Behavioural activation therapy for depression in adults.
Behavioural activation is a brief psychotherapeutic approach that seeks to change the way a person interacts with their environment. Behavioural activation is increasingly receiving attention as a potentially cost-effective intervention for depression, which may require less resources and may be easier to deliver and implement than other types of psychotherapy. To examine the effects of behavioural activation compared with other psychological therapies for depression in adults. To examine the effects of behavioural activation compared with medication for depression in adults. To examine the effects of behavioural activation compared with treatment as usual/waiting list/placebo no treatment for depression in adults. We searched CCMD-CTR (all available years), CENTRAL (current issue), Ovid MEDLINE (1946 onwards), Ovid EMBASE (1980 onwards), and Ovid PsycINFO (1806 onwards) on the 17 January 2020 to identify randomised controlled trials (RCTs) of 'behavioural activation', or the main elements of behavioural activation for depression in participants with clinically diagnosed depression or subthreshold depression. We did not apply any restrictions on date, language or publication status to the searches. We searched international trials registries via the World Health Organization's trials portal (ICTRP) and ClinicalTrials.gov to identify unpublished or ongoing trials. We included randomised controlled trials (RCTs) of behavioural activation for the treatment of depression or symptoms of depression in adults aged 18 or over. We excluded RCTs conducted in inpatient settings and with trial participants selected because of a physical comorbidity. Studies were included regardless of reported outcomes. Two review authors independently screened all titles/abstracts and full-text manuscripts for inclusion. Data extraction and 'Risk of bias' assessments were also performed by two review authors in duplicate. Where necessary, we contacted study authors for more information. Fifty-three studies with 5495 participants were included; 51 parallel group RCTs and two cluster-RCTs. We found moderate-certainty evidence that behavioural activation had greater short-term efficacy than treatment as usual (risk ratio (RR) 1.40, 95% confidence interval (CI) 1.10 to 1.78; 7 RCTs, 1533 participants), although this difference was no longer evident in sensitivity analyses using a worst-case or intention-to-treat scenario. Compared with waiting list, behavioural activation may be more effective, but there were fewer data in this comparison and evidence was of low certainty (RR 2.14, 95% CI 0.90 to 5.09; 1 RCT, 26 participants). No evidence on treatment efficacy was available for behavioural activation versus placebo and behavioural activation versus no treatment. We found moderate-certainty evidence suggesting no evidence of a difference in short-term treatment efficacy between behavioural activation and CBT (RR 0.99, 95% CI 0.92 to 1.07; 5 RCTs, 601 participants). Fewer data were available for other comparators. No evidence of a difference in short term-efficacy was found between behavioural activation and third-wave CBT (RR 1.10, 95% CI 0.91 to 1.33; 2 RCTs, 98 participants; low certainty), and psychodynamic therapy (RR 1.21, 95% CI 0.74 to 1.99; 1 RCT,60 participants; very low certainty). Behavioural activation was more effective than humanistic therapy (RR 1.84, 95% CI 1.15 to 2.95; 2 RCTs, 46 participants; low certainty) and medication (RR 1.77, 95% CI 1.14 to 2.76; 1 RCT; 141 participants; moderate certainty), but both of these results were based on a small number of trials and participants. No evidence on treatment efficacy was available for comparisons between behavioural activation versus interpersonal, cognitive analytic, and integrative therapies. There was moderate-certainty evidence that behavioural activation might have lower treatment acceptability (based on dropout rate) than treatment as usual in the short term, although the data did not confirm a difference and results lacked precision (RR 1.64, 95% CI 0.81 to 3.31; 14 RCTs, 2518 participants). Moderate-certainty evidence did not suggest any difference in short-term acceptability between behavioural activation and waiting list (RR 1.17, 95% CI 0.70 to 1.93; 8 RCTs. 359 participants), no treatment (RR 0.97, 95% CI 0.45 to 2.09; 3 RCTs, 187 participants), medication (RR 0.52, 95% CI 0.23 to 1.16; 2 RCTs, 243 participants), or placebo (RR 0.72, 95% CI 0.31 to 1.67; 1 RCT; 96 participants; low-certainty evidence). No evidence on treatment acceptability was available comparing behavioural activation versus psychodynamic therapy. Low-certainty evidence did not show a difference in short-term treatment acceptability (dropout rate) between behavioural activation and CBT (RR 1.03, 95% CI 0.85 to 1.25; 12 RCTs, 1195 participants), third-wave CBT (RR 0.84, 95% CI 0.33 to 2.10; 3 RCTs, 147 participants); humanistic therapy (RR 1.06, 95% CI 0.20 to 5.55; 2 RCTs, 96 participants) (very low certainty), and interpersonal, cognitive analytic, and integrative therapy (RR 0.84, 95% CI 0.32 to 2.20; 4 RCTs, 123 participants). Results from medium- and long-term primary outcomes, secondary outcomes, subgroup analyses, and sensitivity analyses are summarised in the text. This systematic review suggests that behavioural activation may be more effective than humanistic therapy, medication, and treatment as usual, and that it may be no less effective than CBT, psychodynamic therapy, or being placed on a waiting list. However, our confidence in these findings is limited due to concerns about the certainty of the evidence. We found no evidence of a difference in short-term treatment acceptability (based on dropouts) between behavioural activation and most comparison groups (CBT, humanistic therapy, waiting list, placebo, medication, no treatment or treatment as usual). Again, our confidence in all these findings is limited due to concerns about the certainty of the evidence. No data were available about the efficacy of behaioural activation compared with placebo, or about treatment acceptability comparing behavioural activation and psychodynamic therapy, interpersonal, cognitive analytic and integrative therapies. The evidence could be strengthened by better reporting and better quality RCTs of behavioural activation and by assessing working mechanisms of behavioural activation.


High-quality-factor photonic crystal ring resonator.
A design for enhancing the quality (Q) factor of a photonic crystal ring resonator (PCRR) is introduced. The highest Q factor based on simulations is 121,000. The analysis of momentum space distributions of the electric field profile for PCRR resonance shows that a high Q factor of a PCRR is attributed to the reduction of tangential k-vector component inside the leaky region. A high Q factor of 75,200 is experimentally demonstrated for a modified PCRR on a silicon-on-insulator wafer. The high-Q-factor PCRR demonstrated here will be beneficial for channel drop filters, lasers, sensors, and other applications.


Medical use of cannabis in Switzerland: analysis of approved exceptional licences.
In recent years, the Swiss Federal Office of Public Health (FOPH) granted exceptional licenses for the medical use of cannabinoids, typically for 6 months with possible extensions. A systematic review of cannabinoids for medical use commissioned by the FOPH supports the use of cannabinoids for the treatment of chronic pain and spasticity. However, little is known about the patients treated with cannabinoids. We aimed to study medical uses of cannabinoids as part of the FOPH's programme of exceptional licenses. We examined all requests for medical use of cannabinoids sent to FOPH in 2013 and 2014. A standardised data sheet was developed to extract data from the files of approved requests. We extracted the duration of the licence, the year it was granted, and the payer of the therapy. At the level of the patient we collected the date of birth, sex, region of residence, diagnosis and the indication. Ethical approval was granted by the Ethics Committee of the Canton of Bern. We analysed 1193 patients licenced for cannabinoid treatment in 2013 or 2014. During 2013, 542 patients were treated under the exceptional licencing programme (332 requesting physicians) compared with 825 in 2014 (446 physicians). Over half of patients (685; 57%) were women. The mean age was 57 years (standard deviation 15.0), chronic pain (49%) and spasticity (40%) were the most common symptoms, and co-medication was reported for 39% of patients. Seventy-eight different diagnoses were recorded, including multiple sclerosis (257 patients, 22%), soft tissue disorders (119, 10%), dorsalgia (97, 8.1%), spinal muscular atrophy (65, 5.5%) and paraplegia/tetraplegia (62, 5.2%). Licence extensions were granted to 143 patients (26.4%) in 2013 and 324 patients (39.3%) in 2014. There were substantial regional variations of the rates of patients treated with cannabinoids. On average, eight patients per 100 000 residents received an exceptional licence. Most patients (1083, 91%) paid out of pocket. Exceptional licences for medical use of cannabinoids have increased substantially in Switzerland, with the programme including patients with a wide range of conditions.


Ubiquitination of tumor suppressor PML regulates prometastatic and immunosuppressive tumor microenvironment.
The tumor microenvironment plays an important role in tumor growth and metastasis. However, the mechanism by which tumor cells regulate the cell and non-cell constituents of surrounding stroma remains incompletely understood. Promyelocytic leukemia (PML) is a pleiotropic tumor suppressor, but its role in tumor microenvironment regulation is poorly characterized. PML is frequently downregulated in many cancer types, including lung cancer. Here, we identify a PML ubiquitination pathway that is mediated by WD repeat 4-containing cullin-RING ubiquitin ligase 4 (CRL4WDR4). Clinically, this PML degradation pathway is hyperactivated in lung cancer and correlates with poor prognosis. The WDR4/PML axis induces a set of cell-surface or secreted factors, including CD73, urokinase-type plasminogen activator receptor (uPAR), and serum amyloid A2 (SAA2), which elicit paracrine effects to stimulate migration, invasion, and metastasis in multiple lung cancer models. In xenograft and genetically engineered mouse models, the WDR4/PML axis elevates intratumoral Tregs and M2-like macrophages and reduces CD8+ T cells to promote lung tumor growth. These immunosuppressive effects were all reversed by CD73 blockade. Our study identifies WDR4 as an oncoprotein that negatively regulates PML via ubiquitination to promote lung cancer progression by fostering an immunosuppressive and prometastatic tumor microenvironment, suggesting the potential of immune-modulatory approaches for treating lung cancer with aberrant PML degradation.


