, and it is not known if competitive interactions with previously established generalist predators will negatively impact their effectiveness. The behavior and daily activity patterns of adult females of each species were documented in single- and paired-predator assays under simulated spring and summer conditions. Behavior varied qualitatively and quantitatively by species, and did not appear to be highly coordinated temporally or spatially. All species exhibited continuous activity patterns that were punctuated by longer periods of rest. Extensive and intensive searching behavior occurred in all species, with intensive searching being highly variable. Specialist predators appeared to be more selective of feeding and oviposition sites, and rested at more concealed locations than the generalist species. In spring conditions, L. nigrinus had greater activity and a more even behavior distribution than S. tsugae or H. axyridis, which were skewed towards resting. In summer, the latter two species showed increased activity at higher temperatures. Conspecifics significantly altered the time allocated to specific behaviors for L. nigrinus and H. axyridis, resulting in reduced predator effectiveness by reducing time and energy expenditure on activities that directly impact the adelgids. In contrast, S. tsugae conspecifics and all heterospecific combinations showed non-interference. The activity of each species varied with time of day; L. nigrinus was more active at night, while S. tsugae and H. axyridis were more active during the day. All predator groupings maintained a high degree of spatial separation relative to assay size. The use of multiple-predator species combinations that include the specialist predators, is recommended over single-species for biological control of A. tsugae, as temporal and spatial patterns were not highly coordinated. Low-density releases may reduce the potential negative effects of intraspecific competition.


Discomfort and factual recollection in intensive care unit patients.
A stay in the intensive care unit (ICU), although potentially life-saving, may cause considerable discomfort to patients. However, retrospective assessment of discomfort is difficult because recollection of stressful events may be impaired by sedation and severe illness during the ICU stay. This study addresses the following questions. What is the incidence of discomfort reported by patients recently discharged from an ICU? What were the sources of discomfort reported? What was the degree of factual recollection during patients' stay in the ICU? Finally, was discomfort reported more often in patients with good factual recollection? All ICU patients older than 18 years who had needed prolonged (>24 hour) admission with tracheal intubation and mechanical ventilation were consecutively included. Within three days after discharge from the ICU, a structured, in-person interview was conducted with each individual patient. All patients were asked to complete a questionnaire consisting of 14 questions specifically concerning the environment of the ICU they had stayed in. Furthermore, they were asked whether they remembered any discomfort during their stay; if they did then they were asked to specify which sources of discomfort they could recall. A reference group of surgical ward patients, matched by sex and age to the ICU group, was studied to validate the questionnaire. A total of 125 patients discharged from the ICU were included in this study. Data for 123 ICU patients and 48 surgical ward patients were analyzed. The prevalence of recollection of any type of discomfort in the ICU patients was 54% (n = 66). These 66 patients were asked to identify the sources of discomfort, and presence of an endotracheal tube, hallucinations and medical activities were identified as such sources. The median (min-max) score for factual recollection in the ICU patients was 15 (0-28). The median (min-max) score for factual recollection in the reference group was 25 (19-28). Analysis revealed that discomfort was positively related to factual recollection (odds ratio 1.1; P < 0.001), especially discomfort caused by the presence of an endotracheal tube, medical activities and noise. Hallucinations were reported more often with increasing age. Pain as a source of discomfort was predominantly reported by younger patients. Among postdischarge ICU patients, 54% recalled discomfort. However, memory was often impaired: the median factual recollection score of ICU patients was significantly lower than that of matched control patients. The presence of an endotracheal tube, hallucinations and medical activities were most frequently reported as sources of discomfort. Patients with a higher factual recollection score were at greater risk for remembering the stressful presence of an endotracheal tube, medical activities and noise. Younger patients were more likely to report pain as a source of discomfort.


Clinical and radiographic outcomes of failed repairs of large or massive rotator cuff tears: minimum ten-year follow-up.
Little information exists regarding the long-term outcome after structural failure of rotator cuff repair. We previously reported clinical improvement, despite a 94% rate of failure of healing, at two years of follow-up in a cohort of eighteen patients who had undergone arthroscopic repair of massive rotator cuff tears. The purpose of the present study was to evaluate the ten-year results for these patients with known structural failures of rotator cuff repairs. Fifteen (83%) of eighteen patients were available for follow-up at ten years. Patients were evaluated with use of the American shoulder and elbow surgeons (ASES) score, the simple shoulder test (SST), a visual analog scale pain score, and the constant score. Radiographs and sonograms were assessed. The average age was 74.6 years at the time of the latest follow-up. The average ASES score was 79.4 points (range, 50 to 95 points) and the average visual analog scale pain score was 2.2 points (range, 1 to 4 points); both scores were unchanged from those at two years. The average SST score was 9.2 points (range, 6 to 12 points), and the average age-adjusted Constant score was 73.2 points (range, 58.7 to 89.7 points). Of the patients with structurally failed repairs, all but one had radiographic signs of proximal humeral migration or cuff tear arthropathy: three had Hamada grade-2 changes, five had grade-3 changes, and three had Grade-4 changes (with two having grade-4a changes and one having grade-4b changes). Ultrasound confirmed the persistence of all tears that had been seen at two years. Clinical improvements and pain relief after arthroscopic rotator cuff repair of large and massive tears are durable at the time of long-term (ten-year) follow-up, despite early structural failure of repair. Shoulders had a high rate of progression of radiographic signs associated with large rotator cuff tears. These results demonstrate that healing of large rotator cuff tears is not critical for long-term satisfactory clinical results in older patients.


