Prevalences of various hemoplasma species among cats in the United States with possible hemoplasmosis.
To determine prevalences of various hemoplasma species among cats in the United States with possible hemoplasmosis and identify risk factors for and clinicopathologic abnormalities associated with infection with each species. Cross-sectional study. Animals-310 cats with cytologic evidence of hemoplasmosis (n = 9) or acute or regenerative anemia (309). Blood samples were tested by means of a broad-spectrum conventional PCR assay for hemoplasma DNA and by means of 3 separate species-specific real-time PCR assays for DNA from "Candidatus Mycoplasma haemominutum" (Mhm), Mycoplasma haemofelis (Mhf), and "Candidatus Mycoplasma turicensis" (Mtc). Overall prevalences of Mhm, Mhf, and Mtc infection were 23.2% (72/310), 4.8% (15/310), and 6.5% (20/310), respectively. Mixed infections were detected in 20 (6.5%) cats. Cats infected with hemoplasmas were more likely to be male than were uninfected cats. Infection with FeLV or FIV was significantly associated with infection with Mhf. Compared with uninfected cats, cats infected with Mhf had higher reticulocyte counts, nucleated RBC counts, and mean corpuscular volume; cats infected with Mhm had higher mean corpuscular volume; and cats infected with Mtc had higher monocyte counts. Results supported the suggestion that these 3 hemoplasma species commonly occur among cats in the United States and that pathogenicity of the 3 species varies.


Pathophysiological changes of the liver-muscle axis in end-stage liver disease: what is the right target?
Liver diseases and in particular end stage liver diseases are frequently complicated by muscle modifications that are linked to worse clinical outcome. In addition, recent studies have demonstrated the negative impact of these muscle changes on liver function leading to the hypothesis of a bidirectional relationship referred in the literature as "muscle-liver axis". In a context of evolution towards a more holistic and less organocentric vision of medicine, studying frailty, myosteatosis and sarcopenia and their underlying pathophysiological mechanisms has led to many publications in the last five years. These studies are describing several pathophysiological mechanisms, highlighting the extremely complex character of this relationship. This review aims to summarize these mechanisms as well as potential therapeutic targets, independently of liver disease etiology.


Factors Influencing Receipt of Interventional Pain Management Among Medicaid Beneficiaries with Cancer.
Pain is common among cancer patients. Nonclinical factors may affect receipt of pain management among Medicaid beneficiaries with cancer. To examine associations of patient characteristics and US state-level Medicaid policies on receipt of interventional pain management among Medicaid beneficiaries with breast or colorectal cancer. A retrospective analysis of 2006-2008 Medicaid claims data. Claims data from facilities providing care to Medicaid beneficiaries. Interventional pain management among Medicaid beneficiaries aged 18-64 years with breast or colorectal cancer was identified using procedure codes in Medicaid claims data. State-level Medicaid policy variables included physician visit reimbursements, required patient copayments, and time period for Medicaid eligibility recertification (12 vs. < 12 months). Analyses also examined beneficiary race/ethnicity, age, comorbidities, and cancer treatment. Generalized estimating equations controlling for clustering by state assessed factors influencing receipt of interventional pain management. The study included 8,438 Medicaid beneficiaries with breast or colorectal cancer. Colorectal cancer (vs. breast cancer) patients were significantly more likely to receive interventional pain management. Medicaid policies were not significantly associated with receipt of interventional pain services. Among breast cancer patients, older age and non-Hispanic white race/ethnicity were associated with decreased likelihood of receiving interventional pain management; more comorbidities and receipt of breast conserving surgery were associated with increased likelihood. Demographic characteristics were not significantly associated with receipt of interventional pain management among colorectal cancer patients. Sample size of Medicare beneficiaries with cancer receiving interventional pain management; limited information included in Medicare claims data. State-level Medicaid policies were not significantly associated with receipt of interventional pain management for breast or colorectal cancer patients; disparities in receipt of these services were observed only for breast cancer patients. These results may help develop policies to enhance access to appropriate pain management services. Cancer pain, pain management, Medicaid, health care disparities, breast neoplasms, colorectal neoplasms, health policies, physician practice patterns, retrospective studies, claims analyses.


Group foraging in Socotra cormorants: A biologging approach to the study of a complex behavior.
Group foraging contradicts classic ecological theory because intraspecific competition normally increases with aggregation. Hence, there should be evolutionary benefits to group foraging. The study of group foraging in the field remains challenging however, because of the large number of individuals involved and the remoteness of the interactions to the observer. Biologging represents a cost-effective solution to these methodological issues. By deploying GPS and temperature-depth loggers on individuals over a period of several consecutive days, we investigated intraspecific foraging interactions in the Socotra cormorant Phalacrocorax nigrogularis, a threatened colonial seabird endemic to the Arabian Peninsula. In particular, we examined how closely birds from the same colony associated with each other spatially when they were at sea at the same time and the distance between foraging dives at different periods of the day. Results show that the position of different birds overlapped substantially, all birds targeting the same general foraging grounds throughout the day, likely following the same school of fish. There were as many as 44,500 birds within the foraging flock at sea at any time (50% of the colony), and flocking density was high, with distance between birds ranging from 8 to 1,380 m. Birds adopted a diving strategy maximizing time spent underwater relative to surface time, resulting in up to 72% of birds underwater in potential contact with prey at all times while foraging. Our data suggest that the benefits of group foraging outweigh the costs of intense aggregation in this seabird. Prey detection and information transmission are facilitated in large groups. Once discovered, shoaling prey are concentrated under the effect of the multitude. Fish school cohesiveness is then disorganized by continuous attacks of diving birds to facilitate prey capture. Decreasing population size could pose a risk to the persistence of threatened seabirds where group size is important for foraging success.


Identification of quantitative trait loci associated with egg quality, egg production, and body weight in an F2 resource population of chickens.
Egg production and egg quality are complex sex-limited traits that may benefit from the implementation of marker-assisted selection. The primary objective of the current study was to identify quantitative trait loci (QTL) associated with egg traits, egg production, and body weight in a chicken resource population. Layer (White Leghorn hens) and broiler (Cobb-Cobb roosters) lines were crossed to generate an F2 population of 508 hens over seven hatches. Phenotypes for 29 traits (weekly body weight from hatch to 6 weeks, egg traits including egg, albumen, yolk, and shell weight, shell thickness, shell puncture score, percentage of shell, and egg shell colour at 35 and 55 weeks of age, as well as egg production between 16 and 55 weeks of age) were measured in hens of the resource population. Genotypes of 120 microsatellite markers on 28 autosomal groups were determined, and interval mapping was conducted to identify putative QTL. Eleven QTL tests representing two regions on chromosomes 2 and 4 surpassed the 5% genome-wise significance threshold. These QTL influenced egg colour, egg and albumen weight, percent shell, body weight, and egg production. The chromosome 4 QTL region is consistent with multiple QTL studies that define chromosome 4 as a critical region significantly associated with a variety of traits across multiple resource populations. An additional 64 QTL tests surpassed the 5% chromosome-wise significance threshold.


Clearance of calcium pyrophosphate dihydrate crystals in vivo. III. Effects of synovial hemosiderosis.
Synthetic triclinic calcium pyrophosphate dihydrate crystals, uniformly labeled with 85Sr and 45Ca, were injected into the knee joints of 2 normal adult rabbits and 2 rabbits previously injected repeatedly with autologous blood. The "half clearance time" of the injected crystal mass was 20.4 and 19 days from control joints, nearly identical to previously reported values in 6 rabbits (19.1 +/- 1.4), and 28.8 and 34 days from the joints injected with blood, a significant difference (P less than 0.05). Iron stains showed hemosiderin granules in the superficial synovium in these joints. Electron microscopy showed crystals with a molar calcium/phosphorus ratio of 1.0 and particles containing iron within synovial cells. We hypothesize that the decreased clearance rate from hemosiderotic synovium is due to inhibition of one or more intracellular pyrophosphatases by iron.


PERFORMANCE OF SIX SCREENING SCORES FOR OBSTRUCTIVE SLEEP APNOEA IN AN AFRICAN POPULATION.
A screening tool for obstructive sleep apnoea (OSA) is useful in low-income countries where it may be difficult to access sleep recordings. The objective of this study was to assess the performance of six screening scores compared with objective sleep recording in an African population sample. This analysis is based on the "Benin Sleep and Society" (BeSAS) populational study in which respiratory polygraphy (PG) was performed using a type III device and OSA screening questionnaires (STOP, STOP-Bang, Berlin, NOSAS [≥ 8 and ≥ 5), No-Apnea, GOAL) were administered to participants. PG-defined OSA severity categories were defined according to the apnoea-hypopnoea index (AHI): mild (AHI 5 to <15/h), moderate (AHI 15 to <30/h) or severe (AHI≥30/h), and these were compared to score findings. A total of 1810 subjects (mean age 45.4±14.6 years; 57.3% women) were included. For moderate to severe OSA, the area under the receiving operating characteristic (ROC) curve was greatest for GOAL and No-Apnea (0.70), followed by NoSAS5 (0.69). The highest sensitivity values were for NoSAS5 (0.73), No-Apnea (0.72), and GOAL (0.69), while NoSAS8 had the highest specificity (0.91), followed by Berlin (0.88) and GOAL (0.71). All scores performed poorly with respect to the positive predictive value (PPV), which was highest with NoSAS8 (0.38). Conclusion: This study provides the first comparison of the performance of screening scores for OSA in an African population. Although still low, PPV was highest with NoSAS8. Hence, NoSAS8 would be the screening method of choice for OSA in resource-constrained settings where formal sleep recordings are not accessible.


Standing out in Canada and Japan.
The need for separation or individuation is held to be a prime motive in Western psychology. Varied accounts of the meaning of selfhood in Japan indicate that separation may be much less important-or as important-for understanding the construction of self-identity in that culture. We focus here on personal distinctiveness, one vehicle for separation from others. We propose that the desire for distinctiveness is not absent or negligible in Japan, but is subject to more constrained expression than in the West. The results of two studies comparing Japanese and Canadian students suggest that Japanese are less desirous of standing out for their own sake and more likely to experience this form of distinctiveness as aversive. The results also suggest that although Japanese and Canadians derive positive distinctiveness from much the same sources, Japanese are less gratified by this type of experience.


