ADHD in adults with major depressive or bipolar disorder: does it affect clinical features, comorbidity, quality of life, and global functioning?
This study compared clinical characteristics, concurrent disorders, level of function, and quality of life in adults with bipolar (BD) or major depressive disorder (MDD) in those with/without adult attention defici1t hyperactivity disorder (AADHD). The participants were recruited among adult inpatients and outpatients with MDD or BD in their current partial remission in a psychiatric hospital. They were evaluated using the interview for adults with ADHD (DIVA-5), Conners' Adult ADHD Rating Scales-Self-Report-Screening Version (CAARS-SR-SV), Structured Clinical Interview for DSM-V (SCID-5), Beck Depression Inventory-II and Young Mania Rating Scale, Global Assessment of Functioning (GAF) and World Health Organization Quality of Life Scale-Brief (WHOQoL-BREF). In those with MDD (n = 105) and BD (n = 103), AADHD was detected as 13.3% and 16.5%, respectively. The inattentive presentation was the most prevalent type among patients with AADHD. Compared to the patients without AADHD, the results regarding the prevalence of comorbidities, suicidal attempts, severity of affective episodes, the early emergence of the affective disorders, and level of quality of life and global functioning were poorer in the group with AADHD (p < 0.05). The participants were individuals with major depressive or bipolar type I disorder with a mostly manic episode, chosen among the referrals to a tertiary psychiatric hospital with high comorbidity and more severe psychopathology. This may limit the generalizability of the findings. ADHD was common in adults with MDD and BD, along with high psychiatric comorbidity and negative consequences. Clinicians are suggested to screen adults with mood disorders for the symptoms of ADHD for a more precise and comprehensive diagnosis and to provide a more appropriate therapeutic intervention.


A pivotal role for PINK1 and autophagy in mitochondrial quality control: implications for Parkinson disease.
The PTEN-induced putative kinase 1 (PINK1) is a mitochondrially targeted serine-threonine kinase, which is linked to autosomal recessive familial parkinsonism. Current literature implicates PINK1 as a pivotal regulator of mitochondrial quality control, promoting maintenance of respiring mitochondrial networks through cristae stabilization, phosphorylation of chaperones and possibly regulation of mitochondrial transport or autophagy. Pulse-chase studies indicate that PINK1 is rapidly processed into at least two shorter forms, which are distributed in both mitochondrial and cytosolic compartments. Through indirect regulation of mitochondrial proteases and Drp1, PINK1 may act to facilitate localized repair and fusion in response to minor mitochondrial stress. With severe mitochondrial damage, PINK1 facilitates aggregation and clearance of depolarized mitochondria through interactions with Parkin and possibly Beclin1. This switch in function most probably involves altered processing, post-translational modification and/or localization of PINK1, as overexpression of full-length PINK1 is required for mitochondrial Parkin recruitment. Under conditions of PINK1 deficiency, dysregulation of reactive oxygen species, electron transport chain function and calcium homeostasis trigger altered mitochondrial dynamics, indicating compromise of mitochondrial quality control mechanisms. Nevertheless, Parkin- and Beclin1-regulated mitochondrial autophagy remains effective at recycling PINK1-deficient mitochondria; failure of this final tier of mitochondrial quality control contributes to cell death. Thus, PINK1 plays a pivotal, multifactorial role in mitochondrial homeostasis. As autophagic recycling represents the final tier of mitochondrial quality control, whether PINK1 levels are enhanced or reduced, strategies to promote selective mitophagy and mitochondrial biogenesis may prove effective for multiple forms of Parkinson's disease.


Significant liver fibrosis assessed using liver transient elastography is independently associated with low bone mineral density in patients with non-alcoholic fatty liver disease.
Metabolic bone disorders frequently occur in patients with chronic liver disease; however, the association between liver fibrosis and bone mineral density in patients with non-alcoholic fatty liver disease (NAFLD) is unclear. This is a cross-sectional analysis of 231 asymptomatic subjects (160 women, 61.6 years old) from a university hospital setting, between February 2012 and December 2014. Bone mineral density (BMD) was measured at the lumbar spine, femur neck, and total hip using dual-energy X-ray absorptiometry (DXA). Liver fibrosis and steatosis were assessed using transient elastography. Among a total of 231 individuals, 129 subjects (55.8%) had NAFLD. BMDs at lumbar spine, femur neck, and total hip were significantly lower in patients having NAFLD with significant fibrosis, compared with patients having NAFLD without significant fibrosis (Ps<0.005). In patients with NAFLD, significant liver fibrosis revealed marked negative correlations with BMD at the lumber spine (r = -0.19, P = 0.032), femur neck (r = -0.19, P = 0.034), and total hip (r = -0.21, P = 0.016). A multivariate linear regression analysis revealed that significant liver fibrosis was independently correlated with low BMD at the femur neck (β = -0.18, P = 0.039) and total hip (β = -0.21, P = 0.005) after adjustment for age, sex, BMI, fasting plasma glucose, alanine aminotransferase, high-density lipoprotein cholesterol, and liver steatosis among patients with NAFLD. Using multivariable logistic regression, significant liver fibrosis was independently associated with overall osteopenia and osteoporosis in subjects having NAFLD (OR = 4.10, 95% CI = 1.02-16.45). The presence of significant liver fibrosis assessed via TE was independently associated with low BMD in NAFLD subjects.


Lipid profile in nonobese pregnant women with polycystic ovary syndrome: a prospective controlled clinical study.
Alterations in lipid pattern and increased risk for obstetric/neonatal complications have been observed in patients with polycystic ovary syndrome (PCOS). Pregnancy leads to physiologic changes in lipoprotein metabolism, and alterations in lipid profile have been related with adverse pregnancy outcomes. Based on these considerations, the aim of the present prospective controlled clinical study was to test the hypothesis that the changes in the lipid profile in patients with PCOS during pregnancy are characteristic and potentially related to the increased risk of obstetric/neonatal complications. One hundred and fifty nonobese PCOS women and 150 age- and body mass index (BMI)-matched healthy controls were enrolled. Serum lipids, glucose, insulin, and androgens levels were serially assayed in all subjects before and throughout pregnancy. Serum low-density lipoprotein (LDL) and triglyceride (TG) concentrations were significantly (P<0.05) higher in PCOS group than in healthy controls at each assessment. Throughout pregnancy, serum LDL and TG levels increased significantly (P<0.05) in both groups, although the change from pre-pregnancy values was significantly (P<0.05) greater in PCOS patients than in healthy controls. A significant (P<0.05) relationship was observed between serum LDL and TG changes and changes in both insulin sensitivity indexes and androgen levels in PCOS patients alone. After adjusting for maternal age, pre-pregnancy BMI and lipid levels, body weight gain, and insulin-resistance markers, serum TG concentrations during pregnancy were directly and independently associated with obstetric complications in both groups, whereas serum LDL levels only in PCOS patients. We can conclude that nonobese PCOS patients had specific changes in lipid profile during pregnancy, and that the lipid pattern typical of PCOS may account for the more frequent adverse pregnancy outcomes. PCOS-related hormonal and metabolic features, such as insulin resistance and high androgen levels, may mediate this phenomenon.


Genome-Wide Association Study of Arabidopsis thaliana Identifies Determinants of Natural Variation in Seed Oil Composition.
The renewable source of highly reduced carbon provided by plant triacylglycerols (TAGs) fills an ever increasing demand for food, biodiesel, and industrial chemicals. Each of these uses requires different compositions of fatty acid proportions in seed oils. Identifying the genes responsible for variation in seed oil composition in nature provides targets for bioengineering fatty acid proportions optimized for various industrial and nutrition goals. Here, we characterized the seed oil composition of 391 world-wide, wild accessions of Arabidopsis thaliana, and performed a genome-wide association study (GWAS) of the 9 major fatty acids in the seed oil and 4 composite measures of the fatty acids. Four to 19 regions of interest were associated with the seed oil composition traits. Thirty-four of the genes in these regions are involved in lipid metabolism or transport, with 14 specific to fatty acid synthesis or breakdown. Eight of the genes encode transcription factors. We have identified genes significantly associated with variation in fatty acid proportions that can be used as a resource across the Brassicaceae. Two-thirds of the regions identified contain candidate genes that have never been implicated in lipid metabolism and represent potential new targets for bioengineering.


Yttrium-Iron Garnet Film Magnetometer for Registration of Magnetic Nano- and Submicron Particles: In Vitro and in Vivo Studies.
In the current article, we present a new kind of magnetometer for quantitative detection of magnetic objects (magnetic nano- and submicron particles) in biological fluids and tissues. The sensor is based on yttrium-iron garnet film with optical signal registration system. Inheriting the working principle of a fluxgate magnetometers, the sensor works at a room-temperature, its wide dynamic range allows the measurements in an unshielded environment. A small size of sensitive element combined with a short recovery time after the excitation coils are off provide us with a potentially high spatial and temporal resolution of measurements. We show the feasibility of the developed devices by sensing the remanent magnetization of magnetic nanoparticles (MNPs) both in vitro (test tubes, dry MNPs) and in vivo (local injection of the MNPs into mice).


Phase I trial of ImmTher, a new liposome-incorporated lipophilic disaccharide tripeptide.
A phase I clinical trial was conducted to evaluate the toxicology and biological activity of a new liposome-incorporated lipophilic disaccharide tripeptide, ImmTher. Twelve patients with advanced nonhematological malignant disease received 13 courses of therapy at dose levels of 200-1,200 micrograms/m2. A course of therapy consisted of once-weekly administration of the drug for 2-12 weeks. The major clinical toxicities observed were chills and hypotension. No renal, hepatic, cardiac, or hematological toxicity was observed. A small decrease in pulmonary diffusion capacity was observed. Biological activity was demonstrated by changes in plasma cytokine levels, changes in in vitro monocyte cytotoxicity, and by a decrease in tumor size. Improvement was observed in three of three patients with metastatic disease to the liver. Response in these three patients correlated with an increase in their tumor necrosis factor and neopterin levels compared with nonresponders. These preliminary indications of biological and clinical activity of a liposome-incorporated lipophilic disaccharide tripeptide in patients with advanced metastatic hepatic disease suggest a potential new therapeutic approach to this common problem.


