Costs of a work-family intervention: evidence from the work, family, and health network.
To estimate the cost to the workplace of implementing initiatives to reduce work-family conflict. Prospective cost analysis conducted alongside a group-randomized multisite controlled experimental study, using a microcosting approach. An information technology firm. Employees (n = 1004) and managers (n = 141) randomized to the intervention arm. STAR (Start. Transform. Achieve. Results.) to enhance employees' control over their work time, increase supervisor support for employees to manage work and family responsibilities, and reorient the culture toward results. A taxonomy of activities related to customization, start-up, and implementation was developed. Resource use and unit costs were estimated for each activity, excluding research-related activities. Economic costing approach (accounting and opportunity costs). Sensitivity analyses on intervention costs. The total cost of STAR was $709,654, of which $389,717 was labor costs and $319,937 nonlabor costs (including $313,877 for intervention contract). The cost per employee participation in the intervention was $340 (95% confidence interval: $330-$351); $597 ($561-$634) for managers and $300 ($292-$308) for other employees (2011 prices). A detailed activity costing approach allows for more accurate cost estimates and identifies key drivers of cost. The key cost driver was employees' time spent on receiving the intervention. Ignoring this cost, which is usual in studies that cost workplace interventions, would seriously underestimate the cost of a workplace initiative.


The mobilization of CD34 positive mononuclear cells after myocardial infarction is abolished by revascularization of the culprit vessel.
The mobilization of hematopoietic progenitor cells from bone marrow has been proposed to play a role in cardiac regeneration after myocardial infarction (MI). Accordingly, an increase in CD34 positive cells (CD34+) has been observed in the peripheral blood of patients after acute myocardial infarction. Here, we evaluated the influence of an acute percutaneous coronary intervention (PCI) of the occluded artery on the mobilization of CD34+ in acute MI. CD34 positive cells were quantified by flow cytometry (FACS analysis) and expressed as number per million white blood cells. Peripheral blood was obtained and analyzed at day 5 after the onset of symptoms from patients with acute MI without early PCI (n=11, age 63+/-5 years), acute MI with rapid PCI (n=7, age 63+/-3), patients with pneumonia (n=5, age 51+/-6), patients without angiographical signs of coronary artery disease (control, n=5, age 66+/-8) and young healthy volunteers (n=11, age 28+/-1). Patients with MI but without PCI had a higher CD34+ count at day 5 (312+/-48 per 10(6) leukocytes) than control (156+/-40, P=0.03) and MI with PCI (173+/-31, P=0.03). No increase in CD34+ was observed in patients who underwent PCI vs. control. Patients with pneumonia had higher CD34+ (350+/-44) than patients with MI with PCI (P=0.01) and control (P=0.01). Healthy individuals who were much younger than all other groups (28+/-1 years, P<0.0001 vs. all groups) had the highest CD34+ (526+/-51, P=0.006 vs. MI without PCI, P=0.00003 vs. MI with PCI, P=0.02 vs. pneumonia, P=0.00006 vs. control). Shorter time of ischemia and reduced cell death may be the reasons for reduced CD34+ cell count after acute MI with early percutaneous intervention vs. acute MI without intervention. Besides ischemia, also inflammation as present in pneumonia may cause a mobilization of CD34+ cells. Age may be a major factor that influences the mobilization of CD34+ cells and the regenerative capacity of the heart.


A novel FPCL model producing directional contraction through induction of fibroblast alignment by biphasic pulse direct current electric field.
Although parallel alignment of fibroblasts to the tension lines of scar has been evidenced in vivo, how scar contracture generates directional contraction remains largely unclear due to the lack of effective in vitro model. Fibroblast populated collagen lattice (FPCL), a widely used in vitro model, fails to mimic scar contracture since it produces concentric contraction with the random orientation of fibroblast. We hypothesized that a novel FPCL model with fibroblast alignment might produce directional contraction and then simulate scar contracture better. Here, we showed that although direct current electric fields (DCEFs) enabled fibroblasts aligned perpendicularly to the field vector, it also promoted electrotactic migration of fibroblast in FPCL. By contrast, biphasic pulse direct current electric fields (BPDCEFs), featured by reversal of the EF direction periodically, abolished the electrotactic migration, but induced fibroblast alignment in a pulse frequency dependent manner. Specifically, BPDCEF at a pulse frequency of 0.0002 Hz induced fibroblast alignment comparable to that induced by DCEF under the same field strength (300 mV/mm), leading to an enhanced contraction of FPCL along the direction of cell alignment. FPCL pretreated by BPDCEF showed an elliptical contraction whereas it was concentric in control FPCL. Further study revealed that F-actin redistributions acted as a key mechanism for the induction of fibroblasts alignment by BPDCEF. Cytochalasin D, an inhibitor of actin dynamics, abolished F-actins redistribution, and significantly suppressed the fibroblasts alignment and the directional contraction of FPCL. Importantly, BPDCEF significantly increased RhoA activity in fibroblasts, while this response was attenuated by C3 transferase pre-treatment, a potent inhibitor of RhoA, caused F-actin depolymerization and actin filament bundle randomly distributed. Taken together, our study suggests a crucial role for fibroblast orientation in scar contracture, and provides a novel FPCL model that may be feasible and effective for investigating scar contracture in vitro.


The association between vitamin deficiency and otolaryngologic diseases: A therapeutic target.
Vitamins are indispensable nutrients for metabolism. Adequate vitamin intake plays vital role in physiological processes including embryonic development, cellular and immunity proliferation and differentiation, DNA synthesis and oxidative response. In contrast, insufficient vitamin levels usually lead to a large number of clinical manifestations including xerophthalmia, nyctalopia, hyperpigmentation, vitiligo, jaundice, megaloblastic anemia, glossitis, scurvy, stroke, cancer, coronary heart disease, Alzheimer's disease, multiple sclerosis and Parkinson's disease. In recent years, more and more researches have focused on the relationship between vitamin family and otorhinolaryngologic diseases. This review will summarize the current knowledge of vitamin family and vitamin-mediated regulating role in those related otorhinolaryngologic diseases.


The role of nitric oxide in the effects of cumin (Cuminum Cyminum L.) fruit essential oil on the acquisition of morphine-induced conditioned place preference in adult male mice.
OBJECTIVE: Nitric oxide is a neural messenger molecule in the central nervous system that is generated from L-arginine via the nitric oxide synthase (NOS) and is involved in many important oplold-induced effects. In Iranian ancient medicine, Cuminum cyminum L (green seed) has been used for the treatment of some diseases. In the present study, the effect of intraperitoneal (ip) administration of different doses of cumin fruit essential oil (FEO) on the acquisition of morphine-induced conditioned place preference (GPP) in L-arginine-treated mice was investigated. METHODS: A total of 213 adult male albino Wistar mice were used in these experiments. The CPP paradigm was carried out in 5 continuous days, pre-conditioning, conditioning and post-conditioning. Animals were randomly assigned to one of the two groups for place conditioning. CPP was induced by subcutaneous (sc) injection of morphine (5 mg/kg) in 3 days conditioning schedule. On the test day, conditioning scores and locomotor activity were recorded by Ethovision software. RESULTS: Sole administration of different doses of cumin FEO (0.01%, 0.1%, 0.5%, 1% and 2%; lp) or L-arginine (50, 100 and 200 mg/kg; lp) during the CPP protocol could not induce CPP. Nonetheless, morphine-induced CPP was decreased by different doses of cumin FEO (0.01%-2%), whereas it was increased by L-arginine (50-200 mg/kg) when they were injected before morphine (5 rug/kg) during a 3-day conditioning phase (acquisition period). Additionally, cumin FEO could interestingly attenuate the raising effect of L-arginine on morphine-induced CPP in a dose-dependent manner. CONCLUSIONS: It is suggested that some components of the Cuminum cyminum L. seed attenuate the excessive effect of L-arginine on morphine-induced CPP through the NOS inhibitory mechanism. It seems that cumin FEO possibly acts as a NOS inhibitor.


Characterization and functional analysis of hsp18.3 gene in the red flour beetle, Tribolium castaneum.
Small heat shock proteins (sHSPs) are diverse and mainly function as molecular chaperones to protect organisms and cells from various stresses. In this study, hsp18.3, one Tribolium castaneum species-specific shsp, has been identified. Quantitative real-time polymerase chain reaction illustrated that Tchsp18.3 is expressed in all developmental stages, and is highly expressed at early pupal and late adult stages, while it is highly expressed in ovary and fat body at the adult period. Moreover, it was up-regulated 4532 ± 396-fold in response to enhanced heat stress but not to cold stress; meanwhile the lifespan of adults in ds-Tchsp18.3 group reduced by 15.8% from control group under starvation. Laval RNA interference (RNAi) of Tchsp18.3 caused 86.1% ± 4.5% arrested pupal eclosion and revealed that Tchsp18.3 played an important role in insect development. In addition, parental RNAi of Tchsp18.3 reduced the oviposition amount by 94.7%. These results suggest that Tchsp18.3 is not only essential for the resistance to heat and starvation stress, but also is critical for normal development and reproduction in T. castaneum.


[Angiosarcoma of the breast: a case report].
We report a breast's angiosarcoma case admitted at the maternity hospital Souissi of Rabat in 1997. We discussed epidemiologic, diagnostic and therapeutic aspects of this type of tumor insisting on the difficulties of diagnosis.


Controlling the Editor: The Many Roles of RNA-Binding Proteins in Regulating A-to-I RNA Editing.
RNA editing is a cellular process used to expand and diversify the RNA transcripts produced from a generally immutable genome. In animals, the most prevalent type of RNA editing is adenosine (A) to inosine (I) deamination catalyzed by the ADAR family. Throughout development, A-to-I editing levels increase while ADAR expression is constant, suggesting cellular mechanisms to regulate A-to-I editing exist. Furthermore, in several disease states, ADAR expression levels are similar to the normal state, but A-to-I editing levels are altered. Therefore, understanding how these enzymes are regulated in normal tissues and misregulated in disease states is of profound importance. This chapter will both discuss how to identify A-to-I editing sites across the transcriptome and explore the mechanisms that regulate ADAR editing activity, with particular focus on the diverse types of RNA-binding proteins implicated in regulating A-to-I editing in vivo.


Molecular characterization of PeNhaD1: the first member of the NhaD Na+/H+ antiporter family of plant origin.
PeNhaD1 encodes a putative Na+/H+ antiporter from the salt-resistant tree Populus euphratica. It is the first characterization of a member of the NhaD type ion transporter family of plant origin. Homology searches revealed its close relation to functionally characterized microbial Na+/H+ antiporters VpNhaD and VcNhaD. Na+/H+ antiporters have proven to play a key role in salt resistance, both in plants and bacteria. Under salt stress transcript levels of PeNhaD1 were maintained only in the salt-resistant P. euphratica, but collapsed in Populus x canescens, a salt-sensitive species. To address the function of PeNhaD1, complementation studies with the salt-sensitive Escherichia coli EP432 mutant strain, lacking activity of the two Na+/H+ antiporters EcNhaA and EcNhaB were carried out. PeNhaD1 was able to restore growth of EP432 under stress imposed by up to 400 mM NaCl demonstrating its protective function. Growth rates of EP432 were always highest at pH 5.5 while growth was suppressed under salt stress at pH 7.0 and pH 8.0 suggesting that the antiporter activity is strongly pH dependent. Element analyses of EP432 cells complemented with PeNhaD1 growing under salt stress showed that salt resistance was correlated with a significant reduction in sodium accumulation. These results suggest that PeNhaD1 might play a role in the salt resistance of P. euphratica.


