The in vitro antiosteoporotic activity of some glycosides in Dioscorea spongiosa.
In the investigation of chemical constituents in antiosteoporotic active fraction, 90% ethanol fraction of water extract of the rhizomes of Dioscorea spongiosa, twenty-two glycosides were isolated and their structures were elucidated. In order to know the role of each compound played in the fraction and to find the excellent antiosteoporotic constituent, they were subjected to some in vitro assay experiments with cell lines and an animal organ culture system: stimulation on osteoblasts proliferation and mineralization, inhibition on osteoclasts formation and inhibition on bone resorption. Glycosides 1, 3, 4, 7, 8, 9, 10, 12, 13, 14, 16, 17, 18, 19 and 21 showed significant stimulatory activity on proliferation of osteoblasts. Especially, pregnane glycoside 4, showed the strongest stimulatory activity. The stimulatory activity on osteoblasts mineralization of the compounds stimulating the proliferation significantly was examined and compounds 8, 10, 13 and 16 showed stronger stimulation on osteoblasts mineralization. Their inhibitory activity on bone resorption indicated that only glycosides 5, 13, 14 and 21 possessed significant inhibitory activity at high concentration. Glycosides 9, 11, 14, 18 and 19, isolated in large amount, all showed very strong inhibitory activity on formation of osteoclasts at high concentration, which may be induced by cytotoxicity to bone marrow cells and osteoblasts due to the observation under microscope. It implied that their inhibition on bone resorption may origin from their inhibition on formation of osteoclasts.


Failure mode and effects analysis of skin electronic brachytherapy using Esteya® unit.
Esteya® (Nucletron, an Elekta company, Elekta AB, Stockholm, Sweden) is an electronic brachytherapy device used for skin cancer lesion treatment. In order to establish an adequate level of quality of treatment, a risk analysis of the Esteya treatment process has been done, following the methodology proposed by the TG-100 guidelines of the American Association of Physicists in Medicine (AAPM). A multidisciplinary team familiar with the treatment process was formed. This team developed a process map (PM) outlining the stages, through which a patient passed when subjected to the Esteya treatment. They identified potential failure modes (FM) and each individual FM was assessed for the severity (S), frequency of occurrence (O), and lack of detection (D). A list of existing quality management tools was developed and the FMs were consensually reevaluated. Finally, the FMs were ranked according to their risk priority number (RPN) and their S. 146 FMs were identified, 106 of which had RPN ≥ 50 and 30 had S ≥ 7. After introducing the quality management tools, only 21 FMs had RPN ≥ 50. The importance of ensuring contact between the applicator and the surface of the patient's skin was emphasized, so the setup was reviewed by a second individual before each treatment session with periodic quality control to ensure stability of the applicator pressure. Some of the essential quality management tools are already being implemented in the installation are the simple templates for reproducible positioning of skin applicators, that help marking the treatment area and positioning of X-ray tube. New quality management tools have been established as a result of the application of the failure modes and effects analysis (FMEA) treatment. However, periodic update of the FMEA process is necessary, since clinical experience has suggested occurring of further new possible potential failure modes.


Different inter-annual responses to availability and form of nitrogen explain species coexistence in an alpine meadow community after release from grazing.
Plant species and functional groups in nitrogen (N) limited communities may coexist through strong eco-physiological niche differentiation, leading to idiosyncratic responses to multiple nutrition and disturbance regimes. Very little is known about how such responses depend on the availability of N in different chemical forms. Here we hypothesize that idiosyncratic year-to-year responses of plant functional groups to availability and form of nitrogen explain species coexistence in an alpine meadow community after release from grazing. We conducted a 6 year N addition experiment in an alpine meadow on the Tibetan Plateau released from grazing by livestock. The experimental design featured three N forms (ammonium, nitrate, and ammonium nitrate), crossed with three levels of N supply rates (0.375, 1.500 and 7.500 g N m-2 yr-1 ), with unfertilized treatments without and with light grazing as controls. All treatments showed increasing productivity and decreasing species richness after cessation of grazing and these responses were stronger at higher N rates. Although N forms did not affect aboveground biomass at community level, different functional groups did show different responses to N chemical form and supply rate and these responses varied from year to year. In support of our hypothesis, these idiosyncratic responses seemed to enable a substantial diversity and biomass of sedges, forbs, and legumes to still coexist with the increasingly productive grasses in the absence of grazing, at least at low and intermediate N availability regimes. This study provides direct field-based evidence in support of the hypothesis that idiosyncratic and annually varying responses to both N quantity and quality may be a key driver of community structure and species coexistence. This finding has important implications for the diversity and functioning of other ecosystems with spatial and temporal variation in available N quantity and quality as related to changing atmospheric N deposition, land-use, and climate-induced soil warming.


Dietary fat, hypothalamic glutamate decarboxylase, and food intake of streptozotocin-diabetic rats.
The association among changes in glucose status, glutamate decarboxylase (GAD) activity, and food intake was evaluated in several hypothalamic areas of streptozotocin-diabetic rats fed a low- (12% of calories as fat) or high-fat diet (59% of calories as fat). Control rats consumed approximately 90 kcal/24 h of either diet, whereas diabetic rats consumed approximately 150 kcal/24 h of the low-fat diet and approximately 100 kcal/24 h of the high-fat diet. At the end of the study, diabetic rats fed the high-fat diet weighed more and had higher retroperitoneal fat depot weights (P less than 0.05) than diabetic rats fed the low-fat diet. In diabetic rats, GAD activity was 15-20% higher in the ventromedial nucleus (P less than 0.01) but similar to controls in the lateral hypothalamus, paraventricular nucleus, and area postrema. Diet did not affect GAD activity in the brain areas studied. The increase in ventromedial nucleus GAD activity was not associated with the level of food intake and was the likely result of altered glucose homeostasis in diabetic rats.


A comparison of cytochrome P450-dependent testosterone 2alpha-hydroxylase in rat (P4502C11) and mouse (P4502alpha).
Hepatic P450 2C11 in the rat and P450(2alpha) in the mouse are unique in being the only isoforms in their respective species with testosterone 2alpha-hydroxylase activity. Comparing gender differences, tissue distribution and physicochemical properties, we investigated whether this uncommon catalytic activity shared by the two isoforms is dependent upon a high degree of homology. Using additional substrates (e.g. androstenedione, hexobarbital), we observed that P450(2alpha) and P450 2C11 produced no metabolites in common. Moreover, concentrations of antisera prepared against purified P450(2alpha) that inhibited 95% of P450(2alpha)-dependent testosterone 2alpha-hydroxylase activity had only a minimal inhibitory effect (< 20%) on P450 2C11-dependent testosterone 2alpha-hydroxylase and were similarly unreactive to the rat isoform isolated on Western blots. Comparison of the isoforms' N-terminal amino acid residues and two internal peptide fragments indicated almost no sequence homology (< 4%). Gender-dependent tissue expression levels of P450(2alpha) and P450 2C11 revealed additional dichotomies. Whereas hepatic P450(2alpha) was moderately female-predominant (M/F; 0.62), hepatic P450 2C11 was clearly male-specific (M/F; 32.9). Murine P450(2alpha) mRNA was equally and substantially expressed in liver, kidney and brain; by contrast earlier studies reported that rat P450 2C11 was exclusively expressed in liver. The present results indicate that the unique testosterone 2alpha-hydroxylase activities of P450(2alpha) and P450 2C11 are expressed by two very different proteins exhibiting minimal homology.


Cortical localization of a calcium release channel in sea urchin eggs.
We have used an antibody against the ryanodine receptor/calcium release channel of skeletal muscle sarcoplasmic reticulum to localize a calcium release channel in sea urchin eggs. The calcium release channel is present in less than 20% of immature oocytes, where it does not demonstrate a specific cytoplasmic localization, while it is confined to the cortex of all mature eggs examined. This is in contrast to the cortical and subcortical localization of calsequestrin in mature and immature eggs. Immunolocalization of the calcium release channel reveals a cortical reticulum or honeycomb staining network that surrounds cortical granules and is associated with the plasma membrane. The network consists of some immunoreactive electron-dense material coating small vesicles and elongate cisternae of the endoplasmic reticulum. The fluorescent reticular staining pattern is lost when egg cortices are treated with agents known to affect sarcoplasmic reticulum calcium release and induce cortical granule exocytosis (ryanodine, calcium, A-23187, and caffeine). An approximately 380-kD protein of sea urchin egg cortices is identified by immunoblot analysis with the ryanodine receptor antibody. These results demonstrate: (a) the presence of a ryanodine-sensitive calcium release channel that is located within the sea urchin egg cortex; (b) an altered calcium release channel staining pattern as a result of treatments that initiate the cortical granule reaction; and (c) a spatial and functional dichotomy of the ER which may be important in serving different roles in the mobilization of calcium at fertilization.


The twin arginine protein transport pathway exports multiple virulence proteins in the plant pathogen Streptomyces scabies.
Summary Streptomyces scabies is one of a group of organisms that causes the economically important disease potato scab. Analysis of the S. scabies genome sequence indicates that it is likely to secrete many proteins via the twin arginine protein transport (Tat) pathway, including several proteins whose coding sequences may have been acquired through horizontal gene transfer and share a common ancestor with proteins in other plant pathogens. Inactivation of the S. scabies Tat pathway resulted in pleiotropic phenotypes including slower growth rate and increased permeability of the cell envelope. Comparison of the extracellular proteome of the wild type and DeltatatC strains identified 73 predicted secretory proteins that were present in reduced amounts in the tatC mutant strain, and 47 Tat substrates were verified using a Tat reporter assay. The DeltatatC strain was almost completely avirulent on Arabidopsis seedlings and was delayed in attaching to the root tip relative to the wild-type strain. Genes encoding 14 candidate Tat substrates were individually inactivated, and seven of these mutants were reduced in virulence compared with the wild-type strain. We conclude that the Tat pathway secretes multiple proteins that are required for full virulence.