Efficacy and safety profiles of a new S(-)-amlodipine nicotinate formulation versus racemic amlodipine besylate in adult Korean patients with mild to moderate hypertension: an 8-week, multicenter, randomized, double-blind, double-dummy, parallel-group, phase III, noninferiority clinical trial.
"Chiral switching" from an existing racemate to a pure enantiomeric compound is a popular theme in drug development, especially when the enantiomer is found to have better efficacy and safety profiles. Amlodipine is a racemic mixture, composed of the S(-)-enantiomer, which is the pharmacologically active isomer, and the R(+)-enantiomer, which is 1000-fold less active. S(-)-amlodipine nicotinate, a chirally switched form of amlodipine nicotinate, has been developed and found to be bioequivalent to amlodipine besylate in Phase I clinical trials in Korea. The aim of this study was to compare the efficacy and safety profiles of S(-)-amlodipine nicotinate with those of amlodipine besylate in adult Korean patients with mild to moderate hypertension (diastolic blood pressure [DBP] >or=90 mm Hg and <or=109 mm Hg). This was an 8-week, multicenter, randomized, double-blind, double-dummy, parallel-group, Phase III, noninferiority clinical trial. After an initial 2-week placebo run-in period, patients aged 18 to 75 years with sitting DBP (SiDBP) >or=90 and <or=109 mm Hg at day 0 (baseline) were randomly allocated to receive S(-)-amlodipine nicotinate 2.5 mg QD or amlodipine besylate 5 mg QD for 8 weeks. The dose of study medication was doubled after 4 weeks in patients who had not responded to treatment (SiDBP >or=90 mm Hg). The primary end point was noninferiority of the difference in mean SiDBP from baseline to week 8 for S(-)-amlodipine nicotinate compared with amlodipine besylate. Secondary end points were as follows: (1) noninferiority of the difference in mean sitting systolic blood pressure (SiSBP) from baseline to week 8 between the study groups; and (2) SiDBP response rate (defined as the proportion of patients whose SiDBP was <90 mm Hg or whose SiDBP reduction was >or=10 mm Hg from baseline) after the 8-week treatment. Also, the incidence and severity of adverse events (AEs) and adverse drug reactions (ADRs) were reported. Severe AEs/ADRs were defined as those associated with any of the following: death; an event associated with a high risk of mortality; an event requiring hospitalization; or development of a permanent disability or congenital malformation. One hundred fifty-seven patients were assessed for inclusion in the study. Of these, 124 patients were randomly allocated to receive S(-)-amlodipine nicotinate (42 men, 21 women; mean [SD] age, 52.4 [10.3] years [range, 23-70 years]; weight, 67.7 [10.8] kg [range, 44-92 kg]) or amlodipine besylate (45 men, 16 women; mean [SD] age, 54.5 [10.0] years [range, 30-73]; weight, 68.9 [9.8] kg [range, 49-95 kg]). One hundred sixteen patients completed the study, but 11 patients (8.9%) were dropped from the per-protocol analysis due to violations; therefore, 105 patients were included in the modified intent-to-treat population analysis (S[-]-amlodipine nicotinate, 55 patients; amlodipine besylate, 50 patients). There were no significant between-group differences in the baseline characteristics. Baseline mean (SD) SiSBP and SiDBP were 142.6 (11.3) and 94.9 (4.8) mm Hg in the S(-)-amlodipine nicotinate group, and 141.8 (8.3) and 96.1 (4.9) mm Hg in the amlodipine besylate group. Mean (SD) changes in SiSBP were 17.6 (11.2) mm Hg in the S(-)-amlodipine nicotinate group and 18.6 (12.3) mm Hg in the amlodipine besylate group. The SiDBP response rates were 92.7% in the S(-)-amlodipine nicotinate group and 88.0% in the amlodipine besylate group. There were no significant between-group differences in the prevalence of AEs and ADRs. In the S(-)-amlodipine nicotinate group, 15 patients (23.8%) reported a total of 28 AEs, and 19 patients (31.1%) reported a total of 27 AEs in the amlodipine besylate group. Six patients (9.5%) in the S(-)-amlodipine nicotinate group and 7 patients (11.4%) in the amlodipine besylate group experienced a total of 19 ADRs (11 and 8, respectively). The most common ADRs were liver enzyme elevation (3/63 [4.8%]) in the S(-)-amlodipine nicotinate group and facial flushing (3/61 [4.9%]) in the amlodipine besylate group. No cases of severe AEs or ADRs were reported in either group. The reduction of SiDBP after 8 weeks of treatment with S(-)-amlodipine nicotinate was noninferior compared with that of racemic amlodipine besylate in these adult Korean patients with mild to moderate hypertension. The SiDBP response rate and the reduction of SiSBP after 8 weeks of treatment with S(-)-amlodipine nicotinate were not significantly different from those with racemic amlodipine besylate. Both treatments were generally well tolerated.


Rhombencephalic neural crest segmentation is preserved throughout craniofacial ontogeny.
To investigate the influence of hindbrain segmentation on craniofacial patterning we have studied the long term fate of neural crest (NC) subpopulations of individual rhombomeres (r), using quail-chick chimeras. Mapping of all skeletal and muscle connective tissues developing from these small regions revealed several novel features of the cranial neural crest. First, the mandibular arch skeleton has a composite origin in which the proximal elements are r1+r2 derived, whereas more distal ones are exclusively midbrain derived. The most proximal region of the lower jaw is derived from second arch (r4) NC. Second, both the lower jaw and tongue skeleton display an organisation which precisely reflects the rostrocaudal order of segmental crest deployment from the embryonic hindbrain. Third, cryptic intraskeletal boundaries, which do not correspond to anatomical landmarks, form sharply defined interfaces between r1+r2, r4 and r6+r7 crest. Cells that survive the early apoptotic elimination of premigratory NC in r3 and r5 are restricted to tiny contributions within the 2nd arch (r4) skeleton. Fourth, a highly constrained pattern of cranial skeletomuscular connectivity was found that precisely respects the positional origin of its constitutive crest: each rhombomeric population remains coherent throughout ontogeny, forming both the connective tissues of specific muscles and their respective attachment sites onto the neuro- and viscerocranium. Finally, focal clusters of crest cells, confined to the attachment sites of branchial muscles, intrude into the otherwise mesodermal cranial base. In the viscerocranium, an equally strict, rhombomere-specific matching of muscle connective tissues and their attachment sites is found for all branchial and tongue (hypoglossal) muscles. This coherence of segmental crest populations explains how cranial skeletomuscular pattern can be implemented and conserved despite evolutionary changes in the shapes of skeletal elements.


The contribution of the posterior surface to the corneal aberrations in eyes after keratoplasty.
To investigate the contribution of posterior corneal surfaces to higher-order aberrations (HOAs) of the cornea, optical quality, and visual acuity after keratoplasty. Corneal topography of anterior and posterior surfaces and pachymetry were conducted using anterior segment optical coherence tomography (AS-OCT) in 40 eyes (10 eyes after penetrating keratoplasty [PK], 10 eyes after deep anterior lamellar keratoplasty [DALK], 10 eyes after Descemet's stripping automated endothelial keratoplasty [DSAEK], and 10 normal eyes). Anterior, posterior, and total corneal HOAs were calculated using ray-tracing and decomposition into Zernike polynomials and were evaluated as root mean square values. Modulation transfer functions (MTFs) were also evaluated. Topography maps of the anterior and posterior surfaces showed reverse patterns in the normal, PK, and DALK eyes, but not in DSAEK eyes. In the normal, PK, and DALK eyes, the total corneal HOAs were significantly smaller (~10%) than were the HOAs of the anterior surface (P < 0.01), whereas there was no significant difference between total and anterior HOAs in the DSAEK eyes (P = 0.483). In the normal, PK, and DALK eyes, the MTFs of the total cornea were slightly better than those of the anterior surface. In the DSAEK eyes, the MTFs of the total cornea were lower than those of the anterior surface. Visual acuity was significantly correlated with total and anterior surface HOAs (P < 0.05). Posterior surfaces compensate for anterior aberrations in normal, PK, and DALK eyes. In DSAEK eyes, the posterior surface increased total corneal HOAs and had a negative influence on MTFs.


Human GLUD1 and GLUD2 glutamate dehydrogenase localize to mitochondria and endoplasmic reticulum.
Mammalian glutamate dehydrogenase (GDH), an enzyme central to glutamate metabolism, is thought to localize to the mitochondrial matrix, although there are also suggestions for the extramitochondrial presence of this protein. Whereas GDH in mammals is encoded by the GLUD1 gene, humans and the great apes have, in addition, a GLUD2 gene showing a distinct expression pattern. The encoded hGDH1 and hGDH2 isoenzymes are highly homologous, but their leader sequences are more divergent. To explore their subcellular targeting, we constructed expression vectors in which hGDH1 or hGDH2 was fused with the enhanced green fluorescent protein (EGFP) and used these to transfect COS 7, HeLa, CHO, HEK293, or neuroblastoma SHSY-5Y cells. Confocal microscopy revealed GDH-EGFP fluorescence in the cytoplasm within coarse structures. Cotransfection experiments using organelle-specific markers revealed that hGDH1 or hGDH2 colocalized with the mitochondrial marker DsRed2-Mito and to a lesser extent with the endoplasmic reticulum marker DsRed2-ER. Western blots detected two GDH-EGFP specific bands: a ~90 kDa band and a ~95 kDa band associated with the mitochondria and the endoplasmic reticulum containing cytosol, respectively. Deletion of the signal sequence, while altering drastically the fluoresce distribution within the cell, prevented GDH from entering the mitochondria, with the ~90 kDa band being retained in the cytosol. In addition, the deletion eliminated the ~95 kDa band from cell lysates, thus confirming that it represents the full-length GDH. Hence, while most of the hGDHs translocate into the mitochondria (a process associated with cleavage of the signal sequence), part of the protein localizes to the endoplasmic reticulum, probably serving additional functions.


Hand Hygiene during the Early Neonatal Period: A Mixed-Methods Observational Study in Healthcare Facilities and Households in Rural Cambodia.
Globally, infections are the third leading cause of neonatal mortality. Predominant risk factors for facility-born newborns are poor hygiene practices that span both facilities and home environments. Current improvement interventions focus on only one environment and target limited caregivers, primarily birth attendants and mothers. To inform the design of a hand hygiene behavioural change intervention in rural Cambodia, a formative mixed-methods observational study was conducted to investigate the context-specific behaviours and determinants of handwashing among healthcare workers, and maternal and non-maternal caregivers along the early newborn care continuum. Direct observations of hygiene practices of all individuals providing care to 46 newborns across eight facilities and the associated communities were completed and hand hygiene compliance was assessed. Semi-structured interactive interviews were subsequently conducted with 35 midwives and household members to explore the corresponding cognitive, emotional and environmental factors influencing the observed key hand hygiene behaviours. Hand hygiene opportunities during newborn care were frequent in both settings (n = 1319) and predominantly performed by mothers, fathers and non-parental caregivers. Compliance with hand hygiene protocol across all caregivers, including midwives, was inadequate (0%). Practices were influenced by the lack of accessible physical infrastructure, time, increased workload, low infection risk perception, nurture-related motives, norms and inadequate knowledge. Our findings indicate that an effective intervention in this context should be multi-modal to address the different key behaviour determinants and target a wide range of caregivers.