Gender bias in nursing care? Gender-related differences in patient satisfaction with the quality of nursing care.
Gender-related differences in experience with nursing care, was studied using data from a Norwegian survey of patient-satisfaction. The survey included 1469 male and 1226 female patients. Results showed that young female patients were less content with all aspects of nursing care when compared with young male patients. Female patients experienced, quite contrary to their male counterparts, that the nursing staff was less committed and caring, has less time and was less skilled. The young women were also less content with what they felt was a lack of opportunity to provide the staff with information they believed to be important to their condition or ailment. Analysis also revealed that female patients, compared with their male counterparts, indicated a higher score on the subjective importance of the different aspects of care. These findings are discussed on the basis of gender-related research in general. The finding of lower satisfaction amongst younger female patients could be ascribed to the power-balance between nursing staff and patients. The discussion shows, however, that there are a number of possible interpretations as to why female patients are less content with nursing care compared with male patients. As the reasons for the findings may be derived from several sources it becomes evident that there is a need for further research using alternative approaches.


The prevalence of Onchocerca spp. in cattle in northern Togo in 1979.
The prevalences of three species of Onchocerca parasitising the Somba race of cattle occurring in the Kara region in northern Togo were investigated. Onchocerca ochengi was common in the cattle rearing areas of Keran (42% of head infected) and Kozah (29% of head infected). The prevalences of O. dukei ranged from 35 to 73.5% and of O. gutturosa from 23.2 to 49.1%. No differences were noted in the percent of bulls and cows parasitised.


Cyclophilin, a primary molecular target for cyclosporine. Structural and functional implications.
An understanding of the mechanism of action of cyclosporine requires the identification and functional characterization of its molecular target or targets in the cell. Our laboratory has presented evidence that cyclophilin (CYP), a low-molecular-weight (Mr 17,737) basic protein, is the primary cytosolic receptor for CsA. The high affinity of CYP for CsA (Kd 30 nM) and specificity for immunosuppressive cyclosporine analogs implicate CYP as a pivotal regulator of T cell and B cell activation. CYP exists in at least two isoforms, is abundant (0.05% to 0.4% of total protein) in the cytosol, and is ubiquitous in cells and tissues of eukaryotic organisms. Its amino acid sequence is highly conserved and there is strong evidence that CYP is a member of a new multigene family. These features suggest that one or more CYP isoforms must play a crucial role in lymphocyte activation and perhaps a multifunctional role in cellular physiology. The ability of CsA to suppress expression of several lymphokine and proto-oncogene products via a transcriptional control mechanism suggests that CYP may function at some level in a signaling pathway linking membrane receptor stimulation to gene regulatory elements in lymphocytes, and possibly nonlymphoid cell types as well.


[Epidemiologic study of mortality of workers of metallurgy enterprise in Nizhni Tagil].
The article studies long-term effects of occupational factors on metallurgists' health. The epidemiologic research revealed that hard physical work in chronic and intensive heating microclimate with high levels of dust increases the mortality risk among workers engaged into open-hearth, necking, converter and blast furnace shops (the death causes--arterial hypertension, coronary heart disease, pneumonia, bronchitis, tracheal and bronchial cancer, lung and pancreatic carcinoma). The auxiliary workers of those shops, who face intermittent influence of the same factors demonstrated the mortality levels insignificantly different from those of a reference region. Influence of chemicals containing carcinogens increases the mortality among workers or non-coke and coke shops (the death causes--tracheal, bronchial and lung cancer.


Model-based analysis of coupled equilibrium-kinetic processes: indirect kinetic studies of thermodynamic parameters using the dynamic data.
Thermodynamic studies of equilibrium chemical reactions linked with kinetic procedures are mostly impossible by traditional approaches. In this work, the new concept of generalized kinetic study of thermodynamic parameters is introduced for dynamic data. The examples of equilibria intertwined with kinetic chemical mechanisms include molecular charge transfer complex formation reactions, pH-dependent degradation of chemical compounds and tautomerization kinetics in micellar solutions. Model-based global analysis with the possibility of calculating and embedding the equilibrium and kinetic parameters into the fitting algorithm has allowed the complete analysis of the complex reaction mechanisms. After the fitting process, the optimal equilibrium and kinetic parameters together with an estimate of their standard deviations have been obtained. This work opens up a promising new avenue for obtaining equilibrium constants through the kinetic data analysis for the kinetic reactions that involve equilibrium processes.


Neurokinin 3 receptor antagonism rapidly improves vasomotor symptoms with sustained duration of action.
Seventy percent of postmenopausal women experience vasomotor symptoms, which can be highly disruptive and persist for years. Hormone therapy and other treatments have variable efficacy and/or side effects. Neurokinin B signaling increases in response to estrogen deficiency and has been implicated in hot flash (HF) etiology. We recently reported that a neurokinin 3 receptor (NK3R) antagonist reduces HF in postmenopausal women after 4 weeks of treatment. In this article we report novel data from that study, which shows the detailed time course of this effect. Randomized, double-blind, placebo-controlled, single-center, crossover trial of an oral NK3R antagonist (MLE4901) for vasomotor symptoms in women aged 40 to 62 years, experiencing ≥7 HF/24 hours some of which were reported as bothersome or severe (Clinicaltrials.gov NCT02668185). Thirty-seven women were randomized and included in an intention-to-treat analysis. To ascertain the therapeutic profile of MLE4901, a post hoc time course analysis was completed. By day 3 of treatment with MLE4901, HF frequency reduced by 72% (95% CI, -81.3 to -63.3%) compared with baseline (51 percentage point reduction compared with placebo, P < 0.0001); this effect size persisted throughout the 4-week dosing period. HF severity reduced by 38% compared with baseline by day 3 (95% CI, -46.1 to -29.1%) (P < 0.0001 compared with placebo), bother by 39% (95% CI, -47.5 to -30.1%) (P < 0.0001 compared with placebo), and interference by 61% (95% CI, -79.1 to -43.0%) (P = 0.0006 compared with placebo); all continued to improve throughout the 4-week dosing period (to -44%, -50%, and -70%, respectively by day 28, all P < 0.0001 compared with placebo). NK3R antagonism rapidly relieves vasomotor symptoms without the need for estrogen exposure.


A hybrid FLIM-elastic net platform for label free profiling of breast cancer.
We report a label-free fluorescence lifetime profiling strategy to classify breast cancer cells, MCF10CA1h (malignant), MCF10A (nonmalignant), and MCF10AneoT (premalignant) in different stages of malignancy. Fluorescence Lifetime Imaging Microscopy (FLIM) was used to record the lifetime of autofluorescence of endogenous flavin in MCF10 cells in different stages of malignancy. Predominant differences in lifetimes ascertained by multi-exponential fitting curves can be attributed to the different forms of flavin protein; flavin mononucleotide (FMN), free flavin adenine dinucleotide (FAD), semiquinone, and bound FAD. A lifetime map of the metabolite was derived from the contribution of the lifetime of each metabolite by iterative reconvolution fitting of the Time Correlated Single Photon Counting (TCSPC) decay curves. Lifetime maps were constructed by mapping the average lifetime values pixel by pixel using MATLAB. The FLIM image (150 × 150 pixels) of each cell was extracted, resized and centered into 100 × 100 pixels using the nearest neighbor algorithm. Principal Component Analysis (PCA) in conjunction with Elastic net Analysis (EnA) was then used to classify the different stages of MCF10 cell lines based on average lifetime values. The EnA model provided an excellent classification of the cells at different stages of tumorigenesis yielding 100% accuracy.


Evaluation of patient education materials for stereotactic radiosurgery from high-performing neurosurgery hospitals and professional societies.
Little is known about the readability and utility of patient education materials for stereotactic radiosurgery (SRS). Therefore, the goal of this investigation was to evaluate such materials from high-performing neurosurgery hospitals and professional societies through an analysis of readability and educational content. In this cross-cross sectional study, 61 websites associated with the top 50 neurosurgery and neurology hospitals according to U.S. News & World Report (USNWR) and 11 predetermined professional medical societies were queried. Identified SRS education materials were analyzed by 6 readability indices. Educational content was assessed by 10 criteria based on surveys of patients' perspectives about SRS. Fifty-four materials were identified from the target population (45 from USNWR hospital websites and 9 from professional society websites). Mean readability of materials ranged from 11.7 to 15.3 grade level, far more difficult than national recommendations of sixth and eighth grade. Materials were found to have deficiencies in educational content. Compared with high-performing hospitals, materials from websites of professional societies were longer (P = .002), and more likely to discuss risks and benefits specific to SRS (P = .008), alternative treatment options (P = .05) and expected outcomes or postprocedure descriptions (P = .004). Hospital materials were also more likely to favor brand-specific terminology (eg, GammaKnife) over generic terminology (eg, radiosurgery; P = .019). Publicly available online patient educational materials for SRS are written at reading levels above national recommendations. Furthermore, many lack information identified as important by patients. Reevaluation and improvement of online SRS educational materials on a national scale are warranted.


Protective role of Trpc6 knockout in the progression of diabetic kidney disease.
Diabetic kidney disease (DKD) is a chronic kidney pathology that leads to end-stage renal disease. Previous studies from our laboratory indicate that there is an association between the development of DKD and the transient receptor potential canonical 6 (TRPC6) channel. Trpc6 expression and activity were increased in the streptozotocin (STZ)-treated Dahl Salt-sensitive (Dahl SS) rat, an established model of type 1 diabetes. Here, using a Trpc6 knockout created on the Dahl SS rat background (SSTrpc6-/-), we test the hypothesis that the absence of Trpc6 will protect podocytes and kidney function during the development of DKD. Four groups of animals (control SSWT, SSTrpc6-/-, STZ-treated SSWT, and STZ-SSTrpc6-/-) were utilized in this study. Diabetes development was monitored for 11 wk after STZ injection with periodic weight, glucose, and urinary output measurements. There was an increase in albuminuria and glomerular injury following STZ treatment, which was not different between Dahl SS and SSTrpc6-/- groups. Western blot analysis revealed elevated levels of nephrin in urine samples of STZ-SSWT rats, which was higher compared with STZ-SSTrpc6-/- rats. Furthermore, pathological increases in basal [Ca2+]i levels and foot process damage of podocytes during the development of DKD was attenuated in the STZ-SSTrpc6-/- compared with STZ-SSWT rats. Overall, our data indicate that TRPC6 channel inhibition may have at least partial renoprotective effects, which could lead to the development of new pharmacological tools to treat or prevent the progression of DKD.