Development and validation of a new standardised data collection tool to aid in the diagnosis of canine skin allergies.
Canine atopic dermatitis (cAD) is a common hereditary clinical syndrome in domestic dogs with no definitive diagnostic tests, which causes marked morbidity and has a high economic impact internationally. We created a novel questionnaire for Labrador (LR) and Golden retriever (GR) owners to evaluate canine skin health with respect to clinical signs of cAD. 4,111 dogs had fully completed questionnaires (2,803 LR; 1,308 GR). 'Cases' (793) had a reported veterinary diagnosis of cAD, and 'controls' (1652) had no current or past clinical signs of cAD and were aged >3 years. Remaining dogs (1666) were initially categorised as 'Other'. Simulated annealing was used comparing 'Cases' and 'Others' to select a novel set of features able to classify a known case. Two feature sets are proposed, one for use on first evaluation and one for dogs with a history of skin problems. A sum for each list when applied to the whole population (including controls) was able to classify 'Cases' with a sensitivity of 89% to 94% and specificity of 71% to 69%, respectively, and identify potentially undiagnosed cases. Our findings demonstrate for the first time that owner questionnaire data can be reliably used to aid in the diagnostic process of cAD.


TPRA40/GPR175 regulates early mouse embryogenesis through functional membrane transport by Sjögren's syndrome-associated protein NA14.
TPRA40/GPR175 is an orphan receptor whose physiological functions have not been found to date. In an attempt to generate transgenic mice that express an shRNA of TPRA40, we observed that the cell division of early mouse embryos that injected the short hairpin RNA expression vector was significantly accelerated compared with the control vector. The regulation of cell division by TPRA40 was also observed in HeLa cells. Since the C-terminal region of TPRA40 has been shown to be essential for the regulation of cell division, we performed yeast two-hybrid screening using the C-terminal region as bait. Nuclear antigen of 14 kDa (NA14), an autoantigen of Sjögren's syndrome, was identified as a binding protein to the C-terminal region of TPRA40. The binding of TPRA40 and NA14 was confirmed by GST pull-down assay and co-immunoprecipitation assay. FLAG-TPRA40 is transported from the cytosol to the plasma membrane in time-dependent manner and the translocation was inhibited by GFP-NA14DeltaN, an N-terminal deletion mutant that cannot bind to microtubules but binds to TPRA40. TPRA40DeltaC, which cannot bind to NA 14, shows impaired transport to the plasma membrane. Finally, we found that the effect of TPRA40 on mouse embryogenesis is strengthened by GFP-NA14, but not by GFP or GFP-NA14DeltaN. These observations indicate that the functional plasma membrane transport of TPRA40 that regulates cell division of mouse embryos is mediated by NA14.


Regulation of atrophin by both strands of the mir-8 precursor.
In Drosophila melanogaster, miR-8-3p regulates mRNA levels of atrophin, a factor involved in neuromotor coordination, and we found that Blattella germanica with suppressed atrophin showed motor problems. Bionformatic predictions and luciferase-reporter tests indicated that B. germanica atrophin mRNA contains target sites for miR-8-3p and miR-8-5p. Suppression of miR-8-3p or miR-8-5p appeared to increase atrophin mRNA. The effects of suppression of Argonaute (AGO) 1 or AGO2 expression on miR-8-3p and miR-8-5p suggested that miR-8-3-p might predominantly bind to AGO1, whereas miR-8-5p might bind to a moderate extent to both AGO1 and AGO2 in the respective RNA-induced silencing complexes (RISCs). We propose that the interplay of miR-8-3p, miR-8-5p, AGO1 and AGO2, maintain the appropriate levels of atrophin mRNA. This would be the first example of two strands of the same miRNA precursor regulating a single transcript.


My First Twenty Rhinoplasties Using Dorsal Preservation Techniques.
Dorsal preservation involves eliminating the dorsal hump by performing reduction while preserving the patient's natural dorsal anatomy. This can involve surface manipulation or foundational techniques or a combination of both. When surgeons begin performing dorsal preservation, there are important factors to consider to avoid complications. In an effort to inform surgeons on how to avoid unfavorable outcomes, I will discuss my first 20 cases where I performed dorsal preservation. I review less than ideal outcomes and how these issues can be prevented.


Femoral hypoplasia-unusual facies syndrome, from another viewpoint.
A female infant with the "femoral hypoplasia-unusual facies" syndrome is presented. Most of the findings observed in this child have also been described in the "caudal regression syndrome". The similarity and probable identity between these two syndromes is discussed on the basis of our patient and others from the literature.


Molecular mechanisms of odor sensing. VI. Some biochemical characteristics of a possible receptor for amino acids from the olfactory epithelium of the skate Dasyatis pastinaca and carp Cyprinus carpio.
The 25 000 x g pellet of skate and carp olfactory tissue was found to contain structures with high affinity for amino acids (Kd approximately 10(-10) M). Results from competition experiments suggest that a multiplicity of types of olfactory binding sites exists in the skate and carp. Some parameters of a possible receptor for amino acids were evaluated. The isoelectric point of these sites solubilized with Triton X-100 was 5.35 and the molecular weight was about 120 000-150 000.


Predictors of poor ovarian response in in vitro fertilization: a prospective study comparing basal markers of ovarian reserve.
To identify and quantify predictors of poor ovarian response in in vitro fertilization (IVF). DESIGN; Prospective study. SETTING; Tertiary fertility center. One hundred twenty women undergoing their first IVF cycle. Measurement of the number of antral follicles and the total ovarian volume by ultrasound, and of basal levels of FSH, E(2), and inhibin B on cycle day 3. Ovarian response, and clinical and ongoing pregnancy rates. RESULT(S); The antral follicle count was the best single predictor for poor ovarian response: area under the receiver operating characteristic curve = 0.87. Addition of basal FSH and inhibin B levels to a logistic model with the antral follicle count significantly improved the prediction of poor response; the addition of basal E(2) levels and total ovarian volume did not improve the prediction. To express the discriminative performance of this model toward poor response, a maximum area under the receiver operating characteristic curve of 0.92 was calculated. Poor responders had significantly lower clinical and ongoing pregnancy rates than did normal responders. Our data demonstrate that the antral follicle count provides better prognostic information on the occurrence of poor response during hormone stimulation for IVF than does the patient's chronological age and the currently used endocrine markers. However, endocrine tests remain informative. Multivariate models can achieve more accurate predictions of outcomes of complex events like ovarian response in IVF.


Prenatal diagnosis of a partial 6q trisomy: a case report.
To present a case of partial 6q trisomy diagnosed prenatally. A 28-year-old woman underwent genetic amniocentesis at 23 weeks of gestation on the detection of an enlarged nuchal fold (8.5 mm), which was the only clinical abnormality on routine ultrasound examination. Fetal karyotyping revealed a partial trisomy 6q (q21-q22) caused by a balanced maternal chromosomal insertion. A female infant was delivered at 38 weeks of gestation. At birth, minor dysmorphisms were recorded, which included low set ears, macrocephaly and a webbed neck. At 17 months of age, neurological developmental assessment was normal. The appearance of phenotypic expression and clinical outcome of partial 6q trisomy depends on the specific chromosomal region involved in the segmental aneusomy.


Intracavernous papaverine for impotence in spinal cord injured patients.
The majority of the spinal cord injury patients in our centre are young healthy males aged between 20 and 40 years. Loss of erection and inability to have coitus and father children have been responsible for inadequate sociosexual rehabilitation. In 1985, under urologist supervision, intracavernosal papaverine injection treatment was started in 101 volunteers, 65 paraplegics and 36 tetraplegics. Satisfactory erection sufficient for coital penetration was possible in 98 patients. Three had prolonged erection lasting beyond 4 hours. Only one required irrigation of the corpus with saline to achieve detumscence. One patient developed cavernosal fibrosis necessitating discontinuing the injection. Administration was under medical supervision so that possible complications of priapism/systemic effects could be promptly managed.


Association of comorbid-socioeconomic clusters with mortality in late onset epilepsy derived through unsupervised machine learning.
Late-onset epilepsy is a heterogenous entity associated with specific aetiologies and an elevated risk of premature mortality. Specific multimorbid-socioeconomic profiles and their unique prognostic trajectories have not been described. We sought to determine if specific clusters of late onset epilepsy exist, and whether they have unique hazards of premature mortality. We performed a retrospective observational cohort study linking primary and hospital-based UK electronic health records with vital statistics data (covering years 1998-2019) to identify all cases of incident late onset epilepsy (from people aged ≥65) and 1:10 age, sex, and GP practice-matched controls. We applied hierarchical agglomerative clustering using common aetiologies identified at baseline to define multimorbid-socioeconomic profiles, compare hazards of early mortality, and tabulating causes of death stratified by cluster. From 1,032,129 people aged ≥65, we identified 1048 cases of late onset epilepsy who were matched to 10,259 controls. Median age at epilepsy diagnosis was 68 (interquartile range: 66-72) and 474 (45%) were female. The hazard of premature mortality related to late-onset epilepsy was higher than matched controls (hazard ratio [HR] 1.73; 95% confidence interval [95%CI] 1.51-1.99). Ten unique phenotypic clusters were identified, defined by 'healthy' males and females, ischaemic stroke, intracerebral haemorrhage (ICH), ICH and alcohol misuse, dementia and anxiety, anxiety, depression in males and females, and brain tumours. Cluster-specific hazards were often similar to that derived for late-onset epilepsy as a whole. Clusters that differed significantly from the base late-onset epilepsy hazard were 'dementia and anxiety' (HR 5.36; 95%CI 3.31-8.68), 'brain tumour' (HR 4.97; 95%CI 2.89-8.56), 'ICH and alcohol misuse' (HR 2.91; 95%CI 1.76-4.81), and 'ischaemic stroke' (HR 2.83; 95%CI 1.83-4.04). These cluster-specific risks were also elevated compared to those derived for tumours, dementia, ischaemic stroke, and ICH in the whole population. Seizure-related cause of death was uncommon and restricted to the ICH, ICH and alcohol misuse, and healthy female clusters. Late-onset epilepsy is an amalgam of unique phenotypic clusters that can be quantitatively defined. Late-onset epilepsy and cluster-specific comorbid profiles have complex effects on premature mortality above and beyond the base rates attributed to epilepsy and cluster-defining comorbidities alone.