Relationship of the ApoE polymorphism to plasma lipid traits among South Asians, Chinese, and Europeans living in Canada.
The prevalence of cardiovascular risk factors and atherosclerosis vary between ethnic groups. We examined the apolipoprotein E (ApoE) polymorphism, its association with lipid traits and atherosclerosis, and its influence on ethnic variations on lipid traits. In a randomly sampled cross-sectional study of 985 South Asian, Chinese, and European Canadians, three common isoforms of ApoE (E2, E3 and E4), plasma lipid concentrations and atherosclerosis of the carotid artery were measured. The E2, E3 and E4 allele frequencies were 5.7%, 84.0%, and 10.2%, respectively, and differed significantly between ethnic groups. There was a strong, stepwise association between ApoE and each plasma lipid trait, except triglycerides. The E4 genotype was associated with higher low-density lipoprotein cholesterol (p for trend<0.001), ApoB (p<0.001), ApoB/ApoA ratio (p<0.001) and lipoprotein (a) (p<0.001), and lower ApoA (p<0.001) and high-density lipoprotein cholesterol (HDL-C) (p=0.005). A similar pattern of effects was observed across all ethnic groups. Ethnicity accounted for modest variation in ApoA, ApoB/ApoA ratio and HDL-C (4.2-5.0%), whereas ApoE isoforms explained only a small proportion of variability (0.3-1.4%). Dietary and lifestyle factors accounted for modest variation in several traits including HDL-C (5.6% and 5.0%, respectively). Carotid atherosclerosis was lower among individuals with E2 isoform in keeping with the effect of E2 on lipid levels. The ApoE isoform is associated with plasma lipoproteins in all ethnic groups, yet explains only a small proportion of the inter-ethnic variation for most plasma lipoproteins. Additional genetic variants and/or health behaviors likely contribute to ethnic variations in plasma lipid traits.


Syk mutation in Jurkat E6-derived clones results in lack of p72syk expression.
The human leukemic Jurkat cell line is commonly used as a model cellular system to study T lymphocyte signal transduction. Various clonal derivatives of Jurkat T cells exist which display different characteristics with regard to responses to external stimuli. Among these, the E6-1 clone of Jurkat T cells has been used as a parental line from which numerous important somatic mutant clones have been generated. During the course of experiments examining signals initiated by the T cell antigen receptor in an E6-1-derived Jurkat cell clone J.CaM1, we observed that the 72-kilodalton Syk protein tyrosine kinase previously found in other Jurkat cells was not detected. Upon further analysis it was determined that Syk transcripts from the J.CaM1 cells as well as the parental E6-1 cells contain a single guanine nucleotide insertion at position 92. This nucleotide insertion results in a shift in the Syk open reading frame leading to alternate codon usage as well as the generation of a termination codon at position 109. Thus, Syk transcripts in E6-1 cells and E6-1-derived clones are predicted to be capable of encoding only the first 33 amino acids of the 630-amino acid wild type Syk. These findings are incompatible with a recently proposed model of T cell antigen receptor signal transduction based, in part, on experiments conducted using E6-1-derived cells, suggesting that Syk might play a role upstream of Lck and Zap70.


Changing epidemiology of immune-mediated inflammatory diseases in immigrants: A systematic review of population-based studies.
Immune-mediated inflammatory diseases (IMIDs) are systemic diseases of multifactorial etiology that share aberrant immune responses as the common final pathway. With rising globalization, their incidence is increasing in developing countries and among immigrants. Our primary objective was to systematically review the epidemiology of IMIDs in immigrants and conduct a meta-analysis to estimate the risk of IMIDs in immigrant populations according to their origin and destination countries. We systematically searched five biomedical databases and reviewed population-based studies, from inception through August 2018, that reported incidence or prevalence data of inflammatory bowel disease (IBD), multiple sclerosis (MS), type 1 diabetes (T1D), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ankylosing spondylitis (AS) or psoriasis and psoriatic arthritis (PPA) among immigrants and the host population. The incidence and prevalence of IMIDs among immigrants differ from host populations, and evolve over subsequent generations. The risk of IBD among immigrants approximates that in hosts, especially among South Asians, with ulcerative colitis incidence changing prior to Crohn's disease incidence. MS risk is highest in Iranian immigrants, T1D in African immigrants and SLE in African and Iraqi immigrants. Data on other IMIDs are sparse. Significant heterogeneity between the studies precluded meta-analysis. Based on our systematic review, the epidemiology of IMIDs among immigrants varies according to native and host countries, immigrant generation, and IMID type. The rapid evolution suggests a role for non-genetic factors and gene-environment interactions. Future studies should focus on these pattern shifts, given implications of rising global burden of IMIDs and immigration.


[Immunotyping of Japanese encephalitis viral strains].
Immunological typing of 15 Japanese encephalitis (JE) virus strains was done by HI and AGDP tests with preliminary cross adsorption of antibodies with antigens, observing standard quantitative adsorption conditions. Most of the strains (12) were found to belong to the immunological type Jagar-01, including the strains isolated in the USSR, Korean People's Democratic Republic, most strains isolated in Japan (6 out of 7) and Chinese People's Republic (3 out of 4). The Hanoi-60 strain isolated in Socialist Republic of Vietnam belongs to the Nakayama immunological type. A correlation was shown between strain grouping by the immmunological type and genetic markers (hemagglutinin thermoresistance at 42 degrees C/20 min and optimal pH range for HA test). Two strains were found to represent transitional variants between the above two immunological types.


Impaired auditory sensory memory in Cystinosis despite typical sensory processing: A high-density electrical mapping study of the mismatch negativity (MMN).
Cystinosis, a genetic rare disease characterized by cystine accumulation and crystallization, results in significant damage in a multitude of tissues and organs, such as the kidney, thyroid, eye, and brain. While Cystinosis' impact on brain function is relatively mild compared to its effects on other organs, the increased lifespan of this population and thus potential for productive societal contributions have led to increased interest on the effects on brain function. Nevertheless, and despite some evidence of structural brain differences, the neural impact of the mutation is still not well characterized. Here, using a passive duration oddball paradigm (with different stimulus onset asynchronies (SOAs), representing different levels of demand on memory) and high-density electrophysiology, we tested basic auditory processing in a group of 22 children and adolescents diagnosed with Cystinosis (age range: 6-17 years old) and in neurotypical age-matched controls (N = 24). We examined whether the N1 and mismatch negativity (MMN) significantly differed between the groups and if those neural measures correlated with verbal and non-verbal IQ. Individuals diagnosed with Cystinosis presented similar N1 responses to their age-matched peers, indicating typical basic auditory processing in this population. However, whereas both groups showed similar MMN responses for the shortest (450 ms) SOA, suggesting intact change detection and sensory memory, individuals diagnosed with Cystinosis presented clearly reduced responses for the longer (900 ms and 1800 ms) SOAs. This could indicate reduced duration auditory sensory memory traces, and thus sensory memory impairment, in children and adolescents diagnosed with Cystinosis. Future work addressing other aspects of sensory and working memory is needed to understand the underlying bases of the differences described here, and their implication for higher order processing.


The accuracy of 'power' maps to display curvature data in corneal topography systems.
To quantify the error introduced by videokeratographic corneal topography devices in using a paraxial formula to calculate power over the entire corneal surface, including areas removed from the central paraxial region where the formula is known to be invalid. Corneal refractive power and two paraxial power approximations were computed as a function of distance from the apex for three theoretical surfaces, a sphere and two ellipsoids with 0.3 and 0.5 eccentricities. Color dioptric maps were then theoretically created. For the spherical surface, both curvature-based paraxial power approximations were uniform over the entire surface because curvature is constant. However, the corneal refractive power increased from center to periphery, demonstrating the known phenomenon of spherical aberration. For the ellipsoids, which have been shown to model the human cornea, curvature-based power approximations decreased from center to periphery because the curvature flattens peripherally. However, refractive power increased from center to periphery. The limits of the central paraxial region for these surfaces was shown to be approximately 2 mm in diameter for the paraxial power approximation used by videokeratographic devices to measure 8 mm in diameter. The direct correlation between corneal curvature and power with which clinicians are familiar is not valid in the peripheral regions measured by videokeratographic devices. Topographic devices measure curvature, which should not be interpreted as corneal power except in the central region. A recommendation to device manufacturers is to display "color curvature maps" instead of color dioptric maps, and to label the color bar with curvature values instead of power.


Regulation of human eosinophil viability, density, and function by granulocyte/macrophage colony-stimulating factor in the presence of 3T3 fibroblasts.
Normodense human peripheral blood eosinophils were isolated under sterile conditions from the 22/23 and 23/24% interfaces and the cell pellet of metrizamide gradients. After culture for 7 d in RPMI media in the presence of 50 pM biosynthetic (recombinant) human granulocyte/macrophage colony-stimulating factor (rH GM-CSF), 43 +/- 7% (mean +/- SEM, n = 8) of the cells were viable; in the absence of rH GM-CSF, no eosinophils survived. The rH GM-CSF-mediated viability was concentration dependent; increased survival began at a concentration of 1 pM, a 50% maximal response was attained at approximately 3 pM, and a maximal effect was reached at concentrations of greater than or equal to 10 pM rH GM-CSF. In the presence of rH GM-CSF and mouse 3T3 fibroblasts, 67 +/- 6% (mean +/- SEM, n = 8) of the eosinophils survived for 7 d. In a comparative analysis, there was no difference in eosinophil viability after 7 and 14 d (n = 3) in the presence of 50 pM GM-CSF and fibroblasts. Culture with fibroblasts alone did not support eosinophil survival. The addition of fibroblast-conditioned media to rH GM-CSF did not further improve eosinophil viability, indicating a primary role for GM-CSF in supporting these eosinophil cell suspensions ex vivo and a supplementary role for 3T3 fibroblasts. Eosinophils cultured for 7 d localized on density gradient sedimentation at the medium/18, 18/20, and 20/21 interfaces of metrizamide gradients, indicating a change to the hypodense phenotype from their original normodense condition. In addition, the cultured eosinophils generated approximately 2.5-fold more LTC4 than freshly isolated cells when stimulated with the calcium ionophore A23187 and manifested sevenfold greater antibody-dependent killing of S. mansoni larvae than the freshly isolated, normodense cells from the same donor. Thus we demonstrate the rH GM-CSF dependent conversion in vitro of normodense human eosinophils to hypodense cells possessing the augmented biochemical and biological properties characteristic of the hypodense eosinophils associated with a variety of hypereosinophilic syndromes. In addition, these studies provide a culture model of at least 14 d suitable for the further characterization of hypodense eosinophils.