Zeolites are no longer a challenge: atomic resolution data by aberration-corrected STEM.
Transmission electron microscopy is undoubtedly an indispensable tool for materials characterization, which can currently reach sub-angstrom resolution down to the elemental building blocks of matter, isolated single atoms of most elements. In addition to the phenomenal image resolution, if the material is strong enough, it can be accompanied with chemical information, converting electron microscopy into a unique method for the analysis of a great variety of materials. Unfortunately, extracting all this valuable information is not simple as most materials in one way or another are affected by the strong and localized electron beam. Radiolysis is one kind of reaction between electrons and matter than can cause irreversible structural transformations in our materials. This effect is the predominant factor in zeolites, zeotypes and the majority of molecular sieves. In the present work some results, taken at high voltage (300 kV) and minimizing the exposure to the beam, are presented proving the feasibility of the technique to obtain unprecedented atomic resolution information of different zeolites and microporous solids.


[Urinary diversion--the key to reducing surgical complications--ileal conduit].
The ileal conduit, first described by Bricker in 1950, continues to be the most common form of incontinent urinary diversion. We have evaluated the surgical methods, pre- and post-operative management, complications and quality of life in the patients treated with ileal conduit urinary diversion. Between January, 1980 and December, 2004, ileal conduit was performed in 97 cases (82 male, 15 female) and median follow-up was 37.7 months (11 to 121 months). Early complications occurred in 38 patients (39%); however, none of them resulted in post-operative death within one month. Late complications were noticed in 60 patients (62%). The most frequent complications include stoma related complications (34 cases, 35%). Renal dysfunction was seen in only 7 cases (7.2%). A questionnaire survey on 13 patients with ileal conduit revealed that 93% of them were satisfied with the current conditions. The ileal conduit is considered an appropriate method of continent urinary diversion because of the simplicity of surgical method, few complications and high satisfaction in the quality of life.


Uptake of duck hepatitis B virus into hepatocytes occurs by endocytosis but does not require passage of the virus through an acidic intracellular compartment.
The infectious entry pathway of duck hepatitis B virus (DHBV) was investigated with primary duck hepatocytes. Virus uptake was measured by a selective PCR technique which allows for the detection of a successful infection without the need for viral replication or gene expression. To test whether DHBV uptake occurs by endocytosis, the effects of energy depletion were analyzed. The requirement for an acidic intracellular pH was tested with the lysosomotropic agent ammonium chloride. The data show that energy depletion prevents the uptake of DHBV into primary hepatocytes whereas ammonium chloride has no effect. From these data, we conclude that DHBV is taken up by its host cells by endocytosis. However, in contrast to that of most other enveloped viruses, escape of DHBV from the endocytotic route does not depend on an acidic intracellular compartment.


The accident at the Fukushima Daiichi Nuclear Power Plant in 2011.
A huge earthquake struck the northeast coast of the main island of Japan on 11 March 2011, triggering a tsunami with more than 10-m-high waves hitting the area. The earthquake was followed by numerous sustained aftershocks. The earthquake and aftershocks left almost 16,000 people dead and more than 2,800 missing (as of 11 March 2014). The earthquake affected the Fukushima Daiichi Nuclear Power Plant (NPP) of Tokyo Electric Power Company (TEPCO), causing serious damage to the NPP and resulting in large amounts of radioactive materials being released into not only controlled areas but also the environment. Damage was caused to the cooling systems of the NPP, although they automatically shut down after the earthquake. The trouble with the cooling systems led to hydrogen explosions and core meltdown. The major nuclides released on land were ¹³¹I, ¹³⁴Cs, and ¹³⁷Cs. The release of these radioactive materials resulted in contamination of first responders and workers and also a high ambient dose of radiation around the NPP. The local hospital system, including that for radiation emergency medicine, was dysfunctional. Hospitals that had been designated as radiation emergency facilities were not able to function because the earthquake and tsunami had caused damage to their facilities; some of these were located within a 20-km radius of the NPP and in the evacuation areas. Local fire department personnel were also ordered to evacuate. Fukushima prefecture changed the screening level required for decontamination from 13,000 to 100,000 cpm, with decontamination by wiping being performed for over 13,000 cpm. However, as hospitals and fire departments had to abide by lower levels than that of the prefecture for receiving or transporting contaminated patients, these personnel could not accept or transport contaminated people from the NPPs. In addition, hospitals not designated as radiation emergency facilities would not receive patients from the NPPs because of concerns about the health effects of radiation. From this disaster, it was learned that basic knowledge of radiation and its effects is extremely important for health care providers.


Sertraline treatment of panic disorder: response in patients at risk for poor outcome.
More than one third of panic disorder patients have a chronic and/or recurrent form of the disorder, accounting for much of the individual and societal cost associated with the illness. Six clinical variables have been most consistently identified as high-risk predictors of poor outcome: (1) panic severity, (2) presence of agoraphobia, (3) comorbid depression, (4) comorbid personality disorder, (5) duration of illness, and (6) female sex. No published research has systematically examined the differential antipanic efficacy of selective serotonin reuptake inhibitors in patients at high risk for poor outcome. Data were pooled (N = 664) from 4 double-blind, placebo-controlled studies of the efficacy of sertraline for the treatment of DSM-III-R panic disorder. Two of the studies were 12-week fixed-dose studies with starting daily doses of sertraline, 50 mg, and 2 were 10-week flexible-dose studies with starting daily doses of sertraline, 25 mg. All other study design features were the same, except for the exclusion of women of childbearing potential in the 2 fixed-dose studies. Exclusion of patients with marked personality disorders and depression meant that only 4 of the poor-outcome variables could be evaluated. Clinical improvement was similar for patients treated with sertraline whether or not they carried an agoraphobia diagnosis, had a duration of illness > 2 years, or were female. Patients with high baseline panic severity had significantly (p = .01) less improvement on the endpoint Clinical Global Impressions-Improvement (CGI-I) scale than patients with moderate severity, although the Clinical Global Impressions-Severity of Illness scale change score was higher in the patients with high severity (-2.00 vs. -1.31). For patients with 3 or more high-risk variables, there was a modest, but statistically significant, tendency for reduced global improvement (endpoint CGI-I score of 2.7 for the high-risk vs. 2.4 for the non-high-risk group; p = .017), although the high-risk group actually had a similar endpoint reduction in frequency of panic attacks (82%) compared with the non-high-risk group (78%). Treatment of panic disorder with sertraline was generally effective, even in the presence of baseline clinical variables that have been associated with poor treatment response. The main limitations of the analysis were the reliance on pooled data from 4 studies (even if the designs were similar) and our inability to examine the impact of depression and personality disorders on response to treatment because of the exclusion criteria of the clinical trials.


Biochemical markers of neurotoxicity. A review of mechanistic studies and applications.
Neurotoxicology presents major challenges to the development of biological markers in accordance to conventional research strategies. Because of the inaccessibility of the nervous system, one of the proposed alternatives is the study of biochemical signals in peripheral tissues which can easily and ethically be obtained in humans, and which could represent surrogate indicators of equivalent parameters in the nervous tissue. Considerable scientific support to this approach is provided by the results of recent investigations in major areas of pharmacology and psychobiology. Studies examining parameters of neurotransmission and second messenger systems in peripheral blood cells, and variations in the peripheral body fluid content of endogenous substances reflecting nervous tissue dysfunction or damage are presented in this paper as examples of efforts toward rational development and validation of novel indicators of nervous system toxicity. Cholinergic muscarinic receptors and calcium signalling in peripheral blood lymphocytes, myelin basic protein in cerebrospinal fluid, and blood polyamines are discussed as potential surrogate indicators based on the results of in vitro or in vivo animal studies of neurotoxic metals (mercury, triethyltin), pesticides (disulfoton), drugs of abuse (d-fenfluramine) and model epileptogenic compounds (kainic acid). Data from investigations examining serum prolactin, type B monoamine oxidase (MAO-B) and dopamine beta-hydroxylase (DBH) in workers occupationally exposed to manganese, lead or styrene are also presented. Although research in this field is still at its very early stage, current evidence suggests that (i) certain neurochemical markers may be valuably used in animal studies as a complement to conventional laboratory tests to augment their sensitivity or predictivity; (ii) a mechanistic research approach is required to establish which markers offer the greatest promise for application in human biomonitoring.


Social participation of school-aged survivors of pediatric brain tumors: A daily diary report.
Difficulties with social functioning are common among survivors of pediatric brain tumors. Social participation is an understudied measure of social functioning that is associated with emotional health across the lifespan. This paper uses a diary method to assess the social participation of survivors of pediatric brain tumors in middle childhood. Survivors of pediatric brain tumors (N = 47; age 10.6 ± 1.4 years; 51.1% male, 89.4% White) who were 5.3 (SD = 2.4, range: 2-9.9) years post therapy completed a daily diary assessment of social interaction (5-7 days) and an objective measure of facial affect recognition. The participant's caregiver completed the NIH Toolbox Emotion Measures and a background information questionnaire. Overall, frequency and quality of reported social interactions were low for survivors, with a large subset of survivors (n = 16, 34%) endorsing fewer than 10 social interactions over the course of a typical school week, and almost half of parents (48.9%) reporting that their child participates in zero social activities outside of school during a typical week. Participants engaged in more positive social participation exhibited stronger social skills (facial affect recognition (F(2,44) = 4.85, p < .05). School-aged survivors of pediatric brain tumors seemed to be infrequently engaged in social participation and quality interaction with peers. More specifically, the interactions most commonly reported on the diary assessment are not indicative of friendship development and maintenance. Survivors of pediatric brain tumors would likely benefit from interventions designed to increase quality time spent with peers.