Clinical and imaging outcomes of cerebrospinal fluid-venous fistula embolization.
We report outcomes of spontaneous intracranial hypotension (SIH) patients who underwent transvenous embolization of cerebrospinal fluid-venous fistulas (CSFVFs) confirmed on digital subtraction myelography (DSM) performed at our institution. This is a retrospective evaluation of a prospectively collected database of SIH patients who underwent transvenous embolization of CSFVFs. Only patients who had fistulas confirmed on DSM performed at our institution were included. All patients had a baseline MRI and an MRI performed at least 90 days post-embolization, as well as clinical evaluation using the six item Headache Impact Test (HIT-6) and the Patient Global Impression of Change (PGIC) scales. Paired t-test was used to report changes in Bern MRI scores and HIT-6 scores at follow-up. 40 patients were included (29 female, 11 male). Mean age was 57.4±10.3 years. Mean Bern score improved from 5.7±3.0 at baseline to 1.3±2.0 at follow-up (p<0.0001). Mean HIT-6 score at baseline was 67.2±11.1 and at follow-up was 41.5±10.1 (p<0.0001). Median PGIC was 1, with 36 patients (90.0%) reporting at least minimal improvement and 32 patients (82.5%) reporting much or very much improvement. Complications included persistent local site pain in 12 patients (30%), suspected rebound intracranial hypertension requiring medical intervention in 7 patients (17.5%), and asymptomatic tiny Onyx emboli to the lungs in 3 patients (7.5%). Transvenous embolization of CSFVFs using Onyx is safe and effective, resulting in significant improvement in headache and overall clinical outcomes in nearly 90% of patients, and substantial improvements in brain MRI abnormalities.


Inheritance of human plasma dopamine-beta-hydroxylase thermal stability.
Although the structural gene for human dopamine-beta-hydroxylase (DBH) has been cloned, the mechanism by which DBH physical properties and activity are regulated is not well understood. Previous reports have suggested that three-allele or two-locus models may account for the genetic regulation of these traits in human blood. It is an interesting challenge to determine the extent to which quantitative analyses will complement or guide molecular genetic studies. In this study we analyzed data on the physical property of DBH thermal stability and DBH activity in 230 individuals in 53 families in an attempt to clarify genetic mechanisms for the inheritance of these traits. Commingling and segregation analyses of the thermal stability data provided the first clear evidence of a major gene polymorphism for DBH thermal stability analyzed as a quantitative trait. Major gene transmission was supported within a mixed model (chi 2[3] = 13.39, P less than .004). In keeping with earlier findings, similar analyses of DBH activity provided strong evidence of genetic transmission. However, in our data support for a major gene polymorphism was equivocal (chi 2(2) = 2.99, P = .22).


Hyperbaric oxygen therapy for treatment of adverse radiation effects after stereotactic radiosurgery of arteriovenous malformations: case report and review of literature.
Adverse radiation effects are a known complication after the use of SRS for AVMs, although it is difficult to predict which patients will manifest with these side effects. Treatment of swelling due to ARE is usually medical, but refractory cases may require surgical decompression. This report presents a case of a patient who experienced AREs after SRS (edema, headaches, and nausea) that failed to respond to steroid treatment but was successfully treated with HBO. The treatment characteristics of this and of 5 other cases of radiation injury after SRS for AVM managed with HBO therapy are reviewed, and the pathophysiology is discussed. Hyperbaric oxygen therapy provides a therapeutic option to treat AREs following SRS of cerebral AVMs.


Hysteroscopic and laparoscopic management of caesarean scar (niche) defects in symptomatic patients.
Worldwide, rates of caesarean section are rising. The term 'niche' describes the presence of an hypoechoic area within the myometrium of the lower uterine segment, reflecting a discontinuation of the myometrium at the site of a previous caesarean section. A defect in caesarean section scar is associated with symptoms like abnormal uterine bleeding, infertility and complications in subsequent pregnancy including: risk of rupture and morbidly adherent placenta. It can also increase rates of complications during gynaecological procedures: IUCD insertion, evacuation of retained products of conception, hysteroscopy and risk of ectopic pregnancy at scar site. To assess the use of surgical techniques to repair niche defects in symptomatic patients, with regards to operative complications, symptomatic relief, postop lower segment thickness and fertility. Patients were identified between August 2015-March 2017. Patients who had one previous caesarean section, symptomatic i.e. abnormal uterine bleeding, dysmenorrhoea, dyspareunia, infertility. Asymptomatic patients. No previous caesarean section. Between August 2015 and March 2017, six patients underwent surgical management of niche defect. Four patients reported post menstrual bleeding, one patient had infertility and one had intermenstrual bleeding and dyspareunia. All patients had one caesarean section previously. Mean lower segment measurement preoperatively was 2.5 mm ± 1.6 mm. EBL intraoperatively was 130 ml (10-180 ml). Mean operating time was 90 mins (70-150 min). One patient was pregnant after niche repair and delivered by CS at 38 w. In all six cases, TVS in 3-5 months after surgery revealed restored lower segment to normal thickness 9.2 mm ± 1.8 mm. Symptom resolution was noted in all patients. There were no operative complications. Anterior uterine wall should be explored in the case of symptomatic patients with previous caesarean section scar. Hysteroscopic resection should not be proposed when RMT is <3 mm. Laparoscopic/vaginal repair allows restoration of the anatomy of the lower uterine segment when residual myometrium is <3 mm. Laparoscopic repair allows antefixation in cases of retroverted uterus. Consideration of a surgical approach should be determined by the patient's plans for fertility and by niche thickness. For women who do not desire pregnancy and whose niche thickness is >3 mm, a hysteroscopic approach should be considered. Women with symptomatic caesarean scar defects who do not desire fertility may also be candidates for hysterectomy. Patients who desire future fertility, especially those with <3 mm of myometrium at the niche site, should undergo laparoscopic resection.


The endogenous calcium ions of horseradish peroxidase C are required to maintain the functional nonplanarity of the heme.
Horseradish peroxidase C (HRPC) binds 2 mol calcium per mol of enzyme with binding sites located distal and proximal to the heme group. The effect of calcium depletion on the conformation of the heme was investigated by combining polarized resonance Raman dispersion spectroscopy with normal coordinate structural decomposition analysis of the hemes extracted from models of Ca(2+)-bound and Ca(2+)-depleted HRPC generated and equilibrated using molecular dynamics simulations. Results show that calcium removal causes reorientation of heme pocket residues. We propose that these rearrangements significantly affect both the in-plane and out-of-plane deformations of the heme. Analysis of the experimental depolarization ratios are clearly consistent with increased B(1g)- and B(2g)-type distortions in the Ca(2+)-depleted species while the normal coordinate structural decomposition results are indicative of increased planarity for the heme of Ca(2+)-depleted HRPC and of significant changes in the relative contributions of three of the six lowest frequency deformations. Most noteworthy is the decrease of the strong saddling deformation that is typical of all peroxidases, and an increase in ruffling. Our results confirm previous work proposing that calcium is required to maintain the structural integrity of the heme in that we show that the preferred geometry for catalysis is lost upon calcium depletion.


Perceptual auditory aftereffects on voice identity using brief vowel stimuli.
Humans can identify individuals from their voice, suggesting the existence of a perceptual representation of voice identity. We used perceptual aftereffects--shifts in perceived stimulus quality after brief exposure to a repeated adaptor stimulus--to further investigate the representation of voice identity in two experiments. Healthy adult listeners were familiarized with several voices until they reached a recognition criterion. They were then tested on identification tasks that used vowel stimuli generated by morphing between the different identities, presented either in isolation (baseline) or following short exposure to different types of voice adaptors (adaptation). Experiment 1 showed that adaptation to a given voice induced categorization shifts away from that adaptor's identity even when the adaptors consisted of vowels different from the probe stimuli. Moreover, original voices and caricatures resulted in comparable aftereffects, ruling out an explanation of identity aftereffects in terms of adaptation to low-level features. In Experiment 2, we show that adaptors with a disrupted configuration, i.e., altered fundamental frequency or formant frequencies, failed to produce perceptual aftereffects showing the importance of the preserved configuration of these acoustical cues in the representation of voices. These two experiments indicate a high-level, dynamic representation of voice identity based on the combination of several lower-level acoustical features into a specific voice configuration.


Central nervous system prophylaxis in diffuse large B-cell lymphoma.
Central nervous system (CNS) involvement with diffuse large B-cell lymphoma (DLBCL) is a relatively uncommon manifestation; with most cases of CNS involvement occuring during relapse after primary therapy. CNS dissemination typically occurs early in the disease course and is most likely present subclinically at the time of diagnosis in many patients who later relapse in the CNS. CNS relapse in these patients is associated with poor outcomes. Based on a CNS relapse rate of 5% in DLBCL and weighing the benefits against the toxicities, universal application of CNS prophylaxis is not justified. The introduction of rituximab has significantly reduced the incidence of CNS relapse in DLBCL. Different studies have employed other agents for CNS prophylaxis, such as intrathecal chemotherapy and high-dose systemic agents with sufficient CNS penetration. If CNS prophylaxis is to be given, it should be preferably administered during primary chemotherapy. However, there is no strong evidence that supports any single approach for CNS prophylaxis. In this review, we outline different strategies of administering CNS prophylaxis in DLBCL patients reported in literature and discuss their advantages and drawbacks.


Loco-regional treatment of hepatocellular carcinoma in the era of molecular targeted therapies.
The treatment of hepatocellular carcinoma (HCC) is rapidly evolving as developments in loco-regional therapies continue to improve. Image-guided radiofrequency (RF) ablation is established as the treatment of choice for patients with early-stage HCC when transplantation or resection are precluded. Recent refinements in technique have substantially increased the ability of RF ablation to achieve sustained complete response of target tumors in properly selected patients, and new alternate thermal and non-thermal methods for local tumor treatment are currently under investigation. Transarterial chemoembolization (TACE) is the standard of care for patients with multinodular disease at the intermediate stage. The introduction of drug-eluting beads--that enhance drug delivery to the tumor and reduce systemic exposure--appears to improve anticancer activity and the safety profile of TACE compared to conventional regimens. Despite these advances, the long-term outcomes of patients treated with loco-regional therapies remain unsatisfactory because of the high rate of tumor recurrence. The introduction of molecular targeted therapies that inhibit tumor proliferation and angiogenesis has opened new prospects in this regard. Clinical trials focused on combining interventional treatment with systemically active drugs are ongoing. The outcomes of such studies are eagerly awaited, as they have the potential to revolutionize treatment of HCC.