Post-operative Sensorineural Hearing Loss After Middle Ear Surgery.
Chronic suppurative otitis media is managed by tympanomastoid surgery often requires mastoid drilling. Sometimes patients develop sensorineural hearing loss after middle ear surgery. Objective of the study was to compare pre and post operative bone conduction thresholds after middle ear surgeries. The study was conducted on 90 patients who had undergone middle ear surgeries, 30 patients of tympanoplasty (group I), modified intact canal wall mastoidectomy and tympanoplasty type-I (group II) and modified radical mastoidectomy (group III) each ware included. Demographic and clinical data were reviewed. Duration of surgery, ossicular and middle ear status and drilling time noted. Pre operative and post operative (after 3-4 months) bone conduction thresholds were compared statistically. A value of p < 0.05 was considered statistical significant. The average pre-operative hearing loss of study group was 43.78 ± 14.22 dB. Though postoperatively mean air conduction threshold improved to 36.07 ± 13.05 dB, six patients presented with deterioration of hearing. Mastoidectomy has been performed in all six. Post-operative worsening of bone conduction was seen in three patients (13.75-21.5 dB), one patient of group II and two patients of group III developed postoperative worsening of bone conduction thresholds. Significant hearing losses may occur after tympanomastoid surgery in few patients. While we are evaluating the results besides reporting average results such individual patient should be identified.


Neurochemical and behavioral analyses of the lateral hypothalamic syndrome: a look back.
Philip Teitelbaum is one of the great physiological psychologists of his generation. His early research clarified key issues regarding the effects of electrolytic lesions of the ventromedial or ventrolateral hypothalamus on food intake in rats, a subject of paramount interest during the 1950s and 1960s. Perhaps best known were his extensive studies of the lateral hypothalamic syndrome in rats, which focused on the complex and changing array of symptoms after experimental brain damage. It soon became clear from later work that his research interests were not in the brain's control of food intake but in the effects of lesions to fragment behavior and thereby allow investigators to view its components. He was the foremost proponent of the use of exquisite behavioral analysis to reveal details in movement that allowed insights into brain function, and that approach - old fashioned physiological psychology made modern and at its finest - has infiltrated the entire field of experimental psychology, including studies of ingestive behavior, even while the new field of behavioral neuroscience emerged. He extended his analytic approach to neurological issues such as autism in humans, a promising arena that fully occupied his attention during the later phases of his career. But his influence on his scientific colleagues went well beyond his careful and powerful thinking; his articles and books have been models of clarity and concision. I write in behalf of a grateful field to salute his many great contributions.


Sleep duration trajectories from adolescence to emerging adulthood: Findings from a population-based birth cohort.
This study aimed to describe longitudinal trajectories of sleep duration, among adolescents and adults from the Pelotas (Brazil) 1993 Birth Cohort, as well as characterize different trajectories groups according to socioeconomic, demographic and behavior characteristics. Sleep duration, hours per day (from Monday to Friday), bedtime and wake-up time were self-reported by participants at ages 11, 18 and 22 years. Covariables included socioeconomic, demographic, health and behavior characteristics. Trajectory analysis was performed using a semi-parametric, group-based modelling approach. Prevalence and 95% confidence interval were obtained to describe covariables and sleep trajectory groups. Chi-square test was employed in statistical analysis and all analyses were stratified by sex. A total of 3.395 individuals were included in the analysis. In both sexes, bedtime became later across years, while wake-up time presented little variation. Differences according sex were more pronounced from 18 years onwards. Three trajectories of sleep duration from 11 to 22 years were identified for males: "increase and maintenance" (3.4%), "fast reduction and maintenance" (45.0%) and "constant reduction" (51.6%). While in females the trajectories identified were: "increase and decrease" (2.4%), "fast reduction and maintenance" (25.6%) and "constant reduction" (72.0%). Men and women who belong to trajectories with longer sleep durations were more likely to present higher percentages of some risk behaviors and poor socioeconomic condition. Our results have provided longitudinal information regarding sleep duration trajectories in a medium-sized city in Brazil, aiming at filling an existing gap in literature from low- and middle-income countries.


[Primary exploration of individual biological boosting target volume for locally advanced nasopharyngeal carcinoma].
To explore the methods of detecting and defining the biological boosting target volume (BBTV) in patients with locally advanced nasopharyngeal carcinoma (NPC). Ten patients with locally advanced NPC treated at our center during September to December 2010 were enrolled. The following factors were used to define and contour BBTV, including dose-deficient area locating at skull-base of gross tumor volume in conventional irradiation, hypoxia area detected by (99m)Tc-HL91 Single-photon emission computed tomography/computed tomography (SPET/CT) imaging and tumor-burdened area evaluated by comparing the pre-treatment and 36 Gy irradiation's CT images scanning at the same treatment position. The volume of BBTV was (17 ± 7) cm(3), accounting for 51% ± 19% of gross tumor volume. In BBTV, the volumes and proportion of skull base dose-deficient, hypoxia and tumor-burdened area were (5.8 ± 2.5) cm(3), (7.7 ± 3.6) cm(3), (9.0 ± 5.8) cm(3) and 34.4%, 45.7% and 53.3% respectively. However, the proportion of overlapping volume between three areas was only 33.1%. BBTV may be composed of skull base dose-deficient, hypoxia and tumor-burdened volume. It provides a new reference for individualized radiotherapy in locally advanced NPC.


IFN-γ secretion of PBMC from non-drug-allergic control persons: Considerations for the validity of a positive lymphocyte transformation test.
The lymphocyte transformation test (LTT) is used for the in vitro detection of a drug sensitization in assumed drug allergic patients. It is based on the detection of antigen (drug)-specific activation of T cells indicated by e.g. proliferation or cytokine secretion. However, occasional stimulatory effects of the drug unrelated to specific drug-allergic mechanisms can only be detected if a larger number of non-drug allergic control persons are tested with this specific drug. In this respect, the overall specificity of the LTT with ELISA read-out is summarized in several review articles, but the impact of a specific drug on the specificity has not yet been analyzed in a larger set of control persons. Do amoxicillin, cefuroxime and clindamycin induce an interferon (IFN)-y or interleukin (IL)-5 secretion of PBMC from control persons using the LTT with ELISA read-out? We performed LTTs with amoxicillin, cefuroxime and clindamycin and determined drug-specific IFN-γ and IL-5 secretion measured by ELISA read-out. We included PBMC from 60 non-drug allergic control persons, who were unexposed to the tested drug at the time of blood donation. PBMC from 12 out of 23 control persons tested with amoxicillin gave a positive stimulation index (SI > 3.0) for IFN-γ resulting in a specificity of 47.8%. The corresponding specificity was 75% for cefuroxime (5/20 if SI > 3.0) and 58.8% for clindamycin (7/17, if SI > 2.0), respectively. In a next step, we calculated the Δ IFN-γ concentration by subtracting the background IFN-γ concentration in the unstimulated sample from the stimulated sample. After stimulation with amoxicillin, a mean concentration of 21.0 pg/mL IFN-γ was secreted. The less outlier prone median concentration was 7.4 pg/mL and much higher than for cefuroxime (1.7 pg/mL) and clindamycin (1.0 pg/mL). Remarkably, IL-5 concentrations were below the detection limit (< 1 pg/mL) for all drugs in all control persons who responded to TT. Consideration of these observations may be helpful since a positive LTT result in a control patient may challenge the validity of a positive LTT result in the same experiment for a patient with assumed drug allergy.


The new synthetic matrix metalloproteinase inhibitor (Roche 28-2653) reduces tumor growth and prolongs survival in a prostate cancer standard rat model.
The therapeutic efficacy of synthetic inhibitors of matrix-metalloproteinases (MMPs) in various cancers has been demonstrated. A novel inhibitor, Ro 28-2653, with high selectivity for MMP2, MMP9 and membrane type 1-MMP was evaluated in an orthotopic prostate cancer rat model. Efficacy was determined by recording tumor growth and survival endpoints. Prostate cancer was induced by inoculating R3327 Dunning tumor cells (MatLyLu) into the ventral lobe of the prostates of 148 Copenhagen rats. Daily oral treatment with Ro 28-2653 (10-300 mg/kg per day) was started on day 1 or on day 6 after tumor cell injection. Animals were sacrificed on day 20 for determination of tumor weights. For survival studies, rats received daily oral Ro 28-2653 (100 mg/kg per day) or vehicle for up to 30 days. Tumor induction was successful in 100% of the animals. Ro 28-2653 reproducibly reduced the tumor weights by up to 90% in a dose-dependent manner. In addition, an inhibitory effect in rats with established tumors (treatment start at day 6) was shown. A significantly prolonged survival of Ro 28-2653-treated rats was also demonstrated. Selective inhibition of MMP activity is a novel therapeutic approach, which bears promise for studies in patients with prostate cancer.


Differential effects of gemfibrozil on migration, proliferation and proteoglycan production in human vascular smooth muscle cells.
The aim of this study was to determine, if gemfibrozil has anti-atherogenic actions on human vascular smooth muscle cells (SMCs) and whether these actions are affected by high glucose concentrations, which mimic the hyperglycemia of diabetes. Proliferation of SMCs treated with gemfibrozil was estimated by cell counting (Coulter Counter) and [3H]thymidine incorporation, migration in a scrape-wound assay, proteoglycan (PG) biosynthesis and glycosaminoglycan (GAG) synthesis on xyloside by [35S]sulfate labeling and sizing by sodium dodecyl sulphide-polyacrylamide gel electrophoresis (SDS-PAGE). Gemfibrozil (100 micromol/l) did not affect migration in low or high glucose media. Gemfibrozil caused concentration-dependent inhibition of proliferation in low glucose media (24% inhibition at 100 micromol/l, P<0.01) and inhibited the re-initiation of DNA synthesis by 33.3% (100 micromol/l, P<0.05) in low glucose and 31.4% (100 micromol/l, P<0.001) in high glucose conditions. In low and high glucose media, gemfibrozil (100 micromol/l) reduced total PG production in the presence of TGF-beta 1, which was associated with a decrease in the apparent size of PGs. Gemfibrozil and another PPAR-alpha ligand, WY-14643, significantly inhibited basal and TGF-beta1 stimulated GAG synthesis. We conclude that some SMCs properties associated with atherogenesis are favorably affected by gemfibrozil. Hence, direct vascular actions of gemfibrozil observed in this study may contribute to the reduction in cardiovascular disease observed in clinical studies with gemfibrozil.


Altered metabolic function of the pulmonary microcirculation. Early detection of lung injury and possible functional significance.
The normal lung is the site of intense metabolic activity, largely associated with the endothelial cell. Depressed pulmonary metabolic function is seen in a wide variety of experimental animal models of acute lung injury, and is also demonstrated in ARDS patients. The evaluation of lung metabolic activity may prove to be a sensitive probe for the detection of the earliest phases of acute lung injury, as well as a guide to the severity of injury or response to therapy. Depressed lung metabolic function may play a role in the intrapulmonary and/or systemic pathophysiology of ARDS.