Improving the implementation of patient safety by nursing students using nursing instructors trained in the use of quality circles.
It is recognised worldwide that the skills of nursing students concerning patient safety is still not optimal. The role of clinical instructors is to instil in students the importance of patient safety. Therefore, it is important to have competent clinical instructors. Their experience can be enhanced through the application of quality circles. This study identifies the effect of quality circles on improving the safety of patients of nursing students. Patient safety is inseparable from the quality of nursing education. Existing research shows that patient safety should be emphasised at all levels of the healthcare education system. In hospitals, the ratio between nursing students and clinical instructors is disproportionately low. In Indonesia, incident data relating to patient safety involving students is not well documented, and the incidents often occur in the absence of a clinical instructor. This study used a quasi-experimental research design with pre-test and post-test non-equivalent control groups. The aim of the project was to explore the implications of the quality circle on clinical instructors by comparing the students' knowledge, attitudes, and practices of control and intervention groups. A questionnaire will be conducted to evaluate the implementation of patient safety and the impact of the intervention. The data were statistically analysed using independent t tests. The intervention was the implementation of quality circles that focused on patient safety issues for the use of clinical instructors to assess and guide student nurse behaviour in regard to patient safety. The authors of this study trained the clinical instructors on how to use quality circle methods to solve nursing problems especially with relevance to the patient safety issues of students. The results showed a significant increase in the behaviour of nursing students towards patient safety issues (p < 0.001; α = 0.05). The implementation of quality circles has a significant effect on patient safety. Therefore, it is recommended to implement quality circles as a problem-solving technique to optimize patient safety.


[A case of neuro-neutrophilic disease presenting with 5 months' with cognitive decline, meningoencephalitis, and marked systemic inflammatory findings, and diagnosed with brain biopsy].
A 63-year-old man was admitted to our hospital with cognitive decline. On admission, he had a fever and mild cognitive dysfunction, suggesting chronic meningoencephalitis. Apart from a mild increase in serum C-reactive protein level and marked neutrophilia, laboratory findings were unremarkable. Brain magnetic resonance (MR) imaging showed multiple small T2-hyperintense lesions in the white matter. Systemic evaluations for infectious organisms, autoantibodies, and malignancy were all negative. For 5 months we conducted therapeutic trials of various antibacterial, antifungal, and antituberculous drugs, but these were completely ineffective, and both meningoencephalitis and inflammatory signs persisted. Repeated brain MRI during the clinical course showed growth of the white matter lesions and progressive cerebral atrophy. C11-methionine positron emission tomography demonstrated a bright focus in the right frontal lobe, and this was biopsied. Key neuropathological findings were neutrophilic infiltration in the subarachnoid space and the frontal lobe without necrotic angiitis. These findings confirmed the diagnosis of neuro-neutrophilic disease, although skin tissue findings characteristic of Sweet disease and a B51, B54, or Cw1 HLA-profile were absent. After intravenous bolus administration of steroid and prolonged oral steroid therapy, fever and inflammatory signs diminished and cognitive symptoms improved.


Migration and clinical outcome of mobile-bearing versus fixed-bearing single-radius total knee arthroplasty.
Background and purpose - Mobile-bearing total knee prostheses (TKPs) were developed in the 1970s in an attempt to increase function and improve implant longevity. However, modern fixed-bearing designs like the single-radius TKP may provide similar advantages. We compared tibial component migration measured with radiostereometric analysis (RSA) and clinical outcome of otherwise similarly designed cemented fixed-bearing and mobile-bearing single-radius TKPs. Patients and methods - RSA measurements and clinical scores were assessed in 46 randomized patients at baseline, 6 months, 1 year, and annually thereafter up to 6 years postoperatively. A linear mixed-effects model was used to analyze the repeated measurements. Results - Both groups showed comparable migration (p = 0.3), with a mean migration at 6-year follow-up of 0.90 mm (95% CI 0.49-1.41) for the fixed-bearing group compared with 1.22 mm (95% CI 0.75-1.80) for the mobile-bearing group. Clinical outcomes were similar between groups. 1 fixed-bearing knee was revised for aseptic loosening after 6 years and 2 knees (1 in each group) were revised for late infection. 2 knees (1 in each group) were suspected for loosening due to excessive migration. Another mobile-bearing knee was revised after an insert dislocation due to failure of the locking mechanism 6 weeks postoperatively, after which study inclusion was preliminary terminated. Interpretation - Fixed-bearing and mobile-bearing single-radius TKPs showed similar migration. The latter may, however, expose patients to more complex surgical techniques and risks such as insert dislocations inherent to this rotating-platform design.


A review of the relationship between leg power and selected chronic disease in older adults.
This review investigates the relationship between leg muscle power and the chronic conditions of osteoarthritis, diabetes mellitus, and cardiovascular disease among older adults. Current literature assessing the impact of chronic disease on leg power has not yet been comprehensively characterized. Importantly, individuals with these conditions have shown improved leg power with training. A search was performed using PubMed to identify original studies published in English from January 1998 to August 2013. Leg power studies, among older adults ≥ 50 years of age, which assessed associations with osteoarthritis, diabetes mellitus, and/or cardiovascular disease were selected. Studies concerning post-surgery rehabilitation, case studies, and articles that did not measure primary results were excluded. Sixteen studies met inclusion criteria, addressing osteoarthritis (n=5), diabetes mellitus (n=5), and cardiovascular disease (n=6). Studies generally supported associations of lower leg power among older adults with chronic disease, although small sample sizes, cross-sectional data, homogenous populations, varied disease definitions, and inconsistent leg power methods limited conclusions. Studies suggest that osteoarthritis, diabetes mellitus, and cardiovascular disease are associated with lower leg power compared to older adults without these conditions. These studies are limited, however, by the heterogeneity in study populations and a lack of standardized measurements of leg power. Future larger studies of more diverse older adults with well-defined chronic disease using standard measures of leg power and interventions to improve leg power in these older adults with chronic disease are needed.


[Pharmacokinetic analysis of alpha- and beta-adrenoreceptors in the chick embryo amnion].
Following a stimulation with acetylcholine, the beta-adrenergic agonists adrenaline (A), noradrenaline (NA), isoproterenol (Iso) and salbutamol (Sal) induced a concentration-dependent decrease in the tone and (or) rate of amnion contraction with EC50 ISO < NA << A < Sal. Metaprolol, a specific beta 1-antagonist, induced a rightward shift in the dose-response curves of Iso, NA and A, whereas beta-antagonist butoxamine was ineffective. pA2 values for beta-antagonists were propranolol 8.3, metoprolol 7.0, butoxamine 5.6. EC50 values of alpha-adrenergic agonists form a sequence: clonidine < NA << methoxamine < phenylephrine. Specific alpha-antagonists yohimbine and idazoxan were found to antagonise competitively the effects of NA. The data obtained characterize the adrenergic receptors mediating stimulation of amniotic contractile activity as alpha 2-adrenergic receptors. Inhibition of contractile receptors in amnion is mainly mediated by beta 1-adrenergic receptor activation.


High-throughput oncogene mutation profiling shows demographic differences in BRAF mutation rates among melanoma patients.
Because of advances in targeted therapies, the clinical evaluation of cutaneous melanoma is increasingly based on a combination of traditional histopathology and molecular pathology. Therefore, it is necessary to expand our knowledge of the molecular events that accompany the development and progression of melanoma to optimize clinical management. The central objective of this study was to increase our knowledge of the mutational events that complement melanoma progression. High-throughput genotyping was adapted to query 159 known single nucleotide mutations in 33 cancer-related genes across two melanoma cohorts from Ireland (n=94) and Belgium (n=60). Results were correlated with various clinicopathological characteristics. A total of 23 mutations in 12 genes were identified, that is--BRAF, NRAS, MET, PHLPP2, PIK3R1, IDH1, KIT, STK11, CTNNB1, JAK2, ALK, and GNAS. Unexpectedly, we discovered significant differences in BRAF, MET, and PIK3R1 mutations between the cohorts. That is, cases from Ireland showed significantly lower (P<0.001) BRAF(V600E) mutation rates (19%) compared with the mutation frequency observed in Belgian patients (43%). Moreover, MET mutations were detected in 12% of Irish cases, whereas none of the Belgian patients harbored these mutations, and Irish patients significantly more often (P=0.027) had PIK3R1-mutant (33%) melanoma versus 17% of Belgian cases. The low incidence of BRAF(V600E)(-) mutant melanoma among Irish patients was confirmed in five independent Irish cohorts, and in total, only 165 of 689 (24%) Irish cases carried mutant BRAF(V600E). Together, our data show that melanoma-driving mutations vary by demographic area, which has important implications for the clinical management of this disease.


Effect of SEN virus coinfection on outcome of lamivudine therapy in patients with hepatitis B.
Interactions between hepatitis B virus (HBV) and other viral hepatitis infections are well known, whether the newly discovered SEN virus (SENV) has any effect on lamivudine antiHBV activity is unclear. Our aim was to clarify the effect on treatment outcome of coinfection with SEN virus in patients with hepatitis B during lamivudine therapy. Nested polymerase chain reaction (PCR) amplification was used to detect SENV-D and SENV-H strains in serum from 45 patients with chronic hepatitis B treated with lamivudine 100 mg daily for 12 mo. HBV DNA load was detected with fluorescence quantitative PCR (FQ-PCR) and YMDD (tyrosine, methionine, aspartate, aspartate) motif mutation of HBV DNA was investigated with cDNA microarray. SENV DNA was detected in 5 of 45(11.1%) cases after 12 mo they received lamivudine treatment. SENV-D and SENV-H were 4.4% and 6.7% respectively. HBV DNA failed to respond to lamivudine therapy in 4 of 5 SENV coinfected patients while only 10 of 40 patients became SENV positive and the difference was statistically significant. Response of ALT and HBeAg to lamivudine had no significant difference between coinfection patients and single HBV infection ones. Coinfection with SEN virus in chronic hepatitis B patients may adversely affect the outcome of lamivudine treatment.


Outcomes of Combined Phacovitrectomy Without Corneal Suturing.
During combined phacovitrectomy, it is common practice to suture the main corneal incision to prevent intraoperative and postoperative wound leak. However, it may be possible to avoid suturing using a self-sealing corneal incision technique as in standard cataract surgery. To evaluate the clinical outcome, safety, and complications of combined phacovitrectomy without preventive suturing. This retrospective case series study included consecutive patients who underwent combined phacovitrectomy between January 2018 and June 2019 for mixed indications. Surgeries were performed at a tertiary university hospital. All surgeries were performed by the same two retinal surgeons. Cataract surgery was performed first, followed by insertion of trocars and vitrectomy. Corneal sutures were not planned but were used at the discretion of the surgeon. The cohort included 106 eyes of 102 patients. Suturing of the main corneal incision was deemed necessary in five cases (5%) because of a main incision leak or anterior chamber shallowing during trocar insertion. No other complications related to the absence of prophylactic corneal sutures were encountered during surgery or follow-up. Preventive corneal suturing may not be necessary in combined phacovitrectomy surgery and can be used in the few cases in which it is indicated during surgery.