Maternal first trimester iron status and its association with obstetric and perinatal outcomes.
To assess the following in singleton pregnant women: (1) associations between first trimester iron deficiency and obstetric and perinatal outcomes, (2) overall first trimester iron status and (3) post-treatment iron status after intensified iron supplementation. A prospective cohort study was conducted with linkage of first trimester hemoglobin and plasma ferritin with obstetric and perinatal data from a hospital database. Blood sample data were obtained from a Danish University Hospital. The cohort was divided into groups according to ferritin and hemoglobin: (1) iron-deficient anemic (ferritin < 30 ng/mL and Hb < 110 g/L), (2) iron-deficient non-anemic (ferritin < 30 ng/mL and Hb ≥ 110 g/L), and (3) iron-replete non-anemic (ferritin 30-200 ng/mL and Hb ≥ 110 g/L). Obstetric and perinatal outcomes in each iron-deficient group were compared to the iron-replete non-anemic group using multivariable logistic regression. The effect of 4 weeks intensified iron supplementation on hemoglobin and ferritin was assessed by groupwise comparisons. The cohort comprised 5763 singleton pregnant women, of which 14.2% had non-anemic iron deficiency, and 1.2% had iron-deficiency anemia. Compared to iron-replete non-anemic women, iron-deficient anemic women had a higher risk of gestational diabetes (aOR 3.8, 95% CI 1.4-9.0), and iron-deficient non-anemic women had a higher risk of stillbirth (aOR 4.0, 95% CI 1.0-14.3). In group 1 and 2, 81.5% and 67.7% remained iron-deficient after intensified iron supplementation. Iron-deficiency anemia was associated with gestational diabetes, and non-anemic iron deficiency with stillbirth, although risk estimates were imprecise due to few events. Iron deficiency was present in 15.4% and often persisted despite 4 weeks intensified iron supplementation.


The net of life: reconstructing the microbial phylogenetic network.
It has previously been suggested that the phylogeny of microbial species might be better described as a network containing vertical and horizontal gene transfer (HGT) events. Yet, all phylogenetic reconstructions so far have presented microbial trees rather than networks. Here, we present a first attempt to reconstruct such an evolutionary network, which we term the "net of life". We use available tree reconstruction methods to infer vertical inheritance, and use an ancestral state inference algorithm to map HGT events on the tree. We also describe a weighting scheme used to estimate the number of genes exchanged between pairs of organisms. We demonstrate that vertical inheritance constitutes the bulk of gene transfer on the tree of life. We term the bulk of horizontal gene flow between tree nodes as "vines", and demonstrate that multiple but mostly tiny vines interconnect the tree. Our results strongly suggest that the HGT network is a scale-free graph, a finding with important implications for genome evolution. We propose that genes might propagate extremely rapidly across microbial species through the HGT network, using certain organisms as hubs.


Photoactivated voltage imaging in tissue with an archaerhodopsin-derived reporter.
Photoactivated genetically encoded voltage indicators (GEVIs) have the potential to enable optically sectioned voltage imaging at the intersection of a photoactivation beam and an imaging beam. We developed a pooled high-throughput screen to identify archaerhodopsin mutants with enhanced photoactivation. After screening ~105 cells, we identified a novel GEVI, NovArch, whose one-photon near-infrared fluorescence is reversibly enhanced by weak one-photon blue or two-photon near-infrared excitation. Because the photoactivation leads to fluorescent signals catalytically rather than stoichiometrically, high fluorescence signals, optical sectioning, and high time resolution are achieved simultaneously at modest blue or two-photon laser power. We demonstrate applications of the combined molecular and optical tools to optical mapping of membrane voltage in distal dendrites in acute mouse brain slices and in spontaneously active neurons in vivo.


The role of intelligence in decision-making in early adolescence.
This study investigated the role of intelligence and its development across childhood in decision-making in adolescence (age 11 years). The sample was 12,514 children from the UK's Millennium Cohort Study, followed at ages 3, 5, 7, and 11 years. Decision-making (risk-taking, quality of decision-making, risk adjustment, deliberation time, and delay aversion) was measured with the Cambridge Gambling Task. Even after adjustment for confounding, intelligence was positively associated with risk adjustment and quality of decision-making in both boys and girls. Furthermore, in girls risk adjustment was related positively to IQ gains. Our findings suggest that there are important, substantively, associations between intelligence and adapting behaviour to risk at the cusp of adolescence, the period when the response to risk can shape life trajectories. Statement of Contribution What is already known on this subject In children, intelligence and decision-making, measured with gambling tasks, are inconsistently linked. This could be due to gambling tasks not separating risk-taking from contingency-learning. What the present study adds This study measured 11-year-olds' decision-making using a gambling task in which probabilities of different outcomes are presented explicitly. IQ was positively associated with risk adjustment and quality of decision-making. Also significant were IQ gains (for risk adjustment, only in girls). There are links between intelligence and adapting behaviour to statistical risk in children.


Evidence of augmented central pain processing in idiopathic chronic low back pain.
For many individuals with chronic low back pain (CLBP), there is no identifiable cause. In other idiopathic chronic pain conditions, sensory testing and functional magnetic resonance imaging (fMRI) have identified the occurrence of generalized increased pain sensitivity, hyperalgesia, and altered brain processing, suggesting central augmentation of pain processing in such conditions. We compared the results of both of these methods as applied to patients with idiopathic CLBP (n = 11), patients with widespread pain (fibromyalgia; n = 16), and healthy control subjects (n = 11). Patients with CLBP had low back pain persisting for at least 12 months that was unexplained by MRI/radiographic changes. Experimental pain testing was performed at a neutral site (thumbnail) to assess the pressure-pain threshold in all subjects. For fMRI studies, stimuli of equal pressure (2 kg) and of equal subjective pain intensity (slightly intense pain) were applied to this same site. Despite low numbers of tender points in the CLBP group, experimental pain testing revealed hyperalgesia in this group as well as in the fibromyalgia group; the pressure required to produce slightly intense pain was significantly higher in the controls (5.6 kg) than in the patients with CLBP (3.9 kg) (P = 0.03) or the patients with fibromyalgia (3.5 kg) (P = 0.006). When equal amounts of pressure were applied to the 3 groups, fMRI detected 5 common regions of neuronal activation in pain-related cortical areas in the CLBP and fibromyalgia groups (in the contralateral primary and secondary [S2] somatosensory cortices, inferior parietal lobule, cerebellum, and ipsilateral S2). This same stimulus resulted in only a single activation in controls (in the contralateral S2 somatosensory cortex). When subjects in the 3 groups received stimuli that evoked subjectively equal pain, fMRI revealed common neuronal activations in all 3 groups. At equal levels of pressure, patients with CLBP or fibromyalgia experienced significantly more pain and showed more extensive, common patterns of neuronal activation in pain-related cortical areas. When stimuli that elicited equally painful responses were applied (requiring significantly lower pressure in both patient groups as compared with the control group), neuronal activations were similar among the 3 groups. These findings are consistent with the occurrence of augmented central pain processing in patients with idiopathic CLBP.


The in situ transcriptomic landscape of breast tumour-associated and normal adjacent endothelial cells.
Triple Negative Breast Cancer (TNBC) is associated with increased angiogenesis, which is known to aid tumour growth and metastasis. Anti-angiogenic therapies that have been developed to target this feature have mostly generated disappointing clinical results. Further research into targeted approaches is limited by a lack of understanding of the in situ molecular profile of tumour-associated vasculature. In this study, we aimed to understand the differences in the molecular profiles of tumour endothelial cells vs normal-adjacent endothelial cells in TNBC tissues. We have applied unbiased whole transcriptome spatial profiling of in situ gene expressions of endothelial cells localized in full-face patient TNBC tissues (n = 4) and normal-adjacent regions of the same patient breast tissues. Our comparative analysis revealed that 2412 genes were differentially expressed (padj < 0.05) between the tumour endothelial cells and normal-adjacent endothelial cells. Pathway enrichment showed the enrichment of gene sets related to cell-cell, cell-ECM adhesion, chromatin organization and remodeling, and protein-DNA complex subunit organization. Overall, the results revealed unique molecular profiles and signalling pathways of tumour-associated vasculature, which is a critical step towards larger cohort studies investigating potential targets for TNBC prognosis and anti-angiogenic treatments.


Inducible inactivation of hepatic LRP gene by cre-mediated recombination confirms role of LRP in clearance of chylomicron remnants.
The multifunctional low density lipoprotein (LDL) receptor-related protein (LRP) has been postulated to participate in a number of diverse physiological and pathological processes ranging from the homeostasis of plasma lipoproteins, atherosclerosis, and fibrinolysis to neuronal regeneration and survival. It has not been possible to demonstrate in vivo the physiological significance of LRP for each of these complex processes by a conventional gene knockout approach because LRP is essential for embryonic development. Here we have used the Cre/loxP recombination system to achieve inducible, tissue-specific and quantitative disruption of the LRP gene in adult mice. Inactivation of LRP in the livers of LDL receptor-deficient mice resulted in the accumulation of cholesterol-rich remnant lipoproteins in the circulation. In normal animals, this caused a compensatory upregulation of the LDL receptor in the liver. Conditional gene targeting has thus allowed us to isolate a specific physiological function of LRP for in vivo analysis and has provided unequivocal evidence for another LDL receptor-independent cholesterol clearance pathway in liver.


Evaluating the Effects of Cell Sorting on Gene Expression.
Cell sorting is a commonly used technology to isolate highly purified cell populations for downstream applications. Because the sorted cells are destined for further analysis, i.e., gene expression assays or functional assays, ensuring that the sorting process itself has little effect on the cells is of utmost importance. Previous studies examining the effects of sorting on cellular function have primarily focused on a specific cell type or condition. One of the goals of the Flow Cytometry Research Group of the Association of Biomolecular Resource Facilities is to establish best practice guidelines for cell sorting conditions that minimize cell stress, perturbation, or injury to the sorted cell population. In this study, the effects of nozzle size, sample pressure, UV exposure, and instrument type were evaluated for their effects on gene expression and cell cycle using both established cell lines and primary cells across several flow cytometry shared facilities. Results indicate that nozzle size and pressure, as well as UV exposure and instrument type, have only minor effects on gene expression, which were diminished by subsequent culturing of the sorted cells. In this assessment, these data demonstrate that cell sorting itself, regardless of instrumentation used, has minimal effects on downstream cellular applications.