Superoxide scavenging and antimicrobial activities of novel transition metal complexes of oxydiacetate dianion as primary ligand: spectral characterization, cyclic voltammetric investigations and crystal structure.
Complexes of stoichiometries [M(oda)(4-pic)H(2)O]·xH(2)O [M = Cu(1), x = 2; Co (2), x = 4; Ni (3), x = 2; ] [Fe(oda)(4-pic)]·Cl (4) and {[Cu(2-pa)(2)]·2H(2)O}(n) (5) (H(2)oda = oxydiacetic acid, 4-pic = 4-picoline and 2-paH = 2-picolinic acid) were prepared to explore their uses as possible models for mono- and poly-nuclear metallo-pharmaceuticals. The chemical structures were elucidated by IR, FAB-Mass, (1)H, (13)C NMR, EPR and UV-visible (ligand field) spectral analyses. Electrochemical investigations are consistent with formation of stable quasi-reversible redox Co(II/III) and Cu(II/III) couples in the solution. Single crystal X-ray data of the complex (5) indicated a 1D coordination polymeric structure with extensive H-bonding to form supramolecular frameworks. The antimicrobial activities were examined against Escherichia coli (k-12), Bacillus subtilis (MTC-121), Staphylococcus aureus (IOASA-22), Salmonella typhimurium (MTCC-98), Candida albicans, Aspergillus fumigatus and Penicillium marneffei. The superoxide dismutase (SOD) activities of the Cu(II) complexes (1 and 5) were assessed employing nitrobluetetrazolium (NBT) assay.


Detection of asymptomatic recurrence following curative surgery improves survival in patients with gastric cancer: A systematic review and meta-analysis.
To date, there is no evidence that intensive follow-up provides survival benefit in gastric cancer patients undergoing curative gastrectomy. The aim of this study is to investigate the efficacy of detection of asymptomatic recurrence using intensive surveillance strategy in long-term survival after curative gastric cancer surgery. A systematic review of electronic databases including PubMed, Embase, Web of Science, the Cochrane Library and China National Knowledge Infrastructure, Clinical Trials Registry and Google Scholar was performed up to April 2022. The primary outcomes were survival outcomes: overall survival, recurrence-free survival and post-recurrence survival. The secondary endpoints were clinicopathological features, recurrence patterns and treatment after recurrence. The registration number of this protocol is PROSPERO CRD42022327370. A total of 11 studies including 1898 participants were included. In the pooled analysis, the detection of asymptomatic recurrence was significantly associated with an improved overall survival compared to patients showing symptoms of recurrence (HR=0.67; 95%CI: 0.57-0.79; P<0.001), which was primarily driven by the prolongation of post-recurrence survival (HR=0.51; 95%CI: 0.42-0.61; P<0.001), since there was no significant difference observed in recurrence-free survival (HR=1.12; 95%CI: 0.81-1.55; P=0.48) between the two groups. Meanwhile, male sex and advanced T stage were more frequently observed in the symptomatic recurrence group. Furthermore, patients in the symptomatic recurrence group had a higher proportion of peritoneal relapse but lower proportion of distant lymph node metastasis. Additionally, patients in the symptomatic recurrence group were less likely to receive surgery treatment and post-recurrence chemotherapy. The detection of asymptomatic recurrence using intensive follow-up was associated with an appreciable improvement in overall survival. However, more robust data from high-quality studies are still required to verify this issue. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=327370, identifier CRD42022327370.


Release of rRNA from liver nuclei during the early stages of the acute-phase reaction.
Liver nuclei isolated from rats 5 h after turpentine injection show an increased release of rRNA, of the transport-related nucleoside-triphosphatase activity and of the amount of nuclear RNA; RNA methylation is also likely to undergo some activation. These changes occur when RNA synthesis is still normal.


Predictors of false negative diffusion-weighted MRI in clinically suspected central cause of vertigo.
Vertigo is classified as peripheral and central. Differentiation of stroke mimics is the most important diagnostic challenge. There is no clinical guidance for the indications of neuroimaging in isolated vertigo patients. The primary aim of this study is to test the diagnostic value of a DWI-MRI protocol to rule-out a central cause in patients with acute isolated vertigo in the ED. We prospectively enrolled 144 patients who were presented with isolated vertigo to the ED. A detailed neurological examination and maneuvers were performed for differential diagnosis. All patients underwent CT and/or DW-MRI either during ED visit or at the follow-up, if necessary. Out-patient follow-up exams and evaluations were repeated until all patients had a definitive diagnosis. In the study, 137 of the 144 patients completed the follow-up period, and 34 of 137 patients were diagnosed with central vertigo. Six of 34 central vertigo patients had normal DW-MRI findings. One was diagnosed with migraine headache and five with vertebra-basilar insufficiency during the out-patient follow-up. One of the 28 patients with a pathological MRI was diagnosed with mass and the rest was stroke. The utility of DW-MRI in vertigo patients was moderately high (sensitivity: 82%, specificity: 100%). We found that age, history of HT, history of CAD and vertigo unresponsive to ED treatment were significantly associated with a central cause of vertigo. We suggest that unresponsiveness to ED treatment, especially in patients with a history of HT and CAD, should alert physicians for central causes and warrant DW-MRI imaging.


[Intramuscular injections in children].
Intramuscular injections are still part of routine care in the treatment of children. Vaccines, premedications and analgesics are administered by this route. The pain associated with an intramuscular injection is severe, the risk of complications is increased, and pharmacodynamics and pharmacokinetics are unpredictable. In many cases, equivalent alternatives of rectal, oral or intranasal routes of administering pharmacologic agents exist. Intramuscular injection of analgesics and premedications to children are-except in case of emergencies-obsolete. This demand corresponds to the guidelines of the World Health Organization (WHO) and the International Association for the Study of Pain (IASP).


Antigen presentation by proliferating thymic macrophages to A (T,G)-A-L specific T cell line in an H-2 restricted manner.
Long-term cultures of murine homogeneous populations of Ia-bearing thymus-derived murine macrophages were tested for their ability to present antigen to a (T,G)-A-L specific IL-2-dependent continuous T cell line. Thymus-derived macrophages, with and without pretreatment for Ia induction, triggered efficiently antigen-specific T cell proliferation in an MHC restricted way. This experimental system, consisting of two normal proliferating homogeneous populations of macrophages and antigen specific T cells, provides an ideal tool for studying the mechanism of antigen presentation to T cells and for elucidation of the role of macrophages in T-B cell collaboration for antibody production.


Radiocarpal dislocation: A retrospective study of 14 patients.
Radiocarpal dislocation (RCD) is defined as total loss of contact between the carpal and radial joint surfaces. The condition is rare, with few published series. The aim of the present study was to assess functional results of RCD surgery, notably without ligament reconstruction. Functional outcome of RCD surgery is satisfactory for everyday use of the wrist. A retrospective study was performed for the period January 2012 to July 2017. Inclusion criteria comprised: RCD on preoperative X-ray, in adult patients, with a minimum 6months' follow-up; exclusion criteria comprised: unclosed growth plate, and distal radial epiphyseal fracture with large displacement. RCD type was assessed on Dumontier's classification. Functional results were assessed as postoperative range of wrist motion, grip strength (Jamar®), and QuickDASH and Green-O'Brien (modified by Cooney) functional scores. Fourteen patients were followed up at a mean 31months (range, 7-60months). Three showed type I RCD and 11 type II. All were treated surgically; no ligament sutures were performed. Mean flexion was 63° (range, 20-90°), extension 51° (25-90°), pronation 79° (60-90), supination 80° (50-90), and grip strength 27.9kg (8-40). Mean QuickDASH and modified Green-O'Brien scores were respectively 25.6 (4.54-40.9) and 74 (35-100). The present functional results were satisfactory and comparable to those of the literature, despite no use of radiocarpal ligament suture in type-1 RCD. IV.


Pain chronification impacts whole-brain functional connectivity in women with hip osteoarthritis during pain stimulation.
Previous neuroimaging studies have shown that patients with chronic pain display altered functional connectivity across distributed brain areas involved in the processing of nociceptive stimuli. The aim of the present study was to investigate how pain chronification modulates whole-brain functional connectivity during evoked clinical and tonic pain. Patients with osteoarthritis of the hip (n = 87) were classified into 3 stages of pain chronification (Grades I-III, Mainz Pain Staging System). Electroencephalograms were recorded during 3 conditions: baseline, evoked clinical hip pain, and tonic cold pain (cold pressor test). The effects of both factors (recording condition and pain chronification stage) on the phase-lag index, as a measure of neuronal connectivity, were examined for different frequency bands. In women, we found increasing functional connectivity in the low-frequency range (delta, 0.5-4 Hz) across pain chronification stages during evoked clinical hip pain and tonic cold pain stimulation. In men, elevated functional connectivity in the delta frequency range was observed in only the tonic cold pain condition. Across pain chronification stages, we found that widespread cortical networks increase their synchronization of delta oscillations in response to clinical and experimental nociceptive stimuli. In view of previous studies relating delta oscillations to salience detection and other basic motivational processes, our results hint at these mechanisms playing an important role in pain chronification, mainly in women.


Underutilization of Radial Access in Patients Undergoing Percutaneous Coronary Intervention for ST-Segment-Elevation Myocardial Infarction: Insights From the Blue Cross Blue Shield of Michigan Cardiovascular Consortium.
The purpose of this study was to evaluate the frequency and temporal trends in use of transradial access (TRA) for percutaneous coronary intervention (PCI) in ST-segment-elevation myocardial infarction (STEMI). The use of TRA has been associated with less bleeding and improved clinical outcomes in patients undergoing PCI for STEMI. The frequency of TRA compared with transfemoral access for patients undergoing PCI for STEMI or other indications (non-ST-segment-elevation myocardial infarction, unstable angina, and non-acute coronary syndrome) in The Blue Cross Blue Shield of Michigan Cardiovascular Consortium database between 2010 and 2013 was evaluated. Propensity matching was used to assess the relationship of TRA with in-hospital clinical end points of major bleeding, transfusion, and death. The TRA cohort of patients was stratified into deciles based on their predicted bleeding risk and compared with PCI indication. Of 122,728 PCI procedures, 17,912 (14.6%) were via TRA. Among patients with STEMI cases, 8.3% of the PCI cases were performed via TRA. The use of TRA increased over the study period although the growth was slower for STEMI than for other indications, P<0.001. The use of TRA for PCI in STEMI was associated with a lower rate of bleeding (11.7% versus 20.0%; P<0.001) and vascular complications (0.7% versus 2.6%; P=0.001), but no mortality difference (1.25% versus 2.33%; P=0.175). There was a strong negative association between the predicted risk of bleeding and the use of TRA (P<0.001). The use of radial access for PCI in STEMI is increasing but at a slower pace than for patients with other indications. TRA was associated with a reduction in bleeding and transfusion, but there is a strong negative correlation between the predicted risk of bleeding and actual use of TRA in STEMI.