C1-INH defect as an example of deficiency disease.
Primary defect of C1-inhibitor (C1-INH), the regulatory protein of the initial classical pathway of complement, is the cause of hereditary angioedema. Clinical symptoms involve potentially fatal obstruction of the upper respiratory tract, abdominal pains, and subcutaneous edemas. Since the description of functional tests for C1-INH two types of hereditary defect have been known: type I and type II. Sixteen patients with the type I of hereditary angioedema were diagnosed and treated in our hospital. The onset of the disease occurred between 1.5-12 y. of age. Clinical symptoms were observed in skin, gastrointestinal and respiratory tracts. Mean concentration of C1-INH in sera of 16 patients was 3.25 mg/dl, below 8.75 mg/dl that is the critical for well-functioning C1-INH. Inhibitory activity of C1-INH for C1 esterase in plasma was zero in most of the patients, while it was 0.94 +/- 0.20 U/ml in plasma samples of 91 healthy blood donors. Three modalities of treatment are available: substitution with C1-INH concentrate in acute attacks and antifibrinolytic and/or anabolic drugs for prophylaxis. We have obtained good therapeutic results with epsilon-aminocaproic acid (antifibrinolytic), 2g daily during 3 months, with 6 months intervals.


Cognitive behavioral therapy and work outcomes: correlates of treatment engagement and full and partial success in schizophrenia.
Cognitive behavior therapy (CBT) has been found to be generally effective for persons with schizophrenia. Less is known however about those who will engage in this treatment, and among those who engage, who benefits more versus less from this intervention. This study sought to identify factors associated with treatment engagement and response in persons with psychosis engaged in CBT focused on enhancing work function. Participants were 50 adults with schizophrenia-spectrum disorders participating in a randomized control trial that offered both CBT and a protected employment position over 26 weeks. Survival analysis and discriminant analyses were used to analyze the data. RESULTS indicated that poor treatment engagement and engagement in work was associated with lower educational attainment, more severe baseline levels of negative symptoms, and lower baseline scores on the Arithmetic and Digit Symbol subscales of the WAIS-III. Amongst those participants who did engage, younger age and poorer working memory as assessed by the Arithmetic subscale predicted shorter initial job tenure. More severe levels of positive symptoms and lower self-esteem during the later stages of treatment were associated with worse employment outcomes across the study period. These findings evidence differential predictors of engagement and success and suggest that a subgroup of persons with schizophrenia engaged in CBT and a vocational placement are at risk for poor functional outcomes associated with psychological factors that evolve over time.


Data accuracy in the Victorian Perinatal Data Collection: Results of a validation study of 2011 data.
Public health data sets such as the Victorian Perinatal Data Collection (VPDC) provide an important source for health planning, monitoring, policy, research and reporting purposes. Data quality is paramount, requiring periodic assessment of data accuracy. This article describes the conduct and findings of a validation study of data on births in 2011 extracted from the VPDC. Data from a random sample of one percent of births in Victoria in 2011 were extracted from original medical records at the birth hospital and compared with data held in the VPDC. Accuracy was determined for 93 variables. Sensitivity, specificity, positive predictive value and negative predictive value were calculated for dichotomous items. Accuracy of 17 data items was 99% or more, the majority being neonatal and intrapartum items, and 95% or more for 46 items. Episodes of care with the highest proportion of items with accuracy of 95% or more were neonatal and postnatal items at 80 and 64%, respectively. Accuracy was below 80% for nine items introduced in 2009. Agreement between medical records and VPDC data ranged from 48% to 100%, the exception being two highly inaccurate smoking-related items. Reasons for discrepancies between VPDC data and medical records included miscoding, missing and inconsistent information. This study found high levels of accuracy for data reported to the VPDC for births in 2011; however, some data items introduced in 2009 and not previously validated were less accurate. Data may be used with confidence overall and with awareness of limitations for some new items.


An evaluation study of enzyme-linked immunosorbent assay (ELISA) using recombinant protein Pap31 for detection of antibody against Bartonella bacilliformis infection among the Peruvian population.
Reliable laboratory testing is of great importance to detect Bartonella bacilliformis infection. We evaluated the sensitivity and specificity of the enzyme-linked immunosorbent assay (ELISA) using recombinant protein Pap31 (rPap31) for the detection of antibodies against B. bacilliformis as compared with immunofluorescent assay (IFA). Of the 302 sera collected between 1997 and 2000 among an at-risk Peruvian population, 103 and 34 samples tested positive for IFA-immunoglobulin G (IgG) and IFA-IgM, respectively. By using Youden's index, the cutoff values of ELISA-IgG at 0.915 gave a sensitivity of 84.5% and specificity of 94%. The cutoff values of ELISA-IgM at 0.634 gave a sensitivity of 88.2% and specificity of 85.1%. Using latent class analysis, estimates of sensitivity and specificity of almost all the assays were slightly higher than those of a conventional method of calculation. The test is proved beneficial for discriminating between infected and non-infected individuals with the advantage of low-cost and high-throughput capability.


A time series model for influent temperature estimation: application to dynamic temperature modelling of an aerated lagoon.
Thirty-nine linear regression and time series models were built and calibrated for influent temperature (Ti) estimation at the primary aerated facultative lagoon in a municipal wastewater treatment plant. The models were based on mean daily ambient air temperature (Ta) and/or daily rainfall (P), and-optionally-wastewater temperature autoregression. The best fits were achieved with some time series models involving Ta and P, and Ti autoregression. The best-fit model was able to estimate influent temperature with a root-mean-square-error of 0.5 degrees C, and an R2 of 0.925, for the calibration period of 10.5 months. In addition, a dynamic lagoon-temperature (Tw) model from the literature was modified in its terms of solar radiation and aeration latent heat, and applied to the primary lagoon. The model was fed with the estimated influent temperature, and five model parameters were identified by calibration against 10.5-month Tw data. Dynamic lagoon-temperature estimation results were comparable to or better than other results of long-term simulations found in the literature. Sensitivity analyses were run on both models. Further validation with independent sets of data is needed for verification of the predictive capability of the models.


Submentalizing or mentalizing in a Level 1 perspective-taking task: A cloak and goggles test.
It has been proposed that humans possess an automatic system to represent mental states ('implicit mentalizing'). The existence of an implicit mentalizing system has generated considerable debate however, centered on the ability of various experimental paradigms to demonstrate unambiguously such mentalizing. Evidence for implicit mentalizing has previously been provided by the 'dot perspective task,' where participants are slower to verify the number of dots they can see when an avatar can see a different number of dots. However, recent evidence challenged a mentalizing interpretation of this effect by showing it was unaltered when the avatar was replaced with an inanimate arrow stimulus. Here we present an extension of the dot perspective task using an invisibility cloaking device to render the dots invisible on certain trials. This paradigm is capable of providing unambiguous evidence of automatic mentalizing, but no such evidence was found. Two further well-powered experiments used opaque and transparent goggles to manipulate visibility but found no evidence of automatic mentalizing, nor of individual differences in empathy or perspective-taking predicting performance, contradicting previous studies using the same design. The results cast doubt on the existence of an implicit mentalizing system, suggesting that previous effects were due to domain-general processes. (PsycINFO Database Record


Controls on radioactivity in water supplies in England and Wales, with especial reference to radon.
This note describes the legal and administrative controls on concentrations of radioactive materials, with especial reference to radon, in drinking water in England and Wales. These controls follow the EC Drinking Water Directive and Recommendations from the European Union. The Directive relates to radioactivity in drinking water generally, while the Recommendations are specific to radon. A distinction is made between private and public supplies, with more stringent controls on the latter. In general, problems in meeting the recommended levels are not expected in England and Wales.


A near complete snapshot of the Zea mays seedling transcriptome revealed from ultra-deep sequencing.
RNA-sequencing (RNA-seq) enables in-depth exploration of transcriptomes, but typical sequencing depth often limits its comprehensiveness. In this study, we generated nearly 3 billion RNA-Seq reads, totaling 341 Gb of sequence, from a Zea mays seedling sample. At this depth, a near complete snapshot of the transcriptome was observed consisting of over 90% of the annotated transcripts, including lowly expressed transcription factors. A novel hybrid strategy combining de novo and reference-based assemblies yielded a transcriptome consisting of 126,708 transcripts with 88% of expressed known genes assembled to full-length. We improved current annotations by adding 4,842 previously unannotated transcript variants and many new features, including 212 maize transcripts, 201 genes, 10 genes with undocumented potential roles in seedlings as well as maize lineage specific gene fusion events. We demonstrated the power of deep sequencing for large transcriptome studies by generating a high quality transcriptome, which provides a rich resource for the research community.