Genome-wide Analysis of Salmonella enterica serovar Typhi in Humanized Mice Reveals Key Virulence Features.
Salmonella enterica serovar Typhi causes typhoid fever only in humans. Murine infection with S. Typhimurium is used as a typhoid model, but its relevance to human typhoid is limited. Non-obese diabetic-scid IL2rγnull mice engrafted with human hematopoietic stem cells (hu-SRC-SCID) are susceptible to lethal S. Typhi infection. In this study, we use a high-density S. Typhi transposon library in hu-SRC-SCID mice to identify virulence loci using transposon-directed insertion site sequencing (TraDIS). Vi capsule, lipopolysaccharide (LPS), and aromatic amino acid biosynthesis were essential for virulence, along with the siderophore salmochelin. However, in contrast to the murine S. Typhimurium model, neither the PhoPQ two-component system nor the SPI-2 pathogenicity island was required for lethal S. Typhi infection, nor was the CdtB typhoid toxin. These observations highlight major differences in the pathogenesis of typhoid and non-typhoidal Salmonella infections and demonstrate the utility of humanized mice for understanding the pathogenesis of a human-specific pathogen.


p73 as a pharmaceutical target for cancer therapy.
About half of all human tumors contain an inactivating mutation of p53, while in the remaining tumors, the p53 pathway is frequently abrogated by alterations of other components of its signaling pathway. In humans, the p53 tumor suppressor is part of a small gene family that includes two other members, p73 and p63, structurally and functionally related to p53. Accumulating evidences indicate that all p53-family proteins function as molecular hubs of a highly interconnected signaling network that coordinates cell proliferation, differentiation and death in response to physiological inputs and oncogenic stress. Therefore, not only the p53-pathway but the entire "p53-family pathway" is a primary target for cancer drug development. In particular, the p53-related protein p73 has a crucial role in determining cellular responses to chemotherapy, and can vicariate p53 functions in triggering cell death after DNA damage in multiple experimental models. The biology and regulation of p73 is complex, since the TP73 gene incorporates both tumor-suppressive and proto-oncogenic functions. However, the p73 gene is rarely mutated in tumors, so appropriate pharmacological manipulation of the p73 pathway is a very promising approach for cancer therapy. Here we provide an overview of the principal mechanism of p73 regulation, and describe several examples of pharmacological tools that can induce p73 accumulation and function by acting on upstream p73 modulators or displacing inhibitory p73 interactors. A better understanding of how the p73 pathway works is mandatory to discover additional players intervening in this pathway and has important implications for the improvement of cancer treatment with the development of new molecules or with the reposition of currently available drugs.


Management of acute biliary disease.
Acute biliary disease is the commonest general surgical reason for urgent admission to hospital in the over-65 age group. With an ever-increasing elderly population to treat, cholelithiasis and its complications will continue to present both surgeons and physicians with difficult decisions regarding its proper management.


The initiation of diving apnoea in the frog, Rana pipiens.
1. Diving apnoea in Rana pipiens was initiated by submerging the external nares. As the water level was raised above the frog, both buccal and lung pressure increased by an amount corresponding to the water head. During submergence the external nares remained closed, although the apnoeic period was punctuated by ventilation movements which moved gas between the lungs and buccal cavity. 2. Bilateral section of the ophthalmic nerves did not alter the normal pattern of ventilation in air, although it often resulted in the intake of water into the buccal cavity on submergence. Introduction of water into the buccal cavity, either naturally as in denervates or by injection through a catheter in intact frogs, triggered sustained electromyographical activity in some respiratory muscles. 3. Electroneurograms recorded from the cut peripheral end of an ophthalmic nerve showed that receptors in the external narial region were stimulated by movement of a water meniscus across them. Activity could also be recorded in the ophthalmic nerve in response to water flow past the submerged nares. Punctate stimulation of the narial region confirmed that these receptors were mechanosensitive. 4. Bilateral electrical stimulation of the central ends of cut ophthalmic nerves in lightly anaesthetized frogs caused apnoea with a latency of less than 200 ms. The external nares remained closed throughout the period of stimulation although buccal pressure events, resembling underwater ventilation movements, occurred when stimulation was prolonged.


Transgenic mice with high levels of superoxide dismutase activity are protected from the neurotoxic effects of 2'-NH2-MPTP on serotonergic and noradrenergic nerve terminals.
Administration of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) analog 1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH2-MPTP; 4 x 15 mg/kg) to CD-1 mice was found to cause substantial decreases in cortical and hippocampal 5-hydroxytryptamine (5-HT) and norepinephrine (NE) to 20-30% of control 3 weeks after treatment. The magnitude of these depletions was similar to those reported previously in Swiss Webster and C57BL/6 mice given 4 x 20 mg/kg 2'-NH2-MPTP, and in keeping with these prior studies, striatal dopamine levels were unchanged by 2'-NH2-MPTP treatment in CD-1 mice. Subsequently, transgenic CD-1 mice producing high levels of human cytosolic Cu-Zn superoxide dismutase (SOD) were studied to assess the role of oxygen radicals in the mechanism of action of 2'-NH2-MPTP. In contrast to the results described above, 5-HT and NE levels were almost completely unaffected by 2'-NH2-MPTP treatment in homozygous SOD mice bearing 5-fold increases in brain SOD activity. In 2'-NH2-MPTP-treated heterozygous SOD mice, which showed an average 3-fold increase in brain SOD activity, only moderate depletions in cortical and hippocampal 5-HT (50-60% of control) and NE (30-40% of control) were observed. Additionally, the density of [125I]RTI-55-labeled 5-HT uptake sites was studied to further assess possible 5-HT terminal loss. In various cortical and hippocampal subregions of nontransgenic mice, 5-HT uptake sites were reduced to 20-35% of control after 2'-NH2-MPTP treatment, in comparison with homozygous SOD mice, which were affected only minimally by 2'-NH2-MPTP administration, and heterozygous SOD mice, which showed intermediate reductions in 5-HT uptake site density on the order of 55-80% of control. Together, these data indicate that mice genetically endowed with increased SOD activity are protected from 2'-NH2-MPTP-induced toxicity, thereby implicating superoxide radicals in the mechanism of action of a neurotoxin that selectively depletes 5-HT and NE without affecting dopamine.


Social norms and climate-friendly behavior of adolescents.
Adolescents are the decision-makers of the future, and as educational research shows, behaviors, habits, and attitudes established at young age strongly shape behavior in adulthood. Therefore, it is important to understand what factors shape young people's climate-relevant behavior. In this study, we examine how information about peer behavior affects adolescents' perception of prevailing social norms and own decision-making. Experimentally, we manipulated whether adolescents received information about other young people's (lack of) support for climate protection, operationalized as a donation to a CO2 offsetting scheme. We find that empirical expectations shifted for all age groups when the information revealed that peers donated nothing or only small amounts. Donation behavior and the normative assessment, however, changed only in the younger age groups. Our study illustrates the caution that must be exercised when others' behavior becomes visible or is deliberatively made salient in order to induce behavioral change, especially among young individuals.


Arabidopsis sterol endocytosis involves actin-mediated trafficking via ARA6-positive early endosomes.
In contrast to the intense attention devoted to research on intracellular sterol trafficking in animal cells, knowledge about sterol transport in plant cells remains limited, and virtually nothing is known about plant endocytic sterol trafficking. Similar to animals, biosynthetic sterol transport occurs from the endoplasmic reticulum (ER) via the Golgi apparatus to the plasma membrane. The vesicle trafficking inhibitor brefeldin A (BFA) has been suggested to disrupt biosynthetic sterol transport at the Golgi level. Here, we report on early endocytic sterol trafficking in Arabidopsis root epidermal cells by introducing filipin as a tool for fluorescent sterol detection. Sterols can be internalized from the plasma membrane and localize to endosomes positive for the early endosomal Rab5 GTPase homolog ARA6 fused to green fluorescent protein (GFP) (ARA6-GFP). Early endocytic sterol transport is actin dependent and highly BFA sensitive. BFA causes coaccumulation of sterols, endocytic markers like ARA6-GFP, and PIN2, a polarly localized presumptive auxin transport protein, in early endosome agglomerations that can be distinguished from ER and Golgi. Sterol accumulation in such aggregates is enhanced in actin2 mutants, and the actin-depolymerizing drug cytochalasin D inhibits sterol redistribution from endosome aggregations. Early endocytic sterol trafficking involves transport via ARA6-positive early endosomes that, in contrast to animal cells, is actin dependent. Our results reveal sterol-enriched early endosomes as targets for BFA interference in plants. Early endocytic sterol trafficking and recycling of polar PIN2 protein share a common pathway, suggesting a connection between plant endocytic sterol transport and polar sorting events.


Frequent inactivation of the TP53 gene in esophageal squamous cell carcinoma from a high-risk population in China.
Esophageal squamous cell carcinoma (ESCC) is one of the most common fatal cancers worldwide, and north central China has some of the highest rates in the world. Previous studies from tumors in this area of China have shown high frequencies of allelic loss on chromosome 17p13-11, which includes the region where the TP53 gene is found. We examined 56 ESCC patients using single-strand conformation polymorphism and DNA sequencing to assess the frequency and spectrum of TP53 mutation and the association between allelic loss at microsatellite marker TP53 and TP53 mutations. Ninety-six % of cases were found to have at least one genetic alteration, including TP53 mutation (77%), allelic loss within the TP53 gene (73%), and/or loss of heterozygosity at the TP53 microsatellite marker (80%); 75% had two or more such alterations, including 59% with both a point mutation and an intragenic allelic loss ("two hits"). The majority of mutations observed were in exon 5, where the most common type of nucleotide substitution was a G:C-->A:T or C:G-->T:A transition, including half that occurred at CpG sites. Allelic loss was most commonly found in exon 4 but was very common in exon 5 as well. Taken together, the multiple genetic alterations of TP53 in this population at high risk for ESCC indicate that there is a very high degree of genetic instability in these tumors, that TP53 is a primary target for inactivation, and that this tumor suppressor gene plays a critical role in the carcinogenesis process for ESCC.