Diuretic-induced ventricular ectopic activity.
The need to avoid hypokalemia during diuretic therapy in nondigitalized patients has been questioned. Twenty-one patients with (1) mild essential hypertension, (2) plasma potassium of less than 3.5 meq/liter during previous diuretic treatment, and (3) normal findings [less than 6 unifocal ventricular premature beats/hour] on 24-hour ambulatory electrocardiographic monitoring and exercise testing were treated with hydrochlorothiazide (50 mg twice a day) for four weeks and then ambulatory electrocardiographic monitoring and exercise testing were repeated. Ambulatory electrocardiographic monitoring revealed that ventricular ectopic activity developed in seven patients and complex ventricular ectopic activity (multifocal ventricular premature beats, ventricular couplets and/or ventricular tachycardia) in four. Only two of these seven had ventricular ectopic activity during exercise testing while they were hypokalemic. Potassium repletion in these seven patients with spironolactone abolished complex ventricular ectopic activity and reduced unifocal ventricular premature beats significantly (p less than 0.01) from an average of 71.2 ventricular premature beats/hour/patient during hydrochlorothiazide treatment to 5.4 ventricular premature beats/hour/patient after potassium repletion. Although complex ventricular ectopic activity was more likely to occur with plasma potassium less than 3.0 meq/liter, restoration of normokalemia was required in several patients to abolish residual ventricular ectopic activity. Persistent ventricular ectopic activity in one patient suggested that myocardial injury sustained during hypokalemia may initiate chronic ventricular ectopic activity. Even in nondigitalized patients, the hazard of diuretic-induced ventricular ectopic activity warrants correction of hypokalemia.


[The experience of moral distress in nursing: the nurses' perception].
With the objective to understand the nurses' perception of moral distress, as well as its frequency and intensity, this study used a survey utilizing a six-point Likert scale, with 124 nurses working in hospitals in southern Brazil in 2008. Using a self-administered questionnaire and factorial analysis, four constructs were identified and validated. The final results were obtained through three different analyses: 1) descriptive statistical analysis; 2) analysis of variance; and 3) multiple regression. The construct that showed the highest intensity of perception regarding moral distress was the lack of competency in the work team (4.55), followed by the nurse's denial of their role as patient advocate (4.30), therapeutic obstinacy (3.60) and disrespecting the patient's autonomy (3.57). Regarding the perception of the frequency of moral distress, once again, the highlighted construct was the lack of competency within the work team (2.42), followed by therapeutic obstinacy (2.26), the nurse's denial of their role as patient advocate (1.71) and disrespecting the patient's autonomy (1.42).


Antimicrobial activity of carbon monoxide-releasing molecule [Mn(CO)3(tpa-κ3N)]Br versus multidrug-resistant isolates of Avian Pathogenic Escherichia coli and its synergy with colistin.
Antimicrobial resistance is a growing global concern in human and veterinary medicine, with an ever-increasing void in the arsenal of clinicians. Novel classes of compounds including carbon monoxoide-releasing molecules (CORMs), for example the light-activated metal complex [Mn(CO)3(tpa-κ3N)]Br, could be used as alternatives/to supplement traditional antibacterials. Avian pathogenic Escherichia coli (APEC) represent a large reservoir of antibiotic resistance and can cause serious clinical disease in poultry, with potential as zoonotic pathogens, due to shared serotypes and virulence factors with human pathogenic E. coli. The in vitro activity of [Mn(CO)3(tpa-κ3N)]Br against multidrug-resistant APECs was assessed via broth microtitre dilution assays and synergy testing with colistin performed using checkerboard and time-kill assays. In vivo antibacterial activity of [Mn(CO)3(tpa-κ3N)]Br alone and in combination with colistin was determined using the Galleria mellonella wax moth larvae model. Animals were monitored for life/death, melanisation and bacterial numbers enumerated from larval haemolymph. In vitro testing produced relatively high [Mn(CO)3(tpa-κ3N)]Br minimum inhibitory concentrations (MICs) of 1024 mg/L. However, its activity was significantly increased with the addition of colistin, bringing MICs down to ≤32 mg/L. This synergy was confirmed in time-kill assays. In vivo assays showed that the combination of [Mn(CO)3(tpa-κ3N)]Br with colistin produced superior bacterial killing and significantly increased larval survival. In both in vitro and in vivo assays light activation was not required for antibacterial activity. This data supports further evaluation of [Mn(CO)3(tpa-κ3N)]Br as a potential agent for treatment of systemic infections in humans and animals, when used with permeabilising agents such as colistin.


Physical Inactivity and Obesity in the United States Through the Lens of the 2012 and 2016 Presidential Elections.
The physical inactivity (PI) and obesity pandemics in the United States (U.S.) have undauntingly persisted in recent history. We have previously demonstrated differences in PI, obesity, socioeconomics, race, and regional culture according to county-level results for the 2020 presidential election. This commentary extends this analysis by considering if the 2020 trend is consistent with the 2 previous presidential election cycles. On a national level, during both the 2012 and 2016 presidential elections, counties where the Democratic candidate received more votes than the Republican one had a significantly lower PI and obesity prevalence. Counties where the Democratic candidate received more votes also had higher median national incomes, a higher proportion of the population who identify as Black, and a higher percentage of people who had completed at least some college. However, at a U.S. regional level, unique, region-specific cultural identities and partisan coalition demographics were apparent and showed some variation between election cycles. In most of the distinct U.S. cultural regions defined by the American Nations model, PI and obesity prevalence were lower in democratic-majority counties, although there were exceptions. These results support our previous findings demonstrating PI and obesity trends in the U.S. are influenced by cultural and political factors that are likely interrelated and which warrant further attention.


Visual Attention and Emotion Analysis Based on Qualitative Assessment and Eyetracking Metrics-The Perception of a Video Game Trailer.
Video game trailers are very useful tools for attracting potential players. This research focuses on analyzing the emotions that arise while viewing video game trailers and the link between these emotions and storytelling and visual attention. The methodology consisted of a three-step task test with potential users: the first step was to identify the perception of indie games; the second step was to use the eyetracking device (gaze plot, heat map, and fixation points) and link them to fixation points (attention), viewing patterns, and non-visible areas; the third step was to interview users to understand impressions and questionnaires of emotions related to the trailer's storytelling and expectations. The results show an effective assessment of visual attention together with visualization patterns, non-visible areas that may affect game expectations, fixation points linked to very specific emotions, and perceived narratives based on the gaze plot. The innovation in the mixed methodological approach has made it possible to obtain relevant data regarding the link between the emotions perceived by the user and the areas of attention collected with the device. The proposed methodology enables developers to understand the strengths and weaknesses of the information being conveyed so that they can tailor the trailer to the expectations of potential players.


Incidence, risk factors, and heritability estimates of hind limb lameness caused by hip dysplasia in a birth cohort of boxers.
To determine incidence, risk factors, and heritability estimates of hind limb lameness caused by hip dysplasia in a birth cohort of Boxers. 1733 Boxers from 325 litters. Status of Boxers with respect to clinical signs of canine hip dysplasia (cCHD) was registered during an 8-year period. Survival analysis accounted for dogs lost to follow-up. Effective heritability for developing cCHD was estimated by use of a proportional hazard model on the basis of the Weibull distribution. Parametric survival models were developed to identify the influence of potential risk factors. Cumulative hazard rate for cCHD from 7 weeks to 8 years of age was 8.5%. Dogs that were kept on a floor covered with a slippery material were 1.6 times as likely to develop cCHD, compared with dogs kept on a nonslippery floor. Risk of cCHD doubled in dogs from litters with a high preweaning mortality rate. Dogs that were neutered at 6 months prior to a diagnosis of CHD were 1.5 times as likely to develop cCHD, compared with sexually intact dogs. Dogs >5 years of age were 1.8 times as likely to develop cCHD, compared with younger dogs. Estimated effective heritability of cCHD was 0.11. In terms of the risk of cCHD in progeny, mean estimated breeding value (EBV) of the 10 best and 10 worst sires was -0.32 and 0.42, respectively. Registration of Boxers that develop cCHD may provide a strategy for disease prevention. In addition to diagnostic evaluation of radiographs, sire EBVs provide useful information for breeding selection decisions.


Cluster-driven dynamical arrest in concentrated lysozyme solutions.
We present a detailed experimental and numerical study of the structural and dynamical properties of salt-free lysozyme solutions. In particular, by combining small-angle X-ray scattering (SAXS) data with neutron spin echo (NSE) and rheology experiments, we are able to identify that an arrest transition takes place at intermediate densities, driven by the slowing down of the cluster motion. Using an effective pair potential among proteins, based on the combination of short-range attraction and long-range repulsion, we account remarkably well for the peculiar volume fraction dependence of the effective structure factor measured by SAXS. We show that a transition from a monomer to a cluster-dominated fluid happens at volume fractions larger than ϕ ≳ 0.05 where the close agreement between NSE measurements and Brownian dynamics simulations confirms the transient nature of the clusters. Clusters even stay transient above the geometric percolation found in simulation at ϕ > 0.15, though NSE reveals a cluster lifetime that becomes increasingly large and indicates a divergence of the diffusivity at ϕ ≃ 0.26. Macroscopic measurements of the viscosity confirm this transition where the long-lived-nature of the clusters is at the origin of the simultaneous dynamical arrest at all length scales.


Creation of a diagnostic wait times measurement framework based on evidence and consensus.
Public reporting of wait times worldwide has to date focused largely on treatment wait times and is limited in its ability to capture earlier parts of the patient journey. The interval between suspicion and diagnosis or ruling out of cancer is a complex phase of the cancer journey. Diagnostic delays and inefficient use of diagnostic imaging procedures can result in poor patient outcomes, both physical and psychosocial. This study was designed to develop a framework that could be adopted for multiple disease sites across different jurisdictions to enable the measurement of diagnostic wait times and diagnostic delay. Diagnostic benchmarks and targets in cancer systems were explored through a targeted literature review and jurisdictional scan. Cancer system leaders and clinicians were interviewed to validate the information found in the jurisdictional scan. An expert panel was assembled to review and, through a modified Delphi consensus process, provide feedback on a diagnostic wait times framework. The consensus process resulted in agreement on a measurement framework that identified suspicion, referral, diagnosis, and treatment as the main time points for measuring this critical phase of the patient journey. This work will help guide initiatives designed to improve patient access to health services by developing an evidence-based approach to standardization of the various waypoints during the diagnostic pathway. The diagnostic wait times measurement framework provides a yardstick to measure the performance of programs that are designed to manage and expedite care processes between referral and diagnosis or ruling out of cancer.