Free energy calculations for rings and chains formed by dipolar hard spheres.
We employ a method based on Monte Carlo grand-canonical simulations to precisely calculate partition functions of non-interacting chains and rings formed by dipolar hard spheres (DHS) at low temperature. The extended low temperature region offered by such cluster calculations, compared to what had been previously achieved with standard simulations, opens up the possibility of exploring a part of the DHS phase diagram which was inaccessible before. The reported results offer the unique opportunity of verifying well-established theoretical models based on the ideal gas of cluster approximation in order to clarify their range of validity. They also provide the basis for future studies in which cluster-cluster interactions will be included.


Functionally distinct tendon fascicles exhibit different creep and stress relaxation behaviour.
Most overuse tendinopathies are thought to be associated with repeated microstrain below the failure threshold, analogous to the fatigue failure that affects materials placed under repetitive loading. Investigating the progression of fatigue damage within tendons is therefore of critical importance. There are obvious challenges associated with the sourcing of human tendon samples for in vitro analysis so animal models are regularly adopted. However, data indicates that fatigue life varies significantly between tendons of different species and with different stresses in life. Positional tendons such as rat tail tendon or the bovine digital extensor are commonly applied in in vitro studies of tendon overuse, but there is no evidence to suggest their behaviour is indicative of the types of human tendon particularly prone to overuse injuries. In this study, the fatigue response of the largely positional digital extensor and the more energy storing deep digital flexor tendon of the bovine hoof were compared to the semitendinosus tendon of the human hamstring. Fascicles from each tendon type were subjected to either stress or strain controlled fatigue loading (cyclic creep or cyclic stress relaxation respectively). Gross fascicle mechanics were monitored after cyclic stress relaxation and the mean number of cycles to failure investigated with creep loading. Bovine extensor fascicles demonstrated the poorest fatigue response, while the energy storing human semitendinosus was the most fatigue resistant. Despite the superior fatigue response of the energy storing tendons, confocal imaging suggested a similar degree of damage in all three tendon types; it appears the more energy storing tendons are better able to withstand damage without detriment to mechanics.


Autoantibody levels in myositis patients correlate with clinical response during B cell depletion with rituximab.
To determine the longitudinal trends in serum levels of four myositis-associated autoantibodies: anti-Jo-1, -transcription intermediary factor 1 γ (TIF1-γ), -signal recognition particle (SRP) and -Mi-2, after B cell depletion with rituximab, and to determine the longitudinal association of these autoantibody levels with disease activity as measured by myositis core-set measures (CSMs). Treatment-resistant adult and pediatric myositis subjects (n = 200) received rituximab in the 44-week Rituximab in Myositis Trial. CSMs [muscle enzymes, manual muscle testing (MMT), physician and patient global disease activity, HAQ, and extramuscular disease activity] were evaluated monthly and anti-Jo-1 (n = 28), -TIF1-γ (n = 23), -SRP (n = 25) and -Mi-2 (n = 26) serum levels were measured using validated quantitative ELISAs. Temporal trends and the longitudinal relationship between myositis-associated autoantibodies levels and CSM were estimated using linear mixed models. Following rituximab, anti-Jo-1 levels decreased over time (P < 0.001) and strongly correlated with all CSMs (P < 0.008). Anti-TIF1-γ levels also decreased over time (P < 0.001) and were only associated with HAQ, MMT and physician and patient global disease activity. Anti-SRP levels did not change significantly over time, but were significantly associated with serum muscle enzymes. Anti-Mi-2 levels significantly decreased over time and were associated with muscle enzymes, MMT and the physician global score. Anti-Jo-1, anti-TIF1-γ and anti-Mi-2 levels in myositis subjects decreased after B cell depletion and were correlated with changes in disease activity, whereas anti-SRP levels were only associated with longitudinal muscle enzyme levels. The strong association of anti-Jo-1 levels with clinical outcomes suggests that anti-Jo-1 autoantibodies may be a good biomarker for disease activity.


Fast and Epsilon-Optimal Discretized Pursuit Learning Automata.
Learning automata (LA) are powerful tools for reinforcement learning. A discretized pursuit LA is the most popular one among them. During an iteration its operation consists of three basic phases: 1) selecting the next action; 2) finding the optimal estimated action; and 3) updating the state probability. However, when the number of actions is large, the learning becomes extremely slow because there are too many updates to be made at each iteration. The increased updates are mostly from phases 1 and 3. A new fast discretized pursuit LA with assured ε -optimality is proposed to perform both phases 1 and 3 with the computational complexity independent of the number of actions. Apart from its low computational complexity, it achieves faster convergence speed than the classical one when operating in stationary environments. This paper can promote the applications of LA toward the large-scale-action oriented area that requires efficient reinforcement learning tools with assured ε -optimality, fast convergence speed, and low computational complexity for each iteration.