A distinct variant of focal cortical dysplasia type I characterised by magnetic resonance imaging and neuropathological examination in children with severe epilepsies.
Focal Cortical Dysplasias (FCDs) present with a large clinicopathological spectrum. FCDs are believed to relate directly to an epileptogenic condition, although seizure control by surgical resection is variable. This applies in particular to young children with multilobar FCDs, suffering from severe epilepsies and psychomotor retardation. Herein, we performed a comparative analysis of presurgically available data and microscopic inspection of resected cortical specimens to further characterise the pathomorphological spectrum of FCD. Multilobar resection procedures were performed in a consecutive series of 18 young children (mean 7.6 years) with severe pharmaco-resistant epilepsies following extensive presurgical surface-/invasive video-EEG monitoring intraoperative electro-corticography (iECoG), as well as high resolution MRI. In all cases, systematic neuropathological examination of surgical specimens was performed with respect to architectural abnormalities and cell density measurements. These histomorphological data were compared with volumetric MRI analysis. Histopathological examination revealed increased neuronal densities correlating with decreased cortical thickness and abundance of neuronal microcolumns in all cases. Intriguingly, the affected cerebral hemisphere was significantly smaller, relative to the non-epileptogenic contralateral side, in 16 children of our patient series. In conclusion, hypoplastic neocortex and columnar architectural disorganisation point to compromised cortical development, and appear as distinct FCD I subtype in children suffering from severe epilepsies and psychomotor retardation.


Two-year survival with nivolumab in previously treated advanced non-small-cell lung cancer: A real-world pooled analysis of patients from France, Germany, and Canada.
Immune checkpoint inhibitors have become the standard of care for metastatic non-small-cell lung cancer (NSCLC) progressing during or after platinum-based chemotherapy. Real-world clinical practice tends to represent more diverse patient characteristics than randomized clinical trials. We sought to evaluate overall survival (OS) outcomes in the total study population and in key subsets of patients who received nivolumab for previously treated advanced NSCLC in real-world settings in France, Germany, or Canada. Data were pooled from two prospective observational cohort studies, EVIDENS and ENLARGE, and a retrospective registry in Canada. Patients included in this analysis were aged ≥18 years, had stage IIIB/IV NSCLC, and received nivolumab after at least one prior line of systemic therapy. OS was estimated in the pooled population and in various subgroups using the Kaplan-Meier method. Timing of data collection varied across cohorts (2015-2019). Of the 2585 patients included in this analyses, 1235 (47.8 %) were treated in France, 881 (34.1 %) in Germany, and 469 (18.1 %) in Canada. Median OS for the total study population was 11.3 months (95 % CI: 10.5-12.2); this was similar across France, Germany, and Canada. The OS rate was 49 % at 1 year and 28 % at 2 years for the total study population. In univariable Cox analyses, the presence of epidermal growth factor receptor mutations in nonsquamous disease, liver, or bone metastases were associated with significantly shorter OS, whereas tumor programmed death ligand 1 expression and Eastern Cooperative Oncology Group performance status 0-1 were associated with significantly prolonged OS. Similar OS was noted across subgroups of age and prior lines of therapy. OS rates in patients receiving nivolumab for previously treated advanced NSCLC in real-world clinical practice closely mirrored those in phase 3 studies, suggesting similar effectiveness of nivolumab in clinical trials and clinical practice.


Melatonin Ameliorates Coxsackievirus B3-Induced Myocarditis by Regulating Apoptosis and Autophagy.
Current therapeutics options for viral myocarditis are unsatisfactory. Melatonin (MLT), a hormone secreted by the pineal gland and other organs, has protective effects on ischemic heart injury. However, the potential therapeutic effect of MLT on viral myocarditis is unknown. In this study, we investigated the protective effect of MLT on viral myocarditis in a mouse model of myocarditis infected with coxsackievirus B3 (CVB3) and explored the probable mechanisms. Mice with CVB3-induced myocarditis displayed inflammatory cell infiltration and interstitial edema. MLT treatment significantly ameliorated the myocardial injuries. In addition, the rate of autophagy changed, although apoptosis was inhibited in mouse hearts following treatment with MLT. These results suggest that MLT has a strong therapeutic effect on acute viral myocarditis, which is associated with changes in autophagy and apoptosis in the heart. Thus, MLT could be a promising novel therapeutic approach against viral myocarditis.


The avian proghrelin system.
To understand how the proghrelin system functions in regulating growth hormone release and food intake as well as defining its pleiotropic roles in such diverse physiological processes as energy homeostasis, gastrointestinal tract function and reproduction require detailed knowledge of the structure and function of the components that comprise this system. These include the preproghrelin gene that encodes the proghrelin precursor protein from which two peptide hormones, ghrelin and obestatin, are derived and the cognate receptors that bind proghrelin-derived peptides to mediate their physiological actions in different tissues. Also key to the functioning of this system is the posttranslational processing of the proghrelin precursor protein and the individual peptides derived from it. While this system has been intensively studied in a variety of animal species and humans over the last decade, there has been considerably less investigation of the avian proghrelin system which exhibits some unique differences compared to mammals. This review summarizes what is currently known about the proghrelin system in birds and offers new insights into the nature and function of this important endocrine system. Such information facilitates cross-species comparisons and contributes to our understanding of the evolution of the proghrelin system.


Time-lapse systems for embryo incubation and assessment in assisted reproduction.
Embryo incubation and assessment is a vital step in assisted reproductive technology (ART). Traditionally, embryo assessment has been achieved by removing embryos from a conventional incubator daily for assessment of quality by an embryologist, under a light microscope. Over recent years time-lapse systems (TLSs) have been developed which can take digital images of embryos at frequent time intervals. This allows embryologists, with or without the assistance of computer algorithms, to assess the quality of the embryos without physically removing them from the incubator.The potential advantages of a TLS include the ability to maintain a stable culture environment, therefore limiting the exposure of embryos to changes in gas composition, temperature and movement. Additionally a TLS has the potential advantage of improving embryo selection for ART treatment by utilising additional information gained through monitoring embryo development. To determine the effect of a TLS compared to conventional embryo incubation and assessment on clinical outcomes in couples undergoing ART. A comprehensive search of all the major electronic databases, including grey literature, was undertaken in co-ordination with the Trials Search Co-ordinator of the Cochrane Menstrual Disorders and Subfertility Group in July 2014 and repeated in November 2014 to confirm that the review is up to date. Two authors (SA and NA) independently scanned the titles and abstracts of the articles retrieved by the search. Full texts of potentially eligible randomised controlled trials (RCTs) were obtained and examined independently by the authors for their suitability according to the review inclusion criteria. In the case of doubt between the two authors, a third author (LC) was consulted to gain consensus. The selection process is documented with a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart. Data were obtained and extracted by two authors. Disagreement was resolved by consensus. Trial authors were contacted by e-mail to obtain further study information and data. All extracted data were dichotomous outcomes and odds ratios (OR) were calculated on an intention-to-treat basis. Where enough data were available, meta-analysis was undertaken. Three studies involving 994 women were found for inclusion. Data from all three studies were used to address comparison one, TLS with or without cell-tracking algorithms versus conventional incubation. No studies were found to address comparison two, TLS utilising cell-tracking algorithms versus TLS not utilising cell-tracking algorithms.There was only one study which reported live birth (n = 76). The results demonstrated no conclusive evidence of a difference in live birth rate per couple randomly assigned to the TLS and conventional incubation arms of the study (OR 1.1, 95% CI 0.45 to 2.73, 1 RCT, n = 76, moderate quality evidence).All three studies reported miscarriage (n = 994). There was no conclusive evidence of a difference in miscarriage rates per couple randomly assigned to the TLS and conventional incubation arms (OR 0.70, 95% CI 0.47 to 1.04, 3 RCTs, n = 994, I(2) = 0%, low quality evidence).Only one study reported stillbirth rates (n = 76). There were equal numbers of stillbirths in both the TLS and conventional incubation arms of the study. Therefore, there was no evidence of a difference in the stillbirth rate per couple randomly assigned to TLS and conventional incubation (OR 1.0, 95% CI 0.13 to 7.49, 1 RCT, moderate quality evidence).All three studies reported clinical pregnancy rates (n = 994). There was no conclusive evidence of a difference in clinical pregnancy rate per couple randomly assigned to the TLS and conventional incubation arms (OR 1.23, 95% CI 0.96 to 1.59, 3 RCTs, n = 994, I(2) = 0%, low quality evidence). None of the included studies reported cumulative clinical pregnancy rates. There is insufficient evidence of differences in live birth, miscarriage, stillbirth or clinical pregnancy to choose between TLS and conventional incubation. Further data explicitly comparing the incubation environment, the algorithm for embryo selection, or both, are required before recommendations for a change of routine practice can be justified.


Influence of sample type on soluble CD40 ligand assessment in patients with acute coronary syndromes.
Several studies have consistently shown that soluble CD40 ligand (sCD40L) concentrations are elevated in patients with acute coronary syndromes (ACS) and that it can be used as a biomarker for risk stratification. However, recently we could demonstrate that sampling techniques have impact on sCD40L measurements. Thus, it was the aim of our prospective study to evaluate the impact of sampling techniques on sCD40L concentrations of patients with acute coronary syndromes compared to controls. We included a total of 60 patients, - 30 with an acute coronary syndrome, 10 with cardiovascular risk factors but no relevant coronary artery disease and 20 healthy individuals. Blood samples were collected in gel filled tubes without additives, EDTA filled tubes, or in citrate filled tubes. In EDTA or citrate plasma samples, sCD40L values were higher in patients with ACS compared to controls. In contrast, no difference in sCD40L values between ACS patients and controls was observed for serum samples. Our data show that only plasma samples, but not serum samples are appropriate for sCD40L measurements. In general, preanalytic conditions are crucial for the assessment of sCD40L concentration and, thus, should be carefully considered for future studies.