Vitamin B12 Deficiency in a Patient Presenting with Dyspnea: A Case Report.
Pancytopenia can be caused by underlying disorders such as certain autoimmune conditions, leukemia or even a few nutritional deficiencies such as vitamin B12 deficiency. Vitamin B12 deficiency most commonly presents as megaloblastic anemia but can also be associated with pancytopenia. It can present with a range of symptoms associated with anemia and gastrointestinal or neurological systems. Understanding the etiology of the deficiency is crucial for initiating proper treatments. A 19-year-old patient presented with complaints of dyspnea and fever, myalgia and generalized tiredness. Examinations found him to suffer pancytopenia and esophageal candidiasis caused by vitamin B12 deficiency. This deficiency can be associated to inadequate intake and the diet of the patient as a vegetarian. Parenteral B12 treatment led the patient to symptomatically improve. Vitamin B12 deficiency is a reversible cause of bone marrow failure and can be easily treated if diagnosed early enough. Eggs and animal-derived foods constitute the usual source of this vitamin. Vitamin B12 deficiency should therefore be of high index suspicion to a clinician if the patient presents in similar conditions with a vegetarian diet. In the event of the deficiency being caused by inadequate intake or intrinsic factor deficiency, the treatment can be started quickly leading to the dramatic improvement of the patient's condition.


Strength of braided polyblend polyethylene sutures versus braided polyester sutures in Achilles tendon repair: a cadaveric study.
Various techniques may be used to repair Achilles tendon ruptures; however, we contend that using the strongest suture with the least amount of suture material is ideal. To compare the strength of 2-0 FiberLoop (Arthrex Inc, Naples, Florida) and #2 Ethibond (Ethicon Inc, Somerville, New Jersey) suture materials in Achilles tendon repairs, 12 Achilles tendons were harvested from cadavers aged 18 to 62 years (median age, 42 years). The tendons were transected and repaired using a modified Krackow suture technique. All of the right limbs were repaired with 2-0 FiberLoop, and the contralateral side was repaired with #2 Ethibond. The specimens were mounted to a materials testing system, and the repairs were pulled to failure in an anatomical direction. The mean +/- SD yield loads of 2-0 FiberLoop and #2 Ethibond were 233 +/- 48 N and 134 +/- 34 N, respectively (P = .002). The mean +/- SD ultimate load of 2-0 FiberLoop was 282 +/- 58 N, and that of #2 Ethibond was 135 +/- 33 N (P < .001). The cross-sectional area of one pass of 2-0 FiberLoop was calculated to be 0.21 mm(2), and one pass of #2 Ethibond was 0.28 mm(2). The smaller-caliber 2-0 FiberLoop was significantly stronger than #2 Ethibond. This study suggests that there is no advantage to using the traditional larger suture material for Achilles tendon repairs; however, further clinical testing is needed to determine the optimal repair technique.


Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) for Peritoneal Metastases in Solid Organ Graft Recipients: First Experience.
BACKGROUND Therapy of peritoneal metastases (PM) in solid organ transplant recipients is challenging. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) might constitute a new therapeutic opportunity for these patients. MATERIAL AND METHODS This was a single-center, retrospective analysis of prospective registry data (NCT03210298) in a tertiary care center between 1.7.2016 and 31.12.2017. Intraperitoneal administration of oxaliplatin 92 mg/m² body surface or a combination of cisplatin 7.5 mg/m² and doxorubicin 1.5 mg/m², repeated every 6 weeks. Objective tumor response was documented via histology (Peritoneal Regression Grading Score, PRGS), adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) 4.0. RESULTS Out of 71 consecutive patients treated with PIPAC, 2 patients (2.8%) were solid organ transplant recipients. The first patient had metachronous PM of colonic cancer origin after liver transplantation. The second patient had synchronous PM of pancreatic cancer origin after combined kidney-pancreas transplantation. After repeated combined systemic and PIPAC chemotherapy, objective histological response was documented in both patients. No adverse events >CTCAE 2 were recorded. There was no measurable liver or renal toxicity. PIPAC procedures could be repeated (2, resp. 3 cycles) without any interruption of immunosuppressive medication or impairment of respective plasmatic drug levels. The first patient passed away 7 months after the first PIPAC, the second patient was still alive after 8 months. CONCLUSIONS PIPAC can induce objective regression of PM in solid organ transplant recipients without inducing organ toxicity or interfering with immunosuppressive therapy.


Strategies aimed at preventing chronic opioid use in trauma and acute care surgery: a scoping review protocol.
Globally every year, millions of patients sustain traumatic injuries and require acute care surgeries. A high incidence of chronic opioid use (up to 58%) has been documented in these populations with significant negative individual and societal impacts. Despite the importance of this public health issue, optimal strategies to limit the chronic use of opioids after trauma and acute care surgery are not clear. We aim to identify existing strategies to prevent chronic opioid use in these populations. We will perform a scoping review of peer-reviewed and non-peer-reviewed literature to identify studies, reviews, recommendations and guidelines on strategies aimed at preventing chronic opioid use in patients after trauma and acute care surgery. We will search MEDLINE, EMBASE, PsycINFO, CINHAL, Cochrane Central Register of Controlled Trials, Web of Science, ProQuest and websites of trauma and acute care surgery, pain, government and professional organisations. Databases will be searched for papers published from 1 January 2005 to a maximum of 6 months before submission of the final manuscript. Two reviewers will independently evaluate studies for eligibility and extract data from included studies using a standardised data abstraction form. Preventive strategies will be classified according to their types and targeted trauma populations and acute care surgery procedures. Research ethics approval is not required as this study is based on the secondary use of published data. This work will inform research and clinical stakeholders on the required next steps towards the uptake of effective strategies aimed at preventing chronic opioid use in trauma and acute care surgery patients.


Fatty Pancreas: Should We Be Concerned?
The metabolic consequences of visceral fat deposition are well known, and the presence of intrapancreatic fat (IPF) has been recognized for decades. However, our knowledge about the distribution of fat in the pancreas and its clinical implications is in a nascent stage. Various terms have been proposed to describe IPF; for the purpose of this narrative review, we chose the general term fatty pancreas. Herein, we describe the radiologic, endoscopic, and histopathologic aspects of diagnosing fatty pancreas and provide an overview of the diseases associated with this condition. Our purpose is to highlight diagnostic challenges and identify specific clinical questions that would benefit from further study. As evident in this review, IPF is associated with various metabolic diseases, pancreatitis, pancreatic cancer, and precancer-yet establishing causality needs careful, further study.


Modeling of growth kinetics for Pseudomonas spp. during benzene degradation.
A modeling study was conducted on growth kinetics of three different strains of Pseudomonas spp. (Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas putida) during benzene degradation to determine optimum substrate concentrations for most efficient biodegradation. Batch tests were performed for eight different initial substrate concentrations to observe cell growth and associated substrate degradation using benzene-adapted cells. Kinetic parameters of both inhibitory (Haldane-Andrews, Aiba-Edwards) and noninhibitory (Monod) models were fitted to the relationship between specific growth rate and substrate concentration obtained from the growth curves. Results showed that half-saturation constant of P. fluorescens was the highest among the three strains, indicating that this strain could grow well at high concentration, while P. putida could grow best at low concentration. The inhibition constant of P. aeruginosa was the highest, implying that it could tolerate high benzene concentration and therefore could grow at a wider concentration range. Estimated specific growth rate of P. putida was lower, but half-saturation constant was higher than those from literature study due to high substrate concentration range used in this study. These two kinetic parameters resulted in substantial difference between Monod- and Haldane-type models, indicating that distinction should be made in applying those models.


Increased 12-lipoxygenase expression in breast cancer tissues and cells. Regulation by epidermal growth factor.
The interaction of growth factors, such as epidermal growth factor (EGF) with their receptors, on breast cancer cells can lead to the hydrolysis of phospholipids and release of fatty acids, such as arachidonic acid, which can be further metabolized by the lipoxygenase (LO) pathway. Several LO products have been shown to stimulate oncogenes and have mitogenic and chemotactic effects. In this study, we have evaluated the regulation of 12-LO activity and expression in breast cancer cells and tissues. Leukocyte-type 12-LO messenger RNA (mRNA) expression was studied by a specific RT-PCR method in matched, normal, uninvolved and cancer-involved breast tissue RNA samples from six patients. In each of these six patients, the cancer-involved section showed a much higher level of 12-LO mRNA than the corresponding normal section. 12-LO mRNA levels also were greater in two breast cancer cell lines, MCF-7 and COH-BR1, compared with the nontumorigenic breast epithelial cell line, MCF-10F. The growth of the MCF-7 cells was significantly inhibited by two specific LO blockers but not by a cyclooxygenase blocker. Treatment of serum-starved MCF-7 cells with EGF for 4 h led to a dose-dependent increase in the formation of the 12-LO product, 12-hydroxyeicosatetraenoic acid. EGF treatment also increased the levels of the leukocyte-type 12-LO protein expression at 24 h. These results suggest that activation of the 12-LO pathway may play a key role in basal and EGF-induced breast cancer cell growth.


Atopic characteristics of adult patients with eosinophilic esophagitis.
The association of sensitization to food allergens, atopic disorders, and eosinophilic esophagitis (EE) is well known in children, but not in adults. Our purpose was to identify the spectrum of specific allergic sensitivities to environmental and food allergens within a series of adult patients with EE. The case series consisted of 23 adult patients with biopsy-proven EE referred for allergy evaluation at an academic clinic. All patients had data that included serum measurement of specific immunoglobulin (Ig)E antibodies to common foods and spices. Patients diagnosed with allergic rhinitis had a relevant clinical history of respiratory allergy and evidence of specific IgE to environmental aeroallergens. The series consisted of 16 men and 7 women with a median age of 34 years (range, 18-57 y). Eighteen of 23 had an atopic diathesis, allergic rhinitis being the most common. Seventeen of 21 patients were polysensitized to several different environmental allergens, and 19 of 23 (82%) had serum IgE specific for one or more food-associated allergens (median, 5 foods), with wheat, tomato, carrot, and onion identified most commonly. The preponderance of environmental and food allergy was similar across all age groups and did not favor younger adults. By using objective measures, our series confirms the high degree of atopy in adults with EE, similar to that seen in the pediatric population. These patients tend to be polysensitized to several environmental allergens, and the profiles of serum IgE specific for food allergens suggest that sensitization may partly be a response to inhaled allergens.