Solution structure and dynamics of the human-Escherichia coli thioredoxin chimera: insights into thermodynamic stability.
We have determined the high-resolution solution structure of the oxidized form of a chimeric human and Escherichia coli thioredoxin (TRX(HE)) by NMR. The overall structure is well-defined with a rms difference for the backbone atoms of 0.27 +/- 0.06 A. The topology of the protein is identical to those of the human and E. coli parent proteins, consisting of a central five-stranded beta-sheet surrounded by four alpha-helices. Analysis of the interfaces between the two domains derived from the human and E. coli sequences reveals that the general hydrophobic packing is unaltered and only subtle changes in the details of side chain interactions are observed. The packing of helix alpha(4) with helix alpha(2) across the hybrid interface is less optimal than in the parent molecules, and electrostatic interactions between polar side chains are missing. In particular, lysine-glutamate salt bridges between residues on helices alpha(2) and alpha(4), which were observed in both human and E. coli proteins, are not present in the chimeric protein. The origin of the known reduced thermodynamic stability of TRX(HE) was probed by mutagenesis on the basis of these structural findings. Two mutants of TRX(HE), S44D and S44E, were created, and their thermal and chemical stabilities were examined. Improved stability toward chaotropic agents was observed for both mutants, but no increase in the denaturation temperature was seen compared to that of TRX(HE). In addition to the structural analysis, the backbone dynamics of TRX(HE) were investigated by (15)N NMR relaxation measurements. Analysis using the model free approach reveals that the protein is fairly rigid with an average S(2) of 0.88. Increased mobility is primarily present in two external loop regions comprising residues 72-74 and 92-94 that contain glycine and proline residues.


Stent placement versus surgical palliation for adults with malignant gastric outlet obstruction.
Malignant gastric outlet obstruction is the clinical and pathological consequence of cancerous disease causing a mechanical obstruction to gastric emptying. It usually occurs when malignancy is at an advanced stage; therefore, people have a limited life expectancy. It is of paramount importance to restore oral intake to improve quality of life for the person in a manner that has a minimal risk of complications and a short recovery period. To assess the benefits and harms of endoscopic stent placement versus surgical palliation for people with symptomatic malignant gastric outlet obstruction. In May 2018 we searched the Cochrane Central Register of Controlled Trials, Ovid MEDLINE, Ovid Embase and Ovid CINAHL. We screened reference lists from included studies and review articles. We included randomised controlled trials comparing stent placement with surgical palliation for people with gastric outlet obstruction secondary to malignant disease. Two review authors independently extracted study data. We calculated the risk ratio (RR) with 95% confidence intervals (CI) for binary outcomes, mean difference (MD) or standardised mean difference (SMD) with 95% CI for continuous outcomes and the hazard ratio (HR) for time-to-event outcomes. We performed meta-analyses where meaningful. We assessed the quality of evidence using GRADE criteria. We identified three randomised controlled trials with 84 participants. Forty-one participants underwent surgical palliation and 43 participants underwent duodenal stent placement. There may have been little or no difference in the technical success of the procedure (RR 0.98, 95% CI 0.88 to 1.09; low-quality evidence), or whether the time to resumption of oral intake was quicker for participants who had undergone duodenal stent placement (MD -3.07 days, 95% CI -4.76 to -1.39; low-quality evidence).Due to very low-quality evidence, we were uncertain whether surgical palliation improved all-cause mortality and median survival postintervention.The time to recurrence of obstructive symptoms may have increased slightly following duodenal stenting (RR 5.08, 95% CI 0.96 to 26.74; moderate-quality evidence).Due to very low-quality evidence, we were uncertain whether surgical palliation improved serious and minor adverse events. The heterogeneity for adverse events was moderately high (serious adverse events: Chi² = 1.71; minor adverse events: Chi² = 3.08), reflecting the differences in definitions used and therefore, may have impacted the outcomes. The need for reintervention may have increased following duodenal stenting (RR 4.71, 95% CI 1.36 to 16.30; very low-quality evidence).The length of hospital stay may have been shorter (by approximately 4 to 10 days) following stenting (MD -6.70 days, 95% CI -9.41 to -3.98; moderate-quality evidence). The use of duodenal stent placement in malignant gastric outlet obstruction has the benefits of a quicker resumption of oral intake and a reduced inpatient hospital stay; however, this is balanced by an increase in the recurrence of symptoms and the need for further intervention.It is impossible to draw further conclusions on these and the other measured outcomes, primarily due to the low number of eligible studies and small number of participants which resulted in low-quality evidence. It was not possible to analyse the impact on quality of life each intervention had for these participants.