Nonlinear effects on the carrier-envelope phase.
Calculations, using the Maxwell equations, are presented of nonlinear effects on the carrier-envelope phase for pulse durations in the two-optical-cycle range for pulses propagating in sapphire. Initially, with increasing pulse intensity the carrier-envelope phase increases monotonically. However, at higher intensities there is a turnabout in the direction of the phase change and a large change in the phase that is caused by a warping of the envelope from strong nonlinear effects. The Kerr nonlinear response occurs on a time scale of approximately 1 fs and gives significantly different results from those obtained by assuming an instantaneous response.


Fine particulate air pollution, resuspended road dust and respiratory health among symptomatic children.
The short-term association of particulate air pollution with peak expiratory flow rate (PEF) and respiratory symptoms was examined. Forty-nine children with chronic respiratory symptoms aged 8-13 yrs were followed daily for six weeks in spring, 1995, in Kuopio, Finland. Daily concentrations of particulate material with a 50% cut-off aerodynamic diameter < or = 10 microm and < or = 2.5 microm (PM10 and PM2.5, respectively), black carbon, and the number concentrations of particles from 0.01-10 microm diameter were measured. During the study period, PM10 were mainly resuspended soil and street dust, and the concentration was estimated using aluminum content of PM10 samples. No consistent effect of particles was found as the associations varied by lag. Of the lags examined, only 1-day lagged PM2.5 was statistically significantly associated with morning PEF (beta=-1.06, SE=0.52 (per interquartile increase in pollutant)). Evening PEF was significantly associated with the 1-day lagged number of particles in the size range 0.1-1.0 microm (beta=-1.56, SE=0.72). One-day lagged PM10, PM2.5-10, PM2.5 and resuspended PM10, and 4-day average of PM2.5 were significantly associated with increased risk of cough. Given the short duration of the study, separating the effects of different types of particles was difficult. The present study demonstrates the highly variable size and number distribution and chemical composition of particles in Finland, and underlines the importance of measuring the size and chemical composition of particles to determine which types of particles are associated with health effects.


The diagnostic performance of scoring systems to identify symptomatic colorectal cancer compared to current referral guidance.
To determine the discrimination characteristics of a new algorithm and two existing symptom scoring systems for identification of patients with suspected colorectal cancer. Derivation of algorithm by a case-control study and assessment of discrimination characteristics using receiver operating characteristics (ROC) curves. Three colorectal cancer scoring systems were investigated. The Bristol-Birmingham (BB) equation, which we derived from a large primary care dataset; the CAPER score, previously derived from a primary care case-control study and a symptom score derived from National Institute of Clinical Excellence (NICE) guidance for urgent referral of symptomatic patients. Their discrimination characteristics were investigated in two datasets: the BB derivation dataset and the CAPER score derivation dataset. The main analyses were ROC curves and the areas under them for all three algorithms in both datasets. Setting Electronic primary care databases. Main outcome measures Diagnosis of colorectal cancer. In the BB dataset, areas under the curve were: BB equation 0.83 (95% CI 0.82 to 0.84); CAPER 0.79 (95% CI 0.79 to 0.80); the NICE guidelines 0.65 (95% CI 0.64 to 0.66). In the CAPER dataset, areas under the curve were: BB 0.92 (95% CI 0.91 to 0.94); CAPER 0.91 (95% CI 0.89 to 0.93); NICE guidelines 0.75 (95% CI 0.72 to 0.79). In subjects under 50 the discrimination characteristics of NICE referral guidelines were no better than chance. Both multivariable symptom scoring systems performed significantly better than NICE referral guidelines.


The relationship between leg stepping pattern and yaw torque oscillations in curve walking of two crayfish species
Curve walking in two species of crayfish, Procambarus clarkii and Astacus leptodactylus, was investigated to test whether the mechanism underlying curve walking is the synchronous action of a centrally pre-programmed leg tripod or whether it is the action of one principal leg that produces the main body yaw torque. Curve walking was induced by an optomotor visual stimulus, and the yaw torque produced by the tethered animals was measured in open-loop conditions. Our main results suggest that the yaw torque oscillations in both P. clarkii and A. leptodactylus are related to the movement of outer leg 4 (i.e. leg 4 on the outside of the turn). That is, the peaks in the yaw torque occur, on average, in synchrony with the power stroke of outer leg 4. When comparing the results of this open-loop experiment on P. clarkii with results previously obtained for curve walking in untethered individuals of the same species, we found a much higher variability in leg coordination in the open-loop situation. Similarly, here we did not find the same level of synchrony in the tripod (formed by outer leg 4 and inner legs 2 and 5) observed during untethered free walking. Therefore, we suggest that tethered conditions may diminish the need for stability and thus allow outer leg 4 to produce a body rotation regardless of the leg stepping configuration. The characteristics of leg 4 are in line with its major role in turning. According to previous studies, legs 4 provide the largest force and the largest step amplitude during walking, and their force includes both a pulling and a pushing component which can facilitate the control of turning. Although it is apparent that outer leg 4 is not the only leg that can produce an inward yaw torque, its major role in modulating the yaw torque suggests that there may be a specific, centrally generated control of outer leg 4 during curve walking in crayfish.


The developmental dynamics of the Populus stem transcriptome.
The Populus shoot undergoes primary growth (longitudinal growth) followed by secondary growth (radial growth), which produces biomass that is an important source of energy worldwide. We adopted joint PacBio Iso-Seq and RNA-seq analysis to identify differentially expressed transcripts along a developmental gradient from the shoot apex to the fifth internode of Populus Nanlin895. We obtained 87 150 full-length transcripts, including 2081 new isoforms and 62 058 new alternatively spliced isoforms, most of which were produced by intron retention, that were used to update the Populus annotation. Among these novel isoforms, there are 1187 long non-coding RNAs and 356 fusion genes. Using this annotation, we found 15 838 differentially expressed transcripts along the shoot developmental gradient, of which 1216 were transcription factors (TFs). Only a few of these genes were reported previously. The differential expression of these TFs suggests that they may play important roles in primary and secondary growth. AP2, ARF, YABBY and GRF TFs are highly expressed in the apex, whereas NAC, bZIP, PLATZ and HSF TFs are likely to be important for secondary growth. Overall, our findings provide evidence that long-read sequencing can complement short-read sequencing for cataloguing and quantifying eukaryotic transcripts and increase our understanding of the vital and dynamic process of shoot development.


Genetic diversity and evolutionary convergence of cryptic SARS- CoV-2 lineages detected via wastewater sequencing.
Wastewater-based epidemiology (WBE) is an effective way of tracking the appearance and spread of SARS-COV-2 lineages through communities. Beginning in early 2021, we implemented a targeted approach to amplify and sequence the receptor binding domain (RBD) of SARS-COV-2 to characterize viral lineages present in sewersheds. Over the course of 2021, we reproducibly detected multiple SARS-COV-2 RBD lineages that have never been observed in patient samples in 9 sewersheds located in 3 states in the USA. These cryptic lineages contained between 4 to 24 amino acid substitutions in the RBD and were observed intermittently in the sewersheds in which they were found for as long as 14 months. Many of the amino acid substitutions in these lineages occurred at residues also mutated in the Omicron variant of concern (VOC), often with the same substitutions. One of the sewersheds contained a lineage that appeared to be derived from the Alpha VOC, but the majority of the lineages appeared to be derived from pre-VOC SARS-COV-2 lineages. Specifically, several of the cryptic lineages from New York City appeared to be derived from a common ancestor that most likely diverged in early 2020. While the source of these cryptic lineages has not been resolved, it seems increasingly likely that they were derived from long-term patient infections or animal reservoirs. Our findings demonstrate that SARS-COV-2 genetic diversity is greater than what is commonly observed through routine SARS-CoV-2 surveillance. Wastewater sampling may more fully capture SARS-CoV-2 genetic diversity than patient sampling and could reveal new VOCs before they emerge in the wider human population.


Modern Photodynamic Glioblastoma Therapy Using Curcumin- or Parietin-Loaded Lipid Nanoparticles in a CAM Model Study.
Natural photosensitizers, such as curcumin or parietin, play a vital role in photodynamic therapy (PDT), causing a light-mediated reaction that kills cancer cells. PDT is a promising treatment option for glioblastoma, especially when combined with nanoscale drug delivery systems. The curcumin- or parietin-loaded lipid nanoparticles were prepared via dual asymmetric centrifugation and subsequently characterized through physicochemical analyses including dynamic light scattering, laser Doppler velocimetry, and atomic force microscopy. The combination of PDT and lipid nanoparticles has been evaluated in vitro regarding uptake, safety, and efficacy. The extensive and well-vascularized chorioallantois membrane (CAM) of fertilized hen's eggs offers an optimal platform for three-dimensional cell culture, which has been used in this study to evaluate the photodynamic efficacy of lipid nanoparticles against glioblastoma cells. In contrast to other animal models, the CAM model lacks a mature immune system in an early stage, facilitating the growth of xenografts without rejection. Treatment of xenografted U87 glioblastoma cells on CAM was performed to assess the effects on tumor viability, growth, and angiogenesis. The xenografts and the surrounding blood vessels were targeted through topical application, and the effects of photodynamic therapy have been confirmed microscopically and via positron emission tomography and X-ray computed tomography. Finally, the excised xenografts embedded in the CAM were analyzed histologically by hematoxylin and eosin and KI67 staining.