Analysis of organellar genomes in brown algae reveals an independent introduction of similar foreign sequences into the mitochondrial genome.
Kelp species (Laminariales, Phaeophyceae) are globally widespread along temperate to Polar rocky coastal lines. Here we analyse the mitochondrial and chloroplast genomes of Laminaria rodriguezii, in comparison to the organellar genomes of other kelp species. We also provide the complete mitochondrial genome sequence of another endemic kelp species from a Polar habitat, the Arctic Laminaria solidungula. We compare phylogenetic trees derived from twenty complete mitochondrial and seven complete chloroplast kelp genomes. Interestingly, we found a stretch of more than 700 bp in the mitochondrial genome of L.rodriguezii, which is not present in any other yet sequenced member of the Phaeophyceae. This stretch matches a protein coding region in the mitochondrial genome from Desmarestia viridis, another brown seaweed. Their high similarity suggests that these sequences originated through independent introduction into the two species. Their origin could have been by infection by yet unknown similar mitoviruses, currently only known from fungi and plants.


Risk Assessment for Mobile Systems Through a Multilayered Hierarchical Bayesian Network.
Mobile systems are facing a number of application vulnerabilities that can be combined together and utilized to penetrate systems with devastating impact. When assessing the overall security of a mobile system, it is important to assess the security risks posed by each mobile applications (apps), thus gaining a stronger understanding of any vulnerabilities present. This paper aims at developing a three-layer framework that assesses the potential risks which apps introduce within the Android mobile systems. A Bayesian risk graphical model is proposed to evaluate risk propagation in a layered risk architecture. By integrating static analysis, dynamic analysis, and behavior analysis in a hierarchical framework, the risks and their propagation through each layer are well modeled by the Bayesian risk graph, which can quantitatively analyze risks faced to both apps and mobile systems. The proposed hierarchical Bayesian risk graph model offers a novel way to investigate the security risks in mobile environment and enables users and administrators to evaluate the potential risks. This strategy allows to strengthen both app security as well as the security of the entire system.


An unusual cutaneous manifestation of group A streptococcal bacteremia.
A case of streptococcal bacteremia presenting with disseminated nodular lesions is presented. Although the incidence of group A streptococcal bacteremia has declined, the disease may affect both normal and immunologically compromised children. Early recognition and prompt antibiotic therapy are required to ensure a favorable outcome.


Social status and housing factors affect reproductive performance of pregnant sows in groups.
Group-housing systems for pregnant sows are considered a welfare-promoting alternative to the individual stall. A major concern associated with pregnant sows housed in group pens is increased aggression at mixing and at feeding, which may cause chronic stress among some of the sows in the group due to low feed intake and social stress. Prolonged activation of the stress axis, based on elevated cortisol levels, may inhibit or impair reproductive success via disruption of the reproductive axis. Mixing sows into groups shortly after insemination evokes a stress response, which may affect fertilization and implantation due to sustained, elevated cortisol levels that disrupt reproductive processes. Yet, most studies reported minimal effects of group housing sows during pregnancy on reproduction or cortisol-related stress response. Differences between housing systems-in terms of group size, floor-space allowance, feeding system, and genetics-could account for these unexpected results. Indeed, interrupted feed intake, especially in early pregnancy, and sustained aggression in late pregnancy are two unfavorable social stresses that deserve special attention in order to achieve good reproductive performance. Unfortunately, most studies do not consider other factors, such as social rank and parity, which may interactively affect reproductive success and aggressive behavior of sows, especially in group-pen systems.


Training and practice of wound ostomy continence nurse specialists in China.
In China, with chronic wound patients increasing by 10% per year and more than 1 million stoma patients, there is an increasing demand for wound ostomy continence care. Accordingly, specialized wound care in China is developing rapidly and the gap with developed countries is narrowing. This paper aims to describe the status of training, practice, and management of wound nurses in China. Data on the training and practice of wound specialist nurses in the Chinese Mainland were collected through literature review and hospital surveys. The training system of Chinese Wound, Ostomy and Continence (WOC) specialist nurses is developing rapidly, but lacks a unified access standard, curriculum, teaching materials, and assessment system. Specialist nurses play an important role in education, clinical practice, and scientific research, but home care and independent nursing practices are still in their infancy. The developing momentum of wound care in China is encouraging, but it is necessary to unify and standardize WOC nurses' qualification certification, scope of practice, level-to-level administration, and other aspects to cultivate higher-quality specialized wound nurses.


Carnitine and brown adipose tissue metabolism in the rat during development.
1. The content of carnitine, acylcarnitine and total acid soluble carnitine in brown adipose tissue of rats increases rapidly after birth, attaining a peak on about day 10 and then decreases. Similar changes with age were found for carnitine acetyltransferase activity in mitochondria from brown adipose tissue and heart. The activity of this enzyme in brain and in liver is much smaller, but also increases postnatally. 2. The activity of carnitine palmitoyltransferase in brown adipose tissue, however, decreases after birth then increases later in life. 3. Exposure of 18-day-old rats to the cold for 20 days leads to an increase in carnitine content in brown adipose tissue and raises the activity of carnitine acetyltransferase. The activity of carnitine palmitoyltransferase is not affected by cold adaptation.


Influencing the Crystalline Domains of Poly(vinylidenedifluoride) Composites Using Fluorinated Silica Nanoparticles as Drop-In Modifiers.
Improvements to fluoropolymer processing techniques by way of utilizing nanoparticles as drop-in processing aids have pronounced effects on bulk composite properties. In this work, we prepared fluoroalkyl-silanized silica nanoparticles (F-SiNPs, ca. 200 nm) that were solvent-blended with polyvinylenedifluoride (PVDF) in order to prepare composites with varying weight fractions. We demonstrated that the ability to functionalize SiNPs with long fluoroalkylchains that induced co-crystallization with the PVDF matrix, resulting in uniform particle dispersion and improved interlaminate adhesion. This was quantitatively investigated using calorimetry and thermogravimetric analysis, which showed a decrease in the bulk crystallinity of the virgin PVDF from 37% to 10% with minimal 10 wt % F-SiNP loading, rendering a nearly amorphous PVDF. Additional discussions in this work include the effects of various bare and fluoroalkyl-functionalized SiNP loadings on the amorphous and crystalline domains of the PVDF matrix, as well as thermal decomposition.


[Stable inheritance of hpt gene in transgenic rice plants mediated by biolistic bombardment].
Japonica rice cv 77170 was transformed with pBI222 carrying hygromycin phosphotransferase gene (hpt) by using biolistic bombardment and fertile transgenic rice plants were obtained. In T1 and most T2 generation the performance of hygromycin resistance was normal. Only in T2 progeny of SG-15 some lines showed decreased resistance. Mendelian inheritance of hygromycin resistance was showed as single dominant locus and proved by Southern blotting analysis in T1 and T2 generation of all transgenic plants. Multiple copies of hpt integrated into rice genome. These copies linked closely and inherited stablly. Msp I digested Southern blotting showed that methylation of hpt existed commonly in transgenic plants and their progeny, therefore uncomplete silencing of hpt in some T2 progeny of SG-15 was not associated with hpt methylation probably.


Perioperative management of patients who are receiving a novel oral anticoagulant.
The use of novel oral anticoagulants (NOACs) is increasing since these drugs are at least as efficacious and safe as vitamin K antagonists (VKAs) for the management of patients with non-valvular atrial fibrillation and venous thromboembolism. Compared with VKAs, NOACs have a faster onset and offset of action, a predictable and consistent pharmacokinetic profile, fewer drug interactions, and ease of use since anticoagulant monitoring is not required. Current perioperative management will be affected by these characteristics, with the potential to obviate the need for heparin bridging. This review aims to summarize the current evidence of perioperative thromboembolic and bleeding risk during anticoagulant interruption, which is derived predominantly from patients receiving VKA therapy, and early studies involving NOACs which mainly focus on patients who are receiving dabigatran. The role of heparin bridging is discussed. We also provide a practical approach for the perioperative management of patients who are receiving NOAC therapy.


Ultrahigh-Throughput Directed Evolution of Polymer-Degrading Enzymes Using Yeast Display.
Enzymes that degrade synthetic polymers have attracted intense interest for eco-friendly plastic recycling. However, because enzymes did not evolve for the cleavage of abiotic polymers, directed evolution strategies are needed to enhance activity for plastic degradation. Previous directed evolution efforts relied on polymer degradation assays that were limited to screening ∼104 mutants. Here, we report a high-throughput yeast surface display platform to rapidly evaluate >107 enzyme mutants for increased activity in cleaving synthetic polymers. In this platform, individual yeast cells display distinct mutants, and enzyme activity is detected by a change in fluorescence upon the cleavage of a synthetic probe resembling a polymer of interest. Highly active mutants are isolated by fluorescence activated cell sorting and identified through DNA sequencing. To demonstrate this platform, we performed directed evolution of a polyethylene terephthalate (PET)-depolymerizing enzyme, leaf and branch compost cutinase (LCC). We identified activity-boosting mutations that substantially increased the kinetics of degradation of solid PET films. Biochemical assays and molecular dynamics (MD) simulations of the most active variants suggest that the H218Y mutation improves the binding of the enzyme to PET. Overall, this evolution platform increases the screening throughput of polymer-degrading enzymes by 3 orders of magnitude and identifies mutations that enhance kinetics for depolymerizing solid substrates.


Prognostic features of pathologic stage T1 renal cell carcinoma after radical nephrectomy.
To assess the effect of renal cell carcinoma (RCC) subtype, tumor size, and Fuhrman grade on clinical outcome in patients with pathologic T1 (pT1) RCC treated with radical nephrectomy. Between 1970 and 1998, 840 patients underwent radical nephrectomy for pT1 RCC. Tumors were subtyped and graded. Univariate and multivariate Cox proportional hazards models were fitted to assess the features associated with metastasis-free survival (MFS) and cancer-specific survival (CSS). We identified a range of tumor sizes of clear cell RCC in which a transition occurred from low to high risk. Cox proportional hazards models were then fitted by using size cutoffs. The mean follow-up (+/- SD) was 9.4 +/- 6.6 years among the patients alive at latest follow-up. At 10 years, the CSS and MFS for clear cell RCC (n = 682) were 89.1% and 88.6%, respectively; for papillary RCC (n = 122), they were 95.5% and 93.8%; and for chromophobe RCC (n = 33), they were both 100%. The differences in CSS (P = 0.013) and MFS (P = 0.023) between clear cell RCC and the other subtypes were statistically significant. For clear cell RCC, tumor size and Fuhrman grade were independently associated with CSS and MFS (P <0.001). A transition in risk occurred for tumor sizes between 4.5 and 5.0 cm, and the tumor size cutoff of 5.0 cm had the highest concordance index for predicting CSS and MFS. RCC subtype is a strong independent prognostic variable for patients with pT1 RCC treated with radical nephrectomy. For clear cell RCC, Fuhrman grade and tumor size are independently associated with CSS and MFS.