Factors Influencing Participation in Clinical Trials: Emergency Medicine vs. Other Specialties.
This study investigated factors that influence emergency medicine (EM) patients' decisions to participate in clinical trials and whether the impact of these factors differs from those of other medical specialties. A survey was distributed in EM, family medicine (FM), infectious disease (ID), and obstetrics/gynecology (OB/GYN) outpatient waiting areas. Eligibility criteria included those who were 18 years of age or older, active patients on the day of the survey, and able to complete the survey without assistance. We used the Kruskal-Wallis test and ordinal logistic regression analyses to identify differences in participants' responses. A total of 2,893 eligible subjects were approached, and we included 1,841 surveys in the final analysis. Statistically significant differences (p≤0.009) were found for eight of the ten motivating factors between EM and one or more of the other specialties. Regardless of a patient's gender, race, and education, the relationship with their doctor was more motivating to patients seen in other specialties than to EM patients (FM [odds ratio {OR}:1.752, 95% confidence interval {CI}{1.285-2.389}], ID [OR:3.281, 95% CI{2.293-4.695}], and OB/GYN [OR:2.408, 95% CI{1.741-3.330}]). EM's rankings of "how well the research was explained" and whether "the knowledge learned would benefit others" as their top two motivating factors were similar across other specialties. All nine barriers showed statistically significant differences (p≤0.008) between EM and one or more other specialties. Participants from all specialties indicated "risk of unknown side effects" as their strongest barrier. Regardless of the patients' race, "time commitment" was considered to be more of a barrier to other specialties when compared to EM (FM [OR:1.613, 95% CI{1.218-2.136}], ID [OR:1.340, 95% CI{1.006-1.784}], or OB/GYN [OR:1.901, 95% CI{1.431-2.526}]). Among the six resources assessed that help patients decide whether to participate in a clinical trial, only one scored statistically significantly different for EM (p<0.001). EM patients ranked "having all material provided in my own language" as the most helpful resource. There are significant differences between EM patients and those of other specialties in the factors that influence their participation in clinical trials. Providing material in the patient's own language, explaining the study well, and elucidating how their participation might benefit others in the future may help to improve enrollment in EM-based clinical trials.


Assessing the carbon balance of circumpolar Arctic tundra using remote sensing and process modeling.
This paper reviews the current status of using remote sensing and process-based modeling approaches to assess the contemporary and future circumpolar carbon balance of Arctic tundra, including the exchange of both carbon dioxide and methane with the atmosphere. Analyses based on remote sensing approaches that use a 20-year data record of satellite data indicate that tundra is greening in the Arctic, suggesting an increase in photosynthetic activity and net primary production. Modeling studies generally simulate a small net carbon sink for the distribution of Arctic tundra, a result that is within the uncertainty range of field-based estimates of net carbon exchange. Applications of process-based approaches for scenarios of future climate change generally indicate net carbon sequestration in Arctic tundra as enhanced vegetation production exceeds simulated increases in decomposition. However, methane emissions are likely to increase dramatically, in response to rising soil temperatures, over the next century. Key uncertainties in the response of Arctic ecosystems to climate change include uncertainties in future fire regimes and uncertainties relating to changes in the soil environment. These include the response of soil decomposition and respiration to warming and deepening of the soil active layer, uncertainties in precipitation and potential soil drying, and distribution of wetlands. While there are numerous uncertainties in the projections of process-based models, they generally indicate that Arctic tundra will be a small sink for carbon over the next century and that methane emissions will increase considerably, which implies that exchange of greenhouse gases between the atmosphere and Arctic tundra ecosystems is likely to contribute to climate warming.


Effects of delaying binge drinking on adolescent brain development: a longitudinal neuroimaging study.
Onset of alcohol use by 14 relative to 21 years of age strongly predicts elevated risk for severe alcohol use problems, with 27% versus 4% of individuals exhibiting alcohol dependence within 10 years of onset. What remains unclear is whether this early alcohol use (i) is a marker for later problems, reflected as a pre-existing developmental predisposition, (ii) causes global neural atrophy or (iii) specifically disturbs neuro-maturational processes implicated in addiction, such as executive functions or reward processing. Since our group has demonstrated that a novel intervention program targeting personality traits associated with adolescent alcohol use can prevent the uptake of drinking and binge drinking by 40 to 60%, a crucial question is whether prevention of early onset alcohol misuse will protect adolescent neurodevelopment and which domains of neurodevelopment can be protected. A subsample of 120 youth at high risk for substance misuse and 30 low-risk youth will be recruited from the Co-Venture trial (Montreal, Canada) to take part in this 5-year follow-up neuroimaging study. The Co-Venture trial is a community-based cluster-randomised trial evaluating the effectiveness of school-based personality-targeted interventions on substance use and cognitive outcomes involving approximately 3800 Grade 7 youths. Half of the 120 high-risk participants will have received the preventative intervention program. Cognitive tasks and structural and functional neuroimaging scans will be conducted at baseline, and at 24- and 48-month follow-up. Two functional paradigms will be used: the Stop-Signal Task to measure motor inhibitory control and a modified version of the Monetary Incentive Delay Task to evaluate reward processing. The expected results should help identify biological vulnerability factors, and quantify the consequences of early alcohol abuse as well as the benefits of early intervention using brain metrics.


Contributions Made by Undergraduates to Research Projects: Using the CREDIT Taxonomy to Assess Undergraduate Research Experiences.
The authors developed a novel tool, the CREDIT URE, to define and measure roles performed by undergraduate students working in research placements. Derived from an open-source taxonomy for determining authorship credit, the CREDIT URE defines 14 possible roles, allowing students and their research mentors to rate the degree to which students participate in each role. The tool was administered longitudinally across three cohorts of undergraduate student-mentor pairs involved in a biomedical research training program for students from diverse backgrounds. Students engaged most frequently in roles involving data curation, investigation, and writing. Less frequently, students engaged in roles related to software development, supervision, and funding acquisition. Students' roles changed over time as they gained experience. Agreement between students and mentors about responsibility for roles was high.


Long-term outcomes of cochlear implantation in patients with high-frequency hearing loss.
To demonstrate the long-term benefits of implantation in patients with high-frequency sensorineural hearing loss, this report provides 5-year follow-up on a group of implant recipients who were subjects of the Cochlear™ Nucleus® Hybrid™ L24 Implant System pivotal clinical study. The results of three related clinical studies were compiled to provide outcome data after 1, 3, and 5 years of implant use in a group of subjects who presented with preoperative high-frequency hearing loss and were implanted with a Nucleus Hybrid L24 (Cochlear Ltd., Sydney, Australia) cochlear implant. A subset of the 50 adult subjects (N = 32) who participated in the Hybrid L24 pivotal Investigational Device Exemption (IDE) completed comprehensive evaluations at 12 months postactivation, 3 years postactivation, and then as part of a postapproval study at 5 years postactivation. Testing included audiometric, speech perception, and subjective satisfaction measures. Mean unilateral speech perception performance was significantly improved at all postoperative intervals compared to preoperative best-aided results and has remained stable to 5 years postactivation. Ninety-four percent of subjects had measurable hearing, and 72% continued to use electric-acoustic stimulation in the implanted ear after 5 years of implant use. Subjective satisfaction results support objective performance improvements. Results demonstrate long-term success of patients with high-frequency hearing loss following Hybrid L24 (Cochlear) cochlear implantation. Benefits include speech perception abilities significantly better than those in the preoperative best-aided condition, with additional benefit in those using electric-acoustic stimulation in the implanted ear. 2b. Laryngoscope, 1939-1945, 2018.


Sex offenders and insanity: an examination of 42 individuals found not guilty by reason of insanity.
Although currently there is a large body of research on the characteristics and treatment of sex offenders, very little research has been conducted to investigate the characteristics of sex offenders who have been adjudicated insane. This study included 42 patients at Napa State Hospital who were adjudicated not guilty by reason of insanity (NGRI) for a sex offense. The sample was further divided into offenders whose victims were children and those whose victims were adults. Data were collected with a structured chart review instrument. A large percentage of the sex offenders received a primary diagnosis of schizophrenia or schizoaffective disorder, and many had a comorbid substance use disorder. The high percentage of sex offenders in the current study with diagnosed schizophrenia or schizoaffective disorder may represent a previously unstudied subgroup of sex offenders. An alternative explanation is that the experts did not evaluate substance use and intoxication adequately, assess for malingering, or apply the proper legal standard for insanity.


Bacterial fermentation of recombinant major wasp allergen Antigen 5 using oxygen limiting growth conditions improves yield and quality of inclusion bodies.
A process for bacterial expression and purification of the recombinant major wasp allergen Antigen 5 (Ves v 5) was developed to produce protein for diagnostic and therapeutic applications for type 1 allergic diseases. Special attention was focused on medium selection, fermentation conditions, and efficient refolding procedures. A soy based medium was used for fermentation to avoid peptone from animal origin. Animal-derived peptone required the use of isopropyl-beta-D-thiogalactopyranoside (IPTG) for the induction of expression. In the case of soy peptone, a constitutive expression was observed, suggesting the presence of a component that mimics IPTG. Batch cultivation at reduced stirrer speed caused a reduced biomass due to oxygen limitation. However, subsequent purification and processing of inclusion bodies yielded significantly higher amount of product. Furthermore, the protein composition of the inclusion bodies differed. Inclusion bodies were denatured and subjected to diafiltration. Detailed monitoring of diafiltration enabled the determination of the transition point. Final purification was conducted using cation-exchange and size-exclusion chromatography. Purified recombinant Ves v 5 was analyzed by RP-HPLC, CD-spectroscopy, SDS-PAGE, and quantification ELISA. Up to 15 mg highly purified Ves v 5 per litre bioreactor volume were obtained, with endotoxin concentrations less than 20 EU mg(-1) protein and high comparability to the natural counterpart. Analytical results confirm the suitability of the recombinant protein for diagnostic and clinical applications. The results clearly demonstrate that not only biomass, but especially growth conditions play a key role in the production of recombinant Ves v 5. This has an influence on inclusion body formation, which in turn influences the renaturation rate and absolute product yield. This might also be true for other recombinant proteins that accumulate as inclusion bodies in Escherichia coli.


Increased susceptibility of spinal muscular atrophy fibroblasts to camptothecin is p53-independent.
Deletion or mutation(s) of the survival motor neuron 1 (SMN1) gene causes spinal muscular atrophy (SMA). The SMN protein is known to play a role in RNA metabolism, neurite outgrowth, and cell survival. Yet, it remains unclear how SMN deficiency causes selective motor neuron death and muscle atrophy seen in SMA. Previously, we have shown that skin fibroblasts from SMA patients are more sensitive to the DNA topoisomerase I inhibitor camptothecin, supporting a role for SMN in cell survival. Here, we examine the potential mechanism of camptothecin sensitivity in SMA fibroblasts. Camptothecin treatment reduced the DNA relaxation activity of DNA topoisomerase I in human fibroblasts. In contrast, kinase activity of DNA topoisomerase I was not affected by camptothecin, because levels of phosphorylated SR proteins were not decreased. Upon camptothecin treatment, levels of p53 were markedly increased. To determine if p53 plays a role in the increased sensitivity of SMA fibroblasts to camptothecin, we analyzed the sensitivity of SMA fibroblasts to another DNA topoisomerase I inhibitor, beta-lapachone. This compound is known to induce death via a p53-independent pathway in several cancer cell lines. We found that beta-lapachone did not induce p53 activation in human fibroblasts. In addition, SMA and control fibroblasts showed essentially identical sensitivity to this compound. By immunofluorescence staining, SMN and p53 co-localized in gems within the nucleus, and this co-localization was overall reduced in SMA fibroblasts. However, depletion of p53 by siRNA did not lessen the camptothecin sensitivity in SMA fibroblasts. Even though p53 and SMN are associated, the increased sensitivity of SMA fibroblasts to camptothecin does not occur through a p53-dependent mechanism.