An assessment of pediatric after-hours telephone care: a 1-year experience.
Pediatric after-hours telephone triage by call center nurses is an important part of pediatric health care provision. To use a computerized database including the after-hours telephone calls for 90% of the pediatricians in Colorado to examine: (1) the epidemiology of after-hours calls during a 1-year period including the volume, seasonality, and timing of after-hours calls, the age of the patients, the presenting complaint, the triage dispositions, and mean rates of calls per pediatrician; (2) the process of care measures at the call center, including waiting times for nurse telephone call-backs, the length of triage calls, and how these factors varied by season; and (3) the frequency and content of calls requesting information but not requiring triage. Descriptive study. All telephone calls from the After-Hours Telephone Care Program, Denver, Colo, received between June 21, 1999, and June 20, 2000, were retrieved from a computerized database and categorized by age, season, triage disposition, and algorithm. The volume, seasonality, timing, age distribution, algorithms used, and triage dispositions of after-hours calls. The reasons for calls requesting information. During the 1-year period 141 922 calls were returned by the call center. Of the total calls, 88% were for a clinical illness; 5%, for information or advice; 5%, for calls in which the parent could not be recontacted; 1%, for duplicate calls, and 1%, for miscellaneous reasons. Listed in rank order for the year, the 10 most common algorithms used for illness calls were vomiting, colds, cough, earache, sore throat, fever, diarrhea, croup, head trauma, and eye infection. Of illness calls, 21% of callers were told to go in for urgent evaluation, 30% were told to contact their primary care physician either the next day or at a later time, 45% were given home care instructions, and 4% were referred to call the on-call physician. This study describes the epidemiology of after-hours telephone calls regarding children in 90% of the private practices in Colorado. Data provided are useful in guiding the planning of health care provision, providing staffing of after-hours facilities, and planning for the educational training of telephone care staff. They also highlight opportunities for patient education that might decrease unnecessary after-hours calls.


Adjustment of supercontinua via the optical feedback phase--experimental verifications.
The manipulation of a supercontinuum via delayed optical feedback is investigated experimentally. The supercontinuum is generated in a microstructured fiber and a feedback ring resonator introduces the optical feedback and leads to the formation of different regimes of nonlinear dynamics. Via the feedback phase the optical spectrum and the regimes of nonlinear dynamics can be adjusted systematically. The impact of delay detuning on two different length scales, namely on a sub-wavelength scale and on a larger scale in the order of 10 μm are discussed. Additionally, the adjustment of the optical spectrum without changing the regime of nonlinear dynamics is demonstrated.


[Diagnostic imaging of vascular leiomyosarcomas].
Primary vascular leiomyosarcomas are very rare tumors, with the venous variety most often arising from the inferior caval vein and the arterial variety from the pulmonary artery. The tumors show either an exclusive intra- or extravascular pattern or a mixed growth pattern. The clinical symptoms depend on tumor location, with intraluminal tumors of the inferior caval vein causing edema or a Budd-Chiari syndrome. Leiomyosarcomas of the pulmonary artery can mimic chronic central or recurrent peripheral pulmonary embolism. Contrast enhanced spiral CT with multiplanar reconstruction is the diagnostic method of choice when a vascular leiomyosarcoma is suspected. MRI with MR-angiography can be added. If a tumor of undetermined origin shows a broad contact with a vessel and/or an intraluminal component, possible primary vascular leiomyosarcoma should be included in the differential diagnosis.


Thymic depletion in pregnancy: kinetics of thymocytes and immunologic capacities of the hosts.
In the present study we observed a significant depression of thymocytes during pregnancy and investigated the influences of this thymic change on the immunologic capacities of peripheral lymphocytes. Thymocytes in pregnant mice began to decrease in number from Day 10 and reached about 0.1-fold of the nonpregnant level at Day 19, just before parturition. At late stage of pregnancy, thymocyte subpopulation expressing CD4+CD8+ and Thy1.2+PNA+ was selectively depressed. On the contrary, peripheral lymphocytes including splenocytes, peripheral blood lymphocytes and peripheral lymph node cells showed no depression. As to the immunologic capacities of the pregnant hosts, delayed footpad reaction and phagocytic activity of fixed liver macrophages in vivo were remarkably suppressed, but MLR reactivity and antibody response to SRBC or haptens were well preserved. Transfer of pregnant sera or administration with steroid hormones especially E3 into nonpregnant mice induced similar changes in the thymus and peripheral lymphocytes in number and subsets but this could not mimic the immunologic reactivities of the pregnant mice. These results suggest that sex steroid hormones such as E3 play an important role in the changes in cell populations of each lymphoid organ and the immune reactivities of the hosts during pregnancy. However, other factors also contribute to the immunologic capacities of the maternal hosts.


MURF-1 and MURF-2 target a specific subset of myofibrillar proteins redundantly: towards understanding MURF-dependent muscle ubiquitination.
MURF-1, MURF-2 and MURF-3 are a specific class of RING finger proteins that are expressed in striated muscle tissues. MURF-1 has been suggested to act as an ubiquitin ligase, thereby controlling proteasome-dependent degradation of muscle proteins. Here, we performed yeast two-hybrid (YTH) screens of skeletal muscle cDNA libraries with MURF-1 baits to identify potential myocellular targets of MURF-1-dependent ubiquitination. This identified eight myofibrillar proteins as binding partners of MURF-1: titin, nebulin, the nebulin-related protein NRAP, troponin-I (TnI), troponin-T (TnT), myosin light chain 2 (MLC-2), myotilin and T-cap. YTH mating studies with MURF-1,2,3 baits indicated that these eight myofibrillar proteins are all targeted redundantly by both MURF-1 and MURF-2. Western blot studies on cardiac tissues from wild-type and MURF-1-deficient mice suggested that titin and nebulin were ubiquitinated at similar levels, and MLC-2 and TnI at reduced levels in MURF-1 KO mice. Mapping of the TnI and titin binding sites on MURF-1 peptide scans demonstrated their binding to motifs highly conserved between MURF-1 and MURF-2. Our data are consistent with a model in which MURF-1 and MURF-2 together target a specific set of myofibrillar proteins redundantly, most likely to control their ubiquitination-dependent degradation. Finally, our YTH screens identified the interaction of MURF-1 with 11 enzymes required for ATP/energy production in muscle including the mitochondrial ATP synthase and cytoplasmic creatine kinase. These data raise the possibility that MURF-1 may coordinately regulate the energy metabolism of mitochondrial and cytoplasmic compartments.


Effect of Mannitol Infusion on Optic Nerve Injury After Acute Traumatic Subarachnoid Hemorrhage and Brain Injury.
The primary aim of this paper is to investigate the neuroprotective and antiinflammatory effects of mannitol on optic nerve injury after acute traumatic subarachnoid hemorrhage and brain injury in rat models. Traumatic brain injury (TBI) and traumatic subarachnoid hemorrhage (tSAH) were produced by a custom-made weight-drop impact acceleration device. Thirty male Wistar rats were divided into 3 groups. Group I (n = 10) was the sham group, group II (n = 10) received TBI, and group III (n = 10) received TBI + mannitol (1 mg/kg intravenously). Optic nerve tissue glutathione peroxidase (GPx) and interleukin 1 beta (IL-1β) levels were measured 4 hours after the trauma. The authors used Kruskal-Wallis variance analysis and Mann-Whitney U tests for statistical analysis. Optic nerve tissue GPx levels were significantly higher in group III than in groups I and II (P < 0.05). Optic nerve tissue IL-1β levels were significantly lower in group III than in group II (P < 0.05) and higher than in group I (P < 0.05).Mannitol increased the antioxidant GPx levels and decreased the IL-1β levels, which can protect the optic nerve from secondary injury after severe acute trauma. Mannitol plays an important role in the treatment of acute severe indirect optic nerve injury after TBI and tSAH.


Tolerance, sensitization and dependence to diazepam in Balb/c mice exposed to a novel open space anxiety test.
Balb/c mice were exposed to an elevated platform that is extended on two opposite sides with lowered steep slopes. They were tested for 12min per session in 6 successive days. They received i.p. administration of either saline or one dose of diazepam (DZP 0.5, 1, 3mg/kg) in sessions 1-3, and saline in sessions 4 and 5. All groups of mice received a single dose of DZP (1mg/kg) in session 6. DZP produced inverted U-shaped dose-responses on the number of entries into different areas of the apparatus, with a peak in mean response at 1mg/kg whereas its effect on the duration of entries was mostly comparable between the 3 doses. It increased the number of crossings on the surface of the platform and facilitated entries onto the slopes. DZP-treated mice crossed frequently onto and spent longer time on the slopes in sessions 1-3 whereas saline-treated mice remained on the platform in sessions 1-6. Withdrawal of DZP in sessions 4-5 increased the latency of first entry and decreased the number and duration of entries onto the slopes which was reversed with the administration of 1mg/kg of DZP in the next session. This ON-OFF the drug may be due to the half-life of DZP which is very short in mice and rats ( approximately 0.88h). It also indicates that DZP-treated mice did not benefit from previous experience of entries onto the slopes which suggests a possible "state-dependent" effect. Administration of DZP after repeated exposures to the test did not facilitate entries onto the slopes but instead increased significantly the number of crossings on the surface of the platform; this increase was much higher than that observed in mice initially treated with DZP and exposed to the test. There is no evidence of habituation in saline-treated mice: the number of crossings on the platform was comparable between the first 5 sessions of the test. These results demonstrate that repeated exposures to the same anxiogenic environment resulted in avoidance responses developing tolerance and approach responses developing sensitization. They suggest that tolerance and sensitization are two opposite sides of the habituation process to the same stimulus and may account for the maintained state of anxiety.


N-acetylcysteine dose-dependently improves the analgesic effect of acetaminophen on the rat hot plate test.
Acetaminophen (APAP) induced hepatotoxicity is a clinically important problem. Up to now, interventive therapy with n-acetylcysteine (NAC) has been considered as a gold-standard treatment for APAP overdose. However, no study has focused on the efficacy of these drugs' concurrent administration on probable enhancing therapeutic outcomes. Thus, this study was aimed to investigate the analgesic effect of co-administration of NAC and acetaminophen in male rats. The NAC-APAP drug formulation may demonstrate the stranger antinociceptive effect. Forty-eight male Sprague-Dawley rats (12-14 weeks) randomly divided into six equal groups; control, APAP (received 300 mg/kg APAP), NAC (received 600 mg/kg NAC) and APAP+ NAC groups that received simultaneously 300 mg/kg APAP with 200-600 mg/kg NAC (AN200, AN400, AN600). All administrations were done orally for once. The antinociceptive effect was recorded by measurement of latency period on a hot plate in 30, 60, and 90 min after administrations. The results showed that NAC's concurrent administration with APAP, dose-dependently increased APAP analgesic effects (p< 0.0001). Moreover, NAC treatment exhibited an antinociceptive effect in 60 and 90 min, per se. The treatments had no adverse effect on liver enzymes and oxidative stress. Co-administration of NAC with APAP can improve the antinociceptive effect of APAP. It is suggested that this compound can enhance analgesic effects of APAP and eventually lead to a reduction in acetaminophen dose. Further studies are needed to evaluate the molecular mechanism of this hyper analgesic effect.