Direct effects of the pyrimido-pyrimidine derivative RA 233 (Rapenton) on rat 13762NF mammary tumor cell clones in vitro.
Studies with the pyrimido-pyrimidine analogue RA 233 (Rapenton) suggest that its antimetastatic action may not be mediated entirely by inhibition of platelet function. Little is known about its direct effects on tumor cells. We investigated the in vitro effects of RA 233 on clones MTLn3 and MTC of differing metastatic potentials, isolated from the 13762NF rat mammary adenocarcinoma. The results indicated that RA 233 is cytostatic (EC50 of approximately 140 microM and approximately 180 microM for MTLn3 and MTC cells, respectively) rather than cytotoxic by determining changes in viable cell number, thymidine uptake, and incorporation of thymidine and methionine. In both clones RA 233 inhibited cAMP-dependent phosphodiesterase activity and affected cAMP accumulation in intact cells. In contrast, clonal heterogeneity in drug-induced morphological changes, such as vacuole formation and altered organization of cytoskeletal structures, as well as increased tumor cell growth at 50 microM RA 233 was observed between clones MTLn3 and MTC. These data could explain the conflicting results obtained with RA 233 when evaluated as an antimetastatic agent.


Assessment of oil refinery wastewater and effluent integrating bioassays, mechanistic modelling and bioavailability evaluation.
Water is used in petroleum oil refineries in significant volumes for cooling, steam generation and processing of raw materials. Effective water management is required at refineries to ensure their efficient and responsible operation with respect to the water environment. However, ascertaining the potential environmental risks associated with discharge of refinery effluents to receiving waters is challenging because of their compositional complexity. Recent European research and regulatory initiatives propose a more holistic approach including biological effect methods to assess complex effluents and surface water quality. The study presented here investigated potential effects of effluent composition, particularly hydrocarbons, on aquatic toxicity and was a component of a larger study assessing contaminant removal during refinery wastewater treatment (Hjort et al 2021). The evaluation of effects utilised a novel combination of mechanistic toxicity modelling based on the exposure composition, measured bioavailable hydrocarbons using biomimetic solid phase microextraction (BE-SPME), and bioassays. The results indicate that in the refinery effluent assessments measured bioavailable hydrocarbons using BE-SPME was correlated with the responses in standard bioassays. It confirms that bioassays are providing relevant data and that BE-SPME measurement, combined with knowledge of other known non-hydrocarbon toxic constituents, provide key tools for toxicity identification. Overall, the results indicate that oil refinery effluents treated in accordance to the EU Industrial Emissions Directive requirements have low to negligible toxicity to aquatic organisms and their receiving environments. Low-cost, animal-free BE-SPME represents a compelling tool for rapid effluent characterization.


[The face, the mask and the times. Natural history of the segmental architecture of the face].
Extending from the supra-occipital region down to both clavicles, the face is an original anatomical entity which constituTes the main field of interaction between the brain and the external world. We here demonstrate that essential structures arise from the neural crest cells and that the segmental migratory pathway of these cells leads to the segmental ontogenesis of the head, and of the anterior neck area from seven distinct morphogenetic units which enjoy each of an independEnt growth potential. In the adult, the neural and segmental origin of the face is temporarily masked by the superficial musculoaponevrotic system which supports its cutaneous cover. Nevertheless, this fundamental architecture appears fugitively in the mimics of facial expression, then more obviously in the ptotic and folding phenomenons involved in cephalic skin ageing.


IgE synthesis in man. I. Development of specific IgE antibodies after immunization with tetanus-diphtheria (Td) toxoids.
Specific IgE and IgG antibodies were measured in 39 adolescent and adult humans preselected to have less than 0.125 antitoxin units (AU) ml to tetanus antitoxin (IgG) irrespective of previous immunization history. Mean antitoxin values (IgG) measured by sheep red cell hemagglutination (SRBC) increased by 2 logs to 1.49 AU/ml sera for tetanus and by 1 log to 0.025 AU/ml sera for diphtheria. Specific tetanus IgE was noted to increase after immunization from a mean 2.0 +/- 0.2% counts bound to 3.1 +/- 0.6% counts bound, but was not statistically significant. Diphtheria-specific IgE rose significantly (p less than 0.05) from a mean 1.5 +/- 0.2% counts bound to a mean 4.0 +/- 1.2% counts bound in atopic individuals and from a mean 1.2 +/- 0.0% counts bound to a mean 2.2 +/- 0.5% counts bound in nonatopics. These data document the development of tetanus and diphtheria IgE antibodies after booster immunization.


Variation of the McKusick-Kaufman gene and studies of relationships with common forms of obesity.
Obesity is a prominent feature of the Bardet-Biedl syndrome (BBS), one subset of which, BBS6, is due to mutations in the chaperonin-like gene termed the McKusick-Kaufman syndrome (MKKS) gene. We tested whether variation in MKKS contributes to common and probably polygenic forms of obesity by performing mutation analysis of the coding region in 60 Danish white men with juvenile-onset obesity. Five variants were identified, including two synonymous mutations (Pro(39)Pro and Ile(178)Ile) and three nonsynonymous variants (Ala(242)Ser, Arg(517)Cys, and Gly(532)Val). Furthermore, the rare Ala(242)Ser was identified in two families and showed partial cosegregation with obesity. The Pro(39)Pro, Ile(178)Ile, and Arg(517)Cys variants are in complete linkage disequilibrium and defined a prevalent haplotype. In a case-control study, the Arg(517)Cys polymorphism allele prevalence was 11.4% [95% confidence interval (CI), 9.7-13.0] among 744 men with juvenile-onset obesity and 9.3% (CI, 7.9-10.7) among 867 control subjects (P = 0.048). However, among middle-aged men the allelic prevalence was 9.7% (CI, 7.9-11.4) among 523 obese men and 12.2% (CI, 10.8-13.6) among 1051 lean men (P = 0.037). In conclusion, it is unlikely that MKKS variants play a major role in the pathogenesis of nonsyndromic obesity, although in rare cases the A242S allele may contribute to obesity.


Mutational analysis of the Acropora millepora PaxD paired domain highlights the importance of the linker region for DNA binding.
Pax transcription factors are found in animals, from simple sponges to insects and vertebrates. The defining feature of Pax proteins is the DNA-binding paired domain (PD), which consists of two helix-turn-helix subdomains, joined with a linker region. Despite high specificity in vivo, the paired domains of different Pax proteins bind similar consensus DNA sequences in vitro. Using bandshift techniques, we show here that the paired domain of the Acropora millepora PaxD protein, which unambiguously belongs to the Pax3/7 group, does not bind to three defined paired domain-binding sites. Domain swapping experiments and site-directed mutagenesis identified two amino acid residues in the linker region of the paired domain as critical to DNA binding; G70 and S71 are highly conserved in Pax proteins, but differ in PaxD (L70 and N71). The PaxD data thus highlight the importance of the linker region, and particularly G70 and S71, in DNA binding by Pax proteins.


Safety and pharmacokinetics of an intraocular fluocinolone acetonide sustained delivery device.
To determine the safety and pharmacokinetics of an intraocular fluocinolone acetonide sustained drug delivery device. Nonbiodegradable drug delivery devices containing 2 or 15 mg of a synthetic corticosteroid, fluocinolone acetonide, were constructed. The long-term in vitro release rates of these devices were determined in protein-free buffer or buffer containing 50% plasma protein. Fifteen-milligram devices were also implanted into the vitreous cavities of rabbit eyes. Intravitreal drug levels, the amount of drug remaining in explanted devices, and the release rate of explanted devices were determined over a 1-year time period. Drug toxicity was assessed over this same time period by slit lamp examination, indirect ophthalmoscopy, electroretinography, and histologic examination. The drug release rates for the 2-mg device, 1.9 +/- 0.25 microg/d, and for the 15-mg device, 2.2 +/- 0.6 microg/d, remained linear over the 6-month and 45-day testing period, respectively. The release rate increased by approximately 20% when devices were transferred from protein-free buffer to buffer that contained protein (P: < 0.0001). Vitreous levels remained fairly constant (0.10-0.21 microg/ml) over a 1-year period. No drug was present in the aqueous humor during this time period. Based on the device release rates, the predicted life span of the 2- and 15-mg devices are 2.7 and 18.6 years, respectively. There was no evidence of drug toxicity by clinical examination, electroretinography, or histologic examination. It is feasible to construct a nontoxic fluocinolone acetonide drug delivery device that reproducibly releases fluocinolone acetonide in a linear manner over an extended period. These devices show great promise in the treatment of ocular diseases such as uveitis, which are often managed with chronic corticosteroid therapy.


Between a rock and a hard polytomy: rapid radiation in the rupicolous girdled lizards (Squamata: Cordylidae).
Girdled lizards (Cordylidae) are sub-Saharan Africa's only endemic squamate family and contain 80 nominal taxa, traditionally divided into four genera: Cordylus, Pseudocordylus, Chamaesaura and Platysaurus. Previous phylogenetic analysis revealed Chamaesaura and Pseudocordylus to be nested within Cordylus, and the former genera were sunk into the later. This taxonomic revision has received limited support due to the study's poor taxon sampling, weakly supported results and possible temporary nomenclatural instability. Our study analyzes three nuclear and three mitochondrial genes from 111 specimens, representing 51 in-group taxa. Parsimony, likelihood and Bayesian analyses of concatenated and partitioned datasets consistently recovered a comb-like tree with 10, well-supported, monophyletic lineages. Our taxonomic reassessment divides the family into 10 genera, corresponding to these well-supported lineages. Short internodes and low support between the non-platysaur lineages are consistent with a rapid radiation event at the base of the viviparous cordylids.


Israeli general practitioners' dissatisfaction with their own primary healthcare.
Many physicians treat themselves despite established guidelines against such practice. To examine whether general practitioners (GPs) are satisfied with their personal primary care and how this could be improved. We sent a questionnaire to GPs in Israel. We examined the gap between preference to use formal medical care and use in practice, satisfaction with physicians' primary healthcare, self-prescribing and ways to improve physician access to care. There were 203 respondents (response rate 203/985; 21%). Sixty-one per cent reported not having a GP. Older respondents were less likely to have their own GP. Thirty-seven per cent of physicians reported receiving less formal medical care than they desired. This gap was higher in those reporting self-prescription of benzodiazepines and anti-depressants (P < 0.05) and was significantly associated with dissatisfaction with primary healthcare. Odds for being satisfied with personal care was reduced by more than 85% in GPs who reported receiving less formal medical care than they desired (odds ratio 0.146; 95% confidence interval 0.064-0.333). Our findings inform the profile of physician self-treatment and the dissatisfaction associated with it. Dissatisfaction was associated with a gap between desired and actual care rather than with having or not having a personal GP. There was no consensus regarding what would assist physicians to access GPs.