Quality of life five years after myocardial infarction.
In 539 patients 5 years after myocardial infarction (MI), quality of life and factors influencing life quality were studied. All patients originally participated in an early intervention trial with metoprolol. A cardiac follow-up questionnaire and the Nottingham Health Profile were answered by 82%. In the former, information about subjective symptoms, smoking, work and current medication was obtained; the latter described health-related quality of life in terms of energy, sleep, emotions, mobility, pain and social isolation. The rate of and the reasons for rehospitalization were registered in the patients' records. The MI patients reported a comparatively high quality of life. Compared with 'normal' population, a decrease was noted in energy, sleep and mobility, and in sex life, hobby-activity and holiday activity. A nonparametric multivariate analysis disclosed that dyspnoea, angina pectoris and anxiety were closely associated with decreased quality of life. In conclusion, 5 years after MI most patients seemed well-adjusted. Impaired quality of life was reported by patients suffering from angina pectoris, dyspnoea and emotional distress. No relationship was found between health-related quality of life and the beta blocker, metoprolol, which was the most frequently used drug.


Metal Ion-dependent Heavy Chain Transfer Activity of TSG-6 Mediates Assembly of the Cumulus-Oocyte Matrix.
The matrix polysaccharide hyaluronan (HA) has a critical role in the expansion of the cumulus cell-oocyte complex (COC), a process that is necessary for ovulation and fertilization in most mammals. Hyaluronan is organized into a cross-linked network by the cooperative action of three proteins, inter-α-inhibitor (IαI), pentraxin-3, and TNF-stimulated gene-6 (TSG-6), driving the expansion of the COC and providing the cumulus matrix with its required viscoelastic properties. Although it is known that matrix stabilization involves the TSG-6-mediated transfer of IαI heavy chains (HCs) onto hyaluronan (to form covalent HC·HA complexes that are cross-linked by pentraxin-3) and that this occurs via the formation of covalent HC·TSG-6 intermediates, the underlying molecular mechanisms are not well understood. Here, we have determined the tertiary structure of the CUB module from human TSG-6, identifying a calcium ion-binding site and chelating glutamic acid residue that mediate the formation of HC·TSG-6. This occurs via an initial metal ion-dependent, non-covalent, interaction between TSG-6 and HCs that also requires the presence of an HC-associated magnesium ion. In addition, we have found that the well characterized hyaluronan-binding site in the TSG-6 Link module is not used for recognition during transfer of HCs onto HA. Analysis of TSG-6 mutants (with impaired transferase and/or hyaluronan-binding functions) revealed that although the TSG-6-mediated formation of HC·HA complexes is essential for the expansion of mouse COCs in vitro, the hyaluronan-binding function of TSG-6 does not play a major role in the stabilization of the murine cumulus matrix.


Association of household income and education with eating behaviors in Japanese adults: a cross-sectional study.
Socioeconomic inequalities as social determinants of health are important issues in public health and health promotion. However, the association between socioeconomic status and eating behaviors has been investigated poorly in Japanese adults. To fill this gap, the present study examines the association of eating behaviors with household income and education. The sample comprised 3,137 Japanese adults (1,580 men and 1,557 women) aged 30 to 59 years who responded to an Internet-based cross-sectional survey in 2014. Data on the following eating behaviors were collected via self-report: "taking care of one's diet for health," "eating vegetables," "frequency of eating breakfast," "frequency of family breakfasts," "frequency of family dinners," "using the information on nutrition labels," and "conversations with family or friends during meals." Self-reported data on socioeconomic status (household income and education) and demographic variables (gender, age, district of residence, marital status, residence status, and employment status) were also collected. The associations between eating behaviors and household income or education were tested using binomial logistic regression analysis with eating behaviors as dependent variables and household income and education as independent variables. A trend P -value was calculated for three categories of household income (less than 3,000,000 JPY, 3,000,000-7,000,000 JPY, and over 7,000,000 JPY) and education (junior high/high school, 2-year college, and 4-year college/graduate school). Higher household income and education were significantly associated with higher rates of eating vegetables, using the information on nutrition labels, and conversation with family or friends during meals in Japanese men and women. Higher household incomes were significantly associated with lower rates of frequency of family breakfasts in Japanese men and lower rates of frequency of family dinners in Japanese men and women. Higher socioeconomic status as indicated by household income or education was associated with eating more vegetables and conversation with family or friends during meals in Japanese men and women. Socioeconomic status should be considered in health promotion and diet improvement.


Acculturation or unequal assimilation? Smoking during pregnancy and duration of residence among migrants in Sweden.
A growing corpus of evidence reveals that smoking patterns of migrant women tend to converge with that of the host population over time ('acculturation paradox'). In this paper we aim to adopt a health equity perspective by studying the extent to which this pattern reflects a convergence with the group of natives who are more socioeconomically disadvantaged. Using population-based registers, we study 1,194,296 women who gave birth in Sweden between 1991 and 2012. Using logistic regression, we estimated odds ratios to assess the effect of duration of residence on the association between smoking during pregnancy and women's origin (classified according to inequality-adjusted Human Development Index (iHDI) of the country of birth). Sibling information and multilevel models were used to assess the extent to which our results might be affected by the cross-sectional nature of the data. Smoking during pregnancy increases with duration of residence among migrants from all levels of iHDI to such an extent that they tend to converge or increase in relation to the levels of the Swedish population with low education and low income, leaving behind the native population with high education and income. The results are robust to possible selection bias related to the cross-sectional nature of the data. Our findings indicate the need of a health equity perspective and suggest the use of 'unequal assimilation' rather than 'acculturation paradox' as a more suitable framework to interpret these findings.


Deficits in controlled processing may predict dementia: a twin study.
This study tested for differential patterns of cognitive decline in 33 twin pairs for which both were nondemented, but 1 member of the pair went on to develop dementia. Compared with their nondemented twin partners, twins who later developed dementia already showed poorer performance on tests of memory and attention, visuospatial-reasoning skills, and perceptual speed and the Mini-Mental State Examination (MMSE). The authors suggest that this cluster of tests reflects deficits in controlled rather than automatic cognitive processes. Nondemented twin partners of the twins who became demented were also compared with 33 matched controls selected from pairs in which both members remained nondemented. Nondemented twin partners scored lower than matched controls on tests of verbal ability, memory and attention, and perceptual speed and the MMSE. This finding indicates that nondemented twin partners of demented twins are at elevated risk themselves for becoming demented, and further suggests that certain areas of cognition are compromised prior to diagnosis of dementia.


Order Under Uncertainty: Robust Differential Expression Analysis Using Probabilistic Models for Pseudotime Inference.
Single cell gene expression profiling can be used to quantify transcriptional dynamics in temporal processes, such as cell differentiation, using computational methods to label each cell with a 'pseudotime' where true time series experimentation is too difficult to perform. However, owing to the high variability in gene expression between individual cells, there is an inherent uncertainty in the precise temporal ordering of the cells. Pre-existing methods for pseudotime estimation have predominantly given point estimates precluding a rigorous analysis of the implications of uncertainty. We use probabilistic modelling techniques to quantify pseudotime uncertainty and propagate this into downstream differential expression analysis. We demonstrate that reliance on a point estimate of pseudotime can lead to inflated false discovery rates and that probabilistic approaches provide greater robustness and measures of the temporal resolution that can be obtained from pseudotime inference.


Hepatic binding of DNA is mediated by a receptor on nonparenchymal cells.
During cell death, nuclear material is released into the cellular environment and into the circulation. Studies in experimental animals have shown that circulating DNA is rapidly removed by the liver and broken down to oligonucleotides. The authors have used a perfused liver system in the mouse to study hepatic binding of single-stranded DNA. DNA binding to the liver was rapid and efficient, and did not require serum factors. Binding was saturable and temperature independent, suggesting a receptor-mediated process. Electron microscope autoradiography demonstrated DNA binding to sinusoidal lining cells, primarily Kupffer cells. In vitro studies with isolated cells confirmed that DNA bound to a trypsin-sensitive receptor on the adherent subset of hepatic nonparenchymal cells. The integrity of the perfused liver was confirmed by the demonstration of appropriate uptake and breakdown of asialoorosomucoid. Despite rapid binding of DNA, however, the perfused liver did not digest DNA or release DNA breakdown products. Infusion of DNAse at intervals after DNA perfusion demonstrated that significant amounts of DNA remained bound to the cell surface, and that serum nucleases were able to cleave this surface bound DNA. It is concluded that DNA binding to the liver is mediated by a receptor on Kupffer cells, but that DNA breakdown may occur at the cell surface or in circulation and may not require cell interiorization.