Morphometric study for estimation and validation of trunk transverse surface area to assess human drag force on water.
The aim of this study was to compute and validate estimation equations for the trunk transverse surface area (TTSA) to be used in assessing the swimmer's drag force in both genders. One group of 133 swimmers (56 females, 77 males) was used to compute the estimation equations and another group of 131 swimmers (56 females, 75 males) was used for its validations. Swimmers were photographed in the transverse plane from above, on land, in the upright and hydrodynamic position. The TTSA was measured from the swimmer's photo with specific software. Also measured was the height, body mass, biacromial diameter, chest sagital diameter (CSD) and the chest perimeter (CP). With the first group of swimmers, it was computed the TTSA estimation equations based on stepwise multiple regression models from the selected anthropometrical variables. For males TTSA=6.662*CP+17.019*CSD-210.708 (R(2)=0.32; Ra (2)=0.30; P<0.01) and for females TTSA=7.002*CP+15.382*CSD-255.70 (R(2)=0.34; Ra (2)=0.31; P<0.01). For both genders there were no significant differences between assessed and estimated mean TTSA. Coefficients of determination for the linear regression models between assessed and estimated TTSA were R(2)=0.39 for males and R(2)=0.55 for females. More than 80% of the plots were within the 95% interval confidence for the Bland-Altman analysis in both genders.


Life course impairment and quality of life over time.
The concepts of cumulative life course impairment (CLCI) and health-related quality of life (QoL) are analyzed, in order to find shared and divergent aspects. The concept of QoL includes the patients' perception of their health and their personal experiences concerning the psychosocial impact of the disease on their life. CLCI aims to investigate the impact of a chronic disease on the milestones of life, such as education, work, relationships, children, social life, (briefly - on the whole trajectory of life) and on how the disease influenced the possibility of patients of living their life up to its full potential. QoL is a cross-sectional measure, while CLCI takes into account the lifetime. However, it is clear that the possibility of reaching one's full life potential and QoL at a certain time are correlated. There are few studies in dermatology in this field; however, both in the case of atopic dermatitis and of vitiligo it has been shown that patients with a severe condition in childhood endured severe psychosocial and physical consequences in adulthood and experienced a profound negative impact of the disease on their current quality of life. It is thus important to take into account both CLCI and QoL when evaluating the impact of a chronic condition on a patient's life.


Disparities in food habits across Europe.
Socially-and culturally-patterned differences in food habits exist both between and within European populations. Daily individual food availability data, collected through the national household budget surveys (HBS) and harmonized in the context of the Data Food Networking (DAFNE) project, were used to assess disparities in food habits of seven European populations and to evaluate dietary changes within a 10-year interval. The availability of selected food items was further estimated according to the educational level of the household head and, based only on the Greek HBS data, according to quintiles of the household's food purchasing capacity. Results for overall food availability support the north-south differentiation in food habits. Generally, the availability of most food items, including foods such as vegetable fats, animal lipids and sugar products, has decreased over the 10 years. Households in which the head was in the higher education categories reported lower availability for most food items, with the exception of low-fat milk, fresh fruit, animal lipids and soft drinks; the latter showing a sharp increase even within southern European households. The household's food purchasing capacity can be used as an indicator of socio-economic status, with higher values being associated with lower status. Greek households of lower social class follow a healthier diet in terms of greater availability of vegetable oils, fresh vegetables, legumes, fish and seafood. Data from the DAFNE databank may serve as a tool for identifying and quantifying variation in food habits in Europe, as well as for providing information on the socio-economic determinants of food preferences.


Therapeutic implications of the warburg effect: role of oxalates and acetates on the differential survival of mrc-5 and a549 cell lines.
Lung cancer is a one of the most prevalent and deadly cancers in United States. Research has shown that cancer cells exhibit higher glycolytic rates than normal cells. In attempting to exploit this unique cancer-dependent ATP generation phenomenon (Warburg effect), we hypothesize that exposure of cancer cells to organic inhibitors of glycolysis would have a negative impact on their survival and will alter their growth and viability due to a vast decrease in their essential glycolytic ATP production with the resultant energetic collapse and that no negative consequences will be seen on normal lung cells. The human lung fibroblast cell line MRC-5 and the human alveolar epithelial cell line A549 were used in this study as models for normal lung and lung cancer in vitro. Using standard methods, both cell lines were maintained and exposed to oxalic acid and zinc acetate reagents at concentration levels ranging from 31.3-2,000 µg/ml in 96 well plates in quadruplets and experiments were repeated at least three times using MTT, and cell counting (T4 Cellometer) assays as well as phase-contrast photo-imaging. Our results indicate that exposure of both cell lines to these organics resulted in concentration dependent cell destruction/cell survival depending on the cell line exposed. Oxalic acid and zinc acetate showed statistically significant (p<0.05) differential negative effects on the A549 line in comparison to its unexposed control as well as to their effects on the MRC-5 cell line, presenting promising indicators for their cancer therapeutic potential.


Using Self-Regulated Learning Microanalysis to Examine Regulatory Processes in Clerkship Students Engaged in Practice Questions.
Self-regulated learning is a cyclical process of forethought, performance, and self-reflection that has been used as an assessment tool in medical education. No prior studies have evaluated SRL processes for answering multiple-choice questions (MCQs) and most evaluated one or two iterations of a non-MCQ task. SRL assessment during MCQs may elucidate reasons why learners are successful or not on these questions that are encountered repeatedly during medical education. Internal medicine clerkship students at three institutions participated in a SRL microanalytic protocol that targeted strategic planning, metacognitive monitoring, causal attributions, and adaptive inferences across seven MCQs. Responses were transcribed and coded according to previously published methods for microanalytic protocols. Forty-four students participated. In the forethought phase, students commonly endorsed prioritizing relevant features as their diagnostic strategy (n = 20, 45%) but few mentioned higher-order diagnostic reasoning processes such as integrating clinical information (n = 5, 11%) or comparing/contrasting diagnoses (n = 0, 0%). However, in the performance phase, students' metacognitive processes included high frequencies of integration (n = 38, 86%) and comparing/contrasting (n = 24, 55%). In the self-reflection phase, 93% (n = 41) of students faulted their management reasoning and 84% (n = 37) made negative references to their abilities. Less than 10% (n = 4) of students indicated that they would adapt their diagnostic reasoning process for these questions. This study describes in detail student self-regulatory processes during MCQs. We found that students engaged in higher-order diagnostic reasoning processes but were not explicit about it and seldom reflected critically on these processes after selecting an incorrect answer. Self-reflections focused almost exclusively on management reasoning and negative references to abilities which may decrease self-efficacy. Encouraging students to identify and evaluate diagnostic reasoning processes and make attributions to controllable factors may improve performance.


Dealloying of platinum-aluminum thin films: dynamics of pattern formation.
The application of focused ion beam (FIB) nanotomography and Rutherford backscattering spectroscopy (RBS) to dealloyed platinum-aluminum thin films allows for an in-depth analysis of the dominating physical mechanisms of nanoporosity formation during the dealloying process. The porosity formation due to the dissolution of the less noble aluminum in the alloy is treated as result of a reaction-diffusion system. The RBS and FIB analysis yields that the porosity evolution has to be regarded as superposition of two independent processes, a linearly propagating diffusion front with a uniform speed and a slower dissolution process in regions which have already been passed by the diffusion front. The experimentally observed front evolution is captured by the Fisher-Kolmogorov-Petrovskii-Piskounov (FKPP). The slower dissolution is represented by a zero-order rate law which causes a gradual porosity in the thin film.


HUI: Beautiful scars.
This article is the written account of a discussion between a group of indigenous women (trained both in Western and Indigenous knowledge systems), on the relevance of diagnosis in their conceptualisations of health and illness.


Comparison of Language Features, Autism Spectrum Symptoms in Children Diagnosed with Autism Spectrum Disorder, Developmental Language Delay, and Healthy Controls.
Language and communication is very important in social, emotional, and cognitive development of children. Delay in language is the first complaint for children diagnosed with autism spectrum disorder (ASD) or developmental language delay (DLD). In this study it is aimed to evaluate and compare language profiles and autistic symptoms between children diagnosed with ASD, DLD, and healthy controls. Twenty-six children who are diagnosed with ASD, 43 children who are diagnosed with DLD, and 47 healthy controls are included to study; and all children are in the age of 48-72 months. Test of Early Language Development was used to evaluate language profiles, and autism spectrum symptoms were evaluated with social communication questionnaire (SCQ). The sociodemographic features of groups were similar. The statistical significant differences were found in all language subscales and subscales of SCQ among three groups. Both children who were diagnosed with ASD and DLD had more autism spectrum symptoms when compared to controls. In present study, it is indicated that developmental language trajectories are different in ASD and DLD group. Children, who are diagnosed with ASD, have more receptive language difficulties while children, who are diagnosed with DLD, have more language difficulties in expressive language area. The finding, children who are diagnosed with DLD have more autistic symptoms, shows that autistic symptoms are related with language development, and it is very important to give preference to language education in the treatment.


Redox-Active Polymeric Ionic Liquids with Pendant N-Substituted Phenothiazine.
Polymers that are elastic while supporting charge transport are desirable for flexible and soft electronics. Many polymers with bulky and conjugated redox-active pendant units have high glass transition temperatures (Tg) in their neutral form that will not lead to elasticity at room temperature. Their behavior in charged form in the solid state without an electrolyte has not been extensively studied. Here, the design strategy of polymeric ionic liquid where two weakly interacting ionic groups are used to maintain a low Tg is shown to lead to flexible redox active polymers. The use of a flexible ethylene backbone and redox-active phenothiazine (PTZ)-based pendant group resulted in polymers with relatively low Tg that are electrically conductive. PTZ that was N-substituted with 2-(2-ethoxyethoxy)ethoxy)ethyl was found to promote solubility of the polymer and lower the Tg of the neutral polymer by ∼150 °C relative to that of the Tg of a variant without the N-substituent. Doping with trifluoromethanesulfonimide leads to an electrically conductive polymer without significantly increasing the Tg. Physical characterization by UV-vis-NIR spectroscopy, electron spin resonance spectroscopy, and impedance spectroscopy verified that the molecular design leads to an efficient charge hopping between the PTZ groups.