A qualitative study of the barriers and facilitators to retention-in-care among HIV-positive women in the rural southeastern United States: implications for targeted interventions.
Retention in HIV medical care has been recognized as critical for long-term favorable clinical outcomes among HIV-positive patients. However, relatively little is known about specific factors related to HIV medical care adherence among HIV-positive women in rural areas in the United States, where the epidemic is rapidly growing among minorities and women. The objective of the current study was to assess barriers and facilitators to HIV clinic visit adherence among HIV-positive women in the rural southeastern region of the United States. Forty HIV-positive women were recruited from four outpatient clinics providing services to HIV-positive patients residing in 23 predominately rural counties in Alabama. Four focus groups were conducted ranging from 5 to 16 participants each. Content analysis was used to analyze and interpret the data. Data coding and sorting was conducted using QRS NVivo 8 software. Participants were predominately African American (92.3%) ranging in age from 29 to 69 years (mean = 46.1 years). On average, participants reported living with HIV for 8.8 years. Factors that impacted participants' ability to maintain clinic visit appointments included personal, contextual, and community/environmental factors that included: patient/provider relationships, family support, access to transportation, organizational infrastructure of the health care facility visited and perceived HIV stigma within their communities. The current study highlights the myriad of retention-in-care barriers faced by HIV-positive women living in rural areas in the southeastern United States. Innovative multilevel interventions that address these factors are sorely needed to increase long-term retention-in-care among HIV-positive women residing in rural areas.


Towards a unified analysis of brain maturation and aging across the entire lifespan: A MRI analysis.
There is no consensus in literature about lifespan brain maturation and senescence, mainly because previous lifespan studies have been performed on restricted age periods and/or with a limited number of scans, making results instable and their comparison very difficult. Moreover, the use of nonharmonized tools and different volumetric measurements lead to a great discrepancy in reported results. Thanks to the new paradigm of BigData sharing in neuroimaging and the last advances in image processing enabling to process baby as well as elderly scans with the same tool, new insights on brain maturation and aging can be obtained. This study presents brain volume trajectory over the entire lifespan using the largest age range to date (from few months of life to elderly) and one of the largest number of subjects (N = 2,944). First, we found that white matter trajectory based on absolute and normalized volumes follows an inverted U-shape with a maturation peak around middle life. Second, we found that from 1 to 8-10 y there is an absolute gray matter (GM) increase related to body growth followed by a GM decrease. However, when normalized volumes were considered, GM continuously decreases all along the life. Finally, we found that this observation holds for almost all the considered subcortical structures except for amygdala which is rather stable and hippocampus which exhibits an inverted U-shape with a longer maturation period. By revealing the entire brain trajectory picture, a consensus can be drawn since most of the previously discussed discrepancies can be explained. Hum Brain Mapp 38:5501-5518, 2017. © 2017 Wiley Periodicals, Inc.


[Supratentorial extra-axial arachnoid brain cysts].
Supratentorial extra-axial arachnoidal cysts are congenital benign formations of intracranial location filled with cerebrospinal fluid. The clinical symptomatology of arachnoidal cysts depended on the age of the patient and presence of complications. The pathogenetically justified surgical method of treatment of arachnoidal cysts in children is excision of cyst wall, emptying of its cavity, creation of shunt with the subarachnoidal spaces and basal cisternae in association with cystoperitoneostomy. In the adult patients additional cystoperitoneotomy is not performed.


Regional patterns of δ 13C and δ 15N for European common cuttlefish (Sepia officinalis) throughout the Northeast Atlantic Ocean and Mediterranean Sea.
Stable isotope compositions of carbon and nitrogen (expressed as δ 13C and δ 15N) from the European common cuttlefish (Sepia officinalis) were measured in order to evaluate the utility of using these natural tracers throughout the Northeast Atlantic Ocean and Mediterranean Sea (NEAO-MS). Mantle tissue was obtained from S. officinalis collected from 11 sampling locations spanning a wide geographical coverage in the NEAO-MS. Significant differences of both δ 13C and δ 15N values were found among S. officinalis samples relative to sampling location. δ 13C values did not show any discernable spatial trends; however, a distinct pattern of lower δ 15N values in the Mediterranean Sea relative to the NEAO existed. Mean δ 15N values of S. officinalis in the Mediterranean Sea averaged 2.5‰ lower than conspecifics collected in the NEAO and showed a decreasing eastward trend within the Mediterranean Sea with the lowest values in the most eastern sampling locations. Results suggest δ 15N may serve as a useful natural tracer for studies on the population structure of S. officinalis as well as other marine organisms throughout the NEAO-MS.


Preliminary evidence that high levels of nicotine on children's hands may contribute to overall tobacco smoke exposure.
Dust and surfaces are important sources of lead and pesticide exposure in young children. The purpose of this pilot study was to investigate if third-hand smoke (THS) pollutants accumulate on the hands of children who live in environments where tobacco is used and if hand nicotine levels are associated with second-hand smoke (SHS), as measured by salivary cotinine. Participants were parents and children (n=25; age mean (SD)=5.4 (5.3) years) presenting to the emergency department with a potentially SHS-related illness. A convenience sample of participants were recruited at baseline from an ongoing two-group, randomised controlled trial of a SHS reduction and tobacco cessation intervention. Parents were current smokers; thus, all children were at risk of SHS and THS exposure to varying extents. Primary outcome measures, which were assessed in child participants only, were hand nicotine and salivary cotinine. Parents reported sociodemographics and smoking patterns; children's medical records were abstracted for chief complaint, medical history and discharge diagnosis. All children had detectable hand nicotine (range=18.3-690.9 ng/wipe). All but one had detectable cotinine (range=1.2-28.8 ng/mL). Multiple linear regression results showed a significant positive association between hand nicotine and cotinine (p=0.009; semipartial r2=0.24), independent of child age. The higher-than-expected nicotine levels and significant association with cotinine indicate that THS may play a role in the overall exposure of young children to tobacco smoke toxicants and that hand wipes could be a useful marker of overall tobacco smoke pollution and a proxy for exposure. ClinicalTrials.gov Identifier: NCT02531594.


Transcatheter closure of ruptured sinus Valsalva aneurysm with retrograde approach.
A three-year-old girl with multiple heart malformations admitted to the pediatric cardiology unit because of excessive sweating and fatigue. Abnormal color Doppler flow was detected into the right atrium from the dilated coronary sinus on the echocardiographic examination, and ruptured sinus Valsalva aneurysm (SVA) was diagnosed. Although in most such cases, an antegrade transcatheter approach has been used, a retrograde approach can be used as a cost-effective treatment modality in those cases with selective high-risk surgery. In this report, we present a patient with ruptured SVA, which was closed via Amplatzer vascular plug-4 by retrograde approach.


[Seasonal variations of blood pressure in normal subjects and patients with chronic disease].
The characteristics and determining factors of seasonal variations of the blood pressure (BP) were studied in 20 normal subjects and 219 chronic stable chronically all patients, most of whom were ambulatory. The BP was measured repetitively over twelve months and measurements in the lying position repeated after one minute of orthostatism were performed in Winter and in Summer. In normal subjects, the BP decreased from June to reach its lowest value in August to return to the Winter values from October. The mean BP of the three Winter months was 130/79 mmHg and the seasonal lowering averages 5 +/- 5/5 +/- 6 mmHg (m +/- SD) (p < 0.01), with marked individual differences. The Summer decrease in BP was observed both lying down (3/4 mmHg) (p = 0.01) and standing (5/6) (p = 0.0001). In the patient group, the Summer decrease in BP was 4/3 mmHg. During the orthostatic measurements, it was 4/4 mmHg lying down and 6/5 mmHg when upright. Symptoms of orthostatic hypotension were reported spontaneously 10 times during the Winter and 21 times during the Summer months (p = 0.04) and occurred in the upright position in 12 patients (6%) in Winter and 25 patients (12%) in Summer (p = 0.025). The Summer decrease was greater in women than in men. Blood pressure lowering drugs increased this effect and the association of several drugs had an additive effect. It increased with age but disappeared after 70-80 years of age. The very elderly patients on antihypertensive therapy showed a marked decrease in BP during the Summer, especially in the upright position. The Summer decrease in BP is important for the management of elderly patients with hypertension or cardiac failure. It may favorize symptoms of orthostatic hypotension and increase the risk of malaise.