Macro- and microstructure of the superior cervical ganglion in dogs, cats and horses during maturation.
The superior cervical ganglion (SCG) provides sympathetic input to the head and neck, its relation with mandible, submandibular glands, eyes (second and third order control) and pineal gland being demonstrated in laboratory animals. In addition, the SCG's role in some neuropathies can be clearly seen in Horner's syndrome. In spite of several studies published involving rats and mice, there is little morphological descriptive and comparative data of SCG from large mammals. Thus, we investigated the SCG's macro- and microstructural organization in medium (dogs and cats) and large animals (horses) during a very specific period of the post-natal development, namely maturation (from young to adults). The SCG of dogs, cats and horses were spindle shaped and located deeply into the bifurcation of the common carotid artery, close to the distal vagus ganglion and more related to the internal carotid artery in dogs and horses, and to the occipital artery in cats. As to macromorphometrical data, that is ganglion length, there was a 23.6% increase from young to adult dogs, a 1.8% increase from young to adult cats and finally a 34% increase from young to adult horses. Histologically, the SCG's microstructure was quite similar between young and adult animals and among the 3 species. The SCG was divided into distinct compartments (ganglion units) by capsular septa of connective tissue. Inside each ganglion unit the most prominent cellular elements were ganglion neurons, glial cells and small intensely fluorescent cells, comprising the ganglion's morphological triad. Given this morphological arrangement, that is a summation of all ganglion units, SCG from dogs, cats and horses are better characterized as a ganglion complex rather than following the classical ganglion concept. During maturation (from young to adults) there was a 32.7% increase in the SCG's connective capsule in dogs, a 25.8% increase in cats and a 33.2% increase in horses. There was an age-related increase in the neuronal profile size in the SCG from young to adult animals, that is a 1.6-fold, 1.9-fold and 1.6-fold increase in dogs, cats and horses, respectively. On the other hand, there was an age-related decrease in the nuclear profile size of SCG neurons from young to adult animals (0.9-fold, 0.7-fold and 0.8-fold in dogs, cats and horses, respectively). Ganglion connective capsule is composed of 2 or 3 layers of collagen fibres in juxtaposition and, as observed in light microscopy and independently of the animal's age, ganglion neurons were organised in ganglionic units containing the same morphological triad seen in light microscopy.


Radiology of COVID-19 - Imaging the pulmonary damage.
A large part of the world is presently in the grip of the coronavirus disease (COVID-19) by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 virus), declared a pandemic in March 2020. This document is a brief commentary of the imaging modalities used in the screening, diagnosis and management of COVID-19 pneumonia. Chest x-rays, especially portable, still form a part of majority of official guidelines, with reports of the suggestive radiologic features. The potential of CT scan and ultrasound is also realised, with earlier detection rate. Typical radiologic findings of bilateral, asymmetrical, crazy-paved ground glass opacification, consolidation, reverse halo sign, opacities, progressing to fibrosis are well described for both the X-ray and CT scan. Atypical findings include airway changes, pleural effusion, pulmonary nodules and acute pulmonary embolism. Absence of lymphadenopathy, pleural effusion and pneumothorax is notable. The role of portable lung ultrasound, reported to be useful in emergency, is yet to be established in the guidelines. Disinfection of the equipment is a major concern. Governmental guidelines still advocate X-ray despite professional societies increasingly recommending CT scan.


An Evidence-Based Tool for Safe Configuration of Electronic Health Records: The eSafety Checklist.
Electronic health records (EHRs) are transforming the way health care is delivered. They are central to improving the quality of patient care and have been attributed to making health care more accessible, reliable, and safe. However, in recent years, evidence suggests that specific features and functions of EHRs can introduce new, unanticipated patient safety concerns that can be mitigated by safe configuration practices. This article outlines the development of a detailed and comprehensive evidence-based checklist of safe configuration practices for use by clinical informatics professionals when configuring hospital-based EHRs. A literature review was conducted to synthesize evidence on safe configuration practices; data were analyzed to elicit themes of common EHR system capabilities. Two rounds of testing were completed with end users to inform checklist design and usability. This was followed by a four-member expert panel review, where each item was rated for clarity (clear, not clear), and importance (high, medium, low). An expert panel consisting of three clinical informatics professionals and one health information technology expert reviewed the checklist for clarity and importance. Medium and high importance ratings were considered affirmative responses. Of the 870 items contained in the original checklist, 535 (61.4%) received 100% affirmative agreement among all four panelists. Clinical panelists had a higher affirmative agreement rate of 75.5% (656 items). Upon detailed analysis, items with 100% clinician agreement were retained in the checklist with the exception of 47 items and the addition of 33 items, resulting in a total of 642 items in the final checklist. Safe implementation of EHRs requires consideration of both technical and sociotechnical factors through close collaboration of health information technology and clinical informatics professionals. The recommended practices described in this checklist provide systems implementation guidance that should be considered when EHRs are being configured, implemented, audited, or updated, to improve system safety and usability.


TALEN/CRISPR-mediated eGFP knock-in add-on at the OCT4 locus does not impact differentiation of human embryonic stem cells towards endoderm.
Human embryonic stem cells (hESCs) have great promise as a source of unlimited transplantable cells for regenerative medicine. However, current progress on producing the desired cell type for disease treatment has been limited due to an insufficient understanding of the developmental processes that govern their differentiation, as well as a paucity of tools to systematically study differentiation in the lab. In order to overcome these limitations, cell-type reporter hESC lines will be required. Here we outline two strategies using Transcription Activator Like Effector Nucleases (TALENs) and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR-Associated protein (Cas) to create OCT4-eGFP knock-in add-on hESC lines. Thirty-one and forty-seven percent of clones were correctly modified using the TALEN and CRISPR-Cas9 systems, respectively. Further analysis of three correctly targeted clones demonstrated that the insertion of eGFP in-frame with OCT4 neither significantly impacted expression from the wild type allele nor did the fusion protein have a dramatically different biological stability. Importantly, the OCT4-eGFP fusion was easily detected using microscopy, flow cytometry and western blotting. The OCT4 reporter lines remained equally competent at producing CXCR4+ definitive endoderm that expressed a panel of endodermal genes. Moreover, the genomic modification did not impact the formation of NKX6.1+/SOX9+ pancreatic progenitor cells following directed differentiation. In conclusion, these findings demonstrate for the first time that CRISPR-Cas9 can be used to modify OCT4 and highlight the feasibility of creating cell-type specific reporter hESC lines utilizing genome-editing tools that facilitate homologous recombination.


Central Role of Glutamate Metabolism in the Maintenance of Nitrogen Homeostasis in Normal and Hyperammonemic Brain.
Glutamate is present in the brain at an average concentration-typically 10-12 mM-far in excess of those of other amino acids. In glutamate-containing vesicles in the brain, the concentration of glutamate may even exceed 100 mM. Yet because glutamate is a major excitatory neurotransmitter, the concentration of this amino acid in the cerebral extracellular fluid must be kept low-typically µM. The remarkable gradient of glutamate in the different cerebral compartments: vesicles > cytosol/mitochondria > extracellular fluid attests to the extraordinary effectiveness of glutamate transporters and the strict control of enzymes of glutamate catabolism and synthesis in well-defined cellular and subcellular compartments in the brain. A major route for glutamate and ammonia removal is via the glutamine synthetase (glutamate ammonia ligase) reaction. Glutamate is also removed by conversion to the inhibitory neurotransmitter γ-aminobutyrate (GABA) via the action of glutamate decarboxylase. On the other hand, cerebral glutamate levels are maintained by the action of glutaminase and by various α-ketoglutarate-linked aminotransferases (especially aspartate aminotransferase and the mitochondrial and cytosolic forms of the branched-chain aminotransferases). Although the glutamate dehydrogenase reaction is freely reversible, owing to rapid removal of ammonia as glutamine amide, the direction of the glutamate dehydrogenase reaction in the brain in vivo is mainly toward glutamate catabolism rather than toward the net synthesis of glutamate, even under hyperammonemia conditions. During hyperammonemia, there is a large increase in cerebral glutamine content, but only small changes in the levels of glutamate and α-ketoglutarate. Thus, the channeling of glutamate toward glutamine during hyperammonemia results in the net synthesis of 5-carbon units. This increase in 5-carbon units is accomplished in part by the ammonia-induced stimulation of the anaplerotic enzyme pyruvate carboxylase. Here, we suggest that glutamate may constitute a buffer or bulwark against changes in cerebral amine and ammonia nitrogen. Although the glutamate transporters are briefly discussed, the major emphasis of the present review is on the enzymology contributing to the maintenance of glutamate levels under normal and hyperammonemic conditions. Emphasis will also be placed on the central role of glutamate in the glutamine-glutamate and glutamine-GABA neurotransmitter cycles between neurons and astrocytes. Finally, we provide a brief and selective discussion of neuropathology associated with altered cerebral glutamate levels.


Risk analysis for the highly pathogenic avian influenza in Mainland China using meta-modeling.
A logistic model was employed to correlate the outbreak of highly pathogenic avian influenza (HPAI) with related environmental factors and the migration of birds. Based on MODIS data of the normalized difference vegetation index, environmental factors were considered in generating a probability map with the aid of logistic regression. A Bayesian maximum entropy model was employed to explore the spatial and temporal correlations of HPAI incidence. The results show that proximity to water bodies and national highways was statistically relevant to the occurrence of HPAI. Migratory birds, mainly waterfowl, were important infection sources in HPAI transmission. In addition, the HPAI outbreaks had high spatiotemporal autocorrelation. This epidemic spatial range fluctuated 45 km owing to different distribution patterns of cities and water bodies. Furthermore, two outbreaks were likely to occur with a period of 22 d. The potential risk of occurrence of HPAI in Mainland China for the period from January 23 to February 17, 2004 was simulated based on these findings, providing a useful meta-model framework for the application of environmental factors in the prediction of HPAI risk.


Acetaminophen decreases adenosine 3'-phosphate 5'-phosphosulfate and uridine diphosphoglucuronic acid in rat liver.
The purpose of this investigation was to determine the effects of acute administration of acetaminophen on adenosine 3'-phosphate 5'-phosphosulfate (PAPS) and UDP-glucuronic acid concentrations in fed male rats. Acetaminophen produced a dosage-dependent decline in rat hepatic PAPS concentrations which was significant after dosages of 150, 300, or 600 mg/kg, ip. The time course of the decline in PAPS values after 600 mg acetaminophen/kg showed that PAPS concentrations reached a nadir 1 hr after dosing (40% of control values). Serum sulfate concentrations were also decreased by large dosages of acetaminophen (32 and 15% of control 2 hr after 150 and 600 mg/kg, respectively) and a significant, positive correlation between serum sulfate and hepatic PAPS concentrations was noted. In addition, hepatic cysteine and glutathione concentrations were lowered by high dosages of acetaminophen. Hepatic UDP-glucuronic acid concentrations were greatly decreased for 2 hr after a dosage of 600 mg acetaminophen/kg (15, 23, and 42% of control 0.5, 1.0, and 2.0 hr after dosing, respectively) whereas 150 mg/kg produced a less pronounced and more transient decrease. These findings demonstrate that both PAPS and UDP-glucuronic acid concentrations in liver are decreased after administration of acetaminophen and imply that capacity-limited sulfation and glucuronidation of acetaminophen are due to a decrease in co-substrate availability.