Caspase-independent cell death in AML: caspase inhibition in vitro with pan-caspase inhibitors or in vivo by XIAP or Survivin does not affect cell survival or prognosis.
Survivin and XIAP, members of the protein family known as the inhibitors of apoptosis, interfere with the activation of caspases, called the "cell death executioners." We examined Survivin (n = 116) and XIAP (n = 172) expression in primary acute myeloid leukemia (AML) blasts and assessed the impact of their expression on prognosis. They were detected in all samples analyzed. However, no correlation was observed with cytogenetics, remission attainment, or overall survival of patients with AML. To investigate the importance of caspases in chemotherapy-induced apoptosis in AML, we treated OCI-AML3 cells with Ara-C, doxorubicin, vincristine, and paclitaxel, which induced caspase cleavage and apoptosis. Blocking of caspase activation by pan-caspase inhibitor abolished poly(adenosine diphosphate [ADP]-ribose) polymerase cleavage and DNA fragmentation but did not prevent chemotherapy-induced cell death and did not inhibit, or only partially inhibited, mitochondrial release of cytochrome c, Smac, apoptosis-inducing factor (AIF), or loss of mitochondrial membrane potential. Caspase inhibition also did not protect AML blasts from chemotherapy-induced cell death in vitro. These results suggest that expression levels of Survivin or XIAP have no prognostic impact in AML patients. Although anticancer drugs induced caspase cleavage and apoptosis, cell killing was caspase independent. This may partially explain the lack of prognostic impact of XIAP and Survivin and may suggest caspase-independent mechanisms of cell death in AML.


Polymer chain collapse induced by many-body dipole correlations.
We present a simple analytical theory of a flexible polymer chain dissolved in a good solvent, carrying permanent freely oriented dipoles on the monomers. We take into account the dipole correlations within the random phase approximation (RPA), as well as a dielectric heterogeneity in the internal polymer volume relative to the bulk solution. We demonstrate that the dipole correlations of monomers can be taken into account as pairwise ones only when the polymer chain is in a coil conformation. In this case the dipole correlations manifest themselves through the Keesom interactions of the permanent dipoles. On the other hand, the dielectric heterogeneity effect (dielectric mismatch effect) leads to the effective interaction between the monomers of the polymeric coil. Both of these effects can be taken into account by renormalizing the second virial coefficient of the monomer-monomer volume interactions. We establish that in the case when the solvent dielectric permittivity exceeds the dielectric permittivity of the polymeric material, the dielectric mismatch effect competes with the dipole attractive interactions, leading to polymer coil expansion. In the opposite case, both the dielectric mismatch effect and the dipole attractive interaction lead to the polymer coil collapse. We analyse the coil-globule transition caused by the dipole correlations of monomers within the many-body theory. We demonstrate that accounting for the dipole correlations higher than the pairwise ones smooths this pure electrostatics driven coil-globule transition of the polymer chain.


[Reactions of the neurons of various hypothalamic structures to tooth pulp and sciatic nerve A beta-fiber stimulation in the cat].
Responses of single units from lateral and medial areas of the posterior, tuberal and anterior hypothalamus to electrical stimulation of dental pulp and sciatic nerve A beta afferents were recorded in anesthetized curarized cats. 80.7%, 81.5% and 71.4% of units, respectively, responded to stimulation in posterior tuberal and anterior hypothalamus. The shortest latency of responses was recorded in the postero-lateral hypothalamus. Nociceptive responses in the lateral hypothalamus were of shorter latency than responses of medial hypothalamic units. Marked predominance of excitatory responses in the posterior hypothalamus and almost an equal proportion of excitatory and inhibitory responses in the tuberal and anterior hypothalamus were found. High degree of convergence (85.8%) of noxious and nonnoxious (sciatic nerve A beta afferents) impulses was revealed. Unidirectional, similar pattern of responses of convergent type neurons to stimulation of the tooth pulp and sciatic nerve A beta afferents indicate a nonspecific character of responses of the majority of polysensory neurons. 14.2% of hypothalamic units were monomodal, specific nociceptive neurons. Hypothalamic nociceptive units were characterized by a long recovery cycle (200-500 ms) and low reproducibility of responses to repetitive stimulation of the tooth pulp afferents (1.5-2/s). The neuronal organization of the nociceptive afferent system of the hypothalamus and the functional role of convergent and specific nociceptive neurons of the hypothalamus are discussed.


Do occupational health assessments match guidelines for low back pain?
Audit is an important facet of clinical governance and good occupational health practice. There are well-established clinical guidelines for the management of low back pain. Occupational Health Guidelines for the Management of Low Back Pain at Work were launched by the Faculty of Occupational Medicine in March 2000, based on an extensive, systematic review of the scientific literature predominantly from occupational settings or concerning occupational outcomes. To determine whether documented National Health Service occupational health assessment of low back pain in the North West region of England conforms to the published guidelines. A retrospective audit of case notes was conducted. Six performance indicators were derived from the Occupational Health Guidelines for the Management of Low Back Pain at Work in order to evaluate the performance by occupational physicians. Two hundred and seventy-seven case notes were identified from eight different occupational health departments. Low rates of compliance with national standards were observed for recording of some performance indicators, notably for the assessment and documentation of 'red' and 'yellow flags'. Our findings suggest that the quality of documentation of key information in the notes leaves significant room for improvement. For future audits, we recommend having two external auditors and seek to demonstrate a high degree of agreement between observers by conducting a reproducibility exercise. Future Faculty guidelines should emphasize documentation of the assessment and perhaps consider assessment tools to improve documentation.


Mitochondrial morphogenesis, dendrite development, and synapse formation in cerebellum require both Bcl-w and the glutamate receptor delta2.
Bcl-w belongs to the prosurvival group of the Bcl-2 family, while the glutamate receptor delta2 (Grid2) is an excitatory receptor that is specifically expressed in Purkinje cells, and required for Purkinje cell synapse formation. A recently published result as well as our own findings have shown that Bcl-w can physically interact with an autophagy protein, Beclin1, which in turn has been shown previously to form a protein complex with the intracellular domain of Grid2 and an adaptor protein, nPIST. This suggests that Bcl-w and Grid2 might interact genetically to regulate mitochondria, autophagy, and neuronal function. In this study, we investigated this genetic interaction of Bcl-w and Grid2 through analysis of single and double mutant mice of these two proteins using a combination of histological and behavior tests. It was found that Bcl-w does not control the cell number in mouse brain, but promotes what is likely to be the mitochondrial fission in Purkinje cell dendrites, and is required for synapse formation and motor learning in cerebellum, and that Grid2 has similar phenotypes. Mice carrying the double mutations of these two genes had synergistic effects including extremely long mitochondria in Purkinje cell dendrites, and strongly aberrant Purkinje cell dendrites, spines, and synapses, and severely ataxic behavior. Bcl-w and Grid2 mutations were not found to influence the basal autophagy that is required for Purkinje cell survival, thus resulting in these phenotypes. Our results demonstrate that Bcl-w and Grid2 are two critical proteins acting in distinct pathways to regulate mitochondrial morphogenesis and control Purkinje cell dendrite development and synapse formation. We propose that the mitochondrial fission occurring during neuronal growth might be critically important for dendrite development and synapse formation, and that it can be regulated coordinately by multiple pathways including Bcl-2 and glutamate receptor family members.


Human retrosplenial cortex displays transient theta phase locking with medial temporal cortex prior to activation during autobiographical memory retrieval.
The involvement of retrosplenial cortex (RSC) in human autobiographical memory retrieval has been confirmed by functional brain imaging studies, and is supported by anatomical evidence of strong connectivity between the RSC and memory structures within the medial temporal lobe (MTL). However, electrophysiological investigations of the RSC and its interaction with the MTL have mostly remained limited to the rodent brain. Recently, we reported a selective increase of high-frequency broadband (HFB; 70-180 Hz) power within the human RSC during autobiographical retrieval, and a predominance of 3-5 Hz theta band oscillations within the RSC during the resting state. In the current study, we aimed to explore the temporal dynamics of theta band interaction between human RSC and MTL during autobiographical retrieval. Toward this aim, we obtained simultaneous recordings from the RSC and MTL in human subjects undergoing invasive electrophysiological monitoring, and quantified the strength of RSC-MTL theta band phase locking. We observed significant phase locking in the 3-4 Hz theta range between the RSC and the MTL during autobiographical retrieval. This theta band phase coupling was transient and peaked at a consistent latency before the peak of RSC HFB power across subjects. Control analyses confirmed that theta phase coupling between the RSC and MTL was not seen for other conditions studied, other sites of recording, or other frequency ranges of interest (1-20 Hz). Our findings provide the first evidence of theta band interaction between the human RSC and MTL during conditions of autobiographical retrieval.


Information technology for patient safety.
Research on patient care has identified substantial variations in the quality and safety of healthcare and the considerable risks of iatrogenic harm as significant issues. These failings contribute to the high rates of potentially avoidable morbidity and mortality and to the rising levels of healthcare expenditure seen in many health systems. There have been substantial developments in information technology in recent decades and there is now real potential to apply these technological developments to improve the provision of healthcare universally. Of particular international interest is the use of eHealth applications. There is, however, a large gap between the theoretical and empirically demonstrated benefits of eHealth applications. While these applications typically have the technical capability to help professionals in the delivery of healthcare, inadequate attention to the socio-technical dimensions of their use can result in new avoidable risks to patients. Given the current lack of evidence on quality and safety improvements and on the cost-benefits associated with the introduction of eHealth applications, there should be a focus on implementing more mature technologies; it is also important that eHealth applications should be evaluated against a comprehensive and rigorous set of measures, ideally at all stages of their application life cycle.


Origin of the "endo rule" in Diels-Alder reactions.
Detailed density functional theory calculations definitively rationalize the preference for the endo cycloadduct (also known as endo rule) in text-book thermal Diels-Alder reactions involving maleic anhydride and cyclopentadiene or butadiene. This selectivity is mainly caused by an unfavorable steric arrangement in the transition-state region of the exo pathway which translates into a more destabilizing activation strain. In contrast with the widely accepted, orbital-interaction-based explanation for the endo rule, it is found that neither the orbital interactions nor the total interaction between the deformed reactants contributes to the endo selectivity.