Generation of a human induced pluripotent stem cell line from a patient diagnosed with schizophrenia carrying a 16p11.2 deletion.
16p11.2 copy number variations have been associated with neurodevelopmental disorders. Human induced pluripotent stem cells were generated from fibroblasts obtained from a patient diagnosed with schizophrenia with a 16p11.2 deletion. The generated cell line was further validated for its pluripotency and potential to differentiate into the three germ layers.


Hydroxyethylcellulose-graft-poly (N,N-dimethylacrylamide) copolymer as a multifunctional separation medium for CE.
A new multifunctional separation medium, hydroxyethylcellulose-graft-poly (N,N-dimethylacrylamide) copolymer synthesized in our laboratory for application in both basic protein separation and dsDNA separation by CE, is presented in this paper. As a noncovalent coating, this medium showed a powerful capability in resisting basic protein adsorption. Highly efficient and rapid protein separation had been obtained at four different pH values. Meanwhile, the 11 fragments of the dsDNA sample could be baseline separated using this grafted copolymer as sieving matrix at an appropriate concentration.


[The stepchild of intestinal diagnosis. Evaluation of radiologic methods in the diagnosis of leiomyoma of the small intestine].
Various radiological methods to diagnose small bowel neoplasms and problems of differential diagnosis specially considering leiomyomas are discussed. Two patients with leiomyoma of the ileum underwent enteroclysis, computed tomography of the abdomen, intra-arterial DSA and colour Doppler sonography. Another patient with leiomyosarcoma just underwent CT of the abdomen with CT-guided biopsy. Due to the homogenous density and the smooth surface of the tumors in computed tomography and respectively enteroclysis and the presentation of the tumor vascularisation in the angiography and Colour Doppler sonography in both patients a leiomyoma of the small bowel was diagnosed. Postoperatively this diagnosis was histologically confirmed. The CT-findings of the patient with leiomyosarcoma were not suspicious of a malignant tumor. Radiologically it is not possible to determine the dignity of smooth muscle cell tumors safely. That is the reason why the diagnosis has to be achieved operatively. But the histopathological diagnosis based on the mitotic rate may be difficult. Therefore the after care has to be carried out thoroughly.


Hitting the Ground Running in 2022: A New Face and a Renewed Commitment From the JOSPT Editorial Board.
This month, we welcome Dr Jackie Whittaker, PT, PhD, to the role of JOSPT Editor. Dr Whittaker joins Dr Joshua Cleland, Dr Bryan Heiderscheit, Dr Steven Kamper, Dr Christopher Hughes, and Dr Clare Ardern on the senior editorial team of JOSPT. J Orthop Sports Phys Ther 2022;52(1):1-2. doi:10.2519/jospt.2022.0101.


Asymptotic adaptive output feedback event-triggered control of uncertain strict-feedback nonlinear systems with sensors triggering.
In this paper, event-triggered output feedback control of a class of high-order nonlinear strict-feedback systems with parametric uncertainties is investigated, in which both of the controller and the parameter estimator are triggered based on a set of event-triggered conditions. Firstly a new one-step control design framework is proposed for the strict-feedback nonlinear systems, therefore both expressions of the controller and the parameter estimate laws are much more simple than those of the recursive design approaches such as backstepping control. Secondly observers are designed to estimate the unknown states, and a set of event-triggering mechanism is proposed for the sensors such that the states are transmitted through the communication network only at the triggering points. The estimated parameter is obtained without real-time integration due to the event-triggered estimator. It is proved that our proposed control law guarantees the closed-loop system is globally bounded and the system output converges to zero asymptotically. It is also proved that the Zeno behavior is excluded. Simulation results demonstrate the effectiveness of the proposed control scheme.


The automatic implantable cardioverter-defibrillator in drug-refractory ventricular tachyarrhythmias.
To assess the efficacy of the automatic implantable cardioverter-defibrillator in preventing sudden death in high-risk patients. Nonrandomized cohort study. A university teaching hospital with 500 beds. Consecutive sample of 78 patients with symptomatic, sustained ventricular tachyarrhythmias that were previously drug-refractory. Before February 1985, patients received treatment with the defibrillator and amiodarone if they presented with loss of consciousness (group A) and amiodarone alone if they did not lose consciousness (group C). After February 1985, because the availability of the defibrillator was severely curtailed, patients who lost consciousness received treatment with amiodarone alone (group B). The risk for recurrent arrhythmias was similar between groups. The actuarial risk for sudden death in group B was 31% (95% confidence interval, 11% to 51%) at 1 and 2 years, a value that was significantly higher than that for group A (p less than 0.003) or group C (p less than 0.03). The risk for dying suddenly with the first recurrence was 0.78 in group B, a value that was significantly higher than that for group A (p less than 0.003) or group C (p less than 0.002). The defibrillator is highly effective in preventing sudden death in patients whose presenting arrhythmias caused loss of consciousness (group A). In patients whose presenting arrhythmias did not result in loss of consciousness (group C), initial treatment with the defibrillator appears unnecessary.


Effect of cytokines on Japanese encephalitis virus production by human monocytes.
Japanese encephalitis (JE) virus was shown to grow in in vitro cultures of human monocytes. Interferon (IFN)-alpha and IFN-gamma inhibited JE virus production by the infected monocytes in the absence of anti-JE virus antibody, but interleukin (IL)-1 alpha, IL-2, IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte-CSF (G-CSF), and tumor necrosis factor (TNF)-alpha did not show a significant inhibition. Antibody against JE virus increased the JE virus production by the infected monocytes probably by enhanced uptake of virus-antibody complexes via Fc receptors. IFN-gamma and GM-CSF increased JE virus production by monocytes in the presence of anti-JE virus antibody, whereas IFN-alpha inhibited JE virus production even in the presence of the antibody. The other 5 cytokines (IL-1 alpha, IL-2, IL-3, G-CSF, and TNF-alpha) did not show a significant effect on JE virus production by monocytes in the presence or absence of the antibody.


Pharmacokinetics and Safety of Ferric Pyrophosphate Citrate in Chinese Subjects with and without Hemodialysis-Dependent Stage 5 Chronic Kidney Disease.
Anemia caused by iron depletion is common in patients with hemodialysis-dependent stage 5 chronic kidney disease (CKD-5HD) patients. To maintain the iron levels, external administration of iron is essential. Ferric pyrophosphate citrate (FPC) is a novel, water-soluble complex iron salt. The present study was conducted to evaluate the pharmacokinetic (PK) parameters and safety of FPC in adult healthy Chinese subjects and patients with CKD-5HD. Two open-label, single-center studies were conducted in healthy subjects and patients with CKD-5HD. Healthy subjects received a single intravenous dose of 6.5 mg FPC solution, while CKD-5HD patients were randomized to two different sequences of FPC administration at two sequential hemodialysis (HD) treatments (dose 1 and dose 2). Patients received 27.2 mg of FPC at a dialysate concentration of 95 μg/L for 4 h or a single 6.5 mg dose of FPC administered intravenously via the pre-dialyzer blood circuit. The primary objective was to determine the PK parameters of total serum iron (Fetot), while the secondary objective was the safety of the FPC solution. PK parameters were calculated using Phoenix WinNonlin 8.1 and other parameters were analyzed using SAS 9.4 software. Comparison between HD dose 2 and HD dose 1 was performed using the Wilcoxon rank-sum test and analysis of variance (ANOVA). A total of 14 healthy subjects with a mean age of 30.8 ± 5.92 years and 12 HD patients with a mean age of 54.3 ± 16.47 years were included. In healthy subjects, the peak serum concentration was reached at the end of infusion of FPC, with an adjusted mean maximum concentration (Cmax,) of 33.46 ± 4.83 μmol/L at a mean time to reach Cmax (Tmax) of 4.09 ± 0.19 h. In patients with CKD-5HD, the adjusted mean Cmax of HD dose 2 was 25.37 ± 4.30 μmol/L at a Tmax, of 3.09 ± 0.32 h, whereas the Cmax, of HD dose 1 was 24.59 ± 4.77 μmol/L at a Tmax, of 3.96 ± 0.26 h. The Fetot concentration-time curves were observed to be similar for both administration methods (HD doses 1 and 2), while the PK parameters differed significantly for Tmax (p = 0.001; baseline correction) and area under the concentration-time curve from time zero to time t (AUCt) [p = 0.031 for cycle variance; without baseline correction] between HD doses 1 and 2. The geometric mean ratios (HD dose 1/HD dose 2) for Cmax and AUCt were within the 85-125% range (Cmax 96.56%; AUCt 96.07%). A total of three and two incidences of adverse events were reported in healthy subjects and patients with CKD-5HD, respectively. FPC showed a good PK and safety profile and hence can be used as maintenance therapy for patients with CKD-5HD by choosing a better method of administration based on clinical feasibility and requirement. CTR20181113 and CTR20181119.


A novel fate and transport model for evaluating the presence and environmental risk of per-/poly-fluoroalkyl substances (PFASs) among multi-media in Lingang hybrid constructed wetland, Tianjin, China.
Accurately revealing and predicting the presence and risks of per-/poly-fluoroalkyl substances (PFASs) in constructed wetlands (CWs) is great significant for the construction and management of CWs, but very challenging. In this work, a novel fate and transport model was for the first time established to evaluate the spatially continuous distribution and environmental risks of PFASs among multi-media in Lingang hybrid CW fed by industry tailwater. 20 PFASs were detected from the Lingang CW, and the total concentration of the detected PFASs in water and sediments were in the range of 38.94-81.65 ng/L and 1.23-4.31 ng/g, respectively. PFOA, PFOS and PFBS were the main pollutants in water and sediments. A fate and transport model describing the distribution characteristics and fate of PFASs in Lingang hybrid CW was constructed, and its reliability was verified. The simulated results suggested that PFASs were mainly accumulated in sediments and long-chain PFASs were more easily adsorbed by sediments compared with short-chain PFASs. According to the principal component analysis-multiple linear regression (PCA-MLR), PFASs mainly came from the tailwater from the surrounding sewage treatment plants. Besides, the environmental risks were predicted by this novel model, suggesting that the risks still cannot be neglected due to the accumulation and continuous input of PFASs although the environmental risks of Lingang CW were low. This work provides a novel model for the understanding of presence and risks of PFASs among multi-media in CWs.