Existing general population models inaccurately predict lung cancer risk in patients referred for surgical evaluation.
Patients undergoing resections for suspicious pulmonary lesions have a 9% to 55% benign rate. Validated prediction models exist to estimate the probability of malignancy in a general population and current practice guidelines recommend their use. We evaluated these models in a surgical population to determine the accuracy of existing models to predict benign or malignant disease. We conducted a retrospective review of our thoracic surgery quality improvement database (2005 to 2008) to identify patients who underwent resection of a pulmonary lesion. Patients were stratified into subgroups based on age, smoking status, and fluorodeoxyglucose positron emission tomography (PET) results. The probability of malignancy was calculated for each patient using the Mayo and solitary pulmonary nodules prediction models. Receiver operating characteristic and calibration curves were used to measure model performance. A total of 189 patients met selection criteria; 73% were malignant. Patients with preoperative PET scans were divided into four subgroups based on age, smoking history, and nodule PET avidity. Older smokers with PET-avid lesions had a 90% malignancy rate. Patients with PET-nonavid lesions, PET-avid lesions with age less than 50 years, or never smokers of any age had a 62% malignancy rate. The area under the receiver operating characteristic curve for the Mayo and solitary pulmonary nodules models was 0.79 and 0.80, respectively; however, the models were poorly calibrated (p<0.001). Despite improvements in diagnostic and imaging techniques, current general population models do not accurately predict lung cancer among patients referred for surgical evaluation. Prediction models with greater accuracy are needed to identify patients with benign disease to reduce nontherapeutic resections.


Molecular cloning, chromosomal localization, and expression of murine dipeptidyl peptidase I.
Dipeptidyl peptidase I (DPPI) is a lysosomal cysteine protease that catalyzes the sequential removal of dipeptides from the amino termini of various protein substrates. We have isolated a cDNA coding for murine DPPI from mouse thymus and spleen cDNA libraries. The deduced amino acid sequence codes for a protein of 462 amino acid residues; comparison of this deduced sequence with that of rat and human DPPI revealed 90.1% and 77.8% identity, respectively. Using DPPI cDNA, we obtained two BAC (Bacterial Artificial Chromosome) clones that contained the murine DPPI locus. The DPPI gene consists of seven exons and 6 introns, and spans approximately 20 kilobases. Using fluorescence in situ chromosome hybridization, we localized murine DPPI to chromosome 7D3-E1.1. We determined that DPPI protein is widely distributed in mouse tissues, although its relative abundance varies from tissue to tissue. In contrast to previous reports, we show here that DPPI mRNA and protein levels and enzymatic activity are unchanged during in vitro T cell activation, implying that this enzyme is not rate-limiting for granzyme processing.


Effect of inhaled prostaglandin D2 in normal and atopic subjects, and of pretreatment with leukotriene D4.
Prostaglandin (PG) D2 is a potent bronchoconstrictor mediator and is found, together with leukotriene (LT) D4, in bronchoalveolar lavage fluid during the early response to allergen challenge in asthmatic subjects. The potency of PGD2 has not been established in normal and atopic non-asthmatic subjects, nor has the contribution of cholinergic mechanisms to PGD2 induced bronchoconstriction in normal subjects. Mediators released simultaneously may interact, so the effect of pre-inhalation of LTD4 on PGD2 responsiveness was investigated. Six normal and six atopic non-asthmatic subjects performed histamine and PGD2 challenges on separate occasions. Eight normal subjects performed PGD2 challenges immediately before and 45 minutes after inhalation of 200 micrograms oxitropium bromide or placebo. Bronchial responsiveness to PGD2 was established in six normal subjects immediately after pretreatment with saline or non-bronchoconstricting doses of methacholine or LTD4 (challenge 1), and again at six hours (challenge 2). All studies were performed in a double blind, randomised, crossover fashion. PGD2 was 25-fold and 18-fold more potent as a bronchoconstrictor than histamine in atopic non-asthmatic and normal subjects, respectively. Responsiveness (PC35sGaw) to histamine and PGD2 correlated significantly (r = 0.917, n = 12, p < 0.001). Oxitropium bromide in a dose of 200 micrograms inhibited PGD2 induced bronchoconstriction by 37.5%, although in two of these subjects no inhibition was seen. Pre-inhalation of LTD4 and methacholine shifted the dose-response curve of PGD2 to the left by 4.6-fold and 2.4-fold, respectively. PGD2 is a potent bronchoconstrictor in normal subjects, which is partly mediated by cholinergic mechanisms in some subjects. No significant interaction was found between LTD4 and PGD2 in six normal subjects.


The genopolis microarray database.
Gene expression databases are key resources for microarray data management and analysis and the importance of a proper annotation of their content is well understood. Public repositories as well as microarray database systems that can be implemented by single laboratories exist. However, there is not yet a tool that can easily support a collaborative environment where different users with different rights of access to data can interact to define a common highly coherent content. The scope of the Genopolis database is to provide a resource that allows different groups performing microarray experiments related to a common subject to create a common coherent knowledge base and to analyse it. The Genopolis database has been implemented as a dedicated system for the scientific community studying dendritic and macrophage cells functions and host-parasite interactions. The Genopolis Database system allows the community to build an object based MIAME compliant annotation of their experiments and to store images, raw and processed data from the Affymetrix GeneChip platform. It supports dynamical definition of controlled vocabularies and provides automated and supervised steps to control the coherence of data and annotations. It allows a precise control of the visibility of the database content to different sub groups in the community and facilitates exports of its content to public repositories. It provides an interactive users interface for data analysis: this allows users to visualize data matrices based on functional lists and sample characterization, and to navigate to other data matrices defined by similarity of expression values as well as functional characterizations of genes involved. A collaborative environment is also provided for the definition and sharing of functional annotation by users. The Genopolis Database supports a community in building a common coherent knowledge base and analyse it. This fills a gap between a local database and a public repository, where the development of a common coherent annotation is important. In its current implementation, it provides a uniform coherently annotated dataset on dendritic cells and macrophage differentiation.


Nuclear PKC-θ facilitates rapid transcriptional responses in human memory CD4+ T cells through p65 and H2B phosphorylation.
Memory T cells are characterized by their rapid transcriptional programs upon re-stimulation. This transcriptional memory response is facilitated by permissive chromatin, but exactly how the permissive epigenetic landscape in memory T cells integrates incoming stimulatory signals remains poorly understood. By genome-wide ChIP-sequencing ex vivo human CD4(+) T cells, here, we show that the signaling enzyme, protein kinase C theta (PKC-θ) directly relays stimulatory signals to chromatin by binding to transcriptional-memory-responsive genes to induce transcriptional activation. Flanked by permissive histone modifications, these PKC-enriched regions are significantly enriched with NF-κB motifs in ex vivo bulk and vaccinia-responsive human memory CD4(+) T cells. Within the nucleus, PKC-θ catalytic activity maintains the Ser536 phosphorylation on the p65 subunit of NF-κB (also known as RelA) and can directly influence chromatin accessibility at transcriptional memory genes by regulating H2B deposition through Ser32 phosphorylation. Furthermore, using a cytoplasm-restricted PKC-θ mutant, we highlight that chromatin-anchored PKC-θ integrates activating signals at the chromatin template to elicit transcriptional memory responses in human memory T cells.


Information transfer from causal history in complex system dynamics.
In a multivariate evolutionary system, the present state of a variable is a resultant outcome of all interacting variables through the temporal history of the system. How can we quantify the information transfer from the history of all variables to the outcome of a specific variable at a specific time? We develop information theoretic metrics to quantify the information transfer from the entire history, called causal history. Further, we partition this causal history into immediate causal history, as a function of lag τ from the recent time, to capture the influence of recent dynamics, and the complementary distant causal history. Further, each of these influences are decomposed into self- and cross-feedbacks. By employing a Markov property for directed acyclic time-series graph, we reduce the dimensions of the proposed information-theoretic measure to facilitate an efficient estimation algorithm. This approach further reveals an information aggregation property, that is, the information from historical dynamics are accumulated at the preceding time directly influencing the present state of variable(s) of interest. These formulations allow us to analyze complex inter-dependencies in unprecedented ways. We illustrate our approach for: (1) characterizing memory dependency by analyzing a synthetic system with short memory; (2) distinguishing from traditional methods such as lagged mutual information using the Lorenz chaotic model; (3) comparing the memory dependencies of two long-memory processes with and without the strange attractor using the Lorenz model and a linear Ornstein-Uhlenbeck process; and (4) illustrating how dynamics in a complex system is sustained through the interactive contribution of self- and cross-dependencies in both immediate and distant causal histories, using the Lorenz model and observed stream chemistry data known to exhibit 1/f long memory.


The measurement of breathlessness induced in normal subjects: individual differences.
Normal subjects show wide variability in their sensory scaling of breathlessness for equivalent degrees of ventilatory stimulation and behave "characteristically' irrespective of stimulus type. Observed differences are not explained by physical characteristics, ventilatory sensitivity or pattern of breathing although there is a weak association with the degree of physical fitness. Differences are seen when scaling is performed with reference to both rigidly defined extremes of breathlessness (visual analogue scaling) and a subject's own relative changes in the intensity of this sensation (magnitude estimation). These findings may explain the common observation, in patients with respiratory disease, of dyspnoea out of proportion to the pathophysiological state.


Reaching with alien limbs: visual exposure to prosthetic hands in a mirror biases proprioception without accompanying illusions of ownership.
In five experiments, we investigated the effects of visual exposure to a real hand, arubber hand, or a wooden block on reaching movements made with the unseen left hand behind a parasagittal mirror. Participants reached from one of four starting positions, corresponding to four levels of conflict between the proprioceptively and visually specified positions of the reaching hand. Reaching movements were affected most by exposure to the real hand, intermediately by the rubber hand, and least of all by the wooden block When the posture and/or movement of the visible hand was incompatible with that of the reaching hand, the effect on reaching was reduced. A "rubber hand illusion" questionnaire revealed that illusions of ownership of the rubber hand were not strongly correlated with reaching performance. This research suggests that proprioception is recalibrated following visual exposure to prosthetic hands and that this recalibration is independent of the rubber hand illusion.