Staging and surgical approaches in gastric cancer: a clinical practice guideline.
Resection is the cornerstone of cure for gastric adenocarcinoma; however, several aspects of surgical intervention remain controversial or are suboptimally applied at a population level, including staging, extent of lymphadenectomy (lnd), minimum number of lymph nodes that have to be assessed, gross resection margins, use of minimally invasive surgery, and relationship of surgical volumes with patient outcomes and resection in stage iv gastric cancer. Literature searches were conducted in databases including medline (up to 10 June 2016), embase (up to week 24 of 2016), the Cochrane Library and various other practice guideline sites and guideline developer Web sites. A practice guideline was developed. One guideline, seven systematic reviews, and forty-eight primary studies were included in the evidence base for this guidance document. Seven recommendations are presented. All patients should be discussed at a multidisciplinary team meeting, and computed tomography (ct) imaging of chest and abdomen should always be performed when staging patients. Diagnostic laparoscopy is useful in the determination of M1 disease not visible on ct images. A D2 lnd is preferred for curative-intent resection of gastric cancer. At least 16 lymph nodes should be assessed for adequate staging of curative-resected gastric cancer. Gastric cancer surgery should aim to achieve an R0 resection margin. In the metastatic setting, surgery should be considered only for palliation of symptoms. Patients should be referred to higher-volume centres and those that have adequate support to manage potential complications. Laparoscopic resections should be performed to the same standards as those for open resections, by surgeons who are experienced in both advanced laparoscopic surgery and gastric cancer management.


EUELC project: a multi-centre, multipurpose study to investigate early stage NSCLC, and to establish a biobank for ongoing collaboration.
The European Early Lung Cancer (EUELC) project aims to determine if specific genetic alterations occurring in lung carcinogenesis are detectable in the respiratory epithelium. In order to pursue this objective, nonsmall cell lung cancer (NSCLC) patients with a very high risk of developing progressive lung cancer were recruited from 12 centres in eight European countries: France, Germany, southern Ireland, Italy, the Netherlands, Poland, Spain and the UK. In addition, NSCLC patients were followed up every 6 months for 36 months. A European Bronchial Tissue Bank was set up at the University of Liverpool (Liverpool, UK) to optimise the use of biological specimens. The molecular-pathological investigations were subdivided into specific work packages that were delivered by EUELC Partners. The work packages encompassed mutational analysis, genetic instability, methylation profiling, expression profiling utilising immunohistochemistry and chip-based technologies, as well as in-depth analysis of FHIT and RARbeta genes, the telomerase catalytic subunit hTERT and genotyping of susceptibility genes in specific pathways. The EUELC project engendered a tremendous collaborative effort, and it enabled the EUELC Partners to establish protocols for assessing molecular biomarkers in early lung cancer with the view to using such biomarkers for early diagnosis and as intermediate end-points in future chemopreventive programmes.


Development of broad-acting clays for the tight adsorption of benzo[a]pyrene and aldicarb.
People and animals can be unintentionally exposed to complex mixtures of hazardous chemicals that can threaten the safety of food and water supplies following natural and man-made disasters and emergencies. Our research has focused on the development of broad-acting adsorbents that will tightly bind environmental contaminants in the gastrointestinal tract and decrease their bioavailability to humans and animals during these events. In this study, benzo[a]pyrene (BaP) and aldicarb were used as representative chemicals due to their high toxicity and extensive distribution in the environment. Both chemicals have been commonly detected in water and sediments in the US, and their distribution and concentrations can be enhanced during disasters. To address this problem, we have amended and functionalized montmorillonite clays with the nutrients, L-carnitine and choline to enhance their attraction for lipophilic toxins, such as BaP and aldicarb. Based on equilibrium isothermal analyses, we have demonstrated a significantly increased binding capacity (Qmax) and affinity (Kd) for BaP and aldicarb compared to the parent clay. Adsorption isotherms also showed that talc bound strongly to BaP with the highest Qmax, which was twice that of activated carbon. Additionally, cultures of adult hydra with a metabolism activation package were used as an in vivo toxicity indicator to confirm the ability of test adsorbents to protect against toxicity at low inclusion levels. We anticipate that the optimal adsorbents developed can be delivered in food and flavored water, or administered by sachet or capsule during emergencies and disasters to decrease human and animals exposures to environmental toxins.


Development of a Human Estrogen Receptor Dimerization Assay for the Estrogenic Endocrine-Disrupting Chemicals Using Bioluminescence Resonance Energy Transfer.
Endocrine-disrupting chemicals (EDCs) are found in food and various other substances, including pesticides and plastics. EDCs are easily absorbed into the body and have the ability to mimic or block hormone function. The radioligand binding assay based on the estrogen receptors binding affinity is widely used to detect estrogenic EDCs but is limited to radioactive substances and requires specific conditions. As an alternative, we developed a human cell-based dimerization assay for detecting EDC-mediated ER-alpha (ERα) dimerization using bioluminescence resonance energy transfer (BRET). The resultant novel BRET-based on the ERα dimerization assay was used to identify the binding affinity of 17β-estradiol (E2), 17α-estradiol, corticosterone, diethylhexyl phthalate, bisphenol A, and 4-nonylphenol with ERα by measuring the corresponding BRET signals. Consequently, the BRET signals from five chemicals except corticosterone showed a dose-dependent sigmoidal curve for ERα, and these chemicals were suggested as positive chemicals for ERα. In contrast, corticosterone, which induced a BRET signal comparable to that of the vehicle control, was suggested as a negative chemical for ERα. Therefore, these results were consistent with the results of the existing binding assay for ERα and suggested that a novel BRET system can provide information about EDCs-mediated dimerization to ERα.


Persistence of TBT and copper in excess on leisure boat hulls around the Baltic Sea.
A handheld XRF-analyzer specially calibrated for measurements of metals on plastic boat hulls has been used on leisure boats in Denmark (DK), Finland (FI), and Germany (DE). The results on tin and copper are presented as μg metal/cm2. Tin is a proxy for the occurrence of organotin compounds on the boat. Two or three sites were visited in each country and between 25 and 90 boats were measured at each site. Every boat was measured at six to eight places, and the results are presented both as mean and median values. Linear regression of mean to median values of the 377 data pairs shows high relationship with R2 = 0.9566 for tin and R2 of 0.9724 for copper and thus both ways of calculation may be used. However, for regulative use, it is suggested that all individual measurements on each boat should be presented and used for decisions of removal or sealing of boat hulls. The results are compared with published data from different parts of Sweden, i.e., boats in fresh water, brackish water, and salt water. The results show that tin with mean values > 50 μg Sn/cm2 is still found on 42, 24, and 23% of the boats in DK, FI, and DE, respectively. The corresponding percentages based on median values are 38, 22, and 18% for DK, FI, and DE, respectively. The variation among boats is high with a maximum mean value of 2000 μg Sn/cm2. As comparison, one layer of an old TBT antifouling paint Hempels Hard racing superior, corresponds to 300 μg Sn/cm2. The percentage of boats with tin > 400 μg Sn/cm2 content based on mean values was 10% in DK, 5% in FI, and 1% in DE. The corresponding median values were 9, 6, and 1% for DK, FI, and DE. Copper, > 100 μg Cu/cm2, was detected on all measured boats in DK and in DE and on all but 3% of the FI boats. One layer of Hempels MilleXtra corresponds to ̴ 4000 μg Cu/cm2. The recommendation on the can is to apply two layers. The proportion of boats with higher mean copper values than 8000 μg Cu/cm2 was 51, 56, and 61 for boats in DK, FI, and DE, respectively. The proportion based on median values > 8000 μg Cu/cm2 was 50, 54, and 61% for DK, FI, and DE. The conclusion is that many leisure boats around the Baltic Sea still display or possess antifouling paints containing organotin compounds and that more than half of the boats have more copper than needed for one boat season according to the paint producers. Much of these known toxic compounds will probably be released into the environment and harm the biota. The calibrated XRF-method, intended for area measurements on boat hulls, is an easy and cheap way to detect boats with organotin compounds and high copper content. We recommend environmental authorities to use this method for identification of such boats and to use the results for requesting measures to minimize further leakage to the environment.


Duplicated inferior vena cava with associated ilio-femoral deep vein thrombosis.
We present the case of a fit and well 20-year-old gentleman who presented to our emergency department with unilateral lower limb pain and swelling. Subsequent imaging revealed a left ilio-femoral deep vein thrombosis, with associated duplication of his inferior vena cava. He was treated conservatively with a heparin infusion, warfarin and compression therapy prior to being discharged following a short inpatient stay.


Disrupted circadian rhythms of body temperature, heart rate and fasting blood glucose in prediabetes and type 2 diabetes mellitus.
We report a progressive disruption of 24-h rhythms in fasting blood glucose (FBG), body temperature (BT) and heart rate (HR) associated with metabolic dysfunction and the development of prediabetes (PD) and type 2 diabetes mellitus (T2DM) in overweight middle-aged (40-69 years old) humans. Increasing BT and HR mean values and declining 24-h BT and HR amplitudes accompany adverse changes in metabolic state. Increased nocturnal BT and a phase delay of the 24-h BT rhythm, deviant 24-h HR profile and a phase advance of the 24-h HR and FBG rhythms are early signs of the PD metabolic state. In T2DM, the 24-h FBG rhythm is no longer detectable, and the 24-h amplitudes of BT and HR are greatly diminished. In addition, lepton and creatinine values were lowered in T2DM. Moreover, positive correlations between FBG and body mass index, BMI, and negative correlations between the 24-h amplitude of FBG and BMI indicate that overweight is an additional factor causing disruption of the circadian rhythms. Further studies on circadian disruption as a consequence of metabolic dysfunction are necessary. The quantitative analysis of changing circadian BT and HR rhythms may provide prognostic markers of T2DM and therapeutic targets for its prevention and correction.


Alpha-fetoprotein levels correlate with the pathologic grade and surgical outcomes of pediatric retroperitoneal teratomas.
Retroperitoneal teratomas (RTs) are rare neoplasms that comprise 2-5% of all pediatric teratomas and 10% of all pediatric retroperitoneal tumors. Although alpha-fetoprotein (AFP) is a recognized tumor marker for immature teratomas, its prognostic value in neonates and children with RTs is unknown due to physiologic elevation of this marker. The aim of this study was to determine whether AFP level correlates with pathologic grade of pediatric RT and patient outcome. A retrospective analysis of all RTs seen at our institution over a 20-year period was performed. Thirteen patients with RTs were identified; their AFP levels were correlated with tumor grade, patient age, and outcome. Twelve patients were less than 1 year of age at diagnosis. There were nine patients with immature, and four with mature RTs. All patients with mature RTs had AFP levels within the normal range, while eight out of nine patients with immature RTs had elevated AFP levels. A statistically significant elevation in AFP was noted in grade III RTs compared with mature RTs (P = 0.036), regardless of age. Major complications including vascular injury, sepsis, and death were more prevalent in high-grade RTs. We conclude that AFP levels correlate with tumor immaturity and predict operative morbidity even in patients less than 2 months of age. Despite the increased morbidity associated with surgical excision of high-grade RTs, complete resection results in long-term disease-free survival in the majority of infants with this rare pediatric neoplasm.