Depolymerization of lignosulfonates by submerged cultures of the basidiomycete Irpex consors and cloning of a putative versatile peroxidase.
Lignosulfonates are abundantly available byproducts of the paper and pulping industry, and they therefore represent a promising feedstock for new sustainable processes. For industrial applications of lignosulfonates, their molecular weight distribution is a critical factor. In order to decrease the average molecular weight of lignosulfonates, Seventeen basidiomycetes were screened for their capability to depolymerize lignosulfonates from spent sulfite liquor (SSL) in surface and liquid cultures. Five basidiomycetes polymerized the lignosulfonates under the selected conditions. Only Irpex consors was found to efficiently degrade calcium lignosulfonates when SSL (0.5%, w/w) was used as the sole carbon and nitrogen source. The average molecular weight of the lignosulfonates was reduced from ∼26 to ∼4 kDa as determined by size exclusion chromatography (SEC) within two weeks. Various extracellular enzyme activities of I. consors were determined over the culture period. High peroxidase activities were correlating with a high degradation rate and the culture was harvested at the day of highest peroxidase activity. A putative versatile peroxidase was isolated by fast protein liquid chromatography (FPLC) and its encoding cDNA was cloned.


Real-time in-depth imaging of gap formation in bulk-fill resin composites.
This study visualized in real-time the gap forming of bulk-fill resin composites during polymerization using optical coherence tomography (OCT). Light-cured bulk-fill resin composites; Tetric N-ceram Bulk Fill (TNB), SonicFill (SNF), Surefil SDR (SDR), dual-cured bulk-fill resin composite Bulk EZ (BEZ), and light-cured core resin composite Clearfil Photo Core (CPC) were investigated. Swept-source OCT real-time cross-sectional monitoring was obtained during resin composite placement and curing procedure. Gap formation was observed in bonded cylindrical resin composite molds (4-mm depth, 3-mm diameter) and free shrinkage volume was observed at the top and bottom of a tube with similar dimensions (n=10). OCT 3D data were analyzed to calculate sealing floor area percentage (SFA%) and volumetric shrinkage in bonded tube (VS%). Data were analyzed by ANOVA at significance level of 0.05. The bottom-top degree of conversion ratio (DC%-R) through 4-mm depth was measured using the XploRA Plus micro-Raman spectroscopy. BEZ showed no gap formation at the cavity floor in any specimens while SNF showed the highest gap formation; the statistical order in terms of SFA% was BEZ (100±0)>TNB (84.97±2.98)>CPC (52.13±8.23)=SDR (45.97±9.21)>SNF (16.23±6.00) (p<0.05). On the other hand, total VS% was statistically ordered as BEZ (3.40±0.14)>SDR (3.22±0.09)>TNB (1.82±0.11)>SNF (1.65±0.04)=CPC (1.56±0.04) (p<0.05). Unlike BEZ, the light-cured resin composites showed larger shrinkage at specimen bottom than top. TNB showed the lowest DC%-R followed by SNF (p<0.05). Light-cured bulk-fill resin composites showed various degrees of gap formation and shrinkage at 4-mm deep cavity. The dual-cured bulk-filled resin composite showed no decrease of degree of conversion through the depth and the highest cavity adaptation despite its tendency for higher volumetric shrinkage.


SK channel activation potentiates auranofin-induced cell death in glio- and neuroblastoma cells.
Brain tumours are among the deadliest tumours being highly resistant to currently available therapies. The proliferative behaviour of gliomas is strongly influenced by ion channel activity. Small-conductance calcium-activated potassium (SK/KCa) channels are a family of ion channels that are associated with cell proliferation and cell survival. A combined treatment of classical anti-cancer agents and pharmacological SK channel modulators has not been addressed yet. We used the gold-derivative auranofin to induce cancer cell death by targeting thioredoxin reductases in combination with CyPPA to activate SK channels in neuro- and glioblastoma cells. Combined treatment with auranofin and CyPPA induced massive mitochondrial damage and potentiated auranofin-induced toxicity in neuroblastoma cells in vitro. In particular, mitochondrial integrity, respiration and associated energy generation were impaired. These findings were recapitulated in patient-derived glioblastoma neurospheres yet not observed in non-cancerous HT22 cells. Taken together, integrating auranofin and SK channel openers to affect mitochondrial health was identified as a promising strategy to increase the effectiveness of anti-cancer agents and potentially overcome resistance.


DNA methylation influences the CTCF-modulated transcription of RASSF1A in lung cancer cells.
Ras-association domain family 1A (RASSF1A) is one of the most methylated genes in lung cancer (LC). We investigate whether the high DNA methylation level of RASSF1A can relieve the resistance of RASSF1A to LC by inhibiting RASSF1A's transcription factor binding to RASSF1A. RASSF1A expression in tissues and cells was tested utilizing quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot. RASSF1A expression and RASSF1A methylation level in LC cells exposed to 5-Aza-dc were assessed by qRT-PCR and quantitative methylation-specific PCR. The association between CTCF and RASSF1A was assessed using hTFtarget, ChIP, and luciferase reporter gene analysis. The effects of 5-Aza-dc, CTCF, and RASSF1A on cell biological behaviors and epithelial-mesenchymal transition (EMT)-related markers were assessed by cell function experiments and Western blot. Moreover, we constructed the xenograft tumor and pulmonary nodule metastasis models, and assessed tumor volume and weight. RASSF1A expression and pulmonary nodule metastasis were tested utilizing qRT-PCR, Western blot, and H&E staining. RASSF1A was under-expressed in LC tissues and cells. 5-Aza-dc enhanced RASSF1A level and weakened RASSF1A methylation level in LC cells. RASSF1A silencing neutralized 5-Aza-dc-mediated repressing effects on LC cell biological function and EMT. The loss of CTCF binding to RASSF1A in LC cells was associated with DNA methylation. The effect of 5-Aza-dc on RASSF1A level, LC cell malignant behaviors, and EMT-related factors were strengthened by CTCF upregulation. RASSF1A overexpression suppressed LC tumor growth and pulmonary nodule metastasis in vivo. DNA methylation blocked the modulation of RASSF1A expression by CTCF and relieved the resistance of RASSF1A to LC.


Polysaccharides of Grifola frondosa ameliorate oxidative stress and hypercholesterolaemia in hamsters fed a high-fat, high-cholesterol diet.
This study was to evaluate the antioxidant and anti-hypercholesterolaemia activities of Grifola frondosa in hamsters fed a high-fat, high-cholesterol (HFHC) diet. G. frondosa, including fruiting bodies (FGF), fermented mycelia (MGF) and polysaccharides extracted from fruiting bodies (FPS), fermented mycelia (MIP) and fermented broth (BEP) were received intragastrically. Lipid profile and antioxidant status in the blood and liver of hamsters were assessed. FGF decreased weight gain, serum triglycerides and cholesterol and increased hepatic mRNA expression of cholesterol-7α-hydroxylase expression. FGF, MGF, FPS and MIP decreased the HFHC diet-increased area under the curve (AUC) of serum cholesterol. FGF and FPS further decreased AUC of serum triglycerides. When evaluating the redox status of erythrocytes, FPS and MIP increased non-protein sulfhydryl (NP-SH) groups, reduced glutathione (GSH) and catalase activity and FPS further increased GSH peroxidase activity. In the liver, MGF increased NP-SH groups and GSH and decreased triglycerides content. FPS, MIP and BEP decreased oxidized GSH and triglycerides content. Moreover, all treatments alleviated HFHC diet-increased LDL oxidation. Fruiting bodies of G. frondosa may improve hypercholesterolaemia via increased bile acid synthesis. Additionally, fermented biomass and polysaccharides of G. frondosa may have the potential to prevent hepatic lipid accumulation.


Appendectomy by residents is safe and not associated with a higher incidence of complications: a retrospective cohort study.
The purpose of this retrospective cohort study was to investigate whether current practice where residents perform appendectomies affects quality of care. Therefore, we investigated whether there was a difference in incidence of complications and mortality in appendectomies performed by surgeons (S), supervised residents (SR), or unsupervised residents (UR). Appendicitis is among the most frequent conditions requiring urgent surgery. Admittance and surgery are often managed by residents. Recent studies have shown that laparoscopic appendectomy can be safely performed by residents. It is not known whether these results are applicable on appendectomies in general. All patients undergoing appendectomy in our hospital between January 1, 2000, and December 31, 2009, were included in the analysis. Patients undergoing appendectomy by surgeons, supervised residents, and unsupervised residents were compared. Primary endpoints were complications and mortality. During the study period, 1538 patients were operated. The risk of complications (S: 20% vs SR: 17% vs UR: 16%; P = 0.209, S vs SR; P = 0.149, S vs UR; and P = 0.872, SR vs UR) and mortality (S: 0.3% vs SR: 0.2% vs UR: 0.4%, P = 1.000 for all comparisons) were similar in all groups. In the multivariate model, the odds ratio for complications in the group operated by supervised residents was 0.84 (95% CI: 0.58-1.22, P = 0.357) versus 0.81 (95% CI: 0.55-1.18, P = 0.265) in the unsupervised residents' group. Current practice where residents perform appendectomies either unsupervised or supervised by an experienced surgeon should not be discouraged. We found that it is safe and does not lead to more complications or negatively affect quality of care.


Ten years' experience of antenatal mean corpuscular volume screening and prenatal diagnosis for thalassaemias in Hong Kong.
To determine the prevalence of thalassaemia carriers in Hong Kong. From 1988 to 1997, 25,834 (53.7%) of 48,089 mothers were screened for thalassaemias by mean corpuscular volume (MCV) at the first antenatal visit. In the screened population of 25,834, 2229 (8.6%) had MCV < or = 75 fl. Of these, 1121 (4.3%) were alpha-thal, 715 (2.8%) were beta-thal, 23 (0.1%) were alpha beta-thal, 57 (0.2%) were other haemoglobin variants, and 281 (1.1%) had either iron deficiency or uncertain causes. Out of 200 pregnancies at risk for homozygous alpha-thal-1 and 32 at risk for beta-thal major, 27 homozygous alpha-thal-1 and 7 beta-thal major were identified, compared favourably with the expected figures of 23 and 9. Antenatal screening for thalassaemias by MCV is simple, effective and reliable. Universal screening has a different impact as bone marrow or cord blood stem cell transplant provides cure for beta-thal major. At risk couples have, as an alternative to termination of pregnancy, the option of early detection and treatment for their affected newborns or fetuses.


Image quality and radiation dose of a prospectively electrocardiography-triggered high-pitch data acquisition strategy for coronary CT angiography: The multicenter, randomized PROTECTION IV study.
Concerns have been raised about radiation dose of coronary CT angiography. Although high-pitch acquisition technique yields high potential for radiation dose savings, it is more vulnerable to artifacts, which impair diagnostic image quality. The purpose of this study was to compare 2 scan strategies for coronary CT angiography: a high-pitch helical scan first or a conventional scan first strategy. In this prospective, multicenter trial, we randomized 303 consecutive patients with a low and stable heart rate to either of the aforementioned mentioned strategies. Intravenous β-blockers were administered to achieve target heart rates. All scans were performed on a second-generation dual-source CT scanner. In case of nondiagnostic image quality, coronary CT angiography was allowed to be repeated. The primary end point was to demonstrate noninferior image quality in the high-pitch group. Image quality was assessed on a 4-point scale (1: nondiagnostic, 4: excellent). Secondary end point was total radiation dose. In the high-pitch helical first group, repeat scanning was necessary in 21 patients compared with 14 patients in the conventional first scan group (P = .25). Image quality in the high-pitch group was noninferior compared to the conventional scan group (3.81 ± 0.35 vs. 3.83 ± 0.37; P for noninferiority <.0001). The total effective radiation dose estimate was 58% lower in the high-pitch group (2.0 ± 2.4 vs. 4.7 ± 4.8 mSv; P < .0001). In patients with a low and stable heart rate diagnostic image quality can be maintained with a high-pitch helical scan first strategy while 58% of radiation dose can be saved.