Risk-reducing medications for primary breast cancer: a network meta-analysis.
Breast cancer is the most frequently occurring malignancy and the second cause of death for cancer in women. Cancer prevention agents (CPAs) are a promising approach to reduce the burden of breast cancer. Currently, two main types of CPAs are available: selective estrogen receptor modulators (SERMs, such as tamoxifen and raloxifene) and aromatase inhibitors (AIs, such as exemestane and anastrozole). To assess the efficacy and acceptability of single CPAs for the prevention of primary breast cancer, in unaffected women, at an above-average risk of developing breast cancer.Using a network meta-analysis, to rank single CPAs, based on their efficacy and acceptability (an endpoint that is defined as the inverse of CPA-related toxicity). We searched the Cochrane Breast Cancer Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP), and ClinicalTrials.gov on 17 August 2018. We handsearched reference lists to identify additional relevant studies. We included randomized controlled trials (RCTs) that enrolled women without a personal history of breast cancer but with an above-average risk of developing a tumor. Women had to be treated with a CPA and followed up to record the occurrence of breast cancer and adverse events. Two review authors independently extracted data and conducted risk of bias assessments of the included studies, and assessed the certainty of the evidence using GRADE. Outcome data included incidence of breast carcinoma (both invasive and in situ carcinoma) and adverse events (both overall and severe toxicity). We performed a conventional meta-analysis (for direct comparisons of a single CPA with placebo or a different CPA) and network meta-analysis (for indirect comparisons). We included six studies enrolling 50,927 women randomized to receive one CPA (SERMs: tamoxifen or raloxifene, or AIs: exemestane or anastrozole) or placebo. Three studies compared tamoxifen and placebo, two studies compared AIs (exemestane or anastrozole) versus placebo, and one study compared tamoxifen versus raloxifene. The risk of bias was low for all RCTs.For the tamoxifen versus placebo comparison, tamoxifen likely resulted in a lower risk of developing breast cancer compared to placebo (risk ratio (RR) 0.68, 95% confidence interval (CI) 0.62 to 0.76; 3 studies, 22,832 women; moderate-certainty evidence). In terms of adverse events, tamoxifen likely increased the risk of severe toxicity compared to placebo (RR 1.28, 95% CI 1.12 to 1.47; 2 studies, 20,361 women; moderate-certainty evidence). In particular, women randomized to receive tamoxifen experienced a higher incidence of both endometrial carcinoma (RR 2.26, 95% CI 1.52 to 3.38; high-certainty evidence) and thromboembolism (RR 2.10, 95% CI 1.14 to 3.89; high-certainty evidence) compared to women who received placebo.For the AIs versus placebo comparison, AIs (exemestane or anastrozole) reduced the risk of breast cancer by 53% (RR 0.47, 95% CI 0.35 to 0.63; 2 studies, 8424 women; high-certainty evidence). In terms of adverse events, AIs increased the risk of severe toxicity by 18% (RR 1.18, 95% CI 1.09 to 1.28; 2 studies, 8352 women; high-certainty evidence). These differences were sustained especially by endocrine (e.g. hot flashes), gastrointestinal (e.g. diarrhea), and musculoskeletal (e.g. arthralgia) adverse events, while there were no differences in endometrial cancer or thromboembolism rates between AIs and placebo.For the tamoxifen versus raloxifene comparison, raloxifene probably performed worse than tamoxifen in terms of breast cancer incidence reduction (RR 1.25, 95% CI 1.09 to 1.43; 1 study, 19,490 women; moderate-certainty evidence), but its use was associated with lower toxicity rates (RR 0.87, 95% CI 0.80 to 0.95; 1 study, 19,490 women; moderate-certainty evidence), particularly relating to incidence of endometrial cancer and thromboembolism.An indirect comparison of treatment effects allowed us to compare the SERMs and AIs in this review. In terms of efficacy, AIs (exemestane or anastrozole) may have reduced breast cancer incidence slightly compared to tamoxifen (RR 0.67, 95% CI 0.46 to 0.98; 5 RCTs, 31,256 women); however, the certainty of evidence was low. A lack of model convergence did not allow us to analyze toxicity data. For women with an above-average risk of developing breast cancer, CPAs can reduce the incidence of this disease. AIs appear to be more effective than SERMs (tamoxifen) in reducing the risk of developing breast cancer. AIs are not associated with an increased risk of endometrial cancer and thromboembolic events. However, long-term data on toxicities from tamoxifen are available while the follow-up toxicity data on unaffected women taking AIs is relatively short. Additional data from direct comparisons are needed to fully address the issues of breast cancer prevention by risk-reducing medications, with special regards to acceptability (i.e. the benefit/harm ratio).


Inhibition of hTAFII32-binding implicated in the transcriptional repression by central regions of mutant p53 proteins.
We previously identified a movable and regulable inactivation function within the central region (CRts247) of a temperature-sensitive p53 (p53(ts)) mutant, p53(N247I). Here we showed that central regions from several p53(ts) mutants behaved similarly, i.e. they repressed a neighboring activation domain only when existing in the mutant status. Using chimeric protein GAL4VP16-CRts247 as an example, we demonstrated that de novo protein synthesis was not required for the reactivation of the chimeric protein, indicating that a post-translational mechanism was involved in the control of CRts247 activity. The CRts247-conferred thermo-regulability did not work via a mechanism demanding either an alteration of the subcellular compartmentalization of or the inactivation of DNA-binding activity of the GAL4 chimera. Further, CRts247 did not function in trans, eliminating the possibility that the observed repression was because of the competition for a putative factor(s) by the mutant p53 domain. Rather, CRts247 bestowed temperature-dependent interaction with hTAFII32 to the VP16 activation domain. In a parallel experiment, CRts247 also caused a large reduction in the affinity of hTAFII32 to the p53 activation domain at the nonpermissive temperature. These results strongly suggested that inhibition of hTAFII32 binding could be one of the mechanisms responsible for the transcriptional repression by mutant p53 central regions.


A comprehensive view of parental satisfaction with pediatric emergency department visits.
We develop a comprehensive view of aspects of care associated with parental satisfaction with pediatric emergency department (ED) visits, using both quantitative and qualitative data. This was a retrospective observational study using data from an institution-wide system to measure patient satisfaction. For this study, 2,442 parents who brought their child to the ED were interviewed with telephone survey methods. The survey included closed-ended (quantitative) and open-ended (qualitative data) questions, in addition to a cognitive interview-style question. Overall parental satisfaction was best predicted by how well physicians and nurses work together, followed by wait time and pain management. Issues concerning timeliness of care, perceived quality of medical care, and communication were raised repeatedly by parents in response to open-ended questions. A cognitive interview-style question showed that physicians and nurses sharing information with each other, parents receiving consistent and detailed explanations of their child's diagnosis and treatments, and not having to answer the same question repeatedly informed parent perceptions of physicians and nurses working well together. Staff showing courtesy and respect through compassion and caring words and behaviors and paying attention to nonmedical needs are other potential satisfiers with emergency care. Using qualitative data to augment and clarify quantitative data from patient experience of care surveys is essential to obtaining a complete picture of aspects of emergency care important to parents and can help inform quality improvement work aimed at improving satisfaction with care.


Telomere Length and Risk of Major Adverse Cardiac Events and Cancer in Obstructive Sleep Apnea Patients.
Telomere length (TL) is associated with cardiovascular disease (CVD) and cancer. Obstructive sleep apnea (OSA) is also linked to higher risk of CVD and cancer, and to TL. We investigated the association between TL and risk of major adverse cardiac events (MACE) and cancer in OSA patients. We studied 210 individuals undergoing sleep-related studies between 2000 and 2007. Baseline characteristics and follow-up data (available in 164 subjects) were obtained from clinic records. Incidence rates were calculated for the entire group and by OSA status. Hazard ratios were calculated to estimate effects of OSA and TL on risk of MACE and cancer. In total, 32 individuals (20%) developed MACE and/or cancer during 12.7-year follow-up. The OSA group had a higher likelihood of cancer (16.0 vs. 4.9 events per 1000 person-years, P = 0.044) but no clear evidence of an elevated incidence of MACE (10.8 vs. 4.8 events per 1000 person-years, P = 0.293) compared to the non-OSA group. There was no association between TL and MACE- (HR = 1.01, 95% CI 0.78-1.28), or cancer-risk (HR = 1.18, 95% CI 0.96-1.43). Our study warrants further investigation of any modulating effect of OSA on TL and the risk of MACE and cancer.


Stage I non-small-cell lung cancer: long-term results of lobectomy versus sublobar resection from the Polish National Lung Cancer Registry.
Anatomical lobar resection and mediastinal lymphadenectomy remain the standard for the treatment of early stage non-small-cell lung cancer (NSCLC) and are preferred over procedures such as segmentectomy or wedge resection. However, there is an ongoing debate concerning the influence of the extent of the resection on overall survival. The aim of this article was to assess the overall survival for different types of resection for Stage I NSCLC. We performed a retrospective analysis of the results of the surgical treatment of Stage I NSCLC. Between 1 January 2007 and 31 December 2013, the data from 6905 patients who underwent Stage I NSCLC operations were collected in the Polish National Lung Cancer Registry (PNLCR) and overall survival was assessed. A propensity score-matched analysis was used to compare 3 groups of patients, each consisting of 231 patients who underwent lobectomy, segmentectomy, or wedge resection. In the unmatched and matched patient groups, lobectomy and segmentectomy were associated with a significant benefit compared to wedge resection regarding overall survival (log-rank P < 0.001 and P = 0.001). The Cox proportional hazard ratio comparing segmentectomy and lobectomy to wedge resection was 0.54 [95% confidence interval (CI): 0.37-0.77) and 0.44 (95% CI: 0.38-0.50), respectively, indicating a significant improvement in survival. There was no difference in the 5-year survival of patients after lobectomy (79.1%; 95% CI: 77.7-80.4%) or segmentectomy (78.3%; 95% CI: 70.6-86.0%). The 30-day mortality rate was 1.6, 2.6 and 1.4% for lobectomy, segmentectomy and wedge resection, respectively. Wedge resection was associated with a significantly lower 5-year survival rate (58.1%; 95% CI: 53.6-62.5%) compared to segmentectomy (78.3%; 95% CI: 70.6-86.0%) and lobectomy (79.1%; 95% CI: 77.7-80.5%). The propensity score matched analysis confirmed most of the results of the comparisons of unmatched study groups. Wedge resection was associated with significantly lower 3-year and 5-year survival rates compared to the other methods of resection. There was no significant difference in 3-year or 5-year survival rates between lobectomy and segmentectomy. Segmentectomy, but not wedge resection, could be considered an alternative to lobectomy in the treatment of patients with Stage I NSCLC.


Tetraspanins, Another Piece in the HIV-1 Replication Puzzle.
Despite the great research effort placed during the last decades in HIV-1 study, still some aspects of its replication cycle remain unknown. All this powerful research has succeeded in developing different drugs for AIDS treatment, but none of them can completely remove the virus from infected patients, who require life-long medication. The classical approach was focused on the study of virus particles as the main target, but increasing evidence highlights the importance of host cell proteins in HIV-1 cycle. In this context, tetraspanins have emerged as critical players in different steps of the viral infection cycle. Through their association with other molecules, including membrane receptors, cytoskeletal proteins, and signaling molecules, tetraspanins organize specialized membrane microdomains called tetraspanin-enriched microdomains (TEMs). Within these microdomains, several tetraspanins have been described to regulate HIV-1 entry, assembly, and transfer between cells. Interestingly, the importance of tetraspanins CD81 and CD63 in the early steps of viral replication has been recently pointed out. Indeed, CD81 can control the turnover of the HIV-1 restriction factor SAMHD1. This deoxynucleoside triphosphate triphosphohydrolase counteracts HIV-1 reverse transcription (RT) in resting cells via its dual function as dNTPase, catalyzing deoxynucleotide triphosphates into deoxynucleosides and inorganic triphosphate, and as exonuclease able to degrade single-stranded RNAs. SAMHD1 has also been related with the detection of viral nucleic acids, regulating the innate immune response and would promote viral latency. New evidences demonstrating the ability of CD81 to control SAMHD1 expression, and as a consequence, HIV-1 RT activity, highlight the importance of TEMs for viral replication. Here, we will briefly review how tetraspanins modulate HIV-1 infection, focusing on the latest findings that link TEMs to viral replication.