Discrete Choice Model of Food Store Trips Using National Household Food Acquisition and Purchase Survey (FoodAPS).
Where households across income levels shop for food is of central concern within a growing body of research focused on where people live relative to where they shop, what they purchase and eat, and how those choices influence the risk of obesity and chronic disease. We analyzed data from the National Household Food Acquisition and Purchase Survey (FoodAPS) using a conditional logit model to determine where participants shop for food to be prepared and eaten at home and how individual and household characteristics of food shoppers interact with store characteristics and distance from home in determining store choice. Store size, whether or not it was a full-service supermarket, and the driving distance from home to the store constituted the three significant main effects on store choice. Overall, participants were more likely to choose larger stores, conventional supermarkets rather than super-centers and other types of stores, and stores closer to home. Interaction effects show that participants receiving Supplemental Nutrition Assistance Program (SNAP) were even more likely to choose larger stores. Hispanic participants were more likely than non-Hispanics to choose full-service supermarkets while White participants were more likely to travel further than non-Whites. This study demonstrates the value of explicitly spatial discrete choice models and provides evidence of national trends consistent with previous smaller, local studies.


A highly sensitive immunoassay system involving antibody-coated tubes and liposome-entrapped dye.
In this colorimetric immunoassay for digoxin, large, unilamellar phospholipid vesicles approximately 0.2 micron in diameter are loaded with high concentrations of Sulforhodamine B. Digoxigenin coupled to phosphatidylethanolamine, incorporated into the lipid formulation, confers immunological specificity. The liposomes are then used as tracers in simple competitive-binding immunoassays with antibody-coated tubes. Results are amplified by 10(3) to 10(4) of what could be achieved with one label group attached to each hapten, so that the results can be read spectrophotometrically. The stability of the liposomes is excellent. The method should be applicable to measuring a wide variety of analytes.


The international standard for anti-Brucella-abortus serum.
In field trials on the eradication of brucellosis from dairy herds in Great Britain, which began in 1933, a serum standard of reference was used for the examination of agglutinating suspensions prepared in different laboratories. In 1937, the Office International des Epizooties (OIE) adopted this standard and made recommendations for its use internationally. These recommendations were revised by OIE in 1948, by the Third Inter-American Congress on Brucellosis and by the Joint FAO/WHO Expert Panel on Brucellosis in 1950, and again by the latter body in 1952. A new batch equivalent in potency to the original standard was established by the WHO Expert Committee on Biological Standardization in 1952 as the International Standard for Anti-Brucella abortus Serum.The International Standard, or a national standard of equivalent potency, ensures comparability of the titres obtained in different countries by different methods, and the results of such comparisons can be expressed in a simple manner by describing the titres in terms of International Units of Brucella antibody.


Linking Dysregulated AMPK Signaling and ER Stress in Ethanol-Induced Liver Injury in Hepatic Alcohol Dehydrogenase Deficient Deer Mice.
Ethanol (EtOH) metabolism itself can be a predisposing factor for initiation of alcoholic liver disease (ALD). Therefore, a dose dependent study to evaluate liver injury was conducted in hepatic alcohol dehydrogenase (ADH) deficient (ADH-) and ADH normal (ADH+) deer mice fed 1%, 2% or 3.5% EtOH in the liquid diet daily for 2 months. Blood alcohol concentration (BAC), liver injury marker (alanine amino transferase (ALT)), hepatic lipids and cytochrome P450 2E1 (CYP2E1) activity were measured. Liver histology, endoplasmic reticulum (ER) stress, AMP-activated protein kinase (AMPK) signaling and cell death proteins were evaluated. Significantly increased BAC, plasma ALT, hepatic lipids and steatosis were found only in ADH- deer mice fed 3.5% EtOH. Further, a significant ER stress and increased un-spliced X-box binding protein 1 were evident only in ADH- deer mice fed 3.5% EtOH. Both strains fed 3.5% EtOH showed deactivation of AMPK, but increased acetyl Co-A carboxylase 1 and decreased carnitine palmitoyltransferase 1A favoring lipogenesis were found only in ADH- deer mice fed 3.5% EtOH. Therefore, irrespective of CYP2E1 overexpression; EtOH dose and hepatic ADH deficiency contribute to EtOH-induced steatosis and liver injury, suggesting a linkage between ER stress, dysregulated hepatic lipid metabolism and AMPK signaling.


Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) 87Sr/86Sr isotope data from scythian Iron age barrows in Altai, Russia.
This paper reports LA-ICP-MS 87Sr/86Sr isotopic data collected from archaeological human remains uncovered in Manzherok region, Altai Republic, Russian Federation ("Mobility of nomads in central Asia: chronology and 87Sr/86Sr isotope evidence from the Pazyryk barrows of northern Altai, Russia" [1]. The skeletal remains derive from Scythian barrows dated to 6th - 3rd century BC located at Chultukov Log 1 cemetery. The Chultukov Log cemetery, located approximately 470km south of Novosibirsk, is considered the biggest nomadic burial ground in the Upper Altai and the Sayan Mountains. To enrich the information on prehistoric mobility of ancient nomadic populations in Central Asia, strontium isotopic data were collected using a Nu plasma (II) MC-ICP-MS equipped with ESI NWR193-based laser ablation system from premolar teeth of 8 adult individuals (4 males and 4 females), associated mainly with the Pazyryk culture. Additionally, we report bioavailable strontium data from single Equus caballus specimen (found at Chultukov Log 9 settlement) from Manzherok territory. In this study we have successfully applied and tested new in-depth decontamination protocol for total (<95%) removal of contaminants, necrotic tissue and dental calculus in archaeological materials based on a clinical irrigation procedure with NaOCl and EDTA. Strontium LA-ICP-MS 87Sr/86Sr isotopic data presented in this paper were obtained from prehistoric human teeth previously decontaminated according to this method. These data will provide valuable resources for isotopic analyses of prehistoric transportation systems in Central Asia, including residential mobility of ancient nomads inhabiting steppe zone, Mongolia and NW China.


Tuberculosis outcome monitoring--is it time to update European recommendations?
We discuss tuberculosis treatment outcome monitoring and the adherence of countries in the WHO European Region to modifications introduced in 2001 to enhance inter-country comparability. Outcomes for definite pulmonary tuberculosis cases were compared for cases reported in 2001 and 2000. Reporting was considered complete if 98% or more of cases originally notified had outcome reported. In both years, maximal period of observation was 12 months from start of treatment. In 2000, countries reported outcome as 'cured', 'completed', 'died', 'failed', 'defaulted', 'transferred' and 'other, not evaluated' for cohorts of new and retreated cases. In 2001, following changes, countries were also requested to monitor cases with unknown treatment history and two outcome categories were added--'still on treatment' and 'unknown'. Of 42 countries reporting outcomes in 2001, 74% (31) had nationwide, complete data, up from 50% (19/38) in 2000. Twelve of 21 countries that reported on observation period complied with that recommended. 'Defaulted' and 'transferred' were applied interchangeably with 'unknown'. Among new cases, 'still on treatment' was used by 15/31 countries (range: 1%-15%). 'Failed' was rarely recorded in western European countries (<1%). European tuberculosis outcome monitoring should include all definite pulmonary cases, applying the standard period of observation and revised categories, and preferably reported using individual data.


Reduced Intracellular c-di-GMP Content Increases Expression of Quorum Sensing-Regulated Genes in Pseudomonas aeruginosa.
Cyclic-di-GMP (c-di-GMP) is an intracellular secondary messenger which controls the biofilm life cycle in many bacterial species. High intracellular c-di-GMP content enhances biofilm formation via the reduction of motility and production of biofilm matrix, while low c-di-GMP content in biofilm cells leads to increased motility and biofilm dispersal. While the effect of high c-di-GMP levels on bacterial lifestyles is well studied, the physiology of cells at low c-di-GMP levels remains unclear. Here, we showed that Pseudomonas aeruginosa cells with high and low intracellular c-di-GMP contents possessed distinct transcriptome profiles. There were 535 genes being upregulated and 432 genes downregulated in cells with low c-di-GMP, as compared to cells with high c-di-GMP. Interestingly, both rhl and pqs quorum-sensing (QS) operons were expressed at higher levels in cells with low intracellular c-di-GMP content compared with cells with higher c-di-GMP content. The induced expression of pqs and rhl QS required a functional PqsR, the transcriptional regulator of pqs QS. Next, we observed increased production of pqs and rhl-regulated virulence factors, such as pyocyanin and rhamnolipids, in P. aeruginosa cells with low c-di-GMP levels, conferring them with increased intracellular survival rates and cytotoxicity against murine macrophages. Hence, our data suggested that low intracellular c-di-GMP levels in bacteria could induce QS-regulated virulence, in particular rhamnolipids that cripple the cellular components of the innate immune system.


Generation and characterization of monoclonal antibodies to the phenolic glycolipid of Mycobacterium leprae.
Nine cloned cell lines producing antibodies to the unique phenolic glycolipid of Mycobacterium leprae have been established as a result of fusions with spleens from mice immunized with the glycolipid complexed with methylated bovine serum albumin. One of the antibodies was relatively nonspecific, binding to a related glycolipid from Mycobacterium kansasii, but the remaining antibodies were specific for the M. leprae lipid. Some of the antibodies required the intact (trisaccharide) carbohydrate portion for recognition of the glycolipid antigen, whereas others recognized partially hydrolyzed forms lacking one or two sugar residues. Monoclonal antibodies directed at the terminal saccharide of the glycolipid showed the greatest specificity for M. leprae in enzyme-linked immunoassays. These antibodies brightly labeled whole mycobacteria in indirect immunofluorescence experiments, demonstrating the surface location of M. leprae-specific determinants of the glycolipid antigen. In addition to their use in providing information about the antigenic properties of the phenolic glycolipid, these antibodies have potential applications for elucidating the roles of glycolipid in the pathogenesis of leprosy.