Synthesis of a bicyclobutane fatty acid identified from the cyanobacterium Anabaena PCC 7120.
By design: a carbanion-mediated cyclization reaction cascade serves as the key final step in the total synthesis of a novel oxylipin, which features a strained bicyclo[1.1.0]butane conjugated to a labile vinyl epoxide.


Improving treatment and survival: a population-based study of current outcomes after a hepatic resection in patients with metastatic colorectal cancer.
Population-based studies historically report underutilization of a resection in patients with colorectal metastases to the liver. Recent data suggest limitations of the methods in the historical analysis. The present study examines trends in a hepatic resection and survival among Medicare recipients with hepatic metastases. Medicare recipients with incident colorectal cancer diagnosed between 1991 and 2009 were identified in the SEER(Surveillance, Epidemiology and End Results)-Medicare dataset. Patients were stratified into historical (1991-2001) and current (2002-2009) cohorts. Analyses compared treatment, peri-operative outcomes and survival. Of 31.574 patients with metastatic colorectal cancer to the liver, 14,859 were in the current cohort treated after 2002 and 16,715 comprised the historical control group. The overall proportion treated with a hepatic resection increased significantly during the study period (P < 0.001) with pre/post change from 6.5% pre-2002 to 7.5% currently (P < 0.001). Over time, haemorrhagic and infectious complications declined (both P ≤ 0.047), but 30-day mortality was similar (3.5% versus 3.9%, P = 0.660). After adjusting for predictors of survival, the use of a hepatic resection [hazard ratio (HR) = 0.40, 95% confidence interval (CI): 0.38-0.42, P < 0.001] and treatment after 2002 (HR = 0.88, 95% CI: 0.86-0.90, P < 0.001) were associated with a reduced risk of death. Case identification using International Classification of Diseases, 9th Revision (ICD-9) codes is imperfect; however, comparison of trends over time suggests an improvement in multimodality therapy and survival in patients with colorectal metastases to the liver.


Acute cardiac tamponade secondary to nonpenetrating injury from gunshot with beanbag round: A case report and literature review.
Over the past twenty years, "less-lethal" munitions have caused a variety of significant, life-threatening injuries. However, evidence of blunt cardiac injury due to these weapons is sparse. A healthy 44-year old man presented with hemodynamic instability due to cardiac tamponade after he was shot with a beanbag, ultimately requiring operative intervention. This case report describes a unique clinical presentation of blunt cardiac injury and the diagnostic and therapeutic steps that the trauma surgery team took to appropriately manage this rare injury.


Extended inheritance from an organizational point of view.
In this paper, I argue that the increasing data about non-genetic inheritance requires the construction of a new conceptual framework that should complement the inclusive approaches already discussed in the literature. More precisely, I hold that this framework should be epistemologically relevant for evolutionary biologists in capturing the limits of extended inheritance and in reassessing the boundaries of biological systems that transmit traits to their offspring. I outline the first elements of an organizational account of extended inheritance. In this account, the category of inherited factors is neither restricted to genes nor extended to stable resources related to trans-generational similarities. Instead, it includes persisting constitutive elements appearing as difference makers for heterogeneous organizational constraints, namely for heterogeneous constitutive parts whose specific role is to harness flows of matter and energy across generations of clearly delimited extended organized systems. This both inclusive and restrictive framework opens an additional way to apprehend how extended inheritance may affect evolutionary trajectories.


Inhibition of osteoclasts differentiation by CDC2-induced NFATc1 phosphorylation.
Bone homeostasis is regulated by a balance of bone formation and bone resorption; dysregulation of bone homeostasis may cause bone-related diseases (e.g., osteoporosis, osteopetrosis, bone fracture). Members of the nuclear factor of activated T cells (NFAT) family of transcription factors play crucial roles in the regulation of immune system, inflammatory responses, cardiac formation, skeletal muscle development, and bone homeostasis. Of these, NFATc1 is a key transcription factor mediating osteoclast differentiation, which is regulated by phosphorylation by distinct NFAT kinases including casein kinase 1 (CK1), glycogen synthase kinase 3 (GSK3), and dual-specificity tyrosine-phosphorylation-regulated kinases (DYRKs). In this study, we report that cell division control protein 2 homolog (cdc2) is a novel NFAT protein kinase that inhibits NFATc1 activation by direct phosphorylation of the NFATc1 S263 residue. Cdc2 inhibitors such as Roscovitine and BMI-1026 induce reduction of phosphorylation of NFATc1, and this process leads to the inhibition of NFATc1 translocation from the nucleus to the cytoplasm, consequently increasing the nuclear pool of NFATc1. Additionally, the inhibition of cdc2-mediated NFATc1 phosphorylation causes an elevation of osteoclast differentiation or TRAP-positive staining in zebrafish scales. Our results suggest that cdc2 is a novel NFAT protein kinase that negatively regulates osteoclast differentiation.


Radionuclides in shoreline waters of the northeast Irish Sea.
The shoreline waters of the Irish Sea along the Cumbrian coast near the British Nuclear Fuels plc works at Sellafield have been sampled at three locations over a 31/2 year period from December 1980. The particulate content was analysed for 238Pu, 239 + 240Pu, 241Am, 137Cs and stable Al. In some cases the radionuclide concentrations in filtered seawater were also determined. The results showed that the suspended particulate loads were high (typically about 100 mg l-1) and variable, and that they contained about 65 mg g-1 of aluminium. The isotopic ratio 238Pu/239 + 240Pu, which can indicate the chronology of the discharge, was about 0.26, which suggested that the Sellafield discharges over at least 5 years contributed to the observed concentrations. The 239 + 240Pu and 241Am annual average concentrations in the particulate material were in the ranges 3.0-5.1 and 3.3-5.2 Bq g-1, respectively. The individual values were very variable in time, but highly correlated with each other. No significant downward trends in the concentrations could be identified over this period. This is consistent with the behaviour of a reservoir (the northeast Irish Sea) where Pu and Am, which are available for suspension in particulate material, are fed by the Sellafield discharges and are subject to a mean removal time of several years. Thus the effects of the large reduction in the Sellafield discharges which occurred over this period should only be observable over a longer time interval. The concentrations in the dissolved fractions in seawater were negligible compared with the particulate fraction concentrations, in sharp contrast with the situation in offshore seawater.(ABSTRACT TRUNCATED AT 250 WORDS)


Involvement of FATP2-mediated tubular lipid metabolic reprogramming in renal fibrogenesis.
Following a chronic insult, renal tubular epithelial cells (TECs) contribute to the development of kidney fibrosis through dysregulated lipid metabolism that lead to lipid accumulation and lipotoxicity. Intracellular lipid metabolism is tightly controlled by fatty acids (FAs) uptake, oxidation, lipogenesis, and lipolysis. Although it is widely accepted that impaired fatty acids oxidation (FAO) play a crucial role in renal fibrosis progression, other lipid metabolic pathways, especially FAs uptake, has not been investigated in fibrotic kidney. In this study, we aim to explore the potential mechanically role of FAs transporter in the pathogenesis of renal fibrosis. In the present study, the unbiased gene expression studies showed that fatty acid transporter 2 (FATP2) was one of the predominant expressed FAs transport in TECs and its expression was tightly associated with the decline of renal function. Treatment of unilateral ureteral obstruction (UUO) kidneys and TGF-β induced TECs with FATP2 inhibitor (FATP2i) lipofermata restored the FAO activities and alleviated fibrotic responses both in vivo and in vitro. Moreover, the expression of profibrotic cytokines including TGF-β, connective tissue growth factor (CTGF), fibroblast growth factor (FGF), and platelet-derived growth factor subunit B (PDGFB) were all decreased in FATP2i-treated UUO kidneys. Mechanically, FATP2i can effectively attenuate cell apoptosis and endoplasmic reticulum (ER) stress induced by TGF-β treatment in cultured TECs. Taking together, these findings reveal that FATP2 elicits a profibrotic response to renal interstitial fibrosis by inducing lipid metabolic reprogramming including abnormal FAs uptake and defective FAO in TECs.


Thalidomide analogs and PDE4 inhibition.
N-Phthaloyl 3-amino-3-arylpropionic acid analogs of thalidomide that are potent inhibitors of tumor necrosis factor-alpha are reported. These compounds were found to be potent inhibitors of phosphodiesterase 4.


Cost-Utility Analysis of Nivolumab in Adjuvant Treatment of Melanoma in France.
The aim of the current study is to estimate the cost-effectiveness of adjuvant treatment with nivolumab relative to clinically relevant comparators in adult patients with melanoma with lymph node involvement or metastatic disease who have undergone complete resection from a French societal perspective. The comparators were observation, low-dose interferon and pembrolizumab. A subgroup analysis was carried out in patients with BRAF mutation, adding dabrafenib plus trametinib. A three-state partitioned survival model was developed to project costs and health benefits over a 20-year time horizon. Extrapolation for recurrence-free survival (RFS) and overall survival (OS) was carried out using spline-based models. Because of the immaturity of OS data in pivotal trials for nivolumab and pembrolizumab, a predictive model of OS treatment effect based on RFS effect was developed using a correlation equation. Health state utilities and adverse events disutilities were derived from the CheckMate 238 trial and literature. Costs were estimated in 2019 euros. The model's primary outcome was efficiency frontier. Deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of results. Observation, low-dose interferon and nivolumab were on the efficiency frontier. The incremental cost-utility ratio of nivolumab versus low-dose interferon (closest therapy on the efficiency frontier) was €37,886/quality-adjusted life year (QALY). Probabilistic sensitivity analysis reported an 80% probability of nivolumab being a cost-effective strategy for a willingness-to-pay threshold of €52,000/QALY. In the subgroup with BRAF mutation, the efficiency frontier was not changed by the addition of dabrafenib plus trametinib. Nivolumab is a cost-effective strategy as adjuvant treatment in adult patients with surgically resected melanoma in France.