Diagnosing Conductive Dysfunction in Infants Using Wideband Acoustic Immittance: Validation and Development of Predictive Models.
Purpose The aims of this study were (a) to validate the wideband acoustic immittance (WAI) model developed by Myers et al. (2018a) in a new sample of neonates and (b) to develop a prediction model for diagnosing middle ear dysfunction in infants aged 6-18 months using wideband absorbance, controlling for the effect of age. Method Tympanometry, distortion product otoacoustic emissions, and WAI were measured in 124 neonates and longitudinally in 357 infants at 6, 12, and 18 months of age. Results of tympanometry and distortion product otoacoustic emissions were used to assess middle ear function of each infant. For the first study, results from the neonates were applied to the diagnostic WAI model developed by Myers et al. (2018a). For the second study, a prediction model was developed using results from the 6- to 18-month-old infants. Results from 1 ear of infants in each age group (6, 12, and 18 months) were used to develop the model. The amount of bias (overfitting) was estimated with bootstrap resampling and by applying the model to the opposite ears (the test sample). Performance was assessed using measures of discrimination (c-index) and calibration (calibration curves). Results For the validation study, the Myers et al. (2018a) model was well calibrated and had a c-index of 0.837 when applied to a new sample of neonates. Although this was lower than the apparent performance c-index of 0.876 reported by Myers et al., it was close to the bias-corrected estimate of 0.845. The model developed for 6- to 18-month-old infants had satisfactory calibration and apparent, bias-corrected, and test sample c-index of 0.884, 0.867, and 0.887, respectively. Conclusions The validated and developed models may be clinically useful, and further research validating, updating, and assessing the clinical impact of the models is warranted.


Gene expression profiling of blood in brain arteriovenous malformation patients.
Brain arteriovenous malformations (BAVMs) are an important cause of intracranial hemorrhage (ICH) in young adults. Gene expression profiling of blood has led to the identification of stroke biomarkers, and may help identify BAVM biomarkers and illuminate BAVM pathogenesis. It is unknown whether blood gene expression profiles differ between 1) BAVM patients and healthy controls, or 2) unruptured and ruptured BAVM patients at presentation. We characterized blood transcriptional profiles in 60 subjects (20 unruptured BAVM, 20 ruptured BAVM, and 20 healthy controls) using Affymetrix whole genome expression arrays. Expression differences between groups were tested by ANOVA, adjusting for potential confounders. Genes with absolute fold change ≥ 1.2 (false discovery rate corrected p ≤ 0.1) were selected as differentially expressed and evaluated for over-representation in KEGG biological pathways (p ≤ 0.05). Twenty-nine genes were differentially expressed between unruptured BAVM patients and controls, including 13 which may be predictive of BAVM. Patients with ruptured BAVM compared to unruptured BAVM differed in expression of 1490 genes, with over-representation of genes in 8 pathways including MAPK, VEGF, Wnt signaling and several inflammatory pathways. These results suggest clues to the pathogenesis of BAVM and/or BAVM rupture and point to potential biomarkers or new treatment targets.


Serum 25-Hydroxyvitamin D Is Inversely Associated with Monocyte Percentage to HDL Cholesterol Ratio among Young Healthy Adults in Qatar.
Low serum 25-hydroxyvitamin D [25(OH)D] is linked to an altered lipid profile. Monocytes play an important role in inflammation and lipid metabolism. Recently, monocyte percentage to HDL-cholesterol ratio (MHR) has emerged as a novel marker of inflammation. We investigated the association between serum 25(OH)D concentrations and MHR and serum lipids in young healthy adults. Data from the Qatar Biobank were utilized to investigate the relation between serum 25(OH)D and inflammation and serum lipid concentrations in healthy Qatari adults using multivariate regression analysis. Prevalence of serum 25(OH)D concentrations <12 ng/mL (deficiency), 12-20 ng/mL (insufficiency), and ≥20 ng/mL (sufficiency) were 55.8%, 29.9%, and 14.3%, respectively. Serum 25(OH)D was significantly inversely associated with monocyte percentage, MHR, total cholesterol, LDL-cholesterol, and triacylglycerol in multivariable adjusted analysis. MHR could be a potential biomarker to predict cardiometabolic diseases among young healthy Qataris.


Cluster-in-Molecule Local Correlation Method with an Accurate Distant Pair Correction for Large Systems.
The cluster-in-molecule (CIM) local correlation approach with an accurate distant pair correlation energy correction is presented. For large systems, the inclusion of distant pair correlation energies is essential for the accurate prediction of absolute correlation energies and relative energies. Here, we propose a simple and efficient scheme for evaluating the distant pair correlation energy correction for the CIM approaches. The corrections can be readily extracted from electron correlation calculations of clusters with almost no additional effort. Benchmark calculations show that the improved CIM approach can recover more than 99.94% of the correlation energy calculated by the parent method. By combining the CIM approach with the domain-based local pair natural orbital (DLPNO) local correlation approach, we have provided accurate binding energies at the CIM-DLPNO-CCSD(T) level for a test set consisting of eight weakly bound complexes ranging in size from 200 to 1027 atoms. With these results as the reference data, the accuracy and applicability of other electron correlation methods and a few density functional methods for large systems have been assessed.


Seasonal variation, sources, and gas/particle concentrations of PCBs and OCPs at high altitude suburban site in Western Black Sea Region of Turkey.
Daily gas and particle phase samples were collected during winter and summer seasons in Bolu, which is located in the high altitude Western Black Sea Region of Turkey. Samples were analyzed to determine the concentrations of polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs). Concentrations of endosulfan sulfate and methoxychlor were found to be highest in the summer and winter periods, respectively. The measured average concentration of endrin was considerably higher (10-50 fold) than the values reported in the literature for similar sites. The agricultural areas located to the south, south-east and south-west of the sampling point were identified as source regions. PCBs were found predominantly in the gas phase in both seasons and 3-chlorinated biphenyls were found to be abundant in the winter period, due to pollutants transported from the city centre and a waste incineration plant by southerly and easterly winds. The concentrations of PCB-180 and PCB-194 were found to be higher than values reported in the literature. The correlation between atmospheric concentrations and temperature was obtained by using Clausius-Clapeyron (CC) plots. The CC plots for most of the OCPs showed shallow negative slopes with low r(2) values, which might be due to the presence of local sources, i.e., agricultural areas around the sampling site and the dominance of evaporation. The CC plots showed steep positive slopes for most of the PCB compounds. Most of the PCB compounds were carried from the ongoing local sources.


Protein Splicing Activity of the Haloferax volcanii PolB-c Intein Is Sensitive to Homing Endonuclease Domain Mutations.
Inteins are selfish genetic elements residing in open reading frames that can splice post-translationally, resulting in the ligation of an uninterrupted, functional protein. Like other inteins, the DNA polymerase B (PolB) intein of the halophilic archaeon Haloferax volcanii has an active homing endonuclease (HEN) domain, facilitating its horizontal transmission. Previous work has shown that the presence of the PolB intein exerts a significant fitness cost on the organism compared to an intein-free isogenic H. volcanii. Here, we show that mutation of a conserved residue in the HEN domain not only reduces intein homing but also slows growth. Surprisingly, although this mutation is far from the protein splicing active site, it also significantly reduces in vitro protein splicing. Moreover, two additional HEN domain mutations, which could not be introduced to H. volcanii, presumably due to lethality, also eliminate protein splicing activity in vitro. These results suggest an interplay between HEN residues and the protein splicing domain, despite an over 35 Å separation in a PolB intein homology model. The combination of in vivo and in vitro evidence strongly supports a model of codependence between the self-splicing domain and the HEN domain that has been alluded to by previous in vitro studies of protein splicing with HEN domain-containing inteins.


Health Literacy, Cognitive Impairment, and Diabetes Knowledge Among Incarcerated Persons Transitioning to the Community: Considerations for Intervention Development.
The purpose of this study was to evaluate the relationships of health literacy (HL; Short Test of Functional Health Literacy), cognitive impairment (CI), and diabetes knowledge (DK) among incarcerated persons transitioning to the community. Using preintervention data from a quasi-experimental nonequivalent control group study evaluating the feasibility of a six-session literacy-tailored Diabetes Survival Skills intervention for incarcerated men transitioning to the community, we conducted correlational analyses among the Short Test of Functional Health Literacy, Montreal Cognitive Assessment, and Spoken Knowledge in Low Literacy in Diabetes Scale using the SPSS PROCESS macro and bias-corrected bootstrapping to test the meditational hypothesis: HL mediates the relationship between CI and DK. Participants ( N = 73) were incarcerated for 1-30 years with a mean age of 47 (9.9) years, 40% Black, 19% White, and 30% Hispanic, with 78% having high school/GED or less education. Most (70%) screened positive for CI and had low DK, and 20% had marginal or inadequate HL. HL, CI, and DK were positively associated with each other. Controlling for race, age, and group (control/experimental), cognitive function had a significant direct effect on HL ( b = 0.866, p = 0.0003) but not on DK ( b = 0.119, p = 0.076). Results indicated a significant indirect effect of cognitive functioning on DK via HL, 95% confidence interval [0.300, 0.1882]. Intervention approaches aimed at increasing HL or tailored to low HL in the presence of CI may be effective in increasing DK in this population. Given the low risk to high benefit of implementing literacy-tailored approaches to persons in prison and the population demographics from studies supporting a high degree of CI, nurses should consider implementing literacy-tailored approaches and screening for CI before participation in all educational programs.


Understanding the Structural Arrangement of Islets in Chronic Pancreatitis.
Islet transplantation has become an established method for the treatment of insulin-deficient diabetes such as type 1 and type 3C (pancreatogenic). An effective transplantation necessitates a thorough understanding of the islet architecture and related functions to improve engraftment outcomes. However, in chronic pancreatitis (CP), the structural and related functional information is inadequate. Hence, the present study is aimed to understand the cytoarchitecture of endocrine cells and their functional implications in CP with and without diabetes. Herein, a set of human pancreatic tissue specimens (normal, n=5 and CP, n=20) was collected and processed for islet isolation. Furthermore, immunohistochemistry was used to assess the vascular densities, cell mass, organization, and cell-cell interactions. The glucose-stimulated insulin release results revealed that in chronic pancreatitis without diabetes mellitus altered (CPNDA), at basal glucose concentration the insulin secretion was increased by 24.2%, whereas at high glucose concentration the insulin levels were reduced by 77.4%. The impaired insulin secretion may be caused by alterations in the cellular architecture of islets during CP progression, particularly in chronic pancreatitis with diabetes mellitus and CPNDA conditions. Based on the results, a deeper comprehension of islet architecture would be needed to enhance successful transplantation in CP patients: (J Histochem Cytochem XX.XXX-XXX, XXXX).