[Merkel cell carcinoma and sentinel lymph node dissection: nine cases report].
Merkel cell carcinoma (MCC) is an aggressive cutaneous-neuroendocrine neoplasia with poor prognosis and high propensity for locoregional and distant metastasis. Lack of knowledge about its biological behavior, pathogenesis, and prognostic factors, complicates the prospective evaluation. Sentinel node dissection, concomitant with radical excision of the lesion, has increased in the last few years. The suitability of this technique is linked to the MCC high tendency to spread "in primis" at locoregional nodes such as other malignancies such as cutaneous melanoma. Aim of the study is the prospective evaluation of the sentinel node dissection and of the adjuvant therapies in 9 patients MCC affected. All patients, underwent evaluation and staging of the neoplasia. Diagnosis was made by excisional biopsy and histological examination. Sentinel node dissection was performed in patients without clinical locoregional metastases (8 cases). Patients with sentinel node positive for metastasis underwent radical lymphadenectomy (3 cases). One patient affected by clinically locoregional metastases had, at once, radical lymphadenectomy. Radiotherapy and/or chemotherapy as adjuvant therapy were implemented (4 cases).


Inhibition of leukotriene D4-induced coronary vasoconstriction by leukotriene antagonists in the anesthetized dog.
Anesthetized open-chest dogs were instrumented for the measurement of left circumflex coronary artery (LCX) blood flow and aortic blood flow, systemic arterial blood pressure, heart rate, lead II ECG, left ventricular end-diastolic pressure, left ventricular developed pressure and left ventricular positive and negative dP/dt to study the hemodynamic effects of leukotriene D4 (LTD4) and selective LTD4 antagonists on the coronary vasculature. Administration of LTD4 alone into the LCX (0.625-10 micrograms) produced a dose-dependent decrease in LCX blood flow, dP/dt and aortic blood flow and an increase in left ventricular end-diastolic pressure. Systemic arterial blood pressure, left ventricular developed pressure and heart rate were unchanged by LTD4. During i.v. infusions of the LTD4 antagonists, SK&F 102922 or FPL 55712 (1 mg/kg/min), the dose-dependent decreases in LCX flow, dP/dt and aortic blood flow were blocked whereas the increase in left ventricular end-diastolic pressure remained unchanged. The thromboxane A2 antagonist, SK&F 88046 (5 mg/kg + 0.1 mg/kg/min), which has been reported previously to block the coronary blood flow reducing action of LTC4, had no effect on the LCX blood flow responses to intracoronary LTD4. In a separate study, dogs instrumented in a similar manner were given bolus injections of arginine-vasopressin (1 microgram), the thromboxane A2 mimetic, U-46619 (10 micrograms), LTD4 (10 micrograms), angiotensin II (1 microgram) and prostaglandin F2 alpha (100 micrograms) directly into the LCX to provoke coronary vasoconstriction. SK&F 102922 and FPL 55712 selectively blocked the coronary vasoconstriction produced by LTD4, but had no effect on vasoconstriction produced by the other agonists.(ABSTRACT TRUNCATED AT 250 WORDS)


MIB-1 immunoreactivity reveals different labelling in low-grade and in malignant epithelial neoplasms of the choroid plexus.
MIB-1 immunohistochemistry was carried out on a retrospective biopsy series of epithelial choroid plexus neoplasms in order to assess the proliferation rate of tumour cells. The material included 14 cases of papilloma (WHO grade I) and five cases of carcinoma (WHO grade III). There was one recurrent tumour in the papilloma group, while three patients with carcinoma experienced recurrence. Choroid plexus obtained at autopsy from paediatric and adult patients with unrelated diseases served as control. The average MIB-1 labelling index of choroid plexus papillomas was 3.7%, while that of carcinomas was 14%, and that of normal choroid plexus was 0.02% to 0.06%. The age and sex of the patients as well as the tumour localization were not found to influence MIB-1 reactivity. The labelling index of recurrent lesions was not significantly different from that of the corresponding primary tumours. High MIB-1 labelling indices were associated with less favourable post-operative outcome in choroid plexus carcinomas and in one papilloma with atypical histology. However, most tumours with atypical histological features did not exhibit distinctive MIB-1 labelling indices. Analysis of growth fraction by MIB-1 immunohistochemistry may prove a useful ancillary method for assessing the malignant potential of choroid plexus neoplasms.


Effect of Patient Clinical Variables in Osteoporosis Classification Using Hip X-rays in Deep Learning Analysis.
Background and Objectives: A few deep learning studies have reported that combining image features with patient variables enhanced identification accuracy compared with image-only models. However, previous studies have not statistically reported the additional effect of patient variables on the image-only models. This study aimed to statistically evaluate the osteoporosis identification ability of deep learning by combining hip radiographs with patient variables. Materials andMethods: We collected a dataset containing 1699 images from patients who underwent skeletal-bone-mineral density measurements and hip radiography at a general hospital from 2014 to 2021. Osteoporosis was assessed from hip radiographs using convolutional neural network (CNN) models (ResNet18, 34, 50, 101, and 152). We also investigated ensemble models with patient clinical variables added to each CNN. Accuracy, precision, recall, specificity, F1 score, and area under the curve (AUC) were calculated as performance metrics. Furthermore, we statistically compared the accuracy of the image-only model with that of an ensemble model that included images plus patient factors, including effect size for each performance metric. Results: All metrics were improved in the ResNet34 ensemble model compared with the image-only model. The AUC score in the ensemble model was significantly improved compared with the image-only model (difference 0.004; 95% CI 0.002-0.0007; p = 0.0004, effect size: 0.871). Conclusions: This study revealed the additional effect of patient variables in identification of osteoporosis using deep CNNs with hip radiographs. Our results provided evidence that the patient variables had additive synergistic effects on the image in osteoporosis identification.


Sequence and Dispersity Are Determinants of Photodynamic Antibacterial Activity Exerted by Peptidomimetic Oligo(thiophene)s.
A library of functionalized oligo(thiophene)s with precisely controlled chain length, regioregularity, sequence, and pendant moieties in the side chains was prepared by iterative convergent/divergent organometallic couplings. The cationic and facially amphiphilic structures were designed to mimic the salient physiochemical features of host defense peptides (HDPs) while concurrently exerting a photodynamic mechanism of antibacterial activity. In the dark, the oligothiophenes exert broad-spectrum and rapid bactericidal activity in the micromolar regime, which is the typical range of HDP activity. Under visible light, the antibacterial potency is enhanced by orders of magnitude, leading to potency in the nanomolar concentration range, whereas the toxicity to red blood cells (RBCs) is almost unaffected by the same visible light exposure. We attribute the potent and selective antibacterial activity to a dual mechanism of action that involves bacterial cell binding, combined with reactive oxygen species production in the bound state. Comonomer sequence and chain length dispersity play important roles in dictating the observed biological activities. The most promising candidate compound from a set of screening experiments showed antibacterial activity that is 3 orders of magnitude more potent against bacteria relative to toxicity against RBCs. Importantly, this compound did not induce resistance upon 21 subinhibitory passages, whereas the activity of ciprofloxacin was reduced 32× in the same condition. Cytotoxicity against HeLa cells in vitro is orders of magnitude weaker than antibacterial activity under visible light illumination. Thus, we have established a new class of HDP-mimetic antibacterial compounds with nanomolar activity and cell type selectivity of greater than 1300-fold. These and related compounds may be highly promising candidates in the urgent search for new topical photodynamic antibacterial formulations.


Association of Survival With Shorter Time to Radiation Therapy After Surgery for US Patients With Head and Neck Cancer.
Shortening the time from surgery to the start of radiation (TS-RT) is a consideration for physicians and patients. Although the National Comprehensive Cancer Network recommends radiation to start within 6 weeks, a survival benefit with this metric remains controversial. To determine the association of delayed TS-RT with overall survival (OS) using a large cancer registry. In this observational cohort study, 25 216 patients with nonmetastatic stages III to IV head and neck cancer were identified from the National Cancer Database (NCDB). Patients received definitive surgery followed by adjuvant radiation therapy, with an interval duration defined as TS-RT. Overall survival as a function of TS-RT and the effect of clinicopathologic risk factors and accelerated fractionation. We identified 25 216 patients with nonmetastatic squamous cell carcinoma of the head and neck. There were 18 968 (75%) men and 6248 (25%) women and the mean (SD) age of the cohort was 59 (10.9) years. Of the 25 216 patients, 9765 (39%) had a 42-days or less TS-RT and 4735 (19%) had a 43- to 49-day TS-RT. Median OS was 10.5 years (95% CI, 10.0-11.1 years) for patients with a 42-days or less TS-RT, 8.2 years (95% CI, 7.4-8.6 years; absolute difference, -2.4 years, 95% CI, -1.5 to -3.2 years) for patients with a 43- to 49-day TS-RT, and 6.5 years (95% CI, 6.1-6.8 years; absolute difference, -4.1 years, 95% CI, -3.4 to -4.7 years) for those with a 50-days or more TS-RT. Multivariable analysis found that compared with a 42-days or less TS-RT, there was not a significant increase in mortality with a 43- to 49-day TS-RT (HR, 0.98; 95% CI, 0.93-1.04), although there was for a TS-RT of 50 days or more (HR, 1.07; 95% CI, 1.02-1.12). A significant interaction was identified between TS-RT and disease site. Subgroup effect modeling found that a delayed TS-RT of 7 days resulted in significantly worse OS for patients with tonsil tumors (HR, 1.22; 95% CI, 1.05-1.43) though not other tumor subtypes. Accelerated fractionation of 5.2 fractions or more per week was associated with improved survival (HR, 0.93; 95% CI, 0.87-0.99) compared with standard fractionation. Delayed TS-RT of 50 days or more was associated with worse overall survival. The multidisciplinary care team should focus on shortening TS-RT to improve survival. Unavoidable delays may be an indication for accelerated fractionation or other dose intensification strategies.


Exploring Knowledge and Perceptions of Polio Disease and Its Immunization in Polio High-Risk Areas of Pakistan.
Pakistan is one of the few countries where poliovirus transmission still persists, despite intensive efforts to eradicate the disease. Adequate vaccination coverage is essential to achieve polio eradication, but misconceptions about polio vaccines have hindered vaccination efforts. To address this issue, we conducted a mixed-methods study to explore knowledge and perceptions regarding polio disease and immunization in high-risk areas of Pakistan. We collected quantitative data from 3780, 1258, and 2100 households in Karachi, Bajaur, and Pishin, respectively, and supplemented this with qualitative data from focus group discussions and in-depth interviews. Our findings reveal a high level of awareness about polio and its immunization; however, misperceptions about the polio vaccine persist, leading to refusal for both polio vaccines and routine immunizations. Our study provides up-to-date data on knowledge and perceptions of polio and its immunization and identifies critical gaps. These findings can inform the development of future strategies and innovative approaches to improve the success of the polio program in Pakistan.