Evidence-Based Guideline for the diagnosis and management of eosinophilic granulomatosis with polyangiitis.
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, characterized by asthma, eosinophilia and granulomatous or vasculitic involvement of several organs. The diagnosis and management of EGPA are often challenging and require an integrated, multidisciplinary approach. Current practice relies on recommendations and guidelines addressing the management of ANCA-associated vasculitis and not specifically developed for EGPA. Here, we present evidence-based, cross-discipline guidelines for the diagnosis and management of EGPA that reflect the substantial advances that have been made in the past few years in understanding the pathogenesis, clinical subphenotypes and differential diagnosis of the disease, as well as the availability of new treatment options. Developed by a panel of European experts on the basis of literature reviews and, where appropriate, expert opinion, the 16 statements and five overarching principles cover the diagnosis and staging, treatment, outcome and follow-up of EGPA. These recommendations are primarily intended to be used by healthcare professionals, pharmaceutical industries and drug regulatory authorities, to guide clinical practice and decision-making in EGPA. These guidelines are not intended to limit access to medications by healthcare agencies, nor to impose a fixed order on medication use.


Expression pattern of inositol phosphate-related enzymes in rice (Oryza sativa L.): implications for the phytic acid biosynthetic pathway.
Phytic acid, myo-inositol-hexakisphosphate (InsP(6)), is a storage form of phosphorus in plants. Despite many physiological investigations of phytic acid accumulation and storage, little is known at the molecular level about its biosynthetic pathway in plants. Recent work has suggested two pathways. One is an inositol lipid-independent pathway that occurs through the sequential phosphorylation of 1D-myo-inositol 3-phosphate (Ins(3)P). The second is a phospholipase C (PLC)-mediated pathway, in which inositol 1,4,5-tris-phosphate (Ins(1,4,5)P(3)) is sequentially phosphorylated to InsP(6). We identified 12 genes from rice (Oryza sativa L.) that code for the enzymes that may be involved in the metabolism of inositol phosphates. These enzymes include 1D-myo-inositol 3-phosphate synthase (MIPS), inositol monophosphatase (IMP), inositol 1,4,5-tris-phosphate kinase/inositol polyphosphate kinase (IPK2), inositol 1,3,4,5,6-pentakisphosphate 2-kinase (IPK1), and inositol 1,3,4-triskisphosphate 5/6-kinase (ITP5/6K). The quantification of absolute amounts of mRNA by real-time RT-PCR revealed the unique expression patterns of these genes. Outstanding up-regulation of the four genes, a MIPS, an IPK1, and two ITP5/6Ks in embryos, suggested that they play a significant role in phytic acid biosynthesis and that the lipid-independent pathway was mainly active in developing seeds. On the other hand, the up-regulation of a MIPS, an IMP, an IPK2, and an ITP5/6K in anthers suggested that a PLC-mediated pathway was active in addition to a lipid-independent pathway in the anthers.


Twenty-four-hour patterns in human performance, subjective and physiological variables and differences between morning and evening active subjects.
A study was undertaken to investigate differences between habitually morning active and evening active subjects as regards 24-hr patterns in physiological and subjective arousal and performance efficiency under conditions of 72 hr of sleep deprivation. The results were that very consistent 24-hr rhythmic were present in some of the performance variables, subjective alertness, oral temperature and urinary adrenaline excretion. No significant differences in 24-hr patterns could be detected between a group of habitually morning active and a group of evening active subjects. Significant correlations were obtained between oral temperature and some of the performance measures, while adrenaline excretion was not significantly correlated with performance. There were rather high correlations between subjective alertness ratings and some of the performances.


[Surgical disconnection of hypothalamic hamartomas].
Surgical resection of hypothalamic hamartomas (HHs) associated with drug-resistant gelastic epilepsy carries a considerable risk of neurological and endocrine morbidity. Alternative surgical routes and techniques have therefore been proposed, especially for broadly attached lesions and for those with a third ventricular location. We present an updated series of 43 patients (aged nine months to 34 years), operated on from 1998 through 2005 at our institution. The hamartoma was disconnected using a microsurgical pterional approach of those lesions extending from the hypothalamic floor downward into the interpeduncular cistern. When the HH presented as a paramedian mass, partly or exclusively bulging into the third ventricle, with a rather vertical plane of attachment, we chose a frameless stereotactic endoscopic technique to disconnect the lesion. In several of our patients, both methods were applied subsequently. Surgery-related morbidity was lower with the ventricular endoscopic technique. Twenty-one patients (50%) are seizure-free and two patients (5%) almost seizure-free, while in 17 patients (40%), there was a significant seizure reduction. Two patients (5%) had no postoperative improvement. According to the different topographic features of the HHs, for which we have recently proposed a classification into four subtypes, the intraventricularly located hamartoma had the best prognosis following endoscopic disconnection. Ten of the 12 patients (83%) with this HH location became seizure-free. Resection of epilepsy-related HHs can be replaced by disconnective procedures. Our results confirm their feasibility and acceptable morbidity, with particularly good seizure outcome in patients with intraventricularly located HHs.


A journey from phosphotyrosine to phosphohistidine and beyond.
Protein phosphorylation is a reversible post-translational modification. Nine of the 20 natural amino acids in proteins can be phosphorylated, but most of what we know about the roles of protein phosphorylation has come from studies of serine, threonine, and tyrosine phosphorylation. Much less is understood about the phosphorylation of histidine, lysine, arginine, cysteine, aspartate, and glutamate, so-called non-canonical phosphorylations. Phosphohistidine (pHis) was discovered 60 years ago as a mitochondrial enzyme intermediate; since then, evidence for the existence of histidine kinases and phosphohistidine phosphatases has emerged, together with examples where protein function is regulated by reversible histidine phosphorylation. pHis is chemically unstable and has thus been challenging to study. However, the recent development of tools for studying pHis has accelerated our understanding of the multifaceted functions of histidine phosphorylation, revealing a large number of proteins that are phosphorylated on histidine and implicating pHis in a wide range of cellular processes.


Control of Ostertagia ostertagi infections in Australia.
The control of Ostertagia ostertagi infections in Australia is aimed specifically at young cattle in their first and second year of grazing after weaning. Mature breeding stock are not routinely treated. The recommended strategy is preventive, using an integrated approach of timed anthelmintic treatments in relation to the epidemiology of ostertagiasis in different environments. Best results are obtained when treatments, given at weaning and 6 months later, are combined with a move to 'safe' pastures which have not been grazed by cattle for the previous 6 months. Good results are also obtained in the winter rainfall regions when set-stocked cattle are treated before and during autumn to prevent contamination of pastures at this time. More complicated grazing management, involving the spelling of pastures during autumn and winter, combined with anthelmintic treatments, is needed in some summer rainfall regions where weather conditions are especially favourable for the development and survival of the free-living stages of O. ostertagi.


[A follow-up study on transcatheter closure of patent ductus arteriosus with Amplatzer duct occluder in children].
To document the five-year follow-up results of transcatheter Amplatzer duct occluder (ADO) occlusion of patent ductus arteriosus (PDA) in children and to assess the safety and effectiveness of this method for PDA closure. A retrospective cohort study was completed in patients with PDA underwent transcatheter closure by the ADO in Guangdong Cardiovascular Institute from April 1998 to December 2003. Transcatheter closure of PDA with ADO was attempted in 250 children patients. The median age was 5.3 years and median weight was 15.1 kg. The PDAs were from 1.8 mm to 11.0 mm (median 4.2 mm) in the narrowest diameter, of which 52 were larger than 5 mm (20.0%). All PDAs were occluded with 4 approximately 14 mm ADO through 6F (n = 205) or 7F (n = 45) sheaths. Devices were successfully implanted in 245 patients (98.0%). The Qp/Qs decreased from 1.90 +/- 0.60 to 1.03 +/- 0.21 (P < 0.05). All shapes of the PDA could be closed. Late complication occurred in five patients, including hemolysis in three patients and the los of the pulse of femoral artery in two patients. Follow-up after device implantation was accomplished in 205 patients (82.0%). The incidence of residual shunt at follow-up periods of 1 d, 1 m, 6 m, 12 m, 24 m, 36 m, 48m and 60 m after device occlusion was 9.2%, 2.8%, 1.2%, 0.8%, 0, 0, 0 and 0, respectively. Five patients (2.0%) required re-intervention to treat residual shunt with or without hemolysis. Event-free rates were 98.0% at one year and five years. This long-term follow-up result confirmed the safety and effectiveness of ADO closure of PDAs in children.


Design and Reporting Characteristics of Clinical Trials of Select Chronic and Recurrent Pediatric Pain Conditions: An Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks Systematic Review.
Fewer randomized clinical trials (RCTs) are conducted for chronic or recurrent pain in pediatric populations compared with adult populations; thus, data to support treatment efficacy in children are limited. This article evaluates the design features and reporting practices of RCTs for chronic and recurrent pain that are likely unique to, or particularly important in, a pediatric population to promote improvements in the evidence base for pediatric pain treatments. Areas covered include outcome measure selection and reporting and reporting of adverse events and challenges to recruitment and retention. A search of PubMed and EMBASE identified primary publications describing RCTs of treatments for select chronic and recurrent pain conditions in children or adolescents published between 2000 and 2017. Only 49% of articles identified a primary outcome measure. The primary outcome measure assessed pain intensity in 38% of the trials, specifically measure by verbal rating scale (13%), faces pain scale (11%), visual analogue scale (9%), or numeric rating scale (5%). All of the CONSORT harms reporting recommendations were fulfilled by <50% of the articles. Discussions of recruitment challenges occurred in 64% of articles that enrolled <90% of their target sample. However, discussions regarding retention challenges only occurred in 14% of trials in which withdrawal rates were >10%. The goal of this article is to promote comprehensive reporting of pediatric pain RCTs to improve the design of future trials, facilitate conduction of systematic reviews and meta-analyses, and better inform clinical practice. PERSPECTIVE: This review of chronic and recurrent pediatric pain trials demonstrates inadequacies in the reporting quality of key features specifically important to pediatric populations. It provides recommendations that address these shortcomings to promote continued efforts toward improving the quality of the design and publication of future pediatric clinical pain trials.


Selenium and sulindac are synergistic to inhibit intestinal tumorigenesis in Apc/p21 mice.
Both selenium and non-steroidal anti-inflammatory drug (NSAID) sulindac are effective in cancer prevention, but their effects are affected by several factors including epigenetic alterations and gene expression. The current study was designed to determine the effects of the combination of selenium and sulindac on tumor inhibition and the underlying mechanisms. We fed the intestinal tumor model Apc/p21 mice with selenium- and sulindac-supplemented diet for 24 weeks, and found that the combination of selenium and sulindac significantly inhibited intestinal tumorigenesis, in terms of reducing tumor incidence by 52% and tumor multiplicities by 80% (p<0.01). Mechanistic studies revealed that the combination of selenium and sulindac led to the significant induction of the expression of p27 and p53 and JNK1 phosphorylation, and led to the suppression of β-catenin and its downstream targets. Impressively, the data also showed that demythelation on p21 promoter was associated with tumor inhibition by the combination of selenium and sulindac. The selenium is synergistic with sulindac to exert maximal effects on tumor inhibition. This finding provides an important chemopreventive strategy using combination of anti-cancer agents, which has a great impact on cancer prevention and has a promising translational potential.